JPH03115264A - Antibacterial agent - Google Patents

Abstract

NEW MATERIAL:The benzoheterocyclic compound of formula I [R<1> is cyclopropyl, phenyl, alkyl, alkenyl or thienyl; R<2> is 5- to 9-membered heterocyclic group; R<3> is H, alkyl or halogen; R<4> is alkyl or halogen; R is H or alkyl; R<1> and R<3> may together form the group of formula II (R<31> is H or alkyl); X is halogen] or its salt. EXAMPLE:7-(4-Methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl -1,4- dihydro-4-oxoquinoline-3-carboxylic acid. USE:Remedy for diseases of human, animal, fish, etc., caused by various pathogenic microorganisms. PREPARATION:The exemplified compound can be produced e.g. by using 3-(4- methyl-1-piperazinyl)-4-fluoro-2,5-dimethyl-6-nitro-N-cyclopropylaniline as a starting raw material.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to an antibacterial agent containing a novel benzoheterocyclic compound.

DISCLOSURE OF THE INVENTION The antibacterial agent of the present invention contains as an active ingredient a new compound represented by the following general formula (1), a benzoheterocyclic compound, which has not been described in any literature.

R3R+ [In the formula, R1 is a cyclopropyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a halogen atom as a substituent, a lower alkoxy group, a halogen atom, and a hydroxyl group as a substituent on the phenyl ring It refers to a phenyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkenyl group, or a thienyl group that may have a halogen atom, a lower alkanoyloxy group, or a hydroxyl group as a substituent. R2 represents a 5- to 9-membered saturated or unsaturated heterocyclic residue which may have a substituent. R3 represents a hydrogen atom, a lower alkyl group or a halogen atom. R4 represents a lower alkyl group or a halogen atom. R represents a hydrogen atom or a lower alkyl group. Moreover, R1 and R3 may be taken together to form a group CHCH20-. 31 Here, R31 represents a hydrogen atom or a lower alkyl group. X represents a halogen atom. However, R3 and R4 must not be halogen atoms or atoms at the same time, and when R3 represents a hydrogen atom, R4 represents a lower alkyl group. Furthermore, R1
and R3 together form a group CHCH20-, R4 31 represents a lower alkyl group. ]The above general formula (1
) and its salts exhibit excellent antibacterial activity against a wide range of Durum-positive and Durum-negative bacteria, and are useful as therapeutic agents for diseases caused by various pathogenic bacteria in humans, animals, fish, etc. It is also useful as an external disinfectant or disinfectant for medical instruments, etc.

More specifically, each group shown in the above general formula (1) is as follows.

Examples of halogen atoms include fluorine, chlorine, bromine, and iodine atoms.

Examples of the cyclopropyl group that may have 1 to 3 groups selected from the group consisting of lower alkyl groups and halogen atoms as substituents include cyclopropyl, 2-fluoro-1-cyclopropyl, and 2-chloro-1-cyclo. Propyl, 2-
Bromo-1-cyclopropyl, 2-iodo-1-cyclopropyl, 2゜2-dichloro-1-cyclopropyl, 2
．． 2-dibromo-1-cyclopropyl, 2,2.3-1
Richloro-1-cyclopropyl, 2-methyl-1-cyclopropyl, 2-ethyl-1-cyclopropyl, 2-propyl-1-cyclopropyl, 2-butyl-1-cyclopropyl, 2-pentyl-1-cyclopropyl, 2-hexyl-1-cyclopropyl, 2,2-dimethyl-1-
Cyclopropyl, 2,3-dimethyl-1-cyclopropyl, 2,2゜3-trimethyl-1-cyclopropyl, 2
-Fluoro-3-methyl-1-cyclopropyl, 2.2
- a group selected from the group consisting of a straight or branched alkyl group having 1 to 6 carbon atoms such as diethyl-1-cyclopropyl, 2-methyl-3-propyl-1-cyclopropyl group, and a halogen atom; An example is a cyclopropyl group which may have up to 3 cyclopropyl groups.

Lower alkyl groups include methyl, ethyl, propyl,
Isopropyl, butyl, tCrt-butyl, pentyl,
Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms such as hexyl group.

Examples of 5- to 9-membered saturated or unsaturated heterocyclic residues that may have substituents include lower alkyl groups,
A cycloalkyl group, a phenyl lower alkyl group that may have a lower alkoxy group, a nitro group, or an amino group as a substituent on the phenyl ring, a halogen atom, or a phenyl lower alkyl group that may have 1 to 3 halogen atoms as a substituent on the phenyl ring. A phenyl group, a pyridyl group that may have a certain lower alkyl group, an amino group, a lower alkoxy group, or a halogen atom that may have a hydroxyl group, a lower alkyl group, a lower alkanoyl group, a cycloalkyl group, or a lower alkoxycarbonyl group as a substituent. a lower alkyl group having 1 to 3
A lower alkynyl group, a lower alkanoyl group that may have 1 to 7 halogen atoms, a lower alkenylcarbonyl group, a lower alkoxycarbonyl group, or a lower alkyl group that has 1 to 3 halogen atoms or carboxy groups as a substituent. Certain aminocarbonyl groups, phenyl lower alkoxycarbonyl groups, amino lower alkanoyl groups that may have a phenyl lower alkoxycarbonyl group as a substituent, lower alkoxycarbonyl lower alkyl groups, carboxy lower alkyl groups, anilinocarbonyl lower alkyl groups, substituents As a substituent, an amino group that may have a lower alkyl group, a phenyl lower alkyl group, a lower alkoxycarbonyl group, or a lower alkanoyl group, a hydroxyl group, a lower alkylsulfonyl group that may have 1 to 3 halogen atoms, a phthalide group, A 2(5H)-furanone group, a sulfo-lower alkyl group, an oxo group, a lower alkoxy group, a lower alkenyl group, a halogen atom, a lower alkanoyloxy group, which may have 1 or 2 halogen atoms, or a phenyl group or 2-oxo-1,3-dioxolenemethyl group, cycloalkylamino group, which may have a lower alkyl group, 2, which may have a phenyl group or a lower alkyl group as a substituent
-oxo-1,3-dioxolene Indicates a 5- to 9-membered saturated or unsaturated heterocyclic residue that may have a methylamino group, a lower alkylthio group, or a thio group, such as piperazinyl, piperidinyl, pyrrolidinyl, Homopiperazinyl, morpholino, thiomorpholino, 1,2.5.6-titrahydropyridyl, imidazolyl, 1,4-diazabicyclo(4,3,0)nonan-4-yl, thiomorpholino-4-oxide, thiomorpholino-4 , 4-dioxide, pyrazolidinyl, hexahydrobiridazyl, pyridyl, thiazolidinyl, 2-thio-1-imidazolidinyl, 2-oxo-1-imidazolidinyl, 3,7-diazabicyclo(4,3,0)nonan-3-yl , 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl,
4-propyl-1-piperazinyl, 4-t-butyl-1
-piperazinyl, 4-pentyl-1-piperazinyl, 4
-hexyl-1-piperazinyl, 3-methyl-1-piperazinyl, 3.4-dimethyl-1-piperazinyl, 2.
5-dimethyl-1-piperazinyl, 2,4.5-trimethyl-1-piperazinyl, 3,4.5-trimethyl-1
-piperazinyl, 3-ethyl-1-piperazinyl, 3-
Propyl-4-methyl-1-piperazinyl, 2-n-butyl-5-methyl-1-piperazinyl, 2-pentyl-
5-hexyl-1-piperazinyl, 4-formyl-1-
Piperazinyl, 4-acetyl-1-piperazinyl, 4-
Propionyl-1-piperazinyl, 4-butyryl-1-
piperazinyl, 4-pentanoyl-1-piperazinyl,
4-hexanoyl-1-piperazinyl, 4-(α, α,
α-trifluoroacetyl)-1-piperazinyl, 4-
(β, β, β-trifluoro-α, α-difluoropropionyl)-1-piperazinyl, 4-(γ, γ, γ-trifluoro-β, β-difluoro-α, α-difluorobutyryl)-1-piperazinyl , 4-(α,α-dichloroacetyl)-1-piperazinyl, 4-(α-bromoacetyl)-1-piperazinyl, 4-(α-iodoacetyl)-1-piperazinyl, 4-(β-fluoropropionyl) -1-piperazinyl, 4-(β-fluoro-α-
Fluoropropionyl)-1-piperazinyl, 4-(6
-fluorohexanoyl)-1-piperazinyl, 4-(
4-chloropentanoyl)-1-piperazinyl, 4-benzyl-1-piperazinyl, 4-(2-phenylethyl)-1-piperazinyl, 4-(1-phenylethyl)
-1-piperazinyl, 4- (3-phenylpropyl)
-1-piperazinyl, 4-(4-phenylbutyl)-1
-piperazinyl, 4-(1,1-dimethyl-2-phenylethyl)-1-piperazinyl, 4-(5-phenylpentyl)-1-piperazinyl, 4-(6-phenylhexyl)-1-piperazinyl, 4- (2-methyl-3-phenylpropyl)=1-piperazinyl, 4-amino-1
-piperazinyl, 3-amino-1-piperazinyl, 2-
Amino-1-piperazinyl, 4-methylamino-1-piperazinyl, 3-dimethylamino-1-piperazinyl,
2-ethylamino-1-piperazinyl, 4-propylamino-1-piperazinyl, 4-t-butylamino-1-
Piperazinyl, 3-pentylamino-1-piperazinyl, 2-hexylamino-1-piperazinyl, 4-diethylamino-1-piperazinyl, 4-(N-methyl-N-
n-butylamino)-1-piperazinyl, 3-(N-methyl-N-pentylamino)-1-piperazinyl, 2-
(N-ethyl-N-hexylamino)-1-piperazinyl, 4-acetylamino-1-piperazinyl, 3-formylamino-1-piperazinyl, 2-propionylamino-1-piperazinyl, 4-butyrylamino-1-piperazinyl, 3-Pentanoylamino-1-piperazinyl, 2-hexanoylamino-1-piperazinyl, 4-(
N-methyl-N-acetylamino)-1-piperazinyl, 3-(N-ethyl-N-propionylamino)-1-
piperazinyl, 4-hydroxy-1-piperazinyl, 3
-Hydroxy-1-piperazinyl, 2-hydroxy-1
-piperazinyl, 4-methylsulfonyl-1-piperazinyl, 4-ethylsulfonyl-1-piperazinyl, 4-
Propylsulfonyl-1-piperazinyl, 4-n-butylsulfonyl-1-piperazinyl, 4-pentylsulfonyl-1-piperazinyl, 4-hexylsulfonyl-1
-Piperazinyl, 4-trifluoromethylsulfonyl-
1-piperazinyl, 4-(2-fluoroethylsulfonyl)-1-piperazinyl, 4-(3-fluoropropylsulfonyl)-1-piperazinyl, 4-(4,4,4
-trifluorobutylsulfonyl)-1-piperazinyl, 4-sulfonyl-1-piperazinyl, 4-(phthalid-3-yl)-1-piperazinyl, 4-(3,4-dibromo-2(3H)-furanone-5 -yl)-1-piperazinyl, 4-(3,4-dichloro-2(3H)-furanon-5-yl)-1-piperazinyl, 4-(2(5H)
)-furanon-5-yl)-1-piperazinyl, 4-(
3-chloro-2(5H)-furanon-5-yl)-1-
Piperazinyl, 4-formyl-3-methyl-1-piperazinyl, 4-acetyl-3-ethyl-1-piperazinyl, 4-acetyl-2-methyl-1-piperazinyl, 4-
Methyl-3-hydroxymethyl-1-piperazinyl, 3
-Hydroxymethyl-1-piperazinyl, 4-ethyl-
5-(2-hydroxyethyl)-1-piperazinyl, 3
-(3-hydroxypropyl)-1-piperazinyl, 4
-Methyl-2-(4-hydroxybutyl)-1-piperazinyl, 4-ethyl-5-(5-hydroxypentyl)
-1-piperazinyl, 3-(6-hydroxyhexyl)-di-piperazinyl, 4-(4-methoxybenzyl)
-1-piperazinyl, 4- (3-ethoxybenzyl)
-1-piperazinyl, 4-(2-propoxybenzyl)
-1-piperazinyl, 4-(4-n-butoxybenzyl)-1-piperazinyl, 4-(3-pentyloxybenzyl)-1-piperazinyl, 4-(2-hexyloxybenzyl)-1-piperazinyl, 4- (4-nitrobenzyl)-1-piperazinyl, 4-(3-nitrobenzyl)-1-piperazinyl, 4-(4-aminobenzyl)
-1-piperazinyl, 4-(2-aminobenzyl)-1
-piperazinyl, 4-cyclopropyl-1-piperazinyl, 4-cyclobutyl-1-piperazinyl, 4-cyclopentyl-1-piperazinyl, 4-cyclohexyl-1
-piperazinyl, 4-cyclohebutyl-1-piperazinyl, 4-cyclooctyl-1-piperazinyl, 4-phenyl-1-piperazinyl, 4-(4-fluorophenyl)=1-piperazinyl, 4-(3-bromophenyl) )
-1-piperazinyl, 4-(2-chlorophenyl)-1
-piperazinyl, 4-(4-iodophenyl)-1-piperazinyl, 4-(4-methylphenyl)-1-piperazinyl, 4-(3-ethylphenyl)-1-piperazinyl, 4-(2-propylphenyl) -1-piperazinyl, 4-(4-n-butylphenyl)-1-piperazinyl, 4-(3-pentylphenyl)-1-piperazinyl,
4-(2-hexylphenyl)-1-piperazinyl,
4-(4-trifluoromethylphenyl)-1-piperazinyl, 4-(3-(2-chloroethyl)phenyl)
-1-piperazinyl, 4- (2-(3,3-dibromopropyl)phenyl)-1-piperazinyl, 4- (4
-(4-chlorobutyl)phenyl]-1-piperazinyl, 4-hydroxymethyl-1-piperazinyl, 4-(2
-hydroxyethyl)-1-piperazinyl, 4-(3-
hydroxypropyl)-1-piperazinyl, 4-(3-
Chloropropyl)-1-piperazinyl, 4-(bromomethyl)-1-piperazinyl, 4-(2-fluoroethyl)-1-piperazinyl, 4-(4-chlorobutyl)-1
-piperazinyl, 4- (3-fluoropentyl)-1
-piperazinyl, 4- (2,3-dichlorohexyl)
-1-piperazinyl, 4-(2,2,2-trifluoroethyl)-1-piperazinyl, 4-(trifluoromethyl)-1-piperazinyl, 4-aminomethyl-1-piperazinyl, 4-(3-dimethyl aminopropyl)-1-
Piperazinyl, 4-(2-ethylaminoethyl)-1
-piperazinyl, 4- (4-propylaminobutyl)
-1-piperazinyl, 4-(5-n-butylaminopentyl)-1-piperazinyl, 4-(6-pentylaminohexyl)-1-piperazinyl, 4-(N-methyl-N
-ethylaminomethyl)-1-piperazinyl, 4-(N
-Methyl-N-propylaminomethyl)-1-piperazinyl, 4-(2-diethylaminoethyl)-1-piperazinyl, 4-methoxymethyl-1-piperazinyl, 4-
Ethoxymethyl-1-piperazinyl, 4-(2-propoxyethyl)-1-piperazinyl, 4-(3-butoxypropyl)-1-piperazinyl, 4-(4-pentyloxybutyl)-1-piperazinyl, 4-( 5-hexyloxypentyl)-1-piperazinyl, 4-(6-medoxyhexyl)-1-piperazinyl, 4-propargyl-1-piperazinyl, 4-(2-butynyl)-1-piperazinyl, 4-(3 -butynyl)-1-piperazinyl, 4-(1-methyl-2-propynyl)-1-piperazinyl, 4-(2-pentynyl)-1-piperazinyl, 4
-(2-hexynyl)-1=piperazinyl, 4-ethynyl-1-piperazinyl, 4-vinyl-1-piperazinyl, 4-allyl-1-piperazinyl, 4-(2-butenyl)-1-piperazinyl, 4- (3-butenyl)-1-
Piperazinyl, 4-(1-methylallyl)-1-piperazinyl, 4-(2-pentenyl)-1-piperazinyl, 4-(2-hexenyl)-1-piperazinyl, 2-oxo-1-piperazinyl, 3-oxo- 1-piperazinyl, 4-oxo-3-methyl-1-piperazinyl, 4,
4-dimethyl-1-piperazinyl, 4-(2-pyridyl)-1-piperazinyl, 4-(3-pyridyl)-1-piperazinyl, 4-(4-pyridyl)-1-piperazinyl, 4-carbamoyl-1- Piperazinyl, 4-dimethylaminocarbonyl-1-piperazinyl, 4-ethylaminocarbonyl-1-piperazinyl, 4-propylaminocarbonyl-1-piperazinyl, 4-butylaminocarbonyl-1-piperazinyl, 4-pentylaminocarbonyl-1- Piperazinyl, 4-hexylaminocarbonyl-1-piperazinyl, 4-diethylaminocarbonyl-1-piperazinyl, 4-(N-methyl-N-propylaminocarbonyl)-1-piperazinyl, 4-methoxycarbonyl-1-piperazinyl, 4 -ethoxycarbonyl-1-piperazinyl, 4-propoxycarbonyl-1
-piperazinyl, 4-tcrt-butoxycarbonyl-
1-piperazinyl, 4-pentyloxycarbonyl-1
-piperazinyl, 4-hexyloxycarbonyl-1-
Piperazinyl, 4-benzyloxycarbonyl-1-piperazinyl, 4-(2-phenylethoxycarbonyl)
-1-piperazinyl, 4-(3-phenylpropoxycarbonyl)-1-piperazinyl, 4-(4-phenylbutoxycarbonyl)-1-piperazinyl, 4-(5
-phenylpentyloxycarbonyl)-1-piperazinyl, 4-(6-phenylhexyloxycarbonyl)
-1-piperazinyl, 4-(2-aminoacetyl)-1
-piperazinyl, 4-(3-aminopropionyl)-1
-piperazinyl, 4-(4-aminobutyryl)-1-piperazinyl, 4-(5-aminopentanoyl)-1-
Piperazinyl, 4-(6-aminohexanoyl)-1-
Piperazinyl, 4-(2-benzyloxycarbonylaminoacetyl)-1-piperazinyl, 4-(2-(
2-phenylethoxycarbonylamino)acetyl-1-piperazinyl, 4-[2-(3-phenylpropoxycarbonylamino)acetyl-1-piperazinyl,
4-C2-(4-phenylbutoxycarbonylamino)acetylgo-1-piperazinyl, 4-methoxycarbonylmethyl-1-piperazinyl, 4-ethoxycarbonylmethyl-1-piperazinyl, 4-(2-ethoxycarbonylethyl]-1 -piperazinyl, 4-(3-propoxycarbonylpropyl)-1-piperazinyl, 4-
(4-butoxycarbonylbutyl)-1-piperazinyl, 4-(5-pentyloxycarbonylpentyl)-1
-piperazinyl, 4-(6-hexyloxycarbonylhexyl)-1-piperazinyl, 4-carbonylmethyl-1-piperazinyl, 4-(2-carboxyethyl)-
1-Piperazinyl, 4-(3-carboxypropyl)-
1-Piperazinyl, 4-(4-carboxybutyl)-1
-piperazinyl, 4- (5-carboxypentyl)-
1-piperazinyl, 4-(6-carboxyhexyl)
-1-piperazinyl, 4-(anilinocarbonylmethyl)-1-piperazinyl, 4- (2-anilinocarbonylethyl)-1-piperazinyl, 4- (3-anilinocarbonylpropyl)-1-piperazinyl, 4- (4-
Anilinocarbonylbutyl)-1-piperazinyl, 4-
(5-anilinocarbonylpentyl)-1-piperazinyl, 4-(6-anilinocarbonylethyl)-1-piperazinyl, 4-(3-carboxyacryloyl)-1
-piperazinyl, 4-(3-carboxy-2,3-dichloroacryloyl)-1-piperazinyl, 4-methyl-
1-piperidinyl, 4-ethyl-1-piperidinyl, 4
-propyl-1-piperidinyl, 4-n-butyl-1-
piperidinyl, 4-pentyl-1-piperidinyl, 4-
Hexyl-1-piperidinyl, 4-methoxy-1-piperidinyl, 4-ethoxy-1-piperidinyl, 4-propoxy-1-piperidinyl, 4-n-butoxy-1-piperidinyl, 4pentyloxy-1-piperidinyl, 4
-hexyloxy-1-piperidinyl, 4-acetyloxy-1-piperidinyl, 4-propionyloxy-1
-piperidinyl, 4-butyryloxy-1-piperidinyl, 4-pentanoyloxy-1-piperidinyl, 4-
Hexanoyloxy-1-piperidinyl, 4-methoxycarbonyloxy-1-piperidinyl, 4-ethoxycarbonyl-1-piperidinyl, 4-propoxycarbonyl-1-piperidinyl, 4-n-butoxycarbonyl-
1-piperidinyl, 4-pentyloxycarbonyl-1
-piperidinyl, 4-hexyloxycarbonyl-1-
piperidinyl, 4-benzyl-1-piperidinyl, 4-
(2-phenylethyl)-1-piperidinyl, 4-
(1-phenylethyl)-1-piperidinyl, 4- (
3-phenylpropyl)-1-piperidinyl, 4-(4
-phenylbutyl)-1-piperidinyl, 4-(5-phenylpentyl)-1-piperidinyl, 4-(6-phenylhexyl)-1-piperidinyl, 4-hydroxy-
1-piperidinyl, 3-hydroxy-1-piperidinyl, 2-hydroxy-1-piperidinyl, 4-amino-1
-piperidinyl, 3-amino-1-piperidinyl, 2-
Amino-1-piperidinyl, 4-dimethylamino-1-
piperidinyl, 4-methylamino-1-piperidinyl,
3-ethylamino-1-piperidinyl, 2-propylamino-1-piperidinyl, 4-n-butylamino-1-
Piperidinyl, 3-pentylamino-1-piperidinyl, 4-hexylamino-1-piperidinyl, 3-diethylamino-1-piperidinyl, 4-(N-methyl-N-
propylamino)-1-piperidinyl, 4-carbamoyl-1-piperidinyl, 3-carbamoyl-1-piperidinyl, 3,5-dimethyl-1-piperidinyl, 2,5
-dimethyl-1-piperidinyl, 4-oxo-1-piperidinyl, 3-oxo-1-piperidinyl, 3-hydroxy-1-pyrrolidinyl, 3-amino-1-pyrrolidinyl, 2-hydroxy-1-pyrrolidinyl, 2-amino −
1-pyrrolidinyl, 3-methylamino-1-pyrrolidinyl, 3-dimethylamino-1-pyrrolidinyl, 2-ethylamino-1-pyrrolidinyl, 3-propylamino-1
-pyrrolidinyl, 2-n-butylamino-1-pyrrolidinyl, 3-pentylamino-1-pyrrolidinyl, 2-hexylamino-1-pyrrolidinyl, 3-diethylamino-1-pyrrolidinyl, 3-(N-methyl-N-propyl) amino)-1-pyrrolidinyl, 2-(N-ethyl-N-
n-butylamino)-1-pyrrolidinyl, 3-acetylamino-1-pyrrolidinyl, 3-propionylamino-
1-pyrrolidinyl, 2-butyrylamino-1-pyrrolidinyl, 3-pentanoylamino-1-pyrrolidinyl, 2
-hexanoylamino-1-pyrrolidinyl, 3-hydroxymethyl-1-pyrrolidinyl, 2-(2-hydroxyethyl)-1-pyrrolidinyl, 3-(3-hydroxypropyl)-1-pyrrolidinyl, 2-(4-hydroxy butyl)-1-pyrrolidinyl, 3-(5-hydroxypentyl)-1-pyrrolidinyl, 3-(6-hydroxyhexyl)-1-pyrrolidinyl, 3-aminomethyl-1
-pyrrolidinyl, 3-(2-aminoethyl)-1-pyrrolidinyl, 2-(3-aminopropyl)-1-pyrrolidinyl, 3-(4-aminobutyl)-1-pyrrolidinyl, 3-(5-aminopentyl) -1-pyrrolidinyl, 3
-(6-aminohexyl)-1-pyrrolidinyl, 3-(
methylaminomethyl)-1-pyrrolidinyl, 3-(2-
ethylaminoethyl)-1-pyrrolidinyl, 3-(3
-propylaminopropyl)-1-pyrrolidinyl, 2-
(4-n-butylaminobutyl)-1-pyrrolidinyl,
3-(5-pentylaminopentyl)-1-pyrrolidinyl, 3-(6-hexylaminohexyl)-1-pyrrolidinyl, 3-(dimethylaminomethyl)-1-pyrrolidinyl, 2-(N-methyl-N- ethylaminomethyl)
-1-pyrrolidinyl, 3-(N-ethyl-N-n-butylaminomethyl)-1-pyrrolidinyl, 3-methylaminomethyl-4-methyl-1-pyrrolidinyl, 3-methylaminomethyl-4-fluoro-1 -pyrrolidinyl, 3-
Methylamino-4-methyl-1-pyrrolidinyl, 3-methylamino-4-chloro-1-pyrrolidinyl, 3-methylaminomethyl-4-chloro-1-pyrrolidinyl, 3-
Methylamino-4-fluoro-1-pyrrolidinyl, 3-
ethylaminomethyl-4-ethyl-1-pyrrolidinyl,
4-propylaminomethyl-2-propyl-1-pyrrolidinyl, 4-n-butylaminomethyl-2-fluoro-
1-pyrrolidinyl, 4-pentylaminomethyl-2-n
-butyl-1-pyrrolidinyl, 4-hexylaminomethyl-2-chloro-1-pyrrolidinyl, 4-propylamino-2-chloro-1-pyrrolidinyl, 4-n-butylamino-2-hexyl-1-pyrrolidinyl, 3-pentylamino-4-ethyl-1-pyrrolidinyl, 3-hexylamino-4-fluoro-1-pyrrolidinyl, 4-methyl-1-homopiperazinyl, 4-ethyl-1-homopiperazinyl, 4-propyl-1-homopiperazinyl, 4-n
-butyl-1-homopiperazinyl, 4-pentyl-1-
Homopiperazinyl, 4-hexyl-1-homopiperazinyl, 4-formyl-1-homopiperazinyl, 4-acetyl-1-homopiperazinyl, 4-propionyl-1-homopiperazinyl, 4-butyryl-1-homopiperazinyl, 4-pentanoyl-1-homopiperazinyl , 4-hexanoyl-1-homopiperazinyl, 2-methyl-1-hexahydropyridazyl, 2-ethyl-1-hexahydropyridazyl, 2-propyl-1-hexahydropyridazyl, 2- n-butyl-1-hexahydropyridazyl, 2
-Pentyl-1-hexahydrobibadazyl, 2-hexyl-1-hexahydropyridazyl, 2-formyl-1-
Hexahydropyridazyl, 2-acetyl-1-hexahydropyridazyl, 2-propionyl-1-hexahydropyridazyl, 2-butyryl-1-hexahydropyridazyl, 2-pentanoyl-1- hexahydropyridazyl,
2-hexanoyl-1-hexahydropyridazyl, 2-
Methyl-1-pyrazolidinyl, 2-ethyl-1-pyrazolidinyl, 2-propyl-1-pyrazolidinyl, 2-n
-Butyl-1-pyrazolidinyl, 2-pentyl-1-pyrazolidinyl, 2-hexyl-1-pyrazolidinyl, 2
-Formyl-1-pyrazolidinyl, 2-acetyl-1-
Pyrazolidinyl, 2-propionyl-1-pyrazolidinyl, 2-butyryl-1-pyrazolidinyl, 2-pentanoyl-1-pyrazolidinyl, 2-hexanoyl-1-pyrazolidinyl, 3.5-dimethylmorpholino, 3-methylmorpholino, 3-ethylmorpholino , 2-propylmorpholino, 3-n-butylmorpholino, 3-pentyl-
5-methylmorpholino, 3-hexyl-5-ethylmorpholino, 3-aminomethylmorpholino, 3-methylaminomethylmorpholino, 2-ethylaminomethylmorpholino, 3-propylaminomethylmorpholino, 3-n-butylaminomethylmorpholino , 2-pentylaminomethylmorpholino, 3-hexylaminomethylmorpholino,
3-(2-methylaminoethyl)morpholino, 3-(
3-methylaminopropyl)morpholino, 3-(4-methylaminobutyl)morpholino, 2-(5-methylaminopentyl)morpholino, 3-(6-methylaminohexyl)morpholino, 4-(5-methyl-2- Oxo-1
,3-dioxolen-4-yl)methyl-1-piperazinyl, 4(5-1erl-butyl-2-oxo-1
,3-dioxolen-4-yl)methyl-1-piperazinyl, 4-(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl, 4
-(2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl, 3-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylamino-
1-pyrrolidinyl, 4-(5-methyl-2-oxo-
1,3-dioxolen-4-yl)methylamino-1-
piperidinyl, 3-(5-phenyl-2-oxo-1
, 3-dioxolen-4-yl) methylaminomorpholino, 3.5-dimethyl-1-piperazinyl, 3.3-dimethyl-1-piperazinyl, 4-acetyl-3-methyl-1-piperazinyl, 3-ethyl-1 -piperazinyl,
3-ethyl-4-methyl-1-piperazinyl, 3-trifluoromethyl-1-piperazinyl, 3-fluoromethyl-1-piperazinyl, 3-methylthio-1-piperazinyl, 4-methylthio-1-piperazinyl, 3-ethylthio -1-piperazinyl, 3-methylthiomorpholino,
4-fluoro-1-piperidinyl, 3-fluoro-1-
Piperazinyl, 3-chloro-1-piperazinyl, 3-amino-4-fluoro-1-pyrrolidinyl, 3-amino-
4-hydroxy-1-pyrrolidinyl, 3-amino-4-
Methoxy-1-pyrrolidinyl, 3-amino-4-fluoro-1-piperidinyl, 3-amino-4-hydroxy-
1-piperidinyl, 3-amino-4-methyl-1-pyrrolidinyl, 4-benzyl-3-methyl-1-piperazinyl, 3-fluoromethylmorpholino, 3-chloromethylmorpholino, 4-oxo-1-piperidinyl, 3- Oxo-1-piperidinyl, 2-oxo-1-piperidinyl, 3-acetylaminomethyl-1-pyrrolidinyl, 3-
(N-ethyl-N-acetylamino)methyl-1-pyrrolidinyl, 3-t-butoxycarbonylaminomethyl-
1-pyrrolidinyl, 3-ethylaminomethyl-1-pyrrolidinyl, 4-cyclopropylamino-1-piperazinyl, 3-cyclopropylamino-1-pyrrolidinyl, 4
-Cyclopentylamino-1-piperazinyl, 4-cyclohexylamino-1-piperazinyl, 3-cyclohebutylamino-1-pyrrolidinyl, 4-cyclooctylamino-1-piperidinyl, 4-cyclobropylamino-
1-piperidinyl, 3-cyclopropylaminomorpholino, 4-thio-1-piperidinyl, 3-thio-1-piperazinyl, 3-thiomorpholino, 4-cyclopropylaminomethyl-1-piperazinyl, 3-cyclopropylaminomethyl- 1-pyrrolidinyl, 4-cyclopropylaminomethyl-1-piperidinyl, 3-cyclopropylaminomethylmorpholino, 4-(2-cyclopentylaminoethyl)-1-piperazinyl, 4-(3-cyclohexylaminopropyl)-1 -piperazinyl, 3-(
4-cyclobutylaminobutyl)-1-pyrrolidinyl,
4-(5-cyclooctylaminopentyl)-1-piperidinyl, 4-(6-cyclopropylaminohexyl)
Morpholino, 3-acetylaminomethyl-1-pyrrolidinyl, 4-(2-propionylaminoethyl)-1-
Piperazinyl, 4-(3-butyrylaminopropyl)
-1-piperidinyl, 3-(4-pentanoylaminobutyl)morpholino, 4-(5-hexanoylaminopentyl)-1-piperazinyl, 3-(6-acetylaminohexyl)=1-pyrrolidinyl, 4-(N -acetyl-N-ethylamino)methyl-1-piperazinyl, 4
-(N-cyclopropyl-N-acetylamino)methyl-1-pyrrolidinyl, 4-methoxycarbonylaminomethyl-1-piperazinyl, 4- (2-ethoxycarbonylaminoethyl)-1-piperidinyl, 3- (3-
propoxycarbonylaminopropyl) morpholino, 3
-(4-pentyloxycarbonylaminobutyl)-1
-pyrrolidinyl, 3-(5-hexyloxycarbonylaminopentyl)-1-pyrrolidinyl, 4-(6-t-
butoxycarbonylaminohexyl)-1-piperazinyl, 3-(N-t-butoxycarbonyl-N-ethylaminomethyl)-1-pyrrolidinyl, 3-(N-t-butoxycarbonyl-N-methylaminomethyl)-1- Pyrrolidinyl, 3-(N-t-butoxycarbonyl-N-cyclopropylaminomethyl)-1-pyrrolidinyl, 4-
(N-methoxycarbonyl-N-cyclopropylaminomethyl)-1-piperazinyl, 4-(N-propoxycarbonyl-N-cyclohexylaminomethyl)-1-piperidinyl, etc. as a substituent having 1 to 6 carbon atoms. Having a straight or branched alkyl group, a cycloalkyl group having 3 to 8 carbon atoms, a straight or branched alkoxy group having 1 to 6 carbon atoms, a nitro group, or an amino group as a substituent on the phenyl ring. A phenylalkyl group which is a linear or branched alkyl group in which the alkyl moiety has 1 to 6 carbon atoms, a halogen atom as a substituent on the phenyl ring, or 1 to 3 halogen atoms.
Phenyl group, pyridyl, which may have a straight chain or branched alkyl group having 1 to 6 carbon atoms, a hydroxyl group as a substituent, a straight chain or branched alkyl group having 1 to 6 carbon atoms , a linear or branched alkanoyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a cycloalkyl group having 1 to 8 carbon atoms
6 straight or branched alkoxycarbonyl groups from 1 to 2
an amino group, a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, a straight-chain or branched alkyl group having 1 to 3 halogen atoms, a straight-chain or branched alkyl group having 1 to 3 halogen atoms; Straight chain or branched alkynyl group with 2 to 6 carbon atoms, straight chain or branched alkanoyl group with 1 to 6 carbon atoms, which may have 1 to 7 halogen atoms, a halogen atom or a carboxy group as a substituent Straight chain or branched alkenylcarbonyl group having 1 to 3 carbon atoms, straight chain or branched chain alkenylcarbonyl group having 1 to 6 carbon atoms, straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms, 1 to 6 carbon atoms
An aminocarbonyl group that may have 1 to 2 straight-chain or branched alkyl groups, the alkoxy moiety having 1 carbon number
~6 linear or branched alkoxy group, phenylalkoxycarbonyl group, and the alkoxy moiety has 1 to 6 carbon atoms, as a substituent, a phenylalkoxycarbonyl group, which is a linear or branched alkoxy group. A straight or branched aminoalkanoyl group having 2 to 6 carbon atoms,
An alkoxycarbonylalkyl group, which is a linear or branched alkoxy and alkyl group in which the alkoxy moiety and the alkyl moiety have 1 to 6 carbon atoms, and the alkyl moiety has 1 carbon atom.
A carboxyalkyl group that is a linear or branched alkyl group with ~6 carbon atoms, an anilinocarbonyl alkyl group that is a linear or branched alkyl group with 1 to 6 carbon atoms in the alkyl moiety, and a carbon number as a substituent. Straight chain or branched alkyl group having 1 to 6 carbon atoms, phenylalkyl group whose alkyl moiety is a straight chain or branched alkyl group having 1 to 6 carbon atoms, straight chain or branched chain having 1 to 6 carbon atoms alkoxycarbonyl group or carbon number 1
1 to 3 amino groups, hydroxyl groups, and halogen atoms that may have 1 to 2 linear or branched alkanoyl groups of ~6
A linear or branched alkylsulfonyl group having 1 to 6 carbon atoms, a phthalide group, a 2 (5H)-furanone group that may have 1 to 2 halogen atoms as a substituent, carbon of the alkyl moiety Sulfoalkyl group which is a straight chain or branched alkyl group having 1 to 6 carbon atoms, oxo group, straight chain or branched alkoxy group having 1 to 6 carbon atoms, 2 to 6 carbon atoms
Straight chain or branched alkenyl group, halogen atom, straight chain or branched alkanoyloxy group having 2 to 6 carbon atoms, cycloalkylamino group having 3 to 8 carbon atoms, straight chain having 1 to 6 carbon atoms or a branched alkylthio group, a thio group, or a 2-oxo-1,3-dioxolenemethyl group which may have a phenyl group or a straight or branched alkyl group having 1 to 6 carbon atoms as a substituent. and 1 to 3 groups selected from 2-oxo-1,3-dioxolenemethylamino groups which may have a phenyl group or a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent. Examples include 5- to 9-membered saturated or unsaturated heterocyclic residues that may be present.

In addition, as a 5- to 9-membered saturated or unsaturated heterocyclic residue that may have a substituent, a kyl group, Rh is a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a phenyl lower alkyl group, or a lower alkyl group. A 2-oxo-1,3-dioxolenemethyl group having as a substituent, Rc is a hydrogen atom, a hydrogen atom, or a lower alkyl group, and R is a hydrogen atom, a lower alkyl group, or a lower alkoxycarbonyl group as a substituent. or an amino lower alkyl group which may have one or two lower alkyl groups or lower alkoxycarbonyl groups as an amino group or a substituent of the amino group, R'' represents a hydrogen atom or a lower alkyl group; Examples include an alkyl group, R+ represents a hydrogen atom, a hydroxyl group, a halogen atom, or an oxo group, and R1 represents a hydrogen atom or a lower alkyl group.

Examples of the cycloalkyl group include cycloalkyl groups having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

Examples of the phenyl lower alkyl group which may have a lower alkoxy group, nitro group, or amino group as a substituent on the phenyl ring include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, and 4-phenyl. Butyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3
-Phenylpropyl, 4-methoxybenzyl, 3-ethoxybenzyl, 2-propoxybenzyl, 4-n-butoxybenzyl, 3-pentyloxybenzyl, 2-hexyloxybenzyl, 4-nitrobenzyl, 3-nitrobenzyl, 4 -aminobenzyl, 2-aminobenzyl,
2-(4-methoxyphenyl)ethyl, 1-(3-ethoxyphenyl)ethyl, 3-(2-propoxyphenyl)propyl, 4-(4-n-butoxyphenyl)butyl, 5-(2-nitrophenyl) Pentyl, 6- (3
-The alkyl moiety may have a linear or branched alkoxy group having 1 to 6 carbon atoms, a nitro group, or an amino group as a substituent on the phenyl ring such as (aminophenyl)hexyl group, and the carbon number of the alkyl moiety is 1 to 6. An example is a phenylalkyl group which is a straight or branched alkyl group.

Examples of the phenyl group that may have a halogen atom or a lower alkyl group that may have 1 to 3 halogen atoms as a substituent on the phenyl ring include phenyl, 4-fluorophenyl, 3-bromophenyl, 2-chlorophenyl, 4-iodophenyl, 4-methylphenyl, 3-ethylphenyl, 2-propylphenyl, 4-n-butylphenyl, 3-pentylphenyl, 2-hexylphenyl, 4-trifluoromethylphenyl, 3- (2- chloroethyl)phenyl/L/, 2-(3,3-')10moprovir)phenyl, 4-(4-chlorobutyl)phenyl, 3-(5-iodopentyl)phenyl, 4-(6-
Halogen atom, halogen atom as a substituent on the phenyl ring such as fluorohexyl)phenyl, 2-(1,2,2-trifluoroethyl)phenyl, 4-(2,2,2-)lifluoroethyl)phenyl group An example is a phenyl group which may have a linear or branched alkyl group having 1 to 6 carbon atoms and which may have 1 to 3 carbon atoms.

Examples of the amino group, lower alkoxy group, or lower alkyl group having 1 to 3 halogen atoms that may have a hydroxyl group, lower alkyl group, lower alkanoyl group, cycloalkyl group, or lower alkoxycarbonyl group as a substituent include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 3-chloropropyl, bromomethyl, 2-fluoroethyl, 4-chlorobutyl, 3-fluoropentyl , 2,3-dichlorohexyl, 2. 2゜2-trifluoroethyl, trifluoromethyl, aminomethyl, 2-
Aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 3-dimethylaminopropyl, 2-ethylaminoethyl, 4-propylaminobutyl, 5-n- Butylaminopentyl, 6-pentylaminohexyl, methylaminomethyl, diethylaminomethyl, 2-dipropylaminoethyl, 1-di-n-butylaminoethyl, 3
-diethylaminomethyl, 4-diethylaminomethyl,
N-methyl-N-ethylaminomethyl, N-methyl-N
-propylaminomethyl, methoxymethyl, ethoxymethyl, 2-propoxyethyl, 3-butoxypropyl,
4-pentyloxybutyl, 5-hexyloxypentyl, 6-medoxyhexyl, propoxymethyl, 1-ethoxyethyl, 2-hexyloxyethyl, formylaminomethyl, acetylaminomethyl, 2-propanoylaminoethyl, 3 -butyrylaminopropyl, 4-pentanoylaminobutyl, 5-hexanoylaminopentyl, 6-acetylaminohexyl, propanoylaminomethyl, 1-acetylaminoethyl, 2-hexanoylaminoethyl, N-acetyl-N- Methylaminomethyl, N-acetyl-N-ethylaminomethyl, N-acetyl-N-cyclopropylaminomethyl, N,N-dicyclopropylaminomethyl, cyclopropylaminomethyl, 2-cyclobutylaminoethyl, 3-cyclopentyl Aminopropyl, 1-cyclopropylaminoethyl, 2
-cyclopropylaminoethyl, aminopropyl, 4-
Cyclohexylaminobutyl, 5-cyclohebutylaminopentyl, 6-cyclooctylaminohexyl, N-
Methyl-N-cyclopropylaminomethyl, N-ethyl-N-cyclopropylaminomethyl, methoxycarbonylaminomethyl, 2-ethoxycarbonylaminoethyl, 3-propoxycarbonylaminopropyl, 4-t-
Butoxycarbonylaminobutyl, 5-pentyloxycarbonylaminopentyl, 6-hexyloxycarbonylaminohexyl, t-butoxycarbonylaminomethyl, 2-t-butoxycarbonylaminoethyl, 1-
Substitution of t-butoxycarbonylaminoethyl, N-t-butoxycarbonyl-N-methylaminomethyl, N-t-butoxycarbonyl-N-ethylaminomethyl, N-t-butoxycarbonyl-N-cyclopropylaminomethyl group, etc. As a group, a hydroxyl group, a straight chain or branched alkyl group having 1 to 6 carbon atoms, a straight chain or branched alkanoyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a cycloalkyl group having 1 to 6 carbon atoms. An amino group that may have 1 to 2 straight chain or branched alkoxycarbonyl groups of 6 carbon atoms, a straight chain or branched alkoxy group having 1 to 6 carbon atoms, or 1 to 3 halogen atoms.
Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms.

Lower alkanoyl groups that may have 1 to 7 halogen atoms include formyl, acetyl, propionyl,
Butyryl, pentanoyl, hexanoyl, α, α, α-
Trifluoroacetyl, β.

β, β-trifluoro α, α-difluoropropionyl, γ, γ, γ-trifluoro β, β-difluoro α, α-difluorobutyryl, α.

α-Dichloroacetyl, α-bromoacetyl, α-iodoacetyl, β-fluoropropionyl, β-fluoro-α-fluoropropionyl, 6-fluorohexanoyl, 4-chloropentanoyl, 3.3.3-1 Lifluoro Examples include straight chain or branched alkanoyl groups having 1 to 6 carbon atoms, which may have 1 to 7 halogen atoms, such as propionyl groups.

Examples of lower alkenylcarbonyl groups having 1 to 3 halogen atoms or carboxyl groups as substituents include 3-carboxyacryloyl, 3-carboxy-2,3-dichloroacryloyl, 3-carboxy-2,3-dibromoacryloyl, 4 -Carboxycrotonoyl, 4-carboxyisocrotonoyl, 5-carboxy-3-pentenoyl, 6-carboxy-4-hexenoyl, 4-carboxy-3-fluorocrotonoyl, 5-carboxy-3
, 4-dichloro-3-hexenoyl, etc. having 1 to 3 halogen atoms or carboxy groups as substituents and having 2 carbon atoms
-6 linear or branched alkenylcarbonyl groups can be exemplified.

Examples of lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, 1er
l-butoxycarbonyl, pentyloxycarbonyl,
Examples include linear or branched alkoxycarbonyl groups having 1 to 6 carbon atoms such as hexyloxycarbonyl groups.

Aminocarbonyl groups that may have a lower alkyl group include carbamoyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, n
-butylaminocarbonyl, pentylaminocarbonyl, hexylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, diethylaminocarbonyl, diethylaminocarbonyl, N-methyl-N-propylaminocarbonyl, N-methyl-N-tert-butyl Examples include aminocarbonyl groups that may have 1 to 2 straight or branched alkyl groups having 1 to 6 carbon atoms, such as aminocarbonyl and N-ethyl-N-pentylaminocarbonyl groups.

Examples of the phenyl lower alkoxycarbonyl group include benzyloxycarbonyl, 2-phenylethoxycarbonyl, 1-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl,
1.1-dimethyl-2-phenylethoxycarbonyl,
5-phenylpentyloxycarbonyl, 6-phenylhexyloxycarbonyl, 2-methyl-3-phenylpropoxycarbonyl group, etc. with a carbon number of 1 in the alkoxy moiety
A phenylalkoxycarbonyl group which is a linear or branched alkoxy group of 6 to 6 can be exemplified.

As the amino lower alkanoyl group which may have a phenyl lower alkoxycarbonyl group as a substituent, 2
-Aminoacetyl, 3-aminopropionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 2-benzyloxycarbonylaminoacetyl, 2- (2-phenylethoxycarbonylamino)
Acetyl, 2-(-3-phenylpropoxycarbonylamino)acetyl, 3-(4-phenylbutoxycarbonylamino)propionyl, 4-(1,1-dimethyl-2-phenylethoxycarbonylamino)butyryl, 5-(5- As a substituent for phenylpentyloxycarbonylamino)pentanoyl, 6-(6-phenylhexyloxycarbonylamino)hexanoyl, 2-(2-methyl-3-phenylpropoxycarbonylamino)acetyl group, etc., the number of carbon atoms in the alkoxy moiety is 1. Examples include straight-chain or branched aminoalkanoyl groups having 2 to 6 carbon atoms that may have a phenylalkoxycarbonyl group that is a straight-chain or branched alkoxy group having 6 to 6 carbon atoms.

Examples of the lower alkoxycarbonylalkyl group include methoxycarbonylmethyl, ethoxycarbonylmethyl, 2-
Ethoxycarbonylethyl, 3-propoxycarbonylpropyl, 4-butoxycarbonylbutyl, 5-pentyloxycarbonylpentyl, 6-hexyloxycarbonylhexyl, 2-methoxycarbonylethyl, 3-
Examples include alkoxycarbonylalkyl groups, which are linear or branched alkoxy and alkyl groups having 1 to 6 carbon atoms, such as methoxycarbonylpropyl, 3-ethoxycarbonylpropyl, and 4-ethoxycarbonylbutyl groups.

Examples of carboxy lower alkyl groups include carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4
-Carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, 1-carboxyethyl, 1,1-dimethyl-2-carboxyethyl, 2-methyl-3-carboxypropyl, etc. with 1 to 6 carbon atoms in the alkyl group, etc. Examples include carboxyalkyl groups that are straight-chain or branched-chain alkyl groups.

Examples of the anilinocarbonyl lower alkyl group include anilinocarbonylmethyl, 2-anilinocarbonylethyl, 1
-anilinocarbonylethyl, 3-anilinocarbonylpropyl, 4-anilinocarbonylbutyl, 5-anilinocarbonylbentyl, 6-anilinocarbonylhexyl, 1,1-dimethyl-2-anilinocarbonylethyl, Examples include anilinocarbonylalkyl groups, which are linear or branched alkyl groups having 1 to 6 carbon atoms in the alkyl moiety, such as 2-methyl-3-anilinocarbonylpropyl groups.

Examples of amino groups that may have a lower alkyl group, lower alkanoyl group, lower alkoxycarbonyl group, or phenyl lower alkyl group as a substituent include amino, methylamino, ethylamino, propylamino, t-butylamino, pentylamino, and hexyl. Amino, dimethylamino, diethylamino, di-n-propylamino, di-n
-butylamino, diethylamino, diethylamino, N
-Methyl-N-n-butylamino, N-methyl-N-pentylamino, N-ethyl-N-hexylamino, acetylamino, formylamino, propionylamino, butyrylamino, pentanoylamino, hexanoylamino, N-methyl -N-acetylamino, N-ethyl-N
-propionylamino, N-methyl-N-butyrylamino, N-n-propyl-N-pentanoylamino, N-
Ethyl-N-hexanoylamino, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, t-butoxycarbonylamino, pentyloxycarbonylamino, hexyloxycarbonylamino, butoxycarbonylamino, N-t-butoxycarbonyl-N-methyl Amino, N-t-butoxycarbonyl-N-ethylamino, N-t-butoxycarbonyl-N-benzylamino, benzylamino, (2-phenylethyl)amino, (1-phenylethyl)amino, (
Substituents such as 3-phenylpropyl)amino, (4-phenylbutyl)amino, (5-phenylpentyl)amino, and (6-phenylhexyl)amino groups have 1 to 1 carbon atoms.
6 straight chain or branched alkyl group, straight chain or branched alkanoyl group having 1 to 6 carbon atoms, straight chain or branched alkoxycarbonyl group having 1 to 6 carbon atoms, or number of carbon atoms in the alkyl moiety Examples include amino groups that may have 1 to 2 phenylalkyl groups, which are 1 to 6 linear or branched alkyl groups.

Examples of the 2(5H) furanone group which may have 1 to 2 halogen atoms as a substituent include 2(5H)-furanone-5-yl, 3,4-dibromo-2(3H)-furanone-5-yl, , 3,4-dichloro-2(5H)-furanone-5-yl, 3-chloro-2(5H)-furanone-5
-yl, 4-fluoro-2(5H)-furanon-5-yl, 3-iodo-2(3H)furanon-5-yl, etc. may have 1 to 2 halogen atoms as a substituent.
An example is a (5H)-furanone group.

Sulfo lower alkyl groups include sulfomethyl, 2-sulfoethyl, 1-sulfoethyl, 3-sulfopropyl,
Straight chain or branched chain having 1 to 6 carbon atoms in the alkyl moiety such as 4-sulfobutyl, 5-sulfopentyl, 6-sulfohexyl, 1,1-dimethyl-2-sulfoethyl, 2-methyl-3-sulfopropyl group, etc. Examples include sulfoalkyl groups, which are alkyl groups.

Lower alkylsulfonyl groups that may have 1 to 3 halogen atoms include methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, -Fluoropropylsulfonyl, 4.4.4-1
halogen atoms such as lifluorobutylsulfonyl, 5-chloropentylsulfonyl, 6-bromohexylsulfonyl, 6-iodohexylsulfonyl, 2.2-difluoroethylsulfonyl, 2.3-, 'bromopropylsulfonyl groups, etc. Examples include straight-chain or branched alkylsulfonyl groups having 1 to 6 carbon atoms, which may have 3 alkylsulfonyl groups.

Examples of lower alkoxy groups include those having 1 to 1 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy groups.
6, a straight chain or branched alkoxy group can be exemplified.

Examples of lower alkanoyloxy groups include acetyloxy,
Examples include straight-chain or branched alkanoyloxy groups having 2 to 6 carbon atoms, such as propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, and hexanoyloxy groups.

Examples of lower alkenyl groups include linear or branched alkenyl groups having 2 to 6 carbon atoms such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, and 2-hexenyl groups. can.

Examples of lower alkynyl groups include straight chain or branched carbon atoms having 2 to 6 carbon atoms such as ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, and 2-hexynyl groups. An example is a chain alkynyl group.

The 2-oxo-1,3-dioxolenemethyl group that may have a phenyl group or lower alkyl group as a substituent includes (5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl , (5-1erf-butyl-2
-oxo-1,3-dioxolen-4-yl)methyl,
(5-phenyl-2-oxo-1,3-dioxolene-
4-yl)methyl, (2-oxo-1,3-dioxolen-4-yl)methyl, (5-pentyl-2-oxo-
1,3-dioxolen-4-yl)methyl, (5-hexyl-2-oxo-1,3-dioxolen-4-yl)
Phenyl as a substituent of methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl group, etc. 2-oxo-1,3- which may have a straight-chain or branched alkyl group having 1 to 6 carbon atoms
An example is dioxolenemethyl group.

The 2-oxo-1,3-dioxolenemethylamino group that may have a phenyl group or lower alkyl group as a substituent includes (5-methyl-2-oxo-1,3-dioxolene-4-yl) Methylamino, (5-tert
-butyl-2-oxo-1,3-dioxolen-4-yl)methylamino, (5-phenyl-2-oxo1
．． 3-Dioxolen-4-yl)methylamino, (2-
oxo-1,3-dioxolen-4-yl)methylamino, (5-pentyl-2-oxo-1,3-dioxolen-4-yl)methylamino, (5-hexyl-2-oxo-1,3 -dioxolene-4-yl)methylamino, (5-ethyl-2-oxo-1゜3-dioxolene-
4-yl)methylamino, (5-propyl-2-oxo-1,3-dioxolen-4-yl)methylamino group, etc., as a substituent such as a phenyl group or a linear or branched chain having 1 to 6 carbon atoms. 2-oxo-1 which may have an alkyl group
An example is 3-dioxolenemethylamino group.

Examples of the cycloalkylamino group include cycloalkylamino groups having 3 to 8 carbon atoms, such as cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cyclohebutylamino, and cyclooctylamino groups.

Lower alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, te
Examples include straight-chain or branched alkylthio groups having 1 to 6 carbon atoms, such as rt-butylthio, pentylthio, and hexylthio groups.

Examples of phenyl groups that may have 1 to 3 groups selected from the group consisting of lower alkoxy groups, halogen atoms, and hydroxyl groups as substituents on the phenyl ring include phenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 2- Propoxyphenyl, 4-n-butoxyphenyl, 3-pentyloxyphenyl, 2-hexyloxyphenyl, 3,4-
Dimethoxyphenyl, 2,4.6-)dimethoxyphenyl, 2-fluorophenyl, 4-fluorophenyl, 3
-10lophenyl, 4-chlorophenyl, 4-promophenyl, 2-iodophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 2,4-dichlorophenyl , 2°6-dibromophenyl, 2.4.
6-Drifluorofueni/Iz, 3. 4. 6-Dolichlorophenyl, 4-fluoro-2-methoxyphenyl, 2-fluoro-4-hydroxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,3-dihydroxyphenyl, 2.4-
A substituent having 1 to 6 carbon atoms on the phenyl ring such as dihydroxyphenyl or 2,4.6-doryhydroxyphenyl group.
An example is a phenyl group which may have 1 to 3 groups selected from the group consisting of a linear or branched alkoxy group, a halogen atom, and a hydroxyl group.

Examples of the lower alkyl group that may have a halogen atom, lower alkanoyloxy group, or hydroxyl group as a substituent include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-
Hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 3-chloropropyl, bromomethyl, 2-fluoroethyl, 4-chlorobutyl, 3-fluoropentyl, 2.3-dichlorohexyl, 2.2. 2-) Lifluoroethyl, trifluoromethyl, acetyloxymethyl, 2-propanoyloxyethyl, 3-butyryloxypropyl, 4-pentanoyloxybutyl, 5-hexanoyloxypentyl, 6-acetyloxyhexyl, propane A halogen atom, a linear or branched alkanoyloxy group having 1 to 6 carbon atoms, or a hydroxyl group as a substituent for noyloxymethyl, 1-acetyloxyethyl, 2-acetyloxyethyl, 2-hexanoyloxyethyl, etc. Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms, which may have 1 to 3 carbon atoms.

The compound of the present invention represented by the above general formula (1) can be produced by various methods, and one preferred example thereof is produced by the method shown below.

[Reaction formula-1] 4 (2) 4 (3) 3 (5) (7) R3 (9) 1 (1a) 1 (la') In formula C, R1, R2, R3, R4 and X are the same as above . R
2/ is a halogen atom or R2 (R2 is the same as above)
shows. R5 represents a group -CORI O (here, RIO represents a lower alkyl group) or a group -COORI + (here, R1+ represents a lower alkyl group). R6 represents a lower alkyl R12 group. R7 is a group -N, (where 13 R12 and RI3 each represent a lower alkyl group.)
Or it represents a lower alkoxy group. X2 and X3 each represent a halogen atom. R8 and R9 each represent a lower alkyl group. ] The halogenation reaction of the compound of general formula (2) is carried out by reacting it with a halogenating agent in the presence or absence of a suitable solvent. Solvents used here include aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride, ethers such as dioxane, tetrahydrofuran, and diethyl ether, and dimethylformamide. (DMF), dimethyl sulfoxide (DMF)
SO), etc. As the halogenating agent, common halogenating agents that can convert the hydroxyl group of a carboxy group into a halogen can be used, such as thionyl chloride, phosphorus oxychloride,
Examples include phosphorus oxybromide, phosphorus pentachloride, and phosphorus pentabromide. The ratio of compound (2) and halogenating agent to be used is not particularly limited and is appropriately selected from a wide range, but when the reaction is carried out without a solvent, the latter is usually used in a large excess of the former. Further, when the reaction is carried out in a solvent, the latter is usually used in at least an equimolar amount, preferably 2 to 4 times the molar amount of the former. The reaction temperature and reaction time are also not particularly limited, but are usually carried out at room temperature to about 100°C for about 30 minutes to 6 hours.

The reaction between the compound of general formula (3) and the compound of general formula (4) is carried out in a suitable solvent in the presence of a basic compound.

As the solvent used here, any solvent can be used as long as it does not affect the reaction, such as water, ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, methanol, ethanol, isopropanol, etc. alcohols such as benzene, toluene, xylene, etc., aliphatic hydrocarbons such as n-hexane, heptane, cyclohexane, ligroin, amines such as pyridine, N,N-dimethylaniline, chloroform, Examples include halogenated hydrocarbons such as dichloromethane and carbon tetrachloride, aprotic polar solvents such as DMF, DMSO, and hexamethylphosphoric acid triamide (HMPA), and mixed solvents thereof. Basic compounds used include metallic sodium,
Metal potassium, metal magnesium, sodium hydride,
Inorganic bases such as sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, metal alcoholades such as sodium methylate, sodium ethylate, pyridine, piperidine, quinoline, triethylamine, N, N- Examples include organic bases such as dimethylaniline. The reaction temperature is usually O
The temperature is preferably around 00C to 120C, and the reaction is generally completed in about 0.5 to 20 hours. The amount of the compound of general formula (4) to be used relative to the compound of general formula (3) is usually at least an equimolar amount of the latter to the former, preferably an equimolar to twice the molar amount of the latter. The amount of the basic compound to be used is at least equimolar, preferably equimolar -2 to the compound of general formula (3).
It is better to double the molar amount.

In the compound of general formula (5), when R5 is a group -CORIO, the removal of CORIO from the compound
The reaction is carried out in a suitable solvent in the presence of a basic compound. Examples of the solvent used here include ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, benzene, toluene,
Aromatic hydrocarbons such as xylene, aliphatic hydrocarbons such as n-hexane, heptane, cyclohexane, DMF.

Examples include aprotic polar solvents such as DMSO and HMPA. Basic compounds include ammonia gas, aqueous ammonia, ammonium salts such as ammonium chloride, primary or secondary compounds such as ethylamine, diethylamine, and piperidine.
Examples include grade amines. The reaction temperature is usually 0 to 150
℃, preferably around room temperature to 100℃, and the reaction is generally completed in about 1 to 20 hours.

In the compound of general formula (5), when R5 is a group -COORI +, the removal of COORI of the compound
The I-formation reaction is carried out in an aqueous solution in the presence of an acid catalyst.

Examples of the acid catalyst used here include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as p-toluenesulfonic acid. The reaction temperature is usually 0 to 150°C, preferably room temperature to around 100°C, and the reaction is generally 1 to 2
It ends in about 0 hours.

The reaction between the resulting R5-depleted compound and the compound of general formula (6) is carried out by reacting both in an appropriate solvent. As the solvent used here, in addition to the lower alkanoic anhydride such as acetic anhydride, the
Any of those used in the reaction of pentaminization can be used. The reaction temperature is usually 0 to 200°C, preferably 0 to 150°C.
The reaction is generally completed in about 0.5 to 10 hours. The amount of the compound of general formula (6) to be used is usually equimolar to a large excess, preferably equimolar to twice the molar amount of the compound of general formula (5). When using a compound of general formula (6) in which R7 is a lower alkoxy group, in addition to the above-mentioned solvents, an acid anhydride such as acetic anhydride can be used as a solvent, and the reaction temperature is usually O~
The temperature is preferably around 200°C, preferably 0 to 170°C.

The reaction between the compound of general formula (7) and the compound of general formula (8) is carried out by reacting the two in a suitable solvent. As the solvent used here, any solvent can be used as long as it does not affect the reaction, such as alcohols such as methanol, ethanol, propatool, etc., ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc. , aromatic hydrocarbons such as benzene, toluene, xylene, aliphatic hydrocarbons such as n-hexane, heptane, cyclohexane, ligroin, halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, DMF, DMSOlHMPA
Examples include aprotic polar solvents such as. The reaction temperature is usually 0 to 150°C, preferably around room temperature to 100°C, and the reaction is generally completed in about 0.1 to 15 hours.

The amount of the compound of general formula (8) to be used is as follows:
The amount should be at least equimolar, preferably equimolar to twice the molar amount of the compound. A basic compound may be added to the reaction if desired.

As the basic compound used, any of the basic compounds used in the reaction between the compound of general formula (3) and the compound of general formula (4) in Reaction Formula-1 can be used.

The cyclization reaction of the compound of general formula (9) is carried out in a suitable solvent in the presence of a basic compound. As the solvent used here, any solvent can be used as long as it does not affect the reaction, such as ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, and diglyme, and fatty acids such as n-hexane, heptane, and ligroin. group hydrocarbons, halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, DMF, DMSO.

Examples include aprotic polar solvents such as HMPA. Basic compounds used include metallic sodium,
Metallic potassium, sodium hydride, sodium amide,
Sodium hydroxide, potassium hydroxide, sodium carbonate,
Inorganic bases such as potassium carbonate, metal alcoholades such as sodium methylate, sodium ethylate, 1.8-
Diazabicyclo(5,4,0) undecene-7 (DBU
), N-benzyltrimethylammonium hydroxide, tetrabutylammonium hydroxide, and other organic bases. The reaction temperature is usually 0 to 200
℃, preferably around room temperature to 150°C, and the reaction is generally completed in about 0.5 to 15 hours. The amount of the basic compound to be used is usually a small amount (equimolar, preferably equimolar to twice the molar amount of the compound of general formula (9)).

For the hydrolysis reaction of the compound of general formula (1a), any usual hydrolysis reaction conditions can be applied, and specifically, for example, basic hydrolysis such as sodium hydroxide, potassium hydroxide, barium hydroxide, potassium carbonate, In the presence of compounds, mineral acids such as sulfuric acid, hydrochloric acid, and nitric acid, organic acids such as acetic acid and aromatic sulfonic acids, water, alcohols such as methanol, ethanol, and isopropanol, ketones such as acetone and methyl ethyl ketone, and dioxane. , ethers such as ethylene glycol diethyl ether, solvents such as acetic acid, or mixed solvents thereof. The reaction is usually carried out at room temperature to 200°C.
, preferably at room temperature to around 150°C, and generally at 0.
It will be completed in about 61 to 30 hours. Thus, the general formula (l
Compound a') is produced.

[Reaction formula-2] I (1b) [In the formula, R1, R2, R3, R4 and X are the same as above. x
4 represents a halogen atom. R14 represents hydrogen and RI6 represents an alkyl group. )] In the reaction between the compound of general formula (1b) and the compound of general formula (11), the ratio of the two used is not particularly limited and can be appropriately selected from a wide range, but usually the latter is at least equimolar to the former. It is preferable to use about equimolar to 5 times the molar amount. The reaction is carried out in an inert solvent, specifically water,
Alcohols such as methanol, ethanol, isopropanol, butanol, amyl alcohol, isoamyl alcohol, aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as tetrahydrofuran, dioxane, diglyme, dimethylacetamide, DMF ,D
The reaction is carried out in a solvent such as MSO, HMPA, N-methylpyrrolidone, etc. or a mixed solvent thereof. Among these, DMF, DM
SO, HMPA and N-methylpyrrolidone are preferred.

The reaction can also be carried out in the presence of a deoxidizer, specifically inorganic carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and organic bases such as pyridine, quinoline, triethylamine. Further, an alkali metal halide such as potassium fluoride may be added. The reaction is usually carried out under a pressure of 1 to 20 atm, preferably 1 to 10 atm, and at room temperature to about 250°C, preferably room temperature to 250°C.
The process is carried out at a temperature of 00°C and is generally completed in about 10 minutes to 30 hours.

In the general formula (lb'), when RI4 represents a group -BCORI5, an acid or a base 0C
By treatment with an ORI 6 compound, the chelate can be decomposed to lead to the corresponding compound (lb') in which R14 is a hydrogen atom. Examples of acids used here include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid and p-toluenesulfonic acid. Examples of the basic compound include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, and potassium carbonate, and organic bases such as triethylamine. The reaction is carried out at 0 to 150°C
, preferably at around 0 to 100°C. The amount of the acid or basic compound to be used is usually at least equimolar, preferably 1 to 10 times the amount of the raw material compound.

[Reaction formula-3] (IC) (1d) [In the formula, XX R', R3 and R4 are the same as above. One of Z and W represents a -CH2-1 group and the other represents an -NH group. n represents an integer of 1 to 3.

RI7 is a lower alkyl group, a cycloalkyl group, a phenyl lower alkyl group that may have a lower alkoxy group, a nitro group, or an amino group as a substituent on the phenyl ring, a halogen atom, or one halogen atom as a substituent on the phenyl ring. A phenyl group that may have ~3 lower alkyl groups, a pyridyl group, a hydroxyl group as a substituent,
Lower alkyl group, lower alkanoyl group, cycloalkyl group, amino group which may have 1 to 2 lower alkoxycarbonyl groups, lower alkoxy group or lower alkyl group having 1 to 3 halogen atoms, 1 to 1 halogen atom
A lower alkanoyl group that may have 7 substituents, a lower alkenylcarbonyl group that has 1 to 3 halogen atoms or carboxy groups as a substituent, a lower alkoxycarbonyl group, an aminocarbonyl group that may have a lower alkyl group, phenyl lower alkoxycarbonyl amino lower alkanoyl group, lower alkoxycarbonyl lower alkyl group, carboxy lower alkyl group, anilinocarbonyl lower alkyl group, which may have a phenyl lower alkoxycarbonyl group as a substituent, 1 to 3 halogen atoms
Indicates a lower alkylsulfonyl group, a sulfo-lower alkyl group, a lower alkenyl group, or a lower alkynyl group that may be present. X5 represents a halogen atom. One of Z' and W' represents a -CH2-1 group and the other represents an NH+4 group. ] The reaction between the compound of general formula (IC) and the compound of general formula (12) is carried out in a suitable solvent in the presence of a dehydrohalogenating agent. As a solvent, water, methanol, ethanol, lower alcohols such as isopropanol, acetone,
Ketones such as methyl ethyl ketone, diethyl ether,
Ethers such as dioxane, aromatic hydrocarbons such as benzene, toluene, xylene, etc., and dehydrohalogenating agents such as inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. Alkali metals and organic bases such as pyridine and piperidine can be used, respectively. In this reaction, an alkali metal halide compound such as copper powder, copper halide such as iodized steel, sodium iodide, potassium iodide, etc. may be used as necessary. The compound of general formula (12) is usually used in an equimolar to large excess amount, preferably about 1 to 3 molar amounts, relative to the compound of general formula (IC).
Used in twice the molar amount. The reaction is usually completed at room temperature to 150°C, preferably around 50 to 120°C, in about 1 to 12 hours.

[Reaction formula-4] (1C) [In the formula, R1, R3, R4ZlWln and X are the same as above. R+8 and R+9 each represent a hydrogen atom or a lower alkyl group. Either Z' or W' is a group -CH2
-1 The reaction between the compound of general formula (IC) and the compound of general formula (13) on the other hand is carried out without a solvent or in an appropriate solvent in the presence of a reducing agent. Examples of the solvent used here include water, alcohols such as methanol, ethanol, and isopropanol, lower alkanoic acids such as formic acid and acetic acid, ethers such as dioxane, diethyl ether, diglyme, and tetrahydrofuran, benzene, xylene, Examples include aromatic hydrocarbons such as toluene. Reducing agents include formic acid, alkali metal or alkaline earth metal salts of formate such as sodium formate, hydrogen reducing agents such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, palladium black, palladium carbon, and oxidized platinum, platinum black,
Examples include catalytic reducing agents such as Raney nickel. When using formic acid as a reducing agent, the reaction temperature is usually room temperature to 20°C.
A suitable temperature is 0°C, preferably around 50 to 150°C, and the reaction is completed in about 1 to 10 hours. The amount of formic acid to be used is preferably a large excess amount relative to the compound of general formula (1c). Further, when a hydrogenation reducing agent is used, the reaction temperature is usually -30 to 100°C, preferably about 0 to 70°C, and the reaction is completed in about 30 minutes to 12 hours. The amount of the reducing agent to be used is usually equivalent to 20 times, preferably 1 to 6 times, the amount of the compound of general formula (1c). Particularly when lithium aluminum hydride is used as the reducing agent, it is preferable to use ethers such as diethyl ether, dioxane, tetrahydrofuran, and diglyme, and aromatic hydrocarbons such as benzene, toluene, and xylene as the solvent. When using a catalytic reducing agent, it is usually -30 to 100°C in a hydrogen atmosphere at normal pressure to 20 atm, preferably normal pressure to 10 atm.
Preferably, the reaction is carried out at a temperature of 0 to 60°C,
The reaction is usually completed in 1 to 12 hours. The amount of catalyst used is usually 0.1 per compound of general formula (1c).
It is preferable to use 40% by weight, preferably 0.1 to 20% by weight. The amount of the compound of general formula (13) to be used is usually at least equimolar, preferably equimolar to a large excess amount relative to the compound of general formula (IC).

The compound of general formula (2) as a starting material includes a new compound, and the compound is produced, for example, by the method of Reaction Scheme-5 below.

[Reaction formula-5] (14) (14a) 1?4 20 (16) (20) (2a) [
In the formula, X5R2', R4 and x2 are the same as above.

X5 and X6 represent halogen atoms. R20 represents a hydrogen atom or a lower alkyl group. R21 represents a lower alkyl group. Further, R20 and R2+ may be combined with each other to form a 5- to 7-membered ring.

M represents an alkali metal such as sodium or potassium, or a metal such as silver, calcium, or copper. ] In the compound of general formula (16), when R20 and R2+ are bonded to each other to form a 5- to 7-membered ring, R20 in the compound of general formula (20) becomes -R20R21H.

First, the compound of general formula (16) is prepared using an aniline derivative represented by general formula (14) as a starting material, which is first reacted with a halogenating agent, and then the compound represented by general formula (14a) obtained is obtained by adding the general formula It can be obtained by reacting a thio compound represented by (15).

In the above, the reaction between the aniline derivative of general formula (14) and the halogenating agent is usually carried out in a suitable solvent. As the solvent, any of the usual various solvents that do not adversely affect the reaction can be used. Typical examples include halogenated hydrocarbons such as chloroform and methylene chloride, ethers such as dioxane, diethyl ether, and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene, and xylene, methanol, ethanol, isopropanol, etc. lower alcohols, DMSO, HMPA.

Examples include polar solvents such as acetonitrile. Further, as the halogenating agent used in the above reaction, any of various compounds used in ordinary halogenation reactions can be used. Representative examples include N-bromosuccinimide, N-chlorosuccinimide, sodium hypobromite, sodium hypochlorite, mustard powder, thionyl chloride, +er+-butylhypochloride, and the like. The amount of the secondary halogenating agent to be used is usually at least an equimolar amount, preferably about 1 to 6 times the molar amount of the starting material compound.

The reaction temperature is generally from 18°C to room temperature, preferably from 160°C to room temperature.
The temperature is approximately 15°C, and the reaction is completed instantaneously, usually within a few minutes.

In this way, an intermediate represented by general formula (14a) is obtained.

Although this may be taken out from the reaction system and subjected to the subsequent reaction, it is usually subjected to the reaction with the thio compound of general formula (15) without being separated from the reaction system.

The reaction between the intermediate of general formula (14a) and the thio compound of general formula (15) is carried out in the presence of a suitable basic compound, usually in the same solvent as those exemplified above, and under the same temperature conditions. Examples of the basic compounds used include inorganic basic compounds such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, and sodium hydride; and tertiary compounds such as triethylamine, tripropylamine, pyridine, and quinoline. Preferred examples include organic basic compounds such as amines. The amount of the compound of general formula (15) to be used in this reaction is generally at least an equimolar amount, preferably about 1 to 1.5 times the molar amount of the intermediate of general formula (14a). The reaction is usually carried out at room temperature to 150°C, preferably around room temperature to 100°C, at a temperature of about 1 to 100°C.
Completed in 50 hours.

The reaction between the compound of general formula (16) and the compound of general formula (17) is carried out in a suitable solvent in the presence or absence of a basic compound. Examples of solvents used here include water, alcohols such as methanol, ethanol, and isopropanol, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as tetrahydrofuran, dioxane, and diglyme, DMF, and DMSOXHMPA. ,
Examples include polar solvents such as N-methylpyrrolidone, and mixed solvents thereof. Examples of basic compounds include inorganic carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate, organic bases such as pyridine, quinoline, and triethylamine, and phase transfer compounds such as phenyltriethylammonium chloride and tetramethylammonium chloride. Examples include catalysts and the like. General formula (17
The amount of the compound () to be used is usually at least equimolar, preferably equimolar to molar, relative to the compound of general formula (16). The reaction is usually carried out at room temperature
The reaction proceeds suitably at 200°C, preferably around room temperature to 180°C, and is generally completed in about 0.5 to 10 hours.

The desulfurization reaction of the compound of general formula (18) (the reaction for producing the compound of general formula (19)) is usually carried out in a solvent in the presence of a suitable catalyst. Examples of the catalyst include aluminum amalgam, lithium-lower alkylamine, Raney nickel, Raney cobalt, triethyl phosphite, triphenylphosphine, and preferably Raney nickel. Examples of the solvent include alcohols such as methanol, ethanol and isopropanol, and ethers such as dioxane, tetrahydrofuran and diethyl ether. Reaction temperature is approximately O~200℃
, preferably at room temperature to around 100°C, and the reaction takes about 10
It takes about 5 minutes to 5 hours to complete. The amount of catalyst used is determined by the general formula (
It is usually about 1 to 10 times the weight of the compound 18).

The reaction that leads the compound of general formula (19) to the compound of general formula (20) is carried out by reacting it with a nitrite metal salt such as sodium nitrite or potassium nitrite in an appropriate solvent in the presence of an acid. This is carried out by subsequently reacting the product with a metal halide salt such as potassium iodide, cuprous chloride, cuprous bromide, etc., without removing the product. Examples of acids used here include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid.

Solvents used include water, alkanoic acids such as acetic acid, aromatic hydrocarbons such as benzene, toluene, and xylene, alcohols such as methanol, ethanol, and isopropanol, and halogen hydrocarbons such as chloroform, dichloromethane, and dichloroethane. Examples include ethers such as dioxane and tetrahydrofuran, polar solvents such as DMF, DMSO, and HMPA, and mixed solvents thereof. The amounts of the metal nitrite and metal halide used are usually at least equimolar amounts, respectively, relative to the compound of general formula (19);
It is preferable to use an equivalent molar amount of 1.5 times.

The reaction is usually carried out at 0 to 150°C, preferably 0 to 100°C.
The reaction proceeds at around 0.degree. C. and generally ends in about 10 minutes to 5 hours.

The hydrolysis reaction of the compound of general formula (20) can be carried out using a suitable hydrolysis catalyst, such as hydrohalic acids such as hydrochloric acid and hydrobromic acid, inorganic acids such as sulfuric acid and phosphoric acid, sodium hydroxide, potassium hydroxide, etc. Alkali metal hydroxide, sodium carbonate,
In the presence of an inorganic alkali compound such as an alkali metal carbonate or bicarbonate such as potassium carbonate or sodium hydrogen carbonate,
Without a solvent or in an appropriate solvent (e.g., water or a mixed solvent of water and a lower alcohol such as methanol or ethanol)
The reaction is generally carried out at a temperature of 50 to 200°C, preferably 70 to 180°C, and is generally completed in about 1 to 10 hours.

In reaction formula-2, I4 is based on For example, it is produced by the method shown in Reaction Formula-6 below.

[Reaction formula-6] 4 4 1 (1g) [In the formula R1 3 4 1 4 1 as well as 1 is the same as above.

6 represents a lower alkyl group or a hydrogen atom. R14' represents a group -B0CORI5. R22 is lower alkyl 0CO
RI 6 represents a kill group. ] The reaction between the compound of general formula (1f) and the compound of general formula (21) is carried out in a suitable solvent. As the solvent used here, for example, any of the solvents used in the reaction of the R5-removed compound and the compound of general formula (6) in Reaction Formula 1 can be used. The reaction usually proceeds at room temperature to 200°C, preferably around room temperature to 150°C, and is generally completed in about 10 minutes to 5 hours. The amount of the compound of general formula (21) to be used is at least equimolar to the compound of general formula (1f), preferably equimolar - 1 mol.

The compounds of general formula (8) used in Reaction Scheme-1 include some new compounds, and these compounds are produced, for example, by the method shown in Reaction Scheme-7 below.

[Reaction formula-7] (26) (27) [In the formula, X7 represents a halogen atom. R23 represents a phenyl lower alkoxycarbonyl group, R23' represents a phenyl lower alkyl group, and m represents an integer of 1 to 3, respectively. M' represents an alkali metal such as sodium or potassium. M
' represents a hydrogen atom or M'. ] For the reaction of the compound of general formula (22) and the compound of general formula (23), reaction conditions for ordinary amide bond forming reactions can be widely applied. As the amide bond forming reaction, conditions for known amide bond forming reactions can be easily applied. For example, (a) mixed acid anhydride method, that is, a method in which carboxylic acid (22) is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, and this is reacted with azide (23); (b) active ester method, that is, carboxylic acid (22) as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-
A method in which an active ester such as hydroxybenzotriazole ester is reacted with azide (23), and (c) a carbodiimide method, that is, a method in which azide (23) is reacted with a carboxylic acid (22).
23) is condensed in the presence of an activator such as dicyclohexylcarbodiimide or carbonyldiimidazole; (d) Another method is to convert carboxylic acid (22) into a carboxylic acid anhydride using a dehydrating agent such as acetic anhydride; A method in which azide (23) is reacted with this, a method in which azide (23) is reacted with an ester of carboxylic acid (22) and a lower alcohol under high pressure and high temperature, and an acid halide of carboxylic acid (22), that is, a carboxylic acid halide. Examples include a method of reacting azide (23).

The mixed acid anhydride used in the mixed acid anhydride method is obtained by the usual Schotten-Bauman reaction, and the compound of general formula (24) is produced by reacting it with azide (23) without isolation. be done. The Schotten-Baumann reaction is carried out in the presence of a basic compound.

As the basic compound used, compounds commonly used in the Schotten-Baumann reaction are used, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4
,3,0]nonene-5(DBN),1゜8-diazabicyclo[5,4,0)undecene-7(DBU),1
．． 4-Diazabicyclo[2,2°2]octane (DAB
organic bases such as CO), potassium carbonate, sodium carbonate,
Examples include inorganic bases such as potassium hydrogen carbonate and sodium hydrogen carbonate.

The reaction is usually carried out at a temperature of about -20 to 100°C, preferably about O to 100°C.
It is carried out at about 50℃, and the reaction time is usually 5 minutes to 1
0 hours, preferably 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and azide (23) is usually -20 to 1
The reaction is carried out at about 50°C, preferably about 0 to 50°C, and the reaction time is usually 5 minutes to 10 hours, preferably 5 minutes to 50 hours.
It is 5 hours. Mixed anhydride methods are generally carried out in a solvent. Any solvent commonly used in the mixed acid anhydride method can be used as the solvent, and specific examples include water, halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, and aromatic solvents such as benzene, toluene, and xyleph. group hydrocarbons, ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, esters such as methyl acetate and ethyl acetate, ketones such as acetone, DMF, D
M.S.O.

Examples include aprotic polar solvents such as HMPA, mixed solvents thereof, and the like. Examples of the alkylhalocarboxylic acids used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like. The amount of azide (23) to be used is usually at least an equimolar amount, preferably 1.5 times an equimolar amount, relative to the carboxylic acid (22).

Furthermore, when employing a method of reacting azide (23) with a carboxylic acid halide, the reaction is carried out in a suitable solvent in the presence of a basic compound. A wide range of known basic compounds can be used, including, for example, in addition to the basic compounds used in the Schotten-Baumann reaction, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, silver carbonate, and sodium hydroxide. Examples include alcoholades such as methylate and sodium ethylate. In addition to the solvent used in the mixed acid anhydride method described above, examples of the solvent used include methanol, ethanol,
Examples include alcohols such as propatool, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, pyridine, acetone, acetonitrile, and mixed solvents thereof. Azide (23
) and carboxylic acid halide are not particularly limited and may be appropriately selected within a wide range, but usually the latter is at least equimolar to the former, preferably equimolar to equimolar. It is better. The reaction normally proceeds suitably at about -30 to 180°C, preferably about 0 to 150°C, and is generally completed in about 5 minutes to 30 hours. The compound (24) obtained here can also be used in the next reaction without being isolated.

The reaction between the compound of general formula (24) and the compound of general formula (25) is carried out in a suitable solvent or under non-chemical medium, usually at 0 to 150°C.
C1 Preferably, it is carried out at room temperature to around 100°C for 1 to 15 hours. The amount of the compound of general formula (25) to be used is usually at least equimolar, preferably equimolar to molar, relative to the compound of general formula (24).

The reaction for converting the compound of general formula (26) into the compound of general formula (27) is carried out under the same conditions as the dephenyl lower alkyl or dephenyl lower alkoxycarbonylation reaction of the heterocyclic residue of general formula (1). I can do it.

The reaction in which the compound of general formula (22) is directly converted to the compound of general formula (27) is generally called the Schmidt reaction, and the reaction is carried out in a suitable solvent in the presence of an acid. Acids used here include mineral acids such as sulfuric acid and hydrochloric acid;
Examples include phosphorus compounds such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, and phosphorus pentoxide, thionyl chloride, ferric chloride, aluminum chloride, tin chloride, sulfoacetic acid, and phosphoric acid. Examples of the solvent used include aromatic hydrocarbons such as benzene, toluene, and xylene, and halogenated hydrocarbons such as chloroform, dichloromethane, and carbon tetrachloride. The reaction is usually carried out at a temperature of θ to 150°C, preferably around 0 to 100°C, and is completed in about 0.5 to 10 hours. The amount of the compound of general formula (23a) to be used is usually at least an equimolar amount, preferably twice an equimolar amount, relative to the compound of general formula (22).

[Reaction formula-8] (IC) (1h) [In the formula, R24 represents a phenyl group, a lower alkyl group, or a hydrogen atom. X8 represents a halogen atom.

One of z" and w" is a group -CH2- and the other is -
N -CH2' represents a 7-ring R24 group, ) (R1, R3, R4Z, W, X and n are the same as above.) The reaction between the compound of general formula (1c) and the compound of general formula (28) is The reaction can be carried out under the same reaction conditions as the reaction between the compound of general formula (1b) and the compound of general formula (11) in Reaction Scheme-2.

In the compound of general formula (1), the heterocyclic residue includes (a) a phenyl lower alkyl group which may have a lower alkoxy group, nitro group, or amino group as a substituent on the phenyl ring, (b) a halogen atom A lower alkanoyl group that may have 1 to 7 halogen atoms or a lower alkenylcarbonyl group that may have 1 to 3 carboxy groups as a substituent,
(C) lower alkoxycarbonyl group, (d) aminocarbonyl group that may have a lower alkyl group, (e) phenyl lower alkoxycarbonyl group, (f) may have a phenyl lower alkoxycarbonyl group as a substituent. Amino lower alkanoyl group, (g) phthalide group, (
h) a 2(5H)-furanone group which may have 1 to 2 halogen atoms as a substituent and (i) a 2-(5H)-furanone group which may have a phenyl group or a lower alkyl group as a substituent;
A compound having an oxo-1,3-dioxolenemethyl group as a substituent can be derived into a compound (1) having no substituent on the corresponding heterocyclic group, for example, by the method shown below.

Compound (1) having (a) or (e) as a substituent on a heterocyclic residue can be prepared using a suitable solvent such as water, lower alcohols such as methanol, ethanol, and isopropanol, and ethers such as dioxane and tetrahydrofuran. , in a solvent such as acetic acid, or a mixed solvent thereof, in the presence of a catalytic reduction catalyst such as palladium-carbon or palladium-black.
By treating at around 00°C under a hydrogen pressure of 1 to 10 atm for about 0.5 to 10 hours (at this time, a mineral acid such as hydrochloric acid may be added) or by heat treatment in an aqueous solution of hydrobromic acid. Compound (1) having no substituent on the heterocyclic residue can be obtained by dephenyl lower alkyl (for example, debenzyl) or dephenyl lower alkoxycarbonylation.

Compound (1) having (b) to (i) as substituents
can be converted into a compound (1) having no substituent on the heterocyclic residue by decomposing it under the same conditions as the hydrolysis of the general formula (1a).

Among the compounds of general formula (1), the compound having a heterocyclic residue having an amino group as a substituent is similar to the reaction between the compound of general formula (IC) and the compound of general formula (28) in reaction formula-8 above. The reaction can lead to a compound having a heterocyclic residue having the group R2 "T=rCH/NH- as a substituent.

In addition, among the compounds of general formula (1), the compound having a group as a substituent can be hydrolyzed under the same conditions as the hydrolysis reaction of the compound of general formula (1a), so that an amino group can be added as a substituent. This can lead to compounds having a heterocyclic residue.

[Reaction formula-9] R' (1j) [In the formula, R1, R2', R4, X9 and X are the same as above. R20 R3/ represents a group -CH5R21 (R20 and R2+ are the same as above) or R3 (R3 is the same as above). R25
, R26, R27, R28 and R29 each represent a lower alkyl group. ] Compound of general formula (37) and general formula (
The reaction with the compound of formula (8) can be carried out under the same conditions as the reaction between the compound of general formula (1b) and the compound of general formula (11) in Reaction Scheme-2.

The reaction between the compound of general formula (29) and the compound of general formula (30a) or the compound of general formula (30b) is carried out in a solvent or in the absence of a solvent, preferably in the absence of a solvent. Examples of the solvent used here include alcohols such as methanol, ethanol, and isopropyl alcohol, aromatic hydrocarbons such as benzene and toluene, acetonitrile, and DMF.

Examples include polar solvents such as DMSOlHMPA. The amount of the compound of general formula (30a) or the compound of general formula (30b) to be used is usually at least about equimolar, preferably equimolar -1 to the compound of general formula (29).
, 5 mol. The reaction is usually carried out at room temperature
The process progresses suitably at 200° C., preferably around 60 to 200° C., and is generally completed in about 0.5 to 25 hours.

The cyclization reaction of the compound of general formula (31) or the compound of general formula (32) can be carried out according to various conventionally known cyclization reactions. Examples include a heating method, a cyclization method using an acidic substance such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, concentrated sulfuric acid, and polyphosphoric acid. When employing a cyclization method by heating, a solvent such as high-boiling hydrocarbons and high-boiling ethers, such as tetralin, diphenyl ether, diethylene glycol dimethyl ether, etc., is used, and the temperature is usually 100 to 250°C, preferably 150 to 200°C.
A heating condition of 0°C can be adopted. In addition, when employing a cyclization method using an acidic substance, this is combined with the general formula (31) or (32
) is usually used in an equimolar amount to a large excess amount, preferably 10 to 20 times the amount of the compound, and usually at room temperature to 150°C. 1
The reaction may be carried out for about 6 hours. In the case of a cyclization method using an acidic substance, the reaction may be carried out without a solvent or in an appropriate solvent. Examples of the solvent include acid anhydrides such as acetic anhydride, in addition to the solvent used in the cyclization reaction of the compound of general formula (9).

The hydrolysis reaction of the compound of general formula (11) can be carried out under the same reaction conditions as the hydrolysis reaction of the compound of general formula (1a) in Reaction Formula-1 above.

In the compound of general formula (1j), when R3' is a group 2O -CH3R21, a reaction similar to the reaction leading to the compound of general formula (19) from the compound of general formula (18) in Reaction formula-5 above is performed. When processed under the conditions, the corresponding R
A compound in which 3/ is a group -CH2R20 can be derived.

Further, in the compound of general formula (1j), R2' has a lower alkoxycarbonyl group on the secondary nitrogen atom.
In the case of a compound exhibiting a 9-membered saturated or unsaturated heterocyclic residue, it can be treated under the same reaction conditions as the hydrolysis reaction of the compound of general formula (1a) in Reaction Formula-1 above. A compound in which R 2 / represents a 5- to 9-membered saturated or unsaturated heterocyclic residue unsubstituted on the secondary nitrogen atom can be derived.

In the reaction formula-9, the compound of general formula (29) used as a starting material can be represented by, for example, the following reaction formulas-10 to 1.
It is manufactured by the method shown in 3.

[Reaction formula-10] (35) (36) (37g) (39) (29a) (38) [In the formula, R1, R2', R20, R21, X, X5 and X6 are the same as above. R30 is a lower alkanoyl group, X9
indicates a halogen atom. ] The desulfurization reaction of the compound of general formula (16) or the compound of general formula (29b) is carried out using the above general formula (
It is carried out under the same reaction conditions as the desulfurization reaction of the compound in 18).

The reaction leading to the compound of general formula (34) from the compound of general formula (33) is carried out in the presence of a lower alkanoylating agent. Examples of the lower alkanoylating agent used include lower alkanoic acids such as formic acid, acetic acid, and propionic acid, lower alkanoic anhydrides such as acetic anhydride, and lower alkanoic acid halides such as acetyl chloride and propionyl bromide. When using an acid anhydride or an acid halide as the lower alkanoylating agent, a basic compound may be present in the reaction system. Examples of the basic compound used include alkali metals such as sodium metal and potassium metal, hydroxides, carbonates, and bicarbonates of these alkali metals, and organic bases such as pyridine and piperidine. Although the reaction proceeds either without a solvent or in a solvent, it is usually carried out using a suitable solvent. Examples of the solvent include ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, acetic acid, acetic anhydride, water, and pyridine. The amount of the lower alkanoylating agent used is the general formula (33)
The amount is preferably at least equimolar, generally equimolar to large excess, relative to the compound. The reaction is usually carried out at O-15
The reaction proceeds suitably at about 0°C, preferably about 0 to 100°C, and is generally completed in about 5 minutes to 15 hours. In addition, when using a lower alkanoic acid as a lower alkanoylation agent, mineral acids such as sulfuric acid and hydrochloric acid, p-toluenesulfonic acid, benzenesulfonic acid,
It is preferable to add sulfonic acids such as ethanesulfonic acid, and in this case, the reaction temperature is particularly preferably about 50 to 120°C.

The nitration reaction of the compound of general formula (33) or the compound of general formula (34) can be carried out in the absence of a solvent or in a solvent such as acetic acid, acetic anhydride, sulfuric acid, fuming nitric acid, concentrated nitric acid, mixed acids (sulfuric acid, oleum, etc.). , phosphoric acid or acetic anhydride and nitric acid), alkali metal nitrates and sulfuric acid, anhydrides of organic acids and nitric acid such as acetyl nitrate and benzoyl nitrate, or nitrates of nitrogen tetroxide, nitric acid and mercuric nitrate, acetone cyanohydrin, This is carried out by reacting an alkyl nitrate with a nitrating agent such as sulfuric acid or polyphosphoric acid. The amount of the nitrating agent used is the compound of general formula (33) or the compound of general formula (34).
) The amount is usually equivalent to 5 times the molar amount of the compound. The reaction is usually carried out at about -10 to 70°C, and is generally completed in about 10 minutes to 24 hours.

The hydrolysis reaction of the compound of general formula (35) is carried out under the same reaction conditions as the hydrolysis reaction of the compound of general formula (1a).

The reaction between the compound of general formula (37a) or the compound of general formula (38) and the compound of general formula (8) is the reaction between the compound of general formula (1b) and the compound of general formula (11) in the reaction formula-2. The reaction can be carried out under similar reaction conditions.

Halogenation of the compound of general formula (39) is carried out by the above general formula (
It can be carried out under the same reaction conditions as for the halogenation of the compound in 14).

The reaction for converting the compound of the general formula (29b) into the compound of the general formula (29a) is to convert the compound of the general formula (18) into the compound of the general formula (29a).
It can be carried out under similar conditions to the reaction leading to compound 19).

The reaction between the compound of general formula (39a) and the compound of general formula (15) is the reaction between the compound of general formula (14a) and the compound of general formula (15).
can be carried out under similar reaction conditions to the reaction with the compound.

The reaction of converting the compound of general formula (36) to the compound of general formula (37) is carried out with a lower alkanoic acid such as acetic acid, in a solvent such as water, or with an acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, or fluoroboric acid. A diazonium salt is prepared using sodium nitrite, and then copper powder or a copper halide (e.g., cuprous bromide, cuprous chloride, cuprous chloride, etc.) is prepared in the presence of a hydrohalic acid (e.g., hydrobromic acid, hydrochloric acid, etc.). or by reacting with potassium iodide in the presence or absence of copper powder (preferably by reacting with copper halide in the presence of hydrohalic acid). be able to. The amount of sodium nitrite used here is usually an equimolar to twice the molar amount of the compound of general formula (36), preferably an equimolar -1 molar amount. The amount of copper halide to be used is usually an equimolar to 5-fold molar amount, preferably an equimolar 4-fold molar amount, relative to the compound of general formula (36). The reaction is usually carried out at around -20 to 100°C, preferably around -5 to 100°C,
The reaction time is generally about 10 minutes to 5 hours.

A compound of general formula (37a), a compound of general formula (1a),
The halogen atoms represented by R 2 / and X9 in the compound of general formula (la') and the compound of general formula (45) described below are mutually convertible.

[Reaction formula-11] (40) (41n (42) 26 (43) 4 20 (37) [In the formula R2 2 2 3 1 6 and X9 is the same as above.

] The hydrolysis reaction of the compound of general formula (40) can be carried out under the same reaction conditions as the hydrolysis reaction of the compound of general formula (1a).

The halogenation of the compound of general formula (41) is carried out by the reaction formula -
The halogenation of the compound of general formula (14) in 5 can be carried out under the same reaction conditions.

The reaction between the compound of general formula (42) and the compound of general formula (15) can be carried out under the same reaction conditions as the reaction between the compound of general formula (14a) and the compound of general formula (15).

The desulfurization reaction of the compound of general formula (43) is carried out by the reaction formula-5
It can be carried out under the same reaction conditions as the desulfurization reaction of the compound of general formula (18) in .

[Reaction formula-12] (44) (45) (47) (48) (52) (53) (46) (4) (37b) [In the formula R2 3 6 9 R20 and 2 is the same as above.

] [Reaction formula-13] (46) (54) J (55) (56) (53) [In the formula, R2', R3, X6, X9, R20 and R2+ are the same as above. ] The nitration reaction of the compound of the general formula (44), the compound of the general formula (47) and the compound of the general formula (53) is carried out using the general formula (3).
It can be carried out under the same reaction conditions as the nitration reaction of the compound in 3) or (34).

The reduction reaction of the compound of general formula (45) and the compound of general formula (48) can be carried out, for example, by (1) reduction using a catalytic reduction catalyst in an appropriate solvent, or (2) reduction with a metal or metal salt in an appropriate inert solvent. The reduction is carried out by using a mixture of an acid or a metal or a metal salt with an alkali metal hydroxide, sulfide, ammonium salt, etc. as a reducing agent. When using the catalytic reduction described in (2), the solvents used include, for example, water, alcohols such as acetic acid, methanol, ethanol, and isopropanol, hydrocarbons such as hexane and cyclohexane, diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, and diethyl ether. Ethers such as ethyl acetate, esters such as methyl acetate, N
, aprotic polar solvents such as N-dimethylformamide, and the like. Examples of the catalytic reduction catalyst used include palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, and Raney nickel. As for the amount of catalyst used, general formula (45)
Alternatively, it is preferable that the amount is 0.02 to 1.00 times the weight of the compound (48). The reaction is usually carried out at around -20 to 150°C, preferably around 0°C to room temperature, and at a hydrogen pressure of 1 to 10 atm. It takes about 5 to 10 hours. In addition, when using the method (■), iron, zinc, tin or stannous chloride and a mineral acid such as hydrochloric acid or sulfuric acid, or iron, ferrous sulfate, zinc or tin and an alkali metal hydroxide such as sodium hydroxide, sulfide Sulfides such as ammonium, aqueous ammonia, and mixtures with ammonium salts such as ammonium chloride are used as reducing agents. Examples of the inert solvent used include water, acetic acid, methanol, ethanol, and dioxane. The conditions for the above-mentioned reduction reaction may be appropriately selected depending on the reducing agent used. For example, when stannous chloride and hydrochloric acid are used as reducing agents, it is advantageous to carry out the reaction at 0°C to around room temperature for about 0.65 to 10 hours. It's good to do it. The amount of the reducing agent to be used is at least equimolar, usually equimolar, to the raw material compound.

The halogenation of the compound of general formula (46) or (49) and the subsequent reaction with the compound of general formula (15) are as follows:
The reaction can be carried out under the same reaction conditions as the halogenation of the compound of general formula (14) and the subsequent reaction with the compound of general formula (15).

The desulfurization reaction of the compound of general formula (55) or (51) (reaction for producing the compound of general formula (56) and (52), respectively) is similar to the desulfurization reaction of the compound of general formula (18). It can be carried out under reaction conditions.

The compound of the general formula (46) or (56) is converted into the compound of the general formula (47)
Alternatively, the reaction leading to the compound (53) is to react with a nitrite metal salt such as sodium nitrite or potassium nitrite in a solvent such as water in the presence of an acid to form a diazonium salt, and then 15
Heating to about 0 to 200°C, or cuprous bromide-hydrobromic acid, cuprous chloride monohydrochloric acid, hydrobromic acid, potassium iodide,
This is carried out by heating from room temperature to about 150° C. in the presence of an acid such as hydrochloric acid and copper powder. Examples of acids used here include hydrochloric acid, hydrobromic acid, sulfuric acid, tetrafluoroboric acid, and hexafluorophosphoric acid. The amount of the acid and metal nitrite to be used is usually about 1-5 times the mole of the compound of general formula (46) or (56), preferably about 5 times the mole of the former, and the amount of the latter is usually at least the same mole. , preferably about 1.5 times the equivalent molar amount.

The amount of acid to be used when heating the resulting diazonium salt in the presence of an acid is determined by formula (46) or (56).
The amount is usually small (equimolar, preferably about 1.5 times the molar equivalent of the compound).

Deamination reaction of the compound of general formula (52) (- general formula (5)
The reaction for producing the compound 3) is carried out, for example, by reacting the compound of general formula (52) with t-butyl nitrite in a suitable solvent. Examples of the solvent used here include dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, and the like. The amount of t-butyl nitrite used is based on the general formula (5
The amount is usually at least equimolar, preferably twice equimolar, relative to the compound 2). The reaction is usually carried out at room temperature to 150°C, preferably room temperature to around 100°C, and is generally completed in about 0.1 to 5 hours.

[Reaction formula-14] (58) (59) [In the formula R2 X.

5 6 2 as well as 2 electric is the same as above.

] The reaction between the compound of general formula (57) and the halogenating agent and the subsequent reaction with the compound of general formula (15) are the same as the reaction of the compound of general formula (14) and the halogenating agent and the subsequent reaction with the compound of general formula (14). The reaction can be carried out under the same reaction conditions as the reaction with the compound of general formula (15).

The desulfurization reaction of the compound of the general formula (58) (reaction for producing the compound of the general formula (59)) is performed using the compound of the general formula (18).
It can be carried out under the same reaction conditions as the desulfurization reaction of the compound.

In the reaction for converting the compound of general formula (59) into the compound of general formula (60), the compounds of general formulas (46) and (56) are converted into diazonium salts under the same reaction conditions as those used to convert them into diazonium salts, and then This is carried out by reacting with MCN (M is the same as above) in the presence of a copper compound such as copper powder or copper sulfate. The reaction usually proceeds at a temperature of 0 to 100°C, preferably around 0 to 70°C, and is completed in about 0.5 to 5 hours. The amount of MCN to be used is usually at least equimolar, preferably equimolar to the compound of general formula (59).
The amount is preferably 1 mol.

The hydrolysis reaction of the compound of general formula (60) can be carried out under the same reaction conditions as the hydrolysis reaction of the compound of general formula (20).

[Reaction formula-15] (62) (64) (66) (63) (65) (37c) [In the formula, R2', R3, X, X9 and R30 are the same as above. XIO represents a halogen atom. ] The reaction leading to the compound of general formula (61) from the compound of general formula (49) can be carried out under the same reaction conditions as the reaction leading to the compound of general formula (34) from the compound of general formula (33).

The nitration reaction of the compound of general formula (49), (61) or (66) can be carried out under the same reaction conditions as the nitration reaction of the compound of general formula (33) or (34).

The hydrolysis reaction of the compound of general formula (62) can be carried out under the same reaction conditions as the hydrolysis reaction of the compound of general formula (1a).

Deamination reaction of the compound of general formula (63) (- general formula (6)
The reaction for producing the compound of 4) is the reaction of the general formula (
It can be carried out under the same reaction conditions as the deamination reaction of the compound in 52).

The reduction reaction of the compound of general formula (64) is carried out by the above-mentioned - general formula (4)
It can be carried out under the same reaction conditions as the reduction reaction of the compound in 5) or (48).

The reaction leading to the compound of general formula (66) from the compound of general formula (65) is carried out in the same manner as the reaction leading to the compound of general formula (47) or (53) from the compound of general formula (46) or (56). I can do it.

Furthermore, the general formulas (3), (5), (7), (9), (
1a), (la'), (lb'), (29), (31)
In the compound of (32), when R2 is a 5- to 9-membered saturated or unsaturated heterocyclic residue having an oxo group as a substituent, by reducing these, a hydroxy group can be added as a substituent. This can lead to corresponding compounds having a 5- to 9-membered saturated or unsaturated heterocyclic residue.

The reduction reaction can be carried out in a suitable solvent in the presence of a hydrogenation reducing agent. Examples of the reducing agent include sodium borohydride, lithium aluminum hydride, and diborane. The amount of the reducing agent to be used is preferably at least equimolar, preferably 5 times equimolar, relative to the raw material compound to be reduced. Examples of solvents include water,
Lower alcohols such as methanol, ethanol, isopropanol, tetrahydrofuran, diethyl ether,
Examples include ethers such as diglyme.

The reaction is usually carried out at -60°C to 50°C, preferably from 0°C to
The process is completed in about 10 minutes to 5 hours at around room temperature. When lithium aluminum hydride or diborane is used as a reducing agent, it is preferable to use an anhydrous solvent such as diethyl ether, tetrahydrofuran or diglyme.

Moreover, when using sodium borohydride as a reducing agent, an inorganic base such as sodium hydroxide can also be added to the reaction system.

Furthermore, a 5- to 9-membered saturated or unsaturated heterocyclic compound in which R2 has a lower alkyl group, a lower alkanoylamino group, or a lower alkoxycarbonylamino group having at least one lower alkanoylamino group or lower alkoxycarbonylamino group as a substituent. In the case of a compound that is a ring residue, the hydrolysis reaction of the compound results in a saturated or unsaturated 5- to 9-membered ring having a lower alkyl group or an amino group in which the corresponding group has at least one amino group as a substituent. Compounds that are heterocyclic residues of can be derived.

The hydrolysis reaction can be carried out under the same conditions as the hydrolysis reaction of the compound of general formula (1a) in Reaction Formula-1 above.

In addition, R2 has at least one -NH- group in the ring.
In the case of a compound that is a 9-membered ring saturated or unsaturated heterocyclic residue, the same reaction as that for deriving the compound of general formula (34) from the compound of general formula (33) in Reaction Formula-10 above is performed. By subjecting the compound to the reaction described above, a compound in which R2 is a 5- to 9-membered saturated or unsaturated heterocyclic residue having at least one lower alkanoyl group as a substituent can be obtained.

Also, the general formulas (3), (5), (7), (9)% formula%
) In the compounds of (29), (31) and (32) R
When 1 is a phenyl group having at least one lower alkoxy group on the phenyl ring, by heating them in an aqueous hydrobromic acid solution, the corresponding R1 is a phenyl group having at least one hydroxyl group on the phenyl ring. Each of these groups can be derived from a compound that is a group.

Further, in the compound of the general formula (1), R3 or R4
When is a halogen atom, it is treated in a basic compound such as sodium hydroxide, potassium hydroxide, barium hydroxide, etc. and water at usually room temperature to about 200°C, preferably room temperature to about 150°C for 1 to 15 hours. By treating the compound to a certain extent, the corresponding R3 or R4 is a hydroxyl group (1
).

[Reaction formula-16] [In the formula, R2/, R3, R4 and X are the same as above.

R6a represents a hydrogen atom or a lower alkyl group.

Rla is a lower alkyl group having 1 to 3 hydroxyl groups, Rl
b represents a lower alkyl group having 1 to 3 lower alkanoyloxy groups, RIC represents a lower alkyl group having 1 to 3 halogen atoms, and Rld represents a lower alkenyl group. ] In the reaction for leading the compound of general formula (1k) to the compound of general formula (11), the compound of general formula (33) is converted to the compound of general formula (34).
) can be carried out under similar reaction conditions to those leading to the compound.

The hydrolysis reaction of the compound of general formula (11) can be carried out under the same reaction conditions as the hydrolysis reaction of the compound of general formula (1a).

The halogenation reaction of the compound of general formula (1k) can be carried out under the same reaction conditions as the halogenation reaction of the compound of general formula (2).

The reaction for converting the compound of general formula (1k) into the compound of general formula (1n) can be carried out in a suitable solvent or without a solvent, for example, using a hydrohalic acid such as hydrochloric acid or hydrobromic acid, sulfuric acid, boric acid, potassium hydrogen sulfate, etc. It is carried out in the presence of an inorganic acid such as oxalic acid or an organic acid such as oxalic acid. Examples of the solvent used here include water, ethers such as dioxane, tetrahydrofuran, and diethyl ether, halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride, and aromatic hydrocarbons such as benzene, toluene, and xylene. Or a mixed solvent thereof, etc. may be mentioned. The reaction is usually carried out at 50 to 350°C, preferably around 80 to 300°C, and generally takes 10 to 10 minutes.
The reaction is completed in about an hour.

The reaction for converting the compound of general formula (11) into the compound of general formula (1n) is carried out in a suitable solvent or without solvent.

As the solvent used here, any of the solvents exemplified in the reaction for converting the compound of general formula (1k) to the compound of general formula (1n) can be used. The reaction is usually carried out at room temperature to 150°C, preferably room temperature to around 100°C, and is generally completed in about 10 minutes to 10 hours.

The reaction also includes sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide,
The reaction may be carried out in the presence of an inorganic base such as a lithium salt such as potassium hydroxide, lithium chloride, or lithium carbonate, or an organic base such as DBU, pyridine, triethanolamine, or triethylamine.

The reaction of converting the compound of general formula (1m) into the compound of general formula (1n) is carried out in a suitable solvent in the presence of a basic compound. As the basic compound and solvent used here, any of the basic compounds and solvents exemplified in the reaction for converting the compound of general formula (II) into the compound of general formula (1n) can be used. The reaction is usually carried out at room temperature to 200°C.
℃, preferably room temperature to around 150°C, and the reaction is generally completed in about 1 to 10 hours.

In the compounds of general formulas (1k), (11), (1m) and (1n), when R6a represents a lower alkyl group, these are subjected to the same reaction conditions as the hydrolysis reaction of the compound of general formula (1a). can be hydrolyzed to give corresponding compounds in which R 6 a is a hydrogen atom.

In the hydrolysis reaction of the compound of general formula (11), R6
When a is a lower alkyl group, it may be simultaneously hydrolyzed to obtain a compound of general formula (1k) in which R6a is a hydrogen atom, but this compound can be easily separated from the reaction mixture.

Further, in the halogenation reaction of the compound of general formula (1k), when R6a is a hydrogen atom, its carboxy group may be simultaneously halogenated, but this compound can be easily separated from the reaction mixture.

[Reaction formula-17] (67) (68) (69) (70) [X2 in the formula 3 and X4 is the same as above.

3 and R3 each represents a lower alkyl group.

] The esterification reaction of the compound of general formula (67) can be carried out using an acid such as hydrochloric acid or sulfuric acid, or thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, etc. in a lower alcohol such as methanol, ethanol, or isopropanol. This is carried out in the presence of a halogenating agent.

The reaction is usually carried out at a temperature of about 0 to 150°C, preferably about 50 to 150°C.
It is carried out at around 100°C and generally takes about 1 to 10 hours.

The reduction reaction of the compound of general formula (68) is carried out by the above-mentioned - general formula (4
It can be carried out under the same reaction conditions as the reduction reaction of the compound in 5) or (48).

The halogenation reaction of the compound of general formula (69) is carried out in a suitable solvent in the presence of a halogenating agent. Examples of the halogenating agent used here include halogens such as bromine and chlorine, iodine chloride, sulfuryl chloride, N-halogenosuccinimides such as N-bromosuccinimide, and N-chlorosuccinimide. The amount of the halogenating agent to be used is usually about 1 to 10 times the mole of the compound of general formula (69), preferably about 1 times the mole of the compound of general formula (69). The solvents used include dichloromethane,
Examples include halogenated hydrocarbons such as dichloroethane, chloroform, and carbon tetrachloride, lower alkanoic acids such as acetic acid and propionic acid, and water.

A basic compound such as sodium acetate may be present in the reaction system. The above reaction is usually carried out at 0°C to around the boiling point of the solvent, preferably around 0 to 40°C, and generally at 0 to 40°C.
．． The time course reaction is completed in about 1 to 10 hours.

The reaction for converting the compound of general formula (70) into the compound of general formula (71) is similar to the reaction for converting the compound of general formula (46) or (56) into the compound of general formula (47) or (53). can be carried out under reaction conditions.

The hydrolysis reaction of the compound of general formula (71) can be carried out under the same reaction conditions as the hydrolysis reaction of the compound of general formula (1a).

The compound of general formula (1a) in reaction formula-1 and the compounds of general formula (1b) and (lb') in reaction formula-2 are used to obtain a compound of general formula (1) useful as an antibacterial agent of the present invention. It is useful as a synthetic intermediate, and it also has antibacterial activity itself, making it a useful compound as an antibacterial agent.

The compound represented by the general formula (1) of the present invention can be easily formed into a salt by reacting with a pharmaceutically acceptable acid or basic compound. Examples of chain acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, lactic acid, methanesulfonic acid, and propionic acid. Examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate, and the like.

The compound of the present invention thus obtained can be easily isolated and purified by conventional separation means. As the separation means, for example, solvent extraction method, dilution method, recrystallization method, column chromatography, preparative thin layer chromatography, etc. can be employed.

The compounds of the present invention naturally include stereoisomers and optically active forms.

The compound of the present invention or a salt thereof can be used for Mycoplasma, Pseudomonas aeruginosa,
Anaerobic bacteria, bacteria resistant to various antibacterial agents, clinical isolates, E, fa
ecalis and 5laph71ococcus pl
These compounds have remarkable antibacterial activity against Gram-negative and Gram-positive bacteria such as P. ogenes, and are useful as antibacterial agents against diseases caused by these bacteria.In addition, these compounds have low toxicity such as toxicity to cells. It also has the characteristics of having weak side effects, good absorption, and long duration.

Furthermore, the compound of the present invention or a salt thereof is useful as a therapeutic agent for urinary tract infections because of its high urinary excretion rate, and as a therapeutic agent for intestinal infections due to its excellent bile excretion property.

Among the compounds of the present invention represented by general formula (1), the group represented by R1 is preferably an unsubstituted cyclopropyl group.

The halogen atom represented by X is preferably a chlorine atom or a fluorine atom, most preferably a fluorine atom.

The group represented by R4 is preferably a lower alkyl group.

The lower alkyl group represented by R4 is preferably a methyl group or an ethyl group, with a methyl group being most preferred.

The group represented by R3 is preferably a hydrogen atom, a lower alkyl group, or a halogen atom, and most preferably a hydrogen atom. The lower alkyl group represented by R3 is preferably a methyl group or an ethyl group, with a methyl group being most preferred. Further, the halogen atom in the group represented by R3 is preferably a chlorine atom or a fluorine atom, and a fluorine atom is most preferred.

Furthermore, the compound of the present invention can be made more absorbable into the body by forming it into a salt form such as lactate or hydrochloride.

The compounds of the present invention are normally used in the form of common pharmaceutical formulations. The formulation is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, gunpowder, powders, liquids, suspensions, emulsions, granules, capsules, halves, and injections ( solutions, suspensions, etc.). When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propatool, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium sulfate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar At the end,
Laminaran powder, sodium bicarbonate, calcium carbonate,
Disintegrants such as polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, quaternary ammonium bases, sodium lauryl sulfate, etc. absorption enhancers, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. I can give an example. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as dragee-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, or multilayered tablets. When forming an emulsion, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, and tragacanth. Examples include binders such as gelatin and ethanol, and disintegrants such as laminar agar.

When forming the carrier into a halved form, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like. When prepared as injections, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood stasis, and when formed into the form of solutions, emulsions and suspensions, diluents are used. All those commonly used in this field can be used as the solvent, such as water, aqueous lactic acid solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can. In this case, a sufficient amount of salt, glucose, or glycerin may be included in the pharmaceutical preparation to prepare an isotonic solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. You can.

Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals may be included in the pharmaceutical preparation, if necessary.

When forming into a paste, cream or gel form, white vaseline, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like can be used as diluents. In addition, in cases where precipitation of the active ingredient compound occurs in the injection solution,
If necessary, the injection solution can be maintained in the form of a stable solution by appropriately adding an acid such as methanesulfonic acid, propionic acid, hydrochloric acid, succinic acid, or lactic acid.

Furthermore, the antibacterial agent of the present invention can also be in the form of an injection solution containing the compound of general formula (1) or a salt thereof (eg, lactate, etc.) and an acid that does not cause precipitation. Examples of acids that do not cause precipitation include lactic acid, methanesulfonic acid, propionic acid, hydrochloric acid, and succinic acid, preferably lactic acid. When lactic acid is used as the chain acid, the amount of acid that does not cause precipitation to be included in the injection solution is usually about 0.1 to 10% by weight, preferably 0.5% by weight. ~2
The amount is preferably about 0.05 to 4% by weight, preferably about 0.3 to 2% by weight in the solution when an acid other than lactic acid is used as the chain acid. It is better. The above-mentioned injection solution may contain conventional auxiliary agents, if necessary. Examples of such auxiliary agents include thickeners, absorption enhancers, absorption inhibitors, crystallization inhibitors, complexing agents, antioxidants, isotonic agents, and normal hydration agents. The pH of the solution can be appropriately adjusted, for example, by adding an alkali such as sodium hydroxide, and the pH of the solution is usually adjusted within the range of 2.5 to 7.

The above-mentioned infusion solution or injection solution has excellent stability and can be stored and preserved in the solution state for a long period of time.

The amount of the compound of general formula (1) or its salt to be contained in the pharmaceutical preparation of the present invention is not particularly limited and can be appropriately selected within a wide range, but is usually 1 to 70% by weight of the total composition. Good.

There are no particular restrictions on the method of administering the pharmaceutical preparation of the present invention, and the administration method is determined depending on the various preparation forms, age, sex and other conditions of the patient, and the severity of the patient. For example, tablets, gunpowder, liquid,
Suspensions, emulsions, granules and capsules are administered orally. In the case of an injection, it is administered intravenously alone or mixed with a normal replacement fluid such as glucose or amino acids, and furthermore, if necessary, it is administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally. In the case of halving, it is administered rectally.

The dosage of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but the amount of the compound of general formula (1), which is the active ingredient, is usually 1 kg of body weight per day. Approximately 0. The dosage is preferably 2 to 100 mg, and the preparation can be administered in 2 to 4 divided doses per day.

Examples Reference examples, working examples, antibacterial test results, and formulation examples are listed below.

Reference Example 1 200g of 2.6-dichlorotoluene and fuming nitric acid (d=1
．． 52) Add 206zA7 dropwise at 25-30°C. After stirring at room temperature for 30 minutes, the mixture was poured into ice water, extracted with diethyl ether, washed with aqueous sodium bicarbonate, and dried. The solvent was distilled off under reduced pressure to obtain 253.2 g of 2,6-dichloro-3-nitrotoluene.

Yellow crystal' H-NMR (CDC13) δppm: 2.57 (
3H,s), 7.42 (LH,d, J=7Hz), 7.58 (I
H, d, J = 7 Hz) Reference Example 2 253.2 g of 2.6-cyclo-3-nitrotoluene and 1.2 g of anhydrous dimethyl sulfoxide! , Black Cat-F
Add 357 g of (KF) and 62.5 g of 18-crown, and stir at 160° C. for 6 hours. After cooling, pour into ice water, extract with diethyl ether, wash with water, and dry. The solvent was distilled off under reduced pressure, and the residue was distilled under reduced pressure to obtain 96.1 g of 2,6-difluoro-3-nitrotoluene.

Boiling point 110~b'H-NMR (CDCA'3) δppm: 2.30
(3H, t, J=2Hz), 7.01 (IH, dd
d, J = 1.8Hz.

7.7Hz, 9. 5Hz), 7.97 (IH, dt, J=5.8Hz.

8.7 Hz) Reference Example 3 24 g of 5% Pd-C and 238.7 g of 2,6-difluoro-3-nitrotoluene were added to 1.21 g of acetic acid, and catalytic reduction was carried out at room temperature and 4.5 atm. 5% Pd-C is removed, acetic acid is distilled off under reduced pressure, the residue is poured into ice water, neutralized, extracted with dichloromethane, washed with water, and dried. The solvent was distilled off under reduced pressure, and the residue was distilled under reduced pressure to obtain 2,4-difluoro-3-
138 g of methylaniline are obtained.

Colorless oil, boiling point 75℃/l l mm) Ig'H
-NMR (CDC13) δppm: 2.17 (3H,
t, J=2Hz), 3°-3~3. 7 (2H,b
rs), 6, 4-6. 7 (2H, m) Reference Example 4 42% tetrafluoroboric acid 5611 and water 28111 were added to 20 g of 2.4-difluoro-3-methylaniline under water cooling.
is added, and then a solution of 10 g of sodium nitrite in 20 x 1 of water is added dropwise at a temperature below 10°C. After the dropwise addition, the resulting crystals were stirred at 0° C. for 15 minutes, taken out of the oven, washed with an ethanol-diethyl ether (1:2) mixture, then washed with diethyl ether, and dried under reduced pressure. 2,4-difluoro-3-
Methylbenzenediazonium tetrafluoroborate 28
．． Obtain 95g.

Melting point: 114-115°C Reference Example 5 28.95 g of 2.4-difluoro-3-methylbenzenediazonium tetrafluoroborate is heated to 180°C. Decomposition begins and the internal temperature rises to 200°C. Extract the product from the system. After the reaction is completed, 7.05 g of distillate is obtained. This is distilled at normal pressure to obtain 7.02 g of 2.3.6-1 refluorotoluene.

Colorless oil, boiling point 92°C' H-NMR (CDCI13) δppm: 2.22
(3H, t, J=i, 8Hz), 6, 7-7.
1 (2H, m) Reference Example 6 2.3. 36 g of concentrated sulfuric acid to 55 g of rottrifluorotoluene
Add 6yl and cool to 0°C. A solution of 44 g of potassium nitrate in concentrated sulfuric acid 1203FA' is added dropwise at 10° C. or below, and stirred for 15 minutes after the addition. Pour into ice water, extract with diethyl ether, wash with water, and dry.

The solvent was distilled off under reduced pressure, and 2.3. Rotrifluoro-5-
68.25 g of nitrotoluene are obtained.

Yellow oil 'H-NMR (CDCA'3) δppm: 2.36
(3H, t, J=2Hz), 7.83 (LH, q-
like, J=8.2Hz) Reference Example 7 5% Pd-C5.5g and 2°3.6 in 350yl acetic acid
35 g of -1-refluoro-5-nitrotoluene is added and catalytic reduction is carried out at room temperature and pressure. Eliminate 5% Pd-C,
Acetic acid was distilled off under reduced pressure, the residue was poured into ice water, neutralized, extracted with dichloromethane, washed with water, and dried. The solvent was distilled off under reduced pressure, and the resulting residue was distilled under reduced pressure to obtain 2,4.5-
) 22.86 g of refluoro-3-methylaniline are obtained.

Yellow crystals, boiling point 85℃/20 mmHg'H-N
MR (CDCA'3) δppm: 2.19 (3H,
t, J=2Hz), 3, 3~3.7 (2H, brs
), 6.42 (IH, d t, J=8Hz.

11 Hz) Reference Example 8 16.89 g of 2.4.5-)rifluoro-3-methylaniline and 11111 dimethyl sulfide are added to 1701111 anhydrous dichloromethane. Add 17.2 g of N-chlorosuccinimide little by little below 5°C. After stirring for 30 minutes, triethylamine 2111 was added dropwise and the mixture was refluxed overnight.

After cooling, the mixture is made alkaline with 5% sodium hydroxide, extracted with dichloromethane, washed with water, and dried. The solvent was distilled off under reduced pressure and purified by silica gel column chromatography (dichloromethane:n-hexane=1:1) to give a 2.4.
8.3 g of 5-trifluoro-3-methyl-6-methylthiomethylaniline are obtained.

'H-NMR (CDCA'3) δppm: 2.02
(3H,s), 2.20 (3H,t, J=2Hz), 3.79 (2
H, d, J=1.9Hz), 3.9-4.1 (2H,
brs) Reference Example 9 10.67 g of 2.4.5-trifluoro-3-methyl-6-methylthiomethylaniline and 300 r/ml of ethanol
and 100 g (wet) of Raney nickel, and stirred at room temperature for 30 minutes. After eliminating Raney nickel, the furnace solution is concentrated, diluted with water, extracted with dichloromethane, washed with water, and dried. The solvent was distilled off under reduced pressure, and silica gel column chromatography (dichloromethane:n-hexane=
1: Purified by 1), 2,4.5-)refluoro-3
, 5.89 g of 6-dimethylaniline are obtained.

Yellow crystal 'H-NMR (CDCl2) δppm: 2.10
(3H, d, J=1.7Hz), 2, 18 (3H,
5-1ike), 3.4-3.7 (2H, brs) Reference Example 10 A solution of 4.56 g of t-butyl nitrite in 26.5 zl of anhydrous dimethylformamide was heated to 50-52°C with stirring, and 2. A solution of 4.24 g of 4.5-trifluoro-3°6-dimethylaniline in anhydrous dimethylformamide 401 was added dropwise over 30 minutes while keeping the internal temperature at 50-52°C. Stir at the same temperature for 30 minutes. After cooling, pour into ice water, extract with diethyl ether, wash with water, wash with dilute hydrochloric acid, and dry. Diethyl ether is distilled off under normal pressure, and after concentration, the residue is distilled under normal pressure to obtain 1.9 g of 2,3.5-trifluoro-4-methyltoluene.

Yellow oil, boiling point 120-125°C' H-NMR
(CDCA'3) δppm: 2, 17 (3H, 5
-1ike), 2.25 (3H, d, J=1.7Hz
), 6.62 (IH, ddd, J-2Hz, 6.3H
z, 8.3Hz) Reference Example 11 2.3.5-trifluoro-4-methyltoluene 1.9
Add concentrated sulfuric acid 1911 to g, cool to 0°C, and add 1.71 g of potassium nitrate to concentrated sulfuric acid 4.6xi! The solution is added dropwise at 10° C. or below, and stirred for 15 minutes after the addition.

Pour into ice water, extract with diethyl ether, wash with water, and dry. The solvent was distilled off under reduced pressure and subjected to silica gel column chromatography (dichloromethane:n-hexane=1:
6) and 2.3. 1.9 g of rottrifluoro-4-methyl-5-nitrotoluene are obtained.

'H-NMR (CDCl13) δppm: 2.29
(3H, t, J=1.5Hz), 2.32 (3H, d
, J=2.4Hz) Reference Example 12 2.3.6-1 1.9g of refluoro-4-methyl-5-nitrotoluene and 9.9xl of 2-methoxyethanol,
Add 1.1 x CN-methylbiperazine 4.1 x l water and 5.21 A' triethylamine and reflux for 25 hours. After the reaction, water is added, extracted with diethyl ether, washed with water, and dried. The solvent was distilled off under reduced pressure, and silica gel column chromatography (dichloromethane:methanol = 4
0:1) to obtain 1.73 g of 2-(4-methyl-1-piperazinyl)-3,6-difluoro-4-methyl-5-nitrotoluene.

'H-NMR (CDCA!a) δppm: 2.25
(6H, d, J=2.6Hz), 2.36 (3H,
s), 2.4-2.6 (4H, br), 3.0-3.3 (4H, br) Reference Example 13 2-(4-methyl-1-piperazinyl)-3゜6-difluoro-4 -Methyl-5-nitrotoluene 1.73g, anhydrous dimethyl sulfoxide 1811, potassium fluoride 0.
Add 53g and 2.2xl of cyclopropylamine,
Stir at 00°C for 23 hours.

After cooling, pour into ice water, extract with dichloromethane, and dry. The solvent was distilled off under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 40:1) to give 3-(4-methyl-1-piperazinyl)-4-fluoro-2,5-dimethyl-6-di 1.65 g of tro-N-cyclopropylaniline are obtained.

Reference Example 14 100 zI of anhydrous dichloromethane to 5.0 g of 2.4-difluoro-3-methylaniline! and 3.5 xl of dimethyl sulfide. Add 5.6 g of N-chlorosuccinimide at below 0° C. and stir for 15 minutes. Add 4.8xl of triethylamine and reflux for 4 hours. After cooling, pour into ice water and make alkaline with 5% sodium hydroxide solution.

Extract with dichloromethane and dry. The solvent was distilled off under reduced pressure and purified by silica gel column chromatography (dichloromethane:n-hexane=1:1) to obtain 2,4-
4.9 g of difluoro-3-methyl-6-methylthiomethylaniline are obtained.

' H-NMR (CDC13) δppm: 1.99 (
3H, s), 2.17 (3H, t, J=1.8Hz), 3.64
(2H, s), 3.93 (2H, brs), 6.56 (IH, dd, J=1.8Hz.

Reference Example 15 An ethanol solution of 4.79 g of 2,4-difluoro-3-methyl-6-methylthiomethylaniline was added to an ethanol solution of 50 g of Raney nickel under stirring at room temperature.
Add xl and stir at room temperature for 30 minutes. After erasing the Raney nickel and diluting the furnace solution with water, it is extracted with dichloromethane, washed with water, and dried. Distill the solvent under reduced pressure to obtain 2,4-
3.14 g of difluoro-3,6-dimethylaniline are obtained.

' H-NMR (CDC13) δppm: 2, 14
(6H, 5-1ike), 3, 3-3. 6 (2H
,br), 6.56 (IH, dd, J=1.5Hz.

9.7Hz) Reference Example 16 2.4-difluoro-3,6-dimethylaniline 3.1
g, 42% tetrafluoroboric acid 911 and water 4.5 xi! under water cooling and stirring! and then add 1.6 ml of sodium nitrite.
A solution of 3.2 x 1 g of water is added dropwise at a temperature below 10°C. After stirring for 15 minutes at 0°C, the resulting crystals are poured into the bottom of the furnace. This is washed with a mixture of ethanol and diethyl ether (1:2) and then with diethyl ether. Dry under reduced pressure 2,4
1.78 g of -difluoro-3,6-dimethylbenzenediazonium tetrafluoroborate are obtained.

Reference Example 17 1.78 g of 2.4-difluoro-3,6-dimethylbenzenediazonium tetrafluoroborate is heated to 180°C. Decomposition begins and the internal temperature rises to 200°C. The product was taken out of the system to obtain 0.3 g of 2,3° rottrifluoro-4-methyltoluene.

Yellow oil, boiling point 120-b' H-NMR (CDCA'3) δppm: 2, 1
7 (3H, 5-1ike), 2.25 (3H, d,
J=1.7Hz), 6.62 (IH, ddd, J=2
Hz, 6.3H2,s, 3Hz) Reference Example 18 2.4.5-) 35.0 g of refluoroaniline and 530 g of anhydrous dichloromethane/and 24.0 g of dimethyl sulfide.
Add 6xl and cool to 0°C. Add 38.2 g of N-chlorosuccinimide little by little at below 5°C. After stirring at the same temperature for 15 minutes, triethylamine 4'7. Add Txl little by little. After refluxing for 12 hours, the mixture was made basic with 5% aqueous sodium hydroxide, and then extracted with dichloromethane. After drying with sodium sulfate, it was concentrated, and the residue was purified with a column (silica gel, dichloromethane: n-hexane = 1:4).
22.3 g of 2-methylthiomethyl-3,4,6-1-lifluoroaniline are obtained.

'H-NMR (CDCA'3) δppm: 2.03
(3H, s), 3.76 (2H, d, J=1.5Hz), 4.03
(2H, brs), 6.48 (IH, dt, J-7, 2Hz.

10.1 Hz) Reference Example 19 400 yl of ethanol and 200 g of Raney nickel are added to 22.2 g of 2-methylthiomethyl-3,4,6-)lifluoroaniline, and the mixture is stirred at room temperature for 30 minutes. After eliminating the catalyst, water is added to the furnace solution and extracted with dichloromethane. After drying with magnesium sulfate, it is concentrated to give 2-methyl-3,4
, 12.3 g of rottrifluoroaniline are obtained.

'H-NMR (CDCA'3) δppm: 2.13
(3H, d, J=2.1Hz), 3.56 (2H,
br, s), 6.75 (IH, dt, J=7.2Hz.

10, 2Hz) Reference Example 20 2-Methyl-3,4,6-)lifluoroaniline 10.
A mixed solution of 13.82 A' of concentrated sulfuric acid and 4,611 l of water was added to 6 g, and the mixture was cooled. A 2011 aqueous solution of 5.5 g of sodium nitrite is added dropwise at 0-5°C. Add this solution to cupric sulfate 5
10 to 30 g of hydrate to a mixture of 43 g of potassium cyanide, 60 xl of ammonium hydroxide, and 260 zA' of water.
Add little by little at ℃.

Extract with dichloromethane, dry with sodium sulfate, concentrate, and apply the residue to a column (silica gel, dichloromethane: n
2-methyl-3,4,
4.3 g of 6-dolifluorobenzonitrile are obtained.

'H-NMR (CDCA'3) δppm: 2.52
(3H, d, J=2.5Hz), 6.94 (IH,
dt, J = 6.2Hz.

8, 9Hz) Reference Example 21 50% sulfuric acid 4011 was added to 4.3g of 2-methyl-3,4,6-1-lifluorobenzonitrile, and the
Heat at °C for 6 hours. After cooling, pour into ice water and extract with diethyl ether. Add water to the ether layer, make it alkaline with 5% sodium hydroxide solution, and then make the aqueous layer acidic with concentrated hydrochloric acid. Extract with diethyl ether, dry over magnesium sulfate, and concentrate to obtain 3.3 g of 2-methyl-3,4,6-)lifluorobenzoic acid.

'H-NMR (CDCA'3) δppm: 2.47
(3H, d, J=2.6Hz), 6.88 (IH,
dt, J=6.3Hz.

9.5Hz) Reference Example 22 2-Methyl-3,4,6-1-lifluorobenzoic acid 3.2
Thionyl chloride 7111 was added to g, and the mixture was heated under reflux for 1 hour. After concentration, 3.3 g of 2-methyl-3,4°6-dolifluoropenzoyl chloride are obtained.

Magnesium metal 0.4g absolute ethanol 0.9zA
'Add 2 drops of carbon tetrachloride to the solution. Once the reaction starts, add 2.6xll of diethyl malonate and 1.6z of absolute ethanol.
A solution of 1 liter and 6 xi of anhydrous toluene is added dropwise at below 60°C. After stirring at 60°C for 1 hour, cool to 0°C. A 5 yl toluene solution of 2-methyl-3°4.6-4-lifluorobenzoyl chloride obtained above was added dropwise. 3
After stirring for 0 minutes, a mixture of 0.4 zl of concentrated sulfuric acid and 61/6 of water was added, and the mixture was extracted with diethyl ether. After drying over magnesium sulfate, the mixture is concentrated to obtain 5.2 g of diethyl 2-methyl-3,4,6-1-lifluorobenzoylmalonate.

Reference Example 23 20xl of water and 30 mg of p-toluenesulfonic acid were added to 5.1 g of diethyl 2-methyl-3,4,6-1-lifluorobenzoylmalonate, and the mixture was heated under reflux for 2.5 hours. After cooling, the mixture is extracted with diethyl ether, dried over magnesium sulfate, and concentrated to obtain 3.3 g of ethyl 2-methyl-3,4-rotrifluorobenzoylacetate.

Reference Example 24 3.0 g of acetic anhydride and 2.7 g of triethoxymethane are added to 3.2 g of ethyl 2-methyl-3,4,61-lyfluorobenzoylacetate, and the mixture is heated under reflux for 1 hour. After concentration, 3.5 g of ethyl 2-(2-methyl-3,4°rotrifluorobenzoyl)-3-ethoxyacrylate is obtained.

Reference Example 25 3.5 g of ethyl 2-(2-methyl-3,4,6-1-lifluorobenzoyl)-3-ethoxyacrylate was dissolved in 2511 ethanol, and 0.84 g of cyclopropylamine was dissolved.
Add xl dropwise under water cooling. After stirring at room temperature for 30 minutes, concentrate. The residue was filtered into a column (silica gel, dichloromethane: n-
2-(2-methyl-3,
2.7 g of ethyl 4,rotrifluorobenzoyl)-3-cyclopropylaminoacrylate are obtained.

Reference Example 26 Ethyl 2-(2-methyl-3,4,rotrifluorobenzoyl)-3-cyclopropylaminoacrylate 2.
Dissolve 6 g in anhydrous dioxane 2611, and add 0.38 g of 60% sodium hydride little by little while cooling with water. After stirring for 30 minutes at room temperature, the mixture was poured into ice water and extracted with dichloromethane. After drying with magnesium sulfate, concentrate. Diethyl ether is added to the residue and the crystals are poured into the bottom of the furnace. Recrystallized from ethanol to give 1-cyclopropyl-6,7-difluoro-
5-Methyl-1,4-dihydro-4-oxoquinoline-
2.0 g of ethyl 3-carboxylate is obtained.

Melting point 185-187°C Reference Example 27 1.9 g of ethyl 1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, 90% acetic acid 2011 and concentrated hydrochloric acid 5
Add zl and reflux for 2 hours.

After cooling, the precipitated crystals were taken to the bottom of the furnace, washed with water, then ethanol and diethyl ether in order to obtain 1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3. - 1.6 g of carboxylic acid are obtained.

Colorless needle crystals, melting point 294-298°C, 'H-NMR (CF3 GOOD) δppm: 1.4
3-1.55 (2H, m), 1, 65-1. 81 (2H, m), 3.06 (
3H, d, J=2.8Hz), 4.08~4.20 (
IH, m), 8.40 (LH, dd, J=6.8Hz.

10.3Hz), 9, 46 (IH,s) Reference Example 28 Using 5.60g of 2.3,4.5-tetrafluoro-6-methylbenzoic acid and 9.8xll of thionyl chloride,
In the same manner as in Reference Example 22, 5.20 g of 2,3°4,5-tetrafluoro-6-methylbenzoyl chloride was obtained.

Colorless oil, boiling point 82°C/23mmHg NMR (CDC/3) δppm: 2.35 (3H, m) Reference Example 29 2.3,4.5-tetrafluoro-6-methylbenzoyl chloride 5. Using OOg, 8 g of diethyl 2,3,4.5-tetrafluoro-6-methylbenzoylmalonate was obtained in the same manner as in Reference Example 22.

Yellow oil Reference Example 30 2.3.4.5-tetrafluoro-6-methylbenzoylmalonate diethyl 8 g and p-)luenesulfonic acid 8
2. In the same manner as Reference Example 23 using 0 mg. 3. 4
．． 4.5 g of ethyl 5-tetrafluoro-6-methylbenzoylacetate are obtained.

Yellow oily reference example 31 4.20 g of ethyl 2.3,4.5-tetrafluoro-6-methylbenzoylacetate and ethyl orthoformate 4
2- (2,3
,4,5-tetrafluoro-6-methylbenzoyl)-
5 g of ethyl 3-ethoxyacrylate is obtained.

Reference Example 32 2-( 2,3,4゜5-tetrafluoro-6-
4.74 g of ethyl (methylbenzoyl)-3-cyclopropylaminoacrylate are obtained.

Melting point: 78-79°C, white plate crystals (recrystallized from petroleum ether-n-hexane) Reference Example 33 2-(2,3,4,5-tetrafluoro-6-methylbenzoyl)-3-cyclopropylaminoacrylic 4.50 g of ethyl acid and 58 Qmg of 60% sodium hydride
1-cyclopropyl- in the same manner as in Reference Example 26 using
4.19 g of ethyl 6,7,8-1-lifluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate were obtained.

Melting point 180-183℃, white needle crystals (dichloromethane-
(Recrystallized from n-hexane) Reference Example 34 1-Cyclopropyl-6,7,8-trifluoro-5-
Methyl-1,4-dihydro-4-oxoquinoline-3-
4.10 g of ethyl carboxylate and concentrated hydrochloric acid - 90% acetic acid (
1:4) Using 81°2511, 1-cyclopropyl-6,7,8-4-refluoro-5 was prepared in the same manner as in Reference Example 27.
-Methyl-1゜4-dihydro-4-oxoquinoline-3
- 3.47 g of carboxylic acid are obtained.

Melting point: 218-220°C, white needle-like crystals Reference Example 35 2.4.5-1 To 1 g of refluoro-3-methylaniline is added 3 xi of acetic anhydride with stirring at room temperature, and the mixture is stirred for 15 minutes. This reaction solution is poured into ice water, extracted with dichloromethane, washed with water, and dried. The solvent was distilled off under reduced pressure, and 2,4
．． 5-) 1.14 g of refluoro-3-methyl-N-acetylaniline are obtained.

White crystal 'H-NMR (CDCA73) δppm: 2.21
(3H, s), 2.24 (3H, 3J = 2.1Hz), 7.2~
7. 5 (IH, brs), 8.10 (IH,
dt, J = 7.9Hz.

12Hz) Reference Example 36 1.94g of 2.4.5-trifluoro-3-methyl-N-acetylaniline was mixed with 19% of concentrated sulfuric acid. Add v/ and cool to 0°C. Add 2g of potassium nitrate at 20℃ or below,
Stir for a minute. Pour into ice water, extract with dichloromethane,
After drying, the solvent was distilled off under reduced pressure to obtain 2,4.5-1 refluoro-3-methyl-6-nitro-N-acetylaniline 2.
．． Obtain 0.8g.

White crystal'H-NMR (CDCA'3) δppm: 2, -2
1 (3H, s), 2.34 (3H, t, J=2.2Hz), 7.3~7
．． 5 (LH, brs) Reference Example 37 2,4.5-)lifluoro-3-methyl-6-nitro-
2.08g of N-acetylaniline and 30xl of ethanol
and 30xl of 10% hydrochloric acid, and heated under reflux for 3 hours.

After cooling, pour into ice water, neutralize with potassium carbonate, extract with dichloromethane, and dry. The solvent was distilled off under reduced pressure to obtain 2.05 g of 2,4.5-trifluoro-3-methyl-6-nitroaniline.

Brown crystal'H-NMR (CDC/3) δppm: 2, 29
(3H, s), 2.29 (3H, t, J=2.1Hz), 5.5~5
．． 9 (2H, brs) Reference Example 38 A solution of 1.87 g of t-butyl nitrite in 10.9y7 of anhydrous dimethylformamide was stirred at 50 to 52°C, and 2.4.
5-trifluoro-3-methyl-6 nitroaniline2.
After dropping 0.5 g of anhydrous dimethylformamide 16.4zf solution while maintaining the internal temperature at 50 to 52°C, the mixture was stirred at the same temperature for 30 minutes. After cooling, pour into ice water and extract with diethyl ether.
Dry after washing with water. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent; dichloromethane: n-hexane = 1:4) to give 2.3
．． 0.7 g of rottrifluoro-4-nitrotoluene is obtained.

'H-NMR (CDC/3) δppm: 2.35
(3H, t, J=2.1Hz), 7.62 (IH,
ddd, J=2.6Hz.

5.7 Hz, 8.3 Hz) Reference Example 39 0.1 g of 5% palladium-carbon and 2.
3.6-) Add 0.7 g of refluoro-4-nitrotoluene and perform catalytic reduction at room temperature and pressure.

5% palladium-carbon was eliminated, acetic acid was distilled off under reduced pressure,
The residue was poured into ice water, neutralized, and extracted with dichloromethane.
After washing with water, dry. The solvent was distilled off under reduced pressure, and 2,3.5
-) 0.48 g of refluoro-4-methylaniline is obtained.

'H-NMRCCDCl5) δppm+2.08 (
3H, t, J=1°8Hz), 3.6~4.0 (2H
, brs), 6.26 (IH, ddd, J=2.2Hz.

6.8Hz, 9.0Hz) Reference Example 40 Add 0.3g of sodium nitrite to 3yl of concentrated sulfuric acid,
After stirring at 0°C for 10 minutes, cool to 40°C or less, and 2.3.
A solution of 0.48 g of 5-trifluoro-4-methylaniline in acetic acid 5yA' is added dropwise at 40°C or lower. After stirring for 30 minutes, the reaction solution was mixed with 1.04 g of cuprous chloride in concentrated hydrochloric acid.
．． The mixture was added dropwise to the 4yA' solution, stirred at 80°C for 30 minutes, and then cooled. Pour into ice water, extract with dichloromethane, wash with water, and dry. The solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: dichloromethane:n-hexane=1:4) to obtain 0.22 g of 2,3.6-1-lifluoro-4-chlorotoluene.

'H-NMR (CD CI3) δppm: 2.2
0 (3H, t, J=2Hz), 6.90 (IH, d
dd, J=2.5Hz.

5.8Hz, 8.3Hz) Reference Example 41 2.3.6-toIJ fluoro-4-chlorotoluene 0.
Add 3xl of concentrated sulfuric acid to 22g and cool to 0°C. Add 0.18 g of potassium nitrate and stir for 15 minutes under water cooling.

Pour into ice water, extract with dichloromethane, wash with saturated aqueous sodium bicarbonate, then with water, and dry. 2. Remove the solvent under reduced pressure. 2. Rotrifluoro-4-
0.17 g of chloro-5-nitrotoluene is obtained.

'H-NMR (CDC/3) δppm: 2, 33
(3H, t, J = 2.2Hz) Reference Example 42 2.3.6-) Refluoro-4-chloro-5-nitrotoluene 0.17g, ethanol 3.3yl, water 0.5z
A', 0.45xl of N-methylpiperazine and 0.562 A' of triethylamine are added and refluxed for 24 hours. After the reaction, water is added, extracted with diethyl ether, washed with water, and then dried. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent; dichloromethane:methanol = 20:1) to obtain 2-(4-methyl-1-piperazinyl)-3,6- 0.13 g of difluoro-4-chloro-5-nitrotoluene was obtained at 6°C, then 2-(4-methyl-1-piperazinyl)-3 obtained above
,6-difluoro-4-chloro-5-nitrotoluene0
．． 13g of anhydrous dimethylformamide 211A', potassium fluoride 37mg and cyclopropylamine 0.151
/ and stirred at 100°C for 3 hours. After cooling, pour into ice water, extract with dichloromethane, and dry. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent; dichloromethane:methanol = 10
:1) to obtain 0.14 g of 3-(4-methyl-1-piperazinyl)-4-fluoro-5-chloro-2-methyl-6-nitro N-cyclopropylaniline.

'H-NMR (CDCA!3) δppm: 0.4-0
．． 5 (2H, m), 0.6-0.8 (2H, m), 2.22 (3H, s), 2.36 (3H, s),
2.4-2.7 (4H, brs), 3.11-3.3 (4H, brs), 4.1-4.2
(IH, brs) Reference Example 43 3-chloro-2,4,5-1 was prepared in the same manner as in Reference Example 22 using 185 mg of 3-chloro-2,4,5-1 refluoro-6-methylbenzoic acid and 600 μl of thionyl chloride. −
Trifluoro-6-methylbenzoyl chloride 183m
get g.

Reference Example 44 3-chloro-2,4,5-trifluoro-6-methylbenzoylmalone was prepared in the same manner as in Reference Example 22 using 183 mg of 3-chloro-2,4,5-trifluoro-6-methylbenzoyl chloride. 320 mg of diethyl acid are obtained.

Brown oil 'H-NMR (CDCA'3) δppm: 1.02
．． 1°29 and 1.38 (total 6H.

each t, J=7Hz), 2.27 (3H, d, J=1.5Hz), 4.02.
4.21 and 4.39 (all 4H.

Each q, J = 7H2), 3.36 and 13.7 (all IH, each S) Reference example 45 3-chloro-2,4,5-trifluoro-6-methylbenzoylmalonate diethyl 320 mg and p-) Using 3 mg of luenesulfonic acid, 3-
300 mg of ethyl chloro-2,4,5-)lifluoro-6-methylbenzoylacetate are obtained.

Brown oil 'H-NMR (CDCA'3) δppm: 1.25
and 1.35 (all 3H, each t.

J=7Hz), 2, 32 (3H, m), 4.18 and 4.29 (total 2H, each q.

J=7Hz), 3.89.5.25 and 12.35 (all 2H.

Each S) Reference Example 46 2-(
Ethyl 3-chloro-2,4,5-1-lifluoro-6-methylbenzoyl)-3-ethoxyacrylate 360 mg
get.

Brown oil Reference Example 47 Ethyl 2-(3-chloro-2,4,5-trifluoro-6-methylbenzoyl)-3-ethoxyacrylate 36
using 0 mg and 60111 g of cyclopropylamine,
2-(3-chloro-2,4,5
410 mg of ethyl 4-lifluoro-6-methylbenzoyl)-3-cyclopropylaminoacrylate is obtained.

Brown oil H-NMR (CDC13) δppm: 0.90 (4H, m), 1.04 (3H, t, J = 7Hz), 2.14 (3
H, m), 3.01 (IH, m), 3, 99
(2H, q, J=7Hz), 8.29 (IH,
d, J=14Hz), 11.2 (IH, br) Reference Example 48 410 mg of ethyl 2-(3-chloro-2,4,5-trifluoro-6-methylbenzoyl)-3-cyclopropylaminoacrylate and 60% sodium hydride 35m
1-cyclopropyl-6,7-difluoro-8-chloro-5-methyl-1,
70 mg of ethyl 4-dihydro-4-oxoquinoline-3-carboxylate are obtained.

Melting point 153-154°C, pale yellow powder (recrystallized from dichloromethane-n-hexane) Reference Example 49 1-Cyclopropyl-6,7-difluoro-8-chloro-5-methyl-1,4-dihydro-4 -1-Cyclopropyl-8-chloro-6,7-difluoro-5 was prepared in the same manner as in Reference Example 27 using 70 mg of ethyl oxoquinoline-3-carboxylate and concentrated hydrochloric acid-90% acetic acid (1:4) 1zA'. 58 mg of -methyl-1°4-dihydro-4-oxoquinoline-3-carboxylic acid are obtained.

Melting point: 213-215°C, white needle-like crystalsReference Example 50 2-Ethyl-3,4,5,6-titrafluoropenzoyl chloride is obtained in the same manner as in Reference Example 22 using appropriate starting materials.

Boiling point 78°C/14mmHg H-NMR (CDC13) δppm: 1.24 (3H, t, J=7.5Hz), 2.75
(2H, dq, J=2.3Hz.

7.5 Hz) Reference Example 51 Diethyl 2-ethyl-3,4,5,6-titrafluorobenzoylmalonate is obtained in the same manner as in Reference Example 22 using appropriate starting materials.

' HNMR (CDC13) δppm2 1.04
(3H, t, J=7.2Hz), 1.19 (3H,
t, J=7.4Hz), 1.38 (3H, t, J=7
．． 2Hz), 2.5-2.8 (2H, m), 4.03 (2H, q, J=7Hz), 4.39 (2
Reference Example 52 17.2 g of diethyl 2-ethyl-3,4,5,6-titrafluorobenzoylmalonate and 0.25 g of p-toluenesulfonic acid 2- in the same manner as Reference Example 23 using
11.09 g of ethyl 3,4,5,6-titrafluorobenzoylacetate are obtained.

Reference Example 53 8 g of ethyl 2-ethyl-3,4,5,6-tetrafluorobenzoylacetate and 6.1 g of ethyl orthoformate
2-(2-ethyl-3
, 4,5,6-titrafluorobenzoyl)-3-ethoxyacrylate is obtained.

Reference Example 54 2-(
Ethyl 2-ethyl-3,4,5°6-titrafluorobenzoyl)-3-cyclopropylaminoacrylate is obtained.

Reference Example 55 Using 8.71 g of ethyl 2-(2-ethyl-3,4,5,6-titrafluorobenzoyl)-3-cyclopropylaminoacrylate and 1.09 g of 60% sodium hydride, the same procedure as Reference Example 26 was carried out. Similarly, 1-cyclopropyl-6
, 7,8-) 5 g of ethyl fluoro-5-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate are obtained.

Melting point 139-140°C, white powder Reference Example 56 1-cyclopropyl-6,7,8-1 refluoro-5-
Ethyl-1,4-dihydro-4-oxoquinoline-3-
Ethyl carboxylate 5g 1 concentrated hydrochloric acid 112A', water 4.4x
1-Cyclopropyl-6,7°8-trifluoro-5-
Ethyl-1,4-dihydro-4-oxoquinoline-3-
4.2 g of carboxylic acid are obtained.

Melting point 197-198°C, white powder Reference Example 57 1.0 g of ethyl 2-(2-methyl-3,4, lotrifluorobenzoyl)-3-ethoxyacrylate and p-
Using 0.39 g of fluoroaniline, ethyl 2-(2-methyl-3,4,6-)lifluorobenzoyl)-3-(4-fluorophenyl)aminoacrylate was obtained in the same manner as in Reference Example 25, and then 60 in the same manner as Reference Example 26.
% sodium hydride to give 1-(4-fluorophenyl)-5-methyl-6,7-difluoro-
0.64 g of ethyl 1,4-dihydro-4-oxoquinoline-3-carboxylate is obtained.

Melting point 256-259°C, white crystals (recrystallized from ethanol) Reference Example 58 1-(4-fluorophenyl)-5-methyl-6,7-
Difluoro-1,4-dihydro-4-oxoquinoline-
0.56 g of ethyl 3-carboxylate.

1-(4-fluorophenyl)-5- was prepared in the same manner as in Reference Example 27 using 1.5xl of concentrated hydrochloric acid and 6xl of 90% acetic acid.
Methyl-6,7-difluoro-1,4-dihydro-4-
0.49 g of oxoquinoline-3-carboxylic acid is obtained.

Melting point: 255-257°C, white crystals Reference Example 59 Ethyl 2-(2-methyl-3,4, lotrifluorobenzoyl)-3-ethoxyacrylate 1.0 g and 70
Reference Example 25 using 0.2411% ethylamine aqueous solution
Ethyl 2-(2-methyl-3,4,rotrifluorobenzoyl)-3-ethylaminoacrylate was obtained in the same manner as in Reference Example 26, and then treated with 0.15 g of 60% sodium hydride in the same manner as in Reference Example 26. and 1-ethyl-5-methyl-
0.6 g of ethyl 6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate is obtained.

Melting point 157-159°C, white crystal Reference example 60 1-ethyl-5-methyl-6,7-difluoro-1,4
-dihydro-4-oxoquinoline-3-carboxylic acid ethyl 0.55 g, concentrated hydrochloric acid 1.5zA' and 90% acetic acid 6
Using yl, 1-ethyl-5 was prepared in the same manner as in Reference Example 27.
-Methyl-6,7-difluoro-1,4-dihydro-4
0.40 g of -oxoquinoline-3-carboxylic acid is obtained.

Melting point: 300°C or higher, white crystals' H-NMR (DMSO-d6) δppm: 1.37
(3H, t, J=7.2Hz), 2.82 (3H,
d, J=3.2Hz), 4.54 (2H,Q, J=7
．． 2Hz), 8.07 (IH, dd, J=7.2Hz
.

9.8Hz), 9.00 (IH,s), 15.25 (IH,s)
Reference Example 61 Ethyl 2-(2-methyl-3,4,5,6-titrafluorobenzoyl)-3-ethoxyacrylate 10.0 g
Ethyl 2-(2-methyl-3,4°5.6-titrafluorobenzoyl)-3-ethylaminoacrylate 9.0% was prepared in the same manner as in Reference Example 25 using and ethylamine gas.
g (white crystals) was obtained, and then 6 was obtained in the same manner as in Reference Example 26.
Ethyl 1-ethyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate 6 by treatment with 1.30 g of 0% sodium hydride.
．． Obtain 76g.

Melting point 197-198°C, pale yellow needle crystals (recrystallized from dichloromethane-n-hexane) Reference Example 62 1-ethyl-5-methyl-6,7,8-trifluoro-
6.51 g of ethyl 1,4-dihydro-4-oxoquinoline-3-carboxylate and concentrated hydrochloric acid = 90% acetic acid (1:4)
1-ethyl-5-methyl-6°7.8-trifluoro-1,4- was prepared in the same manner as in Reference Example 27 using 100zA'.
Dihydro-4-oxoquinoline-3-carboxylic acid 5.5
Obtain 3g.

Melting point 203-204℃, colorless needle crystals (dichloromethane-
(Recrystallized from n-hexane) Reference Example 63 5.0 g of ethyl 2-(2-methyl-3,4,5,6-titrafluorobenzoyl)-3-ethoxyacrylate and 2.02 g of 2.4-difluoroaniline 2-(2-methyl-3,4,5,6
-Titrafluorobenzoyl)-3-(2,4-difluorophenyl)aminoethyl acrylate was obtained, and then treated with 60% sodium hydride in the same manner as in Reference Example 26 to obtain 1-(2,4-difluorophenyl) )-5-methyl-
4.6 g of ethyl 6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate are obtained.

Melting point 156-157.5°C, pale yellow prismatic crystals (recrystallized from dichloromethane-n-hexane) Reference Example 64 1-(2,4-difluorophenyl)-5-methyl-6
, 4.3 g of ethyl 7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate and concentrated hydrochloric acid = 90% acetic acid (1:4) 8011, Reference Example 27
Similarly, 1-(2゜4-difluorophenyl)-5
2.93 g of -methyl-6,7°8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are obtained.

Melting point: 221-222°C, white powder Reference Example 65 Ethyl 2-(2-methyl-3,4,5,6-titrafluorobenzoyl)-3-ethoxyacrylate 10.0 g
Reference Example 2 using 3.87 g of and 4-methoxyaniline
5 to obtain ethyl 2-(2-methyl-3,4,5,6-titrafluorobenzoyl)-3-(4-methoxyphenyl)aminoacrylate, and then in the same manner as Reference Example 26 to obtain 60 % sodium hydride to give 1-(4-methoxyphenyl)-5-methyl-6,7
, 8-) 8.27 g of ethyl refluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate are obtained.

Melting point 175-176°C1 Pale yellow needle crystals Reference example 66 1-(4-methoxyphenyl)-5-methyl-6,7,
8-) In the same manner as in Reference Example 27, 1-
(4-hydroxyphenyl)-5-methyl-6,7,8
2.82 g of -trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are obtained.

Melting point 287-288.5°C, white powder Reference Example 67 Ethyl 2-(2-methyl-3,4,5,6-titrafluorobenzoyl)-3-ethoxyacrylate5. Reference Example 25 using 2.22 g of Og and 2-aminothiophene
Ethyl 2-(2-methyl-3,4,5,6-titrafluorobenzoyl)-5-(2-thienyl)aminoacrylate was obtained in the same manner as in Reference Example 26, and then 60% hydrogen was added in the same manner as in Reference Example 26. 1-(
1.05 g of ethyl 2-thienyl)-5-methyl-6,7,8-1-refluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate is obtained.

Melting point: 198-200℃, white powder (ethyl acetate-n-
(Recrystallized from hexane) Reference Example 68 1-(2-thienyl)-5-methyl-6,7°8-trifluoro-1,4-dihydro-4-oxoquinoline-3
- 1.05 g of ethyl carboxylate.

1-(2-thienyl)-5-methyl- in the same manner as in Reference Example 27 using concentrated hydrochloric acid 1011 and 90% acetic acid 4011
0.93 g of 6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained.

Melting point 221-222.5°C, white powder Reference Example 69 Ethyl 2-(2-methyl-3,4,5,6-titrafluorobenzoyl)-3-ethoxyacrylate 8.38 g
2-(2-methyl-3,
4,5,6-titrafluorobenzoyl)-3-(23
9.72 g of ethyl-3-hydroxy-2-propyl)aminoacrylate (yellow oil) was obtained, and then treated with 4.25 g of potassium carbonate in the same manner as in Reference Example 26 to obtain 38-9
．． 10-difluoro-3,8-dimethyl-7-oxo-
1.30 g of ethyl 7H-pyrido(1,2,3-de)(1,4)benzoxazine-6-carboxylate is obtained.

Melting point 216-217°C, colorless needle crystals (recrystallized from ethanol) Reference Example 70 38-9.10-difluoro-3,8-dimethyl-7-
Oxo-7H-pyrido(1,2,3-de)[1,4)
3S(-)-9,10-difluoro-
3,8-dimethyl-7-oxo-7H-pyrido (1,2
,3-de)(1,4)benzoxazine-6-carboxylic acid 1.03 g are obtained.

Melting point 249-251°C (decomposed), white powder Reference Example 7
1 In the same manner as in Reference Example 25, 2-(2 -Methyl-3,4,5,6-titrafluorobenzoyl)-3-(2-hydroxyethyl)
Ethyl aminoacrylate is obtained. Next, 10 yl of pyridine and 2.57 x 1 of acetic anhydride are added thereto, and the mixture is stirred at room temperature overnight. After concentration, dilute with water and extract with dichloromethane. After washing with water and saturated saline, drying,
Ethyl (2-methyl-3,4,5,6-titrafluorobenzoyl)-3-(2-acetyloxyethyl)aminoacrylate is obtained. Further, in the same manner as Reference Example 26, 60
% sodium hydride to give 1-(2-acetyloxyethyl)-5-methyl-6,7,8-)lifluoro-1,4-dihydro-4-oxoquinoline-3
-6.15 g of ethyl carboxylate are obtained.

Melting point: 192-193°C1 Colorless prismatic crystals (recrystallized from ethyl acetate) Reference Example 72 1-(2-acetyloxyethyl)-5-methyl-6,
Reference Example 2 using 5.80 g of ethyl 7,8-1-lifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate and 100zi of concentrated hydrochloric acid:90% acetic acid (1:4)
1-(2-hydroxyethyl)-5-methyl-6,7°8-trifluoro-1,4-dihydro-
4.04 g of 4-oxoquinoline-3-carboxylic acid are obtained.

Melting point 244.5-247°C, pale yellow leaf shape (recrystallized from ethanol) Reference Example 73 1-(2-hydroxyethyl)-5-methyl-6,7,
8-Trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid4. Thionyl chloride 2 in OOg
Add 011 and heat under reflux for 1 hour. After concentration, the resulting residue contains ethanol 501! and heated under reflux for 1 hour. After concentration, it is extracted with dichloromethane, washed with water, saturated sodium bicarbonate, water, and saturated brine in that order, and then dried.

The solvent was concentrated, and the resulting residue was subjected to silica gel column chromatography (eluent; ethyl acetate: n-hexane =
1:20) and recrystallized from ethyl acetate-n-hexane to give 1-(2-chloroethyl)-5-methyl-
2.00 g of ethyl 6,7,8-)refluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate are obtained.

Melting point: 161.5-163.5°C (decomposed), colorless prismatic crystals Reference Example 74 1-(2-chloroethyl)-5-methyl-6°7.8-
) DBU2.33z to 1.81g of ethyl refluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate
Add A' and 150 z/ml of toluene, and heat under reflux for 4 hours. After concentration, the residue was extracted with dichloromethane, diluted with diluted hydrochloric acid,
After washing with water and saturated saline, dry. After concentrating the solvent,
The resulting residue was subjected to silica gel column chromatography (
After purification with ethyl acetate:n-hexane=1:20), recrystallization from n-hexane-diethyl ether gave 1-vinyl-5-methyl-6,7,8-trifluoro-1, 0.72 g of ethyl 4-dihydro-4-oxoquinoline-3-carboxylate is obtained.

Melting point 134-135.5°C, colorless needle crystals Reference Example 75 5.0 g of ethyl 2-(2-methyl-3,4,5,6-titrafluorobenzoyl)-3-ethoxyacrylate,
Using 1.74 g of 2-chloroethylamine hydrochloride and 1.97 g of triethylamine, 2-(2-methyl 3.4,5.6-titrafluorobenzoyl)-3-(2-chloroethyl ) 5.52 g of ethyl aminoacrylate was obtained, and then treated with 0.72 g of 60% sodium hydride in the same manner as in Reference Example 26 to obtain 1-(2
-chloroethyl)-5-methyl-6,7゜8-dolifluoro-1,4-dihydro-4-oxoquinoline-3-
3.90 g of ethyl carboxylate are obtained.

Melting point 161.5-163.5°C (decomposition), colorless prismatic crystals (recrystallized from ethyl acetate-n-hexane) Reference Example 76 2-Methyl-3-nitrobenzoic acid 10. Add 100zA' of methanol to Og. At room temperature, thionyl chloride 8
Add 2A' dropwise. After heating under reflux for 2 hours, the reaction mixture is poured into ice water and extracted with dichloromethane. Concentrate the solvent to give 10.8 methyl 2-methyl-3-nitrobenzoate.
get g.

'H-NMR (CDCj?s) δppm: 2.63
(3H,s), 3.94 (3H,s), 7.38 (LH,t, J=8Hz), 7.84 (I
H, d, J=8Hz), 7.99 (IH, d, J=8
Hz) Reference Example 77 10.0 g of methyl 2-methyl-3-nitrobenzoate is dissolved in 50xl of acetic acid, and 1 g of 5% Pd-C is added. Catalytic reduction is carried out at room temperature and 1 atm. After 1.5 hours, the catalyst was separated from the furnace, concentrated, water was added, and the mixture was made alkaline with potassium carbonate. Extract with dichloromethane and concentrate the solvent to obtain 8.6 g of methyl 2-methyl-3-aminobenzoate.

'H-NMR (CD(,/3) δppm: 2.3
4 (3H, s), 3.55-3.85 (2H, brs), 3.87
(3H, s), 6.80 (IH, d, J=8Hz), 7.04 (
LH, t, J=8Hz), 7.20 (LH, d, J=
8 Hz) Reference Example 78 20xl of acetic acid and 1.6 g of sodium acetate are added to 1.6 g of methyl 2-methyl-3-aminobenzoate. 20℃
In the following, a hot solution of 3.1 g of bromine and 5 xi of acetic acid is added dropwise over 10 minutes. After stirring at room temperature for 30 minutes, the reaction mixture was poured into ice water and extracted with diethyl ether. The ether layer is neutralized with potassium carbonate and then dried. Concentrate the solvent and
2.8 g of methyl-3-amino-4,6-dibromobenzoate are obtained.

'H-NMR (CDCA'3) δppm+2, 1
4 (3H, s), 3.93 (3H, s), 4.05-4.30 (2H, brs), 7.52 (
IH, s) Reference Example 79 5 zl of ethanol and 2.5 zA' of 42% tetrafluoroboric acid are added to 1.4 g of methyl 2-methyl-3-amino-4,6-dibromobenzoate. A warm solution of 0.33 g of sodium nitrite in 1 xi of water was added dropwise at a temperature below 5°C. After stirring for 10 minutes, the precipitated crystals were washed at the bottom of the furnace, a small amount of water, ethanol, and diethyl ether in this order to obtain 2-methyl-4,
166 g of methyldiazonium 6-dipromo-3-benzoate tetrafluoroborate are obtained.

Melting point: 202-204°C (decomposition) Reference example 80 1.3 g of methyldiazonium tetrafluoroborate 2-methyl-4,6-dipromo-3-benzoate was dissolved at 200°C.
Heat for 10 minutes. After cooling, ice water is added to the reaction mixture and extracted with dichloromethane. After concentrating the solvent, the resulting residue was purified by silica gel column chromatography (eluent: chloroform:n-hexane = 1:4) to obtain methyl 2-methyl-3-fluoro-4,6-dibromobenzoate. Obtain .6g.

'H-NMR (CDCA's) δppm: 2.27
(3H, d, J=2.5Hz), 3.95 (3H,
s), 7.63 (IH, d, J=5.8Hz) Reference Example 81 460xl of ethanol to 75.5g of methyl 2-methyl-3-fluoro-4,6-dibromobenzoate! and 10%
Add 460 z/ml of aqueous sodium hydroxide solution and heat under reflux for 2 hours. After cooling, the reaction mixture is diluted with water and extracted with diethyl ether. The aqueous layer was made acidic with concentrated hydrochloric acid, and then extracted with gel ether. The solvent is concentrated to obtain 61 g of 2-methyl-3-fluoro-4,6-dibromobenzoic acid.

Melting point: 144-146°C Reference Example 82 4.6-dipromo-3-fluoro-2-methylbenzoic acid 2. Using Og, 4,6-dipromo 3-fluoro-2-methylbenzoyl chloride 2 was prepared in the same manner as in Reference Example 22.
．． Obtain 0g.

H-NMR (CDCA'3) δppm: 2.37 (
3H, d, J=2.5Hz), 7.69 (IH, d,
J=5.8Hz) Reference Example 83 Using 2.0 g of 4.6-dipromo-3-fluoro-2-methylbenzoyl chloride, 4 was prepared in the same manner as in Reference Example 22.
．． 2.6 g of diethyl 6-dipromo-3-fluoro-2-methylbenzoylmalonate are obtained.

Reference Example 84 2.1 g of ethyl 4,6-dipromo 3-fluoro-2-methylbenzoyl acetate was prepared in the same manner as in Reference Example 23 using 2.6 g of diethyl 4,6-dipromo 3-fluoro-2-methylbenzoylmalonate. get. Reference Example 85 2-(4,6-dipromo-3-fluoro-2-methylbenzoyl)-3 was prepared in the same manner as in Reference Example 24 using 2.1 g of ethyl 4.6-dipromo-3-fluoro-2-methylbenzoylacetate. -2.1 g of ethyl ethoxyacrylate are obtained.

Reference Example 86 69.5 g of ethyl 2-(4,6-dipromo-3-fluoro-2-methylbenzoyl)-3-ethoxyacrylate
48.1 g of ethyl 2-(4,6-dipromo-3-fluoro-2-methylbenzoyl)-3-cyclopropylaminoacrylate was obtained in the same manner as in Reference Example 25.

Reference Example 87 A mixture of 45.0 g of ethyl 2-(4,6-dipromo-3-fluoro-2-methylbenzoyl)-3-cyclopropylaminoacrylate, 16.7 g of potassium carbonate, and 450xl of dimethylformamide was heated at 140°C for 30 Heat the reaction for a minute.

After cooling, the reaction mixture was poured into ice water and the precipitated crystals were poured into the bottom of the furnace.

Recrystallized from ethanol to give 1-cyclopropyl-6-fluoro-7-bromo-5-methyl-1,4-dihydro-
Ethyl 4-oxoquinoline-3-carboxylate 33.6g
get.

Melting point: 195-197°C, white crystals Reference Example 88 1-Cyclopropyl-6-fluoro-7-bromo-5-
Methyl-1,4-dihydro-4-oxoquinoline-3-
Using 32.5 g of ethyl carboxylate, 1-cyclopropyl-6-fluoro-7-bromo-5-methyl-1°4-dihydro-4-oxoquinoline-3-carboxylic acid 27. Obtain 2g.

Melting point: 237-239°C, white crystals Reference Example 89 1-Cyclopropyl-6-fluoro-7-bromo-5-
Methyl-1,4-dihydro-4-oxoquinoline-3-
Thionyl chloride 22A' is added to 0.2 g of carboxylic acid and heated under reflux for 1 hour. After cooling, the reaction mixture was poured into ice water and made alkaline with a 10% aqueous sodium hydroxide solution. After stirring for 30 minutes, extract with dichloromethane. The aqueous layer was made acidic with 10% hydrochloric acid, and then extracted with dichloromethane.

After concentrating the solvent, the residue was recrystallized from acetic acid to give 1-cyclopropyl-6-fluoro-7-chloro-5-methyl-1
, 80 mg of 4-dihydro-4-oxoquinoline-3-carboxylic acid are obtained.

Melting point 258-260°C, white crystals Reference Example 90 Using ethyl 2-(2-methyl-3,4, lotrifluorobenzoyl)-3-ethoxyacrylate and 0.5 g of 2,4-difluoroaniline, Reference Example 25 In the same manner as above, 161 g of ethyl 2-(2-methyl-3°4.6-)lifluorobenzoyl)-3-(2°4-difluorophenyl)aminoacrylate was obtained.

'H-NMR (CDCl2) δppm: 0.95
(3H, t, y=7.2Hz), 2.23 (3H,
d, J=2.4Hz), 4.06 (2H,q, J=7
．． 2Hz), 6, 70-6. 83 (IH, m),
6, 91-7. 03 (2H, m), 7, 26
~7. 45 (IH, m), 8, 60 (IH
, d, J=13.8Hz), 11.36 (IH
, d, J=13.8f(z) Reference Example 91 2-(2-methyl-3,4,6-)lifluorobenzoyl)-3-(2,4-difluorophenyl)aminoethyl acrylate 1.1 g and 60% sodium hydride 0.
1-(2,4-
0.7 g of ethyl difluorophenyl-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate is obtained.

'H-NMR (CDCA'3) δppm: L 3
8 (3H, t, J=7.1Hz), 2.91 (3H
, d, J=3Hz), 4.38 (2H,q, J=7.
1Hz), 6.46 (IH, dd, J=6.9H2゜J=11.1Hz), 7, 10-7. 26 (2H, m), 7.38
~7. 56 (IH, m), 8, 26 (IH
,s) Reference Example 92 1-(2,4-difluorophenyl)-5-methyl-6
, 0.7 g of ethyl 7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, Reference Example 2
1-(2,4-difluorophenyl)-
5-methyl-6,7-difluoro-1,4-dihydro-
0.5 g of 4-oxoquinoline-3-carboxylic acid is obtained.

Melting point 280-281°C, colorless needle crystals (recrystallized from acetic acid) Example 1 3-(4-methyl-1-piperazinyl)-4-fluoro-2,5-dimethyl-6-nitro-N-cyclopropylaniline Add 1.45z/ of diethyl ethoxymethylene malonate to 1.65g and heat at 150°C for 25 hours. After cooling, it was purified by silica gel column chromatography (dichloromethane:methanol-10021) to obtain (N-
Diethyl cyclopropyl-N-(3-(4-methyl-1-piperazinyl)-4-fluoro-2,5-dimethyl-6nitrophenyl]amiminethylene)malonate 1.58
get g. Dissolve this in 7.911 acetic anhydride and
3.16 zl of concentrated sulfuric acid is added dropwise at 60°C. Stir for 30 minutes after dropping. Pour into ice water, neutralize, extract with dichloromethane, and dry. The solvent was distilled off under reduced pressure, and silica gel column chromatography (dichloromethane: methanol = 1
0=1) and recrystallized from ethanol-diethyl ether to give 7-(4-methyl-1-piperazinyl)-1.
-cyclopropyl-6-fluoro-5゜8-dimethyl-
28 mg of ethyl 1,4-dihydro-4-oxoquinoline-3-carboxylate is obtained.

Yellow crystals, melting point 146-147°C' H-NMR (CDCA'3) δppm: 0, 7
~0. 8 (2H, m), 1.0-1.2 (2H, m), 1.39 (3H, t, J=7Hz), 2.39 (3
H,s), 2.59 (3H,s), 2.4-2.7
(4H, br), 2.75 (3H, d, J=2.9Hz), 3.1~3
．． 4 (4H, br), 3, 8-4.0 (LH, m), 4.38 (2H, q, J=7.1Hz), 8.54
(LH,s) Example 2 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl 2
5 mg of 10% sodium hydroxide aqueous solution 311 and ethanol 31! 1 and reflux for 1 hour. After cooling, dilute with water, wash with dichloromethane, make the aqueous layer acidic with acetic acid, and then make weakly alkaline with an aqueous sodium hydrogen carbonate solution.

Extract with dichloromethane and dry. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the crystals were boiled at the bottom of the furnace.
Recrystallized from ethanol to give 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5,
14 mg of 8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are obtained.

Yellow crystals, melting point 205-206°C' H-NMR (CDC13) δppm: 0.7-0.
9 (2H, m), 1.1-1.4 (2H, m), 2.39 (3H, s), 2, 5-2. 8 (4H, br), 2.63 (3
H,s), 2.76 (3H,d, J=3Hz), 3, 2-3.
5 (4H, br), 4, 0-4. 2 (
LH, m), 8.85 (LH, s), 14, 3-14. 9 (IH, br) Example 3 6.7-difluoro-1-cyclopropyl-5°8-dimethyl-1,4-difluoro-4-oxoquinoline-3
-Carboxylic acid-B (OCOCH3) 1.0 g of 4-methyl-1-piperazine and 6zA' of dimethylacetamide are added to 1.24 g of (OCOCH3)2 chelate, and the mixture is heated and reacted at 50°C for 20 hours. After concentration, add 20 yl of acetone to the obtained residue and dissolve it.
Add 511 parts of concentrated hydrochloric acid and stir at room temperature for 30 minutes. After distilling off the solvent, water was added and extracted with -dichloromethane. The aqueous layer is neutralized with an aqueous sodium bicarbonate solution and then extracted with dichloromethane. After drying with magnesium sulfate, a mixture of diethyl ether and ethanol was added to the residue, and the precipitated crystals were boiled at the bottom of the furnace and recrystallized from ethanol to give 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro- 5
, 0.1 g of 8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained.

Yellow crystals, melting point 205-206°C Example 4 6.7-difluoro-1-cyclopropyl-5°8-dimethyl-1,4-dihydro-4-oxoquinoline-3-
1.88g of carboxylic acid to N-methylpyrrolidone 51j2
2.02 g of 4-methyl-1-piperazine was added, and the mixture was stirred at 150°C for 3 hours. After the reaction, the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol = 3:1) and recrystallized from ethanol to give 7-(4-methyl-1-piperazinyl)-1-cyclopropyl. -6-Fluoro-5,8-dimethyl-1,4-dihydro-4-oxoquinolyl 3-
0.05 g of carboxylic acid is obtained.

Yellow crystals, melting point 205-206°C Using appropriate starting materials, the following compounds were obtained in the same manner as in Examples 1-4 above.

(1) 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1°4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 185-187°C, pale yellow needle (recrystallized from dimethylformamide) (2) 7-(3-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 183-185°C, colorless powder (3) 7-(3-amino-1-pyrrolidinyl)-1=cyclopropyl-6-fluoro-5,8- dimethyl-1,
4-dihydro-4-okitsuki (4) (5) (6) Noricy 3-carboxylic acid Melting point 96-98°C, pale yellow needles 7-(1-piperazinyl)-1-cyclopropyl-6-
Fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 231-233°C, white powder (recrystallized from dimethylformamide) 7-(4-methyl-1-piperazinyl)-1 -Cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 229-232°C, pale yellow prismatic shape (recrystallized from ethanol) 7-(3-methyl- 1-piperazinyl)-1-, cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (7) (8) (9) Melting point 206-208°C, white Powder (recrystallized from ethyl acetate-ethanol) 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carvone Acid melting point: 267-270°C, white powder (recrystallized from dimethylformamide) 7-(1-piperazinyl)-1-cyclopropyl-6,
8-difluoro-5-methyl-1゜4-dihydro-4-
Oxoquinoline-3-carboxylic acid Melting point: 205-207°C, white powder (recrystallized from ethanol) 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6,8-difluoro-5-methyl-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 229-231°C1 White needles (recrystallized from ethanol) (10) 7-(3-Methyl-1-piperazinyl)-1-
cyclopropyl-6,8-difluoro-5-methyl-1
,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 188-189°C, pale yellow powder (recrystallized from ethanol) (11) 7-(3-amino-1-pyrrolidinyl)-1-
cyclopropyl-6,8-difluoro-5-methyl-1
,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point: 213-216°C, pale yellow powder (recrystallized from dimethylformamide) (12) 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro -8-chloro-5-methyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid Melting point: 214-217°C, pale yellow powder (recrystallized from ethanol) (13) 7-(4-Methyl-1-piperazinyl)-1-
Cyclopropyl-6-fluoro-8-chloro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point: 190-192°C, pale yellow powder (recrystallized from dichloromethane-n-hexane) (14) 7-(3-Methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-8-chloro-5-methyl-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid (15) 7-(3-amino-1-piperazinyl)-1-
Cyclopropyl-6-fluoro-8-chloro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (16) 7-(1-piperazinyl)-1-cyclopropyl-5,6- Difluoro-8-methyl-1゜4-dihydro-4-oxoquinoline-3-carboxylic acid (17) 7-(4-methyl-1-piperazinyl)-1-
cyclopropyl-5,6-difluoro-8-methyl-1
,4-dihydro-4-oxoquinoline-3-carboxylic acid (18) 7-(3-methyl-1-piperazinyl)-1-
cyclopropyl-5,6-difluoro-8-methyl-1
,4-dihydro-4-oxoquinoline-3-carboxylic acid (19) 7-(3-amino-1-pyrrolidinyl)-1-
cyclopropyl-5,6-difluoro-8-methyl-1
,4-dihydro-4-oxoquinoline-3-carboxylic acid (20) 7-(1-piperazinyl)-1-cyclopropyl-5-chloro-6-fluoro-8-methyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid (21) 7-(4-methyl-1-piperazinyl)-1-
Cyclopropyl-5-chloro-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 213-215°C, yellow crystals (22) 7-(3-methyl-1- piperazinyl)-1-
Cyclopropyl-5-chloro-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (23) 7-(3-amino-1-pyrrolidinyl)-1-
Cyclopropyl-5-chloro-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (24) 7-morpholino-1-cyclopropyl-6-fluoro-5-methyl- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 245-247°C, white powder (recrystallized from ethanol) (25) 7-(3-amino-4-methyl-1-pyrrolidinyl)-1 -Cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (trans form) Melting point 272-275°C (decomposition), white powder (methanol-acetic acid) Recrystallized from ethyl) (26)? -(3-aminomethyl-1-pyrrolidinyl)-1-cyclopropyl-
6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride Melting point: 280-283°C (decomposed), white powder (recrystallized from methanol-water) (27)? -(4-hydroxy-1-piperidinyl)-
1-cyclopropyl-6-fluoro-5methyl-1,4
-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 220-221°C, colorless needles (recrystallized from methanol) (28) 7-(4-fluoro-1-piperidinyl)-1
-cyclopropyl-6-fluoro-5-methyl-1,4
-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 204-207°C, white powder (recrystallized from ethanol) (29) 7- (3-(N-t-butoxycarbonyl-N-methylamine)-1 -pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 210-212°C, white powder (recrystallized from ethanol) (30) 7-(3-t-butoxycarbonylamino-4
-Methyl-1-pyrrolidinyl)-1-cyclopropyl-
6-Fluoro-5-methyl-1゜4-dihydro-4-oxoquinoline-3-carboxylic acid (cis form) Melting point 239-241°C, white powder (recrystallized from ethanol) (31) 7- (3- (N-t-butoxycarbonyl-N-ethylaminomethyl)-1-pyrrolidinyl-1-cyclopropyl-6-fluoro-5-methyl-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 175-177°C, white powder (recrystallized from ethanol) (32) 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclo Propyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (cis form) Melting point 280-284°C (decomposition), pale yellow powder (recycled from ethanol) (33) 7-(3-ethylaminomethyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride Melting point: 236-239°C, pale yellow powder (recrystallized from ethanol) (34) 7-(1,4-diazabicyclo(4,3,0
3-nonan-4-yl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 203-205°C, colorless needles (regenerated from ethanol) Crystal) (35) 7-(4-acetyl-1-piperazinyl)-1
-cyclopropyl-6-fluoro-5-methyl-1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid Melting point: 261-263°C, white powder (recrystallized from ethanol) (36) 7-(3-methylamino-1-pyrrolidinyl)
-1-cyclopropyl-6-fluoro-5-methyl-1
,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 194-197°C, white powder (recrystallized from dimethylformamide) (37) 7-(3-t-butoxycarbonylamino-4
-Methyl-1-pyrrolidinyl)-1-cyclopropyl-
6-Fluoro-5-methyl-1゜4-dihydro-4-oxoquinoline-3-carboxylic acid (trans form) Melting point 226-229°C1 White powder (recrystallized from ethanol) (38)? -(4-(5-methyl-2-oxo-1゜3
-dioxolen-4-yl)methyl-1-piperazinyl]-1-cyclopropyl-6-fluoro-5-methyl-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid NMR (CDCA'3) δppm+ 1, 14-1. 24 (2H, m), 1. 2
6-1. 41 (2H, m) , 2, 16 (
3H, s), 2, 72-2. 84 (7H, m), 3, 2
8-3. 53 (7H, m), 7, 29
(IH, d, 8.2Hz), 8.73 (IH, s)
, 15.57 (IH,5) (39)7-(4-benzyl-1-piperazinyl)-1
-cyclopropyl-6-fluoro-5,8-dimethyl-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point: 165-166°C, pale yellow needles (recrystallized from diethyl ether-ethanol) (40) 7-(4-benzyl-3-methyl-1- piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 17
6-178°C1 Pale yellow powder (41) 7-(1,4-
diazabicyclo[:4,3.0]nonan-4-yl)-
1-Cyclopropyl-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point: 194-197°C, pale yellow needles (recrystallized from dichloromethane-n-hexane) (42) 7-morpholino-
1-Cyclopropyl-6°8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 255-259°C1 White needles (recrystallized from ethanol) (43) 7- (4-hydroxy-1-piperidinyl)-
1-Cyclopropyl-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 247-250°C, white needles (recrystallized from ethanol) (44) 7- (4-fluoro-1-piperidinyl)-1
-cyclopropyl-6,8-difluoro-5-methyl-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point: 259-261°C, pale yellow needles (recrystallized from ethanol) (45) 7-(3-methylamino-1-pyrrolidinyl)
-1-Cyclopropyl-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid monohydrochloride Melting point 215-219°C, white powder (recrystallized from ethanol) (46) 7-(3-ethylaminomethyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-5
-Methyl-1,4-dihydro-4-oxoquinoline-3
-Carboxylic acid monohydrochloride Melting point 221-223°C1 White powder (recrystallized from ethanol) (47) 7-(3-aminomethyl-1-pyrrolidinyl)
-1-cyclopropyl-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (4 g) 7-(3-amino-4-methyl-1-pyrrolidinyl)- 1-cyclopropyl-6,8-difluoro-5
-Methyl-1,4-dihydro-4-oxoquinoline-3
-Carboxylic acid monohydrochloride (cis form) Melting point: 209-213°C, pale yellow powder (recrystallized from ethanol) (49) 7-(3-Amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl -6,8-difluoro-5
-Methyl-1,4-dihydro-4-oxoquinoline-3
-Carboxylic acid monohydrochloride (trans form) Melting point 214-216°C1 Pale yellow powder (recrystallized from ethanol) (50) 7- (4-(5-methyl-2-oxo-1°3-dioxolene) 4-yl)methyl-1-piperazinyl]-1-cyclopropyl-6゜8-difluoro-5-
Methyl-1,4-dihydro-4-oxoquinoline-3-
Carboxylic acid (5) 7-(4-acetyl-1-piperazinyl)-1-cyclopropyl-6,8-difluoro-5
-Methyl-1,4-dihydro-4-oxoquinoline-3
-Carboxylic acid melting point 217-220°C, white powder (recrystallized from ethanol) (52) 7- [3-(N-t-butoxycarbonyl-N-methylamino)-1-pyrrolidinyl]-1-cyclopropyl- 6,8-difluoro-5-methyl-1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid Melting point 184-187°C, white powder (recrystallized from ethanol) (53) 7- (3-(N-t-butoxycarbonyl-N-ditylaminomethyl) -1-pyrrolidinyl]-1
-cyclopropyl-6,8-difluoro-5-methyl-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 147-149°C, white powder (recrystallized from ethanol) (54) 7-(3-(N-t-butoxycarbonylaminomethyl)-1 -pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (55)?-(3-t-butoxycarbonylamino-4
-Methyl-1-pyrrolidinyl]-1-cyclopropyl-
6,8-difluoro-5-methyl-1,4-dihydro-
4-Oxoquinoline-3-carboxylic acid (cis form) Melting point 215-217°C, pale yellow powder (recrystallized from ethanol) (56) 7-(3-t-butoxycarbonylamino-4
-Methyl-1-pyrrolidinyl]-1-cyclopropyl-
6,8-difluoro-5-methyl-1,4-dihydro-
4-Oxoquinoline-3-carboxylic acid (trans form) Melting point 223-224°C, white powder (recrystallized from ethanol) (57) 7-(3-amino-1-pyrrolidinyl)-1-
Cyclopropyl-6-fluoro-8-chloro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 194-195°C, pale yellow powder (recrystallized from ethanol) (58) 7 -(1-piperazinyl) -1-(2,4-
difluorophenyl)-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 244-246°C (decomposition), white powder (recrystallized from dimethylformamide) (59 )7-(4-Methyl-1-piperazinyl)-1-(2,4-difluorophenyl)-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid melting point 2
28-230°C (decomposition), white powder (recrystallized from ethanol) (60) 7-(1-piperazinyl')-1-(4-hydroxyphenyl)-6,8-difluoro-5-methyl-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point: 300°C or higher, white powder (61) 7-(4-methyl-1-piperazinyl)-1-
(4-hydroxyphenyl)-6,8-difluoro-5
-Methyl-1,4-dihydro-4-oxoquinoline-3
-Carboxylic acid melting point 300℃ or higher, white powder (62) 7-(1-piperazinyl)-1-ethyl-6゜8-difluoro-5-methyl-1,4-dihydro-4-
Oxoquinoline-3-carboxylic acid Melting point 219-220
°C (decomposition), colorless needle crystals (recrystallized from ethanol) (63) 7-(4-methyl-1-piperazinyl)-1-
Ethyl-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point: 212.5-215°C (decomposed), pale yellow prismatic crystals (recrystallized from ethanol) 64) 7-(3-Methyl-1-piperazinyl)-1-ethyl-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 209.5-211°C (decomposed), white powder (recrystallized from ethanol) (65) 7-(1-piperazinyl)-1-(4-fluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxo Quinoline-3-carboxylic acid Melting point: 278-282°C (decomposition), pale yellow crystals (recrystallized from dimethylformamide) (66)? -(3-t-
Butoxycarbonylamino-1-pyrrolidinyl')-1
-(4-Fluorophenyl)-6-fluoro-5-methyl-1゜4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 249-250°C1 White crystals (recrystallized from ethanol) (67) 7- (3-amino-1-pyrrolidinyl)-1-
(4-Fluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride Melting point 292-295°C (decomposition), pale yellow-white crystals (methanol- (68) 7-(1-piperazinyl)-1-ethyl-6-
Fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 225-227°C, white crystals (recrystallized from dimethylformamide) (69) 7-(3-t-butoxycarbonylamino- 1
-pyrrolidinyl)-1-ethyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 230-231°C, white crystals (recrystallized from ethanol) (To)7- (3-amino-1-pyrrolidinyl)-1-
Ethyl-6-fluoro-5-methyl-1゜4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride Melting point 275-281°C (decomposition), pale yellow crystals (recrystallized from ethanol) (71) 7 -(1-piperazinyl)-1-vinyl-6゜8-difluoro-5-methyl-1,4-dihydro-4-
Ethyl oxoquinoline-3-carboxylate Melting point: 181-183°C (decomposition), pale yellow needles (recrystallized from chloroform-n-hexane) (72) 7-(4-Methyl-1-piperazinyl)-1-
Ethyl vinyl-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate Melting point: 165-166°C (decomposition), pale yellow needles (ethyl acetate-n-hexane) (73) 7-(1-piperazinyl)-1-vinyl-6°8-difluoro-5-methyl-11,4-dihydro-4
-Oxoquinoline-3-carboxylic acid Melting point 205-20
6.5°C (decomposition), pale yellow powder (74) 7-(4-methyl-1-piperazinyl)-1-
Vinyl-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 187.5-189.5°C (decomposition), pale yellow needles (ethyl acetate- (75) 7-(4-methyl-1-piperazinyl)-1-
(4-Fluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 274-276°C (decomposition), white crystals (recrystallized from ethanol) (76) 7-(1-Piperazinyl)-1-(2-thienyl)-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 239-240.5°C ( decomposition), white powder (
(77) 7-(1-piperazinyl)-1-cyclopropyl-6,8-difluoro-5-ethyl-1°4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 161-163 °C, yellow powder (recrystallized from dimethylformamide) (78) 7-(3-methyl-1-piperazinyl)-1-
cyclopropyl-6,8-difluoro-5-ethyl-1
,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 146-147°C, white powder (recrystallized from dimethylformamide-ethanol-diethyl ether) (79) 7-(4-methyl-1-piperazinyl)- 1=
cyclopropyl-6,8-difluoro-5-ethyl-1
,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 201-202°C, white powder (recrystallized from dimethylformamide) (80) 7-(3-amino-1-pyrrolidinyl)-1-
cyclopropyl-6,8-difluoro-5-ethyl-1
,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 164-165°C, white powder (recrystallized from ethanol) (81)3S (-)-10-(4-methyl-1-piperazinyl)-9 -Fluoro-3,8-dimethyl-7-oxo-7H-pyrido(1,2,3-de)[1,4)benzoxazine-6-carboxylic acid Melting point 235-236.5°C (decomposition), colorless prism crystalline (recrystallized from ethanol) [α) g5=-125,
9° (C=0.21, chloroform) (,82) 7- (4-methyl-1-piperazinyl)
-1-(2,4-difluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 226-228°C, pale yellow crystals (recrystallized from ethanol) (83) 7-(1-piperazinyl)-1-(2,4-difluorophenyl)-6-fluoro-5-methyl-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid.
Hydrochloride Melting point: 229-232°C, white crystals (recrystallized from ethanol-water) (84) 7-(3-amino-1-pyrrolidinyl)-1-
(2,4-difluorophenyl)-6-fluoro-5-
Methyl-1,4-dihydro-4-oxoquinoline-3-
carboxylic acid. , hydrochloride melting point 291-294°C, white crystals (recrystallized from ethanol-water) Example 5 7-(3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro -5-Methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (trans form) A mixture of 120 mg of 4 yl of ethanol and 4 xi of 10% hydrochloric acid was added to 30
Heat to reflux for 1 minute. After concentration, the resulting residue was diluted with methanol.
Recrystallization from ethyl acetate gave 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carvone. Acid/hydrochloride (trans form) 60m
get g.

White powder, melting point 272-275°C Using appropriate starting materials, the following compound was obtained in the same manner as in Example 5.

(1) (2) (3) 7-(3-amino-4-methyl-1-pyrrolidinyl)-
1-cyclopropyl-6-fluoro-5-methyl-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid.
Hydrochloride (cis form) Melting point: 280-284°C (decomposed), pale yellow powder (recrystallized from ethanol) 7-(3-ethylaminomethyl-1-pyrrolidinyl)-
1-cyclopropyl-6-fluoro-5-methyl-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid.
Hydrochloride Melting point: 236-239°C, pale yellow powder (recrystallized from ethanol) 7-(3-methylamino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro- 4-Oxoquinoline-3-carboxylic acid Melting point 194-197°C, white powder (recrystallized from di(4) (5) (6) methylformamide) 7-(3-methylamino-1-pyrrolidinyl)-1- cyclopropyl-6,8-difluoro-5-methyl-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid.
1-hydrochloride Melting point: 215-219°C, white powder (recrystallized from ethanol) 7-(3-ethylaminomethyl-1-pyrrolidinyl)-
1-Cyclopropyl-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid monohydrochloride Melting point 221-223°C, white powder (recrystallized from ethanol) 7 -(3-aminomethyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-5-methyl-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid (7) (8) (9) 7-(3-amino-4-methyl-1-pyrrolidinyl)-
1-Cyclopropyl-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid monohydrochloride (cis form) Melting point 209-213°C, pale yellow powder (ethanol (recrystallized from) 7-(3-amino-4-methyl-1-pyrrolidinyl)-
1-Cyclopropyl-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid monohydrochloride (trans form) Melting point 214-216°C1 Pale yellow powder (ethanol 7-(3-amino-1-pyrrolidinyl)-1-(4-fluorophenyl)-6-fluoro-5-methyl-1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid/hydrochloride Melting point: 292-295°C (decomposed), pale yellowish white crystals (recrystallized from methanol-water) (10) 7-(3-amino-1-pyrrolidinyl) )-1-
Ethyl-6-fluoro-5-methyl-1゜4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride Melting point 275-281°C (decomposition), pale yellow crystals (recrystallized from ethanol) (It) 7 -(3-amino-1-pyrrolidinyl)-1-
cyclopropyl-6,8-difluoro-5-ethyl-1
,4-dihydro-4-oxoquinoline-3-carboxylic acid Melting point 164-165°C, white powder (recrystallized from ethanol) Example 6 7-(1-piperazinyl)-1-cyclopropyl-6-
40 mg of fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is dissolved in 2 zl of 5% sodium hydroxide, and 0.1xl of acetic anhydride is added at room temperature. After acidifying with dilute hydrochloric acid, extraction with dichloromethane and drying over magnesium sulfate. After concentration, the residue was recrystallized from ethanol to give 7-(4-acetyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5.
-Methyl-1,4-dihydro-4-oxoquinoline-3
-29 mg of carboxylic acid are obtained.

White powder, melting point 261-263°C 7-(4-acetyl-1-piperazinyl)-1-cyclopropyl-6,8- was prepared in the same manner as in Example 6 using appropriate starting materials.
Difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained.

Example 7 7-(4-benzyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 150
10% Pd-C30m in 20xl solution of mg of ethanol
g was added thereto, and catalytic reduction was carried out at 70°C and normal pressure. 10%Pd
After eliminating -C, the furnace liquid is concentrated. Recrystallization from dimethylformamide gave 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 64m
get g.

7-(3-methyl-
1-Piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained.

Example 8 In the same manner as in Example 1, (N-cyclopropyl-N-(3-(3-ethoxycarbonylamino-1)
-pyrrolidinyl)-4-fluoro-2,5-dimethyl-
7-(3-ethoxycarbonylamino-1-
pyrrolidinyl)-1-cyclopropyl-6-fluoro-
Ethyl 5,8 dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate is obtained.

H-NMR (CDCA'3) δppm: 0, 7-0
．． 9 (2H, m), 1.0-1.2 (2H, m), 1.39 (3H, t, J=7.1Hz), 1.40
(3H, t, J=7.1Hz), 2.1~2.4 (2
H, m), 2.50 (3H, s), 2.75 (3H, d, J=3Hz), 3, 4-3.
7 (4H, m), 3.8-4.0 (IH, m), 4.1-4.5 (5H, m), 5.3-5.5 (IH, m), 8, 54 ( IH,s) Example 9 In the same manner as in Example 1, (N-cyclopropyl-N-C3-(4-benzyl-1-piperazinyl)
-4-fluoro-2,5-dimethyl-6-nitrophenylcoaminomethylene) diethyl malonate,
Ethyl 4-benzyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate is obtained.

'HNMR (CD Cl3) δppm: 0.6-0
．． 8 (2H, m), 1.0-1.2 (2H, m), 1.39 (3H, t, J=7.1Hz), 2.58
(3H, s), 2.4-2.7 (4H, br), 2.74 (3H, d, J=3.0Hz), 3.1-3
．． 4 (4H,br), 3, 60 (2H,s), 3.8~4.0 (IH,m), 4.38 (2H,q, J=7.1Hz), 7, 3
~7.4 (5H, m), 8.53 (IH, s) Example 10 In the same manner as in Example 1, (N-cyclopropyl-N-[3-(4-benzyl-3- Methyl-1-piperazinyl)-4-fluoro-2゜5-dimethyl-6-
7-(4-benzyl-3-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5,8-
Dimethyl-1,4-dihydro-4-oxoquinoline-3
- Obtain ethyl carboxylate.

Melting point: 128-129°C, pale yellow powder Example 11 7-(3-ethoxycarbonylamino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1,4-dihydro-4- Oxoquinoline-3-
3.22 A' of 5% aqueous potassium hydroxide solution was added to 130 mg of carboxylic acid ethyl ester, and the mixture was heated under reflux for 4 hours.

After cooling, acetic acid is added to make it acidic, and then potassium carbonate is added to make it slightly alkaline. After extraction with dichloromethane and drying,
The solvent is removed under reduced pressure. Diethyl ether was added to the resulting residue to dissolve the precipitated crystals, giving 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5.
, 30 mg of 8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are obtained.

Melting point: 96-98°C, pale yellow needles Example 12 In the same manner as in Example 1, (N-cyclopropyl-N-[3-(4-methyl-1-piperazinyl)-
4-fluoro-2-methyl-5-chloro-6-nitrophenylcoaminomethylene) via diethyl malonate, 7
-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5-chloro-8-methyl-1,4
-Ethyl-dihydro-4-oxoquinoline-3-carboxylate is obtained.

Melting point 175-177°C, yellow crystals Example 13 1-Cyclopropyl-6-fluoro-7-bromo-5-
Methyl-1,4-dihydro-4-oxoquinoline-3-
Carboxylic acid 0.58g N-methyl-2-pyrrolidone 5
Add 0.64 g of 4-oxopiperidine to the zA' solution and heat at 90°C for 20 minutes. The solvent was distilled off under reduced pressure, ethanol was added to the resulting residue to dissipate the crystals, and 1
-cyclopropyl-6-fluoro-7-(4-oxo-
1-piperidinyl)-5-methyl-1,4-dihydro-
230 mg of 4-oxoquinoline-3-carboxylic acid are obtained.

Elemental analysis value (as C+ e H+ g N204 F) HN Calculated value (%') 63.68 5.34 7.8
2 Actual measurement value (%') 63.5g 5.39 7
．． 72 [Antibacterial test] In order to investigate the antibacterial effects of the test compounds shown below against various bacteria, the minimum growth-inhibiting concentration was determined by the agar dilution plate method [Chemotherap7゜22.11
26-1128 (1974)].

The results obtained are shown in Table 1 below. In addition, various bacteria are IX
IQ6 bacterial count/xi (0, D, 660 mtt.

0.07 to 0.16 diluted 100 times).

Test compound> 1.7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1,4
-Dihydro-4-Okitsuki2゜3゜4゜5゜6゜Norishi 3-carboxylic acid 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4- Dihydro-4-oxoquinoline-3-carboxylic acid 7-(1-piperazinyl)-1-cyclopropyl-6-
Fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4- Dihydro-4-oxoquinoline-3-carboxylic acid 7-(3-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Acid 7-(3-aminomethyl-1-pyrrolidinyl)7゜8゜9゜l0O -1-cyclopropyl-6-fluoro-5-methyl-1
,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride 7-(3-amino-4-methyl-1-pyrrolidinyl)-
1-cyclopropyl-6-fluoro-5-methyl-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid.
Hydrochloride (trans form) 7-morpholino-1-cyclopropyl-〇-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid 7-(3-ethylaminomethyl-1-pyrrolidinyl)-
1-cyclopropyl-6-fluoro-5-methyl-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid.
Hydrochloride 7-(1,4-diazabicyclo(4,3,0)
4-oxoquinoline-3-carboxylic acid 7-(4-hydroxy- 1-Piperidinyl)-1-cyclopropyl-
6-Fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7-(4-fluoro-1-piperidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid 7-(3-amino-4-methyl-1-pyrrolidinyl)-
1-cyclopropyl-6-fluoro-5-methyl-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid.
Hydrochloride (cis form) 7-(4-acetyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydrota-4-oxoquinoline-3-carboxylic acid 15°16 7 1g .

19゜7-(1-piperazinyl) 7-(3-methylamino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid -1-cyclopropyl-6-
Fluoro-5,8-dimethyl-1゜4-dihydro-4-
Oxoquinoline-3-carboxylic acid 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7 -(3-Methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7-(1-piperazinyl)-1 -cyclopropyl-6,
8-difluoro-5-methyl-1゜20゜21゜22゜23゜4-dihydro-4-oxoquinoline-3-carboxylic acid 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6, 8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7-(3-methyl-1-piperazinyl)-1-cyclopropyl-6,8-difluoro-5-methyl- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-5-methyl-1,4-dihydro-4- Oxoquinoline-3-carboxylic acid 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-5-chloro-6-fluoro-8-methyl-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid 24°25°26°27°28°7-(L,4-diazabicyclo[4,3,0)nonan-4-yl)-1-cyclopropyl- 6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7-morpholino-1-cyclopropyl-6°8-difluoro-5-methyl-1,4-dihydro- 4-Oxoquinoline-3-carboxylic acid 7-(4-hydroxy-1-piperidinyl)-1-cyclopropyl-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate Acid 7-(4-fluoro-1-piperidinyl)-1-cyclopropyl-6,8-difluoro-5-methyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 7-(3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-Schiff 29°30°31°32°lopropyl-6,8-difluoro-5 -methyl-1,4
-dihydro-4-oxoquinoline-3-carboxylic acid trans form) 7-(3-methylamino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-5-methyl-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid.
1 hydrochloride 7-(3-ethylaminomethyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-5
-Methyl-1,4-dihydro-4-oxoquinoline-3
-Carboxylic acid monohydrochloride 7-(3-amino-4-methyl-1-pyrrolidinyl)-
1-Cyclopropyl-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid monohydrochloride (trans form) 7-(3-amino-4-methyl-1 -pyrroli33゜34゜35゜36゜dinyl)-1-cyclopropyl-6,8-difluoro-
5-Methyl-1,4-dihydro-4-oxoquinoline-
3-Carboxylic acid monohydrochloride (cis form) 7-(4-acetyl-1-piperazinyl)-1-cyclopropyl-6,8-difluoro-5-methyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-8-chloro-5-methyl-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid 7-(1-piperazinyl)-1-cyclopropyl-6-
Fluoro-8-chloro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-8-chloro37゜38゜39゜40゜low 5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7-(1-piperazinyl)-1-(2,4-difluorophenyl)-6,8- difluoro-5-methyl-1,4
-dihydro-4-oxoquinoline-3-carboxylic acid 7-(4-methyl-1-piperazinyl)-1-(2,4
-difluorophenyl)-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7-(1-piperazinyl)-1-(4-hydroxyphenyl)-6,8 -difluoro-5-methyl-1
,4-dihydro-4-oxoquinoline-3-carboxylic acid 7-(4-methyl-1-piperazinyl)-1-(4-hydroxyphenyl)-6,8-difluoro-5-methyl-1,4-dihydro -4-Oxoquinoline-3-carboxylic acid 41°42°43°44°45°7-(1-piperazinyl)-1-ethyl-6°8-difluoro-5-methyl-1,4-dihydro-4- Oxoquinoline-3-carboxylic acid 7-(1-piperazinyl)-1
-(4-fluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7-(3-amino-1-pyrrolidinyl)-1-(4-fluorophenyl) )-6-fluoro-5-methyl-1,4
-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride 7-(1-piperazinyl)-1-vinyl-6゜8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3- Carboxylic acid 7-(4-methyl-1-piperazinyl)-1-(4-fluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 46°47° 48°49°33 (-)-10-(4-methyl-1-piperazinyl)-9-fluoro-3,8-dimethyl-7-oxo-7
H-pyrido(1,2,3-de)[1,4)benzoxazine-6-carboxylic acid 7-(4-methyl-1-piperazinyl)-1-(2,4
-difluorophenyl)-6-fluoro-5-methyl-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7-(1-piperazinyl)-1-(2,4difluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4- Oxoquinoline-3-carboxylic acid hydrochloride 7-(3-amino-1-pyrrolidinyl)-1-(2,4
-difluorophenyl)-6-fluoro-5-methyl-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (strain name) A: S, 1ureus DA 09P: p, x6ruginosa -2 Table 1 Formulation Example 1 7-(4-methyl-1-piperazinyl) )-1-cyclopropyl-6-fluoro-5,8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid glucose 00 mg 50 mg 7-(4-methyl-1-piperazinyl) in distilled water for injection )
After dissolving -1-cyclopropyl-6-fluoro-5,8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and glucose, the mixture was poured into a 511 Alpur tube and heated to 121°C after being replaced with nitrogen. The mixture is autoclaved for 15 minutes to obtain an injection having the above composition.

Formulation example 2 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 100
g Avicel (trade name, manufactured by Asahi Kasei ■) 40 g cornstarch 30 g magnesium stearate 2 g TC-5 (trade name, manufactured by Shin-Etsu Chemical ■, hydroxypropyl methylcellulose) 10 g polyethylene glycol-60003
g Castor oil 40g7
-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, avicel, cornstarch and magnesium stearate. take,
After mixing and polishing, tablet with RIQmm kinematics. The obtained tablets were treated with TC-5, polyethylene glycol-6000,
Coating is performed with a film coating agent consisting of castor oil and ethanol to produce film coated tablets having the above composition.

Formulation example 3 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 2
g Refined lanolin 5g White beeswax 5g White petrolatum 88g Total amount
100g of white beeswax is heated to make it liquid, and then 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1,4-dihydro-4-oxoquinoline -3-Carboxylic acid, purified lanolin, and white petrolatum are added, heated until it becomes liquid, and then stirred until it begins to solidify to obtain an ointment having the above composition.

Claims (1)

[Claims] 1 General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 has 1 to 3 groups selected from the group consisting of lower alkyl groups and halogen atoms as substituents A certain cyclopropyl group, a phenyl group that may have 1 to 3 groups selected from the group consisting of a lower alkoxy group, a halogen atom, and a hydroxyl group as a substituent on the phenyl ring, a halogen atom, a lower alkanoyloxy group, or a phenyl group as a substituent. Indicates a lower alkyl group, lower alkenyl group, or thienyl group that may have a hydroxyl group. R^2 represents a 5- to 9-membered saturated or unsaturated heterocyclic residue that may have a substituent. R^3 represents a hydrogen atom, a lower alkyl group, or a halogen atom. R^4 represents a lower alkyl group or a halogen atom. R represents a hydrogen atom or a lower alkyl group. Furthermore, R^1 and R^3 may be combined to form a group ▲There are mathematical formulas, chemical formulas, tables, etc.▼. Here, R^3^1 represents a hydrogen atom or a lower alkyl group. X represents a halogen atom. However, R^3 and R^4 must not be halogen atoms at the same time, and when R^3 represents a hydrogen atom, R^4 shall represent a lower alkyl group. Furthermore, when R^1 and R^3 come together to form the group ▲There are mathematical formulas, chemical formulas, tables, etc.▼, R
^4 shall represent a lower alkyl group. ] An antibacterial agent containing a benzoheterocyclic compound or a salt thereof as an active ingredient. (2) The antibacterial agent according to claim 1, wherein R^3 is a hydrogen atom, a lower alkyl group, or a halogen atom, and R^4 is a lower alkyl group. (3) R^2 may have a lower alkyl group, a lower alkanoyl group, a phenyl lower alkyl group as a substituent, and a phenyl group or a lower alkyl group as a substituent 2
-1-piperazinyl group which may have 1 to 3 groups selected from the group consisting of oxo-1,3-dioxolenemethyl group; An amino group that may have 1 or 2 lower alkyl groups or lower alkoxycarbonyl groups as a substituent of the amino group.
1-pyrrolidinyl group which may have 1 to 3 groups selected from the group consisting of amino lower alkyl groups and lower alkyl groups; morpholino group which may have 1 to 3 lower alkyl groups as substituents group; 1-piperidinyl group which may have 1 to 3 groups selected from the group consisting of lower alkyl group, hydroxyl group, halogen atom and oxo group as a substituent; or 1,4-diazabicyclo [4.3.
0] nonan-4-yl group. The antibacterial agent according to claim (2). (4) R^2 is the base ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (
R^a is a hydrogen atom or a lower alkyl group, and R^b is a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a phenyl lower alkyl group, or a 2-oxo-1,3-dioxolene having a lower alkyl group as a substituent. Methyl group, R^c represents a hydrogen atom or lower alkyl group) ▲ Numerical formula, chemical formula,
There are tables, etc.▼ (R^d indicates a hydrogen atom or a lower alkyl group, R^e indicates a hydrogen atom or a lower alkyl group),
▲There are mathematical formulas, chemical formulas, tables, etc.▼ (R^f is an amino group that may have one or two lower alkyl groups or lower alkoxycarbonyl groups as a substituent, or a lower alkyl group or lower as a substituent of an amino group. Amino lower alkyl group that may have one or two alkoxycarbonyl groups, R^g represents a hydrogen atom or a lower alkyl group)
, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^h is a hydrogen atom or a lower alkyl group, R^i is a hydrogen atom, hydroxyl group, halogen atom, or oxo group, R^j is a hydrogen atom or a lower alkyl group ) or 1,4-diazabicyclo[4.3.0]nonane-
The antibacterial agent according to claim (3), which is a 4-yl group. (5) R^1 is an unsubstituted cyclopropyl group, R^2 is a group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Same), X is a fluorine atom, R^3 is a hydrogen atom or a lower alkyl group, R^ The antibacterial agent according to claim 4, wherein 4 is a lower alkyl group and R is a hydrogen atom. (6) R^1 is an unsubstituted cyclopropyl group, R^2 is a group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^d and R^e are the same as above), X is a fluorine atom, R^ 3 is a hydrogen atom or a lower alkyl group, R^
5. The antibacterial agent according to claim 4, wherein 4 is a lower alkyl group and R is a hydrogen atom. (7) R^1 is an unsubstituted cyclopropyl group, R^2 is a group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^f and R^g are the same as above), X is a fluorine atom, R^ 3 is a hydrogen atom or a lower alkyl group, R^
5. The antibacterial agent according to claim 4, wherein 4 is a lower alkyl group and R is a hydrogen atom. (8) R^1 is an unsubstituted cyclopropyl group, R^2 is a group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^h, R^i and R^j are the same as above) or 1,4 −Diazabicyclo [
4.3.0] nonan-4-yl group, X is a fluorine atom, R^
The antibacterial agent according to claim 4, wherein 3 is a hydrogen atom or a lower alkyl group, R^4 is a lower alkyl group, and R is a hydrogen atom. (9) The antibacterial agent according to claim (5), wherein R^3 is a hydrogen atom and R^4 is a methyl group. (10) 7-(3-methyl-1-piperazinyl)-1-
cyclopropyl-6-fluoro-5-methyl-1,4-
An antibacterial agent containing dihydro-4-oxoquinoline-3-carboxylic acid or a salt thereof. (11) 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4
-An antibacterial agent containing oxoquinoline-3-carboxylic acid or a salt thereof.