Title of Invention

METHOD FOR PRODUCING 2-CHLORO, OR 2-BROMO-4-NITROIMIDAZOLE COMPOUND

Abstract The present invention provides a method for producing a haloderivative of 4-nitroimidazole compound represented by general formula (1) : wherein X2 represents a chlorine atom or bromine atom, comprising iodinating a 4-nitroimidazole compound represented by general formula (2) in the presence of an iodinating agent, wherein the iodinating agent is used to the compound (2) at a molar ratio between 1.5:1 and 15:1 at a temperature between 0°C and 150°C: 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) in the presence of a reducing agent, where, when the reducing agent is hydrogenation reducing agent, the reducing agent is used to the compound (3) at an amount of at least 1 mole at a temperature between 0°C and 150°C, or when the reducing gent is a catalytic hydrogenation reducing agent, the reducing agent is used to the compound (3) at a weight ratio between 0.1% by weight and 40% by weight at a temperature between -30°C and 100°C: wherein X2 is the same as defined above
Full Text DESCRIPTION
TECHNICAL FIELD
The present invention relates to a method for
producing a 2-chlorine atom or 2-bromine atom -4-
nitroimidazole compound.
BACKGROUND ART
A 4-nitroimidazole compound represented by the
following general formula (1):

wherein X2 represents a chlorine atom or bromine atom, is
useful as a synthetic intermediate used for producing
various pharmaceuticals and agricultural chemicals, and
particularly used for producing antitubercular agents.
For example, methods represented by the following
Reaction scheme-1 and -2 have previously been known as
methods for producing the 4-nitroimidazole compound
represented by general formula (1) (Jerzy Suwinski, Ewa
Salwinska, Jan Watras, and Maria Widel, Polish Journal of
Chemistry, 56, 1261-1272 (1982)).


wherein XA represents a halogen atom.
However, these methods have various
disadvantages, and thus, are not adequate as production
methods that are industrially applied.
For example, in the method represented by
Reaction scheme-1, compounds (6) and (7) that are
reaction intermediates are chemically unstable, and
there is a risk that these compounds may explode due to
impacts such as fall or friction. In addition, in this

method, the temperature applied during the reaction to
obtain the compound (7) from the compound (6) by-
heating (approximately 130°C) exceeds the TNR
(Temperature of No Return; the maximal temperature
ranging from 60°C to 70°C, at which the compound can
safely be handled 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
involves a reaction of nitrating the compound (8).
However, the compound (1a) can be obtained only at low
yield by such nitration, and thus, this method is
industrially disadvantageous.
DISCLOSURE OF THE INVENTION
It is an object of the present invention to
provide a method for producing a 4-nitroimidazole
compound represented by general formula (1) at high
yield and at high purity by a safer method causing few
dangers such as explosion.
In order to achieve the aforementioned
object, the present inventors have conducted intensive
studies regarding a method for producing a 4-
nitroimidazole compound represented by general formula
(1) . As a result, 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.
That is to say, the present inventors have found that 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 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.
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):

wherein X2 represents a chlorine atom or bromine atom,
comprising 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.
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, hydriodic acid, or a metal salt of
hydriodic acid.
3. 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.
4. 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.
5. 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 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.
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 to the compound (3) at a molar ratio between
1 : 1 and 10 : 1.
8. 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.
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.
BEST MODE FOR CARRYING OUT THE INVENTION
The method for producing a 4-nitroimidazole
compound represented by general formula (1) of the
present invention will be described below.
Reaction scheme-3

wherein X1 and X2 are the same as defined above.
In the above Reaction scheme-3, 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.
As 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.

Examples of 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.
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, 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. Specific
examples of such a 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,
benzyltriethylairtmonium chloride, phenyltriethylammonium
chloride, tetraethylammonium chloride, and
tetramethylammonium chloride.
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.
In the above reaction, 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.
These hydrogenation reducing agents are used singly 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
singly or in combination of two or more types.
Of these reducing agents, catalytic
hydrogenation reducing agents, in particular, platinum
oxide and palladium-alumina are preferable.
In the present invention, the aforementioned
hydrogenation reducing agents and 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,
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,N-
dimethylacetamide, or l-methyl-2-pyrrolidinone (NMP);
and their mixed solvents.
When diborane or the like is used as a

hydrogenation reducing agent, it is adequate 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 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.
When 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.
In order to promote the reaction, amines such

as trimethylamine, triethylamine, or N-
ethyldiisopropylamine may be added to the reaction
system in which a catalytic hydrogenation reducing
agent is used.
As a result of the aforementioned reduction
reaction, 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 antitube'rcular agent, for example, by the methods
represented by the following Reaction scheme-4 and
Reaction scheme-5:


wherein X2 is the same as defined above; RA represents a
hydrogen atom or lower alkyl group; and RB represents
the following group:

wherein Rc represents a nitro group; RD represents a
halogen atom or lower alkyl group; and a represents 0,
1, or 2, and when a represents 2, two RD may be either
identical or different.
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.
Examples of 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;
2,4,6-coluidine; dimethyl sulfoxide; dimethylformamide;
hexamethyl phosphoric triamide; and their mixed
solvents.
Known inorganic bases and organic bases can

widely be used as basic compounds.
Examples of 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.
Examples of an organic base may include
pyridine, trimethylamine, triethylamine, N-
ethyldiisopropylamine, 2,4,6-coluidine, dimethyl
aniline, dimethylaminopyridine, 1-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 equimolar 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 termination.
During the above reaction, halides such as
cesium fluoride may be added to the reaction system.

wherein RA and X2 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) .
A group represented by general formula (A):

(wherein R3 represents:
A1) a hydrogen atom;
A2) a C1-C6 alkyl group;
A3) a C1-C6 alkoxy-Cl-C6 alkyl group;
A4) a phenyl C1-C6 alkyl group (wherein, on the phenyl
ring, at least one selected from the following group
may be substituted: a phenyl C1-C6 alkoxy group; a
halogen substituted or unsubstituted C1-C6 alkyl group;
and a halogen substituted or unsubstituted C1-C6 .alkoxy
group; and a phenoxy group [wherein, on the phenyl
ring, at least one halogen substituted or unsubstituted
C1-C6 alkoxy group may be substituted]);
A5) a biphenylyl C1-C6 alkyl group;
A6) a phenyl C2-C6 alkenyl group;
A7) a C1-C6 alkylsulfonyl group;
A8) a benzenesulfonyl group wherein a C1-C6 alkyl group
may be substituted;
A9) a C1-C6 alkanoyl group;
A10) a group represented by general formula (Aa):

(wherein R4 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 C1-C6 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 C1-C6 alkoxy group, may be substituted]);
A11) a biphenylyl C1-C6 alkoxycarbonyl group;
A12) a benzoxazolyl C1-C6 alkyl group (wherein, on the
benzoxazole ring, at least one oxo group may be
substituted);
A13) a benzoxazolyl group; or
A14) an oxazolyl C1-C6 alkyl group {wherein, on the
oxazole ring, at least one selected from the group
consisting of a phenyl group and a C1-C6 alkyl group
may be substituted).
A group represented by general formula (B):
-SR5 (B)
(wherein R5 represents a tetrazolyl group [wherein, on
the tetrazole ring, a C1-C6 alkyl group or a phenyl
group which may have a halogen atom may be substituted]
or a benzoxazolyl group).
A group represented by general formula (C):
-COOR6 (C)
(wherein R5 represents a C1-C6 alkyl group).
A carbamoyloxy group represented by general

formula (D):
-OOCNR7R8 (D)
(wherein R7 and R8 each identically or differently
represent:
D1) a hydrogen atom;
D2) a C1-C8 alkyl group;
D3) a halogen substituted C1-C6 alkyl group;
D4) a C1-C6 alkoxycarbonyl-Cl-C6 alkyl group;
D5) a C3-C8 cycloalkyl group;
D6) a phenyl C1-C6 alkyl 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 C1-C6 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-
C6 alkoxy group, a C1-C6 alkanoyl group, a carboxyl
group, a C1-C6 alkoxycarbonyl group, a phenyl C1-C6
alkoxycarbonyl group, a carbamoyl group, a C1-C6
alkylcarbamoyl group, an aminosulfonyl group, and a
morpholino group, may be substituted);
D8) a naphthyl group; or
D9) a pyridyl group; or further,
D10) R7 and R8 may bind to each other together with
nitrogen atoms adjacent thereto directly or through

other heteroatoms or carbon atoms, so as to form a
saturated heterocyclic group represented by any one of
(D10-1) to (D10-3) indicated below or a benzene
condensed heterocylic group represented by any one of
(D10-4) to (D10-7) indicated below:
(D10-1) a piperazinyl group represented by
general formula (Da):

(wherein R9 represents:
(Dal) a hydrogen atom;
(Da2) a C1-C6 alkyl group;
(Da3) a phenyl C1-C6 alkyl 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 C1-C6 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
C1-C6 alkyl group, and a halogen substituted or
unsubstituted C1-C6 alkoxy group, may be substituted);
(Da5) a C1-C6 alkoxycarbonyl group;
(Da6) 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 C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted);
(Da7) a phenyl C3-C6 alkenyloxycarbonyl group (wherein,
on the phenyl ring, at least one halogen substituted or
unsubstituted C1-C6 alkyl group may be substituted); or
(Da8) a phenyl C1-C6 alkylidene substituted amino group
(wherein, on the phenyl ring, at least one halogen
substituted or unsubstituted C1-C6 alkyl group may be
substituted)) ;
(D10-2) a group represented by general
formula (Db):

(wherein the dotted line represents that the bond may
be a double bond; and R10 represents:
(Db1) 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 C1-C6
alkyl group, and a halogen substituted or unsubstituted
C1-C6 alkoxy group, may be substituted);
(Db3) a phenoxy group (wherein, on the phenyl ring, at
least one halogen substituted or unsubstituted C1-C6
alkyl group may be substituted); or
(Db4) a phenylamino group (wherein, on the phenyl ring,

at least one halogen substituted or unsubstituted C1-C6
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);
(D10-5) an isoindolinyl group (wherein, on
the isoindoline ring, at least one halogen atom may be
substituted);
(D10-6) a 1,2,3,4-tetrahydroquinolyl group
(wherein, on the 1,2,3,4-tetrahydroquinoline ring, at
least one halogen atom may be substituted); or
(D10-7) a 1,2,3,4-tetrahydroisoquinolinyl
group (wherein, on the 1,2,3, 4-tetrahydroisoquinoline
ring, at least one halogen atom may be substituted).
A phenoxy group represented by general
formula (E):

[wherein X represents a halogen atom or an amino
substituted C1-C6 alkyl group which may have a C1-C6
alkyl group as a substituent; m represents an integer
between 0 and 3; and R11 represents:
El) a hydrogen atom;
E2) a halogen substituted or unsubstituted C1-C6 alkyl
group;
E3) a halogen substituted or unsubstituted C1-C6 alkoxy

group;
E4) a group represented by general formula (Ea):
- (W) o-NR12R13 (Ea)
(wherein W represents the group -CO- or a C1-C6
alkylene group; o represents 0 or 1; and R12 and R13 each
identically or differently represent:
(Ea1) a hydrogen atom;
(Ea2) a C1-C6 alkyl group;
(Ea3) a C1-C6 alkanoyl group;
(Ea4) a C1-C6 alkoxycarbonyl group;
(Ea5) a phenyl C1-C6 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 C1-C6 alkyl group; a
halogen substituted or unsubstituted C1-C6 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 C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted as a substituent], and further wherein, a
C1-C6 alkoxyimino group may be substituted for a C1-C6
alkyl portion thereof);
(Ea6) 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
C1-C6 alkyl group, and a halogen substituted or
unsubstituted C1-C6 alkoxy group, may be substituted);

(Ea7) 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
C1-C6 alkyl group, and a halogen substituted or
unsubstituted C1-C6 alkoxy group, may be substituted);
(Ea8) a pyridyl group (wherein, on the pyridine ring,
at least one halogen atom may be substituted);
(Ea9) a phenyl C1-C6 alkyl 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 C1-C6 alkoxy group, may be
substituted);
(Ea10) a phenoxy C1-C6 alkyl 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 C1-C6 alkoxy group, may be
substituted); or
(Ea11) a benzoyl C1-C6 alkyl 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 C1-C6 alkoxy group, may be
substituted));
E5) an imidazolyl group;
E6) a triazolyl group;
E7) a morpholino group;

E8) a thiomorpholino group;
E9) an s-oxide thiomorpholino group;
E10) a piperidyl group represented by general formula
(Eaa):

(wherein W and o are the same as defined above; R14R
represents a hydrogen atom, a hydroxyl group, a C1-C6
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 R14 is substituted; and R14 and R14A may bind to each
other together with carbon atoms adjacent thereto, so
as to form a C1-C4 alkylenedioxy group, wherein R14
represents:
(Eaa1) a hydrogen atom;
(Eaa2) a C1-C6 alkoxycarbonyl group;
(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 C1-C6 alkyl group; a halogen substituted
or unsubstituted C1-C6 alkoxy group; a C1-C4
alkylenedioxy group; a C1-C6 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 C1-C6 alkyl group, a carbamoyl
group, and a C1-C6 alkanoyl group; a C1-C6 alkanoyl
substituted C1-C6 alkyl group; a hydroxyl group; a C1-
C6 alkoxycarbonyl substituted C1-C6 alkyl group; a
phenyl C1-C6 alkyl group; a C1-C6 alkanoyl group; a C1-
C6 alkylthio group; 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, on
the piperazine ring, at least one selected from the
group consisting of a C1-C6 alkoxycarbonyl group and a
phenyl C1-C6 alkyl 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 C1-C6 alkoxy group, may be substituted)
may be substituted as a substituent]; a piperidyl group
[wherein, on the piperidine ring, at least one amino
group may be substituted, wherein, on the amino group,
at least one selected from the 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 halogen substituted or
unsubstituted C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted) may be substituted as a substituent]; and
a carbamoyl group);
(Eaa4) ahydroxyl group;

selected from the group consisting of a C1-C6 alkyl
group and a phenyl group [wherein, on the phenyl ring,
at least one halogen atom may be substituted] may be
substituted);
(Eab24) a 2,3-dihydro-lH-indenyloxycarbonyl group;
(Eab25) an adamantane substituted C1-C6 alkoxycarbonyl
group;
(Eab26) a phenyl C3-C6 alkynyloxycarbonyl group;
(Eab27) a phenylthio C1-C6 alkoxycarbonyl group;
(Eab28) a phenyl C1-C6 alkoxy substituted C1-C6
alkoxycarbonyl group;
(Eab29) a C2-C6 alkenyloxycarbonyl group;
(Eab30) a C2-C6 alkynyloxycarbonyl group;
(Eab31) a C3-C8 cycloalkyl substituted C1-C6
alkoxycarbonyl group; or
(Eab32) a benzoyl substituted C1-C6 alkoxycarbonyl
group);
E12) a group represented by general formula (Eb):

(wherein the dotted line represents that the bond may
be a double bond; and R16 represents the.same group as
R15) ;
E13) a group represented by general formula (Ec):


(wherein R17 represents:
(Ee1) a phenyl C1-C6 alkyl 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 C1-C6 alkoxy group, may be
substituted);
(Ec2) a C1-C6 alkoxycarbonyl group; or
(Ec3) 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 C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted)) ;
E14) a pyridyl group;
E15) a group represented by 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 halogen substituted or
unsubstituted C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted]; a phenyl C1-C6 alkyl 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 C1-C6 alkoxy group, may be
substituted]; 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 C1-C6 alkyl group, and a
halogen substituted or unsubstituted C1-C6 alkoxy
group, may be substituted]; or a C1-C6 alkoxycarbonyl
group);
E16) 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
C1-C6 alkyl group, and a halogen substituted or
unsubstituted C1-C6 alkoxy group, may be substituted);
E17) 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
C1-C6 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 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 C1-C6 alkoxy group, may be substituted));

E19) a group represented by the following general
formula (Ef):
-CH=N-NR47R48 (Ef)
(wherein R47 and R48 each identically or differently
represent: a hydrogen atom; a C1-C6 alkyl 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 C1-C6 alkyl group,
and a halogen substituted or unsubstituted C1-C6 alkoxy
group, may be substituted]; or a pyridyl group
[wherein, on the pyridine ring, at least one halogen
substituted or unsubstituted C1-C6 alkyl group may be
substituted as a substituent], and further wherein R47
and R48 may bind to each other together with nitrogen
atoms adjacent thereto directly or through other
heteroatoms, so as to form a 5-7 membered saturated
heterocyclic ring, wherein, on the heterocyclic ring,
at least one phenyl group may be substituted as a
substituent [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 C1-C6 alkoxy
group, may be substituted]);
E20) a phenyl C1-C6 alkoxy 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 C1-C6 alkoxy group, may be

substituted);
E21) an amino substituted C2-C6 alkenyl group (wherein,
on the amino group, at least one selected from the
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
halogen substituted or unsubstituted C1-C6 alkyl group,
and a halogen substituted or unsubstituted C1-C6 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 group represented by general formula.(F):
-NR19R20 (F)
[wherein R19 and R20 each identically or differently
represent:
F1) a hydrogen atom;
F2) a C1-C6 alkyl group;
F3) a phenyl C1-C6 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 C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted]; a halogen atom; a halogen substituted or
unsubstituted C1-C6 alkyl group; a halogen substituted
or unsubstituted C1-C6 alkoxy group; an amino group
(wherein, on the amino group, at least one selected

from the group consisting of a C1-C6 alkyl group and a
phenyl C1-C6 alkyl 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 C1-C6 alkoxy group, may be substituted]
may be substituted); a piperazinyl group [wherein, on
the piperazine ring, at least one phenyl C1-C6 alkyl
group may be substituted (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 C1-C6 alkoxy group, may be substituted)];
and a piperidyl group [wherein, on the piperidine ring,
at least one amino group.may be substituted, 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 C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted) and a C1-C6 alkyl group may be
substituted]);
F4) a phenoxy C1-C6 alkyl 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 C1-C6 alkoxy group, may be

substituted);
F5) an amino C1-C6 alkyl group (wherein, on the amino
group, at least one selected from the group consisting
of a C1-C6 alkyl group, a C1-C6 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
C1-C6 alkyl group may be substituted], may be
substituted);
F6) 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 ph,enyl
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 C1-C6 alkoxy group, may be
substituted], and a C1-C6 alkoxycarbonyl group, may be
substituted);
F7) a C1-C6 alkoxycarbonyl group;
F8) 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 C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted) ;
F9) a group represented by general formula (Fa):


(wherein R21 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 halogen atom, a cyano group, a halogen
substituted or unsubstituted C1-C6 alkyl group, and a
halogen substituted or unsubstituted C1-C6 alkoxy
group, may be substituted); a phenyl C1-C6 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 C1-C6 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
substituted or unsubstituted C1-C6 alkyl group, and a
halogen substituted or unsubstituted C1-C6 alkoxy
group, may be substituted));
F10) a 1-substituted-4-piperidyl group represented by
general formula (Fb):

(wherein R22 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 halogen atom, a halogen substituted or

unsubstituted C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 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 C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted)); or
F11) a piperidyl C1-C6 alkyl group (wherein, on the
piperidine ring, at least one phenoxy group may be
substituted (wherein, on the phenyl ring, at least one
halogen substituted or unsubstituted C1-C6 alkyl group,
may be substituted)); or further,
F12) R19 and R20 may bind to each other together with
nitrogen atoms adjacent thereto directly or through
other heteroatoms or carbon atoms, so as to form a
heterocyclic ring represented by any one of (F12-1) to
(F12-10) indicated below:
(F12-1) a group represented by general formula (Fc):

[wherein the dotted line represents that the bond may
be a double bond; and R23 represents:
(Fc1) a C1-C6 alkyl group;
(Fc2) a phenyl C1-C6 alkyl 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 C1-C6 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 C1-C6 alkyl group; a halogen substituted '
or unsubstituted C1-C6 alkoxy group; an amino group
which may have, as a substituent, a group selected from
the group consisting of a C1-C6 alkyl group and a
phenyl C1-C6 alkyl group [wherein, on the phenyl ring,
at least one selected from the group consisting o,f a
halogen atom, a halogen substituted or unsubstituted
C1-C6 alkyl group, and a halogen substituted or
unsubstituted C1-C6 alkoxy 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 C1-C6
alkyl group, and a halogen substituted or unsubstituted
C1-C6 alkoxy group, may be substituted]; a phenyl C1-C6
alkoxy 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 C1-C6 alkoxy
group, may be substituted]; and a piperidyl group
[wherein, on the piperidine ring, 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 C1-C6 alkyl 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 C1-C6 alkoxy group, may be
substituted) and a C1-C6 alkyl group may be
substituted]);
(Fc4) a phenyl C1-C6 alkoxy 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 C1-C6 alkoxy group, may be
substituted);
(Fc5) a biphenylyl C1-C6 alkoxy group;
(Fc6) 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 C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 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
C1-C6 alkyl group, and a halogen substituted or
unsubstituted C1-C6 alkoxy group, may be substituted);

(Fc9) a C1-C6 alkoxycarbonyl group;
(Fc10) a phenyl C1-C6 alkoxycarbonyl group (wherein, on
the phenyl ring, at least one halogen substituted or
unsubstituted C1-C6 alkoxy group may be substituted);
(Fe11) a phenyl C1-C6 alkylcarbamoyl group wherein, on
the phenyl ring, at least one halogen atom may be
substituted;
(Fc12) 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 C1-C6 alkoxy group, .may be
substituted);
(Fc13) a phenylthio group (wherein, on the phenyl ring,
at least one halogen substituted or unsubstituted C1-C6
alkoxy group may be substituted);
(Fc14) a phenyl sulfoxide (wherein, on the phenyl ring,
at least one halogen substituted or unsubstituted C1-C6
alkoxy group may be substituted);
(Fc15) a pyridyl C1-C6 alkoxy group; or
(Fc16) a group represented by general formula (Fca):
-(C=O)O-NR24R25 (Fca)
(wherein o is the same as defined above; R24. and R25 each
represent:
(Fca1) a hydrogen atom;
(Fca2) a C1-C6 alkyl group;
(Fca3) a phenyl C1-C6 alkyl 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 C1-C6 alkoxy group, 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 halogen substituted or
unsubstituted C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted) ;
(Fca5) a C1-C6 alkanoyl group;
(Fca6) 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
C1-C6 alkyl group, and a halogen substituted or
unsubstituted C1-C6 alkoxy group, may be substituted);
(Fca8) a C1-C6 alkoxycarbonyl group;
(Fca9) 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 C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted) ;
(Fca10) a phenylcarbamoyl group (wherein, on the phenyl
ring, at least one halogen substituted or unsubstituted

C1-C6 alkyl group may be substituted); or
(Fca11) a piperidyloxycarbonyl group (wherein, on the
piperidine ring, at least one phenyl group may be
substituted as a substituent [wherein, on the phenyl
ring, at least one halogen substituted or unsubstituted
C1-C6 alkyl group may be substituted]); or further,
(Fcal2) R24 and R25 may form a 5- or 6-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
C1-C6 alkoxycarbonyl group; 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 C1-C6 alkyl group, and a
halogen substituted or unsubstituted C1-C6 alkoxy
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 C1-C6 alkyl group, and a
halogen substituted or unsubstituted C1-C6 alkoxy
group, may be substituted); a phenyl C1-C6 alkyl 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 C1-C6 alkoxy
group, may be substituted); 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
C1-C6 alkyl group, and a halogen substituted or
unsubstituted C1-C6 alkoxy group, may be substituted);
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 C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted); 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 C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted);
F12-2) a 4-substituted-l-piperazinyl group represented
by general formula (Fd):

(wherein R26 represents:
(Fd1) a hydrogen atom;
(Fd2) a C1-C6 alkyl group;
(Fd3) a C3-C8 cycloalkyl group;
(Fd4) a C3-C8 cycloalkyl C1-C6 alkyl group;
(Fd5) a C1-C6 alkoxycarbonyl C1-C6 alkyl group;
(Fd6) a phenyl C2-C6 alkenyl group;
(Fd7) a phenyl C1-C6 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 C1-C6
alkyl group; a C3-C8 cycloalkyl group; a halogen
substituted or unsubstituted C1-C6 alkoxy group; an
amino group which may have a C1-C6 alkyl group as a
substituent; a C1-C6 alkoxycarbonyl group; a phenoxy
group; a phenyl C1-C6 alkyl group; a phenyl C2-C6
alkenyl group; a pyridyl group; an imidazolyl group;
and a piperidyl group);
(Fd8) biphenylyl C1-C6 alkyl group (wherein, on the
phenyl ring, at least one selected from the group
consisting of a halogen atom, a halogen substitut,ed or
unsubstituted C1-C6 alkyl group, a halogen substituted
or unsubstituted C1-C6 alkoxy group, and an amino group
which may have a C1-C6 alkyl group as a substituent,
may be substituted);
(Fd9) a naphthyl C1-C6 alkyl group;
(Fd10) a phenyl group (wherein, on the phenyl ring, at
least one selected from the following group may be
substituted: a halogen atom; a cyano group; an amino
group which may have a C1-C6 alkyl group as a
substituent; a halogen substituted or unsubstituted Cl-
C6 alkyl group; a halogen substituted or unsubstituted
C1-C6 alkoxy group; a C1-C6 alkoxycarbonyl group; a
carboxyl group; 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 C1-C6 alkyl group, and a halogen

substituted or unsubstituted C1-C6 alkoxy group, may be
substituted]; an amino C1-C6 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 C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted) and a G1-C6 alkyl group may be
substituted]; and a phenyl C1-C6 alkoxy 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 C1-C6 alkoxy
group, may be substituted]);
(Fd11) a biphenylyl group (wherein, on the phenyl ring,
at least one halogen substituted or unsubstituted C1-C6
alkyl group may be substituted);
(Fd12) an amino group, amino group wherein a C1-C6
alkoxycarbonyl group is substituted, phenyl C1-C6
alkylamino group (wherein, on the phenyl ring, at least
one halogen substituted or unsubstituted C1-C6 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 C1-C6 alkyl group
may be substituted);
(Fd13) a benzoyl C1-C6 alkyl group (wherein, on the

phenyl ring, at least one halogen atom may be
substituted);
(Fd14) a phenylcarbamoyl C1-C6 alkyl group (wherein, on
the phenyl ring, at least one halogen substituted or
unsubstituted C1-C6 alkyl group may be substituted);
(Fd15) a thiazolyl C1-C6 alkyl group (wherein, on the
thiazole ring, at least one selected from the group
consisting of a halogen substituted or unsubstituted
phenyl group and a C1-C6 alkyl group may be
substituted);
(Fdl6) an oxazolyl C1-C6 alkyl group (wherein, on the
oxazole ring, at least one selected from the group
consisting of a halogen substituted or unsubstituted
phenyl group and a C1-C6 alkyl group may be
substituted);
(Fdl7) an indolyl C1-C6 alkyl group;
(Fdl8) a furyl C1-C6 alkyl group (wherein, on the furan
ring, at least one halogen substituted or unsubstituted
phenyl group may be substituted);
(Fdl9) an imidazolyl C1-C6 alkyl group (wherein, on the
imidazole ring, a phenyl group may be substituted);
(Fd20) a quinolyl C1-C6 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 C1-C6 alkyl group (wherein, on
the benzoxazole ring, at least one oxo group may be
substituted);
(Fd27) a phenoxy C2-C6 alkanoyl group wherein, on the
phenyl ring, a halogen atom may be substituted;
(Fd28) a phenylthio C2-C6 alkanoyl group wherein, on
the phenyl ring, a halogen atom may be substituted;
(Fd29) 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 C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted);
(Fd30) 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
C1-C6 alkyl group, a halogen substituted or
unsubstituted C1-C6 alkoxy group, and an amino group
which may have a C1-C6 alkyl group as a substituent,
may be substituted);
(Fd31) a biphenylylcarbonyl group;
(Fd32) a pyridylcarbonyl group;
(Fd33) a phenyl C2-C6 alkenylcarbonyl group wherein, on
the phenyl ring, a halogen atom may be substituted;
(Fd34) a phenyl C1-C6 alkylsulfonyl group wherein, on
the phenyl ring, a halogen atom may be substituted;
(Fd35) a benzenesulfonyl group (wherein, on the benzene

ring, at least one selected from the group consisting
of a halogen atom and a C1-C6 alkyl group may be
substituted);
(Fd36) a group represented by general formula (Fda):
-COOR27 (Fda)
(wherein R27 represents:
(Fda1) a halogen substituted or unsubstituted C1-C8
alkyl group;
(Fda2) a C3-C8 cycloalkyl group;
(Fda3) a C3-C8 cycloalkyl-C1-C6 alkyl group;
(Fda4) a C1-C6 alkoxy-Cl-C6 alkyl group;
(Fda5) an amino-C1-C6 alkyl group which may have a C1-
C6 alkyl group;
(Fda6) a group represented by general formula (Fdb):

(wherein each of R28, R29, and R30 represents: a hydrogen
atom; a C1-C6 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 C1-C6 alkyl group, and a
halogen substituted or unsubstituted C1-C6 alkoxy
group, may be substituted));
(Fda7) a phenyl C1-C6 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 C1-C6 alkyl group, a halogen substituted

or unsubstituted C1-C6 alkoxy group, a halogen
substituted or unsubstituted C1-C6 alkylthio group, a
phenyl C1-C6 alkoxy group, a hydroxy group, a C1-C6
alkylsulfinyl group, a C1-C6 alkylsulfonyl group, a C1-
C6 alkylsulfonyloxy group, a cyano group, a C1-C6
alkanoyl group, a benzoyl group, a phenyl C1-C6 alkyl
group which may have a C1-C6 alkoxy group at an alkyl
portion thereof, an amino group, a nitro group, a
carbamoyl group, a C1-C6 alkanoylamino group, a C1-C6
alkoxycarbonyl group, a C1-C6 alkylaminocarbonyl group,
a C1-C6 alkoxycarbonylamino group, a tri C1-C6
alkylsiloxy group, a pyrrolyl group, a
tetrahydropyranyloxy group, and an imidazolyl group,
may be substituted);
(Fda8) a biphenylyl C1-C6 alkyl group;
(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 C1-C6 alkyl 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 C1-C6 alkoxy group, may be
substituted) ;
(Fda11) a phenyl C2-C6 alkynyl group (wherein, on the
phenyl ring, at least one halogen substituted or
unsubstituted C1-C6 alkyl group may be substituted);

(Fda12) a pyridyl C1-C6 alkyl group;
(Fda13) a group represented by general formula (Fdc):

(wherein R31 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 C1-C6 alkyl group, and a
halogen substituted or unsubstituted C1-C6 alkoxy
group, may be substituted]; a phenyl C1-C6 alkyl 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 C1-C6 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 unsubstituted C1-C6 alkyl group, and a
halogen substituted or unsubstituted C1-C6 alkoxy
group, may be substituted]) ;
(Fda14) a piperidino C1-C6 alkyl group (wherein, on the
piperidine ring, a phenoxy group, which may have, as a
substituent, at least one halogen substituted or
unsubstituted alkyl group on the phenyl ring, may be
substituted);
(Fda15) an amino C1-C6 alkyl group (wherein, on the
amino group, at least one selected from the group

consisting of a C1-C6 alkyl group and a phenyl group,
which may have, as a substituent, a halogen substituted
or unsubstituted C1-C6 alkoxy group on the phenyl ring,
may be substituted);
(Fdal6) a 1,2,3,6-tetrahydropyridyl C1-C6 alkyl group
(wherein, on the 1,2,3,6-tetrahydropyridine ring, at
least one phenyl group [wherein, on the phenyl ring, at
least one halogen substituted or unsubstituted C1-C6
alkoxy group may be substituted]);
(Fdal7) a naphthyl C1-C6 alkyl group;
(Fdal8) a fluorenyl C1-C6 alkyl group;
(Fdal9) a pyridyl C1-C6 alkyl group;
(Fda20) a furyl C1-C6 alkyl group (wherein, on the
furan ring, a halogen substituted or unsubstituted
phenyl group may be substituted);
(Fda21) a thienyl C1-C6 alkyl group;
(Fda22) an oxazolyl C1-C6 alkyl group (wherein, on the
oxazole ring, a halogen atom or a halogen substituted
or unsubstituted phenyl group may be substituted);
(Fda23) an oxadiazolyl C1-C6 alkyl'group (wherein, on
the oxadiazole ring, a halogen substituted or
unsubstituted phenyl group may be substituted);
(Fda24) a pyrazolyl C1-C6 alkyl group (wherein, on the
pyrazole ring, a halogen substituted or unsubstituted
phenyl group may be substituted);
(Fda25) a benzothienyl C1-C6 alkyl group (wherein, on
the benzothiophene ring, at least one selected from the
group consisting of a halogen atom and a halogen

substituted or unsubstituted C1-C6 alkoxy group may be
substituted);
(Fda26) a thienyl C1-C6 alkyl group wherein, on the
thiophene ring, a halogen atom may be substituted;
(Fda27) a benzothiazolyl C1-C6 alkyl group;
(Fda28) a benzofuryl C1-C6 alkyl group wherein, on the
benzofuran ring, a halogen atom may be substituted;
(Fda29) an indolinyl C1-C6 alkyl group (wherein, on the
indoline ring, at least one selected from the group
consisting of a C1-C6 alkyl group and an oxo group may
be substituted) ;
(Fda30) a benzoxazolyl C1-C6 alkyl group (wherein, on
the benzoxazole ring, at least one selected from the
group consisting of a halogen atom, a C1-C6 alkyl
group, and an oxo group, may be substituted) ;
(Fda31) a chromenyl C1-C6 alkyl group;
(Fda32) a 1,2,3,4-tetrahydroquinolyl C1-C6 alkyl group
(wherein, on the quinoline ring, at least one selected
from the group consisting of a C1-C6 alkyl group and an
oxo group may be substituted);
(Fda33) a thiazolyl C1-C6 alkyl group (wherein, on the
thiazole ring, at least one selected from the group
consisting of a halogen atom, a halogen substituted or
unsubstituted phenyl group, and a C1-C6 alkyl group,
may be substituted) ; or
(Fda34) a tetrazolyl C1-C6 alkyl group (wherein, on the
tetrazole ring, at least one selected from the group
consisting of a halogen substituted or unsubstituted

phenyl group and a C1-C6 alkyl group may be
substituted);
(Fd37) a group represented by general formula (Fe) :
-Z-NR32R33 (Fe)
(wherein Z represents -C=O or -C=S; R32 and R33 each
identically or differently represent:
(Fe1) a hydrogen atom;
(Fe2) a C1-C6 alkyl group;
(Fe3) a C3-C8 cycloalkyl group;
(Fe4) a phenyl C1-C6 alkyl 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 C1-C6 alkoxy group, may be
substituted);
(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 C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted); or
(Fe6) 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
C1-C6 alkyl group, and a halogen substituted or
unsubstituted C1-C6 alkoxy group, may be substituted);
or further,
(Fe7) R32 and R33 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 C1-C6 alkyl
group may be substituted on the phenyl group);
(Fd38) a group represented by general formula (Ff):

(wherein R34 represents a hydrogen atom or C1-C6 lower
alkyl group; and R35 represents:
(Ff1) a C3-C8 cycloalkyl group;
(Ff2) a C3-C8 cycloalkenyl group;
(Ff3) a group represented by general formula (Ffa):

(wherein each of R36, R37, and R38 represents: a hydrogen
atom; a C1-C6 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 C1-C6 alkyl group, a halogen substituted
or unsubstituted C1-C6 alkoxy group, a C1-C4
alkylenedioxy group, a C1-C6 alkylsulfonyl group, a
halogen substituted or unsubstituted C1-C6 alkylthio

group, a nitro group, and an amino group which may have
a C1-C6 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, a halogen substituted or
unsubstituted C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted]; a biphenylyl group; a furyl group
[wherein, on the furan ring, a phenyl group which may
have a halogen atom as a substituent may be
substituted]; or a thiazolyl group [wherein on 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 may be
substituted: a halogen atom; a halogen substituted or
unsubstituted C1-C6 alkyl group; a C3-C8 cycloalkyl
group; a hydroxyl group; a halogen substituted or
unsubstituted C1-C8 alkoxy group; a C3-C8 cycloalkoxy
group; a C1-C4 alkylenedioxy group; a cyano group; a
nitro group; a phenyl C2-C6 alkenyl group; a C2-C6
alkanoyloxy group; an amino group which may have a C1-
C6 alkanoyl group as a substituent; a C1-C6
alkylsulfonylamino group; a phenyl C1-C6 alkoxy group;
a phenoxy group; an amino group wherein at least one
C1-C6 alkyl group is substituted; an amino group
wherein at least one phenyl group is substituted; an
amino C1-C6 alkoxy group [wherein, on the amino group,

at least one C1-C6 alkyl group may be substituted]; a
C1-C6 alkoxycarbonyl group; a C1-C6 alkoxycarbonylCl-C6
alkoxy group; a C1-C6 alkylthio group; 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, on the
piperazine ring, at least one selected from the group
consisting of a C1-C6 alkyl group, a phenyl C1-C6 alkyl
group, and a benzoyl group which may have at least one
C1-C6 alkyl group, may be substituted as a
substituent]; a quinolyl group [wherein, on the
quinoline ring, at least one selected from the group
consisting of a C1-C6 alkoxy group and an oxo group may
be substituted]; a piperidylcarbonyl group wherein, on
the piperidine ring, a carbostyril group may be
substituted; and a triazolyl group);
(Ff5) a naphthyl group (wherein, on the naphthalene
ring, at least one selected from the group consisting
of a halogen atom, a halogen substituted or
unsubstituted C1-C6 alkoxy group, and an amino group
which may have a C1-C6 alkyl group as a substituent,
may be substituted);
(Ff6) a biphenylyl group (wherein, on the biphenylyl
ring, at least one selected from the group consisting
of a halogen atom, a halogen substituted or
unsubstituted C1-C9 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted);

(Ff7) a fluorenyl group; a pyrenyl group;
(Ff8) a ben2ofuryl group (wherein, on the benzofuran'
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 C1-C6 alkoxy group, may be
substituted);
(Ff9) a benzothienyl group (wherein, on the
benzothiophene 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 C1-C6 alkoxy.
group, may be substituted);
(Ff10) a pyridyl group (wherein, on the pyridine ring,
at least one selected from the group consisting of a
halogen atom, a halogen substituted or unsubstituted
C1-C6 alkyl 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 C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted], a furyl group, and a thienyl group, may
be substituted) ;
(Ff11) a furyl group (wherein, on 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, 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, a
halogen substituted or unsubstituted C1-C6 alkoxy
group, and a nitro group, may be substituted], may be
substituted);
(Ffl2) a benzothiazole group (wherein, on the
benzothiazole ring, at least one phenyl group, which
may have, as a substituent, a C1-C6 alkoxy group on the
phenyl ring, may be substituted);
(Ff13) a thienyl group (wherein, on the thiophene ring,
at least one selected from the group consisting of a
halogen atom, a nitro group, a C1-C6 alkyl group, a
pyrazolyl group wherein, on the pyrazole ring, at- least
one halogen substituted or unsubstituted C1-C6 alkyl
group may be substituted, and a thienyl group wherein,
on the thiophene ring, a halogen atom may be
substituted, may be substituted);
(Ff14) 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 C1-C6 alkyl group, a C1-C6
alkoxycarbonyl group, and a phenyl group, may be
substituted);
(Ff15) 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 C1-C6 alkyl group may be substituted
and a C1-C6 alkyl group may be substituted);
(Ff16) a coumaryl group;

(Ff17) a benzoimidazolyl group (wherein, on the
benzoimidazole ring, at least one thienyl group may be
substituted);
(Ff18) an oxazolyl group (wherein, on the oxazole ring,
at least one phenyl group which may have a halogen atom
may be substituted);
(Ff19) 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);
(Ff21) 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 C1-C6 alkoxy group, a C1-C6
alkyl group, and a phenyl C1-C6 alkoxy group, may be
substituted); a carbostyril group (wherein, on the
carbostyril ring, at least one selected from the group
consisting .of a C1-C6 alkoxy group, a C1-C6 alkyl
group, and a phenyl C1-C6 alkoxy group, may be
substituted);
(Ff23) an imidazo[2,1-b]thiazolyl group;
(Ff24) an imidazo[2,l-a]pyridyl group;
(Ff25) a chromanyl group (wherein, on the chromane
ring, at least one C1-C6 alkyl group may be
substituted) ; or
(Ff26) a 2,3-dihydrobenzofuryl group); or
(Fd39) a group represented by general formula (Ffb):


(wherein R45 represents: a C1-C6 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 C1-C6 alkyl group,
and a halogen substituted or unsubstituted C1-C6 alkoxy
group, may be substituted]; an amino substituted C1-C6
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 C1-C6 alkyl group, and a
halogen substituted or unsubstituted C1-C6 alkoxy
group, may be substituted) and a C1-C6 alkyl 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 C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted]; a phenyl C1-C6 alkyl 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 C1-C6 alkoxy group, may be
substituted] ; 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 C1-C6 alkyl group, and a
halogen substituted or unsubstituted C1-C6 alkoxy
group, may be substituted]; or 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 C1-C6 alkyl group,
and a halogen substituted or unsubstituted C1-C6 alkoxy
group, may be substituted]));
F12-3) a morpholino group;
F12-4) an imidazolyl group;
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-
C6 alkyl group [wherein, on the phenyl ring, at least
one halogen substituted or unsubstituted C1-C6 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 C1-C6 alkoxy group as a substituent, may
be substituted); or
F12-10) an isoindolinyl group; or further
F13) R19 and R20 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):
(F13-1) a succinimide group;
(F13-2) an oxazolidinyl group (wherein, on the
oxazolidine ring, at least one oxo group may be
substituted);
(F13-3) a benzo-l,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 C1-C6 alkyl
group [wherein, on the phenyl ring, 1 to 3 groups
selected from the group consisting of a halogen atom
and a C1-C6 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, a halogen atom, a
halogen substituted or unsubstituted C1-C6 alkyl group,
an amino group which may have a C1-C6 alkyl group as a
substituent, a C1-C6 alkoxycarbonyl group, and a
piperidyl group [wherein, on the piperidine ring, at
least one selected from the group consisting of a C1-C6
alkyl group, a phenyl group wherein, on the phenyl
ring, 1 to 3 halogen atoms may be substituted, a C1-C6
alkoxycarbonyl group, and a phenyl C1-C6 alkoxycarbonyl
group, may be substituted], may be substituted);
(F13-6) a phthalimide group;
(F13-7) an indolinyl group (wherein, on the indoldne
ring, at least one selected from the group consisting
of a C1-C6 alkyl group, a halogen atom, and an oxo
group, may be substituted);
(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):

(wherein R33 represents: a hydrogen atom; a phenyl C1-C6
alkyl group which may have, as a substituent, a halogen
atom on the phenyl ring; a phenoxy C1-C6 alkyl group

which may have, as a substituent, a halogen atom on the
phenyl ring; a phenyl C2-C6 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
C1-C6 alkyl group, a halogen substituted or
unsubstituted C1-C6 alkoxy group, 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, on the
1,3-thiazolidine ring, at least one selected from the
group consisting of an oxo group and a phenyl C1-C6
alkylidene group which may have a halogen substituted
or unsubstituted C1-C6 alkyl group on the phenyl ring,
may be substituted as a substituent).
A group represented by general formula (G):

(wherein R40 represents a C1-C6 alkyl group or a halogen
substituted or unsubstituted phenyl group).
The reaction between a compound (10a) or
(10b) and a compound (11) is carried out in a suitable
solvent or in no 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, 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 N-N-dimethylformamide, dimethyl
sulfoxide, hexamethyl phosphoric triamide,
acetonitrile, N-N-dimethylacetamide, or NMP; and their
mixed solvents.
Known inorganic bases and organic bases can
widely be used as basic compounds.
Examples of 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.

Examples of an organic base may include
acetates such as sodium acetate or potassium acetate,
pyridine, trimethylamine, triethylamine,
diisopropylethylamine, dimethyl aniline, 1-
methylpyrrolidine, N-methylmorpholine, N,N-dimethyl-4-
aminopyridine, l,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).
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. It is generally
carried out for 10 minutes to 48 hours before
termination.
Among the 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. Examples of.such 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 it can
further be purified. Examples of such 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.
According to the present invention, 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.
According to the production method of the
present invention, the 4-nitroimidazole compound of
interest represented by general formula (1) can be
economically produced at high yield and at high purity.
Accordingly, the method of the present
invention is industrially extremely advantageous.
The present invention will be more
specifically described in the following examples.
Reference example 1
Production of 2, 5-dibromo-4-nitroimidazole
A mixture consisting of 4-nitroimidazole (100
g, 884 mmol), sodium bicarbonate (164 g, 1.94 mol), and
water (500 ml) was intensively stirred, and thereafter,
bromine (106 ml, 2.07 mol) was added dropwise to the
mixture at room temperature (23°C to 25°C) over 6 hours
(wherein it intensively foamed during the dropping).
The thus obtained mixture was further stirred under
heating (50°C to 55°C, 4 hours). Thereafter, water (400

ml) and concentrated hydrochloric acid (80 ml) were
added thereto under cooling on ice (10°C or lower), and
the obtained mixture was stirred for 1 hours. Crystals
were collected by filtration. The obtained crystals
were washed with water (on a filter paper, with 400 ml
of water), dispersedly washed (with 800 ml of water,
twice), and air-dried (50°C, 16 hours).
Yield: 213 g (Yield: 88.9%), pale 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-nitroimidazole
A mixture consisting of 2,5-dibromo-4-
nitroimidazole (27.1 g, 100 mmol) and concentrated
hydrochloric acid (434 ml) was stirred under heating
(77°C to 80°C, 16 hours). The reaction mixture was left
to cool, and then stirred under cooling on ice (5°C to
10°C, 2 hours). Thereafter, the precipitated crystals
were collected by filtration and air-dried (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 (MgS04) , followed by vacuum
concentration and exsiccation. The yield of the
exsiccated product was 9.63 g. Thus, 17.9 g (in total)
of 2,5-dichloro-4-nitroimidazole was obtained (yield:
98.3%).
IR (KBr): 1566, 1475, 1403, 1366, 1332, 1272, 1190,
1091, 996, 834, 679 cm"1.

MS (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-nitroimidazole.
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. Thereafter, 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%), pale 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. Thereafter, 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%), pale 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-nitroimidazole
A suspension consisting of 2,5-dibromo-4-
nitroimidazole (2.71 g, 10.0 mmol), sodium iodide (15.0
g, 100 mmol), tetrabutylamruonium 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. Thereafter, 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%), pale 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-nitroimidazole
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 a 57% hydriodic acid
aqueous solution (5.4 ml) was stirred under heating
(50°C to 60°C, 56 hours) . The reaction mixture was
cooled to room temperature. Thereafter, 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%), pale 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 a 57% hydriodic acid aqueous solution (13.6 ml) was
stirred under heating (50°C to 60°C, 36 hours). The
reaction mixture was cooled to room temperature.
Thereafter, 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%), .pale 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 wt %) was stirred under normal pressure in
a hydrogen atmosphere at room temperature for 2 hours.
The filtrate was concentrated and exsiccated 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 (MgS04) , followed
by vacuum concentration and exsiccation.
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 (DMSO-de) 5 ppm: 8.40 (s, 1H), 14.2 (br, s, 1H).
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, 6.00 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
(MgSC>4), followed by vacuum concentration and
exsiccation.
Yield: 365 mg (Yield: 95.1%)
IR (KBr): 1548, 1514, 1453, 1392, 1373, 1258, 1168,
1085, 968, 823, 799, 751, 668 cm-1
NMR (DMS0-d6) 5 ppm: 8.45 (s, 1H) , 14.1 (br, s, 1H) .
Example 8
Production of 2-bromo-4-nitroimidazole

A mixture consisting of 2-bromo-5-iodo-4-
nitroimidazole (636 mg, 2.00 mmol), ethanol (6.4 ml),
triethylamine (607 mg, 6.00 mmol), and 2% Pd alumina
(95.4 mg, 15 wt %) was stirred under normal pressure in
a hydrogen atmosphere at 50°C to 60°C for 15 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 (MgS04) , followed by
vacuum concentration and exsiccation.
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-ds) 8 ppm: 8.45 (s, 1H) , 14.1 (br, s, 1H) .
Example 9
Production of 2-bromo-4-nitroimidazole
A mixture consisting of 2-bromo-5-iodo-4-
nitroimidazole (1.27 g, 4.00 mmol), ethanol (13 ml),
triethylamine (1.21 g, 12.0 mmol),' and 2% Pd alumina
(191 mg, 15 wt %) was stirred while applying pressure
(3 to 4 atmospheres) in a hydrogen atmosphere at room
temperature for 14 hours. The filtrate was ■
concentrated and exsiccated 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 (MgS04), followed by vacuum

concentration and exsiccation.
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-d6) 5 ppra: 8.45 (s, 1H) , 14.1 (br, s, 1H) .
Example 10
Production of 2-bromo-4-nitroimidazole
Tetra-n-butyl ammonium borohydride (602 mg,
2.34 mmol) was added to a solution obtained by
dissolving 2-bromo-5-iodo-4-nitroimidazole (186 mg,
0.585 mmol) in dried dixane (2.8 ml). The obtained
mixture was stirred at 60°C for 28 hours. The reaction
mixture was cooled to room temperature, and it was 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
(MgSCU), followed by vacuum concentration and
exsiccation.
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-d6) 8 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 mmol), isopropyl alcohol
(12.2 ml), water (2.4 ml), triethylamine (2.32 g, 22.9
mmol), 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 exsiccated under reduced pressure, and
the resultant product was then dissolved in water (10
ml). The thus obtained solution was treated with
activated carbon (243 mg) (which was stirred at room
temperature for 1 hour). The filtrate was stirred
under cooling on ice, and 35% concentrated hydrochloric
acid (0.7 ml) was added thereto such that the pH.of the
solution became 2. The thus obtained solution was
further stirred under cooling on ice for 1 hour.
Thereafter, 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-d6) 8 ppm: 8.42 (s, .1H) , 14.1 (br, s, 1H) .
Example 12
Production of 2-bromo-4-nitroimidazole
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
cooling on ice, and then, a 50% to 55% ammonium
bisulfite aqueous solution (3.6 ml, 23.5 mmol with a
content of 52.5%) was added thereto. The obtained
mixture was stirred at room temperature for 3 days.
Thereafter, 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 (MgS04),

followed by vacuum concentration and exsiccation.
Yield: 375 mg (Yield: 62.1%)
NMR (DMSO-d6) 8 ppm: 8.44 (s, 1H) . 14.1 (br, s, 1H) .
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). Thereafter, sodium sulfite (1.22 g,
9.70 mmol) was added to the obtained solution. The
mixture was heated to a temperature between 40°C and
6Q°C, and it was then stirred at the temperature for 20
hours. Thereafter, sodium sulfite (2.44 g, 19.4'mmol)
was further added 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, diluted hydrochloric acid was added, thereto,
followed by extraction with ethyl acetate (3 times, 200
ml in total). The organic layer was dried (MgS04) , and
water (10 ml) was added to the oil-state residue
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-d6) 5 ppm: 8.43 (s, 1H) . 14.1 (br, s, 1H) .
Examples 14 to 19
2-Bromo-4-nitroimidazole was produced in the

same manner as in Example 12 with the exceptions that
sulfites and solvents shown in Table 1 indicated below
were used, and that the reaction temperature and the
reaction time 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 (mole) is a value
determined using 1 mole of 2-bromo-5-iodo-4-
nitroimidazole as a standard. 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 standard.


Example 20
Production of 2-bromo-5-iodo-4-nitroimidazole
A mixture consisting of 2,5-dibromo-4-
nitroimidazole (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). The

residue (brown oil, 172 g) was suspended in chilled
water (422 ml), and concentrated hydrochloric acid (10
ml) was added thereto such that the pH of the solution
became 1 to 2. The thus obtained solution was further
stirred under cooling on ice for 2 hours. Thereafter,
the precipitated crystals were collected by filtration
and then dried at 50°C for 24 hours.
Yield: 89.2 g (Yield: 89.9 %) , pale 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).

(Eaa5) a carboxy group;
(Eaa6) a phenyl group (wherein, on the phenyl ring, at
least one selected from the group consisting of 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 C1-C6
alkyl group, and a halogen substituted or unsubstituted
C1-C6 alkoxy group, may be substituted as a
substituent], a halogen atom, a halogen substituted or
unsubstituted C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted as a substituent);
(Eaa7) a C1-C6 alkoxy group;
(Eaa8) a C3-C8 cycloalkyl-Cl-C6 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 C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted);
(EaalO) a tetrahydropyranyloxy group;
(Eaa11) a 1,3-dioxolanyl group;
(Eaa12) an oxo group;
(Eaa13) a naphthyloxy group (wherein, on the
naphthalene ring, at least one C1-C6 alkyl group may be
substituted);
(Eaa14) a 2,3-dihydrobenzofuryloxy group (wherein, on
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);
(Eaa15) a benzothiazolyloxy group (wherein, on the
benzothiazole ring, at least one C1-C6 alkyl group may
be substituted);
(Eaal6) a 1,2, 3, 4-tetrahydronaphthyloxy group (wherein,,
on the 1,2,3,4-tetrahydronaphthalene ring, at least one
oxo group may be substituted);
(Eaal7) a 1,3-benzoxathiolanyloxy group (wherein, on
the 1,3-benzoxathiolane ring, at least one oxo group
may be substituted);
(Eaa18) an isoquinolyloxy group;
(Eaa19) a pyridyloxy group;
(Eaa20) a quinolyloxy group (wherein, on the quinoline
ring, at least one C1-C6 alkyl group may be
substituted) ;
(Eaa21) a dibenzofuryloxy group;
(Eaa22) a 2H-chromenyloxy group (wherein, on the 2H-
chromene ring, at least one oxo group may be
substituted);
(Eaa23) a benzoisoxazolyloxy group;
(Eaa24) a quinoxalyloxy group;
(Eaa25) a 2,3-dihydro-1H-indenyloxy group (wherein, on
the 2,3-dihydro-1H-indene ring, at least one oxo group
may be substituted);
(Eaa26) a benzofurazanyloxy group; or
(Eaa27) 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 C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 alkoxy group, may be
substituted));
Ell) a group represented by general formula (Eab):

(wherein o is the same as defined above; W1 represents a
lower alkylene group; and R15 represents:
(Eab1) a hydrogen atom;
(Eab2) a C1-C6 alkyl group (wherein, on the alkyl
group, a morpholino group, a benzoyl group, a carbamoyl
group which may have a C1-C6 alkyl group as a
substituent, or a cyano group may be substituted);
(Eab3) a C3-C8 cycloalkyl group;
(Eab4) a phenyl C1-C6 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 C1-C6 alkylthio group, a C1-C6
alkylsulfonyl group, a phenyl C1-C6 alkoxy group, a C2-
C6 alkanoyloxy group, a halogen substituted.or
unsubstituted C1-C6 alkyl group, a halogen substituted
or unsubstituted C1-C6 alkoxy group, and a 1,2,3-
thiadiazole group, may be substituted);
(Eab5) a C2-C6 alkenyl group;
(Eab6) 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 C1-C6 alkoxy group, may be
substituted);
(Eab7) a C1-C6 alkanoyl group;
(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 C1-C6 alkyl group, and a halogen
substituted or unsubstituted C1-C6 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
C1-C6 alkyl group, and a halogen substituted or
unsubstituted C1-C6 alkoxy group, may be substituted);
(Eab10) 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 C1-C6 alkyl group as a substituent, and a C1-C6
alkoxy substituted C1-C6 alkoxy group, may be
substituted);
(Eab11) 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 C1-C6 alkyl group, a
halogen substituted or unsubstituted C1-C6 alkoxy

group, a nitro group, a halogen substituted or
unsubstituted C1-C6 alkylthio group, an amino group
which may have a C1-C6 alkanoyl group, a phenyl C1-C6
alkoxy group, a C1-C6 alkoxycarbonyl group, and a
1,2,3-thiadiazolyl group, may be substituted);
(Eabl2) a phenyl C3-C6 alkenyloxycarbonyl 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 C1-C6 alkoxy
group, may be substituted); •
(Eabl3) a phenoxycarbonyl group (wherein, on the tphenyl
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 C1-C6 alkoxy group, may be
substituted) ;
(Eabl4) a phenyl C1-C6 alkylcarbamoyl 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 C1-C6 alkoxy
group, may be substituted);
(Eab15) 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 C1-C6 alkoxy group, may be

substituted) ;
(Eab16) a benzofuryl substituted C1-C6 alkoxycarbonyl
group (wherein, on the benz'ofuran ring, at least one
halogen atom may be substituted);
(Eabl7) a benzothienyl C1-C6 alkoxycarbonyl group
(wherein, on the benzothiophene ring, at least one
selected from the group consisting of a halogen atom
and a halogen substituted or unsubstituted C1-C6 alkoxy
group may be substituted);
(Eab18) a naphthyl substituted C1-C6 alkoxycarbonyl
group;
(Eab19) a pyridyl substituted C1-C6 alkoxycarbonyl
group (wherein, on the pyridine ring, at least one
halogen atom may be substituted);
(Eab20) a furyl substituted C1-C6 alkoxycarbonyl group
(wherein, on the furan ring, at least one nitro group
may be substituted) ;
(Eab21) a thienyl substituted C1-C6 alkoxycarbonyl
group (wherein, on the thiophene ring, at least one
halogen atom may be substituted); •
(Eab22) a thiazolyl substituted C1-C6 alkoxycarbonyl
group (wherein, on the thiazole ring, at least one
selected from the group consisting of a C1-C6 alkyl
group and a phenyl group [wherein, on the phenyl ring,
at least one halogen substituted or unsubstituted C1-C6
alkyl group may be substituted] may be substituted) ;
(Eab23) a tetrazolyl substituted C1-C6 alkoxycarbonyl
group (wherein, on the tetrazole ring, at least one

wherein, when the reducing agent is hydrogenation reducing agent, the
reducing agent is used to the compound (3) at an amount of at least 1
mole at a temperature between 0°C and 150°C, or when the reducing
gent is a catalytic hydrogenation reducing agent, the reducing agent is
used to the compound (3) at a weight ratio between 0.1% by weight and
40% by weight at a temperature between -30°C and 100°C:

wherein X2 is the same as defined above.

WE CLAIM;
1. A method for producing a haloderivative of 4-nitroimidazole compound
represented by general formula (1) :

wherein X2 represents a chlorine atom or bromine atom, comprising
iodinating a 4-nitroimidazole compound represented by general formula
(2) in the presence of an iodinating agent, wherein the iodinating agent is
used to the compound (2) at a molar ratio between 1.5:1 and 15:1 at a
temperature between 0°C and 150°C:

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) in the presence of a reducing agent,
wherein, when the reducing agent is hydrogenation reducing agent, the

I, Masanori KOMATSU , a national of Japan,
c/o Asamura Patent Office of 331-340, New Ohtemachi Building,
2-1, Ohtemachi-2-chome, Chiyoda-ku, Tokyo, Japan, declare that
to the best of my knowledge and belief the attached is a full,
true, and faithful translation into English made by me of
Japanese Patent Application No. 2004-278999.





The present invention provides a method for producing a haloderivative
of 4-nitroimidazole compound represented by general formula (1) :

wherein X2 represents a chlorine atom or bromine atom, comprising
iodinating a 4-nitroimidazole compound represented by general formula
(2) in the presence of an iodinating agent, wherein the iodinating agent is
used to the compound (2) at a molar ratio between 1.5:1 and 15:1 at a
temperature between 0°C and 150°C:

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) in the presence of a reducing agent,
where, when the reducing agent is hydrogenation reducing agent, the reducing agent is used to the compound (3) at an amount of at least 1 mole at a temperature between 0°C and 150°C, or when the reducing gent is a catalytic hydrogenation reducing agent, the reducing agent is used to the compound (3) at a weight ratio between 0.1% by weight and 40% by weight at a temperature between -30°C and 100°C:
wherein X2 is the same as defined above

Documents:

02205-kolnp-2006-abstract.pdf

02205-kolnp-2006-claims.pdf

02205-kolnp-2006-correspondence others.pdf

02205-kolnp-2006-correspondence-1.1.pdf

02205-kolnp-2006-description(complete).pdf

02205-kolnp-2006-form-1.pdf

02205-kolnp-2006-form-2.pdf

02205-kolnp-2006-form-3.pdf

02205-kolnp-2006-form-5.pdf

02205-kolnp-2006-international publication.pdf

02205-kolnp-2006-international search authority report.pdf

02205-kolnp-2006-pct form.pdf

02205-kolnp-2006-priority document.pdf

2205-KOLNP-2006-CLAIMS.pdf

2205-KOLNP-2006-CORRESPONDENCE 1.1.pdf

2205-KOLNP-2006-CORRESPONDENCE-1.2.pdf

2205-KOLNP-2006-CORRESPONDENCE-1.3.pdf

2205-kolnp-2006-correspondence.pdf

2205-KOLNP-2006-DESCRIPTION (COMPLETE) 1.1.pdf

2205-kolnp-2006-examination report.pdf

2205-KOLNP-2006-FORM 1-1.1.pdf

2205-kolnp-2006-form 18.pdf

2205-KOLNP-2006-FORM 2.1.1.pdf

2205-kolnp-2006-form 26.pdf

2205-kolnp-2006-form 3.1.pdf

2205-KOLNP-2006-FORM 3.pdf

2205-kolnp-2006-form 5.pdf

2205-KOLNP-2006-FORM-27.pdf

2205-kolnp-2006-granted-abstract.1.pdf

2205-kolnp-2006-granted-claims.pdf

2205-kolnp-2006-granted-description (complete).pdf

2205-kolnp-2006-granted-form 1.pdf

2205-kolnp-2006-granted-form 2.pdf

2205-kolnp-2006-granted-specification.pdf

2205-KOLNP-2006-OTHERS.pdf

2205-kolnp-2006-others1.1.pdf

2205-KOLNP-2006-PCT SEARCH REPORT.pdf

2205-kolnp-2006-reply to examination report.pdf

2205-kolnp-2006-translated copy of priority document.pdf

abstract-02205-kolnp-2006.jpg


Patent Number 248249
Indian Patent Application Number 2205/KOLNP/2006
PG Journal Number 26/2011
Publication Date 01-Jul-2011
Grant Date 29-Jun-2011
Date of Filing 04-Aug-2006
Name of Patentee OTSUKA PHARMACEUTICAL CO. LTD.
Applicant Address 9, KANDA-TSUKASACHO, 2-CHOME CHIYODA-KU TOKYO
Inventors:
# Inventor's Name Inventor's Address
1 KOICHI SHINHAMA 3-9-15, KITAJOSANJIMA-CHO, TOKUSHIMASHI, TOKUSHIMA
PCT International Classification Number C07D 233/92
PCT International Application Number PCT/JP2005/002668
PCT International Filing date 2005-02-15
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2004-041381 2004-02-18 Japan
2 2004-278999 2004-09-27 Japan