MXPA06009262A - Method for producing 4-nitroimidazole compound - Google Patents

Abstract

The present invention provides a method for producing a 4-nitroimidazole compound represented by general formula (1) at high yield and at high purity by a safe method causing few dangers such as explosion. The production method of the present invention comprises iodinating a 4-nitroimidazole compound represented by general formula (2):wherein each of X1 and X2 represents a chlorine atom or bromine atom, and then reducing the obtained 5-iodo-4-nitroimidazole compound represented by general formula (3):wherein X2 is the same as defined above.

Description

METHOD FOR PRODUCING A COMPOUND OF 4-NITROIM DAZOL FIELD OF THE INVENTION The present invention relates to a method for producing a 4-nitroimidazole compound.

BACKGROUND OF THE INVENTION A nitroimidazole compound represented by the following general formula (I): wherein X2 represents a chlorine atom or bromine atom, it is useful as a synthetic intermediate used to produce various pharmaceutical and agricultural chemicals, and particularly used to produce anti-tubercular agents. For example, the methods represented by the following reaction scheme 1 and 2 have been previously known as methods for producing the 4-nitroimidazole compound represented by the general formula (1) (Jerzy Suwinski, Ewa Salwinska, Jan Watras and Maria Widel, Polish Journal of Chemistry, 56, 1261-1272 (1982)).

Ref .: 174712 Reaction scheme 1 ? r ~ N HmHH rr - NmH ¡-Wz N (5) (5b) (6) (7) Halogenation (2a) Reaction scheme. 2 -NH NH ¡L N - Nitric acid, 02N ^ Ni sulfuric acid (8) (2a) where XA represents a halogen atom. However, these methods have several disadvantages, and thus are not suitable as production methods that are applied industrially. For example, in the method represented by reaction scheme 1, compounds (6) and (7) which are reaction intermediates are chemically unstable, and there is a risk that these compounds may explode due to impacts such as dropping or friction. . In addition, in this method, the temperature applied during the reaction to obtain the compound (7) of the compound (6) by heating (approximately 130 ° C) exceeds the TNR (Non-Return Temperature, the maximum temperature varying from 60 ° C. at 70 ° C, at which the compound can be handled safely in a chemical processing apparatus) of the compound (6). Thus, it has been extremely dangerous to industrially produce the compound of interest in high volume by this method. The method represented by reaction scheme 2 includes a reaction of nitrating compound (8). However, the compound can only be obtained in a low yield by this nitration, and in this way, this method is industrially inadequate.

BRIEF DESCRIPTION OF THE INVENTION An object of the present invention is to provide a method for producing a 4-nitroimidazole compound represented by the general formula (1) in high yield and in high purity by a safer method that causes few hazards such as explosion . To achieve the objective mentioned above, the present inventors have carried out intensive studies in relation to a method for producing a 4-nitroimidazole compound represented by the general formula (1). As a result, the present inventors have found that the aforementioned objective can be achieved by selectively replacing a chlorine atom or bromine atom at the 5-position of a 4-nitroimidazole compound represented by the general formula (2) indicated below with a iodine atom, and then selectively reducing the 5-position of the obtained 5-iodo-4-nitroimidazole compound represented by the general formula (3) indicated below. That is, the present inventors have found that a 4-nitroimidazole compound represented by the general formula (1) can be produced in high yield and high purity by a safe method that causes few hazards such as explosion, which comprises selectively replacing a chlorine atom or a bromine atom in the 5-position of a 4-nitroimidazole compound represented by the general formula (2) indicated below with an iodine atom, and then selectively reducing the 5-position of the 5-iodo-4- compound obtained nitroimidazole represented by the general formula (3) indicated below. The present invention has been completed based on these findings. 1. The present invention provides a method for producing a 4-nitroimidazole compound represented by the general formula (1): wherein X2 represents a chlorine atom or bromine atom, which comprises iodinating a 4-nitroimidazole compound represented by the general formula (2): wherein each of X1 and X2 represents a chlorine atom or a bromine atom, and then reducing the obtained 5-iodo-4-nitroimidazole compound represented by the general formula (3): where X2 is the same as the one defined above. 2. The present invention provides, in the above production method, a method for producing a 4-nitroimidazole compound, wherein an iodinating agent is a halogen molecule, hydroiodic acid, or a metal salt or hydroiodic acid. 3. The present invention provides, in the above production method, a method for producing a 4-nitroimidazole compound, wherein the metal salt of hydroiodic acid is sodium iodide, potassium iodide, lithium iodide, zinc iodide , magnesium iodide, or aluminum iodide. 4. The present invention provides, in. the above production method, a method for producing a 4-nitroimidazole compound, wherein the iodant agent is used for the compound (2) at a molar ratio of between 1.5: 1 and 15: 1, and the iodinating agent is. sodium iodide. The present invention provides, in the above production method, a method for producing a 4-nitroimidazole compound, wherein the reaction is carried out in the presence of a phase transfer catalyst. 6. The present invention provides, in the above production method, a method for producing a 4-nitroimidazole compound, wherein the phase transfer catalyst is used for the compound (2) at a molar ratio of between 0.01: l and l : 1, and the phase transfer catalyst is a quaternary ammonium salt, phosphonium salt or pyridinium salt. 7. The present invention provides, in the above production method, a method for producing a 4-nitroimidazole compound, wherein the reducing agent is a hydrogenation reducing agent, and the reducing agent is used for the compound (3) a a molar ratio between 1: 1 and 10: 1. 8. The present invention provides, in the above production method, a method for producing a nitroimidazole compound, wherein the reducing agent is a catalytic hydrogenation reducing agent, and the reducing agent is used for the compound (3) at a ratio of weight between 0.1% by weight and 40% by weight. 9. The present invention provides, in the above production method, a method for producing a 4-nitroimidazole compound, wherein the reaction is carried out in the presence of triethylamine, trimethylamine or N-ethyldiisopropylamine.

DETAILED DESCRIPTION OF THE INVENTION The method for producing 4-nitroimidazole compound represented by the general formula (1) of the present invention will be described below.

Reaction scheme 3 (2) (3) (1) where X1 and X2 are the same as those defined above. In the reaction scheme 3, the reaction to obtain the compound (3) from the compound (2) can be carried out in a suitable solvent in the presence of an iodinating agent. As an iodinating agent, the known iodating agents can be used widely. Examples of this iodinating agent may include a halogen atom such as iodine, hydroiodic acid, and metal salts of hydroiodic acid such as sodium iodide, potassium iodide, lithium iodide, zinc iodide, magnesium iodide or aluminum iodide. Of these, sodium iodide is preferred. This iodinating agent is used for compound (2), generally in an excessive amount, and preferably at a molar ratio of between 1.5: 1 and 15: 1. Examples of a solvent may include: water; alcohols such as methanol, ethanol, or isopropanol; ketones such as acetone; acetonitrile; halogenated hydrocarbons such as dichloroethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; esters such as methyl acetate or ethyl acetate; ethers such as tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane or tert-butyl methyl ether; dimethylformamide; and mixed solvents thereof. The solvents. which are preferred are water and alcohols. Acids such as hydroiodic acid and / or catalysts such as a phase transfer catalyst can be added to a reaction system in which the above reaction is carried out. Examples of a phase transfer catalyst may include a quaternary ammonium salt, a phosphonium salt and a pyridinium salt. Examples of a quaternary ammonium salt may include quaternary ammonium salts, in which a group selected from the following group is substituted: a linear or branched alkyl group containing 1 to 18 carbon atoms; a phenylalkyl group in which the alkyl portion is a linear or branched alkyl group containing 1 to 6 carbon atoms and a phenyl group. Specific examples of this quaternary ammonium salt may include tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylammonium bisulfite, tributylmethylammonium chloride, tributylbenzylammonium chloride, tetrapentylammonium chloride, tetrapentylammonium bromide, tetrahexylammonium chloride, benzyldimethyloctylammonium chloride, methyltrihexylammonium chloride, benzyldimethyloctadenylammonium chloride, methyltridecanylammonium chloride, benzyltripropylammonium chloride, benzyltriethylammonium chloride, phenyltriethylammonium chloride, tetraethylammonium chloride, and tetramethylammonium chloride. Examples of a phosphonium salt may include phosphonium salts in which a linear or branched alkyl group containing 1 to 18 carbon atoms is substituted. A specific example of this phosphonium salt may be tetrabutylphosphonium chloride. Examples of a pyridinium salt may include pyridinium salts in which a linear or branched alkyl group containing 1 to 18 carbon atoms is substituted. A specific example of this pyridinium salt may be 1-dodecanylpyridinium chloride. The phase transfer catalyst mentioned above is used individually or in combination of two or more types. The phase transfer catalyst is used, for 1 mole of the compound (2), in an amount generally between 0.01 and 1 mole, and preferably between 0.01 and 0.5 mole. The above reaction is carried out at a temperature generally between 0 ° C and 150 ° C, and preferably between 0 ° C and 120 ° C, and is generally carried out for 1 to 80 hours before the conclusion. In the above reaction, a chlorine atom or bromine atom in the 5-position of the imidazole ring is selectively iodinated, and thus, the compound (3) is efficiently produced.

The reaction to obtain the compound (1) from the compound (3) is carried out in a suitable solvent in the presence of a reducing agent. The known hydrogenation reducing agents, catalytic hydrogenation reducing agents and other agents are used as these reducing agents. Examples of a hydrogenation reducing agent may include: sulfite compounds such as sodium bisulfite, sodium sulfite, sodium pyrosulfite, ammonium sulfite, ammonium sulfide monohydrate or ammonium bisulfite; lower tetra alkylammonium boirohydrides such as tetramethylammonium borohydride, tetraethylammonium borohydride, tetra-n-butylammonium borohydride or tetra-n-butylammonium cyanoborohydride; sodium cyanoborohydride, lithium cyanoborohydride, sodium borohydride and borane. These hydrogenation reducing agents are used individually or in combination of two or more types. Examples of a catalytic hydrogenation reducing agent may include palladium, palladium black, palladium-carbon, palladium hydroxide-carbon, rhodium-alumina, platinum, platinum oxide, copper chromite, palladium acetate, platinum-alumina, platinum- carbon, palladium-alumina, platinum black and Raney nickel. These catalytic hydrogenation reducing agents are used individually or in combination of two or more types.

Of these reducing agents, catalytic hydrogenation reducing agents are preferred, in particular, platinum oxide and palladium-alumina. In the present invention, the hydrogenation reducing agents mentioned above and the catalytic hydrogenation reducing agents can be used in combination. Examples of a solvent used herein may include water; fatty acids such as acetic acid; lower alcohols such as methanol, ethanol or isopropanol; aliphatic hydrocarbons such as n-hexane or cyclohexane; ketones such as acetone or methyl ethyl ketone; ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, monoglyme, diglyme, 1,4-dioxane or dimethoxyethane; aromatic hydrocarbons such as benzene, toluene or xylene; esters such as ethyl acetate, methyl acetate or n-butyl acetate; aprotic polar solvents such as dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide or l-methyl-2-pyrrolidinone (NMP); and its mixed solvents. When diborane or the like is used as a hydrogenation reducing agent, it is suitable to use an anhydrous solvent. When platinum oxide or palladium-alumina is used as a catalytic hydrogenation reducing agent, it is preferable to use mixed solvents containing water, in particular, mixed solvents consisting of water, and fatty acids, ketones, ethers or polar aprotic solvents. A hydrogenation reduction agent is used for 1 mole of the compound (3) in an amount generally of at least 1 mole, and preferably between 1 and 10 mole. The reaction in which the hydrogenation reducing agent is used is carried out at a temperature generally between 0 ° C and 150 ° C, and preferably between 0 ° C and 120 ° C. The reaction is generally carried out for 1 to 30 hours before the conclusion. When a catalytic hydrogenation reducing agent is used, the reaction is carried out in a hydrogen atmosphere under a pressure generally between normal pressure and 20 atmospheres, and preferably between normal pressure and 10 atmospheres, at a temperature generally between -30 ° C and 100 ° C, and preferably between 0 ° C and 80 ° C. The reaction is carried out generally for 1 to 90 hours before the conclusion. A catalytic hydrogenation reducing agent is used for the compound (3) at a weight ratio generally between 0.1% by weight and 40% by weight, and preferably between 0.1% by weight and 20% by weight. To promote the reaction, amines such as trimethylamine, triethylamine or N-ethyldiisopropylamine can be added to the reaction system in which a catalytic hydrogenation reducing agent is used.

As a result of the reduction reaction mentioned above, a substituted iodine atom for the 5-position of the imidazole ring is selectively removed, such that a desired compound represented by the general formula (1) can be obtained efficiently. The present inventors have found this fact for the first time. The 4-nitroimidazole compound represented by the general formula (1) of the present invention can be induced to a compound (13a) or (13b) which is useful as an anti-tubercular agent, for example, by the methods represented by the following Reaction scheme 4 and reaction scheme 5: Reaction scheme 4 where it is the same as the one defined above; RA represents a hydrogen atom or a lower alkyl group; and RB represents the following group: , wherein Rc represents a nitro group; RD represents a halogen atom or a lower alkenyl group; and a represents 0, 1 or 2, and when a represents 2, two RDs may be either identical or different. The reaction between the 4-nitroimidazole compound represented by the general formula (1) and the compound (9a) or (9b) is carried out in a suitable solvent in the presence of a basic compound. Examples of a solvent used herein may include: aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane or diethylene glycol dimethyl ether; halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride; lower alcohols such as methanol, ethanol, isopropanol, butanol or tert-butanol; acetic acid; esters such as ethyl acetate or methyl acetate; ketones such as acetone or methyl ethyl ketone; acetonitrile; pyridine; 2, 4, 6-coluidine; dimethyl sulfoxide; dimethylformamide; hexamethylphosphoric triamide and its mixed solvents. The inorganic bases and known organic bases can be widely used as basic compounds. Examples of an inorganic base may include: alkali metal carbonates such as sodium carbonate or potassium carbonate; alkali metal acid carbonates such as sodium bicarbonate or potassium bicarbonate; alkali metal hydroxides such as sodium hydroxide or potassium hydroxide; alkali metal phosphates such as sodium phosphate or potassium phosphate; alkali metal hydrides such as sodium hydride or potassium hydride; alkali metals such as potassium or sodium; alkali metal amidates such as sodium amide and alkali metal alcoholates such as sodium methylate or sodium ethylate. Examples of an organic base may include pyridine, trimethylamine, triethylamine, N-ethyldiisopropylamine, 2,4,6-coluidine, dimethylaniline, dimethylaminopyridine, l-methyl-2-pyrrolidinone (NMP), N-methylmorpholine, N, N-dimethyl- 4-aminopyridine, 1/5-diazabicyclo [4.3.0] noneno-5 (DBN), 1,8-diazabicyclo [5.4.0] undecene-7 (DBU) and 1,4-diazabicyclo [2.2.2] octane ( DABCO). These basic compounds are used individually or in combination of two or more types.

The compound (1) is used for 1 mole of the compound (9a) or (9b) in an amount generally of at least 1 mole, and preferably between 1 and 3 moles. The basic compound is used for 1 mole of the compound (9a) or (9b) in an amount generally between 1 and 10 moles, and preferably between equi olar and 5 moles. The reaction between the compound (1) and the compound (9a) or (9b) is generally carried out at a temperature generally between room temperature and 150 ° C, and preferably between room temperature and 100 ° C. The reaction is generally carried out for 1 to 100 hours before the conclusion. During the above reaction, halides such as cesium fluoride can be added to the reaction system.

Reaction scheme 5 (1 3 a) (1 3 b) where RA and X2 are the same as those defined above; and R represents a group represented by the following general formula (A), (B), (C), (D), (E), (F) or (G). A group represented by the general formula (A): -OR3 (A) (wherein R3 represents: Al) a hydrogen atom; A2) a C1-C6 alkyl group; A3) an alkoxy group of Cl-C6-C1-C6 alkyl; A4) a phenyl-C1-C6 alkyl group (wherein, on the phenyl ring, at least one selected from the following group can be substituted: a phenylalkoxy group of C1-C6, a C1-C6 alkyl group substituted with halogen or not substituted and a C1-C6 alkoxy group substituted with halogen or unsubstituted, and a phenoxy group [wherein, in the phenyl ring, at least one C1-C6 alkoxy group substituted with halogen or unsubstituted, can be substituted ]); A5) a biphenylylalkyl group of C1-C6; A6) a phenylalkenyl group of C2-C6; A7) a C1-C6 alkylsulfonyl group; A8) a benzenesulfonyl group in which a C1-C6 alkyl group can be substituted; A9) a C 1 -C 6 alkanoyl group; AlO) a group represented by the general formula (Aa): (Wherein R4 represents: an alkoxycarbonyl group C1-C6, a phenylalkoxycarbonyl group C1-C6 [wherein, on the phenyl ring, at least one selected from the group consisting of a phenyl C1-C6, one C 1 -C 6 alkyl group substituted with halogen or unsubstituted and a C 1 -C 6 alkoxy group substituted with halogen or unsubstituted, can be substituted]; or a phenylalkyl group of C 1 -C 6 [in - which, in the phenyl ring , at least one selected from a group consisting of a C1-C6 phenylalkoxy group, a C1-C6 alkyl group substituted with halogen or unsubstituted, and a C1-C6 alkoxy group substituted with halogen or unsubstituted, may be replaced]); All) a biphenylalkyloxycarbonyl group of C 1 -C 6; A12) a benzoxazolylalkyl group of C1-C6 (wherein, in the benzoxazole ring, at least one oxo group can be substituted); A13) a benzoxazolyl group; or A14) a C 1 -C 6 oxazolylalkyl group (wherein, in the oxazole ring, at least one selected from the group consisting of a phenyl group and a C 1 -C 6 alkyl group can be substituted). A group represented by the general formula (B): -SR5 (B) (wherein R 5 represents a tetrazolyl group [wherein, on the tetrazole ring, a C 1 -C 6 alkyl group or a benzyl group which may have a halogen atom may be substituted] or a benzoxazolyl group). A group represented by the general formula (C): -COOR6 (C) (wherein R6 represents a C1-C6 alkyl group). A carbamoyloxy group represented by the general formula (D): -OOCNR7R8 (D) (wherein R7 and R8 each identically or differently represent: Di) a hydrogen atom; D2) a C1-C8 alkyl group; D3) a C1-C6 alkyl group substituted with halogen; D4) an alkoxycarbonyl group of Cl-C6-C1-C6 alkyl; D5) a C3-C8 cycloalkyl group; D6) a phenylalkyl group of C1-C6 (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-C6 alkyl group substituted with halogen or unsubstituted and an alkoxy group of C1-C6 substituted with halogen or unsubstituted, can be substituted; D7) a phenyl group (wherein, on the phenyl ring, 1 to 3 groups selected from the group consisting of a halogen atom, an alkyl group of C1 C6 alkyl substituted with halogen or unsubstituted, an alkoxy group C1-C6 alkyl substituted with halogen or unsubstituted, an alkanoyl group of C1-C6, a carboxyl group, an alkoxycarbonyl group of Cl-C6 a phenylalkoxycarbonyl group C1-C6 , a carbamoyl group, a C1-C6 alkylcarbamoyl group, an aminosulfonyl group, and a morpholino group, can be substituted); D8) a naphthyl group; or D9) a pyridyl group; or in addition, DIO) R7 and R8 can be linked together with nitrogen atoms adjacent thereto directly or through other heteroatoms or carbon atoms, to thereby form a saturated heterocyclic group represented by any of (D10-1) a (D10-3) indicated below or a heterocyclic group fused to benzene represented by any of (D10-4) to (D10-7) indicated below. (D10-1) a piperazinyl group represented by the general formula (Da): (wherein R9 represents: (Dal) a hydrogen atom; (Da2) a C1-C6 alkyl group; (Da3) a phenylalkyl group of C1-C6 (wherein, on the phenyl ring, at least one selected of a group consisting of a halogen atom, a C1-C6 alkyl group substituted with halogen or unsubstituted and a C1-C6 alkoxy group substituted with halogen or unsubstituted, can be substituted); (Da4) a phenyl group (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a C 1 -C 6 alkyl group substituted with halogen or unsubstituted and a C 1 -C 6 alkoxy group substituted with halogen or not substituted, can be substituted); (Da5) an alkoxycarbonyl group of Cl-Cß; (Daß) a phenylalkoxycarbonyl group of C1-C6 (wherein, on the phenyl ring, at least one selected from the group consisting of one atom of halogen, a C1-C6 alkyl group substituted with halogen or unsubstituted and a C1-C6 alkoxy group substituted with halogen or unsubstituted, can be substituted); (Da7) a C3-C6 phenylalkenyloxycarbonyl group (wherein, in the phenyl ring, at least one Cl-Cß alkyl group substituted with halogen or unsubstituted, can be substituted) or (Da8) a phenylalkylidene group of Cl -Cβ substituted with amino (wherein, in the phenyl ring, at least one Cl-Cß alkyl group substituted with halogen or unsubstituted, can be substituted)); (D10-2) a group represented by the general formula (Db): (where the dashed line represents that the bond can be a double bond, and R10 represents: (Dbl) a hydrogen atom; (Db2) a phenyl group (wherein, on the phenyl ring, at least one selected from the a group consisting of halogen, a C1-C6 alkyl group substituted with halogen or unsubstituted and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted); (Db3) a phenoxy group (wherein, in the phenyl ring, at least one Cl-Cß alkyl group substituted by halogen or unsubstituted, or (Db 4) a phenylamino group (wherein, on the phenyl ring, at least one Cl-Cß alkyl group substituted with halogen or unsubstituted, can be substituted)); (D10-3) a morpholino group; (D10-4) an indolinyl group (wherein, in the indoline ring, at least one halogen atom can be substituted); -5) an isoindolinyl group (wherein, in the isoindoline ring, at least one halogen atom can be substituted); (D10-6) a 1, 2, 3, 4-tetrahydroquinoline group (wherein, in the 1, 2, 3, 4-tetrahydroquinoline ring, at least one halogen atom can be substituted); or (D10-7) a 1, 2, 3, 4-tetrahydroisoquinolinyl group (wherein, in the 1, 2, 3, 4-tetrahydroisoquinoline ring, at least one halogen atom can be substituted). A phenoxy group represented by the general formula (E): [where X. represents a halogen atom or an alkyl group of Cl-Cß substituted with amino which may have an alkyl group of Cl-Cß as a substituent; m represents an integer between 0 and 3 and R11 represents: El) a hydrogen atom; E2) a Cl-Cß alkyl group substituted with halogen or unsubstituted; E3) a Cl-Cß alkoxy group substituted with halogen or unsubstituted; E4) a group represented by the general formula (Ea): - (W) o-NR12R13 (Ea) (where W represents the group -CO- or an alkylene group of Cl-Cß; or represents 0 or 1; and R12 and R13 each represent, in an identical or different manner: (Eal) a hydrogen atom; (Ea2) a alkyl group of Cl-Cß; (Ea3) an alkanoyl group of Cl-Cß; (Ea4) an alkoxycarbonyl group of Cl-Cβ; (Ea5 ') a phenylalkyl group of Cl-Cß (wherein, at the phenyl ring, at least one selected from the following group can be substituted: a halogen atom, an alkyl group of Cl-Cβ substituted with halogen or not substituted, a C1-Cß alkoxy group substituted with halogen or unsubstituted, and a phenoxy group [wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, an alkyl group of Cl-Cβ substituted with halogen or unsubstituted and a Cl-Cβ alkoxy group substituted with halogen or unsubstituted, can be substituted as a substituent], and also wherein, an alkoxyimino Cl-Cß group can be substituted by a portion Cl-Cß alkyl thereof); (Eaß) a phenyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted by halogen or unsubstituted and a Cl- alkoxy group Cβ substituted with halogen or unsubstituted, can be substituted); (Ea7) a benzoyl group (wherein, on the phenyl ring, at least one selected from the group consisting of-a halogen atom, a C1-Cß alkyl group substituted by halogen or unsubstituted and an alkoxy group of Cl -Cβ substituted with halogen or unsubstituted, can be substituted); (Ea8) a pyridyl group (wherein, in the pyridine ring, at least one halogen atom can be substituted); (Ea9) a phenylalkyl group of Cl-Cß (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-Cß alkyl group substituted by halogen or unsubstituted and a group Cl-Cß alkoxy substituted with halogen or unsubstituted, can be substituted); (EalO) a phenoxyalkyl group of Cl-Cß (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-Cß alkyl group substituted by halogen or unsubstituted and a group Cl-Cß alkoxy substituted with halogen or unsubstituted, can be substituted); or (Eall) a benzoylalkyl group of Cl-Cß (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-Cß alkyl group substituted by halogen or unsubstituted and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted)); E5) an imidazolyl group; E6) a triazolyl group; E7) a morpholino group; E8) a thiomorpholino group; E9) a s-oxide thiomorpholino group; • E10) a piperidyl group represented by the general formula (Eaa): (where I are the same as those defined above: R 1 A represents a hydrogen atom, a hydroxyl group, an alkoxy group of Cl-Cß or a phenyl group [wherein, in the phenyl ring, a halogen atom can to be substituted], the dotted line represents that the link can be a double bond, and when the dotted line represents this double bond, only R14 is substituted, and R14 and R1 A can be joined together with carbon atoms adjacent to them, to thereby form an alkylenedioxy group of C1-C4, wherein R14 represents: (Eaal) a hydrogen atom; (Eaa2) an alkoxycarbonyl group of Cl-Cß; (Eaa3) a phenoxy group (wherein, on the phenyl ring; , at least one selected from the following group can be substituted: a halogen atom, a C1-Cß alkyl group substituted by halogen or unsubstituted, a Cl-Cß alkoxy group substituted with halogen or unsubstituted, an alkylenedioxy group of C1 -C4; an alkoxycarbonyl group of Cl-Cß; a group c iano, a C2-C6 alkenyl group; a nitro group; a phenyl group; an amino group which may have, as a substituent, a group selected from the group consisting of a phenyl group, an alkyl group of Cl-Cß, a carbamoyl group, and an alkanoyl group of Cl-Cβ; an alkyl group of Cl-Cβ substituted with Cl-Cβ alkanoyl; a hydroxyl group; an alkyl group of Cl-Cβ substituted with Cl-Cβ alkoxycarbonyl; a phenylalkyl group of Cl-Cß; an alkanoyl group of Cl-Cβ; an alkylthio group of Cl-Cβ; a 1,2,4-triazolyl group; an isoxazolyl group; an imidazolyl group; a benzothiazolyl group; a 2H-benzotriazolyl group; a pyrrolyl group; a benzoxazolyl group; a piperazinyl group [wherein, in the piperazine ring, at least one selected from the group consisting of an alkoxycarbonyl group of Cl-Cß and a phenylalkyl group of Cl-Cß (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted with halogen or unsubstituted and a C 1 -C 6 alkoxy group substituted with halogen or unsubstituted, may be substituted); can be substituted as a substituent]; a piperidyl group [wherein, in the piperidine ring, at least one amino group can be substituted, wherein, in the amino group, at least one selected from a group consisting of a C1-C6 alkyl group and a phenyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted by halogen or unsubstituted and a Cl-Cß substituted alkoxy group. with halogen or unsubstituted, can be substituted) can be substituted as a substituent]; and a carbamoyl group); (Eaa4) a hydroxyl group; (Eaa5) a carboxy group; (Eaaß) a phenyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a phenoxy group [wherein, at the phenyl ring, at least one selected from the group consisting of one atom of halogen, a Cl-Cß alkyl group substituted by halogen or unsubstituted and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted as a substituent], a halogen atom, an alkyl group of Cl- Cβ substituted with halogen or unsubstituted and a Cl-Cβ alkoxy group substituted with halogen or unsubstituted, can be substituted as a substituent); (Eaa7) an alkoxy group of Cl-Cß; (Eaad) a C3-C8 cycloalkyl-Cl-Cß alkoxy group; (Eaa9) a phenylcarbamoyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-C3 alkyl group substituted by halogen or unsubstituted and an alkoxy group of Cl -Cβ substituted with halogen or unsubstituted, can be substituted); (EaalO) a tetrahydropyranilloxy group; (Eaall) a 1, 3-dioxolanillo group; (Eaal2) an oxo group; (Eaal3) a naphthyloxy group (wherein, in the naphthalene ring, at least one Cl-Cß alkyl group can be 'substituted); (Eaal4) a 2,3-dihydrobenzofuryloxy group (wherein, in the 2,3-dihydrobenzofuran ring, at least one selected from the group consisting of a C1-C6 alkyl group and an oxo group may be 'substituted); (Eaal5) a benzothiazolyloxy group (wherein, in the benzothiazole ring, at least one Cl-Cß alkyl group can be substituted); (Eaalß) a 1, 2, 3, 4-tetrahydronaphthyloxy group (wherein, in the 1, 2, 3, 4-tetrahydronaphthalene ring, at least one oxo group can be substituted); (Eaal7) a 1,3-benzoxathiolanilloxy group (wherein, in the 1,3-benzoxathiolane ring, at least one oxo group can be substituted); (Eaal8) an isoquinolyloxy group; (Eaal9) a pyridyloxy group; (Eaa20) a quinolyloxy group (wherein, in the quinoline ring, at least one Cl-Cß alkyl group can be substituted); (Eaa21) a dibenzofuryloxy group; (Eaa22) a 2H-chromenyloxy group (wherein, in the 2H-chromene ring, at least one oxo group can be substituted); (Eaa23) a benzoisoxazolyloxy group; (Eaa24) a quinoxalyloxy group; (Eaa25) a 2, 3-dihydro-lH-indenyloxy group (wherein, in the 2,3-dihydro-lH-indene ring, at least one oxo group can be substituted); (Eaa2ß) a benzofurazanilloxy group; or (Eaa27) a C2-C6 phenylalkenyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-C3 alkyl group substituted by halogen or unsubstituted and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted)); Eli) a group represented by the general formula (Eab): (wherein o is the same as defined above, x represents a lower alkylene group and R15 represents: (Eabl) a hydrogen atom; (Eab2) an alkyl group of Cl-Cß (wherein, in the alkyl group, a morpholino group, a benzoyl group, a carbamoyl group which may have an alkyl group of Cl-Cß as a substituent, or a cyano group may be substituted); (Eab3) a C3-C8 cycloalkyl group; (Eab4) a phenylalkyl group; of Cl-Cß. (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a cyano group, a phenyl group, - a nitro group, an alkylthio group of Cl-Cß, an alkylsulfonyl group of Cl-Cß, a phenylalkoxy group of Cl-Cß, a C2-C6 alkanoyloxy group, a C1-C3 alkyl group substituted by halogen or unsubstituted, a C1-C3 alkoxy group substituted with halogen or not substituted and a 1,2,3-thiadiazole group can be substituted); (Eab5) a C2-C6 alkenyl group; (Eabß) a phenyl group (in wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a cyano group, a Cl-Cß alkyl group substituted by halogen or unsubstituted and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted); (Eab7) an alkanoyl group of Cl-Cß; (Eabd) a phenylalkanoyl group of C2-C6 (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-C3 alkyl group substituted by halogen or unsubstituted, and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted); (Eab9) a benzoyl group (wherein, in the benzene ring, at least one selected from the group consisting of a halogen atom, a C1-C3 alkyl group substituted by halogen or unsubstituted, and an alkoxy group of Cl -Cβ substituted with halogen or unsubstituted, can be substituted); (EablO) a C 1 -C 20 alkoxycarbonyl group (wherein, in the alkoxy group, at least one selected from the group consisting of a halogen atom, an amino group which may have an alkyl Cl-Cß group as a substituent, and a Cl-Cβ alkoxy group substituted with Cl-Cβ alkoxy may be substituted); (Eabll) a phenylalkoxycarbonyl group of Cl-Cß (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-Cß alkyl group substituted by halogen or unsubstituted, a group Cl-Cß alkoxy substituted with halogen or unsubstituted, a nitro group, a C1-Cß alkylthio group substituted with halogen or unsubstituted, an amino group which may have an alkanoyl group of Cl-Cβ, a phenylalkoxy group of Cl- Cβ, an alkoxycarbonyl group of Cl-Cβ and a 1,2,3-thiadiazolyl group, can be substituted); (Eabl2) a C3-C6 ~ phenylalkenyloxycarbonyl group (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted with halogen or unsubstituted, and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted); (Eabl3) a phenoxycarbonyl group (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-C3 alkyl group substituted by halogen or unsubstituted, and an alkoxy group of Cl -Cβ substituted with halogen or unsubstituted, can be substituted); (Ebbl4) a phenylalkylcarbamoyl group of Cl-Cß (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-Cß alkyl group substituted by halogen or unsubstituted, and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted); (Eabl5) a phenylcarbamoyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-C3 alkyl group substituted by halogen or unsubstituted, and an alkoxy group of Cl -Cβ substituted with halogen or unsubstituted, can be substituted); (Eablß) an alkoxycarbonyl group of Cl-Cβ substituted with benzofuryl (wherein, in the benzofuran ring, at least one halogen atom can be substituted); (Eabl7) a benzothienylalkoxycarbonyl group of Cl-Cß (wherein, in the benzothiophene ring, at least one selected from the group consisting of a halogen atom and a Cl-Cβ alkoxy group substituted with halogen or unsubstituted, may be replaced); (Eabl8) an alkoxycarbonium group of Cl-Cβ substituted with naphthyl; (Eabl9) a 'C1-Cß alkoxycarbonyl group substituted with pyridyl (wherein, in the pyridine ring, at least one halogen atom can be substituted); (Eab20) a C 1 -C 4 alkoxycarbonyl group substituted with furyl (wherein, in the furan ring, at least one nitro group can be substituted); (Eab21) an alkoxycarbonyl group of Cl-Cβ substituted with thienyl (wherein, in the thiophene ring, at least one halogen atom can be substituted); (Eab22) an alkoxycarbonyl group of Cl-Cβ substituted with thiazolyl (wherein, in the thiazole ring, at least one selected from the group consisting of an alkyl group of Cl-Cß and a phenyl group [wherein, in the phenyl ring, at least one Cl-Cß alkyl group substituted by halogen or unsubstituted, can be substituted] can be substituted); (Eab23) an alkoxycarbonyl group of Cl-Cβ substituted with tetrazolyl (wherein, in the triazole ring, at least one selected from the group consisting of an alkyl group of Cl-Cß and a phenyl group- [wherein, in the phenyl ring, at least one halogen atom can be substituted] can be substituted); (Eab24) a 2,3-dihydro-lH-indenyloxycarbonyl group; (Eab25) an alkoxycarbonyl group of Cl-Cβ substituted with adamantane; (Eab26) a C3-C6 phenylalkynyloxycarbonyl group; (Eab27) a phenylthioalkoxycarbonyl group of Cl-Cß; (Eab28) an alkoxycarbonyl group of Cl-Cß substituted with phenylalkoxy of Cl-Cß; (Eab29) an alkenyloxycarbonyl group of C2-C6; (Eab30) a C2-C6 alkynyloxycarbonyl group; (Eab31) an alkoxycarbonyl group of Cl-Cß substituted with C3-C8 cycloalkyl; or (Eab32) an alkoxycarbonyl group of Cl-Cβ substituted with benzoyl); E12) a group represented by the general formula (Eb): (wherein the dotted line represents that the link can be a double bond, and R16 represents the same group as R15); E13) a group represented by the general formula (Ec): (wherein R17 represents: (Ecl) a phenylalkyl group of C1-C6 (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, an alkyl group of Cl-C6 substituted with halogen or unsubstituted, and a C 1 -C 6 alkoxy group substituted with halogen or unsubstituted, may be substituted); (Eq2) a C 1 -C 6 alkoxycarbonyl group; or (Eq 3) a C 1 -C 6 phenylalkoxycarbonyl group (wherein , in the phenyl ring, at least one selected from the group consisting of a halogen atom, a C 1 -C 6 alkyl group substituted with halogen or unsubstituted, and a C 1 -C 6 alkoxy group substituted with halogen or unsubstituted, can be replaced)); E14) a pyridyl group; E15) a group represented by the general formula (Ee): (wherein R46 represents: a phenyl group [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted with halogen or unsubstituted, and a group C 1 -C 6 -alkyl substituted with halogen or unsubstituted, can be substituted]; a phenylalkyl group of C 1 -C 6 [wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted by halogen or unsubstituted, and a Cl-Cß alkoxy group substituted by halogen or unsubstituted, can be substituted]; a phenylalkoxycarbonyl group of Cl-Cβ [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted with halogen or unsubstituted, and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, may be substituted]; an alkoxycarbonyl group of Cl-Cß); 6) a phenoxy group (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted by halogen or unsubstituted, and a Cl-C alco alkoxy group Cβ substituted with halogen or unsubstituted, can be substituted); E17) a benzoyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-C3 alkyl group substituted by halogen or unsubstituted, and a Cl-C2 alkoxy group Cβ substituted with halogen or unsubstituted, can be substituted); E18) an 8-azabicyclo [3, 2, 1] octyl group (wherein, in the 8-azabicyclo [3, 2, 1] octane ring, at least one phenoxy group can be substituted (where, in the ring of phenyl, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted by halogen or unsubstituted, and a Cl-Cß alkoxy group substituted by halogen or unsubstituted, may be substituted )); El9) a group represented by the following general formula (Ef): -CH = N-NR7R48 (Ef) (wherein R47 and R48 each identical or differently represent: a hydrogen atom; an alkyl group of Cl-Cß; phenyl group [wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-Cß alkyl group substituted by halogen or unsubstituted, and a substituted Cl-Cß alkoxy group; with halogen or unsubstituted, it can be substituted]; or a pyridyl group [wherein, in the pyridine ring, at least one Cl-Cß alkyl group substituted with halogen or unsubstituted, can be substituted as a substituent], and further wherein R47 and R48 may be linked to each other with the halogen atoms adjacent thereto directly or through other heteroatoms, to thereby form a 5-7 membered saturated heterocyclic ring, - wherein, in the heterocyclic ring , at least one phenyl group can be substituted as a substituent [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-Cß alkyl group substituted by halogen or unsubstituted, and a Cl-Cβ alkoxy group substituted with halogen or unsubstituted, can be substituted]); E20) a phenylalkoxy group of Cl-Cß (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-Cß alkyl group substituted by halogen or unsubstituted, and a Cl-Cß alkoxy group substituted with halogen - or unsubstituted, may be substituted); E21). the C2-C6 alkenyl group substituted with amino (wherein, in the amino group, at least one selected from the group consisting of C1-C3 alkyl and a phenyl group [wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted with halogen or unsubstituted, and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, may be substituted] may be substituted); or E22) an oxazolidinyl group (wherein, in the oxazolidine ring, at least one oxo group can be substituted)]. A group represented by the general formula (F): -NR19R20 (F) [wherein R19 and R20 each represent identically or differently :. Fl) a hydrogen atom; F2) a C1-C6 alkyl group; F3) a phenylalkyl group of Cl-Cß (wherein, on the phenyl ring, at least one selected from the following group can be substituted: a phenoxy group [wherein, on the phenyl ring, at least one selected from the group consists of a halogen atom, a C 1 -C 4 alkyl group substituted by halogen or unsubstituted, and a C 1 -C 4 alkoxy group substituted by halogen or unsubstituted, can be substituted], a halogen atom, an alkyl group of Cl-Cβ substituted with halogen or unsubstituted, an alkoxy group of Cl-Cβ substituted with halogen or unsubstituted; an amino group (wherein, in the amino group, at least one selected from the group consisting of an alkyl group of Cl-Cß and a phenylalkyl group of Cl-Cß [wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted with halogen or unsubstituted, and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, may be substituted] may be substituted); a piperazinyl group [wherein, in the piperazine ring, at least one phenylalkyl group of Cl-Cß can be substituted (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted by halogen or unsubstituted, and a Cl-Cß alkoxy group substituted by halogen or unsubstituted, may be substituted)]; and a piperidyl group [wherein, in the piperidine ring, at least one amino group can be substituted, wherein in the amino group, at least one selected from the group consisting of a phenyl group (wherein, in the phenyl, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted with halogen or unsubstituted, and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, may be substituted) and an alkyl group of Cl-Cβ can be substituted]); F4) a phenoxyalkyl group of Cl-Cß (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-Cß alkyl group substituted by halogen or unsubstituted, and a group Cl-Cß alkoxy substituted with halogen or unsubstituted, can be substituted); F5) an aminoalkyl group of Cl-Cß (wherein, at the amino group, at least one selected from the group consisting of an alkyl group of Cl-Cß, an alkoxycarbonyl group of Cl-Cß, and a phenyl group [ wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, and a Cl-Cβ alkyl group substituted with halogen or unsubstituted, can be substituted], can be substituted; Fß) a phenyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a phenoxy group [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, an alkoyl group of Cl-Cβ substituted by halogen or unsubstituted, and a Cl-Cβ alkoxy group substituted with halogen or unsubstituted, can be substituted], and a C 1 -C 6 alkoxycarbonyl group can be substituted ); F7) an alkoxycarbonyl group of Cl-Cß; F8) a phenylalkoxycarbonyl group of Cl-Cß (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-Cß alkyl group substituted by halogen or unsubstituted and a group Cl-Cß alkoxy substituted with halogen or unsubstituted, can be substituted); F9) a group represented by the general formula (Fa): (wherein R21 represents: an alkoxycarbonyl group of Cl-Cß; a phenylalkoxycarbonyl group of Cl-Cß (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, an alkyl group of Cl-Cβ substituted with halogen or unsubstituted, and a Cl-Cβ alkoxy group substituted with halogen or unsubstituted, can be substituted); a phenylalkyl group of Cl-Cβ (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cβ alkyl group substituted by halogen or unsubstituted, can be substituted), a phenyl group (wherein, on the phenyl ring-, at least one selected from a group consisting of a halogen atom, a cyano group, a Cl-Cß alkyl group substituted with halogen or unsubstituted, and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, may be substituted)); FIO) a 1-substituted 4-piperidyl group represented by the general formula (Fb): (wherein R22 represents: an alkoxycarbonyl group of CI-C67 a phenylalkoxycarbonyl group of Cl-Cβ (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted with halogen or unsubstituted, and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, may be substituted); or a phenyl group (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a cyano group, an alkyl group of Cl-Cβ substituted with halogen or unsubstituted, and an alkoxy group of Cl-Cβ substituted with halogen or unsubstituted, can be substituted)); or Fll) a piperidyl group of Cl-Cβ (wherein, in the piperidine ring, at least one phenoxy group can be substituted (wherein, on the phenyl ring, at least one Cl-Cß alkyl group substituted with halogen or unsubstituted, can be substituted)); or in addition, - F12) R19 and R20 can be attached to each other with nitrogen atoms adjacent to them directly or through other heteroatoms or carbon atoms, to thereby form a heterocyclic ring represented by any of (F12-1 ) a (F12-10) indicated below. (F12-1) a group represented by the general formula (Fc): [where the dotted line represents that the link can be a double bond and R23 represents: (Fcl) a group. Cl-Cß alkyl; (Fc2) a phenylalkyl group of Cl-Cß (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted by halogen or unsubstituted, and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted); (Fc3) a phenyl group (wherein, on the phenyl ring, at least one selected from the following group can be substituted: a halogen atom, a C1-C3 alkyl group substituted by halogen or unsubstituted, an alkoxy group of Cl-Cβ substituted with halogen or unsubstituted, an amino group which may have, as a substituent, a group selected from the group consisting of an alkyl group of Cl-Cß and a phenylalkyl group of Cl-Cß [wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted with halogen or unsubstituted, and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, may be substituted], a phenoxy group [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-C3 alkyl group substituted by halogen or unsubstituted, and an alkoxy group of Cl -Cß substituted with halogen or unsubstituted, can to be substituted], a phenylalkoxy group [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-Cß alkyl group substituted by halogen or unsubstituted, and an alkoxy group of Cl-Cβ substituted with halogen or unsubstituted, may be substituted]; and a piperidyl group [wherein, in the piperidine ring, at least one amino group can be substituted, and wherein, in the amino group, at least one selected from the group consisting of a phenylalkyl group of Cl-Cβ (in wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted with halogen or unsubstituted, and a Cl-Cß alkoxy group substituted with halogen or unsubstituted can be substituted) and an alkyl group of Cl-Cβ can be substituted]); (Fc4) a phenylalkoxy group of Cl-Cβ (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted by halogen or unsubstituted, and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted); (Fc5) a biphenylalkyloxy group of Cl-Cβ; (Fcß) a phenylalkenyloxy group of C3-C6 wherein, in the phenyl ring, at least one halogen atom can be substituted; (Fc7) a phenoxy group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a cyano group, a C1-Cß alkyl group substituted by halogen or unsubstituted, and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted); (Fc8) a benzoyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-C3 alkyl group substituted by halogen or unsubstituted, and an alkoxy group of Cl -Cβ substituted with halogen or unsubstituted, can be substituted); (Fc9) a C 1 -C 6 alkoxycarbonyl group; (FclO) a phenylalkoxycarbonyl group of Cl-Cβ (wherein, in the phenyl ring, at least one Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted); (Fcll) a phenylalkylcarbamoyl group of. Cl-Cß wherein, in the phenyl ring, at least one halogen atom can be substituted; (Fcl2) a phenylcarbamoyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-C3 alkyl group substituted by halogen or unsubstituted, and an alkoxy group of Cl -Cβ substituted with halogen or unsubstituted, can be substituted); (Fcl3) a phenylthio group (wherein, in the phenyl ring, at least one Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted); (Fcl4) a phenyl sulfoxide (wherein, in the phenyl ring, at least one Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted); (Fcl5) a pyridylalkoxy group of Cl-Cβ; or (Fclß) a group represented by the general formula (Fca): - (C = 0) or-NR24R25 (Fca) (where or is the same as the one defined above, R24 and R25 each represent: (Fcal) a hydrogen atom; (Fca2) an alkyl group of Cl-Cß; (Fca3) a phenylalkyl group (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted with halogen or unsubstituted, and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, may be - substituted); (Fca4) a phenyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a cyano group, a C1-6 alkyl group substituted with halogen or not substituted, and a C1-C6 alkoxy group substituted with halogen or unsubstituted, can be substituted); (Fca5) an alkanoyl group of Cl-Cß; (Fcaß) a phenylalkanoyl group of C2-C6 wherein, in the ring of phenyl, at least one halogen atom can be substituted; (Fca7) a benzoyl group (wherein, on the phenyl ring, at less one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted with halogen or unsubstituted, and a C 1 -C 6 alkoxy group substituted with halogen or unsubstituted, may be substituted); (Fca8) a C 1 -C 6 alkoxycarbonyl group; (Fca9) a phenylalkoxycarbonyl group of C1-C6 (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-C6 alkyl group substituted with halogen or unsubstituted, and a C 1 -C 6 alkoxy group substituted with halogen or unsubstituted, can be substituted); (FcalO) a phenylcarbamoyl group (wherein, in the phenyl ring, at least one Cl-Cß alkyl group substituted by halogen or unsubstituted, can be substituted); or (Fcall) a piperidyloxycarbonyl group (wherein, in the .piperidine ring, at least one group, phenyl can be substituted as a substituent [wherein, on the phenyl ring, at least one Cl-Cβ alkyl group substituted with • halogen or unsubstituted, can be substituted]); or in addition, (Fcal2) R24 and R25 can form a 5- or 6- membered saturated heterocyclic ring by means of nitrogen atoms adjacent thereto, wherein, in the heterocyclic ring, at least one selected from the following group can be substituted: an alkoxycarbonyl group of Cl-Cβ; a benzoyl group (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-C3 alkyl group substituted by halogen or unsubstituted, and an alkoxy group of Cl-Cβ substituted with halogen or unsubstituted, can be substituted); a phenoxy group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-Cß alkyl group substituted by halogen or unsubstituted, and a substituted Cl-Cß alkoxy group with halogen or unsubstituted, it can be substituted); a phenylalkyl group of Cl-Cß (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-Cß alkyl group substituted with halogen or unsubstituted, and an alkoxy group of Cl-Cβ substituted with halogen or unsubstituted, can be substituted); a phenylalkoxycarbonyl group of Cl-Cβ (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-Cß alkyl group substituted by halogen or unsubstituted, and a group Cl-Cß alkoxy substituted with halogen or unsubstituted, can be substituted); a C2-C6 phenylalkenyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-C3 alkyl group substituted by halogen or unsubstituted, and an alkoxy group of Cl-Cβ substituted with halogen or unsubstituted, can be substituted); and a phenyl group (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted with halogen or unsubstituted, and a Cl-Cβ alkoxy group substituted with unsubstituted halogen c, can be substituted); (F12-2) a 4-substituted 1-piperazinyl group represented by the general formula (Fd): (wherein R represents (Fdl) a hydrogen atom; (Fd2) an alkyl group of Cl-Cß; (Fd3) a C3-C8 cycloalkyl group; (Fd4) a C3-C8 cycloalkyl group-Cl- alkyl; Cβ; (Fd5) an alkoxycarbonyl group of Cl-C6-alkyl of Cl-Cß; (Fdβ) a phenylalkenyl group of C2-C6; (Fd7) a phenylalkyl group of Cl-Cβ (wherein, in the phenyl ring, 1 to 3 groups selected from the following group can be substituted: a halogen atom, a cyano group, an alkyl group of Cl-Cβ substituted with halogen or unsubstituted, a C3-C8 cycloalkyl group, a C1-C3 alkoxy group substituted with halogen or unsubstituted, an amino group which may have an alkyl group of Cl-Cβ as a substituent, an alkoxycarbonyl group of Cl- Cβ, a phenoxy group, a phenylalkyl group of Cl-Cβ, a phenyl-C2-C6-phenyl group, a pyridyl group, an imidazolyl group and a piperidyl group); (Fd8) a biphenylylalkyl group of Cl-Cß (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-Cß alkyl group substituted by halogen or unsubstituted, a group Cl-Cβ alkoxy substituted with halogen or unsubstituted, and an amino group which may have an alkyl Cl-Cβ group as a substituent, may be substituted); (Fd9) a naphthylalkyl group of Cl-Cβ; (FdlO) a phenyl group (wherein, on the phenyl ring, at least one selected from the following group can be substituted: a halogen atom; a group, cyano; an amino group which can have an alguyl group of Cl-Cβ as a substituent, a Cl-Cß alkyl group substituted by halogen or unsubstituted, a Cl-Cß alkoxy group substituted by halogen or unsubstituted, an alkoxycarbonyl group of Cl-Cβ, a carboxyl group, a phenoxy group [wherein , in the phenyl ring, at least one selected from the group consisting of a halogen atom, an alkyl group of Cl-Cβ substituted by halogen or unsubstituted, and an alkoxy group of Cl-Cβ substituted with halogen or unsubstituted, can be substituted]; an aminoalkyl group of Cl-Cß [wherein, in the amino group, at least one selected from the group consisting of a phenyl group (wherein, in the phenyl ring, at least one selected from the group consisting of one atom of halogen, a Cl-Cß alkyl group substituted by halogen or unsubstituted, and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, may be substituted) and an alkyl group of Cl-Cβ may be substituted]; and a phenylalkoxy group of Cl-Cβ [wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-Cß alkyl group substituted by halogen or unsubstituted, and a group Cl-Cß alkoxy substituted with halogen or unsubstituted, can be substituted]); (Fdll) a biphenylyl group (wherein, in the phenyl ring, at least one Cl-Cß alkyl group substituted with halogen or unsubstituted, can be substituted); (Fdl2) an amino group, an amino group in which an alkoxycarbonyl group of Cl-Cβ is substituted, a phenylalkylamino group of Cl-Cβ (wherein, in the phenyl ring, at least one Cl-Cβ alkyl group substituted with halogen or unsubstituted, can be substituted), or a phenylamino group (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom and a Cl-Cβ alkyl group substituted with halogen or unsubstituted, may be substituted); (Fdl3) a benzoylalkyl group of Cl-Cβ (wherein, in the phenyl ring, at least one halogen atom can be substituted); (Fdl4) a phenylcarbamoylalkyl group of Cl-Cβ (wherein, in the phenyl ring, at least one Cl-Cß alkyl group substituted with halogen or unsubstituted, can be substituted); (Fdl5) a thiazolylalkyl group of Cl-Cß (wherein, in the thiazole ring, at least one selected from the group consisting of a phenyl group substituted with halogen or unsubstituted and an alkyl group of Cl-Cβ can be substituted); (Fdlß) an oxazolylalkyl group of Cl-Cß (wherein, in the oxazole ring, at least one selected from the group consisting of a phenyl group substituted with halogen or unsubstituted and an alkyl group of Cl-Cβ can be substituted ); . (Fdl7) an indolylguiloyl group of Cl-Cß; (Fdl8) a C 1 -C 6 furyl alkyl group (wherein, in the furan ring, at least one phenyl group substituted with halogen or unsubstituted, can be substituted); (Fdl9) an imidazolylalguyl group of Cl-Cß (wherein, in the imidazole ring, a phenyl group can be substituted); (Fd20) a quinolyalkyl group of Cl-Cß; (Fd21) a tetrazolyl group (wherein, in the tetrazole ring, a phenyl group can be substituted); (Fd22) a pyrimidyl group in which a phenyl group can be substituted; (Fd23) a pyridyl group; (Fd24) a benzoxazolyl group; (Fd25) a benzothiazolyl group; (Fd26) a benzoxazolylalkyl group of Cl-Cß (wherein, in the benzoxazole ring, at least one oxo group can be substituted); (Fd27) a phenoxyalkanoyl group of C2-C6 wherein, in the phenyl ring, a halogen atom can be substituted; (Fd28) a phenylthioalkanoyl group of C2-C6 wherein, in the phenyl ring, a halogen atom can be substituted; (Fd29) a phenylalkanoyl group of C2-C6 (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-6 alkyl group substituted by halogen or unsubstituted and a group C 1 -C 6 alkoxy substituted with halogen or unsubstituted, can be substituted); (Fd30) a benzoyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-C6 alkyl group substituted with halogen or unsubstituted, a C1-6 alkoxy group C6 substituted with halogen or unsubstituted and an amino group which may have an alkyl group of Cl-Cβ as a substituent may be substituted); (Fd31) a biphenylcarbonyl group; (Fd32) a pyridylcarbonyl group; (Fd33) a phenylalkenylcarbonyl group of C2-C6 wherein, in the phenyl ring, a halogen atom can be substituted; (Fd34) a phenylalkylsulfonyl group of Cl-Cß wherein, in the phenyl ring, a halogen atom can be substituted; (Fd35) a benzenesulfonyl group (wherein, in the benzene ring, at least one selected from the group consisting of a halogen atom and an alkyl group of Cl-Cβ can be substituted); (Fd36) a group represented by the general formula (Fda): -COOR27 (Fda) (wherein R27 represents: (Fdal) - a C1-C8 alkyl group substituted with halogen or unsubstituted; (Fda2) a C3-C8 cycloalkyl group; (Fda3) a C3-C8 cycloalkyl-C1-6 alkyl group; Cβ; (Fda4) an alkoxy group of Cl-C6-algayl of Cl-Cß; (Fda5) an aminoalkyl group of Cl-Cß which may have an alguyl group of Cl-Cß; (Fdaß) a group represented by the formula general (Fdb): (wherein each of R, R and R represents: a hydrogen atom, an alkyl group of Cl-Cß, or a phenyl group (wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted with halogen or unsubstituted and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted)); (Fda7) a phenylalkyl group of Cl-Cß (wherein, on the phenyl ring, 1 to 5 groups selected from the group consisting of a halogen atom, an alkyl group of Cl-Cβ substituted with halogen or unsubstituted, a alkoxy group of Cl-Cβ substituted with halogen or unsubstituted, a substituted alkyl group with halogen or unsubstituted, a phenylalkoxy group of Cl-Cß, a hydroxy group, an alkylsulfinyl group of Cl-Cß, an alkylsulfonyl group of Cl-Cß, a group alkylsulfonyloxy of Cl-Cß, a cyano group, an alkanoyl group of Cl-Cß, a benzoyl group, a phenylalkyl group of Cl-Cß which may have an alkoxy group of Cl-Cß in an alkyl portion thereof, an amino group, a nitro group, a carbamoyl group, an alkanoylamino group of Cl-Cß, an alkoxycarbonyl group of Cl-Cß, an alkylaminocarbonyl group of Cl-Cβ, an alkoxycarbonylamino group of Cl-Cß, a trialkylsiloxy group of Cl-Cβ, a pyrrolyl group, a tetrahydropyranilloxy group and an imidazolyl group, can be substituted); (Fda8) a biphenylylalkyl group of Cl-Cβ; (Fda9) a benzhydryl group (wherein, in the benzene ring, at least one selected from the group consisting of a halogen atom, a trifluoromethyl group and a trifluoromethoxy group can be substituted); (FdalO) a phenoxyalkyl group of Cl-Cβ (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted with halogen or unsubstituted, and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted); (Fdall) a C2-C6 phenylalkyl group (wherein, in the phenyl ring, at least one Cl-Cß alkyl group substituted with halogen or unsubstituted, can be substituted); (Fdal2) a pyridylalkyl group of Cl-Cβ; (Fdal3) a group represented by the general formula (Fdc): (wherein R31 represents: a phenyl group [wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a cyano group, a C1-C3 alkyl group substituted by halogen or unsubstituted and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted]; a phenylalkyl group of Cl-Cβ [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen, a Cl-Cß alkyl group substituted by halogen or unsubstituted and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted], or a benzoyl group [wherein, in the phenyl ring, less one selected from the group consisting of a halogen atom, a Cl-Cß alkyl group substituted by halogen or unsubstituted and a Cl-Cß alkoxy group substituted by halogen or unsubstituted, may be substituted]); (Fdal4) a piperidinalkyl group of Cl-Cß (wherein, in the piperidine ring, a phenoxy group, which may have, as a substituent, at least one alkyl group substituted with halogen or unsubstituted on the phenyl ring, can be substituted); (Fdal5) an aminoalkyl group of Cl-Cß (wherein, in the amino group, at least one selected from the group consisting of an alkyl group of Cl-Cß and a phenyl group, which may have, as a substituent, a alkoxy group of Cl-Cβ substituted with halogen or unsubstituted in the phenyl ring, can be substituted); (Fdald) a 1, 2, 3, 6-tetrahydropyridylalkyl group of Cl-Cß (wherein, in the 1,2,3,6-tetrahydropyridine ring, at least one phenyl group [wherein, in the phenyl ring , at least one Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted]); (Fdal7) a naphthylalkyl group of Cl-Cβ; (Fdal8) a fluorenylalkyl group of Cl-Cβ; (Fdal9) a pyridylalkyl group of Cl-Cβ; (Fda20) a furyalkyl group of Cl-Cß (wherein, in the furan ring, a phenyl group substituted with halogen or unsubstituted, can be substituted); (Fda21) a thienylalkyl group of Cl-Cβ; (Fda22) an oxazolylalkyl group of Cl-Cß (wherein, in the oxazole ring, a halogen atom, or a phenyl group substituted with halogen or unsubstituted, can be substituted); (Fda23) an oxadiazolylalkyl group of Cl-Cß (wherein, in the oxadiazole ring, a phenyl group substituted with halogen or unsubstituted, can be substituted); (Fda24) a pyrazolylalkyl group of Cl-Cß (wherein, in the pyrazole ring, a phenyl group substituted with halogen or unsubstituted, can be substituted); (Fda25) a benzothienylalkyl group of Cl-Cß (wherein, in the benzothiophene ring, at least one selected from the group consisting of a halogen atom and a C1-Cβ alkoxy group substituted with halogen or unsubstituted, can be replaced); (Fda26) a thienylalkyl group of Cl-Cß wherein, in the thiophene ring, a halogen atom can be substituted; (Fda27) a benzothiazolylalkyl group of Cl-Cß; (Fda28) a benzofurylalkyl group of Cl-Cß wherein, in the benzofuran ring, a halogen atom can be substituted; (Fda29) an indolinylalkyl group of Cl-Cβ (wherein, in the indoline ring, at least one selected from the group consisting of an alkyl group of Cl-Cβ and an oxo group can be substituted); (Fda30) a benzoxazolylalguilo group of Cl-Cß (wherein, in the benzoxazole ring, at least one selected from the group consisting of a halogen atom, a C1-C6 alkyl group and an oxo group, can be substituted ); (Fda31) a chromenylalkyl group of Cl-Cß; (Fda32) a 1, 2, 3, 4-tetrahydroquinolyalkyl Cl-Cß group (wherein, in the quinoline ring, at least one selected from the group consisting of an alkyl group of Cl-Cß and an oxo group can be replaced); (Fda33) a thiazolylalkyl group of Cl-Cß (wherein, in the thiazole ring, at least one selected from the group consisting of a halogen atom, a phenyl group substituted with halogen or unsubstituted and an alkyl group of Cl-Cβ can be substituted); or (Fda34) a tetrazolylalkyl group of Cl-Cß (wherein, in the tetrazole ring, at least one selected from the group consisting of a phenyl group substituted with halogen or unsubstituted and an alkyl group of Cl-Cß can be replaced); (Fd37) a group represented by the general formula (Fe): -Z-NR32R33 (Fe) (wherein Z represents -C = 0 or -C = S; R32 and R33 each in an identical or different manner represent: (Fel) a hydrogen atom; (Fe2) an alguyl group of Cl-Cβ; (Fe3) a C3-C8 cycloalkyl group; (Fe4) a phenylalkyl group of Cl-Cβ (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, an alkyl group of Cl-Cβ substituted with halogen or unsubstituted and a Cl-Cβ alkoxy group substituted with halogen or unsubstituted, can be substituted); (Fe5) a C2-C6 phenylalkenyl group (wherein in the phenyl ring, at least one selected from the group consists of a halogen atom, a Cl-Cß alkyl group substituted by halogen or unsubstituted and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted), or (Feß) a phenyl group (wherein , in the phenyl ring, at least one selected from the group consisting of a halogen atom, an alkyl group of Cl-Cß substitute halogen or unsubstituted and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, can be substituted); or in addition, (Fe7) R32 and R33 can be attached to each other along with the nitrogen atoms adjacent thereto through other carbon atoms, to thereby form a piperidine ring or a ring of 1, 2, 3, 6 -tetrahydropyridine, wherein, in the piperidine ring or in the 1,2,3,6-tetrahydropyridine ring, a phenyl group can be substituted, and in addition, at least one selected from the group consisting of a halogen atom and an alkyl group of Cl-Cβ substituted with halogen or unsubstituted, can be substituted in the phenyl group); (Fd38) a group represented by the general formula (Ff): (wherein R34 represents a hydrogen atom or lower alkyl group of Cl-Cß; and R35 represents: (Ffl) a C3-C8 cycloalkyl group; (Ff2) a C3-C8 cycloalkenyl group; (Ff3) a group represented by the general formula! Ffa): (wherein each of R36, R37 and R38 represent: a hydrogen atom, an alkyl group of Cl-Cß, a phenyl group [wherein, in the phenyl ring, 1 to 5 groups selected from the group consisting of halogen atom, a C 1 -C 4 alkyl group substituted by halogen or unsubstituted, a C 1 -C 4 alkoxy group substituted by halogen or unsubstituted, an alkylenedioxy group of C 1 -C 4, an alkylsulfonyl group of Cl-Cß, a group alkylthio of Cl-Cβ substituted with halogen or unsubstituted, a nitro group and an amino group which may have an alkanoyl group of Cl-Cß as a substituent, may be substituted); a benzofuryl group [wherein, in the benzofuran ring, at least one selected from the group consisting of a halogen atom, a C1-C3 alkyl group substituted by halogen or unsubstituted and a C1-C3 alkoxy group substituted with halogen or unsubstituted, it can be substituted]; a biphenylyl group; a furyl group [wherein, in the furan ring, a phenyl group which may have a halogen atom as a substituent may be substituted]; or a thiazolyl group [wherein in the thiazole ring, at least one phenyl group which may have a halogen atom, may be substituted]); (Ff4) a phenyl group (wherein, on the phenyl ring, at least one selected from the following group can be substituted: an atom, halogen, an alkyl group of Cl-Cβ substituted by halogen or unsubstituted, a cycloalkyl group of C3-C8, a hydroxyl group, a C1-C8 alkoxy group substituted with halogen or unsubstituted, a C3-C8 cycloalkoxy group, a C1-C4 alkylenedioxy group, a cyano group, a nitro group, a phenylalkenyl group of C2-Cβ, a C2-C6 alkanoyloxy group, an amino group which may have an alkanoyl group of Cl-Cβ as a substituent, an alkylsulfonylamino group of Cl-Cß, a phenylalkoxy group of Cl-Cß, a phenoxy group; an amino group in which at least one alkyl group of Cl-Cβ is substituted, an amino group in which at least one phenyl group is substituted, an aminoalkoxy group of Cl-Cβ [wherein, in the amino group, less an alkyl group of Cl-Cβ may be substituted], an alkoxycarbonyl group of Cl-Cβ, an alkoxycarbonyl group, Cl-C6-Cl-Cß alkoxy; an alkylthio group of Cl-Cß; a pyrolyl group; an imidazolyl group; a piperidyl group; a morpholino group; a pyrrolidinyl group; a thienyl group; a benzofuryl group; a piperazinyl group [wherein, in the piperazine ring, at least one selected from the group consisting of an alkyl group of Cl-Cß, a phenylalkyl group of Cl-Cß and a benzoyl group which may have at least one alkyl group of Cl-Cß, can be substituted as a substituent]; 'a quinolyl group [wherein, in the quinoline ring, at least one selected from the group consisting of an alkoxy group of Cl-Cβ and an oxo group may be substituted]; a piperidylcarbonyl group wherein, in the piperidine ring, a carbostyril group can be substituted; and a triazolyl group); (Ff5) a naphthyl group (wherein, in the naphthalene ring, at least one selected from a group consisting of a halogen atom, a Cl-Cß alkoxy group substituted with halogen or unsubstituted and an amino group which can be have an alkyl group of Cl-Cß as a substituent, can be ^ substituted); (Ffβ) a biphenylyl group (wherein, in the biphenylyl ring, at least one selected from the group consisting of a halogen atom, a C 1 -C 9 alkyl group substituted with halogen or unsubstituted and a C 1 -C 6 alkoxy group Cβ substituted with halogen or unsubstituted, can be substituted); (Ff7) a fluorenyl group; a pyrenyl group; (Ff8) a benzofuryl group (wherein, in the benzofuran ring, at least one selected from the group consisting of a halogen atom, a C1-C3 alkyl group substituted by halogen or unsubstituted and an alkoxy group of Cl- Cβ substituted with halogen or unsubstituted, can be substituted); (Ff9) a benzothienyl group (wherein, in the benzothiophene ring, at least one selected from the group consisting of a halogen atom, a cyano group, a C1-C6 alkyl group substituted with halogen or unsubstituted and a group C 1 -C 6 alkoxy substituted with halogen or unsubstituted, can be substituted); (FflO) a pyridyl group (wherein, in the pyridine ring, at least one selected from the group consisting of a halogen atom, a C1-C6 alkyl group substituted with halogen or unsubstituted, a phenyl group [wherein , in the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-C6 alkyl group substituted with halogen or unsubstituted and a C1-C6 alkoxy group substituted with halogen or unsubstituted, can to be substituted], a furyl group and a thienyl group, can be substituted); (Ffll) a furyl group (wherein, in the furan ring, 1 to 3 groups selected from the group consisting of a C1-C6 alkyl group, a nitro group and a phenyl group [wherein, in the phenyl ring , at least one selected from the group consisting of a halogen atom, a C1-C6 alkyl group substituted with halogen or unsubstituted, a C1-C6 alkoxy group substituted with halogen or unsubstituted, and a nitro group, can be replaced], can be substituted); (Ffl2) a benzothiazole group (wherein, in the benzothiazole ring, at least one phenyl group, which may have, as a substituent, a C1-C6 alkoxy group in the phenyl ring, may be substituted); (Ffl3) a thienyl group (wherein, in the thiophene ring, at least one selected from the group consisting of a halogen atom, a nitro group, an alkyl group of Cl-Cß, a pyrazolyl group wherein, in the pyrazole ring, at least one C 1 -C 6 alkyl group substituted with halogen or unsubstituted, can be substituted, and a thienyl group, wherein, in the thiophene ring, a halogen atom can be substituted, can be substituted ); (Ffl4) an indolyl group (wherein, in the indole ring, at least one selected from the group consisting of a phenylsulfonyl group which may have an alkyl group of Cl-C6 as a substituent, a phenylalkyl group of C1-C6, a alkoxycarbonyl group of Cl-Cβ and a phenyl group, can be substituted); (Ffl5) a pyrrolyl group (wherein, in the pyrrole ring, at least one selected from the group consisting of a phenyl group in which at least one alkyl group of Cl-Cβ substituted with halogen or unsubstituted, can be substituted and an alkyl group of Cl-Cβ can be substituted); (Fflß) a coumaryl group; (Ffl7) a benzoimidazolyl group (wherein, in the benzoimidazole ring, at least one thienyl group can be substituted); (Ffl8) an oxazolyl group (wherein, in the oxazole ring, at least one phenyl group which may have a halogen atom may be substituted); (Ffl9) a thiazolyl group (wherein, in the thiazole ring, at least one phenyl group can be substituted, and furthermore wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a nitro group, and a phenyl group can be substituted); (Ff21) a quinolyl group; (Ff22) a 3, 4-dihydrocarbostyril group (wherein, in the 3,4-dihydrocarbostyril ring, at least one selected from the group consisting of a Cl-Cß alkoxy group, an alkyl group of Cl-Cß and a phenylalkoxy group of Cl-Cβ can be substituted); a carbostyril group (wherein, in the carbostyril ring, at least one selected from the group consisting of an alkoxy group of Cl-Cβ, an alkyl group of Cl-Cβ and a phenylalkoxy group of Cl-Cβ, can be 'substituted ); (Ff23) an imidazo [2, 1-b] thiazolyl group; (Ff24) an imidazo [2, 1-a] pyridyl group; (Ff25) a chromanillo group (wherein, in the chroman ring, at least one Cl-Cß alkyl group can be substituted); or (Ff26) a 2, 3-dihydrobenzofuryl group); or (Fd39) a group represented by the general formula (Ffb): (wherein R 45 represents: an alkoxycarbonyl group of Cl-Cß; a phenyl group [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, an alkyl group of Cl-Cβ substituted with halogen or unsubstituted and a Cl-Cβ alkoxy group substituted with halogen or unsubstituted, an alkyl group of Cl-Cβ substituted with amino [wherein, at the amino group, at least one selected from the A group consisting of a phenyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-C3 alkyl group substituted by halogen or unsubstituted and an alkoxy group of Cl -Cβ substituted with halogen or unsubstituted, can be substituted) and an alkyl group of Cl-Cβ can be substituted], a benzoyl group [wherein, in the phenyl ring, at least one selected from the group consisting of one atom of halogen, an alkyl group of Cl-Cβ substituted with halogen or unsubstituted and a Cl-Cß alkoxy group substituted with halogen or unsubstituted, may be substituted]; a phenylalkyl group of Cl-Cß [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-C3 alkyl group substituted by halogen or unsubstituted and an alkoxy group of Cl -Cβ substituted with halogen or unsubstituted, can be substituted]; a phenylalkoxycarbonyl group of Cl-Cß [wherein, in the phenyl ring, at least one selected from the group consisting of a halogen atom, an alkyl group of Cl-Cβ substituted with halogen or unsubstituted and a C 1 -C 4 alkoxy group substituted with halogen or unsubstituted, can be replaced]; or a C2-C6 phenylalkyl group [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-C3 alkyl group substituted by halogen or unsubstituted and an alkoxy group of Cl-Cβ substituted with halogen or unsubstituted, can be substituted]); F12-3) a morpholino group; F12-4) an imidazolyl group; F12-5) a 1,4-dioxazaspiro [4, 5] decyl group (wherein, in the 1,4-dioxazaspiro [4, 5] decane ring, at least one oxo group can be substituted); F12-6) a homopiperazinyl group (wherein, in the homopiperazine ring, at least one selected from the group consisting of an alkoxycarbonyl group of Cl-Cß, a phenylalkoxycarbonyl group of Cl-Cß and a phenyl group substituted with phenyl or unsubstituted, can be substituted); F12-7) a piperazinyl group (wherein, in the piperazine ring, at least one selected from the group consisting of an oxo group, an alkyl group of Cl-Cß and a phenylalkyl group of Cl-Cß [wherein, in the phenyl ring, at least one Cl-Cß alkyl group substituted by halogen or unsubstituted, can be substituted); F12-8) a piperidyl group (wherein, in the piperidine ring, at least one oxo group can be substituted); F12-9) a pyrrolidinyl group (wherein, in the pyrrolidine ring, at least one phenoxyalkyl group of Cl-Cβ, which may have a Cl-Cβ alkoxy group substituted with halogen or unsubstituted as a substituent, may be replaced); or F12-10) an isoindolinyl group; or in addition F13) R19 and R20 can be linked together with the nitrogen atoms adjacent thereto directly or through heteroatoms, in order to form a cyclic imide or amide represented by any of the following (F13-1) a (F13-11): (F13-1) a succinimide group; (F13-2) an oxazolidinyl group (wherein, in the oxazolidine ring, at least one oxo group can be substituted); (F13-3) a benzo-1,3-oxazolidinyl group (wherein, in the benzo-1,3-oxazolidine ring, at least one selected from the group consisting of an oxo group, a halogen atom and a phenyl group, can be substituted); '(F13-4) an imidazolidinyl group (wherein, on the imidazolidine ring, at least one selected from the group consisting of an oxo group, a phenylalkyl group of Cl-Cß [wherein, on the phenyl ring, 3 groups selected from the group consisting of a halogen atom and an alkoxy group of Cl-Cβ can be substituted], and a phenyl group, can be substituted); (F13-5) a benzoimidazolidinyl group (wherein, in the benzoimidazolidine ring, at least one selected from the group consisting of an oxo group, a halogen atom, a C1-C3 alkyl group substituted by halogen or unsubstituted , an amino group which may have an alkyl group of Cl-Cß as a substituent, an alkoxycarbonyl group of Cl-Cß, and a piperidyl group [wherein, in the piperidine ring, at least one selected from the group consisting of an alkyl group of Cl-Cß, a phenyl group, wherein, in the phenyl ring, 1 to 3 halogen atoms can be substituted, an alkoxycarbonyl group of Cl-Cβ and a phenylalkoxycarbonyl group of Cl-Cβ, can be substituted], can be substituted); (F13-6) a phthalimide group; (F13-7) an indolinyl group (wherein, in the indoline ring, at least one selected from the group consisting of a C1-C6 alkyl group, a halogen atom and an oxo group can be substituted); (F13-8) a 2,3-dihydrobenzothiazolyl group (wherein, in the 2,3-dihydrobenzothiazole ring, at least one oxo group can be substituted); (F13-9) a 1H-2,4-benzoxazinyl group (wherein, in the 1H-2,4-benzoxazine ring, at least one oxo group may be substituted); (F13-10) a group represented by the general formula (Fga): (wherein R39 represents: a hydrogen atom, a phenylalkyl group of Cl-Cß which can have, as a substituent, a halogen atom on the phenyl ring, a phenoxyalkyl group of Cl-Cß which can have, as a substituent, a halogen atom in the phenyl ring, a C2-C6 phenylalkenyl group which may have, as a substituent, a halogen atom in the phenyl ring, a phenyl group in which, in the phenyl ring, at least one selected from the group consisting of a halogen atom, a C1-Cß alkyl group substituted by halogen or unsubstituted, a Cl-Cß alkoxy group substituted with halogen or unsubstituted and a phenyl group, may be substituted as a substituent, a pyridyl group, or a pyrazinyl group); or (F13-11) a 1,3-thiazolidinyl group (wherein, in the 1,3-thiazolidine ring, at least one selected from the group consisting of an oxo group and a phenylalkylidene group of Cl-Cß which may have an alkyl group of Cl-Cβ substituted with halogen or unsubstituted on the phenyl ring, can be substituted as a substituent). A group represented by the general formula (G): (wherein R40 represents an alkyl group of Cl-Cβ or a phenyl group substituted with halogen or unsubstituted). The reaction between a compound (10a) or (10b) and a compound (11) is carried out in a suitable solvent or without solvents, in the presence or absence of a basic compound. Examples of a solvent used herein may include: water; alcohols such as methanol, ethanol, isopropanol, n-butanol or tert-butanol; aromatic hydrocarbons such as benzene, toluene, xylene, tetralin, o-chlorobenzene, m-chlorobenzene, or 2,3-dichlorobenzene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride, ethers such as diethyl ether, dimethoxyethane, dioxane, tetrahydrofuran, diglyme or dipropyl ether; saturated hydrocarbons such as n-hexane, n-butane, cyclohexane or liquid paraffin; ketones. such as acetone or methyl ethyl ketone; polar solvents such as N-N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, acetonitrile, N-N-dimethylacetamide, or NMP; and its mixed solvents. Known organic and inorganic bases can be widely used as basic compounds. Examples of an inorganic base may include: alkali metal carbonates such as sodium carbonate or potassium carbonate; alkali metal acid carbonates such as sodium bicarbonate or potassium bicarbonate; alkali metal hydroxides such as sodium hydroxide or potassium hydroxide; alkali metal phosphates such as sodium phosphate or potassium phosphate; alkali metal hydrides such as sodium hydride or potassium hydride; alkali metals such as potassium or sodium; alkali metal amidates such as sodium amide; And alkali metal alcohols such as sodium methylate, sodium ethylate or sodium tert-butoxide. Examples of an organic base may include acetates such as sodium acetate or potassium acetate, pyridine, trimethylamine, triethylamine, diisopropylethylamine, dimethylaniline, 1-methylpyrrolidine, N-methylmorpholine, N, N-dimethyl-4-aminopyridine, 1-5. diazabicyclo [4.3.0] noneno-5 (DBN), l, 8-diazabicyclo [5.4.0] undecene-7 (DBU), and 1,4-diazabicyclo [2.2.2] octane (DABCO). The compound (11) is used for 1 mole of the compound (10a) or (10b) in an amount generally of at least 1 mole, and preferably between 1 and 5 mole. The basic compound is used for 1 mole of the compound (10a) or (10b) in an amount generally between 0.1 and 1 mole, and preferably between 0.1 and 0.5 mole. The reaction between the compound (10a) or (10b) and the compound (11) is carried out at a temperature generally between room temperature and 150 ° C, and preferably between room temperature and 120 ° C. It is usually carried out for 10 minutes to 24 hours before the conclusion. The reaction to obtain a compound (13a) from a compound (12a) and the reaction to obtain a compound (13b) from a compound (12b) are carried out in a suitable solvent or without solvents, in the presence of a basic compound. All solvents and basic compounds that can be used in the reaction mentioned above between the compound (10a) or (10b) and the compound (11) can also be used here as solvent and basic compounds. The basic compound is used for 1 mole of the compound (12a) or (12b) in an amount generally of at least 1 mole, and preferably between 1 and 2 moles. The above reaction is carried out at a temperature generally between 0 ° C and 150 ° C, and preferably between 0 ° C and 120 ° C. It is usually carried out for 10 minutes to 48 hours before the conclusion. Among the 4-nitroimidazole compounds represented by the formula (1) of the present invention, those having a basic group can easily form a salt together with a generally pharmacologically acceptable acid. Examples of this acid may include: inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid, or hydrobromic acid; and organic acids such as acetic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, citric acid, succinic acid, malic acid, tartaric acid, malonic acid, lactic acid or benzoic acid. A compound of interest obtained as a result of each of the above reactions is separated from the reaction mixture by common separation means, and can be further purified. Examples of these separation and purification media may include distillation, recrystallization, column chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, preparative thin layer chromatography and the solvent extraction method. According to the present invention, the compound of interest represented by the general formula (1) can be produced without passing the state of an intermediate, such as an explosion hazard. The production method of the present invention includes simple operations, and does not require a complicated purification process. According to the production method of the present invention, the 4-nitroimidazole compound of interest represented by the general formula (1) can be produced economically in a high yield and in high purity. Accordingly, the method of the present invention is extremely suitable in the industry. The present invention will be described more specifically in the following examples.

Reference Example 1 Production of 2,5-dx-bromo-4-nitroimidazole A mixture consisting of 4-nitroimidazole (100 g, 884 mmol), sodium bicarbonate (164 g, 1.94 mol) and water (500 ml) was stirred vigorously , and subsequently, bromine (106 ml, 2.07 mole) was added dropwise to the mixture at room temperature (23 ° C to 25 ° C) for 6 hours (where it foamed intensely during dripping). The mixture obtained in this way was stirred further under heating (50 ° C to 55 ° C, 4 hours). Subsequently, they were added to. the same water (400 ml) and concentrated hydrochloric acid (80 ml) under cooling on ice (10 ° C or less), and the obtained mixture was stirred for 1 hour. The crystals were collected by filtration. The obtained crystals were washed with water (on a filter paper, with 400 ml of water), washed in dispersed form (with 800 ml of water, twice), and air-dried (50 ° C, 16 hours). Yield: 213 g (Yield: 88.9%), as a light yellow crystal. IR (KBr): 3074, 1548, 1468, 1392, 1361, 1345, 1310, 1259, 1172, 1066, 975, 830, 667 cm "1.

Reference Example 2 Production of 2,5-dichloro-4-ni, broimidazole A mixture consisting of 2,5-dibromo-4-nitroimidazole (27.1 g, 100 mmol) and concentrated hydrochloric acid (434 ml) was stirred with heating (77 ° C to 80 ° C, 16 hours) . The reaction mixture was allowed to cool, and then stirred under cooling with ice (5 ° C to 10 ° C, 2 hours).

Subsequently, the precipitated crystals were collected by filtration and dried in air (50 ° C, 5 hours). The yield of the dried product was 8.26 g. The filtrate was further extracted with ethyl acetate (300 ml) and then dried (MgSO), followed by concentration in vacuo and external drying. The yield of the drying product was 9.63 g. In this way, 17.9 g (total) of 2,5-dichloro-4-nitroimidazole were obtained (yield: 98.3%). IR (KBr): 1566, 1475, 1403, 1366, 1332, 1272, 1190, 1091, 996, 834, 679 cm "1 M (70 eV) m / z (relative intensity): 183 (15, M +) , 181 (25), 108 (28), 74 (42), 62 (100).

Example 1 Production of 2-chloro-5-iodo-4-nit: roimidazole A suspension consisting of 2,5-dichloro-4-nitroimidazole (7.66 g, 42.1 mmol), sodium iodide (75.7 g, 505 mmol), and water (77 ml) was heated to reflux (102 ° C, 35 hours). The reaction mixture was cooled to room temperature. Subsequently, the crystals were collected by filtration, washed with water (on a filter paper, 77 ml), and then air-dried (50 ° C, 20 hours). Yield: 9.36 g (yield: 81.3%), as light yellow crystal. IR (KBr): 3199, 1538, 1468, 1394, 1346, 1300, 1262, 1166, 1049, 986, 831, 756, 734, 674 cm "1. MS (70 eV) m / z • (relative intensity): 274 (34, M +), 273 (100), 166 (35), 154 (80).

Example 2 Production of 2-bromo-5-iodo-4-nitroimidazole A suspension consisting of 2,5-dibromo-4-nitroimidazole (27.1 g, 100 mmol), sodium iodide (150 g, 1.00 mol) and water ( 271 ml) was heated to reflux (102 ° C, 15 hours). The reaction mixture was cooled to room temperature. Subsequently, the crystals were collected by filtration, washed with water (on a filter paper, 270 ml), and then air-dried (50 ° C, 20 hours). Yield 29.0 g (yield: 91.2%), as light yellow crystal. IR (KBr): 3218, 1537, 1456, 1386, 1336, 1288, 1250, 1156, 1048, 969, 829, 756, 731, 665 cm "1. MS (70 eV) m / z (relative intensity): 319 (80, M +), 317 (82), 154 (100), 106 (78).

Example 3 Production of 2-bromo-5-iodo-4-ni-broimidazole A suspension consisting of 2,5-dibromo-4-nitroimidazole (2.71 g, 10.0 mmol), sodium iodide (15.0 g, 100 mmol), Tetrabutylammonium iodide (185 mg, 0.50 mmol) and water (27 ml) was stirred under heating (80 ° C to 85 ° C, 27 hours). The reaction mixture was cooled to room temperature. Subsequently the crystals were collected by filtration, washed with water (on a filter paper, 27 ml), and then air-dried (50 ° C, 18 hours). Yield: 2.71 g (yield: 85.3%), as light yellow crystal. IR (KBr): 3218, 1537, 1456, 1386, 1336, 1288, 1250, 1156, 1048, 969, 829, 756, 731, 665 cm "1. MS (70 eV) m / z (relative intensity): 319 (80, M +), 317 (82), 154 (100), 106 (78).

Example 4 Production of 2-bromo-5-iodo-4-ni-roimidazole A suspension consisting of 2,5-dibromo-4-nitroimidazole (2.71 g, 10.0 mmol), sodium iodide (15.0 g, '100 mmol) water (27 ml) and an aqueous solution of 57% hydroiodic acid (5.4 ml) was stirred under heating (50 ° C to 60 ° C, 56 hours). The reaction mixture was cooled to room temperature. Subsequently, the crystals were collected by filtration, washed with water (on a filter paper, 27 ml), and then air-dried (50 ° C, 15 hours). Yield: 2.43 g (yield: 76.4%), light yellow crystal. IR (KBr): 3218, 1537, 1456, 1386, 1336, 1288, 1250, 1156, 1048, 969, 829, 756, 731, 665 cm "1. MS (70 eV) m / z (relative intensity): 319 (80, M +), 317 (82), 154 (100), 106 (78).

Example 5 Production of 2-bromo-5-iodo-4-nitroimidazole A suspension consisting of 2,5-dibromo-4-nitroimidazole (2.71 g, 10.0 mmol), water (13.6 ml), and an aqueous solution of hydriodic acid 57% (13.6 ml) was stirred under heating (50 ° C to 60 ° C, 36 hours). The reaction mixture was cooled to room temperature. Subsequently, the crystals were collected by filtration, washed with water (on a filter paper, 27 ml), and then air-dried (50 ° C, 15 hours). Yield: 1.11 g (yield: 34.9%), light yellow crystal. IR (KBr): 3218, 1537, 1456, 1386, 1336, 1288, 1250, 1156, 1048, 969, 829, 756, 731, 665 cm "1. MS (70 eV) m / z (relative intensity): 319 (80, M +), 317 (82), 154 (100), 106 (78).

Example 6 Production of 2-chloro-4-nitroimidazole A mixture consisting of 2-chloro-5-iodo-4-nitroimidazole (273 mg, 1.00 mmol), ethanol (2.7 ml), triethylamine (443 mg, 3.00 mmol) , and platinum oxide (2.9 mg, 1.1% by weight) was stirred under normal pressure in a hydrogen atmosphere at room temperature for 2 hours. The filtrate was concentrated and dried under reduced pressure, and the residue was then dissolved in ethyl acetate (30 ml). The organic layer was washed with 3% diluted hydrochloric acid (10 ml) and saturated saline (5 ml, twice); and then dried (MgSO), followed by concentration under vacuum and drying. Yield: 144 mg (yield: 97.6%) IR (KBr): 1556, 1510, 1472, 1404, 1375, 1358, 1193, 1093, 998, 979, 822, 753, 679, 595, 523 cm "1 NMR (DMS0-d6) d ppm: 8.40 (s, 1H), 14.2 (br, s, 1H).

Example 7 Production of 2-bromo-4-ni roimidazole A mixture consisting of 2-bromo-5-iodo-4-nitroimidazole (607 mg, 2.00 mmol), ethanol (6.4 ml), triethylamine (607 mg, 6.00 mmole) , and platinum oxide (3.4 mg, 0.53% by weight) was stirred under normal pressure in a hydrogen atmosphere at room temperature for 3 hours. The filtrate was concentrated and dried under reduced pressure, and the residue was then dissolved in ethyl acetate (50 ml). The organic layer was washed with 3% diluted hydrochloric acid (10 ml) and saturated saline (10 ml, twice), and then dried (MgSO), followed by concentration in vacuo and drying. Yield: 365 mg (yield: 95.1%) IR (KBr): 1548, 1514, 1453, 1392, 1373, 1258, 1168, 1085, 968, 823, 799, 751, 668 cm "1 NMR (DMSO-de) d ppm: 8.45 (s, ÍH), 14.1 (br, s, ÍH).

Example 8 Production of 2-bromo-4-n-nitroimidazole A mixture consisting of 2-bromo-5-iodo-4-nitroimidazole (636 mg, 2.00 mmol), ethnol (6.4 ml), triethylamine (607 mg, 6.00 mmol) ) and 2% palladium alumina (95.4 mg, 15% by weight) was stirred under normal pressure in a hydrogen atmosphere at 50 ° C at 60 ° C for 15 hours. The filtrate was concentrated and dried under reduced pressure, and the residue was then dissolved in ethyl acetate (50 ml). The organic layer was washed with 3% diluted hydrochloric acid (10 ml) and saturated saline (10 ml, twice), and then dried (MgSO 4), followed by concentration in vacuo and drying. Yield: 364 mg (yield: 94.8%) IR (KBr): 1548-, 1514, 1453, 1392, 1373, 1258, 1168, 1085, 968, 823, 799, 751, 668 cm "1. NMR (DMSO-de) ) d ppm: 8.45 (s, ÍH), 14.1 (br, s, ÍH).

Example 9 Production of 2-bromo-4-ni-broimidazole A mixture consisting of 2-bromo-5-iodo-4-nitroimidazole (1.27 g, Y.00 mmol), ethanol (13 ml), triethylamine (1.21 g) , 12.0 mmoles), and 2% palladium alumina (191 mg, 15% by weight) was stirred while applying pressure (3 to 4 atmospheres) in a hydrogen atmosphere at room temperature for 14 hours. The filtrate was concentrated and dried under reduced pressure, and the residue was then dissolved in ethyl acetate (100 ml). The organic layer was washed with 3% diluted hydrochloric acid (30 ml) and saturated saline (20 ml, twice), and then dried (MgSO 4), followed by concentration in vacuo and drying. Yield: 761 mg (yield: 99.1%) IR (KBr): 1548, 1514, 1453, 1392, 1373, 1258, 1168, 1085, 968, 823, 799, 751, 668 cm "1 NMR (DMSO-de) d ppm: 8.45 (s, ÍH), 14.1 (br, s, 1H).

Example 10 Production of 2-bromo-4-nitroimidazole Tetra-n-butylammonium borohydride (602 mg, 2.34 mmol) was added to a solution obtained by dissolving 2-bromo-5-iodo-4-nitroimidazole (186 mg, 0.585 mmole) in dry dioxane (2.8 ml). The obtained mixture was stirred at 60 ° C for 28 hours. The reaction mixture was cooled to room temperature, and then poured into 10% diluted hydrochloric acid (10 ml). The reaction product was extracted with ethyl acetate, and the ethyl acetate extract solution (40 ml) was dried (MgSO), followed by concentration in vacuo and drying. Yield: 86 mg (yield: 76.6%) IR (KBr): 1548, 1514, 1453, 1392, 1373, 1258, 1168, 1085, - 968, 823, 799, 751, 668 cm "1 NMR (DMSO-de) d ppm: 8.45 (s, 1H), 14.1 (br, s, 1H).

Example 11 Production of 2-bromo-4-nitroimidazole A mixture consisting of 2-bromo-5-iodo-4-nitroimidazole (2.43 g, 7.64 mmoles), isopropyl alcohol (12.2 ml), water (2.4 ml), triethylamine (2.32 g, 22.9 min) and 5% Pd-alumina ((12.2 mg) was stirred while applying pressure (3 to 4 atmospheres) in a hydrogen atmosphere at 60 C for 3 hours The filtrate was concentrated and dried under reduced pressure, and the resulting product was then dissolved in water (10 ml) The solution obtained in this way was treated with activated carbon (243 mg) (which stirred at room temperature for 1 hour.) The filtrate was stirred under ice-cooling, and 35% hydrochloric acid-concentrated (0.7 ml) was added thereto such that the pH of the solution became pH 2. • The The solution obtained in this way was further stirred under cooling on ice for 1 hour, then the precipitated crystals were collected by filtration and then dried at 50 ° C for 16 hours Yield: 1.14 g (yield: 77.7%) NMR (DMSO) -de) d ppm: 8.42 (s, 1H), 14.1 (br, s, ÍH).

Example 12 Production of 2-bromo-4-ni roimidazole 2-Bromo-5-iodo-4-nitroimidazole (1.00 g, 3.15 mmol) was dissolved in dimethylformamide (8 ml) and water (3 ml). The obtained solution was stirred under ice-cooling and then an aqueous solution of 50% -55% ammonium bisulfite (3.6 ml, 23.5 'mmoles with a content of 52.5%) was added thereto. The obtained mixture was stirred at room temperature for 3 days. Subsequently, cold water (30 ml) was added to the reaction product, followed by extraction with ethyl acetate 3 times (167 ml in total). The organic layer was washed with 5% saline twice and then dried (MgSO 4), followed by concentration in vacuo and drying. Yield: 375 mg (yield: 62.1%) NMR (DMSO-d6) d ppm: 8.44 (s, ÍH), 14.1 (br, s, ÍH).

Example 13 Production of 2-bromo-4-nitroimidazole 2-Bromo-5-iodo-4-nitroimidazole (1.54 g, 4.84 mmol) was dissolved in dimethylformamide (12.3 ml) and water (6.2 ml). Subsequently, sodium sulfite (1.22 g, 9.70 mmol) was added to the obtained solution. The mixture was heated to the temperature between 40 ° C and 60 ° C, and then stirred at this temperature for 20 hours. Subsequently, sodium sulfite (2.44 g, 19.4 mmol) was added in addition to the reaction solution, and the obtained mixture was stirred at 60 ° C for 15 hours. The reaction mixture was cooled to room temperature and then dilute hydrochloric acid was added thereto, followed by extraction with ethyl acetate (3 times, 200 ml in total). The organic layer was dried (MgSO), and water (10 ml) was added to the residue in the oil state obtained by concentration. The precipitated crystals were collected by filtration, and then dried at 60 ° C for 15 hours. Yield: 349 mg (yield: 37.5%) IR (KBr): 3201, 3146, 1547, 1514, 1452, 1391, 1373, 1356, 1258, 1167, 1084, 968, 823, 798, 750, 668 cm "1 NMR (DMSO-de) dpm: 8.43 (s, 1H) .14.1 (br, s, H).

Examples 14 to 19 2-Bromo-4-nitroimidazole was produced in the same manner as in Example 12 except that the sulfites and solvents shown in Table 1 indicated below were used, and that the reaction temperature and the time of reaction were determined as shown in Table 1 indicated below. The yields of 2-bromo-4-nitroimidazole are also shown in Table 1. In the table, the amount of sulfite used (mol) is a value determined using 1 mol of 2-bromo-5-iodo-4-nitroimidazole as a parameter. In addition, the amount of a solvent (dimethylformamide (DMF), water or 1-methyl-2-pyrrolidinone (NMP) used is a value determined using 1 millimole of 2-bromo-5-iodo-4-nitroimidazole as a parameter.

Table 1 Example 20 Production of 2-bromo-5-iodo-4-nitroimidazole A mixture consisting of 2,5-bromo-4-nitroimidazole (108.3 g, 400 mmol), ethanol (184 ml), sodium iodide (120 mg, 800 mmol) was heated to reflux in a stream of argon (65-70 ° C, 26 hours). The reaction mixture was cooled to room temperature and the precipitated inorganic salt was removed by filtration. 78% (234 ml) of the filtrate (300 ml) was concentrated and dried under reduced pressure (25-50 ° C). The residue (brown oil, 172 g) was suspended in ice water (422 ml), and concentrated hydrochloric acid (10 ml) was added thereto in such a way that the pH of the solution was made from 1 to 2. The solution obtained in this way it was stirred further under cooling on ice for 2 hours. Subsequently, the precipitated crystals were collected by filtration and then dried at 50 ° C for 24 hours. Yield: 89.2 g (yield: 89.9%), light yellow crystal IR (KBr): 3218, 1537, 1456, 1386, 1336, 1288, 1250, 1156, 1048, 969, 829, 756, 731, 665 cm_1. MS (70 eV) m / z (relative intensity): 319 (80, M *), 317 (82), 154 (100), 106 (78). It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (9)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A method for producing a 4-nitroimidazole compound represented by the general formula (1): wherein X2 represents a chlorine atom or bromine atom, characterized in that it comprises iodinating a 4-nitroimidazole compound represented by the general formula (2): wherein each of X1 and X2 represents a chlorine atom or a bromine atom, and then reducing the obtained 5-iodo-4-nitroimidazole compound represented by the general formula (3): where X2 is the same as the one defined above.

2. The production method according to claim 1, characterized in that an iodinating agent is a halogen molecule, hydriodic acid, or a metal salt or hydriodic acid.

3. The production method according to claim 2, characterized in that the metal salt of hydroiodic acid is sodium iodide, potassium iodide, lithium iodide, zinc iodide, magnesium iodide, or aluminum iodide.

4. The production method according to claim 3, characterized in that the iodinating agent is used for the compound (2) at a molar ratio of between 1.5: 1 and 15: 1, and the iodinating agent is sodium iodide.

5. The production method according to claim 1, characterized in that the reaction is carried out in the presence of a phase transfer catalyst. The production method according to claim 5, characterized in that the phase transfer catalyst is used for the compound (2) at a molar ratio of between 0.01: 1: 1, and the phase transfer catalyst is a quaternary ammonium salt, phosphonium salt or pyridinium salt. The production method according to claim 1, characterized in that the reducing agent is a hydrogenation reducing agent, and the reducing agent is used for the compound (3) at a molar ratio of between 1: 1 and 10: 1. 8. The production method according to claim 1, characterized in that the reducing agent is a catalytic hydrogenation reducing agent, and the reducing agent is used for the compound (3) at a weight ratio of between 0.1% by weight and 40% by weight. 9. The production method according to claim 8, characterized in that the reaction is carried out in the presence of triethylamine, trimethylamine or N-ethyldiisopropylamine.