Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/91—Nitro radicals
  • C07D233/92—Nitro radicals attached in position 4 or 5
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
  • A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles

Definitions

• the present invention relates to a method for producing a 4-nitroimidazole compound.
• X 2 represents a chlorine atom or bromine atom
• X 2 represents a chlorine atom or bromine atom
• Reaction scheme-l and -2 have previously been known as methods for producing the 4-nitroimidazole compound represented by general formula (1) (Jerzy
• the method represented by Reaction scheme-2 involves a reaction of nitrating the compound (8).
• the compound (la) can be obtained only at low yield by such nitration, and thus, this method is industrially disadvantageous.
• the present inventors have conducted intensive studies regarding a method for producing a 4- nitroimidazole compound represented by general formula (1) -
• the present inventors have found that the aforementioned object can be achieved by selectively substituting a chlorine atom or bromine atom at position 5 of a 4-nitroimidazole compound represented by general formula (2) indicated below with an iodine atom, and then selectively reducing position 5 of the obtained 5-iodo-4-nitroimidazole compound represented by general formula (3) indicated below.
• a 4-nitroimidazole compound represented by general formula (1) can be produced at high yield and at high purity by a safe method causing few dangers such as explosion, which comprises selectively substituting a chlorine atom or bromine atom at position 5 of a 4- nitroimidazole compound represented by general fo mula (2) indicated below with an iodine atom, and then selectively reducing position 5 of the obtained 5-iodo- 4-nitroimidazole compound represented by 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 general formula (1):
• X 2 represents a chlorine atom or bromine atom, comprising iodinating a 4-nitroimidazole compound represented by general formula (2) :
• each of X 1 and X 2 represents a chlorine atom or bromine atom, and then reducing the obtained 5-iodo-4-nitroimidazole compound represented by general formula (3) :
• 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, hydriodic acid, or a metal salt of hydriodic acid.
• the present invention provides, in the above production method, a method for producing a 4- nitroimidazole compound, wherein the metal salt of hydriodic acid is sodium iodide, potassium iodide, lithium iodide, zinc iodide, magnesium iodide, or aluminum iodide.
• the present invention provides, in the above production method, a method for producing a 4- nitroimidazole compound, wherein the iodinating agent is used to the compound (2) at a molar ratio 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.
• the present invention provides, in the above production method, a method for producing a 4- nitroimidazole compound, wherein the phase-transfer catalyst is used to the compound (2) at a molar ratio between 0.01 : 1 and 1 : 1, and the • phase-transfer catalyst is a quaternary ammonium salt, phosphonium salt, or pyridinium salt.
• 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 to the compound (3) at a molar ratio between 1 : 1 and 10 : 1.
• the present invention provides, in the above production method, a method for producing a 4- nitroimidazole compound, wherein the reducing agent is a catalytic hydrogenation reducing agent, and the reducing agent is used to the compound (3) at a weight ratio between 0.1% by weight and 40% by weight.
• 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.
• the reaction to obtain compound (3) from the compound (2) can be carried out in a suitable solvent in the presence of an iodinating agent.
• an iodinating agent known iodinating agents can widely be used.
• examples of such an iodinating agent may include a halogen atom such as iodine, hydriodic acid, and metal salts of hydriodic acid such as sodium iodide, potassium iodide, lithium iodide, zinc iodide, magnesium iodide, or aluminum iodide. Of these, sodium iodide is preferable.
• Such an iodinating agent is used to the compound (2) , generally at an excessive amount, and preferably at a molar ratio between 1.5 : 1 and 15 : 1.
• a solvent may include: water; alcohols such as methanol, ethanol, or isopropanol; ketones such as acetone; acetonitrile; halogenated hydrocarbons such as dichloromethane, 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.
• Preferred solvents are water and alcohols.
• Acids such as hydriodic 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.
• 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, wherein a group selected from the following group is substituted: a linear or branched alkyl group containing 1 to 18 carbon atoms; a phenylalkyl group wherein the alkyl portion is a linear or branched alkyl group containing 1 to 6 carbon atoms; and a phenyl group.
• 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, benzyldimethyloctadecanylammonium chloride, methyltridecanylammonium chloride, benzyltripropylammonium chloride, benzyltrieth
• Examples of a phosphonium salt may include phosphonium salts wherein a linear or branched alkyl group containing 1 to 18 carbon atoms is substituted. A specific example of such a phosphonium salt may be tetrabutylphosphonium chloride.
• Examples of a pyridinium salt may include pyridinium salts wherein a linear or branched alkyl group containing 1 to 18 carbon atoms is substituted. A specific example of such a pyridinium salt may be 1- dodecanylpyridinium 'chloride.
• the aforementioned phase-transfer catalyst is used singly or in combination of two or more types.
• the phase-transfer catalyst is used, to 1 mole of the compound (2) , at an amount generally between 0.01 and 1 mole, and preferably between 0.01 and 0.5 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, and it is generally carried out for 1 to 80 hours before termination.
• a chlorine atom or bromine atom at position 5 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 an appropriate solvent in the presence of a reducing agent.
• Known hydrogenation reducing agents, catalytic hydrogenation reducing agents, and other agents are used as such reducing agents.
• Examples of a hydrogenation reducing agent may include: sulfite compounds such as sodium bisulfite, sodium sulfite, sodium pyrosulfite, ammonium sulfite, ammonium sulfite monohydrate, or ammonium bisulfite; tetra lower alkyl ammonium borohydrides such as tetra methyl ammonium borohydride, tetra ethyl ammonium borohydride, tetra-n-butyl ammonium borohydride, or tetra-n-butyl ammonium cyanoborohydride; sodium cyanoborohydride, • lithium cyanoborohydride, sodium borohydride, and diborane.
• sulfite compounds such as sodium bisulfite, sodium sulfite, sodium pyrosulfite, ammonium sulfite, ammonium sulfite monohydrate, or ammonium bisulfite
• catalytic hydrogenation reducing agents are used singly or in combination of two or more types .
• 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 singly or in combination of two or more types.
• catalytic hydrogenation reducing agents in particular, platinum oxide and palladium-alumina are preferable.
• 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, monoglime, diglime, 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,
• diborane or the like When diborane or the like is used as a hydrogenation reducing agent, it is adequate to use an anhydrous solvent.
• platinum oxide or palladium- alumina 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 aprotic polar solvents .
• a hydrogenation reducing agent is used to 1 mole of the compound (3) at an amount of generally at least 1 mole, and preferably between 1 and 10 moles.
• the reaction in which a 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 termination.
• a catalytic hydrogenation reducing agent is used, the reaction is carried out in a hydrogen atmosphere under 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 generally carried out for 1 to 90 hours before termination.
• a catalytic hydrogenation reducing agent is used to 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.
• amines such as trimethyla ine, triethylamine, or N- ethyldiisopropylamine may be added to the reaction system in which a catalytic hydrogenation reducing agent is used.
• a catalytic hydrogenation reducing agent is used.
• an iodine atom substituted for position 5 of the imidazole ring is selectively eliminated, so that a desired compound represented by general formula (1) can efficiently be obtained.
• the present inventors have found such a fact for the first time.
• the 4-nitroimidazole compound represented by general formula (1) of the present invention can be induced to a compound (13a) or (13b) that is useful as an antitubercular agent, for example, by the methods represented by the following Reaction scheme-4 and Reaction scheme-5: Reaction scheme-4
• R a represents a hydrogen atom or lower alkyl group
• R B represents the following group:
• R c represents a nitro group
• R D represents a halogen atom or lower alkyl group
• a 0,
• the reaction between the 4-nitroimidazole compound represented by general formula (1) and the compound (9a) or (9b) is carried out in a suitable solvent in the presence of a basic compound.
• a solvent used herein may include: aromatic hydrocarbons such as benzene, toluene, or xylene; ethers such as diethyl ether, tetrahydrofuran, dixane, 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;
• an inorganic base may include: alkali metal carbonates such as sodium carbonate or potassium carbonate; alkali metal hydrogencarbonates 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 .
• alkali metal carbonates such as sodium carbonate or potassium carbonate
• alkali metal hydrogencarbonates 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
• Examples of an organic base may include pyridine, trimethylamine, triethylamine, N- ethyldiisopropylamine, 2, 4, 6-coluidine, dimethyl aniline, dimethylaminopyridine, l-methyl-2- pyrrolidinone (NMP) , N-methylmorpholine, N,N-dimethyl- 4-aminopyridine, 1, 5-diazabicyclo [4.3.0] nonen-5 (DBN) , 1, 8-diazabicyclo [5.4.0] undecen-7 (DBU) , and 1,4- diazabicyclo[2.2.2] octan (DABCO) . These basic compounds are used singly or in combination of two or more types.
• the compound (1) is used to 1 mole of the compound (9a) or (9b) at an amount of generally at least 1 mole, and preferably between 1 and 3 moles.
• the basic compound is used to 1 mole of the compound (9a) or (9b) at 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
• reaction scheme-5 The reaction is generally carried out for 1 to 100 hours before termination. During the above reaction, halides such as cesium fluoride may be added to the reaction system. Reaction scheme-5
• R A and X 2 are the same as defined above; and R represents a group represented by the following general formula (A) , (B) , (C) , ( D) , (E) , ( F) , or (G) .
• A2) a C1-C6 alkyl group; A3) a Cl-C ⁇ alkoxy-Cl-C6 alkyl group;
• R 4 represents: a C1-C6 alkoxycarbonyl group; a phenyl C1-C6 alkoxycarbonyl group [wherein, on the phenyl ring, at least one selected from the group consisting of a phenyl C1-C6 alkoxy group, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted C1-C6 alkoxy group, may be substituted] ; or a phenyl C1-C6 alkyl group [wherein, on the phenyl ring, at least one selected from the group consisting of a phenyl C1-C6 alkoxy group, a halogen substituted or unsubstituted C1-C6 alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted] ; All) a biphenylyl
• D4 a Cl-C ⁇ alkoxycarbonyl-Cl-C ⁇ alkyl group; D5 ) a C3-C8 cycloalkyl group; D ⁇ ) a phenyl Cl-C ⁇ alkyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted ' or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ; D7) a phenyl group (wherein, on the phenyl ring, 1 to 3 groups selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted C1-C6 alkyl group, a halogen substituted or unsubstituted Cl- C ⁇ alkoxy group, a C1-C6 alkanoyl group,
• (Da3) a phenyl Cl-C ⁇ alkyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ;
• (Da4) a phenyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ; (Da5) a C1-C6 alkoxycarbonyl group; (Da ⁇ ) a phenyl C1-C6 alkoxycarbonyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ; (Da7) a phenyl C3-C6 alkenyloxycarbonyl group (wherein, on the
• R 10 represents: (Dbl) a hydrogen atom
• (Db2) a phenyl group (wherein, on the phenyl ring, at least one selected from the group consisting of halogen, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ; (Db3) a phenoxy group (wherein, on the phenyl ring, at least one halogen substituted or unsubstituted Cl-C ⁇ alkyl group may be substituted) ; or (Db4) a phenylamino group (wherein, on the phenyl ring, at least one halogen substituted or unsubstituted Cl-C ⁇ alkyl group may be substituted) ) ; (D10-3) a morpholino group; (D10-4) an indolinyl group (wherein, on the indoline ring, at least one halogen atom may be substituted
• X represents a halogen atom or an amino substituted Cl-C ⁇ alkyl group which may have a Cl-C ⁇ alkyl group as a substituent; represents an integer between 0 and 3; and R 11 represents:
• E2) a halogen substituted or unsubstituted Cl-C ⁇ alkyl group; E3) a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group; E4) a group represented by general formula (Ea) : -(W)o-NR 12 R 13 (Ea) (wherein W represents the group -CO- or a Cl-C ⁇ alkylene group; o represents 0 or 1; and R 12 and R 13 each identically or differently represent: (Eal) a hydrogen atom; (Ea2) a Cl-C ⁇ alkyl group; (Ea3) a Cl-C ⁇ alkanoyl group; (Ea4) a Cl-C ⁇ alkoxycarbonyl group;
• (Ea5) a phenyl Cl-C ⁇ alkyl group (wherein, on the phenyl ring, at least one selected from the following group may be substituted: a halogen atom; a halogen substituted or unsubstituted Cl-C ⁇ alkyl group; a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group; and a phenoxy group [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted as a substituent] , and further wherein, a Cl-C ⁇ alkoxyimino group may be substituted for a Cl-C ⁇ alkyl portion thereof) ; (Ea ⁇ ) a phenyl group (wherein, on the phenyl
• R 14A represents a hydrogen atom, a hydroxyl group, a Cl-C ⁇ alkoxy group, or a phenyl group [wherein, on the phenyl ring, a halogen atom may be substituted] ; the dotted line represents that the bond may be a double bond, and when the dotted line represents such a double bond, only R 14 is substituted; and R 14 and R 14A may bind to each other together with carbon atoms adjacent thereto, so as to form a C1-C4 alkylenedioxy group, wherein R 14 represents : (Eaal) a hydrogen atom;
• (Eaa3) a phenoxy group (wherein, on the phenyl ring, at least one selected from the following group may be substituted: a halogen atom; a halogen substituted or unsubstituted Cl-C ⁇ alkyl group; a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group; a C1-C4 alkylenedioxy group; a Cl-C ⁇ alkoxycarbonyl group; a cyano group; 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, a Cl-C ⁇ alkyl group, a carbamoyl group, and a Cl-C ⁇ alkanoyl group; a Cl-C ⁇ alkanoyl substituted Cl-C ⁇ alkyl group; a hydroxyl group; a Cl- C ⁇ al
• (Eaa8) a C3-C8 cycloalkyl-Cl-C ⁇ alkoxy group; (Eaa9) a phenylcarbamoyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ;
• (Eaal3) a naphthyloxy group (wherein, on the naphthalene ring, at least one Cl-C ⁇ alkyl group may be substituted) ;
• (Eaal4) a 2, 3-dihydrobenzofuryloxy group (wherein, on the 2, 3-dihydrobenzofuran ring, at least one selected from the group consisting of a Cl-C ⁇ alkyl group and an oxo group may be substituted) ; (Eaal5) a benzothiazolyloxy group (wherein, on the benzothiazole ring, at least one C1-C6 alkyl group may be substituted) ; (Eaal ⁇ ) a 1, 2, 3, 4-tetrahydronaphthyloxy group (wherein,.
• (Eab2) a Cl-C ⁇ alkyl group (wherein, on the alkyl group, a morpholino group, a benzoyl group, a carbamoyl group which may have a Cl-C ⁇ alkyl group as a substituent, or a cyano group may be substituted) ;
• (Eab4) a phenyl Cl-C ⁇ alkyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a cyano group, a phenyl group, a nitro group, a Cl-C ⁇ alkylthio group, a Cl-C ⁇ alkylsulfonyl group, a phenyl Cl-C ⁇ alkoxy group, a C2- C ⁇ alkanoyloxy group, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, and a 1,2,3- thiadiazole group, may be substituted) ;
• (Eab ⁇ ) a phenyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a cyano group, a halogen substituted or unsubstituted C1-C6 alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ;
• (Eab8) a phenyl C2-C6 alkanoyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ;
• (Eab9) a benzoyl group (wherein, on the benzene ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ;
• (EablO) a C1-C20 alkoxycarbonyl group (wherein, on the alkoxy group, at least one selected from the group consisting of a halogen atom, an amino group which may have a Cl-C ⁇ alkyl group as a substituent, and a Cl-C ⁇ alkoxy substituted Cl-C ⁇ alkoxy group, may be substituted) ;
• (Eabll) a phenyl Cl-C ⁇ alkoxycarbonyl group wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a
• (Eabl3) a phenoxycarbonyl group (wherein, on the .phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ;
• (Eabl4) a phenyl Cl-C ⁇ alkylcarbamoyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ; (Eabl5) a phenylcarbamoyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted C1-C6 alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ; (Eabl ⁇ ) a benzofuryl substituted Cl-C ⁇ alkoxycarbonyl group (wherein, on the benzofuran ring, at least one
• R 17 represents: (Eel) a phenyl Cl-C ⁇ alkyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ;
• (Ec3) a phenyl Cl-C ⁇ alkoxycarbonyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ) ; E14) a pyridyl group;
• R 4S represents: a phenyl group [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted] ; a phenyl Cl-C ⁇ alkyl group [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted] ; a phenyl Cl-C ⁇ alkoxycarbonyl group [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsub
• a phenoxy group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ;
• a benzoyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted C1-C6 alkoxy group, may be substituted) ;
• E18) a 8-azabicyclo [3, 2, 1] octyl group (wherein, on the 8-azabicyclo [3, 2, 1] octane ring, at least one phenoxy group may be substituted (wherein, on the
• E21 an amino substituted C2-C6 alkenyl group (wherein, on the amino group, at least one selected from the group consisting of a Cl-C ⁇ alkyl group and a phenyl group [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted] may be substituted) ; or E22) an oxazolidinyl group (wherein, on the oxazolidine ring, at least one oxo group may be substituted) ] .
• a phenyl Cl-C ⁇ alkyl group (wherein, on the phenyl ring, at least one selected from the following group may be substituted: a phenoxy group [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted C1-C6 alkoxy group, may be substituted] ; a halogen atom; a halogen substituted or unsubstituted Cl-C ⁇ alkyl group; a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group; an amino group (wherein, on the amino group, at least one selected from the group consisting of a Cl-C ⁇ alkyl group and a phenyl Cl-C ⁇ alkyl group [wherein, on the phenyl ring, at least one selected from the group may
• an amino Cl-C ⁇ alkyl group (wherein, on the amino group, at least one selected from the group consisting of a Cl-C ⁇ alkyl group, a Cl-C ⁇ alkoxycarbonyl group, and a phenyl group [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom and a halogen substituted or unsubstituted Cl-C ⁇ alkyl group may be substituted] , may be substituted) ; F ⁇ ) 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 phpnyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy
• F9 a group represented by general formula (Fa) : (Fa)
• R 21 represents: a Cl-C ⁇ alkoxycarbonyl group; a phenyl Cl-C ⁇ alkoxycarbonyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a cyano group, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ; a phenyl Cl-C ⁇ alkyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom and a halogen substituted or unsubstituted Cl-C ⁇ alkyl group may be substituted) ; or a phenyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a cyano group, a halogen
• R 22 represents: a C1-C6 alkoxycarbonyl group; a phenyl Cl-C ⁇ alkoxycarbonyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ; or a phenyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a cyano group, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ) ; or Fll) a piperidyl Cl-C ⁇ alkyl group (wherein, on the piperidine ring
• R 23 represents: (Fcl) a Cl-C ⁇ alkyl group; (Fc2) a phenyl Cl-C ⁇ alkyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ; (Fc3) a phenyl group (wherein, on the phenyl ring, at least one selected from the following group may be substituted: a halogen atom; a halogen substituted or unsubstituted Cl-C ⁇ alkyl group; a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group; an amino group which may have, as a substituent, a group selected from the group consisting
• At least one amino group may be substituted, and wherein, on the amino group, at least one selected from the group consisting of a phenyl Cl-C ⁇ alkyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) and a Cl-C ⁇ alkyl group may be substituted] ) ;
• (Fc4) a phenyl Cl-C ⁇ alkoxy group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ;
• (Fc5) a biphenylyl Cl-C ⁇ alkoxy group;
• (Fc ⁇ ) a phenyl C3-C6 alkenyloxy group wherein, on the phenyl ring, at least one halogen atom may 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 halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ; (Fc8) a benzoyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ; (Fc9) a Cl-C ⁇ alkoxycarbonyl group; (FclO) a phenyl Cl-C ⁇ alkoxycarbonyl group (wherein, on the phenyl ring, at least
• (Fcl4) a phenyl sulfoxide (wherein, on the phenyl ring, at least one halogen substituted or unsubstituted Cl-C ⁇ alkoxy group may be substituted) ; (Fcl5) a pyridyl Cl-C ⁇ alkoxy group; or
• R 24 and R 25 each represent : (Fcal) a hydrogen atom
• a phenyl Cl-C ⁇ alkyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ;
• a phenyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a cyano group, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ;
• (Fca ⁇ ) a phenyl C2-C6 alkanoyl group wherein, on ,the phenyl ring, at least one halogen atom may be substituted; (Fca7) a benzoyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ; (Fca8) a Cl-C ⁇ alkoxycarbonyl group;
• a phenyl Cl-C ⁇ alkoxycarbonyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ;
• R 24 and R 25 may form a 5- or ⁇ -membered saturated heterocyclic ring via nitrogen atoms adjacent thereto, wherein, on the heterocyclic ring, at least one selected from the following group may be substituted: a Cl-C ⁇ alkoxycarbonyl group; a benzoyl group (wherein, on the phenyl ring, at least one selected from the
• R ,26 represents (Fdl a hydrogen atom; (Fd2 a Cl-C ⁇ alkyl group; (Fd3 a C3-C8 cycloalkyl group; (Fd4 a C3-C8 cycloalkyl Cl-C ⁇ alkyl group; (Fd5 a Cl-C ⁇ alkoxycarbonyl Cl-C ⁇ alkyl group; (Fd ⁇ a phenyl C2-C6 alkenyl group; (Fd7 a phenyl Cl-C ⁇ alkyl group (wherein, on the phenyl ring, 1 to 3 groups selected from the following group may be substituted: a halogen atom; a cyano group; a halogen substituted or unsubstituted Cl-C ⁇ alkyl group; a C3-C8 cycloalkyl group; a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group; an amino group which may have a Cl-C
• (Fdll) a biphenylyl group (wherein, on the phenyl ring, at least one halogen substituted or unsubstituted Cl-C ⁇ alkyl group may be substituted) ; (Fdl2) an amino group, amino group wherein a Cl-C ⁇ alkoxycarbonyl group is substituted, phenyl Cl-C ⁇ alkylamino group (wherein, on the phenyl ring, at least one halogen substituted or unsubstituted Cl-C ⁇ alkyl group may be substituted) , or phenylamino group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom and a halogen substituted or unsubstituted Cl-C ⁇ alkyl group may be substituted) ; (Fdl3) a benzoyl Cl-C ⁇ alkyl group (wherein, on the phenyl ring, at least one halogen atom may be substitute
• (Fdl8) a furyl Cl-C ⁇ alkyl group (wherein, on the furan ring, at least one halogen substituted or unsubstituted phenyl group may be substituted) ; (Fdl9) an imidazolyl Cl-C ⁇ alkyl group (wherein, on the imidazole ring, a phenyl group may be substituted) ; (Fd20) a quinolyl Cl-C ⁇ alkyl group; (Fd21) a tetrazolyl group (wherein, on the tetrazole ring, a phenyl group may be substituted) ; (Fd22) a pyrimidyl group wherein a phenyl group may be substituted; (Fd23) a pyridyl group; (Fd24) a benzoxazolyl group; (Fd25) a benzothiazolyl group; (Fd26) a benzoxazolyl Cl-C
• each of R 28 , R 29 , and R 30 represents: a hydrogen atom; a Cl-C ⁇ alkyl group; or a phenyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ) ;
• (Fda7) a phenyl Cl-C ⁇ alkyl group (wherein, on the phenyl ring, 1 to 5 groups selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, a halogen substituted or unsubstituted Cl-C ⁇ alkylthio group, a phenyl Cl-C ⁇ alkoxy group, a hydroxy group, a Cl-C ⁇ alkylsulfinyl group, a Cl-C ⁇ alkylsulfonyl group, a Cl- C6 alkylsulfonyloxy group, a cyano group, a Cl-C ⁇ alkanoyl group, a benzoyl group, a phenyl Cl-C ⁇ alkyl group which may have a Cl-C ⁇ alkoxy group at an alky
• (Fda9) a benzhydryl group (wherein, on the benzene ring, at least one selected from the group consisting of a halogen atom, a trifluoromethyl group, and a trifluoromethoxy group, may be substituted) ;
• (FdalO) a phenoxy Cl-C ⁇ alkyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ;
• (Fdall) a phenyl C2-C6 alkynyl group (wherein, on the phenyl ring, at least one halogen substituted or unsubstituted Cl-C ⁇ alkyl group may be substituted) ;
• (Fdal2) a pyr
• R 31 represents: a phenyl group [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a cyano group, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted] ; a phenyl Cl-C ⁇ alkyl group [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted] ; or a benzoyl group [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstitute
• (Fe5) a phenyl C2-C6 alkenyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ; or
• (Fe ⁇ ) a phenyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) ; or further, (Fe7) R 32 and R 33 may bind to each other together with nitrogen atoms adjacent thereto through other carbon atoms, so as to form a piperidine ring or a 1,2,3,6- tetrahydropyridine ring, wherein, on the piperidine ring or the 1, 2, 3, 6-tetrahydropyridine ring, a phenyl group may be substituted, and further, at least one selected from the group consisting of a halogen atom and a halogen substituted or unsubstituted Cl-C ⁇ alkyl group may be substituted on the phenyl group
• R 34 represents a hydrogen atom or Cl-C ⁇ lower alkyl group; and R 35 represents : (Ffl) a C3-C8 cycloalkyl group; (Ff2) a C3-C8 cycloalkenyl group; (Ff3) a group represented by general formula (Ffa) :
• each of R 35 , R 37 , and R 38 represents: a hydrogen atom; a Cl-C ⁇ alkyl group; a phenyl group [wherein, on the phenyl ring, 1 to 5 groups selected from- the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, a C1-C4 alkylenedioxy group, a Cl-C ⁇ alkylsulfonyl group, a halogen substituted or unsubstituted Cl-C ⁇ alkylthio group, a nitro group, and an amino group which may have a Cl-C ⁇ alkanoyl group as a substituent, may be substituted] ; a benzofuryl group [wherein, on the benzofuran ring, at least one selected from the group consisting of a halogen atom,
• (Ffl4) an indolyl group (wherein, on the indole ring, at least one selected from the group consisting of a phenylsulfonyl group which may have a C1-C6 alkyl group as a substituent, a phenyl Cl-C ⁇ alkyl group, a Cl-C ⁇ alkoxycarbonyl group, and a phenyl group, may be substituted) ;
• (Ffl5) a pyrrolyl group (wherein, on the pyrrole ring, at least one selected from the group consisting of a phenyl group wherein at least one halogen substituted or unsubstituted Cl-C ⁇ alkyl group may be substituted and a Cl-C ⁇ alkyl group may be substituted) ; (Ffl ⁇ ) a coumaryl group; (Ffl7) a benzoimidazolyl group (wherein, on the benzoi idazole ring, at least one thienyl group may be substituted) ; (Ffl ⁇ ) an oxazolyl group (wherein, on the oxazole ring, at least one phenyl group which may have a halogen atom may be substituted) ;
• (Ffl9) a thiazolyl group (wherein, on the thiazole ring, at least one phenyl group may be substituted, and further wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a nitro group, and a phenyl group, may be substituted) ; (Ff2l) a quinolyl group;
• (Ff22) a 3, 4-dihydrocarbostyril group (wherein, on the 3, 4-dihydrocarbostyril ring, at least one selected from the group consisting of a Cl-C ⁇ alkoxy group, a Cl-C ⁇ alkyl group, and a phenyl Cl-C ⁇ alkoxy group, may be substituted) ; a carbostyril group (wherein, on the carbostyril ring, at least one selected from the group consisting ,of a Cl-C ⁇ alkoxy group, a Cl-C ⁇ alkyl group, and a phenyl Cl-C ⁇ alkoxy group, may be substituted) ;
• R 45 represents: a Cl-C ⁇ alkoxycarbonyl group; a phenyl group [wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted] ; an amino substituted Cl-C ⁇ alkyl group [wherein, on the amino group, at least one selected from the group consisting of a phenyl group (wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, and a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, may be substituted) and a Cl-C ⁇ alkyl group may be substituted] ; a be
• F12-5) a 1, 4-dioxazaspiro [4, 5] decyl group (wherein, on the 1, 4-dioxazaspiro [4, 5] decane ring, at least one oxo group may be substituted) ;
• F12-6) a homopiperazinyl group (wherein, on the homopiperazine ring, at least one selected from the group consisting of a C1-C6 alkoxycarbonyl group, a phenyl C1-C6 alkoxycarbonyl group, and a phenyl substituted or unsubstituted phenyl group, may be substituted) ;
• F12-7) a piperazinyl group (wherein, on the piperazine ring, at least one selected from the group consisting of an oxo group, a C1-C6 alkyl group, and a phenyl Cl- C ⁇ alkyl group [wherein, on the phenyl ring, at least one halogen substituted or unsubstituted Cl-C ⁇ alkyl group may be substituted] , may be substituted) ; F12-8) a piperidyl group (wherein, on the piperidine ring, at least one oxo group may be substituted) ; F12-9) a pyrrolidinyl group (wherein, on the pyrrolidine ring, at least one phenoxy C1-C6 alkyl group, which may have a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group as a substituent, may be substituted) ; or
• F12-10) an isoindolinyl group; or further F13) R 19 and R 20 may bind to each other together with nitrogen atoms adjacent thereto directly or through heteroatoms, so as to form a cyclic imide or amide represented by any one of the following (F13-1) to (F13-11) :
• (F13-3) a benzo-1, 3-oxazolidinyl group (wherein, on 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, may 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 phenyl Cl-C ⁇ alkyl group [wherein, on the phenyl ring, 1 to 3 groups selected from the group consisting of a halogen atom and a Cl-C ⁇ alkoxy group may be substituted] , and a phenyl group, may be substituted) ; (F13-5) a benzoimidazolidinyl group (wherein, on the benzoimidazolidine ring, at least one selected from the group consisting of an oxo group,
• (F13-8) a 2, 3-dihydrobenzothiazolyl group (wherein, on the 2, 3-dihydrobenzothiazole ring, at least one oxo group may be substituted) ; (F13-9) a 1H-2, 4-benzoxazinyl group (wherein, on the 1H-2, 4-benzoxazine ring, at least one oxo group may be substituted) ; (F13-10) a group represented by general formula (Fga) :
• R 39 represents: a hydrogen atom; a phenyl Cl-C ⁇ alkyl group which may have, as a substituent, a halogen atom on the phenyl ring; a phenoxy Cl-C ⁇ alkyl group which may have, as a substituent, a halogen atom on the phenyl ring; a phenyl C2-C ⁇ alkenyl group which may have, as a substituent, a halogen atom on the phenyl ring; a phenyl group wherein, on the phenyl ring, at least one selected from the group consisting of a halogen atom, a halogen substituted or unsubstituted Cl-C ⁇ alkyl group, a halogen substituted or unsubstituted Cl-C ⁇ alkoxy group, and a phenyl group, may be substituted as a substituent; a pyridyl group; or a pyrazinyl group
• R 40 represents a Cl-C ⁇ alkyl group or a halogen substituted or unsubstituted phenyl group.
• 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, di ethoxyethane, dioxane, tetrahydrofuran, diglime, 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
• an inorganic base may include: alkali metal carbonates such as sodium carbonate or potassium carbonate; alkali metal hydrogencarbonates 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, sodium ethylate, or sodium tert-butoxide .
• alkali metal carbonates such as sodium carbonate or potassium carbonate
• alkali metal hydrogencarbonates 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
• Examples of an organic base may include acetates such as sodium acetate or potassium acetate, pyridine, trimethylan ⁇ ine, triethylamine, diisopropylethylamine, dimethyl aniline, 1- methylpyrrolidine, N-methylmorpholine, N,N-dimethyl-4- a inopyridine, 1, 5-diazabicyclo [4.3.0] nonen-5 (DBN) , 1, 8-diazabicyclo [5.4.0]undecen-7 (DBU) , and 1,4- diazabicyclo[2.2.2]octan (DABCO) .
• acetates such as sodium acetate or potassium acetate
• pyridine trimethylan ⁇ ine
• triethylamine diisopropylethylamine
• dimethyl aniline 1- methylpyrrolidine
• N-methylmorpholine N,N-dimethyl-4- a inopyridine
• DBU 1, 8-diazabicyclo [5.4.0]und
• the compound (11) is used to 1 mole of the compound (10a) or (10b) at an amount of generally at least 1 mole, and preferably between 1 and 5 moles.
• the basic compound is used to 1 mole of' the compound (10a) or (10b) at an amount generally between 0.1 and 1 mole, and preferably between 0.1 and 0.5 moles.
• 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 generally carried out for 10 minutes, to 24 hours before termination.
• 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 in no solvents, in the presence of a basic compound. All the solvents and basic compounds that can be used in the aforementioned reaction between the compound (10a) or (10b) and the compound (11) can be used also herein as solvents and basic compounds.
• the basic compound is used to 1 mole of the compound (12a) or (12b) at an amount of generally 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.
• 4-nitroimidazole compounds represented by general formula (1) of the present' invention those having a basic group can easily form a salt together with generally pharmacologically acceptable acid.
• 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.
• inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid, or hydrobromic acid
• organic acids such as acetic acid, p- toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, oxalic 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 it can further be purified.
• separation and purification means may include distillation, recrystallization, column chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, preparative thin layer chromatography, and the solvent extraction method.
• the compound of interest represented by general formula (1) can be produced without passing the state of an intermediate, which has a danger of explosion.
• the production method of the present invention involves simple operations, and it does not need a complicated purification process.
• the 4-nitroimidazole compound of interest represented by general formula (1) can be economically produced at high yield and at high purity.
• Example 7 Production of 2-bromo-4-nitroimidazole A mixture consisting of 2-bromo-5-iodo-4- nitroimidazole (607 mg, 2.00 mmol), ethanol (6.4 'ml), triethylamine (607 mg, ⁇ .00 mmol), and platinum oxide (3.4 mg, 0.53 wt %) was stirred under normal pressure in a hydrogen atmosphere at room temperature for 3 hours. The filtrate was concentrated and exsiccated 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 (MgS0 4 ) , followed by vacuum concentration and exsiccation.
• the amount of sulfite used (mole) is a value determined using 1 mole of 2-bromo-5-iodo-4- nitroimidazole as a standard.
• 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- j nitroimidazole as a standard.
• Example 20 Production of 2-bromo-5-iodo-4-nitroimidazole A mixture consisting of 2, 5-dibromo-4- nitroi idazole (108.3 g, 400 mmol), ethanol (184 ml), sodium iodide (120 g, 800 mmol) was heated to reflux in an argon stream (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 exsiccated under reduced pressure (25-50°C) .

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