JPS63264461A - Benzohetero ring compound and antibacterial agent containing said compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R<1> is cyclopropyl which may contain 1-3 substituent groups (alkyl or halogen); R<2> is 5-9-membered (substituted)heterocyclic residue; R<3> is alkyl which may contain 1-3 substituent groups (5-6-membered heterocyclic residue, alkylthio, amino OH or alkoxy); X is halogen] or a salt thereof. EXAMPLE:7-(1-Piperazinyl)1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4 -oxoquino line-3-carboxylic acid. USE:An antibacterial agent having excellent antibacterial activity widely against Gram-positive and Gram-negative bacteria. PREPARATION:A compound shown by formula III (R<5> is alkyl) obtained by using a compound shown by formula II (R<2>' is halogen or R<2>; X<2> is halogen) as a raw material is subjected to ring formation to give a compound shown by formula IV, which is hydrolyzed to give a compound shown by formula I.

Description

[Detailed Description of the Invention] Doutojo Gogo Akata! The present invention relates to a novel benzoheterocyclic compound and an antibacterial agent containing the compound.

Disclosure of the Invention The benzoheterocyclic compound of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula (1).

R3+ R word [In the formula, R1 is a cyclopropyl group which may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a halogen atom as a substituent, and R2 is a 5 to 9 substituent group which may have a substituent. A saturated or unsaturated membered heterocyclic residue, R3 is a saturated 5- to 6-membered heterocyclic residue as a substituent, lower alkylthio group, amino group, lower alkylamino group, lower alkanoyloxy group, hydroxyl group, lower alkoxy A lower alkyl group which may have 1 to 3 groups selected from the group consisting of groups and halogen atoms, and X represents a halogen atom. ] The benzoheterocyclic compound represented by the above general formula (1) and its salt exhibit excellent antibacterial activity against a wide range of Gram-negative bacteria and bacteria, and are effective against humans, animals, fish, etc. caused by various pathogenic bacteria. It is useful as a therapeutic agent for diseases, and is also useful as an external disinfectant or disinfectant for medical instruments.

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-dichlorocyclopropyl, 2,2-
Dibromocyclopropyl, 2,2.3-trichlorocyclopropyl, 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-dimethylcyclopropyl, 2,3-
Dimethylcyclopropyl, 2,2.3-trimethylcyclopropyl, 2-fluoro-3-methylcyclopropyl, 2゜2-diethylcyclopropyl, 2-methyl-3-
Examples include a cyclopropyl group that may have 1 to 3 groups selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms, such as a propylcyclopropyl group, and a halogen atom.

Lower alkyl groups include methyl, ethyl, propyl,
Isopropyl, butyl, tert-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 amine carbonyl 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-titrahydrobiridyl, imidazolyl, 1,4-diazabicyclo(4,3,O)nonan-4-yl, thiomorpholino-4-oxide, thiomorpholino- 4,4-dioxide, pyrazolidinyl, hexahydropyridazyl, pyridyl, thiazolidinyl, 2-thio-1-imidazolyl, 2
-oxo-1-imidazolidinyl, 3,7-diazabicyclo[4°3,O]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-trifluoroα, 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-fluorohyperethylsulfonyl)-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(5H)-furanon-5-yl)-1-piperazinyl, 4-(3,4-dichloro-2
(5 days)-furanone-5-yl)-1-piperazinyl,
4-(2(5H)-furanon-5-yl)-1-piperazinyl, 4-(3-chloro-2(5H>-7ranon-5-yl)-1-piperazinyl, 4-formyl-3-methyl-1 -piperazinyl, 4-7cetyl-3-ethyl-1-piperazinyl, 4-acetyl-2-methyl-1-piperazinyl, 4-methyl-3-hydroxymethyl-1-
Piperazinyl, 3-hydroxymethyl-1-piperazinyl, 4-ethyl-3-(2-hydroxyethyl)-1-
Piperazinyl, 3-(3-hydroxypropyl)-1-
Piperazinyl, 4-methyl-2-(4-hydroxybutyl)-1-piperazinyl, 4-ethyl-3-(5-hydroxypentyl)-1-piperazinyl, 3-(6-hydroxyhexyl)-1-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-cyclobenthyl-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-hexyl) phenyl)-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-dimethylaminopropyl)-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, 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-tert-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-aminehexanoyl)-1-piperazinyl, 4-(2-benzyloxycarbonylaminoacetyl)-1 -piperazinyl, 4-
(2-(2-phenylethoxycarbonylamino)acetyl-1-piperazinyl, 4-(2-(3-phenylpropoxycarbonylamino)acetyl-1-piperazinyl, 4-(2-(4-phenylbutoxycarbonylamino)acetyl 2-1-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- Piperazinyl, 4-carbonylmethyl-1-piperazinyl, 4-(2-carboxyethyl-piperazinyl, 4-(3-carboxypropyl)-1-piperazinyl, 4-(4-carboxybutyl)-1-piperazinyl, 4-( 5-carboxypentylboxyhexyl)-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, 4-bentyloxy-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-dimethylamine-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
-hyo')cinyl, 2-hydroxy-1-pyrrolidinyl, 2-amino-1-pyrrolidinyl, 3-methylamino-
1-pyrrolidinyl, 3-dimethylamine-1-pyrrolidinyl, 2-ethylamino-1-pyrrolidinyl, 3-propylamino-1-pyrrolidinyl, 2-n-butylamino-1-piperidinyl, 3-pentylamino-1-pyrrolidinyl , 2-hexylamino-1-pyrrolidinyl, 3-
diethylamino-1-pyrrolidinyl, 3-(N-methyl-N-propylamino)-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-hydroxybutyl)-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-aminehexyl)-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, 3-propylaminemethyl-5-propyl -1
-pyrrolidinyl, 3-n-butylaminomethyl-5-fluoro-1-pyrrolidinyl, 3-pentylaminomethyl-5-n-butyl-1-pyrrolidinyl, 3-hexylaminomethyl-5-chloro-1-pyrrolidinyl, 3-propylamino-5-chloro-1-pyrrolidinyl, 3-n-
Butylamino-5-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-hexahydropyridazyl, 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-methyl Aminomethylmorpholino, 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-tert-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-cyclopropylamino-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 −
Propoxycarbonylaminopropylmorpholino, 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)
- As a substituent for the 1-piperidinyl group, a straight chain or branched alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a straight chain having 1 to 6 carbon atoms as a substituent on the phenyl ring. A phenylalkyl group whose alkyl moiety is a straight or branched alkyl group having 1 to 6 carbon atoms, which may have a chain or branched alkoxy group, nitro group, or amino group; a substituent on the phenyl ring; As a halogen atom, a phenyl group that may have a linear or branched alkyl group having 1 to 6 carbon atoms and a pyridyl group that may have 1 to 3 halogen atoms, a hydroxyl group as a substituent, and a hydroxyl group that has 1 to 6 carbon atoms as a substituent. 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 straight chain or branched chain having 1 to 6 carbon atoms An amine group that may have 1 to 2 alkoxycarbonyl groups, a linear or branched alkoxy group having 1 to 6 carbon atoms, or 1 to 2 halogen atoms.
3g of straight-chain or branched alkyl groups having 1 to 6 carbon atoms, straight-chain or branched alkynyl groups having 2 to 6 carbon atoms, and 1 to 6 carbon atoms that may have 1 to 7 halogen atoms. Straight chain or branched alkanoyl group, having 1 to 3 halogen atoms or carboxy groups as substituents and having 2 to 6 carbon atoms
Straight-chain or branched alkenylcarbonyl group, carbon number 1
~6 linear or branched alkoxycarbonyl groups, aminocarbonyl groups that may have 1 to 2 linear or branched alkyl groups having 1 to 6 carbon atoms, and alkoxy moieties having 1 to 6 carbon atoms. 6, a phenylalkoxycarbonyl group which is a straight chain or branched alkoxy group, and a phenylalkoxycarbonyl group which is a straight chain or branched alkoxy group in which the alkoxy moiety has 1 to 6 carbon atoms as a substituent. A certain linear or branched aminoalkanoyl group having 2 to 6 carbon atoms, an alkoxy moiety and an alkyl moiety having 1 carbon atom
an alkoxycarbonylalkyl group which is a linear or branched alkoxy and alkyl group with ~6 carbon atoms, a carboxyalkyl group which is a linear or branched alkyl group with 1 to 6 carbon atoms in the alkyl moiety, and a carbon alkyl group in the alkyl moiety; Anilinocarbonyl alkyl group which is a straight chain or branched alkyl group having 1 to 6 carbon atoms, a straight chain or branched alkyl group having 1 to 6 carbon atoms as a substituent, and an alkyl moiety having 1 to 6 carbon atoms. A phenylalkyl group which is a straight chain or branched alkyl group, a straight chain or branched alkoxycarbonyl group having 1 to 6 carbon atoms, or a straight chain or branched alkanoyl group having 1 to 6 carbon atoms. ~
An amine group that may have two hydroxyl groups, a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms that may have 1 to 3 halogen atoms, a phthalide group, and 1 to 2 halogen atoms as a substituent. 2 things that I personally have (5H)
- Furanone group, sulfoalkyl group whose alkyl moiety is a straight or branched alkyl group having 1 to 6 carbon atoms, oxo group, straight or branched alkoxy group having 1 to 6 carbon atoms, 2 carbon atoms ~6 straight or branched alkenyl groups, halogen atoms, straight or branched alkanoyloxy groups having 2 to 6 carbon atoms, cycloalkylamino groups having 3 to 8 carbon atoms, cycloalkylamino groups having 1 to 6 carbon atoms Straight chain or branched alkylthio group, thio group, 2-oxo-1,3 which may have a phenyl group or a straight chain or branched alkyl group having 1 to 6 carbon atoms as a substituent
- selected from a dioquinolenemethyl group and a 2-oxo-1,3-dioxolenemethylamino group which may have a phenyl group or a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent; 5-, which may have 1-3 groups
Examples include 9-membered saturated or unsaturated heterocyclic residues.

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-
7 minophenyl) a linear or branched alkoxy group having 1 to 6 carbon atoms as a substituent on the phenyl ring such as hexyl group,
Examples include phenylalkyl groups in which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms and may have a nitro group or an amino 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, 2-(3,3-dibromopropyl)phenyl, 4-(4-chlorobutyl)phenyl, 3-
(5-iodopentyl)phenyl, 4-(6-fluorohexyl)phenyl, 2-(1,2,2-trifluoroethyl)phenyl, 4-(2,2,2-trifluoroethyl)phenyl, etc. Examples include a phenyl group that may have a halogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms and may have 1 to 3 halogen atoms as a substituent on the phenyl ring.

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-phenylethyl, 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-methyl aminomethyl,
N-acetyl-N-ethylaminomethyl, N-acetyl-N-cyclop[copylaminomethyl, N,N-dicyclopropylaminomethyl, cyclopropylaminomethyl, 2-cyclobutylaminoethyl, 3-cyclopentyl, 1- Cyclopropylaminoethyl, 2-cyclopropylaminoethyl, aminopropyl, 4-cyclohexylaminobutyl, 5-cyclohebutylaminopentyl, 6
-cyclooctylaminohexyl, N-methyl-N-cyclopropylaminomethyl, N-ethyl-N-cyclopropylaminomethyl, me]-oxycarbonylaminomethylnylaminoethyl, 3-propoxycarbonylaminopropyl, 4-t- butoxycarbonylaminobutyl lucyl 2-t-butoxycarbonylaminoethyl t-butoxycarbonylaminoethyl butoxycarbonylamino-N-methylaminomethyl,
As a substituent for the N-t-butoxycarbonylamino-N-ethylaminomethylylamino-N-cyclopropylaminomethyl group, a water @ group, a straight or branched alkyl group having 1 to 6 carbon atoms, a carbon number Straight chain or branched alkanoyl group having 1 to 6 carbon atoms, cycloalkyl group having 3 to 8 carbon atoms, or cycloalkyl group having 1 to 6 carbon atoms
An amino group which may have 1 to 2 straight or branched alkoxycarbonyl groups, a straight or branched alkoxy group having 1 to 6 carbon atoms, or a 1 to 3 carbon atom having 1 to 3 halogen atoms. -6 linear or branched alkyl groups can be exemplified.

Lower alkanoylpropionyl, which may have 1 to 7 halogen atoms, 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-trifluoropropionyl Examples include straight-chain or branched alkanoyl groups having 1 to 6 carbon atoms that may have 1 to 7 halogen atoms.

Examples of lower alkenylcarbonyl groups having 1 to 3 halogen atoms or carboxyl groups as substituents include 3-carboxyacryloylxy-2,3-dichloroacryloyl, 3-carboxy-2,3-dibromoacryloyl, 4-carboxycroto Noyl, 4-carboxyincrotonoyl 6-carboxy-4-hexenoyl, 4-carboxy-
Examples of C2-C6 linear or branched alkenylcarbonyl groups having 1-3 halogen atoms or carboxy groups as substituents such as 3-fluorocrotonoyl-3,4-dichloro-3-hexenoyl can.

As the lower alkoxycarbonyl group, a straight or branched alkoxycarbonyl group having 1 to 6 carbon atoms such as methoxycarbonylcarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl group, etc. I can give an example.

Aminocarbonyl groups that may have a lower alkyl group include carbamoyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, n-butylaminocarbonyl, pentylaminocarbonylnyluminocarbonyldiethylaminocarbonyl, diethylaminocarbonyl, N-methyl- N-propylaminocarbonyl, N-methyl-N-tert-butylaminocarbonyl, N
-Ethyl-N-Pentylaminocarbonyl group and the like are 1 to 2 linear or branched alkyl groups having 1 to 6 carbon atoms (aminocarbonyl groups that may be unique are exemplified).

Examples of the phenyl lower alkoxycarbonyl group include benzyloxycarbonyl, 2-phenylethoxycarbonyl, 1-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl,
1,1-dimethyl-2-phenylethoxycarponyl,
1 carbon number in alkoxy moiety such as 5-phenylpentyloxycarbonyl, 6-phenylhexyloxycarbonyl, 2-methyl-3-phenylpropoxycarbonyl group, etc.
-6 linear or branched alkoxy groups) carbonyl groups can be exemplified.

The amino lower alkanoyl group that must have a phenyl lower alkoxycarbonyl group as a substituent includes 2
-Aminoacetyl, 3-aminopropionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminehexanoyl, 2-benzyloxycarbonylaminoacetyl-phenylethoxycarbonylamino)acetyl, 2-
(3-phenylpropoxycarbonylamino)acetyl, 3-(4-phenylbutoxycarbonylamino)propionyl, 4-(1.1-dimethyl-2-phenylethoxycarbonylamino)butyryl, 5-(5-phenylpentyloxycarbonylamino) ) pentanoyl, 6-
(6-phnynylhexyloxycarbonylaminol, 2-(2-methyl-3-phenylpropoxycarbonylamino) as a substituent for acetyl group, etc.) is a linear or branched alkoxy group having 1 to 6 carbon atoms in the alkoxy moiety. Examples include straight-chain or branched aminoalkanoyl groups having 2 to 6 carbon atoms, which may have a phenylalkoxycarbonyl group.

Examples of the lower alkoxycarbonylalkyl group include methoxycarbonylmethyltylopoxycarbonylpropyl, 4-butoxycarbonylbutyl, 5-pentyloxycarbonylpentyl, 6-
As an alkoxycarbonylalkylcarboxy lower alkyl group that is a straight or branched alkoxy or alkyl group having 1 to 6 carbon atoms in hexyloxycarbonylhexyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropoxypropylpropoxypropyltoxybutyl. is an alkyl group such as carboxymethyl, 2-carboxyethyldipropyl, 4-carboxybutylxypentyl, 6-carboxyhexylulpoxyethyl, 1,1-dimethyl-2-carboxyethyl, 2-methyl-3-carboxypropyl group, etc. Examples include carboxyalkyl groups, which are linear or branched alkyl groups having 1 to 6 carbon atoms.

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

Examples of amino groups that may have a lower alkyl group or lower alkanoyl group as a substituent include amino, methylamino, ethylamino, propylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, di-n -propylamino, di-n-
Butylamino, diethylamino, diethylamino, N-
Methyl-Nn-butylamino, N-methyl-N-pentylamino, N-ethyl-N-hexylamino, acetylamino, formylamino, propionylamino, butyrylamino, pentanoylamino, hexanoylamino, N-methyl- N-acetylamino, N-ethyl-N-
Straight chain or branched chain having 1 to 6 carbon atoms as a substituent for propionylamino, N-methyl-N-butyrylamino, N-n-propyl-N-pentanoylamino, N-ethyl-N-hexanoylamino groups, etc. alkyl group or carbon number 1-
Examples include amine groups that may have 1 to 2 straight-chain or branched alkanoyl groups of 6.

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

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-trifluorobutylsulfonyl, 5-chloropentylsulfonyl, 6-bromohexylsulfonyl, 6-iodohexylsulfonyl, 2,2-difluoroethylsulfonyl, 2,3-dibromopropylsulfonyl Examples include straight-chain or branched alkylsulfonyl groups having 1 to 6 carbon atoms that may have 1 to 3 halogen atoms.

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 straight chain 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 which may have a phenyl group or lower alkyl group as a substituent includes (5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl , (5-tert-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.

As a substituent, a group selected from the group consisting of a saturated 5- to 6-membered heterocyclic residue, a lower alkylthio group, an amino group, a lower alkylamino group, a lower alkanoyloxy group, a hydroxyl group, a lower alkoxy group, and a halogen atom is used. Examples of lower alkyl groups that may have three groups include hydroxymethyl, 2-hydroxyethyl, 1
-Hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, fluoromethyl, 3-chloropropyl,
Bromomethyl, 2-fluoroethyl, 4-chlorobutyl, 3-fluoropentyl, difluoromethyl, 2,3-
dichlorohexyl, 2゜2.2-trifluoroethyl,
trifluoromethyl, chloromethyl, dibromomethyl,
iodomethyl, dichloromethyl, methoxymethyl, ethoxymethyl, 2-propoxyethyl, 3-butoxypropyl, 4-pentyloxybutyl, 5-hexyloxypentyl, 6-medoxyhexyl, propoquinemethyl,
1-ethoxyethyl, 2-hexyloxyethyl, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-
Aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-7 minohexyl, 3-dimethylaminepropyl, 2-ethylaminoethyl, 4-propylaminobutyl, 5-n-butylaminopentyl, 6-pentylaminohexyl, Methylaminomethyl, diethylaminomethyl, 2-dipropylaminoethyl, 1-di-n-butylaminoethyl, 3-diethylaminomethyl, 4-di-hexylaminobutyl, N-methyl-N-ethylaminomethyl, N-methyl -N-propylaminomethyl, formyloxymethyl, acetyloxymethyl, 2-propionyloxyethyl, 3-butyryloxypropyl, 4-pentanoyloxybutyl, 5-hexanoyloxypentyl, 6-acetyloxyhexyl, propionyl Oxymethyl, 1-acetyloxyethyl, 2-hexanoyloxyethyl, (1-pyrrolidinyl)methyl, 1-(
1-piperazinyl)ethyl, 2-(1-piperidinyl)
Ethyl, 3-morpholinopropyl, 4-thiomorpholinobutyl, 5-(1-pyrrolidinyl)pentyl, 6-(1
-piperazinyl)hexyl, methylthiomethyl, ethylthiomethyl, 2-propylthioethyl, 1-isopropylthioethyl, 3-butylthiopropyl, 4-ter
t-Butylthiobutyl, 5-pentylthiopentyl, 6
-Saturated 5 as a substituent, such as hexylthiohexyl group
~6-membered heterocyclic residue, a straight or branched alkylthio group having 1 to 6 carbon atoms, a hydroxyl group, an amine group, or having 1 to 2 straight or branched alkyl groups having 1 to 6 carbon atoms Amine group, linear or branched alkoxy group having 1 to 6 carbon atoms, 1 carbon number
Examples of straight-chain or branched alkyl groups having 1 to 6 carbon atoms that may have 1 to 3 groups selected from the group consisting of ~6 straight-chain or branched alkanoyloxy groups and halogen atoms can.

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-ter
t-Butyl-2-oxo-1,3-dioxolene-4-
yl) methylamine, (5-phenyl-2-oxo-1
,3-dioxolen-4-yl)methylamine, (2-
Oxo-1,3-dioxolen-4-yl)methylamine, (5-pentyl-2-oxo-1,3-dioxolen-4-yl)methylamine, (5-hexyl-2-oxo-1,3 -dioxolene-4-yl)methylamine, (5-ethyl-2-oxo-1°3-dioxolene-
4-yl)methylamine, (5-propyl-2-oxo-1,3-dioxolen-4-yl)methylamino group, etc. as a substituent for a phenyl group or a straight or branched chain alkyl group having 1 to 6 carbon atoms. 2-oxo-1 which may have groups
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.

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) R3 (1a) (In the formula, R+, R2, R3 and X are the same as above.

R2/ represents a halogen atom or R2 (R2 is the same as above). R' is a group -COR9 (here R9 represents a lower alkyl group) or a group -GOORI O (here RRI
O represents a lower alkyl group. > indicates. R5 represents a lower alkyl group. R8 is a group -N and 1=<+; (where R1
+ and R12 each represent a lower alkyl group. ) or lower alkoxy group. x2 and x3 each represent a halogen atom. R7 and R8 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. (DM
F>, dimethyl sulfoxide (DMSO>, etc.).As the halogenating agent, common halogenating agents capable of converting the hydroxyl group of a carboxy group into a halogen can be used, such as thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, Examples include phosphorus pentachloride, phosphorus pentabromide, etc.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. For reaction, the latter is usually used in a large excess of the former, and 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. Although the temperature and reaction time are not particularly limited, the reaction is 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 that can be used include inorganic bases such as sodium metal, potassium metal, magnesium metal, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium hydrogen carbonate; Examples include metal alcoholades such as ethylate, sodium ethylate, and organic bases such as pyridine, piperidine, quinoline, triethylamine, and N,N-dimethylaniline. The reaction temperature is usually 0 to 150°C, preferably around room temperature to 120°C, and the reaction is generally completed in about 5 to 15 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, preferably twice an equimolar amount, of the former. The amount of the basic compound used is the general formula (3)
at least equimolar, preferably equimolar to 2 molar relative to the compound.

It is better to use quantity.

In the compound of general formula (5), when R4 is a group -COR9, the CO removal and R9 reaction of the compound 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, and diglyme, aromatic hydrocarbons such as benzene, toluene, and xylene, and fatty acids such as n-hexane, heptane, and cyclohexane. Examples include group hydrocarbons X'jj, aprotic polar solvents such as DMF, DMSO, and HMPA. Examples of the basic compound include ammonia gas, aqueous ammonia, ammonium salts such as ammonium chloride, and primary or secondary amines such as ethylamine, diethylamine, and piperidine. The reaction temperature is usually 0 to 150°C, preferably around room temperature to 100'C, and the reaction is generally completed in about 1 to 20 hours.

In the compound of general formula (5), when R' is a group -COORI O, the removal of COOR of the compound
The 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 completed in about 1 to 20 hours.

Then, the obtained JB2 R' compound and the general formula (
The reaction with the compound 6) is carried out by reacting both in an appropriate solvent. As the solvent used here, in addition to lower alkanoic anhydride such as acetic anhydride, any solvent used in the above-mentioned R4 removal reaction can be used. The reaction temperature is usually 0 to 200'C, preferably 0 to 200'C.
The temperature is around 150°C, and 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 large excess, preferably equimolar to molar amount, relative to the compound of general formula (5). When using a compound of general formula (6) in which R6 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-200 'C1 is preferably around 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, DMSO ,HMPA
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 0.5 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 twice equimolar, relative to 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, DMSOlHMP
Examples include aprotic polar solvents such as A and the like. Basic compounds that can be used include S bases such as metallic sodium, metallic potassium, sodium hydride, sodium amide, sodium hydroxide, and potassium hydroxide; golden alcoholades such as sodium methylate and sodium ethylate; Examples include organic bases such as 1°8-diazabicyclo(5,4,0)undecene-7 (DBU), N-benzyltrimethylammonium hydroxide, and tetrabutylammonium hydroxide.

The reaction temperature is usually 0 to 150°C, preferably air temperature to 12°C.
The temperature is preferably around 0°C, and the reaction is generally completed in about 0.5 to 5 hours. The amount of basic compound used is based on the general formula (
The amount is usually at least equimolar, preferably twice equimolar, based on the compound (9).

For the hydrolysis reaction of the compound of general formula (10), 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, solvents such as acetic acid, or mixed solvents thereof. The reaction usually proceeds at room temperature to 200°C, preferably at air temperature to around 150°C, and is generally completed in about 0.1 to 30 hours. In this way, a compound of general formula (1a) is produced.

[Reaction formula-2] ○ (1b) [In the formula, R1, R3 and X are the same as above. ×4 indicates a halogen atom. R+3 is a hydrogen atom or a group -B0COR1
(R and RI5 represent an Al0COR' 5 kyl group.)] In the reaction between the compound of general formula (1b) and the compound of general formula (11), the proportion of both to be used is not particularly limited and can be selected from a wide range. Although they can be selected as appropriate, it is usually preferable to use at least an equimolar amount of the latter to the former, preferably about equimolar to 5 molar. 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, ethers such as tetrahydrofuran, dioxane, diglyme, dimethylacetamide, DMF, DM
The reaction is carried out in a solvent such as SO, HMPA, N-methylpyrrolidone, etc. or a mixed solvent thereof. Among these, DMFSDMS
O,HMPA and N-methylpyrrolidone are preferred. The reaction can also be carried out in the presence of a deoxidizing agent, 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.
It is carried out at a temperature of 0.00'C, generally between 0.5 and 30
It took about an hour.

In the general formula (1b'), when R+3 represents a group -B 0COR'', an acid or a base 0COR
By treating with a compound having 5 properties, the chelate can be decomposed and lead to the corresponding compound (1b') in which R13 is a hydrogen atom. Examples of acids used here include mineral acids such as hydrochloric acid and sulfuric acid; Examples include organic acids such as acetic acid and p-toluenesulfonic acid. Examples of basic compounds 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, it progresses suitably 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] (1c)' (In the formula, X, R' and R3 are the same as above. Z and W each represent a group of 1cH2-1 and the other -Nl-().

n represents an integer of 1 to 3.

R+6 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. ×5 indicates a halogen atom. One of Z' and W' represents a -CH2-1 group and the other represents an NRIB group. ] The reaction between the compound of general formula (1C) 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 (1G) is usually used in an equimolar to large excess amount, preferably about 1 to 3 moles, relative to the compound of general formula (12).
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, R', R3, Z, W, n and X are the same as above. R
17 and R18 each represent a hydrogen atom or a lower alkyl group. One of Z″ and W″ is a group -CH2-1
The reaction between the compound of formula (1C), where the other is -Iil'2, and the compound of general formula (13) is carried out without a solvent or in the presence of a reducing agent in a suitable solvent. 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. As a reducing agent,
Formic acid, alkali metal or alkaline earth metal salts of formate such as sodium formate, hydrogenation reducing agents such as sodium boron hydride, sodium cyanoborohydride, lithium aluminum hydride, palladium black, palladium carbon, platinum oxide,
Examples include catalytic reducing agents such as platinum black and Raney nickel. When formic acid is used as a reducing agent, the reaction temperature is usually room temperature to 200°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 reducing agent used is determined by the general formula (
It is usually used in an equimolar to 20-fold molar amount, preferably 1 to 6-fold molar amount, relative to the compound 1C). In particular, when using lithium aluminum hydride as a reducing agent, ethers such as diethyl ether, dioxane, tetrahydrofuran, diglyme, benzene, toluene,
It is preferable to use aromatic hydrocarbons such as xylene. When using a catalytic reducing agent, it is usually -3 atm in a hydrogen atmosphere of usually normal pressure to 20 atm, preferably normal pressure to 10 atm.
The reaction is preferably carried out at a temperature of 0 to 100°C, preferably 0 to 60°C, and is usually completed in 1 to 12 hours.

The amount of catalyst used is usually 0.1 to 40% by weight, preferably 0.1 to 20% by weight, based on the compound of general formula (1C).
It is preferable to use % 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 (1C).

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>R word
9 (20) , (2
a>(In the formula, X, R2' and X2 are the same as above. x5 and X6 represent a halogen atom. R+9 represents a hydrogen atom or a lower alkyl group. R20 represents a lower alkyl group.

Further, RI9 and R20 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 R19 and R20 are bonded to each other to form a 5- to 7-membered ring, RI9 in the compound of general formula (20) is -RI9 R
It becomes 2OH.

First, the compound of general formula (16) is prepared using the 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 by general formula It can be obtained by reacting a thio compound represented by (15).

In the above, the reaction between one aniline derivative of general formula (14) and a 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. Examples include lower alcohols, DMSO, HMPA, acetonitrile, and other polar solvents. Further, as the halogenating agent used in the above reaction, any of various compounds used in ordinary halogenation reactions can be used. Representative examples thereof include N-bromosuccinimide, N-chlorosuccinimide, sodium hypobromite, sodium hypochlorite, mustard powder, thionyl chloride, and tert-butylhypochloride. Use of secondary halogenating agent■
Usually, the amount is at least equimolar to the starting material compound, preferably about 1 to 6 times the molar amount.

The reaction temperature is generally -78°C to room temperature, preferably -60°C.
The temperature is about 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 hydrogen carbonate, 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 for the intermediate of general formula (14a) in this reaction is at least an equimolar amount to -1i1'2, preferably may be about 1 to 1.5 times the molar amount.The reaction is usually completed at room temperature to 150°C, preferably around room temperature to 100°C, in about 1 to 5 hours.

-Iilu The reaction between the compound of 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 DMSO. , H.M.
Examples include polar solvents such as PA and 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. The amount of the compound of general formula (17) to be used is usually at least equimolar, preferably equimolar to molar, relative to the compound of general formula (16). The reaction normally proceeds suitably at room temperature to 200°C, preferably at air temperature to around 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, and trinoenyl phosphine, with Raney nickel being preferred. Examples of the solvent include alcohols such as methanol, ethanol and isopropanol, and ethers such as dioxane, tetrahydrofuran and ethyl ether. The reaction temperature is about O~200'
C1 is preferably set at room temperature to around 100°C, and the reaction is completed at about 10 minutes to 5 o'clock. The amount of catalyst used is usually about 1 to 10 times the weight of the compound of general formula (18).

The reaction that leads the compound of general formula (19) to the compound of general formula (20) is obtained by reacting 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 reaction product with a metal halide salt such as potassium iodide, cuprous chloride, cuprous bromide, etc., without removing the reaction 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 DMFXDMSO, 1 (MPA, etc.), and mixed solvents such as DMFXDMSO, 1 (MPA, etc.).As the layer for use of metal sulfite salts and saline metal halides, the general formula (19 ) at least 1 equimol each for each compound
, preferably in 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 process progresses at around °C, and the circuit-opening reaction 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 a suitable solvent (for example, water or a mixed bath of water and a lower alcohol such as methanol or ethanol)
), usually 50-200'C1, preferably 70-180°C
The open circuit reaction is completed at -1iR for about 1 to 10 hours.

In reaction formula-2, R+3 is a group For example, it is produced by the method shown in Reaction Formula-6 below.

[Reaction formula-6] (1) (1Q) (In the formula, R1, R3, X, X4, RI4 and RI5 are the same as above. R51 represents a lower alkyl group or a hydrogen atom.

R13' represents a group -B0COR: ; R2+ represents a lower alkyl COR 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 R4-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 from very low temperature to around 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, preferably equimolar -1 to the compound of general formula (1f).
It is better to use 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) [In the formula, x7 represents a halogen atom. R22 represents an engineering lower alkoxycarbonyl group, R22' 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'. ] -Flu The reaction conditions for a normal amide bond forming reaction can be widely applied to the reaction between the compound of the formula (22) and the compound of the general formula (23). 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), (22) as p-nitrophenyl ester, N-hydroxysuccinimide ester,
A method of preparing an active ester such as 1-hydroxybenzotriazole ester and reacting it with azide (23),
(c) Carbodiimide method, that is, a method in which azide (23) is condensed with carvone M (22>) in the presence of an activator such as dicyclohexylcarbodiimide or carbonyldiimidazole; (d) Other methods include carvone! (22>)
is converted into carboxylic acid anhydride with a dehydrating agent such as acetic anhydride, and this is reacted with azide (23).
A method of reacting azide (23) with an ester of carbon 1 (22) and a lower alcohol under high pressure and high temperature.
Examples include a method of reacting.

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

As the basic compound used, compounds used in the Schotten-Baumann reaction are used, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo(4
, 3, O) nonene-5 (DBN), 1°8-diazabicyclo(5,4, O) undecene-7 (DBtJ>, 1.
4-Diazabicyclo(2,2゜2)octane (DABG
Examples include organic bases such as O), inorganic bases such as potassium carbonate, sodium carbonate, 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 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 examples include water, halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, and aromatic solvents such as benzene, toluene, and xylene. group hydrocarbons, diethyl ether, tetrahydrofuran,
Ethers such as dimethoxyethane, esters such as methyl acetate and ethyl acetate, ketones such as acetone, DMF,
Examples include aprotic polar solvents such as DMSO, HMPA, and mixed solvents thereof. Examples of the alkylhalocarboxylic acids used in the mixed acid anhydride method include methyl chloroformate, methyl proheptaformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like. Azide (23) is used in Carvone! (22>
Usually at least equimolar, preferably equimolar 1
．． It is better to use a 5x molar base.

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. Examples of solvents used include, for example, alcohols such as methanol, ethanol, propatool, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, in addition to the solvents used in the bisynthetic anhydride method (above); Examples include pyridine, acetone, acetonitrile, and mixed solvents thereof. Azide (2
The ratio of 3) and carboxylic acid halide to be used is 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 5 times the molar maximum. It is better to set it as a degree. The reaction normally proceeds suitably at about -30 to 180°C, preferably about 0 to 150°C, and generally opens 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 in the absence of a solvent, usually at O to 150°C.
, preferably 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.

-IIQ The reaction of directly leading the compound of formula (22) to the compound of general formula (27) is generally called 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, phosphorus compounds such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, and phosphorus pentoxide, thionyl chloride, ferric chloride,
Examples include aluminum chloride, stannic 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 0 to 150°C, preferably around 0 to 100°C, and the open circuit reaction 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] (1C) [In the formula, R23 represents a phenyl group, a lower alkyl group, or a hydrogen atom. X8 represents a halogen atom.

Z''' and W''', one of which is a group -CH2-10
0 R', R3, Z, W, X and n C Same as above. ] The reaction between the compound of general formula (1G) and the compound of general formula (28) is 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 Formula-2 above. You can go downstairs.

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, (CI) phthalide group,
(h) 2 (5H)-furanone group that may have 1 to 2 halogen atoms as a substituent and 2 that may have a phenyl group or 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 opening the circuit for about 0.5 to 10 hours at around 00°C under a hydrogen pressure of 1 to 10 atm (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 sulfonylation of , dephenyl lower alkyl (for example, debenzyl) or dephenyl lower alkoxy.

Further, a compound (1) having (b) to (+> as a substituent)
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 (10).

Among the compounds of general formula (1), the compound having a heterocyclic residue having an amine group as a substituent is similar to the reaction between the compound of general formula (1C) and the compound of general formula (28) in reaction formula-8 above. The reaction can lead to a compound having a heterocyclic residue using an apparatus.

In addition, among the compounds of general formula (1), compounds having a group as a substituent can be hydrolyzed under the same conditions as the hydrolysis reaction of the compound of general formula (10), so that an amino group can be added as a substituent. This can lead to compounds having a heterocyclic residue.

[Reaction formula-9] R3' I R' (1j) [In the formula, R1, R2'x9 and X are the same as above.

is the same as above) or R3 (R3 is the same as above).

R24, R25, R2B, R27 and R2B each represent a lower alkyl group. ] The reaction between the compound of general formula (37) and the compound of general formula (8) is 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 Formula-2 above. You can do it at

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, and polar solvents such as acetonitrile, DMF, DMSO, and HMPA. Compound of general formula (30a) or general formula (
The amount of the compound 30b) to be used is usually at least about equimolar, preferably about equimolar - 1.5 molar relative to the compound of general formula (29). The reaction is
It usually proceeds suitably at room temperature to 200°C, preferably around 60 to 200°C, and is generally closed for 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 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 250°C.
Heating conditions of 00'C can be adopted. In addition, when employing a cyclization method using an acidic substance, it is usually used in an equimolar amount to the compound of general formula (31) or (32), in a large excess amount,
Preferably use 10 to 20 times the amount, usually air temperature to 150°C
The circuit may be opened for about 0.1 to 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 (10) in Reaction Formula-1 above.

In the compound of general formula (1j), when R3/ is a group I9 -CH3''R20, the same reaction as that leading from the compound of general formula (18) to the compound of general formula (19) in Reaction formula-5 above is performed. can be treated under the reaction conditions of , to lead to compounds in which the corresponding R3/ is a group -CH2R19.

In addition, in the compound of general formula (1j), R2/ is 5 to 5 having 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 (10) in Reaction Formula-1 above. A compound in which R2/ 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 2.

In the cyclization reaction of the compound of general formula (31) and the compound of general formula (32), R3/ is a lower alkyl group having at least one of a halogen atom, a hydroxy group, or a lower alkoxy group, and an acid is used as a solvent. When an anhydride is used, the group may be acylated under the reaction conditions and converted into a lower alkyl group having at least one lower alkanoyloxy group; Separable.

[Reaction formula-10] [In the formula, R1, R2', R+9, R20, X and x6 are the same as above. R29 represents a lower alkanoyl group, and X9 represents a halogen atom. ] The desulfurization reaction of the compound of general formula (16) or the compound of general formula (29b) is carried out under the same reaction conditions as the desulfurization reaction of the compound of general formula (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 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 to be used is preferably at least equimolar, generally equimolar to large excess, relative to the compound of general formula (33). The reaction normally proceeds suitably at a temperature of about 0 to 150°C, preferably about 0 to 100°C, and the circuit opening is generally completed in about 5 minutes to 10 hours. In addition, when using a lower alkanoic acid as a lower alkanoylating agent,
Furthermore, mineral acids such as sulfuric acid and hydrochloric acid and p
- Sulfonic acids such as toluenesulfonic acid, benzenesulfonic acid, and ethanesulfonic acid are preferably added, 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 acid sulfuric acid, fuming sulfuric acid. , 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 51 ftM or polyphosphoric acid. The amount of the nitrating agent to be used is usually from equimolar to 1.5 times the molar amount of the compound of general formula (33) or the compound of general formula (34). The reaction is usually carried out at about -10 to 70°C, and the opening reaction is generally completed for about 1 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 (10).

The reaction between the compound of the general formula (37a) or the compound of the general formula (38) and the compound of the general formula (8) can be carried out using the reaction formula-2 described above.
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 .

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 that leads the compound of general formula (29b) to the compound of general formula (29a) is the reaction of converting the compound of general formula (18) to the compound of 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 general formula (15))
1q is carried out under the same reaction conditions as 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 such as 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 2 times the molar amount, preferably an equimolar to 1.5 times the molar amount of the compound of general formula (36). The amount of copper halide to be used is usually from equimolar to 5 times the molar amount of the compound of general formula (36), preferably from equimolar to 4 molar. The reaction is usually carried out at -20 to 100'C
The reaction is preferably carried out at a temperature of around -5 to 100°C, and the reaction time is generally 10 minutes to 5 hours open circuit.

The halogen atoms represented by X9 in the compound of general formula (37a) are mutually convertible.

(Reaction formula-11) <42) Changsho (In the formula, R2', R19, R20, R29, x, x6 and x9 are the same as above.) The hydrolysis reaction of the compound of general formula (40) is The reaction can be carried out under the same reaction conditions as the hydrolysis reaction of the compound of general formula (10).

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

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] (48) <29b) [Reaction formula-13] (J) [In each of the above formulas, R', R'', X and X9 are the same as above.

A is a lower alkylene group, m is 0 or 1, and XIO is an engineered sulfonyloxy group (which necessarily has a lower alkyl group) or a halogen atom. Further, R30 is a lower alkyl group, R31 is a lower alkanoyloxy group, R32 and R
33 are the same or different and represent a hydrogen atom or a lower alkyl group. R34 represents a lower alkyl group.

R35 represents a hydrogen atom or a nitro group. ]The above reaction formula-
In 12, the nitration reaction of the compound of general formula (44) can be carried out under the same reaction conditions as the nitration reaction of the compound of general formula (34) in Reaction Scheme-10.

The reduction reaction of the compound of general formula (44) or (45) is usually carried out using a hydrogenation reducing agent. Examples of the hydrogenation reducing agent include sodium borohydride, lithium aluminum hydride, diphoran, etc., and the amount used is usually at least equimolar to the compound of general formula (44) or (45). , preferably in the range of equimolar to 3 molar.

This reduction reaction is usually carried out using a suitable solvent such as water, lower alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran, ethyl ether and diglyme, DMSO, etc., at approximately -60 to 80°C.
C1 Preferably, it is carried out at -30 to 50°C and at an opening time of about 10 minutes to 15 o'clock. In addition, when aluminum hydride or diborane is used as a reducing agent, it is preferable to use an anhydrous solvent such as ethyl ether, tetrahydrofuran, or diglyme.

For the reaction of halogenating the compound of general formula (46) to lead to the compound of general formula (47) in which ) The compound of general formula (46) may be reacted with a halogenating agent in an inert solvent or without a solvent. Examples of the halogenating agent used include hydrohalic acids such as hydrochloric acid and hydrobromic acid, N,N-diethyl-1,2,2-1-lichlorvinylamide, phosphorus pentachloride, phosphorus pentabromide, Phosphorus oxychloride, thionyl chloride, diethylaminosulfa I-refluoride (DAS
T) etc. Examples of the inert solvent include ethers such as dioxane and tetrahydrofuran, and halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride. The proportion of the compound of general formula (46) and the halogenating agent used is such that the latter is at least equimolar to the former, usually in an equimolar excess.

The reaction is usually carried out at 0°C to 150'C, preferably 0°C to 8'C.
The process progresses suitably at 0°C, and the anti-open circuit is generally completed in about 10 minutes to 15 hours. When DAST is used as a halogenating agent, a basic compound such as triethylamine may be added to the reaction system.

Furthermore, by reacting the compound of general formula (46) with a phenylsulfonyl halide that may have a lower alkyl group, a compound of general formula (47) in which XIO is a phenylsulfonyloxy group that may have a lower alkyl group can be obtained. can lead to. The reaction is carried out by the general formula (4
6) to lead to the compound of general formula (49)
It can be carried out under the same reaction conditions as in the method described above.

The reaction between the compound of general formula (48) in which R35 is a nitro group 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 Reaction Formula-2 above. It can be carried out under similar reaction conditions. The compound of the general formula (48) in which R35 is a hydrogen atom can be expressed by the general formula (
After nitration in the same manner as the nitration reaction of the compound of 44), it may be reacted with the compound of general formula (8).

The reaction for converting the compound of general formula (47) into the compound of general formula (48) can be carried out under the same reaction conditions as the reduction reaction of the compound of general formula (45).

In addition, in the above reaction formula-13, various methods are possible for the reaction that leads the compound of general formula (46) to the compound of general formula (49), but for example: , R34X+ 1 (R34 is a lower alkyl group,
(Xl+ represents a halogen atom), ■ A method of reacting with a lower alcohol (straight or branched chain alcohols having 1 to 6 carbon atoms, such as methanol, ethanol, isopropanol, butanol) in the presence of an acid. etc. can be applied.

Examples of solvents used in the method (2) above include ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, and diglyme, alcohols such as methanol, ethanol, and isopropanol, and aromatic solvents such as benzene, toluene, and xylene. Hydrocarbons, aliphatic hydrocarbons such as n-hexane, heptane, cyclohexane, ligroin, pyridine, amines such as N,N-dimethylaniline, halogenated hydrocarbons such as chloroform, dichloromethane, carbon tetrachloride, DMF , DMSO, aprotic polar solvents such as hexamethylphosphoric acid triamide (1-IMPA), or a mixed solvent thereof. Basic compounds that can be used include inorganic bases such as sodium metal, potassium metal, magnesium metal, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium hydrogen carbonate; Examples include metal alcoholades such as lattate and sodium ethylate, and organic bases such as pyridine, piperidine, quinoline, triethylamine, and N,N-dimethylaniline. The reaction temperature is usually 0 to 120°C, preferably around room temperature to IOO'C, and the open circuit reaction is generally completed in about 0.1 to 5 hours. The amount of the compound of general formula (R34XI + ) to be used with respect to the compound of general formula (46) is usually at least an equimolar amount of the latter to the former, preferably three times an equimolar amount.

Examples of acids used in (2) include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid. The reaction is usually carried out at air temperature to 15
1 to 50 at 0°C, preferably around 50 to 120°C
The circuit will be opened for about an hour. It is generally advisable to use a large excess amount of the lower alcohol.

The acylation reaction of the compound of general formula (46) can be carried out under the same conditions as the reaction for converting the compound of general formula (33) into the compound of general formula (34) in Reaction Formula-10.

Reaction of compounds of general formulas (46), (49), (50) and (47) with compounds of general formula (52) and general formula (4)
The reaction between the compound of formula 7) and the compound of general formula (54) can be carried out in a suitable solvent or without a solvent, in the presence or absence of a basic compound. As the chemical compound, the general formula (3
) and the compound of general formula (4) can be used.

Also, general formulas (46), (49), (50) and (47)
In the reaction between each compound and the compound of general formula (52), the compound of general formula (52) may be used as the basic compound.

The amount of each compound of general formulas (52) and (54) to be used is determined by the amount of each raw material compound with which it is reacted, i.e., general formulas (46>, (
It is preferable to use the compound in at least an equimolar amount, preferably in large excess, relative to each of the compounds (49), (50), and (47). The above reaction is carried out from about 0 to 150'C1, preferably from room temperature to 1
The process ends at approximately 3:00 to 15:00 at around 00°C.

The hydrolysis reaction of the compound of general formula (50) is carried out by the above general formula (
The reaction can be carried out under the same conditions as the hydrolysis reaction of the compound in 10).

The compound of general formula (44) and the compound of general formula (45) used as starting materials are produced, for example, according to the method shown in Reaction Scheme-14 below.

[Reaction formula-14] (A') C1-+2 CH2C0OH(A')
CH2C0OHIII [wherein R2', R35, X5X9, M and m are the same as above. A' represents a lower alkylene group. However, the group -(A'
) m CH2- and group (A'> mcH2CH2
The total number of carbon atoms in each of - shall not exceed 6.
36 represents a lower alkyl group. X1+ represents a halogen atom. ] Reduction of the compound of general formula (55) is carried out by reducing the compound of general formula (44)
Alternatively, it can be carried out under the same reaction conditions as the reduction reaction of (45).

The halogenation reaction of the compound of general formula (56) can be carried out under the same reaction conditions as the halogenation reaction of the compound of general formula (46).

The reaction between the compound of general formula (57) and the compound of general formula (58) is carried out in a suitable solvent in the presence of a basic compound at usually room temperature to 200'C, preferably 60 to 120'C.
It will be open for about 24 hours. Examples of solvents used include ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, and diethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, lower alcohols such as methanol, ethanol, and isopropanol, and dimethyl ether. Examples include polar solvents such as formamide and dimethyl sulfoxide.

Basic compounds include sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, potassium hydride, sodium methylate,
Examples include inorganic bases such as sodium ethylate, amines such as triethylamine, tripropylamine, pyridine, and quinoline. The reaction proceeds advantageously by using an alkali metal iodide such as potassium iodide or sodium iodide. The compound of general formula (58) is usually used in an equimolar to large excess amount, preferably in an equimolar to 5-fold molar amount, and more preferably in an equimolar -1 molar amount to the compound (57).

The reaction between the compound of general formula (57) and the compound of general formula (17) is the reaction between the compound of general formula (16) and the compound of general formula (17).
can be carried out under similar reaction conditions to the reaction with the compound.

The hydrolysis reaction of the compound of general formula (59) or 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).

The general formula (3), (5), (7), (9), (10)
, (1a), (1b), (1b') (29), (31)
Among the compounds of (32), compounds in which R3 is a lower alkyl group having a hydroxy group as a substituent are reacted under the same reaction conditions as above, and the corresponding R3 is a saturated 5-6 as a substituent. A lower alkyl group that may have 1 to 3 bases selected from the group consisting of a membered heterocyclic residue, a lower alkylthio group, a lower alkanoyloxy group, an amino group, a lower alkylamino group, a lower alkoxy group, and a halogen atom. can lead to compounds that are respectively.

Furthermore, the general formulas (3), (5), (7), (9), (
10), (1a), (1b), (1b'>(29>,
Among the compounds of (31) and (32), compounds in which R3 is a lower alkyl group having a lower alkanoyloxy group as a substituent are hydrolyzed in the same manner, and R3 is a lower alkyl group having a hydroxy group as a substituent. can lead to a compound that is a group.

Furthermore, the general formulas (3), (5), (7), (9), (
10), (1a), (1b), (1b'), (29),
In the compounds of (31) and (32), when R2 is a 5- to 9-membered saturated or unsaturated heterocyclic residue having an oxo group as a substituent, by reducing these, This can lead to corresponding compounds having a 5- to 9-membered saturated or unsaturated heterocyclic residue having a hydroxy group. 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 the solvent include water, lower alcohols such as methanol, ethanol, and isopropanol, and ethers such as tetrahydrofuran, diethyl ether, and diglyme. The reaction is usually completed at -60°C to 50°C, preferably at about 0°C to room temperature, with the circuit open for 10 minutes to 5 hours. 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 hydride can also be added to the reaction system.

Furthermore, in the case of a compound in which R2 is a 5- to 9-membered saturated or unsaturated heterocyclic residue having a lower alkyl group having at least one lower alkanoyl group or lower alkoxycarbonyl group as a substituent, hydration of the compound By decomposition reaction, a compound in which the corresponding base is a 5- to 9-membered saturated or unsaturated heterocyclic residue having a lower alkyl group having at least one amine group as a substituent can be derived.

The hydrolysis reaction can be carried out under the same conditions as the hydrolysis reaction of the compound of general formula (10) in Reaction Formula-1.

In addition, R2 has at least one -N H- group in the ring.
In the case of a compound that is a 9-membered saturated or unsaturated heterocyclic residue, the compound is subjected to a reaction to derive a compound of general formula (34) from a compound of general formula (33) in Reaction Formula-10 above. By subjecting it to a similar reaction, 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 derived.

A compound of general formula (46), (47) or (48) in which R35 is a hydrogen atom is derived by nitrating the compound in the same manner as the compound of general formula (44) to a corresponding compound in which R35 is a nitro group. can do.

The compound of general formula (10) in reaction formula-1 and the compounds of general formula (1b) and (1b') in reaction formula-2 yield a compound of general formula (1) useful as an antibacterial agent of the present invention. It is a useful compound as a synthetic intermediate for , and 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 nucleic 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, propionic acid, etc. 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. 5 The compound of the present invention or a salt thereof is suitable for use against Pseudomonas aeruginosa, anaerobes, bacteria resistant to various antibacterial agents, clinical isolates, E. faecalis, and 5
taphl/1OcOccjjs pyo(lene
These compounds have remarkable antibacterial activity against Gram-negative and Gram-positive bacteria such as S, and are useful as antibacterial agents for diseases caused by these bacteria.In addition, these compounds have low toxicity, weak side effects, and are easily absorbed. It also has the characteristics of good properties 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 5- to 9-membered saturated or unsaturated heterocyclic residue represented by R2 is preferably a saturated heterocyclic residue, among which piperazinyl group, morpholino group, piperidinyl group, pyrrolidinyl group, and 1,4-diazabicyclo (4,3,O)
A non-4-yl group is preferred. Examples of the substituent on the heterocycle include a pipera atom, an alkyl group having 1 to 6 carbon atoms, and 1 to 6 carbon atoms.
-6 alkanoyl group, cycloalkyl group having 3 to 8 carbon atoms, phenylalkyl group having 1 to 6 carbon atoms in the alkyl portion, or phenyl group or 1 to 6 carbon atoms as a substituent
2-oxo-1,3 which may have 6 alkyl groups
- indicates a dioxolenemethyl group. R8 represents an alkyl group having 1 to 6 carbon atoms. This R8 is 2.3. of the piperazine ring.
It is assumed that it is substituted at the 5th or 6th position. When RA represents a hydrogen atom, p represents an integer of 1 to 3. When RA represents a group other than a hydrogen atom, p represents 1 or 2. ) represents an alkyl group having 1 to 6 preferable atoms or a 2-oxo-1,3-dioxolenemethyl group which may have a phenyl group or an alkyl group having 1 to 6 carbon atoms as a substituent. The alkyl group having 1 to 6 carbon atoms in Ro represents an alkyl group having 1 to 6 carbon atoms. ) is most preferred.

As a piperazinyl group other than the above, a 2-oxo-1,3-dioxomethylenemethyl group (which may have an alkyl group having 1 to 6 radicals) is preferred, and R1 is at the 4th position and has 1 to 6 carbon atoms. 2-oxo-1,3 with alkyl group
-dioxomethylenemethyl group is more preferred.

Indicates an atom or an alkyl group having 1 to 6 carbon atoms. ) is preferred as the 0° piperidinyl group, which may have 1 to 3 groups selected from the group consisting of an oxo group, a halogen atom, a hydroxyl group, and an alkyl group having 1 to 6 carbon atoms as a substituent. A piperidinyl group is preferable, and one halogen atom is added as a substituent.
A 1-piperidinyl group having two groups is more preferable.

As a pyrrolidinyl group, an alkyl group having 1 to 6 carbon atoms as a substituent: hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, and an alkyl group having 1 to 6 carbon atoms as a substituent; having 1 to 3 carbon atoms and having 1 to 3 groups selected from the group consisting of an alkanoyl group, a cycloalkyl group having 3 to 8 carbon atoms, and an amino group which may have 1 to 2 alkoxycarbonyl groups having 1 to 6 carbon atoms Alkyl group of 6:
Also, as a substituent for the amino group, an alkyl group having 1 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, a phenylalkyl group whose alkyl moiety is an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms. A group selected from the group consisting of amino groups that sometimes have 1 to 2 carbonyl groups.
Preferred is a pyrrolidinyl group which may have 2 to 2 amine groups, and 1 to 1 amine group which may have 1 to 2 alkyl groups.
Alkyl group having 1 to 6 carbon atoms, or 1 to 6 carbon atoms
represents an amino group which may have 1 to 22 alkyl groups, and R1 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. > is preferred and indicates an amino group that may have one group. Most preferably, R1 represents an alkyl group having 1 to 6 carbon atoms and having one amino group that may have one alkyl group having 1 to 6 carbon atoms.

As the 1,4-diazabicyclo(4,3,0)non-4-yl group, unsubstituted 1,4-diazabicyclo(4,3
, O) non-4-yl group is preferred.

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

The group represented by R3 is preferably an unsubstituted alkyl group having 1 to 6 carbon atoms, and among these, a methyl group is particularly preferable.

Further, the compound of the present invention can be made into a salt form such as a lactate or a hydrochloride to improve its absorbability into the body.

The compounds of the 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, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, 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, binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone,
Dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose, white sugar, stearin, cocoa butter , disintegration inhibitors such as hydrogenated oils, absorption enhancers such as quaternary ammonium bases and monolithium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Examples include adsorbents, purified talc, stearates, boric acid powder, and lubricants such as polyethylene glycol. Furthermore, the tablets can be made into tablets with conventional coatings as required, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, Examples include binders such as powdered tragacanth, pyratine and ethanol, and disintegrants such as laminalan agar.

When forming into a suppository, a wide range of conventionally known carriers can be used, such as polyethylene glycono-k, cacao butter, Kosaka alcohol, esters of higher alcohols, bilatin, semi-synthetic glycerides, etc. can. When prepared as an injection, the solution, emulsion, or suspension is preferably sterilized and isotonic with blood; when forming these solutions, emulsions, or suspensions, a diluent is added. 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, sufficient amounts 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. It's okay. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals may be included in the pharmaceutical preparation, if necessary. When forming pastes, creams and gels, diluents such as white petrolatum, paraffin,
Glycerin, cellulose derivatives, polyethylene glycol, silicone, and the like can be used. In addition, if the active ingredient compound precipitates in the injection solution, the injection solution can be made stable by appropriately adding an acid such as methanesulfonic acid, propionic acid, hydrochloric acid, succinic acid, or lactic acid, if necessary. It can be kept in solution form.

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 (such as lactate) 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 nucleic 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 to 10% by weight. The amount is preferably about 2% by weight, and when an acid other than lactic acid is used as the nucleic acid, the amount is usually about 0.05 to 4% by weight, preferably about 0.3 to 2% by weight in the solution. It is better. The above-mentioned injection solution may contain conventional auxiliary agents, if necessary. As such an auxiliary agent,
Examples 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, emulsions, liquids,
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, intracranially, subcutaneously, or intraperitoneally. Suppositories are 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 kQ of body weight per day. The dosage is preferably about 0.2 to 100 m/l, 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 90C of N-chlorosuccinimide was added to a solution of 1.2Q of anhydrous dichloromethane containing 100C of 2-bromo-4,5-difluoroaniline] and 49mQ of methyl sulfide at 15°C or lower.
Add 1 gradually. Thereafter, 93 mQ of triethylamine is added little by little at 15°C. After the addition is complete, fast-flow for 7 hours, cold weld, and add 1 10% sodium hydroxide to the reaction mixture.
Add Q and extract with dichloromethane. After drying with magnesium sulfate and concentrating, the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane:hexane = 1:2). Recrystallized from n-hexane to obtain 6-bromo-3, 4-difluoro-2-methylthiomethylaniline 52C1 is obtained.

mp, 60-61°C White crystal reference example 2 6-bromo-3,4-difluoro-2-methylthiomethylaniline 99C], 130 g of HMPA and cyanide
Heat Copper 48Q at 150'C for 4 hours. The reaction mixture was poured into a solution of 50 mQ of ethylenediamine in 500 mQ of water and heated at 60°C for 1 hour. Cold extraction, extraction with ethyl acetate, drying over magnesium sulfate, and concentration. The residue was purified by silica gel column chromatography (eluent: dichloromethane:n-hexane = 11), then recrystallized from ethanol to give 2-amino-4,5-difluoro-
28q of 3-methylthiomethylbenzonitrile is obtained.

mp, 109-110°C White crystal reference example 3 40 mQ of Raney nickel was added to a solution of 4.0 CI of 2-amino-4,5-difluoro-3-methylthiomethylbenzonitrile in 80 mf2 of ethanol in 80 m12 of ethanol.
Wash it in. After stirring at 40-50°C for 30 minutes, filter. Add water to the furnace solution and extract with ethyl acetate. After drying with magnesium sulfate, concentrate. Recrystallization from n-hexane yields 2.40 g of 2-amino-4,5-difluoro-3-methylbenzonitrile.

ff1.114~116℃ White crystal reference example 4 Sodium nitrite 5.69 in concentrated sulfuric acid 70''C
Add 2-amino-4,5-difluoro-3-methylbenzonitrile 1 after heating at 70°C for 10 minutes and cooling.
Add a 123 mQ solution of 2.3 (J) in acetic acid dropwise at 40'C or lower. After stirring at the same temperature for 30 minutes, pour it little by little into a 200 mQ solution of cuprous chloride 209 in salt production, and then add at 80°C for 30 min.
Heat for a minute. Cold welding, ice water was added to the reaction solution, ethyl acetate was distilled off, and the resulting residue was subjected to silica, glu column chromatography (eluent dichloromethane: n-hexane = 1
:1) to produce 2-chloro-4,5-difluoro-
3-Methylbenzonitrile8. Obtain Oa.

mp, 59-61°C White crystal reference example 5 60% sulfur @ 20 mQ was added to 4.0 CI of 2-chloro-4,5-difluoro-3-methylbenzonitrile, and 140
Heat at ~150°C for 3 hours. The reaction mixture was poured into ice water and extracted with dichloromethane. After drying with magnesium sulfate, the solvent is distilled off. n to the obtained residue
- Add hexane and separate the precipitated crystals. 2-chloro-
4,5-difluoro-3-methylbenzoic @3.1 cl is obtained.

mp, 121-122°C White crystal reference example 6 2-chloro-4,5-difluoro-3-methylbenzoic acid 1
Add 6 mf2 of thionyl chloride to 3.1 g and heat under reflux for 1 hour. After concentration under reduced pressure, 3.3 g of 2-chloro-4,
5-difluoro-3-methylbenzoyl chloride is obtained. Next, 0.38% of magnesium metal is suspended in 0.8% of absolute ethanol, and a few drops of carbon tetrachloride are added. After starting the reaction, 2.3 ml of diethyl malonate was added. A solution of 1.5 m12 of absolute ethanol and 6 m12 of anhydrous toluene
The above 2-chloro-4,5-
A solution of 3.3 g of difluoro-3-methylbenzoyl chloride in 5 ml of anhydrous toluene is added dropwise. After the dropwise addition, the mixture was stirred at room temperature for 30 minutes. A mixture of 0.4 mQ of concentrated sulfuric acid and 8 mf2 of water is added to the reaction mixture, and the mixture is extracted with diethyl ether. After drying with magnesium sulfate, the solvent was distilled off and 2
5.1 q of diethyl -chloro-3-methyl-4,5-difluorobenzoylmalonate are obtained.

Reference Example 7 10 mQ of water and 30 mCl of p-toluenesulfone were added to 561 q of diethyl 2-chloro-3-methyl-4,5-difluorobenzoylmalonate, and the mixture was heated under reflux for 4 hours. Cold extraction, extraction with diethyl ether and drying over magnesium sulfate. After distilling off diethyl ether, 3.90 g of ethyl 2-chloro-4,5-difluoro-3-methylbenzoylacetate is obtained.

Reference Example 8 3.1 g of triethoxymethane and 13.1 g of anhydrous vinegar were added to 3.9 g of ethyl 2-chloro-4,5-difluoro-3-methylbenzoylacetate, and heated at 150° C. for 1 hour. After concentration, ethyl 2-(2-chloro-3-methyl-4,5-difluorobenzoyl)-3-ethoxyacrylate is obtained. Add 50ml of ethanol to this and leave at room temperature under 1.
Add 1 bait of cyclopropylamine and stir for 30 minutes.

After distilling off the ethanol, 2-(2-chloro-3-methyl-
Ethyl 4,5-difluorobenzoyl)-3-cyclopropylaminoacrylate is obtained. Add 30 mQ of anhydrous dioxane to this, and add 0.6 mQ of 60% sodium hydride to the colander.
(Add III little by little. Stir at room temperature for 30 minutes, then heat under reflux for 1 hour.

The reaction mixture was poured into a saturated aqueous ammonia chloride solution and extracted with dichloromethane. After drying with magnesium sulfate and concentrating, 1-cyclopropyl-6゜7-difluoro-
8-Methyl-1,4-dihydro-4-oxoquinoline-
2.20 ethyl 3-carboxylate is obtained.

NMR (CDCIQ3) δ: 8.64 (IH,S) 8.10 (IH,t1J=10Hz >4.36 (
2H, q, J = 7.5H7) 3.76-4.10 (I
H, m> 2.76 (3H, d, J=4.5t-1z) 1.3
7 (3H, t, J=7.5Hz >0.86~1.3
0 (4H, m) Reference Example 9 2.2 q of ethyl 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate was mixed with 5 mQ of concentrated hydrochloric acid.

Add 2 ml of water and 20 ml of acetic acid, and reflux for 2 hours.

After cold welding, the precipitated crystals were collected and washed with water, ethanol, and diethyl ether in this order to give 1-cyclopropyl-6,
7-difluoro-8-methyl-1゜4-dihydro-4-
1.8q of oxoquinoline-3-carboxylic acid are obtained.

mp, 240-243°C White crystal reference example 10 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinolicy-3-carvone M1. Og, triacetyloxyboron (B (OC
Add 1.0 CI of OCH3)3) and 10 mf2 of acetic anhydride and heat at 140'C for 15 minutes. After the reaction is completed, it is concentrated, diethyl ether is added to the resulting residue, the precipitated crystals are separated, and 6°7-difluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline- 1.2q of 3-carboxylic acid-B (OCOCH3)2 chelate is obtained.

NMR (CDCQ3) δ: 9.32 (1H, s) 8.23 (1H, t, J=9Hz >4.30-4.
58 (IHlm> 2.97 (3H, d, J=3Hz) 2.03 (6
H,s) 1.13 to 1.60 (4H,m> Reference Example 11 Add 2.2-dichloro-1-cyclopropylcarboxone to make a completely homogeneous solvent. This solution was cooled to 0°C. After that, triethylamine 3.Oq ace[-one 6
Add 0 mQ bath solution. While maintaining the temperature at 0.6C, add 15m of acetone (3.54C of ethyl chlorocarbonate)
Add the solution gradually. After completion of the dropwise addition, stir at OoC for 30 minutes, and add dropwise a solution of 2.519 sodium azide in 10 m of water. After further stirring at OoC for 1 hour, pour the reaction mixture into ice water and extract with diethyl ether. Sulfuric acid. After drying with a magnesium trowel, concentrate. Obtained 2,
2-dichloro-1-cyclopropylcarbonyl azide, 3.35 g of pencil alcohol and 50 n of anhydrous benzene
Add ++2 and heat under reflux for 10 hours while stirring. After the reaction is completed, the residue obtained by concentration is purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane). Recrystallization from dichloromethane-n-hexane yields 2.8 g of 2,2-dichloro-1-benzyloxycarbonylaminocyclopropane.

ml), 79.5-80.5°C Colorless needle crystals The following compound was obtained in the same manner as in Reference Example 11 using appropriate starting materials.

2-chloro-1-benzyloxycarbonylaminocyclopropane (cis-trans mixture) NMR (CD
CQ3) δ: 1,'to ~1.32 (2H, m>2, 76 ~3
．． 10 (2H, m) 4,73 ~5.13 (1H, m) 5, 11 (2H, s), 7.35 (5H, s) 2-
Fluoro-1-benzyloxycarbonylaminocyclopropane (mixture of cis and trans) NMR (CDC
Q3, 60MHz) δ: 0, 60~1.
60 (2 t1, m)2,50 ~3.1 7
(1H, m>4, 07-4.30 and 4.53-5.
00 (2H, m > 5, 08 and 5.1 1 (2H, s) 7, 33 (
5H,s> Reference Example 12 5% Pd-C0.15q to 1.5g of 2,2-dichloro-1-benzyloxycarbonylaminocyclopropane
, add 15 m2 of ethanol and 1.5 m2 of concentrated hydrochloric acid,
Catalytic reduction is carried out at room temperature and normal pressure.

After the reaction is completed, the catalyst is removed and the reactor liquid is concentrated. The obtained residue was recrystallized from ethanol-diethyl ether to give 2
, 2-dichloro-1-aminocyclopropane hydrochloride 0.
Obtain 7g.

rrlp. The following compound was obtained in the same manner as in Reference Example 12 using an appropriate starting material in the form of a white powder at 147 to 148°C (min@).

2-chloro-1-aminocyclopropane hydrochloride (cis-
l lance mixture) NMR (DMSOds) δ: 1.16-1.73 (2H, m> 2.83-3.10 (1) (, m> 3, 57-3.80 (1HSm) 8.60 ~9.26 (3H, m) 2-Fluoro-1-aminocyclopropane hydrochloride (cis-trans mixture) NMR (DMSOds, 200MHz) δ: 1.0
0 to 1.60 (2H, m>, 2.47 to 2.68 and 2.88 to 3.17 (1t-(, m) 4.65 to 4
．． 88 and 4.96-5.20 (1H, m>, 8.3
0 to 9.00 (3H, m) Reference Example 13 2-(2,4,5-trifluorobenzoyl)-3-
A solution of 0.60 C of 2-fluoro-1-cyclopropylamine hydrochloride] in 10 mQ of ethanol is added dropwise to a solution of 10 mQ of ethanol containing 1.78 CI of ethoxyacrylate and 0.60 CI of triethylamine while stirring at air temperature.

After dropping, stir for one hour at the same temperature, concentrate, and add 2-
(2,4,5-trifluorobenzoyl>-3-(2-
Ethyl fluoro-1-cyclopropyl)aminoacrylate is obtained.

To this are added 0.3 CI of 60% sodium hydride and 30 ml of anhydrous dioxane, and the mixture is stirred for 1 hour at room temperature.

After concentrating the reaction mixture, water was added to the residue and extracted with dichloromethane. After washing with water, drying and concentrating the solvent, 1-(
Ethyl 2-fluoro-1-cyclopropyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (cis-trans mixture>1.02C
Get I.

NMR (CDCQ3.60MHz) δ: 1.36 (
3H,t,J=8)(Z)1.44~2.27(2
H, m> 3.50-3.83 (IH, m> 4.28 (2H, q, J=8Hz >4.55-4.
86 and 5.26-5.53 (1H, m) 7, 58 (I H1dd, J=1 1
Hz, 6Hz >7.98 (1HSdd,
J='l OHz, 9Hz >8.31 and 8.51
(1H,s) The following compound is obtained in the same manner as in Reference Example 13 using appropriate starting materials.

1-(2-chloro-1-cyclopropyl)-6゜7-difluoro-1,4-dihydro-4-oxoquinoline-3
-Ethyl carboxylate (cis-trans mixture) NMR (CDCQ3.60MHz) δ: 1.37 (
3H,t,J=7Hz)1.70~2.20(2H
1m> 3.40~3.80 (2H, m> 4.31 (2H, q, J=7Hz) 7, 55
(1H, dd, J=1 4H Otsu, 6 Hillz
)8.07 (1H, dd, J=9Hz, 9Hz
)8.32 and 8.34 (1H,s> 1-(2-methyl-1-cyclopropyl)-6°7-difluoro-1,4-dihydro-4-oxoquinoline-3
-Ethyl carboxylate (cis-trans mixture) NMR (CDCQ3.60MHz) δ: 1.00-2
．． 00 (3H, m> 1.39 (3H, t, J=7Hz >1.41 (3
H1s> 3.00~2.27 (IH, m) 4.37 (IH, q, J=7Hz) 7.55 (1
H, dd, J=11Hz, 6Hz >8.20 (1
H, dd, J=9Hz 19Hz >8.51 (1H
, s> Reference example] 4 l-(2-fluoro-1-cyclopropyl)-6,7-
Difluoro-1,4-dihydro-4-oxoquinoline-
Add 20 ml of 90% acetic acid-concentrated hydrochloric acid (4:1) to 1.02 J of ethyl 3-carboxylate, and stir and reflux for 1 hour.

After concentration, add water to the residue, collect the precipitated crystals, ethanol,
After washing with diethyl ether and drying, 1-(2-fluoro-1-cyclopropyl)-6,7-difluoro-
0.58q of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid (cis-trans mixture) is obtained.

NMR (DMSOds, 200MHz) δ: 1.6
3~2.17 (2t(,m), 3.75~3.97
and 4.20-4.50 (IH, m), 5.09-5
．． 35 and 5.41 to 5.63 (1H, m>, 8.1
2 (dd, J=11.85Hz, 6.67Hz
> and 8.39 (dd, J=12, 08H2, 7,
3Hz, each IH), 8.30 (dd, J=10.3
8Hz, 8.62Hz) and 8.28 (dd, J
= 12.18 Hz, 10.42 Hz, 1 day each) 8.73 and 8.65 (IH,s> In the same manner as in Reference Example 14, using appropriate starting materials, the following compounds are obtained.

1-(2-chloro-1-cyclopropyl)-6゜7-difluoro-1,4-dihydro-4-oxoquinoline-3
-Ethyl carboxylate (cis-1-lance mixture) NMR (DMSOds, 200MHz) δ: 1.8
0-1.99 and U2.04-2.23 (2H, m> 3.94-4.07 (1'H, m> 4, 19-4.34 (1 to 1, m) 7,
98 (1)-1, (jd, J=1 1.8
4 t1z.

6.64Hz) 8.31 (1H, dd, J=10.34Hz.

8.66Hz > 8.69 (1H,s> ]-(2-methyl-1-cyclopropyl)-6゜7-difluoro-1,4-dihydro-4-oxoquinoline-3
-Carvone @ (mixture of cis and trans) NMR (trifluoroacetic acid-ds, 60Hz) δ:
1.33~2.10 (3H, m> 1.58 (3t (1s> 3.66~4.00 (181m> 8, 38 (11-1, dd, J=10Hz)
, 6Hz >8, 53 (I H,
dd, J=9H2, 9H2)9.48 (1H,S
) Reference Example 15 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methylthiomethyl-1,
To a solution of 8.090 4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester in 80 ITII2 of ethanol, 40 rIIQ of Raney nickel was added to 80 m of ethanol.
Wash it with Q. After stirring at 40-50°C for 30 minutes, filter. Water is added to the obtained filtrate and extracted with ethyl acetate. After drying over magnesium sulfate and concentrating, 2.5 g of 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline was obtained. -3-carboxylic acid ethyl ester is obtained.

Reference Example 16 70 mQ of Raney nickel is suspended in a solution of 6.0 OCI of Loebromo 3.4-difluoro-2-methylthiomethylaniline in ethanol 120 times and stirred at 50°C for 30 minutes. After removing the Raney nickel, the furnace solution was concentrated to produce a colorless oil of 3,4-difluoro-2-methylaniline.3.
Subtract 77CI by 1q.

NMR(CD CQ3)δ: 6.72 (1t-1, ddd 1J=10.2l-1
z, 10.2Hz, 8.7Hz) 6.27 (lf-1, ddd, J=10.2Hz
.

6, 0Hz, 2', 7Fll)3
．． 43 (2H, br) 2.02 (3H, d, J = 2.4Hz > Reference Example 17 3.4-difluoro-2-methylaniline 3.27C]
Add 50 mQ of anhydrous vinegar to. After stirring for 10 minutes, acetic anhydride was distilled off and the residue was extracted with dichloromethane. water,
After washing with saturated aqueous sodium hydrogen carbonate solution and saturated saline in this order, drying with anhydrous magnesium sulfate. After distilling off dichloromethane, recrystallization from ethyl acetate-n-hexane gave 3
．． 860 of 3,4-difluoro-2-methylacetanilide is obtained.

mp, 145.5-146.0'C Colorless needle crystal Reference example 18 3.4-difluoro-2-methylacetanilide 100
Add +n+; Then, under ice-cooling, 0.1 mf2 of sodium sulfate was added, and the mixture was stirred at room temperature for 2 hours. Furthermore, 0.1 mQ of concentrated nitric acid was added, and the mixture was stirred at room temperature overnight. A large amount of water is added to the reaction mixture, and the mixture is extracted with dichloromethane. After washing with water, saturated sodium bicarbonate aqueous solution, and saturated saline in this order, anhydrous fi
Dry with LB magnesium. After distilling off dichloromethane, it was recrystallized from ethyl acetate-n-hexane to give 4.5-
Difluoro-6-methyl-2-nitroacetanilide 8
Obtain 0.7 mg.

mp, 152.1-152.6°C Yellow needle-like product Reference example 19 Dissolve 81 mci of 4.5-difluoro-6-methyl-2-nitroacetanilide in 12 rll12 of vinegar, and add salt to this using O″G. say something.10
After stirring at 0°C overnight, concentrate. After neutralizing with saturated aqueous sodium hydrogen carbonate solution, extract with dichloromethane and wash with saturated brine. After drying with 1 ml of anhydrous sulfuric acid magne, dichloromethane was distilled off to obtain 59 ml (l) of 4,5-difluoro-6-methyl-2-nitroaniline.

mp, 87.2-88. O°C Orange prism-shaped reference example 20 Add 30 mQ of sodium nitrite little by little to 0.32 mQ of salt. After stirring at 70°C for 10 minutes, it was cooled to room temperature, and at the same temperature, 4,5-difluoro-6-methyl-2
- A solution of 59 mfj of nitroaniline in 6.5 ml of acetic acid is added dropwise. After stirring at room temperature for 30 minutes, cuprous chloride 107
mCl concentrated hydrochloric acid 1. Add QmQ solution dropwise. Stir for 30 minutes at 80°C. Water is added to the reaction mixture, extracted with ethyl acetate, and washed sequentially with water, saturated sodium hydrogen carbonate, and saturated brine. After drying over anhydrous magnesium sulfate, ethyl acetate was distilled off to give 2-chloro-5,6-difluoro-
Obtain 54 mCl of 3-nitrotoluene.

NMR (CDCQ3) δ near, 58 (1H, dd, J=11.0Hz, 8.0H
z >, 2.40 (3H, s) Reference Example 21 0.3 mQ of ethanol and 0.03 mG of water were added to 54 mg of 2-chloro-5,6-difluoro-3-nitrotoluene at 0°C, and then heated to room temperature. N-methylpiperazine at 0.
A solution of 0.04 mQ and 0.06 ml of triethylamine in 0.1 ml of ethanol is added dropwise. 5 hours at room temperature
Stir at 60°C for 5 hours and at 80°C overnight. The reaction mixture was made acidic with 2N hydrochloric acid, washed with a small amount of diethyl ether, and then neutralized with a saturated aqueous sodium bicarbonate solution. After extraction with dichloromethane, it was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and then dichloromethane was distilled off to give 2-chloro-5-fluoro-6-(4
35 mg of -methyl-1-1:'perazinyl)-3-nitrotoluene are obtained.

NMR (CDCQ3) δ near, 46 (1H, d, J=11.2Hz >3, 1
5 (4H, br), 2°55 (4H, br)2.
46 (3H,s>, 2.73 (3H,s) Reference example 2
2 2-Chloro-5-fluoro-6-(4-methyl-1-piperazinyl)-3-nitrotoluene 17 mg dimethyl sulfoxide 1,5n'IQ solution contains 11 potassium fluoride.
Add 0ml (l) and 1.0ml of cyclopropylamine and stir at 100°C for 13 hours. After diluting the reaction mixture with dichloromethane, wash with water, saturated aqueous sodium bicarbonate solution, and saturated brine in this order. Sulfuric anhydride After drying with 1 ml of magnetic screw, dichloromethane was distilled off. Purification was performed by preparative thin layer chromatography (developing solution: methanol-dichloromethane) to obtain 11 mCl of N-cyclopropyl-4-fluoro-2-methyl-3-( 11 mg of 4-methyl-1-piperazinyl)-6-nitroaniline are obtained.

NMR (CDCQ3) δ near, 69 (1H, d, J = 13H2) 7, 59 (
I H, br) 3.45-3.08 (4H, m> 2.85-2.75 (1H, m> 2.70-2.43 (4H, m) 2.45 (3H, s>, 2.36 (3H, s>1.
0-0.5 (4H, m) Reference Example 23 To a solution of 85.5q of 3.4-difluoroacetanilide in 850TIIf2 of ra acid was added 5% potassium nitrate at room temperature with stirring.
Add 5.5 CI gradually. During this time, the temperature is raised to 60'C. After stirring at 60'C for 1 hour, the reaction mixture was poured into ice water and the precipitated crystals were collected. The precipitated crystals are dissolved in dichloromethane, washed successively with aqueous sodium bicarbonate, water, and saturated saline, and then dried. After concentrating the solvent, it is washed with n-hexane. The crystals are dried several times to obtain 2-ditro-4,5-difluoroaniline of 54Q.

NMR (CDCQ3) δ: 5.76-6.40 <2H, m> 6.60 (1H, dd, J=12Hz, 7Hz)
7.97 (IH, dd, J=10.5Hz, 8.5H
z > Reference Example 24 1.0 g of 2-nitro-4,5-difluoroaniline and 1.79 CI of dimethyl sulfide in dichloromethane 40
Gradually add 3.82 CI of N-chlorosuccinimide to the mQ solution at 15° C. or below while stirring a. After stirring for 30 minutes, add 2.89 CI of triethylamine and heat under reflux for 21 hours. After cooling, the reaction mixture is washed with a 10% aqueous sodium hydroxide solution, water, and brine in this order, and then dried. The solvent was concentrated, and the resulting blue residue was subjected to silica gel column chromatography (eluent: n-hexane: ethyl acetate = 30:
1), recrystallized from n-hexane to obtain 0
．． 47CI of 2-nitro-4,5-difluoro-6-methylthiomethylaniline is obtained.

mp, 110-111.5°C Yellow needle-like crystals Reference example 25 To 15ml of sulfuric acid, add 15q of sodium nitrite, and heat and stir at 70°C for 10 minutes. Next, 40'C
Below, a solution of 0.45Q of 2-nitro-4,5-difluoro-6-methylthiomethylaniline in 4.5ml of acetic acid is added dropwise. Thereafter, after stirring at the same temperature for 45 minutes, a solution of 0.52 C1 of cuprous chloride in 5.2 mQ of concentrated hydrochloric acid was added dropwise. After 7JO hot stirring for 1.5 hours at ao'c, the reaction mixture was poured into ice water and extracted with ethyl acetate. water,
After washing with saturated saline, drying and distilling off the solvent. The obtained residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate = 30:1) to obtain 0.16 CI of 2-chloro-3-methylthiomethyl-4,5-difluoro-1. - Obtain nitrobenzene.

N M R (CD CQ 3 ) δ: 2.15 (3H, s) 3.92 (2H, dd, J=3Hz >7.67 (
IH, dd, J=8.5Hz, 8Hz) Reference Example 26 m 5A m 120 mQ, 2.3. Lotrifluorobenzoic acid 21. Add OCI under water cooling. A solution of 3Qmf2 of concentrated sulfuric acid containing 14.5Q of potassium nitrate was added dropwise to this at 20°C or lower. After dropping, stir at room temperature for 1 hour. The reaction mixture is poured into ice water and extracted with diethyl ether. After drying with magnesium oxide, the solvent is concentrated. Recrystallization from dichloromethane-()-hexane yields 22CI of 2.5.rotrifluoro-3-nitrobenzoic acid.

mp, 98-99°C Colorless prismatic NMR (CDC93) δ: 8.11-8.23 (1H, m> 9.10 (1H, brs) Reference Example 27 10% in anhydrous tetrahydrofuran solution of sodium borohydroxide 44C] ℃ or lower, add 40 mQ solution of 2,5.rotrifluoro-3-nitrobenzoin 122qI7) anhydrous tetrahydrofuran. Subsequently, at 10'C or below, a solution of boron .].refluoride etherate 20- in 40 mQ of anhydrous tetrahydrofuran is added dropwise. After dropping, stir at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with diethyl ether. Dry, concentrate the solvent, and remove from 2.5 of 14Q. Rotrifluoro-3-nitrobenzyl alcohol is obtained.

NMR (CDCQ3) δ: 2,56 (IH, brs) 4.88 (2H, t, J=1.8l-1z) 7.9
2-8.04 (IHSm) Reference Example 28 2.5. A mixture of 11 Cl of 4-ethoxycarbonylpiperazine, 12.5 g of triethylamine and 18 mf2 of ethanol is added at once to a solution of 14 Cl of rottrifluoro-3-nitrobenzyl alcohol in 64 mQ of ethanol and 7 ml of water. After stirring overnight at room temperature, the precipitated crystals were collected. After washing with a small amount of diethyl ether, recrystallization from ethanol gave 8.79 3,6-difluoro-2-(
4-Ethoxycarbonyl-1-piperazinyl)-5-nitrobenzyl alcohol is obtained.

ff1.147-149°C Yellow needle crystals Reference example 29 3.6-Difluoro-2-(4-ethoxycafflebonyl-1-piperazinyl)-5-nitrobenzyl alcohol in 85 mg of chloroform solution was added to a solution of 85 mg of chloroform at room temperature. Add 2.7 mQ of thionyl chloride.

After stirring at the same temperature for 30 minutes, the reaction mixture was placed in ice water, neutralized with sodium hydrogen carbonate, extracted with diethyl ether, dried over magnesium sulfate, and the solvent was distilled off.
8.1 g of 2-(4-ethoxycarbonyl-1-piperazinyl)-3,6-difluoro-5-nitropenzyl chloride are obtained.

NMR (CDCQ3) δ: 1.28 (3HSt, J=7.1H2) 3.08-3
．． 33 <4H, m> 3.46 to 3.75 (4H, m> 4.18 (2H, q, J=7.1Hz >4.77
(2H, d, J=2.5Hz')7.82 (IH, d
d, J=9.2Hz, 7.2Hz) Reference Example 30 2-(4-ethoxycarbonyl-1-piperazinyl)-
3,6-difluoro-5-nitrobenzyl chloride8.
1.8 g of sodium borohydride is added little by little to the dimethyl sulfoxide 90 solution of No. 10 below 30'C. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice water and acidified with concentrated hydrochloric acid. Extract with diethyl ether and evaporate the solvent to obtain 7.1 g of 2-(4-ethoxycarbonyl-1-piperazinyl)-3,6-difluoro-5-nitrotoluene (1 q).

NMR (CDC(13)δ: 1.26 (3H, t, J=7.1Hz) 2.30
(3H, d, J=3Hz >2.76~3.27 (5
H, m> 3.50~3.75 (4H, m> 4.17 (2H, a, J=7.1Hz >7.60
(1H, dd, J=9.3Hz.

7.2l-(Z) Reference Example 31 2-(4-ethoxycarbonyl-nyl)-3.6-difluoro-5-nitrotoluene7.
1 g of anhydrous dimethyl sulfoxide 2 3 mQ, potassium fluoride 2.0 CI and cyclopropylamine 1.5
g and heated at 60"C for 6 hours. The reaction mixture was heated to ψ
Pour into water and extract with dichloromethane. After distilling off the solvent, recrystallization from ethanol yielded 7.4 g of N-
Cyclopropyl-2-methyl-3-(4-ethoxycarbonyl-1-piperazinyl)-4-fluoro-6-nitroaniline is obtained.

ml), 97 to 98°C Orange-red prismatic NMR (CDCQ3) δ: 0,50 to 0.54 (2H, m> 0,66 to 0.74 (2H, m> 1, 28 (3H, t, J=7.1Hz >2,43
(3H,s) 2,63 ~2.90 (1H,m) 3,07 ~3.28 (4H,m) 3,47 ~3.77 (4H,m) 4,20 (2f-1, q , J=7.1Hz)7,
53 (IH, brs) 7, 70 (IHSd, J=13Hz) Reference example 32 N-cyclopropyl-2-methyl-3-(4-ethoxycarbonyl-1-piperazinyl)-4-fluoro-6
- Add 4.69 parts of diethyl ethoxymethylene malonate to 1 g of nitroaniline 7, and add 1 g of nitroaniline at 150-170 °C
Heat and react for 7 hours. After cold welding, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography (eluent;
5.4 g of (N-cyclopropyl-N-
(3-(4-ethoxycarbonyl-1-piperazinyl)
Diethyl-2-methyl-4-fluoro-6-nitrophenylcoaminomethylene)malonate is obtained.

Reference Example 33 (N-cyclopropyl-N-(3-(4-ethoxycarbonyl-1-piperazinyl)-2-methyl-4-fluoro-6-nitrophenyl]aminomethylene)diethyl malonate 1.0 g acetic anhydride In 5mQ solution, 50-7
While keeping the temperature at 0°C, add concentrated sulfuric acid 2+uf2. After stirring for 30 minutes, the reaction mixture is poured into ice water and neutralized with potassium carbonate. After extraction with ethyl acetate, the solvent was concentrated and the resulting residue was subjected to silica gel column chromatography (
Eluent; purified with dichloromethane:methanol=10:1) and recrystallized from ethyl acetate to obtain 0.190 1-
cyclopropyl-7-(4-ethoxycarbonyl-1-
piperazinyl)-6-fluoro-8-methyl-1,4-
Ethyl dihydro-4-oxo-3-quinolinecarboxylate is obtained.

mp. 200 to 202°C Colorless prismatic Compound of Reference Example 8.15.13 is obtained in the same manner as in Reference Example 33 using appropriate starting materials.

Reference Example 34 Under the same conditions as Reference Example 28 and using appropriate starting materials,
The following compound is obtained.

3.6-Sihydro-2-(4-benzyl-3-methyl-
1-piperazinyl)-5-nitrobenzyl alcohol NMR (CDCQ3) δ: 1, 18 (3H, d, J=6 t1z
) 2.20~2.38 (1H, m> 2, 55~2.72 (1 t1, m) 2.72~2
．． 91 (IH, m) 3, 06-3. 44 (5to1, m)4
．． 09 (1H, d, J=13Hz >4, 77 (
2H, brs) 7.12~7.40 (5H, m> 7.71 (1H, dd, J=9.5Hz, 7.2Hz
) Reference Example 35 Under the same conditions as Reference Example 29 and using appropriate starting materials,
The following compound is obtained.

2-(4-benzyl-3-methyl-1-piperazinyl)
-3',6-difluoro-5-nitropenzyl chloride NMR (CDCQ3) δ: 1.21 (3) (, d, J=6Hz) 2.24-2
．． 50 (1H, m) 2.60-3.00 (2)-1, m) 3.00-3.
46 (5H, m> 4, 11 (1H, d, J=13Hz >4, 75
(2H, brs) 7.26-7.45 (5H, m) 7.79 (1H, dd, J=9.5Hz, 7.3Hz
) Reference Example 36 Under the same conditions as Reference Example 30, using appropriate starting materials,
The following compound is obtained.

2-(4-benzyl-3-methyl-1-piperazinyl)
-3,6-difluoro-5-nitrotoluene NMR (CD093) δ: 1, '18 (3H, d, J=6 tIz
)2.25 (3H, d, J=3.3Hz)2.
30~2.48 (1H, m>2, 50~3.38 (7H, m>4.08 (
1H, d, J=13Hz >7, 15-7. 46
(5H, m>7.58 (1H, dd, J=7.5H
z.

9.5Hz) Reference Example 37 Under the same conditions as Reference Example 31, using appropriate starting materials,
The following compound is obtained.

N-cyclopropyl-2-methyl-3-(4-benzyl-3-methyl-1-piperazinyl)-4-fluoro-6
-Nitroaniline NMR (CDC93) δ: 0.52 to 0.68 (2H, m> 0, 70 to CL 87 (2H, m) 1.28
(3H, d, J=6Hz >2.22~2.40 (1
H, m> 2.38 (3H, s> 2.58~3.37 (8H, m> 7.26~7.44 (5H, m> 7,60 (1H, brs) 4.11 (1H, d, J=13Hz >7, 77
(1f-ISdd, J=13.2l-1z) Reference Example 38 The following compound is obtained in the same manner as in Reference Examples 32 and 33 using appropriate starting materials.

1-Cyclopropyl-7-(4-pencyl-3-methyl-1-piperazinyl)-6-fluoro-8-methyl-1
,4-dihydro-4-oxo-3=ethyl quinolinecarboxylate mp, 172-173°C White powder (recrystallized from ethyl acetate) Reference Example 39 Using appropriate starting materials in the same manner as Reference Example 28, the following The compound is obtained.

3.6-difluoro-2-(3-amino-1-pyrrolidinyl)-5-nitrobenzyl alcohol mp, 1'l
7. O ~ 118.5°C (recrystallized from acetic acid I ethyl-n-hexane) Orange prismatic reference example 40 3.6-difluoro-2-(3-amino-1-pyrrolidinyl)-5-nitrobenzyl alcohol 43 m (l) Add acetic anhydride Q and 5 mQ to the solution at room temperature and stir at the same temperature for 10 minutes.The reaction mixture is diluted with water, extracted with dichloromethane, and the sulfuric acid layer is washed with water and saturated brine in that order.Dry sulfuric acid After drying with magnesium, the solvent was evaporated.The resulting residue was subjected to silica gel column chromatography (eluent; dichloromethane-methanol:dichloromethane=L1
:12>, then recrystallized from dichloromethane to give 40
mg of 2-(3-acetylamino-1-pyrrolidinyl)
~3,6-difluoro-5-nitrobenzyl alcohol is obtained.

mp, 142.5-143.5°C Yellow prismatic Reference Example 41 The following compound is obtained in the same manner as in Reference Example 29 using appropriate starting materials.

2-(3-acetylamino-1-pyrrolidinyl)-3,
6-difluoro-5-nitrobenzyl chloride NMR (CDC93) δ near, 74 (1H, dd, J=12.0Hz.

7.5Hz >, 6.16 (1H, d, J=5, 4
Hz), 4. 78 <1 H, dd,
J=11.3Hz, 3.0Hz>, 4.69
(IHldd, J=11.3Hz, 3.0Hz)4
．． 62-4.50 (IH, m) 3.97-3.69 (2H, m) 3.67-3.50 (1H, m> 3.49-3.32 (1H, m) 2.40- 2.18 (1H, m) 2.12-1.93 (IH, m> 1.98 (3H, s> .

2-(3-acetylamino-1-pyrrolidinyl)-3,
6-difluoro-5-nitrol-luene mp, 139.
0-140.3°C Yellow needle-like crystals (recrystallized from dichloromethane) Reference Example 43 The following compound was obtained in the same manner as in Reference Example 31 using appropriate starting materials.

N-cyclopropyl-2-methyl-3-(3-acetylamino-1-pyrrolidinyl)-4-fluoro-6-nitroaniline mp, 162.5-164.0'C Orange prismatic (ethyl acetate-n- (Recrystallized from hexane) Reference Example 44 The following compound was obtained in the same manner as in Reference Example 32 using appropriate starting materials.

(N-cyclopropyl-N-((3-acetylamino-
1-pyrrolidinyl)-4-fluoro-2-methyl-6-
Nitrophenyl]amiminethylene) diethyl malonate NMR (CDCQ3) δ: 7.73 (1H,s>7.68 (1H,d, J=11.6Hz>5.
97 (1H, br) 4.62~4.45 (1H, m) 4.12 (4H, q, J=7.2Hz >3.85~
3.15 (5H,m> 2.42~1.95 (5H,m) 1.98 (3H,s> 1.29 <6H,t, J=7.2Hz >0.9
3 to 0.52 (41-1, m>Reference Example 45 The following compound is obtained in the same manner as in Reference Example 33 using appropriate starting materials.

1-cyclopropyl-7-(3-acetylamino-1-
pyrrolidinyl)-6-fluoro-8-methyl-1,4-
3.6-difluoro-2-( 4-ethoxycarbonyl-
1-piperazinyl)-5-nitrobenzyl alcohol 1
．． 59 was dissolved in 18 m of dichloromethane [2] and heated to O in a water bath.
While stirring at °C, add diethylamine sulfur triple olide (DAST>0.7 mQ and triethylamine 0.7 mQ).
A 78 mQ dichloromethane solution was added dropwise over 5 minutes. After stirring at O℃ for 1.2 hours, further O・, 3-D
Add AST. After 5 minutes, the reaction solution is poured into ice water and the organic layer is separated. After distilling off the solvent under reduced pressure, it was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane = 1:10→1:5 v/v) to obtain 2,5-difluoro-3 of 1.19. -fluoromethyl-4-(4-ethoxycarbonyl-1-piperazinyl)nitrobenzene is obtained.

Reference example 47 3.6-difluoro-2-(4-ethoxycarbonyl-
1-piperazinyl)-5-nitrobenzyl alcohol 1
Dissolve ゜Oq in 10 mQ of pyridine, add 2 mQ of acetic anhydride at room temperature while stirring, and stir at the same temperature for 2 hours. Add 20 mQ of water to the reaction mixture and stir for 5 minutes. After extraction with dichloromethane, the organic layer is washed successively with 10% hydrochloric acid and a saturated aqueous sodium bicarbonate solution, and dried over magnesium sulfate.

The solvent is distilled off under reduced pressure to obtain 1.29 of 3-acetoxymethyl-2,5-difluoro-4-(4-ethoxycarbonyl-1-piperazinyl)nitrobenzene.

Reference Example 48 The following compound is obtained in the same manner as in Reference Example 31 using appropriate starting materials.

N-cyclopropyl-2-acetoxymethyl-3-(4
-ethoxycarbonyl-1-piperazinyl)-4-fluoro-6-nitroaniline N-cyclopropyl-2-methoxymethyl-3-(4-
Methyl-1-piperazinyl)-4-fluoro-6-nitroaniline NMR (CDCQ3) δ: 0.47-0.55 (2H, m> 0.69-0.78 (2H, m) 2.36 (3H ,s) 2.51-2.61 (4H,m) 2.88-2.98 (1H,m) 3.22-3.31 (4H,m) 3.34 (3t-(,s), 4.67 (2H,s
)7.29 (1)-1,s> 7.70 <1t-1,d1J=12.7H2)N-cyclopropyl-2-methoxymethyl-3-(4-ethoxycarbonyl-1-piperazinyl)=4 -Fluoro-6
- Nitroaniline mp, 89-90°C (ethanol-water) orange-red needle crystals Reference Example 49 In the same manner as in Reference Example 32, using appropriate starting materials, the following compound is obtained.

(N-cyclopropyl-N-(3-(4-ethoxycarbonyl-1-piperazinyl)-2-acetoxymethyl-
4-fluoro-6-nitrophenyl] aminomethylene)
Diethyl malonate (N-cyclopropyl-N-(3-(4-methyl-1)
-Piperazinyl)-2-methoxymethyl-4-fluoro-6-nitrophenyl]aminomethylene)diethyl malonate - NMR (CDC123) δ: 0.50-1.10 (4H, m) 1.23 (3H, t , J=7.0Hz >2.37
(3H, s> 2.39-2.60 (4H, m> 3.0-3.20 (IH, m> 3.10-3.50 (4H, m) 3.39 (3H, s> 4 .15 (2H, CI, J=7.0Hz >4.3
0 to 4.55 (2H, m> 7.55 to 7.90 (2H, m> Methyl-
4-fluoro-6-nitrophenyl coamino methylene)
Diethyl malonate NMR (CDCQ3) δ: 0.55-0.73 (2HXm) 0.95-1.15 (2H, m> 1.15-1.45 (9H, m> 3, 0-3.15 ('1 H, m>3.15~3.
35 (4H, m) 3.40 (3H, m) 3.45~3.70 (4H, m) 4゜05~4.40 (6H, m> 4.40~4.60 <2H, m> 7.65-7.90 (2H, m> Reference Example 50 The following compound is obtained in the same manner as in Reference Example 33 using appropriate starting materials.

1-Cyclopropyl-7-(4-ethoxycarbonyl-
Ethyl 1-piperazinyl)-6-fluoro-8-acetoxymethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylaterrD), 172-173°C Yellow powder 1-cyclopropyl-7-(4 -ethoxylcarbonyl-1-piperazinyl)-6-fluoro-8-methoxymethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylate NMR (CDCQ3) δ: 0, 80-0. 95 (2t1, m)1
．． 10~1.22 (2H, m> 1.30 (3HS t, J=7.1Hz >3.13
(3HS s) 3.08~3.30 (4H, m> 3.50~3.85 (5H, m> 3.92 (3H, s> 4.19 (2H, QS J=7.1Hz >5 .1
2 (2H, s) 8.09 (1H, d, J=12.4Hz >8.67
(IH,5) 1-cyclopropyl-7-(4-methyl-1-piperazinyl)-6-fluoro-8-acetoxymethyl-1,4
-Dihydro-4-oxo-3-quinolinecarboxylic acid ethyl mp, 122-125°C Yellow-white powder 1-cyclopropyl-7-(4-ethoxycarbonyl-
Methyl 1-cyclopropyl-7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxo-3-carboxylate
Ethyl 1-piperazinyl)-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxo-3-carboxylate Reference Example 51 In the same manner as Reference Example 28, using appropriate starting materials, the following Obtain the compound.

3.6-difluoro-2-(4-methyl-1-piperazinyl)-5-nitrobenzyl alcohol mp, 138-
139°C Yellow prismatic reference example 52 3.6-difluoro-2-(4-ethoxycarbonyl-
1-piperazinyl)-5-nitrobenzyl alcohol 7
．． 14CI was dissolved in 7701Tl12 of methanol, and 1145mQ of concentrated sulfur was slowly added dropwise while cooling on a water bath. Next, the mixture is heated under reflux for 4 hours.

After cooling the reaction mixture to room temperature, it was poured into 1.5Q of ice water and extracted with dichloromethane. After drying with magnesium sulfate and sodium sulfate, the solvent was concentrated under reduced pressure to obtain 7.3
9CI 3-methoxymethyl-2,5-difluoro-4
-(4-ethoxycarbonyl-1-piperazinyl)nitrobenzene is obtained.

rrD), 85-86°C Yellow powder In the same manner as above, using appropriate starting materials, the following compounds are obtained.

3-methoxymethyl-2,5-difluoro-4-(4-
Methyl-1-piperazinyl) nitrobenpine NMR (CDCQ3) δ: 2, 37 (3H, s> 2.45-2.60 (4H, m> 3.32-3.42 (4H, m) 3.48 (3H ,s>4.53 (2H,d,J=3.5Hz>7.78
(IH, dd, J=7.3Hz, J=11.8Hz) Reference Example 53 1-Cyclopropyl-7-(4-ethoxyl!levonyl-1-piperazinyl)-6-fluoro-8-acetoxymethyl-1, To a solution of 300 mCl of ethyl 4-dihydro-4-oxo-3-quinolinecarboxylate in 3 mg of methanol is added 0.8 mf2 of a 1N aqueous potassium carbonate solution, and the mixture is stirred at room temperature for 3.25 hours.

The reaction mixture was poured into water and extracted with dichloromethane and chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, the solvent was distilled off, and 1-
Cyclopropyl-7-(4-oxycarbonyl-1
-piperazinyl)-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxo-3-carboxylate and 1-cyclopropyl-7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro Ethyl -8-hydroxymethyl-1,4-dihydro-4-oxo-3-carboxylate is obtained as a 2=1 mixture.

Without separating and purifying this mixture, methanol 7m (
Add 1.4 ml of 2 and m sulfuric acid, and heat under reflux for 4 hours.

The reaction mixture was poured into 50 ml of ice water, and potassium carbonate was added to adjust the pH to ~8, followed by extraction with dichloromethane. After drying over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure to obtain 159mc+ of 1=cyclopropyl-7-(4
-ethoxycarbonyl-1-piperazinyl)-6-fluoro-8-methoxymethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylate methyl is obtained.

NMR (CDC123) δ: 0.80-0.95 (2H, m> 1.10-1.22 (2H, m> 1.30 (3H, t, J=7.1Hz >3.13
(3H,s> 3.08~3.30 (4H,m> 3.50~3.85 (5H,m) 3.92 (3H,s> 4.19 (2H,q, J=7.1Hz >5.12'
(2H, s) 8.09 (1HS d, J=12.4Hz) a, 6
7 (it-1,s> Reference Example 54 The following compound is obtained in the same manner as in Reference Example 28 using appropriate starting materials.

3.6-difluoro-2-morpholino-5-nitrobenzyl alcohol NMR (COCO2) δ near, 79 (1H, dd, J-711, 9Hz.

7.2Hz >, 4.86 (2HSs) 4.02~3
．． 66 (4H, m) 3.42-3.20 (41-f, m>3.30-3.
02 (IH, br) ml), 87-89°C (recrystallized from n-hexane-ethyl acetate) Yellow plate-like crystals 2.5-difluoro-3-methoxymethyl-4-morpholinonitrobenzene mp, 61.5- 62°C (recrystallized from n-hexane-ethyl acetate) Yellow needle-shaped crystals 3.6-difluoro-2-(3-acetamidomethyl-
1-pyrrolidinyl)-5-nitrobenzyl alcohol mp, 120-121°C Yellow crystal NMR (COCO2+DMSO-ds) δ: 1.55
~1.83 (11-1, m) 1.95 (3H, s> 1.99-2.10 (1H, m) 2.39-2.57 (1H, m> 3.14-3.82 (6H, m) 4.72 (2H, d, J=2.6Hz >7, 31
(1H1brs) 7.70 (1H, dd, J=7.5Hz, 13.5H
z> 3.6-difluoro-2-(4-benzyl-1-piperazinyl)-5-nitrobenzyl alcohol NMR (CO
CO2) δ: 2.50-2.72 (4H, m> 3.20 (1H, br) 3.25-3.38 (4H, m> 3.58 (2H, s> 4.75-4. 90 (2H, m) 7.20-7.45 (5H, m) 7.76 (1H, dd, J=7.2Hz, 11.6H
z> 2,5-difluoro-3-methoxymethyl-4-(4-
Benzyl-1-piperazinyl) nitrobenzene NMR (COCO2) δ: 2.45-2.68 (4H, m) 3.30-3.45 (4H, m> 3.42 (3H, s) 3.58 (2H ,s>4.52 (2H,d,J=3.4Hz>7.26
~7.40 (5H, m> 7.78 (1H, dd, J=7.3Hz, 11.9H
7) 2,5-difluoro-3-methoxymethyl-4-(4-
benzyl-3-methyl-1-piperazinyl)21helobenzene NMR (COCO2) δ near, 77 (IH, d, J = 7.4Hz, 11.9Hz
) 7.41~7.18 (5H, m> 4.52 (2H, s> 4.11 <18.d, J=13.0Hz) 3.45
~2.89 (4H, m) 3.42 (3H, s) 3.21 (1H, d, J=13.0Hz >2.8
9-2.73 (1H, m> 2.73-2.54 (IH, m> 2.39-2.20 (IH, m> 1, 19 (3H, d, J=6.2Hz >3. 6-
Difluoro-2-(3-<N-methyl-N-benzylamino)-1-pyrrolidinyl]-5-nitrobenzyl alcohol NMR (CD093) δ near, 75 (1H, dd, J=7.5Hz, 13. 1H
2) 7.41~7.20 (5H, m) 3.85~3.60 (4H, m> 3.62 (IH, d, J=13.1!-1z) 3.
52 (1) (,d, J=13.1l-1z)3.2
5-3.05 (IHXm) 2.35-1.92 (3H, m) 2.20 (3H, s) Reference Example 55 The following compound was prepared in the same manner as Reference Example 29 using appropriate starting materials. obtain.

2-morpholino-3,6-difluoro-5-nitrobenzyl chloride NMR (CDCQ3) δ near, 84 (1HSdd, J=11.3Hz.

7, 3 t1z) 4.79 (2H, d, J=2.6Hz) 4.00~
3.78 (4H, m) 3.40-3.15 (4H, m) 2.5-difluoro-3-chloromethyl-4-(3-(
N-methyl-N-benzylamino)-1-pyrrolidinyl]-nitrotoluene NMR (CDCQ3) δ- 7,78 (1H, dd, J=7.6Hz 113.4H
2) 7.42-7.22 (5H, m) 4.78 (1H, dd, J=2.7Hz.

12.1Hz), 4.67 (IH, dd, J=2.
7t-1z, 12.1Hz > 3, 92~3. 55 <4t-1, m>3.67
(1H, d, J=13', 1t-1z)3.53
(1H, d, J-13, 1Hz >3.30~3.'1
0 (1H,m) 2.35-1.88 (2H,m>2.22 (3H,s>2.5-difluoro-3-chloromethyl-4-(3-acetamidomethyl-1-pyrrolidinyl)nitrotoluene mp, 94-98°C Yellow crystal NMR (CD CQ 3 + D M S Od
s) δ:1. 68-1. 90 (1 to 1
, m) 2.07 (3H, s> 2.00~2.25 (IH, m) 2.50~2.68 (IHlm> 3.20~3.79 (6H, m> 4.78 (2H ,dXJ=2.6Hz >7.78
(1H, dd, J=7.5Hz,'13.5Hz
>, s, 18 (it-1, brs) Reference Example 56 The following compound is obtained in the same manner as in Reference Example 30 using appropriate starting materials.

2-morpholino-3,6-difluoro-5-nitrotoluene Orange needles mp, 120.5-'121.5°C (recrystallized from n-hexane) 3,6-difluoro-5-nitrotoluene 2- +, (3-(
N-methyl-N-benzylamino)-1-pyrrolidinyl]toluene NMR (CDC93) δ near, 65 (1H, dd, J = 7.1Hz, 12.8H
z) 7.38~7.20 (5H, m) 3.79~3.45 (4H, m) 3.62 (1H, d, J=13.4Hz >3.50
(1H, d, J=13.4Hz >3-30~3.0
6 (1H, m) 2.35-2.13 (1H, m) 2.25 (3H, d, J=3.2Hz >2.20
(3H,s) 2, 1 1-1. 88 (1H,m)3.6-difluoro-5-nitro-2-(3-acetamidomethyl-1-pyrrolidinyl)toluenerrD), 82-84°C Yellow crystal NMR (CD(,Q3)δ: 1.60 ~1.78 (1H, m> 2.00 (3H, s) 2.02 ~ 2.20 (1H, m) 2.24 (3H, d, J = 3.2Hz) 2.40 ~
2.66 (1H, m) 3.20 to 3.62 (6H, m > 5.67 (IH, brs >, 7.63 (IH, d
d.

J=7.5Hz, 13.5Hz > Reference Example 57 The following compound is obtained in the same manner as in Reference Example 31 using appropriate starting materials.

N-cyclopropyl-2-methyl-3-morpholino-4
-Fluoro-6-nitroaniline red foliar crystals mp, 101.5-102°C (recrystallized from n-hexane) N-cyclopropyl-2-methoxymethyl-3-(4-
Benzyl-1-piperazinyl)-4-fluoro-6-nitroaniline NMR (CDCf23) δ: 0.45-0.57 (2H, m) 0.65-0.77 (2t-1, m) 2.48 ~2.
65 (4H, m> 2.86-3.00 (1H, m> 3.20-3.30 (4H, m) 3.32 (3H, s), 3.58 (21-1, s)
4.81 (2H,s) 7.25-7.38 (5H,m>7.70 (1H,d, J=12.8Hz) N-cyclopropyl-2-methoxymethyl-3-(3-methyl −
4-benzyl-1-piperazinyl)-4-fluoro-6
1N-O aniline NMR (CDCf23) δ near, 70 (1H, d, J=12.9Hz >7.40
~7. '19 (5H, m> 4.65 (2H1s> 4, 11 <IH, d, J=13.3Hz
>3.32 (31-1,s) 3.40~2.88 (5H,m>3.22 (1H,d, J=13.3Hz)2.88
~2.72 (1H,m) 2.72~2.53 (it-(,m)2.38~2
．． 20 (1H, m> 1.20 (3H, d, J=6.2Hz >0.80-
0.63 (2H,m> 0.60-0.45 (2H,m) N-cyclopropyl-2-methyl-3-(3-(N-methyl-N-benzylamino)-1-pyrrolidinyl di-4
-Fluoro-6-nitroaniline NMR<CDC93)
δ Near, 87 (1H1S) 7.69 (1H, d, J=11.7Hz) 7.40
~7.22 (5H, m) 3.81 ~ 3.41 (4H, m) 3.65 (IH, d, J=10.6Hz) 3.55
(1H, d, J=10.6Hz >3.24~3.0
8 <IH,m> 2.86-2.72 (1H,m) 2.32-2.10 (IH,m) 2.29 (3H,s>, 2.21 (3H,s>2.
08-1.90 (1H, m) 0.88-0.56 (3HSm) 0.51-0.41 (1H, m) N-cyclopropyl-2-methoxymethyl-3-morpholino-4-fluoro- 6-nitroaniline rr1.57
-60°C (recrystallized from n-hexane) Red powdery crystals N-cyclopropyl-2-methyl-3-(3-acetamidomethyl-1-pyrrolidinyl)-4-fluoro-6-
Nitroaniline NMR (CDCQ3) δ: 0.40-0.85 (4H, m> 1.60-1.83 (IHlm) 2.01 (3H, s> 2.04-2.20 (1H, m> 2.28 (3H, s) 2.42-2.60 (IH, m> 2.70-2.88 (IH, m) 3.20-3.65 (6H, m> 5, 89 (1H, brs) 7.65 (IH, d, J=14.6Hz >7, 8
6 (1H,brs) Reference Example 58 The following compound is obtained in the same manner as in Reference Example 32 using appropriate starting materials.

(N-cyclopropyl-N-(3-(4-benzyl-1
-Piperazinyl)-2-methoxymethyl-4-fluoro-6-nitrophenyl]aminomethylene)diethyl malonate NMR (CDCQ3) δ: 0.55-0.90 (4H, m) 1 , 15-1. 35 (6t;, m)2.
47-2.70 (4H, m> 3.05-3.45 (4H, m> 3.37 (3H, s>, 3.58 (2H, s) 4.
15 (4H, q, J=7Hz >4.20-4.55
(3H, m> 7.20-7.38 (5H, m> 7.63-7.90 (2H, m> (N-cyclopropyl-N-(3-(4-pencyl-3
-Methyl-1-piperazinyl)-2-methoxymethyl-
4-fluoro-6-nitrophenyl] aminomethylene)
Diethyl malonate NMR (CDC93) δ near, 80 (IH, d, J=12.7Hz >7.78
(1H, s) 7.47-7.15 (5H, m> 4.55-3.98 (71-1, m>3.65-2.
88 (6H, m> 3.38 (3H, s> 2.86 to 2.70 (IH, m) 2.70 to 2.47 (IH, m) 2.32 to 2.18 (1H, m> 1.50~1.08 (681m) 1.19 (31-(, d, J=5.0Hz >1.0
1 to 0.41 (4H, m> ) Diethyl aminomethylene comalonate NMR (CDCQ3) δ near, 85-7.60 (2H, m> 7.40-7.16 (5H, m> 4.25-4.06 (2H,, m> 3 .80~3.05 (81-f, m) 2.19 (6
H, s) 2.32~1.89 (2H, m> 1.23 (6H1t, J=7.1Hz) 1.12~
0.41 (4H, m> (N-cyclopropyl-N-[3-morpholino-2-methyl-4-fluoro-6-nitrophenyl]aminomethylene) diethyl malonate Reference Example 59 Same as Reference Example 33 , the following compounds are obtained using appropriate starting materials.

1-Cyclopropyl-7-morpholino-6-fluoro-
Ethyl 8-methyl-1,4-dihydro-4-oxo-3-quinolinecarboxylate colorless powder mp, 205-206°C (recrystallized from ethyl acetate/L/-rl-hexane) 1-cyclopropyl-7- (4-benzyl-1-piperazinyl)-8-acetoxymethyl-6-fluoro-1,
Ethyl 4-dihydro-4-oxoquinoline-3-carboxylate NMR (CDCQ3) δ: 0.85-1.00 (2H, m) 1.10-1.25 (2H, m) 1.41 (3H, t, J=7.1Hz >2.03
(3H,s) 2.45~2.30 (4H,m) 3.10~3.45 (4H,m) 3.60 (2H,s) 3.85~4.03 (1H,m>4 .39 (2H,a,J=7.1Hz >5.79
(2H, s> 7.23~7.45 (5H, m> 8.11 (1H, d, J=12.3Hz) 8.65
(11-1,s> ethyl 1-cyclopropyl-7-morpholino-8-acelloxymethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate mp, 176-17
8°C (recrystallized from ethyl acetate-diethyl ether-n-hexane) Pale yellow prismatic 1-cyclopropyl-7-(4-methyl-1-piperazinyl)-6-fluoro-8-hydroxymethyl-1,4
-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ml), 216-218°C Pale yellow powder 1-cyclopropyl-7-(4-methyl-1-piperazinyl)-56-fluoro-8-methoxymethyl- 1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid ethyl mp, 200-204°C Pale yellow powder 1-cyclopropyl-7-(4-benzyl-3=methyl-1-piperazinyl)-6-fluoro-8= Acetoxymethyl-1,4-dihydro-4-oxoquinoline-3-
Ethyl carboxylate mp, 170-172.5°C (decomposed) (recrystallized from ethyl acetate-diethyl ether) Light brown powder 1-cyclopropyl-7-(3-(N-benzyl-N-
methylamino)-1-pyrrolidinylcy6-fluoro-
8-Methyl-1,4-dihydro-4-oxoquinoline-
Ethyl 3-carboxylate mp, 145-148.5°C (decomposed) (recrystallized from ethyl acetate-diethyl ether) Pale yellow powder 1-cyclopropyl-7-morpholino-6-fluoro-
Ethyl 8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate m, l), 212-2
16℃ Pale yellow powder 1-cyclopropyl-7-morpholino-6-fluoro-
8-(1-pyrrolidinylmethyl)-1,4-dihydro-
Ethyl 4-oxoquinoline-3-carboxylate ml:), 227-. 232°C Pale yellow powder 1-cyclopropyl-7-morpholino-6-fluoro-
Ethyl 8-ethylthiomethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate mp, 165-167
°C (recrystallized from dichloromethane-diethyl ether) Pale yellow needles 1-cyclopropyl-7-(3-acetamidomethyl-
1-pyrrolidinyl)-6-fluoro-8-methyl-1,
Ethyl 4-dihydro-4-oxoquinoline-3-carboxylate mp, 208-210'C (ethyl J: Rereconsolidation A)
White crystal reference example 60 1-cyclopropyl-7-(4-methyl-1-piperazinyl)-6-fluoro-8-acetoxymethyl-1,4
-Dihydro-4-oxoquinoline-3-ethyl carboxylate 142n+c+ ethanol 1, Q mQ bath solution Potassium carbonate 1 mQ was added and stirred at room temperature for 2.5 hours,
The reaction mixture was extracted with chloroform and then dried over magnesium sulfate. After concentrating the solvent, diethyl ether was added to the residue and crystallized to give 101111 (1-cyclopropyl-7-(4-methyl-1-piperazinyl)-6-
Fluoro-8-hydroxymethyl-1,4-dihydro-
Ethyl 4-oxoquinoline-3-carboxylate is obtained.

mp, 216-218°C Pale yellow powder Reference Example 61 1-Cyclopropyl-7-(4-methyl-1-piperazinyl)-6-fluoro-8-hydroxymethyl-1,4
-160mA of ethyl dihydro-4-oxoquinoline-3-carboxylate in a solution of 10mQ of methanol with 21l of concentrated sulfuric acid.
2 was added and heated under reflux for 6.5 hours. The reaction mixture was adjusted to pH ~8 with a saturated aqueous sodium bicarbonate solution, and then extracted with dichloromethane. The extract is washed with saturated saline and dried over magnesium sulfate. After concentrating the solvent,
Diethyl ether was added to the obtained residue and crystallized to give 125 mg of 1-cyclopropyl-7-(4-methyl-1-piperazinyl)-6-fluoro-8-methoxymethyl-1,4-dihydro-4. -Methyl oxoquinoline-3-carboxylate is obtained.

mp, 200-204°C Pale yellow powder Reference Example 62 3.6-difluoro-2-(4-benzyl-1-piperazinyl)-5-nitrobenzyl alcohol 15.4CI
Chain making 1 was added to 400 m2 of methanol solution under water cooling and stirring.
Slowly add 80mQ. After the addition is complete, the mixture is heated under reflux for 30 hours. Furthermore, 10 mQ of concentrated sulfuric acid was added, and the mixture was heated under reflux for 20 hours. After cooling to room temperature, a saturated aqueous potassium carbonate solution and a saturated aqueous sodium bicarbonate solution are added to adjust the pH to ~8. Extract with ethyl acetate and dry with magnesium sulfate. After evaporating the solvent, the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane) to obtain 12.9 CJ of 2,5-difluoro-4-(4
-benzyl-1-piperazinyl)-3-methoxymethylnitrobenzene is obtained.

NMR (CDCQ3) δ: 2.45 to 2.68 (4H, m) 3.30 to 3.45 (4H, m > 3.42 (3H, s), 3.58 (2H, s > 4.
52 (2H, d, J=3.4Hz) 7.26-7.
40 (5H, m> 7.78 (1H, dd, J=7.3Hz, 11.9H
2) Reference Example 63 1-cyclopropyl-7-morpholino-6-fluoro-
To a solution of 550 mq of ethyl 8-acetoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate in 10 ml of ethanol, 1 m of 2N potassium carbonate (2) is added and stirred at room temperature for 4 hours.The reaction mixture is diluted with water. After dilution, extraction with dichloromethane was performed, and the resulting residue was crystallized by adding diethyl ether to give 353 mg of 1-cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1,4-dihydro-4. -Oxoquinoline-3
- Obtain ethyl carboxylate.

mp, 212-216°C Pale yellow powder Reference Example 64 1-Cyclopropyl-7-morpholino-6-fluoro-
To 80 mc+ ethyl 8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate was added 1 mQ of thionyl chloride, and the mixture was heated at room temperature for 4 hours, then at 50°C.
Stir at C for 1 hour. Concentrate the solvent under reduced pressure to 84 m9
to obtain crude ethyl 1-cyclop-O-pyl-7-morpholino-6-fluoro-8-chloromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate.

Pyrrolidine 1 rnQ is added to this product without purification, and the mixture is stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane, washed with water and saturated brine, and dried over magnesium sulfate. The 2M residue obtained by distilling off the solvent was purified by silica gel column chromatography (eluent: dichloromethannimethanol = 10:1) to obtain 31.
8 mCl of 1-cyclopropyl-7-morpholino-8-
(1-pyrrolidinylmethyl)-6-fluoro-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid is obtained.

mp, 227-232°C Slight yellow powder Reference Example 65 1-Cyclopropyl-7-morpholino-6-fluoro-
Add 1.5 m (2) of thionyl chloride to ethyl 8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (101 mCI) and stir at room temperature for 5.2 hours. After concentrating the solvent under reduced pressure, the obtained To the obtained crude ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8-chloromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate were added 1.5 ml of ethanethiol and 30 μ9 of triethylamine, and the mixture was heated to room temperature. The reaction mixture was extracted with dichloromethane, washed sequentially with water and saturated brine, and dried over magnesium sulfate.The solvent was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent: dichloromethane: methanol = 15:1)
After purification, recrystallization from dichloromethane-diethyl ether gave 49 mg of 1-cyclopropyl-7-morpholino-6-fluoro-8-ethylthiomethyl-1,4-
Ethyl dihydro-4-oxoquinoline-3-carboxylate is obtained.

mp, 165-167°C Pale yellow needles Reference Example 66 2-'7 day potassium fluoride spray-dried in 1.0 CI of 5,6-difluoro-3-nitrotoluene 1.
4g, anhydrous dimethyl sulfoxide 10 precepts and benzene 1
0 ml is added and water is removed by azeotroping with benzene.

Then, 3. at 170-180°C under an argon stream.
Stir for 5 hours. After cooling, the reaction mixture was poured into ice water and extracted with diethyl ether. After washing with water and drying, the solvent is concentrated. The residue) was purified by silica gel column chromatography (eluent: n-hexane) to a concentration of 0.4
．． 2.5 of 5CI. Rotrifluoro-3-nitrotoluene is obtained.

NMR (CDCQ3) δ: 2, 34-2. 37 (3to1, m)7
．． 75-8.00 (1 m per day> Reference Example 67 3-Amino-1-benzyl-4-methylpyrrolidine 9.
59 in methanol 190mf2 solution at room temperature.
ert-butoxycalfone 113. Add Oq and stir for 1 hour. Methanol was distilled off under reduced pressure, water was added to the residue,
Extract with dichloromethane.

After drying with magnesium sulfate, dichloromethane was distilled off and the resulting residue was subjected to silica gel column chromatography (
Purify with eluent (dichloromethane:methanol=19:1). 4:4 g of 3-(tert-butoxycarbonylamino)-1-benzyl-4-methylpyrrolidine (
Isomer A) is obtained.

mp, 131.5-132.7°C Colorless prismatic NMR ('CDCQ3) δ: 1.09 (3H, d, J=6.7Hz) 1.43
(9H1s> 1.86~2.02 (2H, m) 2.62 (2H, d, J=6.1Hz >2.93~
3.05 (1H, m> 3.56 (2H, s), 3.68 (1H, brs
) 4, 84 (1H,brs) 7.20-7.37 (5H,m> Example 68 trans-3-(tert-butoxycarbonylamide 3
, 9g of ethanol 50- and 10% Pd-0780m
g was added thereto, and catalytic reduction was carried out at 60'C and normal pressure. After the catalytic reduction is completed, the catalyst is removed and the furnace liquid is concentrated. The obtained residue was recrystallized from ethyl acetate-petroleum ether to give 2.0
3-(tert-butoxyamino)-4-methylpyrrolidine (isomer A) of ``1(7) is obtained.

rrD), 86. 8-87℃ Colorless prismatic NMR (CDCQ3) δ: 1,08 (3H, d, J=6.8Hz >'1.45
(9H,s) 1,83 ~1.97 (IH,m>2,43 ~2.52 (1H,m) 2,52 ~2.81 (1H,m>3,10 ~3
．． 35 (2H, m> 3,53 - 3.73 (1H, m) 4, 69 (1 H, brs) Reference Example 69 Sodium borohydride 51.6CI was added to a tetrahydrofuran (THF>500m!Q solution with stirring, io'cI
2.5 under X. Lotrifluorobenzoic acid 1 20CJ
A solution of T H F 200 mQ is added dropwise. Next, under water cooling, 8F3 ・(C2 Hs)2 0 232
A solution of 12 m of THF in 500 mQ is added dropwise. Thereafter, the reaction mixture was stirred overnight at room temperature, poured into 1.5Q ice water, and extracted with diethyl ether. After drying with magnesium sulfate, the solvent was concentrated under reduced pressure to obtain 2,3.

112.79 of trifluorobenzyl alcohol is obtained.

Slight yellow oil bp. 112°C (30mmHa) Reference Example 70 2,3.6-trifluorobenzyl alcohol 41Cl
A solution of 50 ml of thionyl chloride in 80 mQ of dichloromethane is added dropwise to a 100 mQ solution of thionyl chloride in 100 mQ of dichloromethane while cooling with water and stirring. After stirring overnight at room temperature, 10 m of triethylamine
12 was added, and the solvent was distilled off under reduced pressure.

28,6Q 2.3.6-trifluorobenzyl chloride is obtained.

Colorless oil bp. 63°C (13mmHg) NMR (CD
C93) δ: 4,66 (2H,s>6,62 to 6.93 (1H,m>7,04 to 7.26 (1H,m>) Reference Example 71 In a 4mQ aqueous solution of 1.94g of sodium cyanide , 0.09cx of phenyltriethylammonium chloride is added.Additionally, 5.Oq of 2,3.6-dorifluoropenzyl chloride is added while stirring, and the mixture is heated at 90 to 100'C for 40
Heat and stir for a minute. The reaction mixture was poured into 20 mQ of water and extracted with diethyl ether. After drying with potassium carbonate, the solvent is distilled off to obtain 3.1 g of 2-(2,3, lotrifluorophenyl)acetonitrile.

bp, 80-85°C (5mmHg) NMR (CDCQ3) δ: 3.76 (2H, d, J=0.8Hz) 6.89-6
．． 98 (1H, m> 7.11 to 7.26 (IH, m>
Carefully add 8.5 mQ of concentrated sulfuric acid and heat the solution to 12.5°C.
Reflux for 7 hours. Cold weld, diethyl ether and water are added to separate the liquid. The ether layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-
(2,3,rotrifluorophenyl)ethyl acetate 1
6.3 g are obtained as a colorless oil.

NMR (CDCQ3) δ: 1.27 (3H, t, J = 7.1Hz) 3.72 (
2H, d, J = 1.2Hz>4.19 (2H, Q, J
=7.1Hz>6.78~6.90 (IH,m>7.00~7.16 (IH,m) Reference Example 73 16.2CJ of ethyl 2-(2,3,rotrifluorophenyl)acetate Dissolve in 60% of ethanol and stir. Add 200 mQ of 3N aqueous sodium hydroxide solution and stir at 70°C for 1 hour. Cold weld, 120% of 6N hydrochloric acid.
m2 was added, the precipitated white powder was dissolved by addition of diethyl ether, and extracted with diethyl ether. The ether layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and
- (2,3°rotrifluorophenyl) vinegar 113.
9 cl are obtained as a white solid.

NMR (CDCI23) δ: 3.79 (2H, s> 6.79 to 6.91 (1H, m> 7.02 to 7.18 (1H, m> 9.75 (IH, s>) Reference Example 74 Hydrogen Lithium aluminum chloride (0,1) was suspended in 5 mQ of dry diethyl ether and stirred, and 2,0q of 2-(2,3, rottrifluorophenyl)acetic acid dissolved in 15 m12 of dry diethyl ether was added dropwise thereto for 30 minutes. Add 0.8 m of water + 0.8 mQ of 2.10% aqueous sodium hydroxide solution and 1.6 m of water (2) in sequence and stir at room temperature.

Add 10 mQ of diethyl ether, and filter the precipitate. The precipitate was washed with THF, combined with the filtrate and concentrated under reduced pressure to obtain 1.9 g of 2-(2,3, lotrifluorophenyl)ethyl alcohol as a colorless oil.

NMR (CDC93) δ: 1.75 (1H, s > 2.98 (2H, t, J = 6.7Hz) 3.85 (
2H,t,J=6.7Hz>6.74~6.87 (1
H. m - Add 2.29 mf2 of toluenesulfonyl and 2.0 mf2 of triethylamine and stir at room temperature for 5 hours. The reaction mixture was poured into water and extracted with diethyl ether.

The ether layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified with silica gel column chromatography (eluent: methylene chloride). Recrystallization from ether/n-hexane yields 3.4q of colorless prismatic crystals of 1-(2-(p-toluenesulfonyloxyethyl))-2,3,rotrifluorobenzene.

mp, 73-74°C NMR (CDC(23)δ: 2.44 (3H, s > 3.03 (2H, t, J = 6.5Hz > 4.23
(2H, t, J=6.5Hz >6.70~6.82
(1H, m> 6.93~7.09 (1H, m> 7.29 (2H, d, J=8.5t-1z) 7.7
0 (2H, d, J = 8.5Hz > Reference Example 76 5.6q of lithium aluminum hydride was suspended in 70ml of dry diethyl ether, and while stirring, 1
1-(2-(p-toluenesulfonyloxyethyl)) dissolved in 170 mQ of dry diethyl ether at below 0°C
23.30 of -2,3,rotrifluorobenzene is added dropwise. After stirring at room temperature for 1 hour, water 5.6mf2.1
0% sodium hydroxide aqueous solution 10.0ml12. Water 5.6
Add 1TIf2 in sequence and stir at room temperature for 30 minutes. After removing the white precipitate by filtration, the filtrate solution was concentrated under normal pressure, and 2, 3. 13.2 CJ of rottrifluoro-1-ethylbenzene is obtained as a colorless oil.

NMR (CDCQ3) δ: 1, , 22 (3H, t, J=7.
1 t1z )2.72 (2H,Q,J=7.
1Hz >6.71~6.82 (1t-1, m>6.
87-7.03 (1H, m> Reference Example 77 2.3. Rotrifluoro-1-ethylbenzene 1.0
Dissolve 9CI in 5.5ml of concentrated sulfuric acid and stir without stirring 0.83CJ of potassium nitrate dissolved in 4mQ of sulfuric acid.
Add dropwise at room temperature and stir for 1 hour.

Pour the reaction into 100 mf2 of cold water and extract with diethyl ether. The ether layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 3-ethyl-2,4,5-i-lifluoronitrobenzene 1.1
4CI is obtained as a yellow oil.

NMR (CDC93) δ: 1.27 (3H, t, J=7.6Hz) 2.77~
2.89 (2H, m> 7, 83 (1tl, dd, J=8.0
Hz.

16, H2> Reference Example 78 1.02C of 3-ethyl-2,4,5-trifluoronitrotobenzene], 4.5 mQ of ethanol and 0.5 m2 of water
Add and stir. 1-methylpiperazine 0.83
mL triethylamine 1.0ml12 and ethanol 0
．． After adding 6mf2 of the mixture and stirring and refluxing for 5 hours, 1.04 of 1-methylpiperazine was added and the mixture was further heated and refluxed for 3 hours. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: methylene chloride).
to give 3-ethyl-2,5-difluoro-4-
(4-Methyl-1-piperazinyl)nitrobenzene1.
120 is obtained as a yellow oil.

NMR (CDC93) δ: 1.21 (3H, t, J=7.5Hz >2.37
(3H, s) 2.42-2.67 (4H, m> 2.81 (2H, dq, J=2.8Hz).

7.5Hz) 3.05-3.23 (4H,, m) 7.63 (1H, dd, J=7.1Hz.

11.3H2) Reference Example 79 3-ethyl-2,5-difluoro-4-(4-methyl-
0.24 g of potassium fluoride, 3.5 mg of N,N-dimethylsulfoxide and 0.4 ml of cyclopropylamine are added to 1-piperazinyl)nitrobenzene 1,'12Cl, and the mixture is stirred at 80-85°C for 1.5 hours. Dilute with ethyl vinegar, wash with water and saturated saline, and dry over anhydrous magnesium sulfate. Concentrate under reduced pressure to obtain 1.0 OCI of N-cyclopropyl-2-ethyl-3-(4-methyl-1-piperazinyl)-4-fluoro-6-nitroaniline.
obtained as a viscous oil.

NMR (CD CQ 3 ) δ: 0.45 to 0.55 (2H, m> 0.66 to 0.78 (2H, m> 1, 14 (3H, t, J=7.4 t1z
)2.37 (3H,s) 2.40~2.62 (4H,m) 2.62~2.85 (IH,m>3,O○(2H,q,J=7.4Hz)3. 05-3
．． 23 (4H, m) 6.82 ('IH,s> 7.54 (IH, d, J=12.4Hz) Reference Example 80 The following compound was prepared in the same manner as Reference Example 67 using appropriate starting materials. Obtained.

3-(t-butoxycarbonylamino)-1-benzyl-4-methyl-pyrrolidine (isomer B) mp, 83-8
3.5°C Colorless needles (recrystallized from n-hexane) NMR (CDCQ3) δ: 0.93 (3H, d, J = 6.98Hz >'1.4
4 (9)-1,s> 2.14-2.54 (3H, m) 2, 60-2. 93 (2 tons 1. m) 3.5
8 (2H, dd, J=13.03Hz.

J=14.91Hz) 4.07-4.31 (IH, m) 4.61-4.82 (1H, m> 7.14-7.39 (5H, m) Reference Example 81 Same as Reference Example 68 Using an appropriate starting material (X), the following compound is obtained.

3-(t-butoxyamino)-4-methylpyrrolidine (isomer B) bp, 106-109°C (0,25ul-1(1)NM
R(CDCQ3)δ: 0, 97 (3H, d, J=6.9 humans
z >1.45 (9f-1,s) 1.93 (1H,brs) 2.10~2.33 (1H,m>2.61~2.79 (IH,m>3, 04~3. 33 (2H, m>3.97~4
．． 21 (1H, m) 4.63-4.87 (IH, m> Reference Example 82 The following compound was obtained in the same manner as in Reference Example 32 using an appropriate starting material (A).

(N-cyclopropyl-N-(3-, (4-methyl-1
-Piperazinyl)-2-ethyl-4-fluoro-6-ditohephenyl)aminomethylene)diethyl malonate Reference Example 83 The following compound is obtained in the same manner as in Reference Example 33 using appropriate starting materials.

Ethyl 1-cyclopropyl-7-(4-methyl-1-piperazinyl)-6-fluoro-8-ethyl-1°4-dihydro-4-oxo-3-quinolinecarboxylate mp, 201-203°C White powder (Recrystallized from ethanol) Example 1 6,7-difluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline 3 #/
Lzbo':/I B (OCOCH3)2 KiL/-
1.6 g of pencil piperazine and 6 ml of dimethyl acetamide were added to 1.2 g of the mixture, and the mixture was heated and reacted at 50'C for 20 hours. After concentration, 20 m of acetone (2
Add and dissolve, add 5 ml of concentrated hydrochloric acid, and stir at room temperature for 30 minutes. After distilling off the solvent, water is 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 diethyl ether-ethanol mixture was added to the residue, the precipitated crystals were collected, and 7-(4-benzyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4- 0.1 g of oxoquinoline-3-carboxylic acid is obtained.

mp, 209-211 °C White crystal NMR (CDCQ3) δ: 8.86 (IH, s > 7.85 (IH, d, J = 12 Hz) 7.35 (
5H, bs) 3.93-4.26 (it-(, m>3.62 (2
H, s> 3.13-3.50 (4H, m) 2.76 (3H, s) 2.53-2.83 (4H, m) 0.73-1.40 (4H, m> Example 2 184 m of 7-(4-benzyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carbon (] and 3 ml of acetic acid and 10% Add Pd-Cloma, 70
' Catalytic reduction for 1 hour at C. After catalytic reduction, cool
Remove the catalyst. The furnace liquid was concentrated, sodium hydrogen carbonate water was added to the residue, the precipitated crystals were separated, and 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4- Oxoquinoline-3-carboxylic acid 45mc+ is obtained.

ml), 291-295°C (decomposition) White crystal NMR (DMSOds) δ: 8.84 (1H,s>7.85 (1H,d, J=12.5Hz) 4.30
~4.48 (1H, m> 3.16~3.50 (8H, m> 2.78 (3H, s) 1, 12~1.28 (21-1, m) 0.84~0.
96 (2H, m) Example 3 1.8 CI of 6.7-difluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid suspended in 5rll12 of N-methylpyrrolidone. The mixture becomes cloudy, 1.8 g of piperazine is added, and the mixture is stirred at 150°C for 3 hours. After the reaction, the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 3:1) to obtain 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-8.
-Methyl-1,4-dihydro-4-oxoquinoline-3
-0.06 CJ of carboxylic acid is obtained.

ml), 291-295°C (decomposition) White crystal NMR (DMSO-ds) δ: 8.84 (1H, s) 7.85 (1H, d, J=12.5Hz) 4.30
~4.48 (11-!, m)3.16~3.50 (
8H, m> 2.78 (3H, s> − 1,12 to 1.28 (2H, m> 0.84 to 0.96 (2H, m>) Example 4 Using appropriate starting materials, Example 1 and the same forest to obtain a compound of "C" or less.

7-(4-Methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1°4-dihydro-4-oxoquinoline-3-carboxylic acid mD, 2'19-220.5° C (etha/-/l, recrystallized from) pale yellow prismatic 7-(1,4-diazabicyclo(4,3,O)nonane-
4-yl)-1-cyclopropyl-6-fluoro-8-
Methyl-1,4-dihydro-4-oxoquinoline-3-
Carboxylic acid mp, 208-212°C (recrystallized from dichloromethane-diethyl ether) Pale yellow powder 7-(1-piperazinyl)-1-(2,2-dichloro-
1-cyclopropyl)-6-fluoro-8-methyl-1
, 4-dihydro-4-oxoquinoline-3-carboxylic acid 7-(1-piperazinyl)-1-(2-fluoro-1-
cyclopropyl)-6-fluoro-8-methyl-1,4
-dihydro-4-oxoquinoline-3-carboxylic acid Example 5 1-cyclopropyl-6-fluoro-8-methyl-7-
(1-piperazinyl), -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 0.20 CI and potassium hydrogen carbonate 70 mCl were suspended in dimethylformamide 3 mf2, and 4-bromomethyl-3-methyl -1
, 0.13 (J) of 3-dioxolen-2-one is added and stirred at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure, water is added to the resulting residue, and extracted with dichloromethane. After evaporation, the residue was recrystallized from dichloromethane-diethyl ether to give 0.24 CJ of 7-(4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl-1- cyclopropyl-6-
Fluoro-8-methyl-1°4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained.

mp, 174-177°C Pale yellowish white crystal Example 6 6.7-difluoro-1-cyclopropyl-8=methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-B (OCOCFh) 2 chelate Dimethylacetamide 1011112 and 4-benzyl-3 in 3.4q
- Add 6.8 g of methylpiperazine and react at 50°C for 3 hours. After the reaction, the solvent was distilled off and 30% acetone was added to the residue.
Add mQ and 5 mQ of concentrated hydrochloric acid, and stir at ¥ temperature for 30 minutes.

After distilling off the solvent, water is added to the residue and the crystals are collected. The aqueous layer is neutralized with sodium hydrogen carbonate and extracted with dichloromethane. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography (eluent; dichloromethane:methanol = 20:1), and then recrystallized from ethanol to obtain 0.45CI of 7-(4-benzyl- 3-
Methyl-1-piperazinyl)-1-cyclopropyl-6
-Fluoro-8-methyl-1°4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained.

ml), 170-171°C Pale yellow powder Example 7 7-(4-benzyl-3-methyl-1-piperazinyl)
-1-cyclopropyl-6-fluoro-8-methyl-1
, 0.30Q of 4-dihydro-4-oxoquinoline-3-carboxylic acid, 10mQ of vinegar M and 50mg of 10% Pd
and catalytic reduction at normal pressure of 70'C for 1 hour. After the catalytic reduction is completed, it is cooled and the catalyst is removed. The filtrate was concentrated, water was added to the residue, and the pH was adjusted to 7.5 with sodium hydrogen carbonate.
Extract with dichloromethane. After distilling off the solvent, diethyl ether is added to the residue and the precipitated crystals are collected. Recrystallized from ethanol to give 0.160 7-(3-methyl-1
-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained.

rrD), 206-208°C Pale yellow powder Example 8 1-Cyclopropyl-7-(4-ethoxycarbonyl-
1-piperazinyl)-6-fluoro-8-methyl-1,
7 mQ of 10% aqueous sodium hydroxide solution in ethyl 4-dihydro-4-oxo-3-quinolinecarboxylate o,act
and heated under reflux for 5 hours. Cold weld, acidify with dilute hydrochloric acid and extract with dichloromethane. The pH of the aqueous layer was adjusted to 7.5 with sodium hydrogen carbonate, and the precipitated crystals were collected as a liquid.
7-(1-piperazinyl)-1-cyclopropyl-6
-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained.

mp, 291-295°C (decomposed) NMR (DMSOds) δ: 8.84 (1t-(,s) 7.85 (IH, d, J=12.5Hz) 4.30
~4.48 (1H,m> 3.16~3.50 (8'H,m>2.78 (3H,s) 1.12~1.28 <2H,m) 0.84~0.96 (2 days, m> Using appropriate starting materials in the same manner as in Example 8, the compound of Example 1.4.5.6.7 is obtained.

Example 9 The following compound is obtained in the same manner as in Examples 1.3 and 8 using appropriate starting materials.

1) 7-(3-amino-1-pyrrolidinyl)-1-
cyclopropyl-6-fluoro-8-methyl-1,4-
dihydro-4-oxoquinoline-3-carboxylic acid rrD), 201.5-203.0'C pale yellow powder (
Recrystallized from ethanol-diethyl ether) 2) 1-Cyclopropyl-7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxo-3- Quinolinecarboxylic acid np, 234-235°C (recrystallized from methanol) White needle-like crystals 3) 1-Cyclopropyl-7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-8-methoxymethyl-1 , 4-dihydro-4-oxo-3-quinolinecarboxylic acid ml), 218-220°C (recrystallized from ethanol) pale yellow prismatic crystals 4) 1-Cyclopropyl-7-(4-methyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-
1,4-dihydro-4-oxo-3-quinolinecarboxylic acid mp, 197-201°C Pale yellow powder 5) 1-Cyclopropyl-7-(1-gopelazinyl)
-6-Fluoro-8-hydroxymethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid mp, 149-152°C (recrystallized from ethanol-acetone-dichloromethane) White powder 6) 1-cyclo Propyl-7-(4-methyl-1-piperazinyl)-6-fluoro-8-methoxymethyl-1
,4-dihydro-4-oxo-3-quinolinecarboxylic acid mp, 208-210'C (recrystallized from ethanol-diethyl ether) White powder 7) 1-Cyclopropyl-7-(1-piperazinyl)
-6-fluoro-8-methoxymethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 8) 1-cyclopropyl-7-(4-methyl-1-piperazinyl)-6-fluoro-8- Fluoromethyl-1
,4-dihydro-4-oxo-3-quinolinecarboxylic acid mp, 187-189°C (decomposition) Pale yellow powder (recrystallized from diethyl ether-dichloromethane) 9) 1-Cyclopropyl-7-(1-piperazinyl) )
-6-fluoro-8-fluoromethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 10) 1-cyclopropyl-7-(4-methyl-1-
1-cyclopropyl-7-(1-piperazinyl)-6-fluoro-8-difluoromethyl -1,4-dihydro-4-oxo-3=quinolinecarboxylic acid 12) 1-cyclopropyl-7-(4-hydroxy-
1-piperidyl)-6-fluoro-8-methyl-1,4
-dihydro-4-oxo-3-quinolinecarboxylic acid mp, 234-236°C (recrystallized from chloroform-ethanol) Pale yellow crystals 13) 1-Cyclopropyl-7-(3-amino-4-
Methyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4=oxo-3-quinolinecarboxylic hydrochloride (isomer A) mp, 226-232°C (decomposition) Yellow powder (Recrystallized from ethyl acetate-ethanol) NM
R(DMSO-d6)δ: 1.18 (3f-(, d, J=6.7Hz >2.6
2 (3H, s) 7.72 (1H, d, J=13.4t-1z)8.
79 (1t-1,5) 14) 1-cyclopropyl-7-(3-aminomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1
, 4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride mp, 195-200°C (recrystallized from ethyl acetate-methanol) Yellow crystals 15) 1-Cyclopropyl-7-(3-methyl-leaamino- 1-pyrrolidinyl)-6-fluoro-8-methyl-
1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ml), 185.5-187.5°C (decomposition) (recrystallized from ethanol-diethyl ether) white powder 16) 1-cyclopropyl-7 -(4-cyclopropyl-1-piperazinyl)-6-fluoro-8-methyl-
1,4-dihydro-4-oxo-3-quinolinecarboxylic acid mp, 224-225.5°C (decomposition) pale yellow prismatic shape (recrystallized from ethanol) 17) 1-Cyclopropyl-7-(3-( 5-Methyl-2-oxo-1,3-dioxolen-4-yl)methylamino-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-
4-Oxo-3-quinolinecarboxylic acid 18) 1-Cyclopropyl-7-morpholino-6-fluoro-8-methyl-1,4-dihydro-4-oxo-
3-quinolinecarboxylic acid mp, 227.5-228°C (
Recrystallized from ethanol) 1 pale yellow powder crystal) 1-Cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1°4-dihydro-4
-oxoquinoline-3-carbonic acid rTD), 218-220'C (methanol recrystallization) pale yellow prismatic shape 20) 1-cyclopropyl-7-(4-benzyl-1
-Piperazinyl)-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp, 229-231°C (recrystallized from dichloromethane-diethyl ether) Pale yellow foliate 21) 1 -cyclopropyl-7-(4-benzyl-3
-Methyl-1-piperazinyl)-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp, 208-209°C (recrystallized from ethanol-diethyl ether) Pale yellow Powder 22) 1-Cyclopropyl-7-(3-methyl-1-
Piperazinyl)-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp, 180-183°C (recrystallized from ethanol-ethyl acetate-diethyl ether) White powder 23) 1-Cyclopropyl-7-(3-(N-benzyl-N-methylamine)-1-pyrrolidinyl)-6-fluoro-8-methyl-1°4-dihydro-4-oxoquinoline-3-carboxylic acid mp, 160.8-161.3°C (recrystallized from ethanol-diethyl ether) Pale yellow powder 24) 1-Cyclopropyl-7-morpholino-6-fluoro-8-(1-pyrrolidinylmethyl)-1 , 4-dihydro-4-oxoquinoline-3-carboxylic acid rrl, 232-236°C (decomposition) (recrystallized from diethyl ether-ethanol-dichloromethane) pale yellow prismatic shape 25) 1-cyclopropylnia-morpholino-6 -Fluoro-8-ethylthiomethyl-1゜4-dihydro-4
-Oxoquinoline-3-carboxylic acid mp, 206-208°C (recrystallized from n-hexane-ethanol) Pale yellow prismatic shape26) 1-Cyclopropyl-7-(4-oxo-1-
piperidyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 247-250°C (recrystallized from ethanol) White crystals 27) 1- Cyclopropyl-7-(3-acetamidomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp, 192-194°C (from chloroform-methanol) Recrystallization) White crystals 28) 1-Cyclopropyl-7-(3-t-butoxycarbonylaminomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1°4-dihydro-4-oxoquinoline-3- Carboxylic acid rTD), 131-135°C (recrystallized from methanol) white powder 29) 1-Cyclopropyl-7-(3-aminomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1
, 4-dihydro-4-oxoquinoline-3-carboxylic hydrochloride mp, 195-200'C (recrystallized from vinegar and 1 ethyl methanol) White powder 30) 1-Cyclopropyl-7-(3-(N -ethylacetamido)methyl-1-pyrrolidinyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp, 167-169°C (recrystallized from ethanol) pale yellow crystals 31) 1 -Cyclopropyl-7-(3-ethylaminomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic hydrochloride mp, 267-271°C (methanol-
Recrystallized from acetonitrile) Yellow powder 32) 1-Cyclopropyl-7-(4-acetyl-3
-methyl-1-piperazinyl)-6-1fluoro-8-
Methyl-1,4-dihydro-4-oxoquinoline-3-
Carboxylic acid mC1, 219-221°C (recrystallized from methanol) White powder 33) 1-Cyclopropyl-7-(4-formyl-3
-Methyl-1-piperazinyl)-6=fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ml), 236-239°C (recrystallized in meta/-/l) White powder 34) 1-cyclopropyl-7-(3,4-dimethyl-1-piperazinyl)-6-fluoro-8-methyl-1
,4-dihydro-4-oxoquinoline-3-carboxylic acid mp, 181-183°C (recrystallized from ethyl acetate) pale yellow powder 35) 1-Cyclopropyl-7-(3,5-dimethyl-1 -piperidyl)-6-fluoro-8-methyl-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid (ml), 176-179°C Pale yellow prismatic shape (recrystallized from ethanol) 36) 1
-cyclopropyl-7-(3-methylmorpholino)-6
-Fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp, 199.5-201°C Colorless needles (recrystallized from ethanol-ethyl acetate) 37)
1-Cyclopropyl-7-(3-aminemethylmorpholino)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 38) 1-Cyclopropyl-7-(3- Fluoromethylmorpholino)-6-fluoro-8-methyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 39) 1-Cyclopropyl-7-(3-chloromethylmorpholino)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carvone acid 40) 1-cyclopropyl-7-(4-ethyl-1-
piperazinyl)-6-fluoro-8-methyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid mp, 208-210'C Pale yellow prismatic shape (recrystallized from dimethylacetamidodiethyl ether) 41) 1-cyclopropyl-7-(4-fluoro-1
-piperidinyl)-6-fluoro-8-methyl-1,4
-dihydro-4-oxoquinoline-3-carboxylic acid mp, 208-210°C Colorless needle crystals (recrystallized from ethanol) 42) 1-Cyclopropyl-7-(3-(5-methyl-2-oxo-1) ,3-dioxolen-4-yl)methylamino-1-pyrrolidinyl]-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid43) 1-cyclopropyl-7-( 4-methyl-1-
piperazinyl)-6-fluoro-8-ethyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid mp, 239-242°C (decomposed) White powder (recrystallized from diethyl ether-ethanol) 44) 1-Cyclopropyl-7-(3-methyl-1-
piperazinyl)-6-fluoro-8-ethyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 45) 1-Cyclopropyl-7-(3-amino-1-
lolidinyl)-6-fluoro-8-ethyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 46) 1-cyclopropyl-7-(3-amino-4-
methyl-1-pyrrolidinyl)-6-fluoro-8-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 47) 1-cyclopropyl-7-(3-amino-4-
Methyl-1-pyrrolidinyl)-6-fluoro-3-methyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride (isomer B) ml), 209-213°C Yellow powder (acetic acid Recrystallized from ethyl-ethanol)NM
R(DMSO-ds) δ: 1.15 (3H, d, J=6.9Hz >2.76
(3H, s> 7.70 (1 day, d, J=13.7H2) 8.77
(IH, 5) 48) 1-Cyclopropyl-7-(3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-
6-Fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carvone @ (isomer A) ml), 157-160°C Yellow crystals (recrystallized from ethyl acetate) NMR (CDC93) δ 21.20 (3H, d, J='6.6Hz >2.57
(3H, s) 7.91 (IH, d, J=13.3l-1z)9.
15 (1H,5) 49) 1-Cyclopropyl-7-(3-t-butoxycarbonylamino-4-methyl-1-gorolidinyl)-
6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid isomer B) mp, 199-202°C Yellow powder (recrystallized from ethyl acetate) NMR (CDCQ3) δ2 1.12 (3H, d, J=6.6l-1z)2.5
8 (3)-1,s) 7.85 (11-1,d, J=13.6Hz >8.
87 (1H,s>50) 1-Cyclopropyl-7-(3-t-butoxycarbonylamino-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3- Carboxylic acid mp, 117-120'C Pale yellow prismatic shape (recrystallized from ethanol) 51) 1
-cyclopropyl-7-morpholino-6-fluoro-8
-Fluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp, 189-192°C (decomposition) Pale yellow powder (recrystallized from n-hexane-acetonitrile) Example 10 1-Cyclopropyl- 7-(4-benzyl-1-piperazinyl)-6-fluoro-8-hydroxymethyl-1,
4-dihydro-4-oxoquinoline-3-carvone Im
Add 10% Pd-C68m (J) and 10 ml of ethanol to 132 ml (l), and catalytically reduce the mixture at 60°C for 6.5 hours in a hydrogen atmosphere. After filtering the catalyst, concentrate the obtained filtrate. Residue was recrystallized from ethanol-acetone-dichloromethane to give 34.2 m(] of 1-cyclopropyl-7-(1-piperazinyl)-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline. -3-carboxylic acid is obtained.

mp, 149-15'2°C White powder Example 11 1-Cyclopropyl-7-(4-oxo-1-piperidyl)-6-fluoro-8-methyl-1°4-dihydro-
0.25 CI of 4-oxoquinoline-3-carboxylic acid to 1
% sodium hydroxide (28 mQ) and add 0.10 mQ of sodium borohydroxide at room temperature. After stirring at the same temperature for 30 minutes, the reaction mixture was poured into ice water and acidified with concentrated sulfuric acid. After extraction with dichloromethane, the solvent is distilled off. The obtained residue was crystallized by adding ethyl acetate, and then recrystallized from chloroform-methanol to obtain 1 of 0.169.
-cyclopropyl-7-(4-hydroxy-1-piperidyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained.

ml), 234-236°C Pale yellow crystals Example 12 1-Cyclopropyl-7-(3-(t-butoxycarbonylaminomethyl)-1-pyrrolidinyl]-6-fluoro-8-methyl-1,4-dihydro Add 4 ml of 10% hydrochloric acid and 2 mg of ethanol to 10.1 g of -4-oxoquinoline-3-carvone, and heat at 70'C for 10 minutes. After concentrating the solvent, add diethyl ether to the residue to crystallize it, and add ethyl acetate. - Recrystallized from methanol, 45
mg of 1-cyclopropyl-7-(3-aminomethyl-
1-pyrrolidinyl)-6-fluoro-8-methyl-1°4-dihydro-4-oxoquinoline-3-carboxylic hydrochloride is obtained.

ml), 195-200°C Yellow crystal Example 13 1-cyclopropyl-7-(3-(N-ethylacetamido)methyl-1-pyrrolidinyl]-6-fluoro-8
-Methyl-1,4-dihydro-4-oxoquinoline-3
- Add 10 mQ of 5% sodium hydroxide to 0.22 CJ of carboxylic acid hydrochloride and heat under reflux for 24 hours. After cold welding, insoluble materials are removed by filtration, and the furnace solution is acidified with concentrated hydrochloric acid. Extracted with dichloromethane, aqueous sodium hydroxide solution was added to the aqueous layer to make it alkaline, and 200 m of t-butoxycarboxylic anhydride was extracted.
g and stirred at room temperature for 30 minutes. After making acidic with 10% hydrochloric acid, the mixture is extracted with dichloromethane. After concentrating the solvent,
Add 5mf2 of 10% hydrochloric acid and 10mf2 of methanol to the residue, and heat at 70'C for 30 minutes. After concentration, the residue was recrystallized from methanol-acetonitrile to give 301+1
1-cyclopropyl-7-(3-ethylaminomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic hydrochloride of CI is obtained.

mp, 267-271°C Yellow crystal Example 14 1-Cyclopropyl-7-(3-methyl-1-piperazinyl)-6-fluoro-8-methyl-1°4-dihydro-4-oxoquinoline-3- Carvone M0.3g 10
% aqueous sodium hydroxide solution, add 3 mQ of acetic anhydride Q and 3 mQ at room temperature, and stir at the same temperature for 30 minutes. The reaction mixture was made acidic with concentrated hydrochloric acid and extracted with dichloromethane. After concentrating the solvent, the residue is purified by silica gel column chromatography (eluent: dichloromethane).

Recrystallization from methanol yielded 0.10 of 1-cyclopropyl-7-(4-acetyl-3-methyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid is obtained.

mp, 219-221°C White powder Example 15 1-Cyclopropyl-7-(3-methyl-1-piperazinyl)-6-fluoro-8-methyl-1°4-dihydro-4-oxoquinoline-3- Carvone M0.4a@O℃
Add to a mixture of 11.7 mQ of ghee and 12.2 m+2 of anhydrous vinegar. After the addition is complete, heat at 80° C. for 2 hours. Water was added to the reaction mixture and extracted with dichloromethane. After concentrating the solvent, the residue was recrystallized from methanol to give 0.13
CI 1-cyclopropyl-7-(4-formyl-3-
methyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained.

mp, 236-239°C White powder Example 16 1-Cyclopropyl-7-(3-methyl-1-piperazinyl)-6-fluoro-8-methyl-1°4-dihydro-4-oxoquinoline-3 - Add 3 mL of formic acid, 37% formalin 311112, and 0.4 CI of sodium formate to Carvone 0.4Q, and heat under reflux for 5 hours. After cooling, the reaction mixture was poured into ice water and diluted with sodium bicarbonate water.
After reaching H~8, extract with dichloromethane. After concentrating the solvent, the residue was recrystallized from ethyl acetate to give 0.12(]
1-cyclopropyl-7-(3,4-dimethyl-1-
piperazinyl)-6-fluoro-8-methyl-1゜4-
Dihydro-4-oxoquinoline-3-carboxylic acid is obtained.

mp, 181-183°C Pale yellow powder In the same manner as in Example 16, using appropriate starting materials, the first compound of Example 4 and Example 9040 4th, 15th, 23rd, and 31st compounds were prepared. and the 40th compound are obtained.

[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 (Chemotherapy).

22.1126-1128 (1974)).

The results obtained are shown in Table 1. In addition, each type of bacteria is 1 x 10
8 bacterial count/mQ (0, D, 660 mμ, 0.07-0.
16) and 1 x 106 bacteria/mQ (100-fold dilution). In addition, bacterial strains such as S, pneumoniae
ypen and S, pneumoniae type
When using (2), the culture medium contained 5% horse blood.

<Test compound> 1, 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4
-oxoquinoline-3-carboxylic acid 2,7-(4-methyl-1-piperazinyl)-1-
cyclopropyl-6-fluoro-8-methyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 3,7-(1,4-diazabicyclo(4,3°O)
nonan-4-yl)-6-fluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 4,7-(4-(5-methyl-2-oxo -1゜3
-dioxolen-4-yl)methyl-1-piperazinyl-1-cyclopropyl-〇-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 5,7-(3-methyl-1-piperazinyl) )-1-
cyclopropyl-6-fluoro-8-methyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 6,7-(1-piperazinyl)-1-(2-fluoro-1-cyclopropyl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3 -carboxylic acid 7, 7-(3-amino-1-pyrrolidinyl)-1-
cyclopropyl-6-fluoro-8-methyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 8, 7-(4-methyl-1-piperazinyl)-1-
Cyclopropyl-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 9, 1-cyclopropyl-17-morpholino-6-fluoro-8-methyl-1,4- dihydro-4-oxo-
3-quinolinecarboxylic acid 10, 1-cyclopropyl-
7-morpholino-6-fluoro-8-hydroxymethyl-1゜4-dihydro-4-oxoquinoline-3-hydrohydroic acid 11, 1-cyclopropyl-7-(3-acetamidomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 12, 1-cyclopropyl-7-(3-methyl-4-
benzyl-1-piperazinyl)-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 13, 1-cyclopropyl-7-(4-oxo-1-
piperidinyl)-6-fluoro-8-methyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 14, 1-cyclopropyl-7-(4-hydroxy-
1-piperidinyl)-6-fluoro-8-methyl-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid 15, 1-cyclopropyl-7-(3-(t-butoxycarbonylaminomethyl)-1-pyrrolidinyl2 6
-Fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 16, 1-cyclopropyl-7-(3-aminomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl- 1
, 4-dihydro-4-oxoquinoline-3-carboxylic acid 17, 1-cyclopropyl-7-(3-(N-methyl-N-benzylamino)-1-pyrrolidinyl-6-fluoro-8-methyl-1° 4-dihydro-4-oxoquinoline-3-carboxylic acid 18, 1-cyclopropyl-7-(3-methylamino-1-pyrrolidinyl)-6-fluoro-8-methyl-1
, 4-dihydro-4-oxoquinoline-3-carboxylic acid 19, 1-cyclopropyl-7-(4-acetyl-3
-Methyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 20, 1-cyclopropyl-7-(3-ethylaminomethyl-1-pyrrolidinyl )-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 21, 1-cyclopropyl-7-(4-formyl-3
-Methyl-1-piperazinyl)-6=fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 22, 1-cyclopropyl-7-(3,4-dimethyl-1-piperazinyl )-6-fluoro, -8-methyl-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid 23, 1-cyclopropyl-7-(4-ethyl-1-
piperazinyl)-6-fluoro-8-methyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 24, 1-cyclopropyl-7-(4-cyclopropyl-1-piperazinyl)-6-fluoro-8-methyl-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid 25, 1-cyclopropyl-7-(3-methylmorpholino)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid 26, 1-cyclopropyl-7-(3-amino-4-
Methyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (isomer A) 27, 1-cyclopropyl-7-(3, 5-dimethyl-1-piperidinyl)-6-fluoro-8-methyl-1
, 4-dihydro-4-oxoquinoline-3-carboxylic acid 28, 1-cyclopropyl-7-(4-fluoro-1
-piperidinyl)-6-fluoro-8-methyl-1,4
-dihydro-4-oxoquinoline-3-carboxylic acid 29, 1-cyclopropyl-7-morpholino-6-fluoro-8-fluoromethyl-1,4-dihydro-4-
Oxoquinoline-3-carboxylic acid (strain group) A S, aureus FDA 209PB
S, pyoc+enesI [D S-23CS, pn
eUmOniae type [) S, pneu
moniae type I [IE P, aerug
inosa E-2F B, frac+1lis
GM7000G E, limosum ATCC84
96HP, anaerobis GM 1003I
p,acnes ATCC6919J P,gra
nulosum ATCC25564K E, fa
eCaliS Table 1 Test compound 1 Test compound 2 Bacterial strain group 106 bacterial count/mf2106 bacterial count/mf2A
O,20,1 B O,390,39 G O,780,39 D 1.56 0.39 E O,390,78 F O,780,2 G O,78- H1,560,78 I O,390 ,2 J O,20,39 K O,390,39 Table 1 (continued) Test compound 3 Test compound 4 Bacterial strain group 1Qe bacterial count/m12106 bacterial count/mQA
O,10,05 B O,390,2 G O,780,39 D O,390,39 E 1.56 0.39 F O,10,2 G-- HO,390,1 1O,20,05 J O,20,1 K 1.56 1.56 Test compound 5 Test compound 6 Bacterial strain base 106 bacterial count/m12 10B bacterial count/mQA
O,20,78 B O,390,39 CO,39- D O,39- E O,780,39 F 0.2- G-- H0,39- I O,2- J O,2- K O ,78- Table 1 (continued) Test compound 7 Test compound 8 Bacterial strain group 106 bacterial count/mQ 106 bacterial count/mQA
O,0480,39 B O,0480,78 C-- D-- E O,1951,56 F-- G-- H-- J-- To-- Table 1 (continued) Test compound 9 Test compound 10 Bacterial strain base 106 bacterial count/mQ 10G bacterial count/mQA
O,0120,048 B O,0480,78 C-- D-- E O,78- F-- G -- H-- J-- K -- Table 1 (continued) Test compound 11 Test compound 12 Bacterial strain base 106 bacterial count/mQ 106 bacterial count/mQA
O,0240,39 B O,0240,048 C-- D-- E-- F-- G-- H-- I-- J-- To-- Table 1 (continued) Test compound 13 Test sample Compound 14 Bacterial strain base 10' bacterial count/mQ 10' bacterial count/mQA
<0.006 0.012B O,097
0,048 C-- D -- E 1.56 0.78 F -- G -- H-- J -- To-- Table 1 (continued) Test compound 15 Test compound 16 Sarabayashi name 10' Number of bacteria/m1210' Number of bacteria/rll12A
0.048 <0.006B 0
．． 195 <0.006C-- D-- E 0.39F-- G-- H-- I-- J-- K --- Table 1 (continued) Test compound 17 Test compound 18 Strain name 108 Number of bacteria /mQ 106i! number/mQA
O,0480,024 B O,1950,048 C-- D -- E 0.39 F-- G-- I -- J-- Table 1 (continued) Test compound 19 Test compound 20 Strain name 106 bacteria count/mQ 106 bacteria count/mQA
0.048 <0.006B O,09
70,012 C-- D-- E 0.78 ■ - Table 1 (continued) Test compound 21 Test compound 22 Strain name 106 bacteria/mi2 106 bacteria/mQA
O,0240,097 B O,0970,39 C-= D-- E' 1.56F-- G-- H-- J-- To-- Table 1 (continued) Test compound 23 Test compound 24 ia! 106 bacteria count/m (210G bacteria count/mQA
O,0970,048 B O,390,39 C-- E 1.56 - F-- G -- H-- I-- J-- Table 1 (continued) Test compound 25 Test compound 26 A O,0120,024 B O,0970,024 C-- D-- E 1.56 0.195F-- G-- H-- I-- J-- To-- Table 1 (continued) Provided Test compound 27 Test compound 28 Strain name 106 bacterial count/mQ105 bacterial count imQA
O,0970,012 B-- C-- D-- E 0.78 F-- G-- I-- J-- To-- Table 1 (continued) Test compound 29 Strain name 10' Number of bacteria/ mQ A 0.097 B-C-D-E-F-G-H-I-J-K- Formulation example 1 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid 200mg glucose 250mc + 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro- in distilled water for injection
After dissolving 4-oxoquinoline-3-carboxylic acid and glucose, it was poured into an ampoule of 5-1, and after nitrogen substitution, 12
The mixture is autoclaved at 1° C. for 15 minutes to obtain an injection having the above composition.

Formulation Example 2 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 100Q Avicel (trade name, manufactured by Asahi Kasei ■) 40C] Cornstarch 30C] Magnesium stearate 2gTC-5 (trade name,
Shin-Etsu Chemical Co., Ltd., droxypropyl methylcellulose) 10g polyethylene glycol-60003Cl
Castor oil 40CJ ethanol 40C17-(1
-Piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, Avicel, cornstarch and magnesium stearate were mixed and polished using a sugar-coated R 10 mm kine. Compress tablets. The obtained tablets are coated with a film coating agent consisting of TC-5, polyethylene glycol-6000, castor oil, and ethanol to produce film-coated tablets having the above composition.

Formulation example 3 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,41 dihydro-4-oxoquinoline-3-carboxylic acid 2g purified lanolin 5g white beeswax 5g warm beeswax to form a liquid, then 7-(1-piperazinyl)-
1-cyclopropyl-6-fluoro-8-methyl-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.

(that's all)

Claims (2)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. , R^2 is a 5- to 9-membered saturated or unsaturated heterocyclic residue that may have a substituent, R^3 is a saturated 5- to 6-membered heterocyclic residue as a substituent, a lower alkylthio group, A lower alkyl group that may have 1 to 3 groups selected from the group consisting of an amino group, a lower alkylamino group, a lower alkanoyloxy group, a hydroxyl group, a lower alkoxy group, and a halogen atom, and X represents a halogen atom. ] A benzoheterocyclic compound or a salt thereof. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 is a cyclopropyl group that may have 1 to 3 groups selected from the group consisting of lower alkyl groups and halogen atoms as substituents. , R^2 is a 5- to 9-membered saturated or unsaturated heterocyclic residue that may have a substituent, R^3 is a saturated 5- to 6-membered heterocyclic residue as a substituent, a lower alkylthio group, A lower alkyl group that may have 1 to 3 groups selected from the group consisting of an amino group, a lower alkylamino group, a lower alkanoyloxy group, a hydroxyl group, a lower alkoxy group, and a halogen atom; X represents a halogen atom.] An antibacterial agent containing a benzoheterocyclic compound or a salt thereof.