JPH03188074A - Novel quinolone derivative and antibacterial agent containing the same - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is H or carboxy-protecting group; R<2> is H, halogen, hydroxy, lower alkoxy, etc.; A is O, S or N-R<3> (R<3> is H or amino-protecting group); X is H or halogen; Y is N or C-R<4> (R<4> is H, halogen, lower alkyl, etc.); Z is halogen or N-containing heterocyclic group)]. EXAMPLE:3-(Oxetan-3-yl-amino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylic acid ethyl ester. USE:An antibacterial agent exhibiting excellent antibacterial activity against Gram-negative bacteria and Gram-positive bacteria. PREPARATION:The objective compound of formula I wherein R<1> is H or lower alkyl can be produced by reacting a compound of formula II (X<1> and X<2> are halogen; R<1a> is lower alkyl) with an orthoformic acid ester and then with a compound of formula III and subjecting the resultant compound of formula IV to cyclization reaction and hydrolysis.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel quinolone derivative or a salt thereof having excellent antibacterial activity and an antibacterial agent containing the same.

[Conventional technology]

New quinolones, which have pyridonecarboxylic acid as their basic skeleton, are attracting attention as synthetic antibacterial agents equivalent to antibiotics because they have excellent antibacterial activity and a wide antibacterial spectrum.
No. 1286), enoxacin (JP-A-55-310)
No. 42), ofloxacin (Japanese Patent Application Laid-Open No. 57-4698)
Publication No. 6), Ciprofloxacin (Japanese Unexamined Patent Publication No. 58-766)
No. 67) and the like are widely used in clinical practice as therapeutic agents for infectious diseases.

[Problem to be solved by the invention]

However, conventionally known double quinolones are not fully satisfactory in terms of antibacterial activity, oral absorption, duration of action, central side effects, etc. In order to solve this problem, we have developed 1st place, 5th place, 6th place
Research continues into substituents at positions 7, 7, and 8.

[Means to solve the problem]

Under these circumstances, the present inventors conducted intensive research in order to provide a clinically excellent synthetic antibacterial agent that improves the above requirements, and as a result, found that an oxetane ring or a thietane ring is added to the 1-position of the quinoline skeleton and naphthyridine skeleton. The quinolone derivative represented by [I] below into which an azetidine ring has been introduced has strong antibacterial activity against Durham-negative bacteria and Durum-positive bacteria, and also has the appropriate balance between hydrophilicity and lipophilicity required for synthetic antibacterial agents. The present invention was completed based on the discovery that the present invention has the following properties.

That is, the present invention provides a quinolone derivative represented by the following general formula [I] or a salt thereof, and an antibacterial agent containing the same.

[During the ceremony, R1: means a hydrogen atom or a carboxy protecting group.

R2: means a hydrogen atom, a halogen atom, a hydroxy group, a lower alkoxy group, an amino group, an aralkylamino group, or a mono- or di-lower alkylamino group.

A: means an oxygen atom, a sulfur atom, or NR' (where R3 represents a hydrogen atom or an amino protecting group).

X: means a hydrogen atom or a halogen atom.

Y: means a nitrogen atom or C-R' (here, R4 represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group).

Z: means a halogen atom or a heterocyclic group containing at least one nitrogen atom as a heteroatom which may have a substituent. ] In the present invention, "lower" used in the explanation of each substituent in formula [1) means, when the substituent is a straight or branched group, a carbon number of 1 to 7, preferably 1 to 4. When it is a cyclic group, it means a group having 3 to 7 carbon atoms.

The carboxy protecting group represented by R1 refers to an ester residue of a carboxylic acid ester, and means any group that is relatively easily cleaved to yield the corresponding free carboxyl group. Specific examples thereof include lower alkyl groups (e.g., methyl group, ethyl group, n-propyl group, t-butyl group, etc.), aralkyl groups (e.g., benzyl group, etc.), aryl groups (e.g., phenyl group, etc.), etc. Those that are eliminated by treatment under mild conditions such as hydrolysis or catalytic reduction; or lower alkanoyloxy lower alkyl groups (e.g. acetoxymethyl group, pivaloyloxymethyl group, etc.), lower alkoxycarbonyloxy lower Alkyl groups (e.g., methoxycarbonyloxymethyl group, 1-ethoxycarbonyloxyethyl group, etc.), lower alkoxymethyl groups (e.g., methoxymethyl group, etc.), lactonyl groups (e.g., phthalidyl group, etc.), di-lower alkylamino lower alkyl groups ( Examples include those that are easily eliminated in vivo, such as (1-dimethylaminoethyl group, etc.) and (5-methyl-2-oxol-4-yl)methyl group.

Examples of the halogen atom represented by R2 include a fluorine atom, a chlorine atom, and a bromine atom, and preferably a fluorine atom or a chlorine atom. Examples of the lower alkoxy group represented by R2 include a methoxy group, an ethoxy group, an isopropyloxy group, and a methoxy group is preferred. Examples of the mono- or di-lower alkylamino group include a methylamino group, an ethylamino group, and a dimethylamino group. Examples of the aralkylamino group represented by R2 include a benzylamino group and a phenethyl amino group.

When A is a group N-R', examples of the amino protecting group represented by R' include lower alkyl groups, lower alkenyl groups, etc., as well as groups used as protecting groups for amino groups in normal peptide synthesis. It will be done. Examples include alkyloxycarbonyl groups (ethoxycarbonyl group, t-butoxycarbonyl group, etc.), acyl groups (acetyl group, benzoyl group, etc.), benzyl-based protecting groups (benzyl group, benzhydryl group, etc.), and the like. Furthermore, examples of lower alkyl groups include linear or branched alkyl groups having 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl group, ethyl group, n
-propyl group, isopropyl group, 1-butyl group, etc. In addition, the lower alkenyl group has 2 to 7 carbon atoms.
, preferably 2 to 5 straight or branched alkenyl groups, such as a vinyl group, an allyl group, a 1-propenyl group, and the like.

Examples of the halogen atom represented by X include those mentioned above for R2, preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

When Y is CR', the halogen atom represented by R4 includes a fluorine atom, a chlorine atom, and a bromine atom, and preferably a fluorine atom or a chlorine atom. R4
Examples of the lower alkyl group represented by include linear or branched alkyl groups having 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl group, ethyl group, n-propyl group, isopropyl group, t- A butyl group may be mentioned, but a methyl group is preferable. Examples of the lower alkoxy group represented by R4 include those mentioned above for R2, preferably a methoxy group.

Examples of the halogen atom represented by Z include those mentioned above as 1li2, but preferably a fluorine atom or a chlorine atom.

In addition, the heterocyclic group containing at least one nitrogen atom as a heteroatom represented by Z may be either a saturated heterocyclic group or an unsaturated heterocyclic group (and may also contain at least one other nitrogen atom). It may be fused with a heterocyclic group containing an atom or a benzene ring. Examples of these heterocyclic groups include azetidine, pyrrolidine, pyrroline, pyrrole, imidazole, pyrazole, pyrazolidine, pyridine, pyrimidine, piperidine, piperazine. Heterogeneous groups containing 1 to 3 nitrogen atoms such as , homopiperazine, and triapur; Heterogeneous atoms selected from one nitrogen atom and an oxygen atom or a sulfur atom such as thiazolidine, thiazole, morpholine, thiomorpholine, etc. Heterocyclic group containing atoms; indole, dihydroindole, isoindole, dihydroiindole, isoindoline, naphthyridine, perhydronaphthyridine, pyrrolidino [:1.2-a] piperazine, pyrrolidino [3,4-c) pyrrolidine , pyrrolidino[3,4-b)morpholine, and other heterocyclic groups fused with other heterocyclic rings; 2,5-diazabicyclo[2°2.1]heptane, 2,5-diazabicyclo[3°1.1 ) Heptane and other cyclic heterocyclic groups such as w4m are mentioned.

Preferably, these heterocyclic groups are 3- to 7-membered rings, and the heterocyclic groups fused with other heterocyclic groups are 8- to 12-membered rings, which are substituted with 1 to 4 suitable substituents. You can leave it there. Such substituents include nitro group, hydroxy group, amino group, halogen atom, lower alkyl group, cyclo-lower alkyl group, lower alkoxy group, mono- or di-lower alkylamino group, cyclo-lower alkylamino group, amino-lower alkyl group. group, hero-lower alkyl group, mono- or di-lower alkylamino lower alkyl group, hydroxy lower alkyl group, alkoxy lower alkyl group, cyclo-lower alkylamino lower alkyl group, optionally substituted acyloxy group, lower alkylthio group, substituted an aryl group which may be
Cyano lower alkyl group, optionally substituted acylamino group, optionally substituted alkoxycarbonylamino group, optionally substituted alkoxycarbonyl group, optionally substituted aminocyclo lower alkyl group,
Optionally substituted acylamino lower alkyl group, optionally substituted alkoxycarbonylamino lower alkyl group, lower alkenyl group, cyano group, mercapto group, formimidoyl group, lower alkylimidoyl group, formimidoylamino group , a lower alkylimidoylamino group, an optionally substituted aralkyl group, a lower alkylidene group, or a mono- or di-lower alkylhydrazino group. These substituents may be substituted on the same or different atoms of the heterocyclic group.

In the heterocyclic group containing at least one nitrogen atom as a heteroatom represented by Z, any atom constituting the ring may be bonded to the quinolone skeleton, but as a more preferable example, These include:

7 3 (a) (C) (e) (f) (6) et al.) The following margins (sha) (i) (p) (q) sweet (j) (goods) (1) (Here, B is oxygen Atom, sulfur atom 1., -NR10-
(1) (n) (e) (o) represents -C-N-, and R5, Ra and R7 may be the same or different, and represent a hydrogen atom, a halogen atom, a nitroxy group, an amino group. , lower alkyl group, halo secondary alkyl group, optionally substituted mono- or di-lower alkylamino group, cyclo-lower alkylamino group, amino lower alkyl group, optionally substituted mono- or di-lower alkylamino group Lower alkyl group, cyclo-lower alkylamino lower alkyl group, optionally substituted alkoxy group, optionally substituted acyloxy group, lower alkylthio group, optionally substituted aryl group, cyano lower alkyl group, substituted optionally substituted acylamino group, optionally substituted alkoxycarbonylamino group, optionally substituted alkoxycarbonyl group, optionally substituted aminocyclo lower alkyl group, optionally substituted acylamino lower alkyl group , optionally substituted alkoxycarbonylamino lower alkyl group, hydroxy lower alkyl group, optionally substituted alkoxy lower alkyl group, lower alkenyl group, cyano group, mercapto group, formimidoylamino group, lower alkylimidoyl It represents an amino group, a mono- or di-lower alkylhydrazino group, or a lower alkylidene group, and R8
represents a hydrogen atom, a lower alkyl group, R11 is a hydrogen atom, a halogen atom, a nitro group, an optionally substituted lower alkyl group, an amino group, an amino lower alkyl group, a mono- or di-lower alkylamino lower alkyl group, a lower It represents an alkoxy group, a hydroxy group, an optionally substituted mono- or di-lower alkylamino group, a formimidoylamino group, or a lower alkylimidoylamino group, and R1
0 is a hydrogen atom, an optionally substituted lower alkyl group,
Optionally substituted cyclo-lower alkyl group, optionally substituted aralkyl group, optionally substituted aryl group, optionally substituted lower alkenyl group, optionally substituted acyl group, an alkoxycarbonyl group, a hydroxy lower alkyl group, a formimidoyl group or a lower alkylimidoyl group, which may be
m represents engineering, 2 or 3, n represents l or 2, 1 represents 3
．． Indicates 4 or 5. ) R', R', R' are
Halogen atoms (e.g. fluorine atoms, chlorine atoms, etc.), hydroxy groups, amino groups, optionally substituted mono- or di-lower alkylamino groups (e.g. methylamino groups,
ethylamino group, n-propylamine group, dimethylamino group, diethylamino group, benzylamino group, benzylethylamino group, pyrrolidinyl group, piperidinyl group, hydroxyethylamino group, methoxyethylamino group, fluoroethylamino group), Cyclo-lower alkylamino group (e.g., cyclopropylamino group, cyclopentylamino group, etc.), lower alkyl group (e.g., methyl group,
ethyl group, n-propyl group, etc.), halo lower alkyl group (e.g., fluoromethyl group, trifluoromethyl group, etc.), amino lower alkyl group (e.g., aminomethyl group, 1-aminoethyl group, 2-aminoethyl group) , ■-amino-1-methylethyl group, etc.), an optionally substituted mono- or di-lower alkylamino-lower alkyl group (e.g., methylaminomethyl group, ethylaminomethyl group, dimethylaminomethyl group, diethylaminomethyl group, n −
Propylmethylaminomethyl group, di(n-propyl)aminomethyl group, isopropylaminomethyl group, methylaminoethyl group, dimethylaminoethyl group, methylamino-n-propyl group, diethylaminoethyl group, dimethylamino-n-propyl group , pyrrolidinylmethyl group, benzylaminomethyl group, benzylmethylaminomethyl group,
2-fluoroethylaminomethyl group, 2-hydroxyethylaminomethyl group, 2-methoxyethylaminomethyl group, 2-aminoethylaminomethyl group, etc.), cyclo-lower alkylamino-lower alkyl group (e.g., cyclopropylaminomethyl group, etc.) ), optionally substituted alkoxy groups (e.g., methoxy group, ethoxy group, n-propoxy group, phenoxy group, p-chlorophenoxy group, p
-fluorophenoxy group, benzyloxy group, etc.), optionally substituted acyloxy group (e.g., acetoxy group, benzoyloxy group, etc.), lower alkylthio group (e.g., methylthio group, ethylthio group, etc.), Good aryl groups (e.g. phenyl group, p-fluorophenyl group, p-methoxyphenyl group, etc.), cyano lower alkyl groups (e.g. cyanomethyl group, etc.),
an optionally substituted alkoxycarbonylamino group (
(e.g., t-butoxycarbonylamino group, etc.), optionally substituted acylamino groups (e.g., acetylamino group, benzoylamino group, etc.), optionally substituted alkoxycarbonyl groups (e.g., methoxycarbonyl group, ethoxycarbonyl group, etc.) groups), optionally substituted aminocyclo lower alkyl groups (e.g. 1-aminocyclopropyl group), optionally substituted acylamino lower alkyl groups (e.g. acetylaminomethyl group), optionally substituted aminocyclo lower alkyl groups (e.g. acetylaminomethyl group), Good alkoxycarbonylamino lower alkyl groups (e.g., t-butoxycarbonylaminomethyl group, benzyloxycarbonylaminomethyl group, etc.), hydroxy lower alkyl groups (e.g., hydroxymethyl group, etc.), optionally substituted alkoxy lower alkyl groups (e.g., methoxymethyl group, etc.), lower alkenyl group (e.g., vinyl group, allyl group, etc.), lower alkylidene group (e.g., methylene group, ethylidene group, etc.) 1, cyano group, mercapto group, formimidoyl group, form imidoylamino group, lower alkylimidoyl group (e.g., acetimidoyl group), mono- or lower alkylhydrazino group (e.g., 2-methylhydrazino group, etc.), lower alkylimidoylamino group (e.g., acetimidoyl group), amino group, etc.).

An optionally substituted lower alkyl group represented by RIG, an optionally substituted cyclolower alkyl group, an optionally substituted aralkyl group, an optionally substituted aryl group, an optionally substituted aryl group In alkenyl groups, optionally substituted acyl groups, optionally substituted alkoxycarbonyl groups, hydroxy lower alkyl groups, and lower alkylimidoyl groups, the lower alkyl groups include, for example, methyl groups, ethyl groups, n -propyl group,
Isopropyl group, n-butyl group, t-butyl group, etc.;
Examples of the cyclo-lower alkyl group include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group; examples of the aralkyl group include a benzyl group, a phenylethyl group,
Examples of aryl groups include phenyl groups; examples of lower alkenyl groups include allyl groups,
Examples include 2-butenyl group, 3-methyl-2-butenyl group, and 3-butenyl group. These groups include halogen atoms (e.g., fluorine atoms, chlorine atoms, etc.), hydroxy groups, and optionally substituted amino groups (e.g.,
amino group, methylamino group, dimethylamino group, ethylamino group, acetamido group, ethoxycarbonylamino group), optionally substituted alkoxy group (e.g. methoxy group, ethoxy group, phenoxy group, benzyloxy group, p- (promobenzyloxy group, etc.), lower alkyl group (e.g., methyl group, ethyl group, etc.), carboxy group, lower alkoxycarbonyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group, etc.), cyano group,
lower alkylthio groups (e.g., methylthio group, etc.), optionally substituted phenyl groups (e.g., phenyl group,
p-fluorophenyl group, p-methoxyphenyl group, etc.), optionally substituted acyl groups (e.g., formyl group, acetyl group, n-propionyl group, benzoyl group, etc.), etc. 1 to 3 substitutions may be made.

Examples of the lower alkyl group represented by Ra include methyl group, ethyl group, n-propyl group, isopropyl group, t
-butyl group, etc.

Examples of the optionally substituted lower alkyl group represented by R1 include methyl group, ethyl group, aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, ethylaminomethyl group, and hydroxymethyl group,
Examples of the optionally substituted mono- or di-lower alkylamino group include a methylamino group, an ethylamino group, and a dimethylamino group.

Examples of the heterocyclic group of formula (H) include piperazinyl group,
Examples thereof include a morpholino group, a thiomorpholino group, a homopiperazinyl group, a thiazolidinyl group, an oxazolidinyl group, and a 1,3-oxo-1-piperazinyl group.

Examples of the two-groove heterocyclic groups represented by formulas (f), (5) to (j), (r) and [I] include the following.

Further, examples of the heterocyclic group represented by the formula (O) include an azetidinyl group, a pyrrolidinyl group, and a piperidino group.

Preferred specific examples of the heterocyclic group represented by formula (a) and formula (odor) are as follows.

3-hydroxyazetidinyl group, 3-aminoazetidinyl group, 3-(Nt-butoxycarbonylamino)azetidinyl group, 3-acetylaminoazetidinyl group, 3-
Methylaminoazetidinyl group, 3-dimethylaminoazetidinyl group, 3-aminomethylazetidinyl group, pyrrolidinyl group, 3-hydroxypyrrolidinyl group, 3.4-dihydroxypyrrolidinyl group, 3-methoxypyrroli Dinyl group, 3-methylpyrrolidinyl group, 3-hydroxy-4-
Methyl-pyrrolidinyl group, 3-aminopyrrolidinyl group,
3-methylaminopyrrolidinyl group, 3-dimethylaminopyrrolidinyl group, 3-ethylaminopyrrolidinyl group, 3
-diethylaminopyrrolidinyl group, 3-acetylaminopyrrolidinyl group, 3-t-butoxycarbonylaminopyrrolidinyl group, 3-(N-acetyl)methylaminopyrrolidinyl group, 3-(t-butoxycarbonyl) Methylaminopyrrolidinyl group, 3-aminomethylpyrrolidinyl group, 3-methylaminomethylpyrrolidinyl group, 3-dimethylaminomethylpyrrolidinyl group, 3-ethylaminomethylpyrrolidinyl group, 3-diethylaminomethyl pyrrolidinyl group, 3-(N-acetyl)aminomethylpyrrolidinyl group, 3-(t-butoxycarbonyl)aminomethylpyrrolidinyl M, 3-(N-acetyl)methylaminomethylpyrrolidinyl group, 3 -(t-butoxycarbonyl)methylaminomethylpyrrolidinyl group, 3-(1-aminoethyl)pyrrolidinyl group, 3-(2-aminoethyl)pyrrolidinyl group, 3-(1-amino-1-methylethyl)pyrrolidinyl group group, 3-(1-methylaminoethyl)pyrrolidinyl group, 3-(1-dimethylaminoethyl)pyrrolidinyl group, 3-amino-4-methylpyrrolidinyl group, 3-
Amino-5-methylpyrrolidinyl group, 3-methylamino-4-methylpyrrolidinyl group, 3-dimethylamino-4
-Methylpyrrolidinyl group, 3-ethylamino-4-methylpyrrolidinyl group, 3-diethylamino-3-methylpyrrolidinyl group, 3-diethylamino-4-methylpyrrolidinyl group, 3-aminomethyl-4 -Methylpyrrolidinyl group, 3-methylaminomethyl-4-methylpyrrolidinyl group, 3-dimethylaminomethyl-4-methylpyrrolidinyl group, 3-ethylaminomethyl-4-methylpyrrolidinyl group, 3 -(1-aminoethyl)-4-methylpyrrolidinyl group, 3-(2-aminoethyl)-4-methylpyrrolidinyl group, 3-amino-4-ethylpyrrolidinyl group, 3
-methylamino-4-ethylpyrrolidinyl group, 3-dimethylamino-4-ethylpyrrolidinyl group, 3-ethylamino-4-ethylpyrrolidinyl group, 3-diethylamino-4-ethylpyrrolidinyl group, 3-aminomethyl-4-
Ethylpyrrolidinyl group, 3-methylaminomethyl-4-
Ethylpyrrolidinyl group, 3-dimethylaminomethyl-4
-ethylpyrrolidinyl group, 3-amino-3-methylpyrrolidinyl group, 3-methylamino-3-methylpyrrolidinyl group, 3-dimethylamino-3-methylpyrrolidinyl group, 3-amino-3 , 4-dimethylpyrrolidinyl group, 3-
Amino-4,4-dimethylpyrrolidinyl group, 3-amino-4,5-dimethylpyrrolidinyl group, 3-amino-2,
4-dimethylpyrrolidinyl group, 3-methylamino-3,
4-dimethylpyrrolidinyl group, 2-methyl-3-aminopyrrolidinyl group, 2-methyl-3-dimethylaminopyrrolidinyl group, 3-7mi/-4-vinylpyrrolidinyl group,
3-amino-4-methoxypyrrolidinyl group, 3-amino-4-methoxymethylpyrrolidinyl group, 3-methylamino-4-methoxypyrrolidinyl group, 3-dimethylamino-4-methoxypyrrolidinyl group ,3-ethylamino-4
-methoxypyrrolidinyl group, 3-dinithylamino-4-
Methoxypyrrolidinyl group, 3-benzylamino-4-methoxypyrrolidinyl group, 3-aminomethyl-4-methoxypyrrolidinyl group, 3-methylaminomethyl-4-methoxypyrrolidinyl group, 3-dimethylamino Methyl-4-
Methoxypyrrolidinyl group, 3-ethylaminomethyl-4
-methoxypyrrolidinyl group, 3-aminomethyl-3-methoxypyrrolidinyl group, 3-methylaminomethyl-3-
Methoxypyrrolidinyl group, 3-dimethylaminomethyl-
3-methoxypyrrolidinyl group, 3-amino-4-ethoxypyrrolidinyl group, 3-methylamino-4-ethoxypyrrolidinyl group, 3-dimethylamino-4-ethoxypyrrolidinyl group, 3-methylamino -4-ethoxypyrrolidinyl group, 3-aminomethyl-4-ethoxypyrrolidinyl group, 3-dimethylaminomethyl-4-ethoxypyrrolidinyl group, 3-amino-4-7minocarponylpyrrolidinyl group, 3-amino-4-dimethylaminocarbonylpyrrolidinyl group, 3-amino-4-hydroxypyrrolidinyl group, 3-amino-4-hydroxymethylpyrrolidinyl group, 3-amino-4-hydroxyethylpyrrolidinyl group basis,
3-amino-4-methyl-4-hydroxymethylpyrrolidinyl group, 3-aminomethyl-4-hydroxypyrrolidinyl group, 3-dimethylaminomethyl-4-hydroxypyrrolidinyl group, 3,4-dihydroxypyrrolidinyl group dinyl group,
3,4-dimethoxypyrrolidinyl group, 3-hydroxy-
4-methylpyrrolidinyl group, 3-amino-4-fluoropyrrolidinyl group, 3-amino-4-fluoromethylpyrrolidinyl group, 3-amino-4-trifluoromethylpyrrolidinyl group, 3-methyl Amino-4-fluoropyrrolidinyl group, 3-dimethylamino-4-fluoropyrrolidinyl group, 3-aminomethyl-4-fluoropyrrolidinyl group, 3-methylaminomethyl-4-fluoropyrrolidinyl group, 3-dimethylaminomethyl-4-fluoropyrrolidinyl group, 3-methylamino-4-chloropyrrolidinyl group, 3-aminomethyl-4-chloropyrrolidinyl group, 3-methylaminomethyl-4-chloropyrrolidinyl group group, 3-(
2-hydroxyethyl)aminomethylpyrrolidinyl group,
3-(2-fluoroethyl)aminomethylpyrrolidinyl group, 3-amino-4-methylthiopyrrolidinyl group, 3
-amino-4-methylsulfinylpyrrolidinyl group, 3
-formimidoylaminopyrrolidinyl group, 3-(2-
dimethylhydrazino)pyrrolidinyl group, 3-amino-4
-Methylenepyrrolidinyl group, piperazinyl group, 4-methylpiperazinyl group, 3-methylpiperazinyl group, 2-methylpiperazinyl group, 3,4-dimethylpiperazinyl group, 3,5-dimethylpipe Radinyl group, 3.3-dimethylpiperazinyl group, 3°4.5-)dimethylpiperazinyl group, 4-ethoxycarbonylpiperazinyl group, 4-t-
Butoxycarbonylpiperazinyl group, 4-acetylpiperazinyl group, 4-penzyloxylponylbiperazinyl group, 4-ethylpiperazinyl! , 3.4-diethylpiperazinyl group, 3.4.5-)diethylpiperazinyl group, 4-ethyl-3,5-dimethylpiperazinyl group, 3-
Methyl-4-acetylpiperazinyl group, 3-methyl-4
-t-butoxycarbonylpiperazinyl group, 4-benzylpiperazinyl group, 4-n-propylpiperazinyl group,
4-isopropylpiperazinyl group, 4-t-butylpiperazinyl group, 4-cyclopropylpiperazinyl group, 4-
Cyclopentylpiperazinyl group, 4-cyclopropylmethylpiperazinyl group, 4-phenylpiperazinyl group, 4
- (p-dimethylaminophenyl)piperazinyl group,
4-(p-methoxyphenyl)piperazinyl group, 4-(
p-fluorophenyl)piperazinyl group, 3-phenylpiperazinyl! , 3-(p-fluorophenyl)piperazinyl group, 3-(p-chlorophenyl)piperazine Jl
/ group, 3-(p-hydroxyphenyl)piperazinyl group, 3-(p-methylphenyl)piperazinyl group, 4
-hydroxyethylpiperazinyl group, 4-aminoethylpiperazinyl group, 4-allylpiperazinyl group, 4-cinnamylpiperazinyl group, 4-cyanoethylpiperazinyl group, 4-carboxyethylpiperazinyl group, 4-carboxymethylpiperazinyl group, 4-(1,2-dicarboxyethyl)piperazinyl group, 4-hydroxypiperazinyl group, 4-aminopiperidinyl group, 3-fluoromethylpiperazinyl group, 3- Trifluoromethylpiperazinyl group, 4-formimidoylpiperazinyl group, 4-acetimidoylpiperazinyl group, 4-dimethylaminopiperidinyl group, 4-hydroxypiperidinyl group, morpholino group, 2- Aminomethylmorpholino group, 2-methylaminomorpholino group, 2-dimethylaminomorpholino group, thiomorpholino group, homopiperazinyl group, 4-methylhomopiperazinyl group, thiazolidinyl group, 3-pyrrolinyl group, 3
-Aminomethyl-3-pyrrolinyl group, oxazolidinyl group, imidazolyl group, pyrrolyl group.

Compounds CI+ of the invention can also form both acid addition salts or base addition salts. As an acid addition salt,
For example, (a) salts with mineral acids such as hydrochloric acid and sulfuric acid, (b) salts with organic carboxylic acids such as formic acid, citric acid, trichloroacetic acid, and trifluoroacetic acid, (c) methanesulfonic acid, benzenesulfonic acid, Salts with sulfonic acids such as p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid, and base addition salts include (a) salts with alkali metals such as sodium and potassium, and (b) salts with alkali metals such as sodium and potassium.
Salts with alkaline earth metals such as calcium and magnesium, (c) ammonium salts, (d) trimethylamine,
triethylamine, tributylamine, pyridine, N,
N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, prolactone, dibenzylamine, N-benzyl-β
-Phenethylamine, 1-ephenamine, NIN'-dibenzylethylenediamine and other salts with nitrogen-containing organic bases can be mentioned.

Furthermore, the compound [I] of the present invention can exist not only in an unsolvated form but also as a hydrate or solvate. Accordingly, the compounds of the present invention include all crystalline forms and hydrated or solvated forms thereof.

Further, the compound CI] of the present invention includes those having an asymmetric carbon atom in the substituent at the 7-position, and these may exist as optically active forms. These optically active substances are also included in the compounds of the present invention.

Furthermore, some of the compounds of the present invention [13] have two asymmetric carbon atoms in the substituent at the 7-position, and they may exist as different stereoisomers (cis type, trans type). . These stereoisomers are also included in the compounds of the present invention.

The compound CI) of the present invention can be produced by any method depending on the type of substituent, etc., and preferred examples thereof are as follows.

[Step 1] Among the compounds represented by general formula [I], R
The metal compound in which ' is a hydrogen atom or a lower alkyl group is produced, for example, by a series of steps shown in the following reaction formula (1).

The following margins [Reaction formula-(1)] (A) [In the formula, R2, XSY and A are the same as above. xl and x2 each represent a halogen atom. Rlm represents a lower alkyl group. R1+ represents a lower alkoxy group or an alkyl group. ) R12 and R'3 each represent a lower alkyl group. Z' represents a group other than the halogen atom in the definition of Z above. ] Compound (C) can be obtained by reacting compound (A) with an orthoformate such as ethyl orthoformate or methyl orthoformate in acetic anhydride, and then reacting the compound (^te)→NH2. The reaction between compound (A) and orthoformic acid ester is usually carried out at 0 to 160°C, preferably 50 to 150°C, and the reaction time is usually 10 minutes to 48 hours, preferably 1 to 10 hours. The amount of orthoformic acid ester used is preferably at least equimolar, especially about 1 to 10 times the molar amount of compound (A).

The reaction of the subsequent compound with 0-NH2 is carried out in a suitable solvent. The solvent used here may be any solvent as long as it does not affect the reaction, such as aromatic hydrocarbons such as benzene, toluene, xylene, etc.;
diethyl ether, tetrahydrofuran, dioxane,
Ethers such as monoglyme, diglyme, etc.; Aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin, etc.; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, etc.; Dimethylformamide; Dimethyl sulfoxide and alcohols such as methanol, ethanol, propatool, etc. This reaction is usually carried out at 0 to 150°C, preferably 0 to 100°C, and the reaction time is usually 10 minutes to 48 hours. Compound A
The amount of H2 used is at least equimolar, preferably equimolar to twice the molar amount of compound (A).

As another method, compound (A) is reacted with acetals such as N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, etc., and then reacted with compound ^)-NH2 to form compound (
It can lead to C).

As the solvent used for the reaction with acetals, any solvent may be used as long as it is inert to this reaction, for example,
Examples include those mentioned above. This reaction is usually 0 to 150℃
, preferably at room temperature to 100°C, and the reaction time is usually 10 minutes to 48 hours, preferably 1 to 10 hours.

The cyclization reaction of compound (C) is carried out in a suitable solvent in the presence of a basic compound. As the solvent used in this reaction, any solvent can be used as long as it does not affect the reaction; for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; diethyl ether, tetrahydrofuran, dioxane, monoglyme. Ethers such as; halogenated hydrocarbons such as methylene chloride, chloroform, hydrogen tetrachloride, etc.; alcohols such as methanol, ethanol, propatool, butanol, etc.; Examples include protic polar solvents. Basic compounds used include alkali metals such as sodium metal and potassium metal; sodium hydride;
Metal hydrides such as calcium hydride; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, etc.; alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.; fluoride Examples include metal fluorides such as sodium and potassium fluoride, triethylamine, and organic bases such as 1,8-diazabicyclo[5,4°0]undecene (DBII). The reaction temperature of this reaction is usually 0
-200°C, preferably room temperature - 180°C (The reaction is usually completed in 5 minutes to 24 hours. The amount of the basic compound used is at least equimolar, preferably equimolar to 2.0°C, relative to compound (C). Double the mole is better.

The hydrolysis reaction of compound (D) or compound (F) can be carried out under any reaction conditions used for ordinary hydrolysis reactions, but for example, a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; or p-)
In the presence of organic acids such as luenesulfonic acid, water, alcohols such as methanol, ethanol, propatool, etc., ethers such as tetrahydrofuran and dioxane, ketones such as acetone, methyl ethyl ketone, etc., and solvents such as acetic acid. or in a mixed solvent thereof. This reaction is usually carried out at room temperature to 180°C, preferably room temperature to 140°C, and the reaction time is usually 1 to 24 hours.

Compound (F) or compound (G) can be obtained by reacting compound (D) or compound (E) with Z'-H. This reaction is performed on aromatic hydrocarbons such as benzene, toluene, xylene, etc.; alcohols such as methanol, ethanol; ethers such as tetrahydrofuran, dioxane, monoglyme, etc.; methylene chloride, chloroform, carbon tetrachloride, etc. halogenated hydrocarbons such as; aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, etc.; acetonitrile, pyridine, etc. in a solvent that does not affect the reaction; The reaction is carried out at room temperature to 160°C in the presence of sodium carbonate, calcium carbonate, sodium hydrogen carbonate, triethylamine, 1,8-diazabicyclo(5,4,0)undecene (DB[I), etc. The reaction time is several minutes to 48 hours, preferably 10
minutes to 24 hours. The amount of Z'-H used is that of compound (D)
Alternatively, it is preferably equimolar or more, preferably equimolar to 5 times the molar amount of compound (E).

Raw material compound A>N11 used in the above reaction. ,Z'
-H or when there is an amino group, imino group, hydroxyl group, mercapto group, carboxyl group, etc. that does not participate in this reaction in the starting compound (A), these groups are used in a protected form, and after the completion of the reaction, The protecting group may be removed by a method. Any protecting group may be used as long as it can be removed without destroying the structure of the compound of the present invention formed by the reaction, and groups commonly used in the fields of peptide, amino sugar, and nucleic acid chemistry may be used. is used.

The raw material compound (A) is produced by the method described in the following literature or by a method analogous thereto.

IJ,) laterocyclic Chem, 2
2.1033(1985)2 Liebigs An
Chem, 29 (1987) 3 J, Mad
, Chem, 31.991 (1988) 4 J,
Org, Chem, 35.930 (1970)5
JP-A-62-246541-6 JP-A-62-26272-7 JP-A-63-145268-8 J, Mad, Chem, 29.2363 (19
86)9) J, Fluorin Chem, 28.
361 (1985) 10) JP-A-63-198664 11) JP-A-63-264461 12) JP-A-63-104974 13) Our, Pat, Appl, 230
94g [Step 2] Among the compounds represented by formula [1],
A compound in which R2 is a hydroxy group, an amino group, or a mono-lower alkylamino group, and R1 is a hydrogen atom or a lower alkyl group can also be produced by the process shown in the following reaction formula-(2). .

Below is a blank space [Reaction formula-(2)] [In the formula, R1a/, X and Z are the same as above. x3 represents a halogen atom, preferably a fluorine atom. 0 represents 10-, -NH- or -NR16- (where R+g represents a lower alkyl group). ] Compound (J) can be obtained by reacting compound (H) with a compound represented by general formula [I], if necessary in the presence of a deoxidizing agent. The solvent used here is
Aromatic hydrocarbons such as benzene, toluene, xylene, etc.; Ethers such as tetrahydrofuran, dioxane, monoglyme, etc.; Halogenated hydrocarbons, such as methylene chloride, chloroform, etc.; Dimethylformamide, dimethyl sulfoxide, etc. Aprotic polar solvents include solvents that do not affect the reaction, such as acetonitrile or pyridine.

The reaction temperature is usually 0 to 150°C, preferably room temperature to 120°C.
The temperature is preferably around 0.degree. C., and the reaction is generally completed in about 10 minutes to 24 hours.

The amount of compound (I') to be used is at least equimolar, preferably equimolar - 1.5 times the molar amount of compound (H). As the deoxidizing agent, a deoxidizing agent used in the reaction between compound (D) or compound (E) and Z'-H can be used.

Debenzylation of compound (J) can be carried out using any reaction conditions used in ordinary catalytic reduction. The reaction is carried out in a solvent such as , tetrahydrofuran, dioxane, ethyl acetate, water, or a mixed solvent thereof, usually by stirring under a hydrogen stream at atmospheric pressure to 100 atm. The reaction temperature is usually from room temperature to around 100°C, and the reaction is usually completed in 1 to 48 hours.

[Step 3] Among the compounds represented by the general formula [I], R
A compound in which 1 is a hydrogen atom or a lower alkyl group and R2 is a hydroxy group, a lower alkoxy group, an amino group, or a mono- or di-lower alkylamino group is alternatively shown in the following reaction formula (3). It can also be manufactured by a process.

[Reaction formula-(3)] [In the formula, R''', A, Indicates an amino group.] Compound (N) can be obtained by reacting compound (L) with a compound represented by general formula (M) in the presence of an acid absorbing agent if necessary. Any solvent can be used as long as it does not affect the reaction, and examples thereof include the solvent used in the reaction between compound (H) and compound CI or a mixed solvent thereof.

The reaction temperature is usually 0 to 150°C, preferably room temperature to 120°C.
The temperature is preferably around 0.degree. C., and the reaction is generally completed in about 10 minutes to 24 hours. The amount of the compound represented by the general formula (M) to be used is usually a large equimolar excess relative to the compound (L). When the compound (L) is volatile, the reaction can be carried out in a closed system using an autoclave or the like. As the deoxidizing agent, those mentioned above can be used.

[Step 4] Among the compounds represented by the general formula [■], R
1 is a hydrogen atom or a lower alkyl group, and Y is C-R”
(Here, R4/ represents a lower alkoxy group.)
A compound in which R2 is a group in the above definition other than a halogen atom can also be produced by the process shown in the following reaction formula (4).

The following blank space [Reaction formula-(4)] [In the formula, R''', A, X and Z are the same as above. R2/
represents a group other than the halogen atom in the definition of R2 above. ×4 represents a halogen atom, preferably a fluorine atom or a chlorine atom. R4/ represents a lower alkoxy group. The symbol indicates an alkali metal atom. ]Compound (Q) is compound (0)
It is obtained by reacting compound (P) with. Solvents used here include alcohols corresponding to R4/, aromatic hydrocarbons such as benzene, toluene, etc.; ethers such as tetrahydrofuran, dioxane, etc.; dimethylformamide, dimethylsulfoxide, )IMP Preferably, an aprotic polar solvent such as ^, N-methylpyrrolidone; a solvent inert to this reaction such as acetonitrile or pyridine, or a mixed solvent thereof. The reaction temperature is usually room temperature to 150°C, preferably room temperature to around 100°C, and the reaction is usually completed in 10 minutes to 24 hours.

The amount of compound (P) to be used is a large equimolar excess, preferably equimolar to 5 times the molar amount of compound (0).

[Step 5] Among the compounds represented by the general formula [■], R
A compound in which 1 is a carboxy protecting group can also be produced, for example, by the process shown in the following reaction formula (5).

Below is a blank space [Reaction formula-(5)] [In the formula, R'', A, X, Y and Zi; ) can be obtained by reacting the compound (R) with a halogen compound (S).Solvents used here include aromatic hydrocarbons such as benzene and toluene; methylene chloride, chloroform, etc. Mention may be made of halogenated hydrocarbons; aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, etc.; and inert solvents such as acetonitrile.

The reaction temperature is usually around room temperature to 100°C. This reaction is preferably carried out in the presence of a basic compound such as triethylamine, diisopropylethylamine, dicyclohexylamine, BU, sodium carbonate, potassium carbonate, sodium hydroxide and the like.

In addition, among the compounds represented by the general formula CI), when the heterocyclic group represented by Z has a primary or secondary amino group, a formimidate ester or a lower alkanecarboximidate ester is added to this amino group. By reacting, a formimidoyl group or a lower alkylimidoyl group can be substituted on the amino group.

The compound of the present invention thus obtained is isolated and purified according to conventional methods. Depending on the isolation and purification conditions, it can be obtained in the form of a salt, a free carboxylic acid, or a free amine, but these can be mutually converted if desired to produce the compound of the present invention in the desired form.

[Effect]

(1) Antibacterial activity Regarding representative compounds of the present invention compound CI), the Japanese Society of Chemotherapy standard method [chemotherapy (C11BMO↑HER)
APY) Vol. 29, No. 1, pp. 76-79 (1981)
], the minimum inhibitory concentration (MIC: μg/ml
! ) was measured. The results are shown in Table-1. The compound numbers in the table are as shown in Examples.

Margin below (2) Distribution coefficient Akira Tsuji at al,: Antim
iclob, Agents Chemother,,
32.19l90-194 (according to the method of 198, 5
0mM phosphate buffer (pH 7,4, t-t =
0.15)/n-octatool partition coefficient was measured. Table 2 shows the results for representative compounds.

Table 2 (3) Interaction with fenbufuene and toxicity test Y
amamoto et al., (Chemotherapy Vo.
l, 36. 300-324, 1988), the test was conducted by simultaneous administration with fenbufuene.

(2) Preparation of test solution Fenbufuene and test compound were each diluted with a 0.5% methylcellulose solution before use.

(2) Test method Fuenbufuene (200 mg/kg) was orally administered to 10 mice (female, ICR, 18-23 g) per group, and then, 90 minutes later, 500 μ/kg of the test compound was orally administered.

The occurrence of convulsions was observed for 2 hours after administration of the compound of the present invention, and the presence or absence of death was further observed for 24 hours.

■Results The results obtained are shown in Table-3.

Table 3 Table 3 shows that the compound of the present invention has excellent resistance to the occurrence of convulsions due to interaction with other anti-inflammatory agents, and has low toxicity.

As mentioned above, the present compound CI) and its salts are both new compounds, exhibit extremely excellent antibacterial activity against Durum-negative bacteria and Durum-positive bacteria, and are highly safe.

When the compound [1] of the present invention is used as an antibacterial agent, it may be formulated as a composition with a pharmaceutically acceptable carrier for injection, parenteral administration such as rectally, oral administration in solid or liquid form, etc. I can do it.

Forms of compositions according to the invention for injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of suitable non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.

Such compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. These compositions may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporation with a sterilizing agent in the form of a sterile solid composition which may be dissolved in sterile water or some other sterile injectable medium immediately before use. can.

Solid preparations for oral administration include capsules, tablets, tablets, powders, granules, and the like. In preparing this solid dosage form, the compound of the invention is generally mixed with a small amount (and one inert diluent such as sucrose, lactose or starch). For example, lubricants such as magnesium stearate may be included. In the case of capsules, tablets and the like, buffers may also be included.

Tablets and tablets can also be provided with enteric coatings.

Liquid preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, including inert diluents commonly used by those skilled in the art, such as water. be done. In addition to such inert diluents, the composition can contain adjuvants such as wetting agents, emulsifying agents, suspending agents, and sweetening agents.
Seasoning and flavoring agents may also be included.

Formulations for rectal administration are preferably suppositories which may contain, in addition to the compound of the invention, excipients such as cocoa butter or suppository waxes.

The dosage of the compound (1) of the present invention depends on the nature of the compound to be administered, the route of administration, the desired treatment period, and other factors, but is generally about 0.1 to 1000 mg per day.
/kg s, especially about 1 to 100 mg/kg is preferred. Moreover, if desired, this daily dose can be divided into 2 to 4 doses and administered.

〔Effect of the invention〕

The compound [I) of the present invention and its salts are extremely valuable as antibacterial agents, and can be used as medicines for humans and animals, as medicines for fish diseases, agricultural chemicals, and food preservatives.

〔Example〕

Next, an example will be given and explained.

Example 1 3-(oxetan-3-yl-amino)-2-(2,3
, 4,5-tetrafluorobenzoyl)acrylic acid ethyl ester (compound 1): 3.3 g of 2.3,4.5-tetrafluorobenzoyl acetic acid ethyl ester, 3.1 ml of ethyl orthoformate, and 5.3-acetic anhydride. , 130
The reaction was carried out at ℃ for 4 hours. After distilling off the fraction under reduced pressure, the residue was dissolved in 60 ml of benzene, and 1 g of 3-aminoxetane was added at room temperature. After reacting at the same temperature for 18 hours, the solvent was distilled off. The residue was subjected to column chromatography (SiO□, chloroform-ethyl acetate, 4:1) to obtain 3.54 g of the above compound as a pale yellow oil.

'H-NMR(CDCj!riδ; 1.11 (t,
J=71(z, 31().

4.08 (Q, J=7tlz, 2H, -CO port CLC
L).

4.7-4.8 (m, 3H), 4.9-5.05 (m
, 2H), 6.95-7.05 (m, 1) 1), 8
．． 09(d, J=13.6Hz, IH) Example 2 Ethyl 1-(oxetan-3-yl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate Ester (compound 2): 1.57 g of compound 1 was dissolved in dimethylformamide 15-
Add 650 mg of potassium carbonate and heat to 160°C.
The mixture was allowed to react for 10 minutes. After distilling off the solvent, chloroform 5
0m1! Extracted with. The organic layer was washed with water and dried (MgS
After O,), the solvent was distilled off. The residue was crystallized from hexane-chloroform, and 1 g of the above compound in the form of slightly yellowish white needle-like crystals was obtained.
Obtained.

Melting point 146-147°C' H-NMR (CDC1') δ; 1.4 (t, J
=7Hz, 3H).

4.4 (q, J=7Hz, 2H), 4.95-5.2
(m, 48).

5.7-5.9 (m, IH), 8.1-8.2 (m,
11 (>, 8.68 (s, IH) Example 3 1-(oxetan-3-yl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ( Compound 3): 1 g of compound 2 was added to ethanol 2
0mf, 4ml of tetrahydrofuran! , 10% sodium carbonate solution under reflux for 1 hour. After distilling off the organic solvent, the mixture was acidified with 1N-HCf and extracted with chloroform. The organic layer was washed with water, dried (MgSL), and then the solvent was distilled off. The residue was crystallized from chloroform-hexane to obtain 790 ml of the above compound in the form of slightly yellowish white needle-like crystals.

Melting point 203-206℃ 'H-NMR (CDCl2 @) δ; 4.98-5
．． 26 (o+, 4H), 5.8-6.0 (m
, [1), 8.22-8J (, IH), 8.9
2(s,1)1) Example 4 6.8-difluoro-1-(oxetan-3-yl)-
7-(pyrrolidin-1-yl)-1,4-dihydro-4
-xoquinoline-3-carboxylic acid (compound 4): 100 mg of compound 3 and 71 mg of pyrrolidine were added to DMFL.
- The reaction was carried out at 80°C for 1 hour. After the solvent was distilled off, the mixture was extracted with chloroform. The organic layer was washed with 5% aqueous acetic acid and water, and then dried (MgSO,). The solvent was distilled off and the residue was
Crystallization from chloroform-ethanol gave 37 mg of the above compound in the form of colorless needles.

Melting point 261-262℃') I-NMR (CDIJ a+ DMSO-ds) δ
; 1.85-2.0 (m, 4H).

3, 6-3.7 (m, 4H), 4.85-5.
1 (m, 4H), 5.8-5.9 (m, LH)
, 7.74(d, J=14)1z, IH), 8,6
6(s,1)1) Example 5 Compounds 5 to 9 and Compounds 11 to 22 shown in Table 4 were obtained in the same manner as in Example 4.

Example 6 6.8-difluoro-7-nitoxy-1-(oxetan-3-yl)-1,4-dihydro-4oxoquinoline-
3-Carboxylic acid (Compound 10): In Example 3, the mother liquor from which Compound 3 was crystallized was concentrated. Hexane was added and solidified to obtain the above compound as a colorless solid.

Melting point 175-176℃ 'H-NMR (CDCj? 3) δ; 1.46 (t
, J=7Hz, 3H).

4, 41 (q, J=7)1z, 2)1), 5.
0-5.2 (m, 4H).

5.8-5.95 (m, 1tl), 8.07 (d, J
=11)1z, IH).

8.83 (s, LH) Example 7 1-(oxetan-3-yl)-5,6,7°8-tetrafluoro-1,4-dihydro-4-oxoquinoline-
3-Carboxylic acid ethyl ester (compound 23): 2.3.4.5.6-pentafluorobenzoylacetic acid ethyl ester 14.1 g, ethyl orthoformate 12.5 m
l! and 21.2 rn1 of acetic anhydride were reacted at 130 t: for 3 hours. The solvent was distilled off under reduced pressure, and 100ml of benzene was added to the oily residue! added. At room temperature, 4.02 g of 3-aminoxetane was added, and the mixture was stirred at the same temperature for 1 day.

Benzene was distilled off and hexane was added to produce a yellow solid. This solid was collected by filtration and reacted with 4.73 g of potassium carbonate in 50% of dimethylformamide at 140°C for 10 minutes. Distill the solvent and add 200ml of chloroform! Extracted with. After washing the organic layer with water and drying (MgSO,), the solvent was distilled off. The residue was subjected to column chromatography (2200 g of SiO2,
The mixture was treated with chloroform-ethyl acetate (2:1) to give the above compound as a yellow oil. When bexane was added to this, it solidified to obtain 7.94 g of the above compound as a yellow solid.

Melting point 110-113℃ 'H-NMR (CDCj! Ri δ; 1.4 (t, J
=7Hz, 3H).

4J9(q, J=7t(z, 2t(), 4.9-5.
2 (m, 4FI).

5.7-5.8 (m, IH), 8.55 (s, LH>
Example 8 5-benzylamino-1-(oxetan-3-yl)-
6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (compound 24): 3 g of compound 23, 931 mg of benzylamine and 2J5 g of potassium carbonate were refluxed in 20 ml of acetonitrile. Below, the reaction was allowed to take place for 1 hour. Distill the solvent and add chloroform 1
Extracted with 00 vessels. Wash the organic layer with water and dry (MgSO,)
The solvent was then distilled off. The residue was subjected to column chromatography for 5i
Oz 100 g, chloroform-ethyl acetate, 10
:1), 2g of the above compound as a yellow solid was obtained.

Melting point 127-128.5℃ 'H-NMR (CDCj! 3) δ; 1.39 (t
, J=7)1z, 3H).

4J9 (Q, J=7) 1z, 2H), 4.6-4.7
5 (m, 2H).

4, 85-5.15 (m, 4N), 5.6-5.
7 (m, 1)1).

7.2-7.5 (m, 5H), 8.43 (s, IH)
Example 9 5-7 minnow 1-(oxetan-3-yl) = 6.7.
8-) Lifluoro-1,4-dihydro-4-year-old xoquinoline-3-carboxylic acid ethyl ester (compound 25)
: 1.2g of compound 24 was added to 17mj2 of tetrahydrofuran.
゜Dissolved in a mixture of 3 o-1 ethanol and 10 rn1 acetic acid,
10% Pd/C500 was added, and the mixture was allowed to react for 16 hours at room temperature under hydrogen gas and normal pressure. After filtration through a Celite pad, the filtrate was concentrated. Ethanol was added to the residue, and the resulting solid was collected by filtration to obtain 830 mg of the above compound as a colorless solid.

Melting point 111-112°C' H-NMR (CDC13) δ; 1.4 (t, J
=7Hz, 3H).

4, 4 (q, J=7)1z, 2H), 4.9
−5.2 (m, 4tl>.

5, 6-5.8 (m, LH), 6.8-7.2
(br, 21().

8,47 (s, LH) Example 10 5-amino-1-(oxetan-3-yl)-6,7,
8-) Lifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (compound 26): 600 mg of compound 25 was mixed with 20 mf of ethanol and 20 mf of tetrahydrofuran! and 15ml of 10% sodium carbonate solution! The mixture was reacted for 30 minutes under reflux. After distilling off the organic solvent, the pH was adjusted to 7 to 6 with acetic acid.

The mixture was centrifuged at 3000 rpm for 10 minutes, and the upper groove was decanted. Using 10 ml each of water, ethanol, and ether, each was added, centrifuged, and decanted repeatedly to wash the precipitate. After decanting the ether, it was dried under reduced pressure to obtain 280 mg of the above compound as a yellow solid.

Melting point 197-198°C' H-NMR (DMSO-d6) δ; 4.8-5.
2 (m, 4H), 5.6-5.8 (m, LH),
7.7-8.0 (br, 2) 1), 8.65 (s, 1
)1) Example 11 5-amino-6,8-difluoro-1-(oxetane-
3-ylcin-7-(pyrrolidin-1-yl)-1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid (Compound 27): 60 mg of Compound 26 and 43 mg of pyrrolidine were reacted in 1 ml of dimethylformamide at 80°C for 1 hour. After the solvent was distilled off, ethanol was added to solidify, so it was collected by filtration. This was washed with ethanol and ether to obtain 13 mg of the above compound as a yellow solid.

Melting point 250-253°C') I-NMR (DMSO-d6) δ; 1.65-
2.0 (brs, 4)1).

3.4-3.8 (brs, 4H), 4.7-5.0 (
m, tfl), 5.6-5.8 (m, IH), 7.
0-7.3 (br, 2) 1), 8.45 (s, IH)
Example 12 Compounds 28 to 32 shown in Table 5 in the same manner as Example 11
and Compounds 148-181 were obtained.

In addition, in the following examples, isomers and B indicate those obtained using the raw material compound (the raw material constituting Z in general formula [I]) separated by the following operation. Silica gel column chromatography (elution solvent: CHCf3
/CH30) The compound obtained using the raw material that was easily crystallized when ether was added to the raw material or solution that was eluted earlier in 1) was converted into isomer A; A compound obtained using a raw material that did not crystallize was designated as isomer B.

Below is the blank space Example 13 6.7-difluoro-1-(oxetan-3-yl)-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (compound 33): 2.4. ．． 5-) 4 g of ethyl fluorobenzoylacetate, 4.06 mf of ethyl orthoformate, and 6.9 rIf of acetic anhydride were reacted at 130°C for 1.5 hours. The fraction was distilled off under reduced pressure to obtain 50ml of benzene.
2 was added thereto, 1.3 g of 3-aminoxetane was added at room temperature, and the mixture was reacted at the same temperature for 15 hours. The solvent was distilled off, hexane was added, and the resulting solid was collected by filtration (about 4.2 g).

4.2 g of this solid and 1.76 g of potassium carbonate were combined with 20 ml of dimethylformamide! The mixture was reacted for 15 minutes at 110°C. The solvent was distilled off and 50 rn of chloroform was added! After extraction with water, drying (MgSO4), the solvent was distilled off. Hexane was added, and the resulting solid was collected by filtration to obtain 2.13 g of the above compound as a yellow solid.

Melting point 177-178℃' H-NMR (CDC1*) δ; 1.42 (t,
J=7Hz, 3H).

4.41 (q, J=7Hz, 2H), 5.0-5.
2(m, 4t(), 5.4-5.6(m, LH>,
6.9-7.0 (m, IH), 8.2-111
．． 4 (m.

IH), 8.59 (s, LH) Example 14 6.7-difluoro-1-(oxetan-3-yl)-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid compound 34): 2.13 g of compound 33, 30-THF, and 30 ml of ethanol! The mixture was heated and dissolved. Here, 10m1 of water
and 10% aqueous sodium carbonate solution 15- were added, and under reflux,
The reaction was allowed to proceed for 1.5 hours. After distilling off the organic solvent, IN-)I
The mixture was acidified with C1 and the resulting solid was collected by filtration.

Washing with 3 portions each of water, ethanol, and ether gave 1.58 g of the above compound as a pale red solid.

Melting point 255-256°C 'H-NMR (DMSO-d6) δ; 4.9-5.
2 (m, 4H), 5.8-5.9 (m, LH),
7.8-8.0 (m, 1tl), 8.2-8.4 (m
, II ().

8,89 (s, IH) Example 15 6-fluoro-7-(4-methylpiperazin-1-yl)-1-(oxetan-3-yl)-1°4-dihydro-4-oxoquinoline-3 -carboxylic acid (compound 35)
: Compound 3480mg and 1-methylpiperazine 100mg
1 ml of dimethylformamide! The mixture was reacted for 1 hour at 80°C. After distilling off the solvent, ethanol 3- was added to solidify. Plus 10m1 of hexane! was added, collected by filtration, and washed with 5 ml of ethanol, 1-chloroform, and 5-hexane to obtain 68 mg of the above compound as a yellow solid.

Melting point 178-180°C') I-NMR (DMSO-d,) δ; 2.2
7 (s, 3H), 2.4-2.6 (s, 4H)
, 3J-3,4(s, 4H), 4.9-5.2(m
, 4H).

5, 9-6.1 (m, IH), 6.84 (d, J
=7.3Hz, LH).

? , 94(d, J=13.6)1z,1N), 8.7
Hs, LH) Example 16 Compounds 36 to 42 shown in Table 6 in the same manner as Example 15
and Compounds 182-188 were obtained.

Example 17 Rhofluoro-7-(imidazol-1-yl)-8-
Methoxy-1-(oxetan-3-yl)-1,4-dihydro-4-year-old xoquinoline-37carboxylic acid (Compound 43): 8158 mg of compound and sodium methoxide (28
% methanol solution) was reacted in 5-methanol under reflux for 15 hours. After distilling off the solvent, add 3mi of water! and further adjust the pH to approximately 6 to 7 with 20% acetic acid water.
The resulting solid was collected by filtration. This solid was washed with a small amount of water and ethanol to obtain 70 mg of the above compound as a pale yellow powder.

Melting point 152-154°C')l-NMR (DMSO-d,)δ; 3.34
(s, 3) 1), 4.8-5.1 (m.

4H), 5.9-6.0m, IH), 7.23(b
rs, 1) I), 7.55 (brs, 01), 8.
03 (brs, 1) I), 8.09 (d, J=10H
z.

LH), 8.84(s, 1t() Example 18 6.8-difluoro-7-(3-methylaminopyrrolidin-1-yl)-1-(oxetan-3-yl)-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid (
Compound 44): Compound 380■, 3-methylaminopyrrolidine dihydrochloride 69mg and triethylamine 162
(2) was reacted in DMSOO, 5- at 80°C for 1 hour.

Two volumes of ethanol and 10 volumes of hexane were added, and the resulting solid was collected by filtration. 3ml each of ethanol and hexane! Wash with
68 quarts of the above compound as a pale yellowish white solid was obtained.

Melting point 252-255°C' H-NMR (DMSO-ds) δ; 1.7-2.
1 (m, 2H).

2.29 (s, 3) 1), 3.1-3.9 (m, 5H
), 4.85-5.05 (m, 4)1), 5.8-
5.9 (m, LH), 7.74 (d, J=14Hz.

1) 1), 8.63 (s, IH) Example 19 Compounds 45 to 5 shown in Table 7 were prepared in the same manner as in Example 18.
9, Compound 85, Compound 112, Compounds 118-147
I got it.

Margin below Example 20 7-chloro-6-fluoro-1-(oxetan-3-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (compound 60)
: 2.6-dichloro-5-fluoronicotinoyl acetic acid ethyl ester 8.4 g, orthoformic acid ethyl ester 7.5 g
- and 12.7 ml of acetic anhydride were reacted at 130°C for 2 hours. The fraction was distilled off under reduced pressure and dichloromethane 30- and 3
-2.56 g of aminooxetane was added and reacted at room temperature for 1.5 hours. The solvent was distilled off, and 100 ml of hexane was added to the resulting solid. was added and filtered.

10.5 g of the solid collected by filtration was dissolved in 140 g of tetrahydrofuran.
- Sodium hydride (60% content) dissolved in water and cooled in water
1.21 g was added portionwise over 30 minutes. Furthermore, the reaction was carried out for 30 minutes at room temperature and for 1 hour under reflux. Tetrahydrofuran was distilled off, and the mixture was extracted with 100% chloroform. chloroform layer IN-hydrochloric acid 30rn! ,,Water 50r+t
i! and dried with Mg5Oa. Chloroform was distilled off, and the residue was solidified by adding 50% each of nihexane and ether, then pulverized and collected by filtration. 5.15 g of the above compound as a pale yellow powder was obtained.

Melting point 163-166℃ 'II-NMR (CDCj! Ri δ; 1.43 (t
, J=7)1z, 3M).

4.40 (qj=7Hz, 2H), 4.97 (t, J
=6.8Hz, 2H).

5.20 (t, J=7.4Hz, 2)1), 5.95
-6.15 (m, LH).

8.47 (d, J=8JHz, IH), 8.81 (s
, IH) Example 21 6-fluoro-7-(4-methylbiperazin-1-yl)-1-(oxetan-3-yl)-1°4-dihydro-4-oxo-1,8-naphthyridin-3- Carboxylic acid (Compound 61): Compound 60 200mg, N-methylpiperazine 64■
and 65 mg of triethylamine, 5 m of chloroform!
The mixture was reacted for 1.5 hours under reflux. Distill the fraction, and add 3 ml of ethanol 5-110% aqueous sodium carbonate solution to the residue.
, water 2- was added thereto, and the mixture was allowed to react under reflux for 1.5 hours. The solvent was distilled off, and 20% acetic acid water was added to the residue to adjust the pH to about 6. The resulting solid was collected by filtration and washed successively with a small amount of water, ethanol, and ether to obtain 13 mg of the above compound as a white solid.

Melting point 235-236.5℃' H-NMR (CDC1,) δ; 2J6 (s, 3H
), 2.5-2,6 (m.

4)1), 3.8-3.9 (m, 4)1),
4.95-5.2 (m, 4H).

5, 8-6.0 (m, 1) 1), 8. Hd, J
=13.2)1z, 11().

8, 76 (s, 11() Example 22 Compounds 62 to 73 shown in Table 8 in the same manner as Example 21
, Compound 88, and Compounds 189 to 196 were obtained.

Blank space below Example 23 6.7-difluoro-8-methoxy-1-(oxetan-3-yl)-1,4-dihydro-4=oxoquinoline-3-carboxylic acid ethyl ester (compound 74): 2-chloro -4,5-difluoro-3-methoxybenzoylacetic acid ethyl ester, 8 g, orthoformic acid ethyl ester, 9.4 - and acetic anhydride, 15.7 rnl, 13
The reaction was carried out at 0°C for 3 hours. After distilling off the fraction, benzene 40
m1 and 2.92 g of 3-aminoxetane were added at room temperature and reacted at the same temperature for 50 minutes. After the solvent was distilled off, ether 30- was added to the residue to solidify it, then it was ground and collected by filtration to obtain 10.4 g of a white solid.

Dissolve this solid in 500rn1 of tetrahydrofuran,
Under ice cooling, 1.28 g of sodium hydride (60% content)
was added and gently refluxed to react for 3 days. The solvent was distilled off, 300 mf of water was added to the residue, and the mixture was extracted with chloroform (200 mf x 3 times). Dry the organic layer (Mg
After SO<) was distilled off, ether 100- was added to the residue,
It was solidified, then ground and filtered to obtain 3.8 g of the above compound as a pale yellow solid.

Melting point 195-198°C' H-NMR (CDCji! a) δ; 1.41
(t, J=7.05Hz, 38).

4.03 (d, J=1.95Hz, 3H), 4.41
(q, J=7.05Hz.

21(), 4.85-5.2(m, 4)1), 5.
8-6.0 (m, LH).

8.0-8.1 (m, IH), 8.67 (s, 1) 1
) Example 24 6.7-difluoro-8-methoxy-1-(oxetan-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (compound 75): 2.7 g of compound 74 , Tetrahydro 7 run 110m
f and 40 m of 2N sodium hydroxide solution! ! The mixture was reacted for 20 minutes under reflux. Tetrahydrofuran was distilled off, and the remaining aqueous solution was acidified (pH approximately 6) with 20% acetic acid.
And so. The resulting solid was collected by filtration, and the filtered solid was mixed with water 10-
, 20 times of ethanol, and 30 times of ether to obtain 1.97 g of the above compound as a white solid.

Melting point 178-179°C 'H-NMR (CDIJs) δ; 4.10 (d,
J=2.48Hz, 3H).

4.85-5.2 (m, 4H), 5.9-6. Hm
, 1) 1), 8.05-8.15 (m, IH),
8.87 (m, IH) Example 25 7-(3-aminopyrrolidin-1-yl)-6fluoro8-methoxy-1-(oxetan-3-yl)-1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid (compound 76): 100 mg of compound 75 and 86 mg of 3-aminopyrrolidine were reacted in DMSOId at 80°C for 30 minutes. In a cold machine, 200 ml of ethanol and 200 ml of ether were added and stirred, and the supernatant was removed by decantation. The residue was diluted with 5 ml of ethanol. After solidification, it was crushed. This solid was collected by filtration and washed with 5-ethanol to obtain 42 mg of the above compound as a colorless solid.

Melting point 199-202°C') I-NMR (DMSOds+DJ) δ; 1.
6-2.1 (m, 2H).

3.46 (s, 3) 1), 3.2-3.9 (m, 5H
), 4.7-5.1 (m.

4) 1), 5.8-6.0 (m, LH), 7.65
(d, J=14.6Hz.

IH), 8.58 (s, IH) Example 26 Compounds 77 to 84 shown in Table 9 in the same manner as Example 25
．． 86.87.89-96.101-103.106.
I got 107.

Below is the blank space Example 27 7-(cis-3-amino-4-methylpyrrolidine-1-
yl)-6,8-difluoro-1-(oxetane-3-
yl)-1,4-dihydro-4-oxoquinoline-3-
Carboxylic acid trifluoroacetate (compound 97): 200 mg of compound 3, 160 mg of cis-3-t-butoxycarbonylamino-4-methylpyrrolidine and 150 mg of triethylamine were dissolved at 80° C. in DMF3-1.
Allowed time to react. DMF was distilled off, ether was added to the residue, and the resulting solid was collected by filtration.

This solid was dissolved in 10 mf of chloroform, 2 rnl of trifluoroacetic acid was added under ice-cooling, and the mixture was incubated at the same temperature for 10 minutes.
The reaction was further continued for 40 minutes at room temperature. The fraction was distilled off, 2rnl of ethanol and 30ml of hexane were added to the residue and stirred, and the supernatant was removed by decant. Ethanol 5- was added to the residual oil to solidify it, then it was ground and collected by filtration to obtain 150 mg of the above compound as a yellow solid.

Melting point 225-227°C 'H-NMR (DMSO-d,) δ; 1.14
(d, J=6.35)1z, 3H).

2.25-2.4 (m, IH), 3.0-4. Hm
, 511), 4.8-5.2 (m, 4H), 5
．． 7-6.0 (m, 11 (), 7.76 (d,
J=14.2Hz.

IH), 8.67 (s, 1) I) Example 28 Compounds 98-1 shown in Table 10 in the same manner as Example 27
00.197-214 were obtained.

Margin Example 29 below? -() Lance-3-amino-4-methylpyrrolidine-
1-yl)-6,8-difluoro-1-(oxetane-
3-yl)-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid hydrochloride (compound 104): Suspend 70 μ of compound 102 in ethanol 3-,
While cooling with water, add saturated hydrochloric acid-ethanol solution little by little.
Completely dissolved. Three drops of ether were added, and the resulting solid was collected by filtration to obtain 60 mg of the above compound as a pale yellow solid.

Melting point 188-190℃' H-NMR (DMSO-dB) δ; 1.10 (d
, J=6.83tlz, 3tl).

2.4-2.6 (m, 1) 1), 3.2-4.2 (m
, 5H), 4.8-5.1 (m, 4H), 5.7
5-6.0 (m, IH), 7.79 (d.

J=13.7Hz, IH), 8.67(s, IH
) Example 30 5-amino-7-(trans-3-amino-4-methylpyrrolidin-1-yl)-6,8-difluoro-1-(
oxetan-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (compound 105)
: Using 100 µm of Compound 103 and carrying out the same procedure as in Example 29, 90 µm of the above compound as a pale yellow solid was obtained.

Melting point 260℃ or higher decomposition'H-NMR (DMSO-ds) δ; 1.0B (d,
J=6.84Hz, 3H).

2.4-2.6 (m, IH), 3.5-4.2 (m,
5tl), 4.7-5.1(m, 4)1), 5.6
-5.9 (m, IH), 7.27.4 (br, 2tl
).

8,45 (s, IH) Example 31 5-amino-6,8-difluoro-7-(4-formimidoylpiperazin-1-yl)-1-(oxetane-
3-yl)-1,4-dihydro-4-oxoquinoline-
3-Carboxylic acid hydrochloride (Compound 108): 100 mg of compound 55 and DBolomg were stirred in 8 mji of ethanol, and 68 mg of benzyl formimidic acid ester hydrochloride was added thereto at room temperature, and the mixture was reacted for 1 hour. Add saturated hydrochloric acid/ethanol solution to this,
It was made weakly acidic. The resulting solid was collected by filtration and washed with 5-ether to obtain 83 mg of the above compound as a pale yellow solid.

Melting point 240-245°C') I-NMR (DMSO-da) δ; 3. O-
3,8 (m, 8ft).

4.8-5.1 (m, 4H), 5.7-5.9 (m,
11(), ? ! -7.6(br, 2)1), 8.
09 (s, IH), 8.56 (s, IH) Example 32 Compounds 109 to 0 shown in Table 11 in the same manner as Example 31
I got 111.

Example 33 5-amino-? -((-)-) lance-3-amino-4
-methylpyrrolidin-1-yl)-6゜8-difluoro-1-(oxetan-3-yl)-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid (compound 113)
: (1) 81.4 g of trans-3-tert-butoxycarbonylamino-4-methylpyrrolidine was reacted with 59 g of benzoyl chloride in methylene chloride in the presence of triethylamine at room temperature to obtain trans-3-tert-
120 g of butoxycarbonylamino-4-methyl-1-benzoylpyrrolidine (a) was obtained.

Then (a) 123 g was reacted with hydrochloric acid in ethanol at room temperature to obtain trans-3-amino-4-methyl-1
- 83g of benzoylpyrrolidine (b) was obtained. Then (b
) 83 g of 1-hydroxybenzotriazole 87
．． (R) in methylene chloride in the presence of 87.4 g of 51-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 46.5 g of triethylamine.
68.4 g of -(-)mandelic acid was reacted at room temperature to produce trans-3-(2-(R)-2-phenyl-2-hydroxyacetylamino)-4-methyl-1-benzoylpyrrolidine diastereomer ( A) (C) 34 g was obtained. Next, 33.6 g of (C) was reacted with acetic acid and hydrochloric acid under reflux to obtain 16.8 g of a white solid of (-)-) lance-3-amino-4-methylpyrrolidine dihydrochloride.

[α] 2' = -10.9°c = 0.53. MeO
fl) 'H-NMR (CD, OD) δ; 1.22 (d, J=
7.3Hz, 311), 2.7-2.85(m, IH
), 3.22-3J5(,1)I), 3.4-3.
7 (m.

2H), 3.75-4.1 (m, 2H) (2) Compound 26 22g, (-)-1-lanse-3- obtained in [I]
Amino-4-methylpyrrolidine dihydrochloride 16.5g,
) 43.4 g of ethylamine and 250 g of DMSO
Using the same procedure as in Example 25, 22 g of the above compound as a pale yellow powder was obtained. This powder was dissolved in methanol 21 under heating under reflux, and after filtering off insoluble matter, it was allowed to cool and crystallize, to obtain 15 g of the above compound in the form of pale yellow needle-like crystals.

Melting point 270-275°C (decomposition) 'H-NMR (DMSO-da) δ; 1.0?
(d, J=7.33Hz, 311).

2.4-2.6(m, 1)1), 3.4-4.1(
m, 511), 4.7-5.1 (m, 48),
5.6-5.8 (m, 18), 7.1-7.4
(brs, 2H).

8.45 (s, 1tl), 9.0-10.0 (br
, 2H) Example 34 5-amino-7-((-)-trans-3-amino-4
-methylpyrrolidin-1-yl)-6゜8-difluoro-1-(oxetan-3-yl)-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid methanesulfonic acid salt (Compound 114): Compound 113 850 mg and methanesulfonic acid 934
45 mg in a mixture of 50 - ethanol and 10 - water
The reaction was carried out at ℃ for 20 minutes. Insoluble matters were removed by filtration, and 400ml of ether was added to the filtrate! was added, and the resulting solid was collected by filtration and washed with ether to obtain 670 mg of the above compound as a yellow powder.

Melting point 242-245°C (decomposition) l-NMR (DMSO-da) δ; 1.08
(d, J=6.811z, 3H).

2J3(s, 31(), 2.5-2.6(m, IH)
, 3.5-4.1 (m.

5H), 4.75-5.0 (m, 4H), 5.
6-5.8 (m, III).

7.1-7.4 (br, 2H), 8.09 (brs
, 311), 8.45 (s.

IH) Example 35 5-amino-7-((-)-trans-3-amino-4
-methylpyrrolidin-1-yl)-6゜8-difluoro-1-(oxetan-3-yl)-1,4-dihydro-
4-Oxoquinoline-3-carboxylic acid p-)luenesulfonic acid salt (Compound 115): 500 mg of compound 113 was suspended in 50 ml of ethanol, and 725 μl of p-)luenesulfonic acid monohydrate was added to the suspension.
30ml of ethanol solution and 80ml of chloroform!
was added and reacted at 45°C for 10 minutes.

Insoluble matter was filtered off, and the filtrate was distilled off under reduced pressure to remove chloroform. 400 d of ether was added, and the resulting solid was collected by filtration to obtain 584 mg of the above compound as a yellow powder.

Melting point 174-190℃ 'H-NMR (MSO-ds) δ; 1.0
8 (d, J=6.8Hz, 3H).

2.28 (s, 3H), 2.4-2.6 (m, 1t
l), 3.4-4.1 (m.

5 old, 4.7-5.1 (+n, 4H), 5
．． 6-5.8 (m, 1ft), 7.1 and 7.4
7 (d, J=7.8)1z, both 48), 8.
07 (brs, 3H), 8.45 (s, 1
ll) Example 36 5-amino-? -((-)-) lance-3-amino-4
-methylpyrrolidin-1-yl)-6゜8-difluoro-1-(oxetan-3-yl)-1,4-dihydro-
4-Oxoquinoline-3-carboxylic acid hydrochloride (compound 116): 10'Omg of compound 113 was dissolved in a mixture of 5 ml of water and 5 mf of ethanol, and the solution was dissolved in lN-HCl under water cooling.
3ml! In addition, the mixture was allowed to react for 5 minutes. ether 30m
j! was added, and the resulting solid was collected by filtration to obtain 70 mg of the above compound as a yellow powder.

Melting point 265-275°C (decomposition)') I-NMR (DMSO-ds) δ; 1.09 (
d, J=6.81(z, 3H).

2.4-2.6 (m, LH), 3.5-4.1 (m,
5H), 4.7-5.1 (m, 4H), 5.6-5
．． 8 (m, IH), 7.1-7.4 (br, 2H).

8, 45 (s, 1) 1), 8.3-8.7 (
brs, 3H) Example 37 5-amino-7-((-)-) lance-3-amino-4
-methylpyrrolidin-1-yl)-6゜8-difluoro-1-(oxetan-3-yl)-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid sulfate (compound 117): 1 g of compound 113 to 6 mj of water! and 18 d of ethanol to obtain 1.53 g of sulfuric acid (97%).
was added at 10 to 15°C and reacted for 10 minutes. The resulting solid was collected by filtration, ethanol (10ml 1.2 times), ether (
10ml! , twice) to obtain 1.08 g of the above compound as a pale yellow solid.

Melting point 290°C or higher (color decomposition) 'H-NMR (DMSO-ds) δ; 1.09 (d
, J=6.8)1z, 3)1).

2.5-2.7 (m, IH), 3.5-4.1 (m,
5B), 4.7-5.1 (m, 4H), 5.6
-5.8 (m, LH), 7.1-7.4 (br,
2)1).

7.9-8.2 (br, 3) 1), 8.45 (s, L
H) Example 38 6-fluoro-7-[(2S,4S)-2-methyl-4
-aminopyrrolidine-nyyl] -1-(oxetan-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (compound 215): Compound 34 100 mg, (2S,4S)-2methyl-
135 mg of 4-pendylaminopyrrolidine hydrochloride and 172 mg of triethylamine were reacted in dimethylformamide 2 at 80°C for 2.5 hours. After distilling off the solvent, column chromatography (Si02
5 g, chloroform/methanol = 10/1), and the corresponding fractions were collected. After evaporating the solvent, the residue was dissolved in 60 ml of methanol, and dissolved in palladium charcoal (ml 00 m).
g was added thereto, and the mixture was reacted for 2 days under hydrogen gas. After filtering the catalyst, the filtrate was distilled off, and the residue was solidified with 5 ml of ethanol and pulverized to obtain 35+ ng of the above compound as a pale yellow solid.

Melting point 217°C or higher (decomposition) 'H-NMR (DMSO-d,) δ; 1.1B (s,
3H), 1.95-2.15 (m, 1tl), 2.
25-2.5 (m, IH), 3.99 (brs, IH
).

4.85-5.2 (m, 4JI), 5.8-6.05
(m, lH), 6.55 (brs, 1) 1), 7.
9Hd, J=13.67t(z, lH), 8.65(
s.

LH) Example 39 Table 1 was prepared in the same manner as in Example 38. 216 and 217 were obtained.

Compound Example 40 shown below in Margin 2 6.7-difluoro-5-hydroxy-1-(oxetan-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (Compound 218)
: Dissolve 6.5g of benzyl alcohol in 150rd benzene and hydrogenate while cooling with water)
%) was added and reacted. Add 2.3 to this solution.
4.6-Tetrafluorobenzoic acid benzyl ester 15
g was added thereto, and the mixture was reacted at room temperature for 1 hour. 3.6 g of acetic acid was added and the solvent was distilled off. 50 d of water and 10 d of methanol to the residue
0m1! Add 6.5 g of potassium hydroxide and 50
The reaction was carried out at ℃ for 30 minutes. 6 g of acetic acid was added and the solvent was distilled off, and 50 mf of benzene and a 7% aqueous potassium hydroxide solution were added to the residue, which was shaken to separate the layers. The aqueous layer was made acidic by adding concentrated hydrochloric acid, extracted twice with 100mf chloroform, treated with anhydrous magnesium sulfate, and the solvent was distilled off to remove the resulting solid.
- Dispersed in hexane and collected by filtration, 4.7 g of 6-benzyloxy-2,3,4-)lifluorobenzoic acid in the form of colorless powder
I got it.

20ml of this benzoic acid (4.6g) and 1 drop of dimethylformamide! After reacting with 3 ml of oxalyl chloride in dichloromethane at room temperature for 1 hour, excess reagent and solvent were distilled off to obtain acid chloride as an oily residue. Magnesium 390mg and diethyl malonate 2.8g
The above acid chloride was dissolved in 10rd tetrahydrofuran and was added dropwise to react while the solution was cooled to -40°C to form a homogeneous solution. The temperature was returned to room temperature, the solvent was distilled off, and the residue was diluted with 2-concentrated hydrochloric acid (20ml). water, 50m1
! of chloroform was added to separate the layers. To the residue obtained by evaporating the chloroform layer, 0.58 p-toluenesulfonic acid monohydrate and 30 mA' of water were added, and the mixture was heated at about 100°C for 2 hours.
The reaction mixture was allowed to react for an hour, returned to room temperature, and extracted with 50-chloroform. The chloroform layer was washed with a 5% aqueous sodium bicarbonate solution and then treated with anhydrous magnesium sulfate. The solvent was distilled off to obtain 6-benzyloxy-2,3,4-)lifluorobenzoylacetic acid ethyl ester as an oily residue.

1.76 g of this benzoyl acetate ethyl ester
m1! was dissolved in benzene, 0.66 g of dimethylformamide dimethyl acetal was added, and the mixture was reacted under reflux for 45 minutes. The solvent was distilled off, 10-dichloromethane and 0.5 g of 3-aminooxetane were added to the residue, and the mixture was heated at room temperature for 45 min.
It was allowed to react for a minute. The solvent was distilled off, and 1 g of anhydrous potassium carbonate and 5 ml of dimethylformamide were added to the residue. Add 100
After reacting at ℃ for 1 hour and cooling, 40-chloroform,
250 d of water was added and shaken to separate the liquids. The chloroform layer was washed with water, treated with anhydrous magnesium sulfate, the solvent was distilled off, and the precipitated colorless crystals were dispersed in a mixture of diisopropyl ether and chloroform and collected by filtration to give 5-benzyloxy-
6,7-difluoro-1-(oxetan-3-yl)-
810 mg of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester was obtained. (Melting point 220-2
(22°C) 1.62 g of this quinolone carboxylic acid ethyl ester was added to a mixture of 8-dichloromethane, 8-methanol, and 6 mf acetic acid together with 250+ g of 10% palladium on carbon, hydrogenated for 2 hours, and the catalyst was filtered off. The solid precipitated by evaporation of the solvent was dispersed in diisopropyl ether and collected by filtration to obtain 1.13 g of the target compound as colorless powdery crystals.

Melting point 242-246°C (decomposition) 'H-NMR (CDcl,) δ; 1.42 (t, J
=711z, 3H), 4.43(q, J=7)1z
, 2H), 4.98-5.22 (m, 4H), 5.
40-5, 42 (m, 1)I), 6.28 (
dd, J=lI11z, J=6Hz, 1)1)
.

8,59 (s, 18) Example 41 6.7-difluoro-5-hydroxy-1-(oxetan-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (compound 219) : 315 mg of Compound 218 was dissolved in 80% tetrahydrofuran, 5.8 g of 10% aqueous tetra-n-butylammonium hydroxide solution was added, and the mixture was reacted at 45°C for 1 hour. After adding 180 mg of acetic acid and water, tetrahydrofuran was distilled off and the precipitated solid was collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain 212 mg of the above compound as colorless powder crystals.

Melting point 273-276°C'H-NMR (DMSO-d, )δ; 4.90
-5.18(m, 4)1), 5.70-5.85(
m, IN), 7.17(cld, J=Il)Iz
, J=6Hz, IN).

8,79 (s, LH) Example 42 6-fluoro-5-hydroxy-1-(oxetane-3
-yl) -7-(piperazin-1-yl)-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid (Compound 220): Compound 21990 mg and piperazine 90 tng were reacted in 500 mg of dimethyl sulfoxide at 90° C. for 15 minutes. After cooling, add 4mf of diisopropyl ether, shake, leave the oily precipitate, and discard the upper layer. Repeat this operation three times, and add 1rnf to the oily precipitate! , and the precipitate was collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain 75 mg of the above compound as a pale yellow powder.

Melting point 266-273℃ (blackening) ') I-NMR (DMSO-d6) δ; 2.84-
2.95 (m, 411), 4.88-5.11 (m
, 4H), 5.81-5.92 (m, IH),
6.23(d, J=6Hz, 1)1), 8.64(
s, LH) Example 43 Compound 221 shown in Table 13 was prepared in the same manner as in Example 42.
222, 224 and 225 were obtained.

Below is the blank space Example 44 5-hydroxy-1-(oxetan-3-yl)-6,
7,8-) Lifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound 223): 220 mg of 60% sodium hydride was dispersed in 50-benzene, and 5.1 g of benzyl alcohol was added. Made it react. 1.7 g of compound 23 was added and reacted at room temperature for 15 minutes, washed twice with 250 g of water, treated with anhydrous magnesium sulfate, the solvent was distilled off, and diisopropyl ether 40- was added to form a precipitated solid. was collected by filtration. This solid
15mf of 15-dichloromethane with 260mg of lO% palladium on carbon! of methanol and 10rrf
! of acetic acid and hydrogenated overnight. The precipitate was dissolved by adding 50% of chloroform, the catalyst was filtered off, the filtrate was concentrated, and the precipitated colorless powdery crystals were collected by filtration and washed with diisopropyl ether to obtain 1 g of the above compound 790II.

Melting point 242-244°C 'II-NMR (DMSO-da) δ; 4.87-5
．． 05 (m, 4H), 5.78-5.91 (m, 1l
l), 8.78 (s, l1l) Example 45 5-amino-6,7-difluoro-1-(oxetane-
3-yl)-1,4-dihydro-4-oxoquinoline-
3-Carboxylic acid ethyl ester (Compound 22[i): 60 g of 2.3.4.6-tetrafluorobenzoic acid methyl ester and 70 g of benzylamine were reacted in 400-g of benzene under reflux for 1 hour.

After cooling, the mixture was washed with 600% water, 1% hydrochloric acid, and 1% aqueous sodium carbonate solution, treated with anhydrous magnesium sulfate, concentrated, and the precipitated product was collected by filtration and washed with methanol. 30g of this was mixed with about 2-palladium black, 100d of acetic acid and 20g of palladium black.
It was added to a mixed solution of 0 ml of methanol and hydrogenated for 1.5 hours. The catalyst was filtered off and the filtrate was concentrated to obtain 6-amino-2,3,4-)lifluorobenzoic acid methyl ester as a crystalline residue.

This total amount was suspended in 200ml of 95g of sodium perborate tetrahydrate! A mixture of 100 ml of acetic acid and 200 ml of trifluoroacetic acid was added little by little to a stirred mixture at 60° C., and reacted at the same temperature for 1.5 hours. Concentrate the solvent to about 1/4,
After adding 11 of water, the mixture was extracted twice with 250 of chloroform. The chloroform layer was washed with water, treated with anhydrous magnesium sulfate, and then the solvent was distilled off to obtain a crystalline residue. 1 for this
0% sulfuric acid 50ml. 60 mA' of acetic acid was added, and the mixture was stirred and refluxed for 3 days. After distilling off most of the acetic acid and adding 60ml of water, 100ml of chloroform was added! After extracting the chloroform layer four times with anhydrous magnesium sulfate, the precipitated colorless powdery solid was dispersed in a mixture of chloroform and n-hexane and collected by filtration. .3
．． 4-)! J fluorobenzoic acid was obtained.

70ml of this benzoic acid 9.3g! of dichloromethane, 4.5 ml! of oxalyl chloride at 40°C, 1.
After reacting for 5 hours, excess reagent and solvent were distilled off,
The acid chloride was obtained as an oily residue. Magnesium 1.1
7.2 g of diethyl malonate were reacted with 6 ml of ethanol in 50-g of tetrahydrofuran to form a homogeneous solution, and while cooling to -60°C, 15 g of the above acid chloride was added.
- was dissolved in tetrahydrofuran and added dropwise to react.

The temperature was returned to room temperature, the solvent was distilled off, 8,5-concentrated hydrochloric acid, 50 rnl of water, and 100 ml of chloroform were added to the residue for branching, and the chloroform layer was concentrated to obtain an oily residue. Add 2g of p-toluenesulfonic acid l hydrate to this total amount, 60ml
of water was added, and the mixture was reacted at about 100°C for 1.5 hours. After cooling, 15 Qrnl of dichloromethane was added, shaken, and branched. The dichloromethane layer was washed with a 1% aqueous sodium bicarbonate solution, treated with anhydrous sodium sulfate, and concentrated to obtain ethyl 6-nitro-2,3,4-trifluorobenzoylacetate as an oily residue.

12.2 g of this benzoylacetic acid ethyl ester was heated to 140° C. and reacted with 12.2 g of acetic anhydride and 9.8 g of orthoformic acid ethyl ester for 20 minutes. Excess reagent was distilled off under reduced pressure at the same temperature, and after cooling, 501 nl of oily residue was collected.
of dichloromethane. 3.1 g of 3-aminoxetane was added to this, and after being left at room temperature for 10 minutes, the solvent was distilled off. To the residue, 8 g of anhydrous potassium carbonate and 50 mj of dimethylformamide! was added and reacted at 80°C for 25 minutes. 2
00d of chloroform and 700ml of water were added and shaken, the precipitated solid was collected by filtration, washed with water, methanol and chloroform in that order to obtain 5.8g of 6.7-difluoro-5-nitro-
1-(oxetan-3-yl)-4-year-old xo-1,4-
Ethyl nisder dihydroquinoline-3-carboxylate was obtained as colorless needles. (Melting point: 233-235°C) 2 g of this quinolone carboxylic acid ethyl ester and 0.2 g of 10% palladium on carbon were added to a mixture of 100 rITl of dichloromethane, 100 methanol, and 2 liters of acetic acid, followed by dehydrogenation and 100 ml of acetic acid. of chloroform and 2
After adding 0rn1 methanol to dissolve the precipitate, the catalyst was separated by filtration, the filtrate was concentrated, and the precipitated colorless needle crystals were collected by filtration.
Washing with chloroform gave 1.6 g of the target compound.

Melting point 272-275°C (decomposition) 'II-NMR (CD (J!, -CD, 00.10:
I) δ; 1.40 (t, J=711z.

311), 4J8(q, J==711z, 211)
, 4.95-5.02 (m, 211).

5.11-5.19 (m, 211), 5.35-5
．． 48 (m, III), 5.94 (dd, J=1
211z, J=611z, 1it), 8.4
2 (s, l1l) Example 46 5-amino-6,7-difluoro-1-(oxetane-
3-yl)-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid (compound 227): compound 226 11
0 mg was added to 20 d of tetrahydrofuran together with 1.5 g (7) 1 Q% aqueous solution of tetra-n-butylammonium hydroxide and reacted at 60° C. for 10 minutes. 1
00 mg of acetic acid and 3 portions of water were added and concentrated, and the precipitate was collected by filtration and washed with water, ethanol, and diisopropyl ether in this order to obtain the above compound 44 as colorless powder crystals.

Melting point 〉300℃ 'It-NMR (DMSO-d,,) δ; 4.85-
5.13 (m, 411), 5.60-5, 71
<m, III), 6.41 (dd, J=121
1z, J=611z, 1ll).

7.95 (br, 211), 8.64 (s, l11)
Example 47 5-Amino-6-fluoro-1-(oxetan-3-yl)-7-(piperazin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound 22
B): Compound 226 810mg, piperazine 810mg 5
g of dimethyl sulfoxide and reacted at about 100° C. for 1 hour. Cool to about 80°C, add 325 mg of potassium hydroxide dissolved in 2 ml of water, react for 5 minutes,
After adding 8,300 mg of vinegar and 8 rnl of ethanol and stirring at the same temperature, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropyl ether.

Recrystallization from chloroform-methanol gave 610+++ g of the above compound as pale yellow powder crystals.

Melting point 244-246℃' II-NMR (DMSO-ds) δ; 2.82-
2.89 (m, 411), 3.11-3.21
(m, 4H), 5.86-5.96 (m, 211),
5.99-6.09 (m, 211), 5.70-5
．． 79 (m, 1tl), 5.81 (d, J=611z
.

l1l), 7J7(brs, 211), 8.50(
s, 11 () Example 48 Compounds 229 to 229 shown in Table 14 in the same manner as Example 47
232 was obtained.

Example 49 1-(oxetan-3-yl)-5,7,8-trifluoro-1,4-dihydro-4-year-old xoquinoline-3-carboxylic acid ethyl ester (Compound 233): 2.3.4. 6-titrafluorobenzoylacetate ethyl 3g1 acetic anhydride 3g1 orthoformic acid ethyl ester 2.7
g was reacted at 140°C for 1.5 hours.

Excess reagent was distilled off under reduced pressure at the same temperature, and the mixture was allowed to cool. 5 residues
The mixture was dissolved in 0rnl of dichloromethane, added with 0.6 g of aminooxetane, and concentrated. Diisopropyl ether 5m
l! was added and allowed to stand, and the precipitated crystals were collected by filtration. These crystals were added to 40% tetrahydrofuran and stirred under reflux for 60%.
% sodium hydride was added, and the mixture was reacted for 10 minutes. After distilling off the solvent, add 100ml of chloroform and 20ml
! The chloroform layer was treated with anhydrous magnesium sulfate, concentrated, and the precipitated colorless crystals were collected by filtration and washed with diisopropyl ether to obtain 1.97 g of the above compound.

Melting point 169-171℃') l-NMR (CDCf δ; 1.40 (t,
J=7Hz, 3H).

4.39 (q, J=7Hz, 2H), 4.93-5
．． 04 (m, 2H).

5.08-5.19 (m, 2H), 5.73-5.
84 (m, IH).

6.96 (dt, J=6Hz, J=11Hz, IH),
8.53(s,1)1) Example 50 1-(oxetan-3-yl)-5,7,8-trifluoro-1,4-dihydro-4-year-old xoquinoline-3-carboxylic acid (Compound 234 ): Compound 233 650mg
, 2N sodium hydroxide aqueous solution i 1.2rn1, benzyltriethylammonium chloride 50cm 20ml
! of tetrahydrofuran and stirred and refluxed for 2.5 hours. Most of the tetrahydrofuran was distilled off, 5-ethanol was added, and the mixture was refluxed for 5 minutes and then allowed to cool to obtain 560 mg of the above compound as a pale brown-yellow powder.

Melting point 〉300℃' H-NMR (DMSO-d,) δ: 4.79-5
．． 03 (m, 4H), 5.67-5.80 (m, 1)
1), 7.40 (dt, J=6Hz, J=11)1z
, 1) 1).

8,55 (s, IH) Example 51 5.8-difluoro-1-(oxetan-3-ylcin-7-(piperazin-1-yl)-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid (compound 235)
: Compound 234 100mg, piperazine 100mg.

400 mg of dimethyl sulfoxide at about 100°C for 20
Stir for a minute. After adding ethanol 1D and refluxing for 2 minutes, the mixture was allowed to cool, and the precipitated pale yellow powdery crystals were collected by filtration and washed with ethanol and chloroforman to obtain 60 mg of the above compound.

Melting point 〉300℃ 'H-NMR (DMSO-d,) δ; 2.76-2
．． 90 (m, 4H), 3.14-3.25 (m, 4
N), 4.81-5.05 (m, 4H), 5.76
-5,89 (m, IH), 7.12 (dd,
J=7Hz, J=14flz, II().

8,64(s, 1N) Example 52 8-chloro-6,7-difluoro-1-(oxetane-
3-yl)-1,4-dihydro-4-oxoquinoline-
3-Carboxylic acid ethyl ester (compound 236): 7 g of 2,3-dichloro-4,5-difluoro-benzoylacetic acid ethyl ester, 7.5 g of acetic anhydride, and 6 g of orthoformic acid ethyl ester were reacted at 140 t' for 40 minutes.

Excess reagent was distilled off under reduced pressure at the same temperature, and the mixture was allowed to cool. 4 residues
The mixture was dissolved in 0rn1 dichloromethane, added with 1.8 g of aminooxetane, and concentrated. The precipitate was dispersed in chloroform-diisopropyl ether and collected by filtration. This precipitate was dissolved in 70rnl of tetrahydrofuran, 640 ml of 60% sodium hydride was added, and the mixture was stirred at 60°C for 30 minutes. The solvent was distilled off, 150 rn1 of chloroform and 50 ml of water were added to the residue, and the layers were separated by shaking. The chloroform layer was treated with anhydrous magnesium sulfate and concentrated, and the precipitated colorless powder crystals were dispersed in chloroform-diisopropyl ether. This was collected by filtration to obtain 3.5 g of the above compound.

Melting point 139-141℃ 'HNMR (CDCL); 1.42 (t, J=7H
z, 3H), 4.42 (q.

J=7Hz, 2H), 4.82-4.91(m, 21
1), 5.14-5.24(+n, 21(), 6.
0f-6,10(m,1)1),8.24(dd,J
=10Hz, J=BHz, 1)1), 8.9
0 (s, II() Example 53 8-chloro-6,7-difluoro-1-(oxetane-
3-yl)-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid (compound 237): compound 236 90
0 mg, 1.5 ml of 2N sodium hydroxide aqueous solution
! Together with 16m1! of tetrahydrofuran, plus 6
The reaction was carried out at 0°C for 40 minutes. Add 200 mg of acetic acid and add 10
After stirring for several minutes, the mixture was allowed to cool, and the precipitated pale yellow powder crystals were collected by filtration and washed with ethanol and diisopropyl ether in this order to obtain 550 mg of the above compound.

Melting point 〉300℃') I-NMR (COCj!, -CD, OO, 10:I
) δ; 4.84-5.93 (m, 2) 1),
5.12-5.23 (m, 2) 1), 6.07-6
．． 18 (m.

1M), 8.2Hdd, J=10Hz, J=8H
z, 1 ft), 9.08 (s, 1) 1) Example 54 8-chloro-6-fluoro-7-(4-methylbiperazin-1-yl)-1-(oxetan-3-yl)-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid (
Compound 238): Compound 237 100 mg 5N-methylpiperazine 100 μ, dimethyl sulfoxide 300
mg was reacted at about 100° C. for 15 minutes. Leave to cool, add 4 ml of diisopropyl ether and shake, discard the upper layer leaving an oily precipitate, add 0.5rn1 ethanol to the oily residue, collect the resulting colorless prism product by filtration, add ethanol and diisopropyl ether in that order. Wash and apply the above compound 8
5 mg was obtained.

Melting point 211-212°C' H-NMR (MSO-d,) δ; 2.
25 (s, 3H), 2.40-2.54 (m, 4H
), 4.72-4.82 (m, 2l-1), 5.0
4-5.15 (m.

2N>, 6.04-6.15 (+n, IH), 7.
95 (d, J=12Hz.

1) 1), 8.98 (s, IH) Example 55 Compounds 239 and 240 shown in Table 15 were obtained in the same manner as in Example 54.

Below is the blank space Example 56 6.7-difluoro-1-(oxetan-3-yl)-
1,4-dihydro-8-methyl-4-oxoquinoline-
3-carboxylic acid ethyl ester (compound 241): 2.1 g of 2-chloro-3-methyl-4,5-difluorobenzoylacetic acid ethyl ester, 2.0- orthoformic acid ethyl ester, and 3.4rn1 of acetic anhydride, 130℃
The reaction was then carried out for 4 hours. The fraction was distilled off under reduced pressure to produce 20ml of benzene! added. At room temperature, 0.6 g of 3-aminoxetane was added, and the mixture was reacted at the same temperature for 15 hours. The solvent was distilled off, hexane was added, and the resulting solid was collected by filtration (approx.
．． 3g).

0.8 g of this solid, 2 g of potassium carbonate OJ, and 8 ml of dimethylformamide! The reaction was carried out at 110° C. for 200 hours. Distill the solvent and add 20ml of chloroform! After extraction with water and drying (MgSO,), the solvent was distilled off. Hexane was added, and the resulting solid was collected by filtration to obtain 0.44 g of the above compound as a yellow solid.

Melting point 157-165°C' H-NNR (CDC63) δ; 1.42 (t,
J=7. IHz, 3H).

2.41 (d, J=2.9Hz, 3H), 4.42
(q, J=7.1Hz, 2H).

4.90-5.20 (m, 4H), 5.61 (m,
IH), 8.08(d, J=9.3)1z, LH)
, 9.07(s,LH) Example 57 6.7-difluoro-1-(oxetan-3-yl)-
1,4-dihydro-8-methyl-4-oxoquinoline-
3-carboxylic acid (compound 242): compound 241 0.
44 g was dissolved in 10 liters of THF. 1 rnl of a 2N aqueous sodium hydroxide solution was added thereto, and the mixture was allowed to react under reflux for 5 hours. After distilling off the organic solvent, acidify with 1N-HCe,
The resulting solid was collected by filtration. 1 each of water, ethanol, and ether
The above compound as a light brown solid was washed with 0.0 mf'.
I got 20g.

Melting point 193-202℃') l-NMR (CDC1s) δ: 2.50 (d
, J=2.9Hz, 3H).

4, 92-5.23 (m, 4H), 5°77 (
m, 1tl), 8.17 (m, J=9.16Hz
, IH), 9,32(s,1)1) Example 58 7-(3-aminopyrrolidin-1-yl)-6-fluoro-1-(oxetan-3-yl)-1°4-dihydro- 8-Methyl-4-year-old xoquinoline-3-carboxylic acid (
Compound 243): Compound 242 100 mg and 3-aminopyrrolidine 8
5 mg was reacted in DMSOId at 80° C. for 2 hours.

After washing three times with diisopropyl ether and distilling off the solvent, it was solidified with ethanol and collected by filtration.

Washing with each of chloroform, ethanol, and hexane gave 38 mg of the above-mentioned brown compound.

Melting point 230°C or higher Carbonization Example 59 5-dimethylamino-6,7,8-)refluoro-1-
(Oxetan-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (Compound 244): 800 mg of Compound 23, 4.6 g of ethylamine, and 1.88 g of dimethylamine hydrochloride and toluene 1
8. Stirred at room temperature for 2 hours. After distilling off the solvent, the residue was subjected to column chromatography (SiO2,6 (L g, chloroform/acetone = 10/1)) to obtain 790 mg of the above compound as a yellow solid.

Melting point 130-134℃') I-NMR (C mouth cg3) δ; 1.3B (t,
, b7) 1z, 3H), 2.98 (s.

3) 1), 2.99 (s, 3tl), 4.38 (q
, J=7Hz, 21(), 4.9-5.0(m, 2H
), 5.05-5.15 (m, 2H), 5.55-
5.7(m, 11(), 8.41(s, 1)1) Example 60 5-dimethylamino-6,7,8-trifluoro-1-
(Oxetan-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound 245): 790 mg of Compound 244 was dissolved in 15 m of tetrahydrofuran.
j! 2.5- IN-sodium hydroxide aqueous solution was added dropwise under heating under reflux, and the mixture was allowed to react for 30 minutes. After distilling off the organic solvent, the mixture was made acidic (about ρ115.0) with 20% acetic acid, and the resulting solid was collected by filtration. Washing with water (5-x2) methanol (3-) ether (5 ml!x2) gave 433 mg of the above compound as a yellow solid.

Melting point 173-175℃' H-NMR (C port C1,) δ; 3.05 (s, 3
H), 3.06 (s, 3) 1).

4, 86-5.2 (m, 48), 5.65-
5.8 (m, 1)1), 8.69 (s.

1) 1) Example 61 5-dimethylamino-6,8-difluoro-7-(4-
Methylpiperazin-1-yl)-1-(oxetane-3
-yl)-1,4-dihydro-4-oxoquinoline-3
-Carboxylic acid (compound 246): Compound 245 1 (10 mg and 100 mg of 1-methylbiperazine were reacted in DMSO1rn! at 80°C for 1.5 hours. Ether 150rn1 was added, stirred, and then decanted, and the residue was dissolved in ethanol. , ether (10m1 each
) was solidified. The resulting solid was collected by filtration to obtain 55 mg of the above compound as a yellow powdery solid.

Melting point 186-187℃ 'H-11MR (CDC63) δ; 2.36 (s, 3
H), 2.54 (s, 4) 1).

2.99 (s, 3H), 3.00 (s, 3H), 3
J7 (s, 4H).

4, 85-4.95 (ff+, 2H), 5.0-
5.1 (m, 2) 1), 5.6-5.75 (m
, E), 8.59 (s, III) Example 62 Compounds 247 and 248 shown in Table 16 were obtained in the same manner as in Example 61.

Blank space below Example 63 6.7.8-) Lifluoro-1-(thietan-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (Compound 249): 2, 3 .4.1.32 g of 5-tetrafluorobenzoylacetic acid ethyl ester and 1 orthoformic acid ethyl ester
．． 25-1 and acetic anhydride 2.13- were reacted at 130°C for 1 hour. The fraction was distilled off under reduced pressure, and benzene 30- and 3
- Aminothiekune 623 mg ethanol solution 5ml
was added and stirred at room temperature for 12 hours.

The solvent was distilled off, hexane was added to the residue, and the resulting solid was collected by filtration to obtain 1.16 g of a white solid. This solid 1.16
g and 440 mg of potassium carbonate, 5 ml of dimethylformamide! The mixture was reacted for 30 minutes at 100°C. The solvent was distilled off, and the mixture was extracted with 50 ml of chloroform. The organic layer was washed with 10ml of water, anhydrous sulfuric acid, and dried over IJum.
Distilled away. Ether was added to the residue, and the resulting solid was collected by filtration to obtain 785 mg of the above compound as a pale yellow solid.

Melting point 160-164℃') I-NMR (CDCffi 3) δ; 1.43 (
t, J=7) 1z, 3H), 3.45-3, 6
5 (m, 2Fl), 3.8-4.0 (m,
2H), 4.42 (q, J=7Hz, 2H
), 6.0-6.2(m, 1t(), 8.08
-8.13 (m.

1) 1),, 8.86 (s, IH) Example 64 6.7.8-) Lifluoro-1-(thietan-3-yl)-1,4-dihydro-4-oxoquinoline-3-carvone Acid (Compound 250): Compound 249 750mg
was dissolved in 5rnl of tetrahydrofuran and heated under reflux.
2N-sodium hydroxide aqueous solution 3mj! Drop 10
Allowed to react for minutes.

The solvent was distilled off, the p value was adjusted to 15-4 with 20% aqueous acetic acid, and the resulting solid was collected by filtration.Water (3mj'X2), ethanol (
5rnl x 2), washed with ether (5mi' x 2),
690 mg of the above compound as a pale red solid was obtained.

Melting point 172-175°C' H-NMR (CDCgs) δ; 3.5-3.6
3 (m, 2H), 3.8-4.0 (m, 2) 1),
6.1-6.3 (m, IH), 8.1-8.15
(m, 1)l).

9,09 (s, LH) Example 65 6.8-difluoro-7-(4-methylpiperazine-1
-yl)-1-(thietan-3-yl)-1,4-dihydro-4-oxoquinoline-3-carvone 112 (compound 251): 25060 mg of compound and 100 mg of 1-methylpiperazine
mg were reacted in 1 rni of dimethylformamide at 80° C. for 40 minutes. The solvent was distilled off and 4rnf of ethanol was added to the residue. was added, solidified, pulverized, and collected by filtration to obtain 41 mg of the above pale yellow compound.

Melting point 204-206℃') I-NMR (CDCff,) δ: 2.38
(s, 3H), 2.58 (s, 4H).

3.44 (s, 411), 3.5-3.65 (m, 2
11), 3.85-4.0 (m, 2tl), 6.
05-6.15 (m, l1l), 7.94 (d,
Jll, 7Hz, 1tl), 8.99(s, I
H) Example 66 Compounds 252~ shown in Table-17 in the same manner as Example 65
I got 256.

Reference Example 3 - Synthesis of aminothietane: (1) 3-phthalimidoylthietane 14 Jg of 3-hydroxythietane, 41.8 g of liphenylphosphine, and 23.4 g of phthalimide were dissolved in 200 g of tetrahydrofuran, and azodicarboxylic acid was dissolved at room temperature. A solution of 27.8 g of diethyl ester in tetrahydrofuran was added dropwise over 1 hour. The reaction was further continued for 12 hours, and the solvent was distilled off. The residue was subjected to column chromatography (Si021 kg, chloroform/ethyl acetate = 5
0/1), the relevant fractions were collected, and the solvent was distilled off.

300-g of isopropyl ether was added to the residue, and the resulting solid was collected by filtration to obtain 9.6 g of the above compound as a slightly yellow solid.

Melting point 118-126°C' If-NMR (CDCf3) δ; 3.15-3
．． 25 (m, 2 old, 4.254.4 (m, 2N),
5.5-5.7 (m, 1) 1), 7.65-7
．． 95 (m.

4H) (2) 3-aminothietane 1.53 g of 3-phthalimidoyl thietane, 0.29 mj of anhydrous hydrazine! were reacted for 1 hour under heating under reflux in 30 mm of methanol. 40 mL of cold soaked ether was added and insoluble matter was filtered off. The filtrate was distilled off under normal pressure, and the residue was used as it was in the reaction.

Example 67 1-(1-diphenylmethylazetidin-3-yl)-
6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (compound 257
): Ethyl-2,4,5-)lifluorobenzoylacetate
) 4.92 g, orthoformic acid ethyl ester 5-1 acetic anhydride 8.5 In! , were reacted at 130°C for 1.5 hours. After distilling off the fraction, 50ml of benzene! and 4.77 g of 3-amino-1-diphenylmethylazetidine were added thereto and reacted at room temperature for 300 minutes. The solvent was distilled off, and 25 mj of dimethylformamide was added to the residue. and potassium carbonate 2
．． 8 g was added and reacted at 140°C for 200 minutes. The solvent was distilled off, and 50ml of hexane was added to the residue. was added, and the resulting solid was collected by filtration and washed with water (10-X2). Dissolved in chloroform 50rrf, dried (anhydrous sodium sulfate),
evaporate, add ether to the residue, collect the resulting solid by filtration,
9 g of the above compound as a pale orange solid was obtained.

Melting point 196-201°C') l-NMR (CDCf,) δ; IJ5 (t,
J=7Hz, 3H), 3J-3,5(m, 2H),
3.85-3.95 (m, 2H), 4.4 (q.

J=7Hz, 2H), 4.42(s, 1 old, 4.8
5-5.0 (m, LH).

7.05-7.15 (m, LH), 7.2-7.5 (
m, 10H), 8.28J5 (m, LH), 8.6
Hs, LH) Example 68 1-(1-diphenylmethylazetidin-3-yl)-
6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (compound 258): 5.0 g of compound 257 was dissolved in 120 g of tetrahydrofuran, and heated under reflux to 9 g of 2N aqueous sodium hydroxide solution. ．． htf! and 13.7ml of water! was added dropwise and allowed to react for 45 minutes. After cooling and evaporating the solvent, the residue was adjusted to pH 4 to 5 with 20% acetic acid water, and the resulting solid was collected by filtration. this,
Water (3mj2), ethanol (5-x3), ether (
4.0 mf) to remove the above compound as a pale yellow solid.
I got 6g.

Melting point 245-247°C') I-NMR (CDC1,) δ; 3.3-3.5
(+++, 2H), 4.85-5.0(m, 2
H), 4.43 (s, IH), 5.0-5.1 (m
, IH), 7.2-7.55 (m, IIH), 8
．． 25-8.35(m, 11(), 8.85(s.

LH) Example 69 1-(azetidin-3-yl)-6,7-difluoro-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (compound 259): 1.0 g of compound 258
, 100ml of tetrahydrofuran! 4N hydrochloric acid/dioxane (0.54%) was added under water cooling, and the mixture was stirred for 30 minutes. The solvent was distilled off and 30ml of ether was added! was added and 1.01 g of solid was collected by filtration. 200 mg of this solid was dissolved in 80 mg of methanol, 40 mg of palladium black was added, and the mixture was stirred at room temperature under hydrogen gas for one day. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give 10 mj of ether! The resulting solid was collected by filtration to obtain 100 mg of the above compound as a slightly yellow solid.

Melting point 250°C or higher Color decomposition 'H-NMR (DMSO-ds) δ; 4.5-4.7
(m, 4N), 5.65-5, 8 (m, II(
), 8.0-8.1 (dd, J=12.5)1z
, J=6.2)1z.

Ift), 8.29-8.36 (dd, J=8.
8) 1z, J=10.3Hz, LH)9, 0(s,
IH) Example 70 1-(azetidin-3-yl)-6-fluoro-7-(
4-Methylbiperazin-1-yl)-1゜4-dihydro-4-oxoquinoline-3-carboxylic acid (compound 260
): Compound 25960+ng and 1-methylpiperazine 80
80 mg in 500 mg of dimethylformamide.
The reaction was carried out at ℃ for 1 hour. After distilling off the solvent, add 5 ml of ethanol to the residue! was added to solidify and collected by filtration.

The mixture was washed with ethanol (5-) and ether (5-) to obtain 50 mg of the above compound as a pale yellow solid.

Melting point 220℃ or higher Carbonization' H-NMfl (DMSD-d,) δ; 2.2 (
s, 311), 2.5 (brs, 4H).

4.0-4.2 (m, 4H), 5.55-5.7 (m
, 1 old, 7.0 (d.

J=6.8) 1z, LH>, 7.94(d, J
=13.8Hz, III), 8.8(s, 1tl
) Example 71 Compounds 261~ shown in Table 18 in the same manner as Example 70
I got 263.

Below is the blank space Example 72 6,7-difluoro-1-(thietane-3-yl)-1
, 4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (compound 264): 2.4. ．． 2.46 g of 5-trifluorobenzoylacetic acid ethyl ester, 2.5 g of orthoformic acid ethyl ester
- and 4.2 rn1 of acetic anhydride were reacted at 130°C for 3 hours. The fraction was distilled off under reduced pressure, and 40% of benzene was added to the residue.
- and 1.3 g of 3-aminothiethane in methanol (20
ml') solution was added and stirred at room temperature for 12 hours. The solvent was distilled off, 20 ml of hexane was added to the residue, and the resulting solid was collected by filtration to obtain 2.5 g of a pale yellow solid. 2.5g of this solid
and 1 g of potassium carbonate, 1 Od of dimethylformamide
The mixture was stirred at 100° C. for 30 minutes. The solvent was distilled off, and the residue was extracted with 100% of chloroform and washed with 20% of water. After drying the organic layer (anhydrous sodium sulfate), the solvent was distilled off. The residue was subjected to column chromatography (SiO=1
0 g, chloroform/ethyl acetate = 8/1), the relevant fractions were collected, and the solvent was distilled off. 30 ether to the residue
rnl was added, and the resulting solid was collected by filtration to obtain 1.29 g of the above compound as a colorless solid.

Melting point 174-177℃' H-NMR (Cj'a) δ; 1.43 (
t, J=7Hz, 3)1), 3.54-3゜60
(dd, 9.77Hz, J=8.33) 1z, 2H)
, 3.90-3, 97 (dd, J=9.7711
z, J=9.27) 1z, 2tl), 4.42(
q, J=7Hz, 2tl), 5.57-5.75(m
, 1) 1), 7.41-7, 48 (dd, J4
1.23Hz, J=5.86Hz, IH), 8.
27-8, 35 (dd, J=10.25Hz, J
=8.79Hz, IH), 8.70(s, IN
) Example 73 6.7-difluoro-1-(thietane-3-yl)-1
,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound 265): 1.24 g of Compound 264 was dissolved in 30-
An aqueous solution of IJ (IN-hydroxide) was added thereto, and the mixture was allowed to react under heating under reflux for 20 minutes. The solvent was distilled off under reduced pressure, the residue was neutralized with 20% aqueous acetic acid, and the resulting solid was collected by filtration. This solid was mixed with water (2-), ethanol (5-X3),
The mixture was washed successively with ether (5rnlx2) to obtain 970 ml of the above compound as a pale yellow solid.

Melting point 251-256℃' H-NMR (CDCf 300 MSO-d s) δ
, 3.60-3.68 (dd.

J=8.3Hz, J=9.76Hz, 2H), 3
．． 97 (t, J=9.2811z.

2H), 5.85-6.05 (m, LH), 7.
84-7.91 (dd.

J=11.23Hz, J=6.35Hz, IH),
8.29-8.36 (dd.

J=8.79)1z, J=9.77Hz, LH), 9
．． 02(s, IH) Example 74 6-Fluoro-7-(4-methylpiperazin-1-yl)-1-(thiecun-3-yl)-1°4-dihydro-
4-oxoquinoline-3-carboxylic acid (compound 266)
: Compound 265 100mg and 1-methylpiperazine 1
00 mg was reacted in 0.5-dimethyl sulfoxide at 80° C. for 1 hour. After cooling, 20 d of ether was added, and the resulting solid was collected by filtration. Washing with ethanol (3mi'x3) and ether (3rdx3) gave 42 lbs of the above compound as a pale yellow powder.

Melting point 231-237°C' H-NMR (CDCes) δ; 2.39 (s, 3
H), 2.65 (t.

J=4.88Hz, 4H), 3J8(t, J=4.
88) 1z, 4H).

3, 56-3.63 (dd, J=8.3Hz, J
=9.77Hz, 2H).

3, 96-4.03 (dd, J=9.28Hz,
J=9.161(z, 2H).

5, 7-5.9 (m, IH), 7.04 (d,
J=6.8411z, LH).

8.06 (d, J=13.19Hz, 1)1), 8
．． 82 (s, 1tl) Example 75 Compounds 267~ shown in Table 19 in the same manner as Example 74
I got 272.

Below is the margin Example 7G 7-chloro-6-fluoro-1-(thietane-3-yl)
-1,4-dihydro-4-oxo-1°8-naphthyridine-3-carboxylic acid ethyl ester (compound 273): 2.8 g of 2,6-dichloro-5-fluoronicotinoyl acetic acid ethyl ester, orthoformic acid ethyl ester 2.5
- and 4.2 ml of acetic anhydride were reacted at 130°C for 3 hours. The fraction was distilled off under reduced pressure, and the residue was mixed with 40 ml of benzene and 1.3 g of 3-aminothiethane in methanol (20 ml).
) solution was added and stirred at room temperature for 12 hours. The solvent was distilled off, 20rnl of hexane was added to the residue, and the resulting solid was collected by filtration to obtain 3.02g of colorless solid. 2.95 g of this solid was dissolved in 40 ml of tetrahydrofuran, and 430 mg of sodium hydride (60% content) was added under water cooling. After stirring at the same temperature for 30 minutes, the mixture was stirred under heating under reflux for 4 hours. The solvent was distilled off, 20rnl of water was added to the residue, and 10ml of chloroform was added.
Extracted at 0d. The organic layer was dried (anhydrous sodium sulfate) and evaporated under reduced pressure. The residue was subjected to column chromatography (SiDz 10 g - chloroform/ethyl acetate = 8/1), the relevant fractions were collected, and the solvent was distilled off. Ether 30- was added to the residue, the resulting solid was collected by filtration,
1.11 g of the above compound as a colorless solid was obtained.

Melting point 157-161°C' H-NMR (CDCffi,) δ; 1.43
(t, J=7.2Hz, 3H).

3, 54-3.62 (dd, J=8.3Hz, J
=9.76Hz, 2N).

3, 86-3.94 (dd, J=9.28Hz,
J=9.76Hz, 28).

4.43 (q, J=7.2Hz, 2H), 6J5-6
．． 55 (m, 1tl).

8.45 (d, J=7.33Hz, 1N), 8.87
(s, IH) Example 77 6-fluoro7-(4-methylpiperazin-1-yl)-1-(thietan-3-yl)-1°4-dihydro-
4-oxo-1,8-naphthyridine-3-carboxylic acid (
Compound 274): 100 mg of compound 273 and 100 μl of 1-methylbiperazine in 10 mf of chloroform.
The reaction was carried out under heating under reflux for 3 hours. After cooling, the solvent was distilled off under reduced pressure. Ethanol 5-110% aqueous sodium carbonate solution 2- was added to the residue, and the mixture was stirred for 4 hours under heating under reflux. After cooling, the solvent was distilled off under reduced pressure, and the residue was neutralized with 20% acetic acid. The resulting solid was collected by filtration and ethanol (3mj!x2)
, and ether (3+n1x2) to obtain 82 mg of the above compound as a pale yellow powder.

Melting point 270-280°C H-NMR' (DMSO-d,) δ; 2.57 (
s, 3) 1), 3.03 (brs.

48), 3.35-3.55 (m, 2H), 3.9
-4.2 (br, 4H).

4.21 (brs, 2H), 6.1-6.25 (m,
IH), 8, 18 (d.

J=14.16Hz, 1)1), 8.87(s, IH
) Example 78 Compounds 275~ shown in Table 20 in the same manner as Example 77
I got 281.

The following margin procedural amendment (voluntary) June 29, 1990 1. Display of the case 1990 Patent Application No. 86706 2. Title of the invention New quinolone derivatives and antibacterial agents containing the same 3. Case of the person making the amendment Relationship with: Applicant name: Yukinaga Pharmaceutical Co., Ltd. 4, agent address: 1-3-6, Nihonbashi Ningyocho, Chuo-ku, Tokyo (postal address:
103) Address space above -:”11 6. Column 7 of “Detailed Description of the Invention” of the specification subject to amendment, Contents of the amendment (1) Change the line next to the table on page 181 of the specification and add a blank text. Insert.

"Example 79 7-((-)-)Lance-3-amino-4-methylpyrrolidin-1-yl)-8-chloro-6fluoro1-
(Oxetan-3-yl)-1°4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound 282): In the same manner as in Example 54, the above compound as a pale yellow solid was obtained.

Melting point 189-193°C' H-NMR (DMSO-d,) δ; 1,01
(d, J=6.8Hz, 3H), 2.1-2.3
(m, 1)1).

3, 2-3.7 ([11,4H), 3.85-4
．． 05 (m, 1)1).

4, 6-4.87 (m, 2H), 4.96-5
．． 18 (m, 2H).

5.9-6.1 (m, LH), 7.79 (d, J=
14) 1z, 1ft).

8.87 (s, 1) 1) J

Claims (1)

[Claims] 1. A quinolone derivative represented by the following general formula [I] or a salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1: means a hydrogen atom or a carboxy protecting group. R^2: means a hydrogen atom, a halogen atom, a hydroxy group, a lower alkoxy group, an amino group, an aralkylamino group, or a mono- or di-lower alkylamino group. A: Oxygen atom, sulfur atom or N-R^3 (here R^3
represents a hydrogen atom or an amino protecting group. ) means. X: means a hydrogen atom or a halogen atom. Y: means a nitrogen atom or C-R^4 (here, R^4 represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group). Z: means a halogen atom or a heterocyclic group containing at least one nitrogen atom as a heteroatom which may have a substituent. 2. An antibacterial agent containing the quinolone derivative or its salt according to claim 1 as an active ingredient.