JPH03218312A - Preventive and treating agent of microbism for animal - Google Patents

Abstract

PURPOSE:To obtain the title preventive and treating agent effective especially for animal respiratory infectious diseases, comprising a specific pyridonecarboxylic acid compound as an active ingredient. CONSTITUTION:The title preventive and treating agent comprising a compound shown by formula I [R<1> is (halo) alkyl, cycloalkyl or (substituted) phenyl; R<2> and R<3> are H, OH, alkoxy, halogen or CH2N (R<5>) R<6> (R<5> and R<6> are H, alkyl, alkenyl, etc.); R<4> is H, oxo, alkoxy, halogen, or CH2N (R<7>) R<8> (R<7> and R<8> are H or alkyl); X is H or halogen; Y is CQ (Q is H or halogen), N or Y is bonded to R<1> to form group shown by formula II (R<9> is H or alkyl); Z is H or NH2; (l) and (n) are 1 or 2; (m) is 0 or 1] or a salt thereof as an active ingredient. The preventive and treating agent is effective against mycoplasma infectious diseases and infectious KORIZA infectious diseases of domestic fowl, swine mycoplasma infectious diseases and haemophilus pleuropneumonia, bovine mycoplasma pneumonia, etc.

Description

[Detailed Description of the Invention] [Industrial Application Field 1] The present invention is an excellent preventive and therapeutic agent for bacterial infectious diseases for animals, particularly for preventing and treating respiratory infections in animals (e.g. caused by Mycoplasma). The present invention relates to an antibacterial agent for animals containing an effective pyridonecarboxylic acid compound as an active ingredient.

[Conventional technology 1] Various pyridonecarboxylic acid derivatives are already on the market as pharmaceuticals, and research to improve their antibacterial activity, spectrum, and pharmacokinetics (oral absorption, distribution, metabolism, and excretion) is currently being actively conducted. ing. However, compared to pharmaceuticals, development research for veterinary drugs is extremely limited in both quality and quantity.

As a prophylactic or therapeutic agent for veterinary bacterial infections related to quinolone compounds (especially antimycoplasma agents), for example, 6-fluoro-3-quinolonecarboxylic acid = 3 having a piperazinyl group at the 7-position (JP-A-62-22716 6-halo 3, which has a biperazinyl group at the 7-position and contains a nitrogen atom and an oxygen atom bonded to the 8-position to form a 6-membered ring.
- Quinolonecarboxylic acid (JP 60-184014), 6-halogeno 3-quinolonecarboxylic acid (PCT/ GB86/00258, WO86/066
3) etc. are known.

The pyridonecarboxylic acid compound used in the present invention has a completely different chemical structure from the compounds described in the above patent specifications.

[Problems to be Solved by the Invention] 4 Mycoplasma, which is a type of bacteria lacking a cell wall, is known to be the causative agent of respiratory infections, meningitis, epicarditis, arthritis, etc. in humans and animals. Tetracytalline and macrolide antibiotics are used to prevent and treat these drugs, but in recent years, bacteria resistant to these prophylactic and therapeutic agents, especially bacteria resistant to macrolide drugs, have been appearing with increasing frequency. Anti-mycoplasma agents that are effective against resistant bacteria are desperately needed. Accordingly, an object of the present invention is to provide an antibacterial agent for animals that has strong antibacterial activity and is effective against bacteria that are resistant to commercially available drugs, especially bacteria that are resistant to macrolide drugs.

[Means for Solving the Problems] Considering the above-mentioned circumstances, the present inventors searched for a substance that is effective against antibiotic-resistant mycoplasma and has a strong antibacterial effect. They discovered a pyridonecarboxylic acid compound with strong antibacterial activity and completed the present invention.

Furthermore, the pyridonecarboxylic acid compound included in the present invention has strong activity against microbial pathogens of livestock other than mycoplasma, and can be used as a prophylactic and therapeutic agent for various infectious diseases. It has also been found that it can also be used as a preventive and therapeutic agent for fish.

The present invention is based on such knowledge.

[Configuration 1 of the Invention] The compound of the present invention has the general formula [wherein Rl is lower alkyl, halo-lower alkyl, lower cycloalkyl, or optionally substituted phenyl;
and R3 are hydrogen, hydroxy, lower alkoxy, halogen, or CH2N(R6; R4 is hydrogen, oxo, hydroxy, lower alkoxy, halogen, or CH2N(R')R@;R' and R6 are hydrogen, lower alkyl, lower alkenyl or hydroxy lower alkyl, R7 and R8 are each hydrogen or lower alkyl; X is hydrogen or halogen; Y represents CQ or N or together with R1 forms =C-OCH2CHR'- Q is hydrogen or halogen), Rl1 is hydrogen or lower alkyl;
2 is hydrogen or NH2. Q is an integer of l or 2; m is 0
or an integer of 1; n represents an integer of 1 or 2] This is an infectious disease prevention and control agent for animals containing a pyridonecarboxylic acid compound as an active ingredient.

In the definitions in the formula, the term "lower" is used to represent a group having 1 to 8 carbon atoms (3 to 8 in the case of a cyclic structure) unless otherwise specified. "As a lower alkyl group,
For example, methyl, ethyl, proyl, isobrobyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl,
Examples include heptyl, octyl, etc., with methyl, ethyl, butyl, inbutyl, and tertiary butyl being preferred. "Lower cycloalkyl" groups include cycloprobyl, nclobutyl, nclopentyl, cycloheptyl, cyclooctyl, preferably cyclobutyl. Examples of "halo-lower alkyl" include fluoroethyl, chloropropyl, and fluorobutyl. "Lower alkoxy" includes methoxy, ethoxy, propoxy, butoxy, isobutoxy and the like. "Halogen" includes fluorine, chlorine, and bromine. Examples of "optionally substituted phenyl" include full phenyl, difur phenyl, and dichloro7enylnato.

Furthermore, the steric configuration of the substituents does not matter.

The pyridonecarboxylic acid compound represented by the general formula (1) used in the present invention may be in a free form or a salt form.

Salts include acid addition salts and salts with bases. Examples of acid addition salts include inorganic acid salts such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydriodic acid, and phosphoric acid, and organic acid salts such as acetic acid, maleic acid, fumaric acid, citric acid, and tartaric acid. Examples of salts with bases include salts with inorganic bases such as sodium, potassium, calcium, and ammonium salts, and salts with organic bases such as ethanolamine and N,N-dialkyl8-ethanolamine. It will be done.

The pyridonecarboxylic acid compound (I) of the present invention can be produced by the following reaction formula.

(I) (n)--→ (I) (L is OH such as halogen or sulfonyloxy
is a reactive group. ) The above reaction can be carried out in a solvent such as water, alcohol, ether, acetonitrile, dimethylsulfoxide (DMSO), dimethylformamide (DMF), or the like.

Although the reaction temperature may be low, a high temperature of about 200°C is desirable, preferably 80 to 120°C or about the boiling point of the solvent, and the reaction is preferably carried out for, for example, 1 to several tens of hours. To accelerate the reaction, triethylamine, pyridine, 1,8-diazabicyclo[5
．． A base such as [4.0] undecene-7 (DBU) may be added.

Further, as a nucleophilic reagent, a metal salt produced by the reaction of butyllithium, phenyllithium, etc. and amine (I[[) may be used. In this case, it is preferable to use anhydrous ether as the solvent and bromide or iodide as the halide.

When the reactive derivative is an ester of an alcohol rather than a halogen, a sulfonic acid ester such as p-toluenesulfonic acid ester (tosylate) is preferred. Toluene sulfonic acid ester can be dissolved in alcohol in the presence of sodium hydride in e.g. ether and a small amount of DMF.
-obtained by adding toluenesulfonyl chloride and heating under reflux.

It is also possible to use trimethylsilyl ether as the OH reactive group and substitute it with amine (nl). Furthermore, using ether as the reactive group of OH and using amine (M1) or its metal salt, HMPA
It is also possible to carry out the reaction inside.

Further, when R+, R2 or R3 is a substituted amino, the amine can be subjected to a deprotection reaction if desired. That is, the deprotection reaction is performed using a base such as sodium hydroxide or potassium hydroxide, or an acid such as hydrochloric acid or acetic acid, in a solvent such as water, a water-alcohol mixture, or a water-monoacetic acid mixture.
It can be easily carried out at temperatures ranging from room temperature to the boiling point of the solvent.

Carboxylic acid (I[) used in this reaction is JP-A No. 612
It can be manufactured by the method described in No. 252 and Japanese Patent Application Laid-Open No. 57-46986.

Moreover, amine (1) can be manufactured, for example, according to the following reference example. In addition, in these reference examples, '
H-NMR was measured using DSS as an internal standard when the solvent was D20, and TMS as an internal standard when the solvent was other than D20. Abbreviations have the following meanings: Tr, trityl; Me, methyl; Et
, -11-thyl; n-Pr, n-proyl; Et-OH,
Hydroxyethyl; Ac, acetyl; Boa,
t-butoxyluponyl; Ms, mesyl; Cbz, carpobenzoxy, etc.

[Reference Example] l1 Reference Example 1 (l R *, 5 S *)-1-methylaminomethyl 3-azabicyclo[3. :3.01 octane hydrochloride (■
l) (a) 2-cyclopentenecarboxylic acid methyl ester [Journal of Organic Chemistry (J
．． Org. Chem. ), Volume 35, Page 3352 (1970)] (1) 4.5g and 3-trityl-5
-xazolidinone (2) ll. 8 gg is dissolved in 100 ml of dry toluene and refluxed on an oil bath for 45 hours.

Toluene was distilled off, and the residue was subjected to silica gel column chromatography (methylene chloride: n-hexane = l: 2
v/v) and oil? Compound (3) 3.9g as a substance
get.

IR (Film): 1720. 1595cm-'
'H-NMR(CDC I3)+? (ppm
): 1.40-3.00 (IIH, m); 3.
67 (3H, s); 7.00-7.60 (15H,
m) (b) Add 2.23 g of compound (3) to 20% NaOH aqueous solution HmQ and 46 mQ of methanol, and reflux for 2 hours.

Methanol is distilled off, and the mixture is neutralized with acetic acid while cooling with water.

Extracted with methylene chloride, washed with water, Na2SO. Dry with
The solvent is distilled off. When the residue is crystallized with isopropyl ether, compound (4) with a melting point of 221-222°C (decomposition) is obtained.
Obtain 1.8 g.

IR (Nujol): 3100-2500. 16
85cm-''H NMRCCDCIs)a:1-2
0-3.05<IIH, m); 7.00-7.55(
15H, m); 10.9 (LH, br) (C) 7.7 g of compound (4) was dissolved in 77 g of dry tetrahydrofuran, and Et3N3. After injecting lmQ, cool on ice. CQ
CO■E t2. After dropping Om4, stir for 5 minutes.

Add 40% CH3NH2-methanol solution lo+IlQ all at once and stir for 30 minutes. Ethyl acetate and saturated brine were added, the layers were separated, and the organic layer was washed with saturated brine and washed with N
Dry over a2SOa and remove the solvent under reduced pressure.

Ethyl acetate was added to the residue, dried over Na2SOa, and the solvent was distilled off again to obtain 8.39 of the desired product (5) as an oil.

' H N M R ( C D C I 3) δ:
1.25-1.38 (3H, m); 1.52-1.7
0(3H, m); 1.97(IH, d, J=9.8H
z); 2.05 (IH, m); 2.80-2.95
(3H, m); 2.93 (3H, d, J=4.9Hz
); 6=49 (IH,brd,J=4.9Hz); 7
．． 14-7.45(15H,m)(d) Compound (5)
8.3 g was dissolved in 83 mQ of dry toluene under heating (40'O), 17 mQ of 70% sodium bis(2-methoxyethoxy)aluminum hydride in toluene solution was added dropwise, and the mixture was stirred at 80'O for 10 minutes. After cooling, the reaction solution was poured into ice water, extracted with ethyl acetate, washed with a saturated aqueous potassium sodium tartrate solution, washed with saturated brine, and extracted with Na
After drying with 2SOa and distilling off the solvent under reduced pressure, the compound (6
) 7.69 is obtained as an oil.

'H NMR (CDCIs) δ: l. 45-1.8
0 (6H, m); 2.02 (3H, m); 2.17 (
IH, d, J = 9.8Hz); 2.25 (IH, d,
J=9.8Hz); 2.37 (lH.m); 2.4
3 (3B, s); 2.53 (IH, d, J=10.7
Hz); 2.60 (IH, d, J=10.7Hz);
7.12 (3H, t, J=7.4Hz); 7.24
(6H, t, J=7.4Hz); 7.48 (6H, d
, J=7.4[{z)(e) Compound (6) 7. After heating (40°C) to dissolve h in 38 mQ of methanol and cooling to room temperature, add 38 mI2 of 10% hydrogen chloride methanol solution and stir for 1 hour. The solvent was distilled off under reduced pressure, ethyl acetate was added, the extracted crystals were collected by filtration, and the compound (I [[ -
1) Obtain 2.5g.

'H-NMR (D20) δ: 1.60 (IH, m);
1.76-1.81 (4H, +n); 1.92 (I
H, m); 2-64 (IH, m); 2.78 (3H
．． s); 3-09 (IH, dd, J=12.2Hz,
6-3Hz); 3.21 (IH, d.J=12.7
Hz); 3.29 (IH, d, J=12.7Hz);
3.50 (IH, d, J=12.7Hz); 3, 5
9 (IH, dd, J=12.7Hz, J=8-3Hz)
The following compound is obtained by the same procedure except that ethylamine is used instead of methylamine in step (C).

'H-NMRCD20, DSS) δ: 1.31 (3H
, t, J=7.0Hz); 1.54-1.98 (6H
, m); 2.62 (IH, m); 3.01-3.3
0 (6H, m); 3.51 (IH, d.J=12.5
Hz); 3.57 (IH, dd, J=l5 12.5Hz, J=8.5Hz) Reference example 2 (IR*, 2R*, 6S*)-2-methylamino 7-azabishikuchi [4.3 .0] Nonane hydrochloride (■2) (a) 4-oxo 4.5,6.7-tetrahydride indole [Journal of Organic Chemistry (J.Org. Chem.), Vol. 43, No. 354
Page (1978)] (7) 3.29, dry pyridine 1
5+++12. Mix 15TRQ of acetic anhydride and 360g of 4-dimethylaminopyridine and stir for 1 hour at room temperature. The solvent was distilled off under reduced pressure, and the residue was dissolved in methylene chloride, washed with IN hydrochloric acid and then with saturated brine, and dissolved in Na2
Dry with SO, and evaporate the solvent. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-n-hexane = 3:2 (v/v), the solvent was distilled off, a diethyl ether-n-hexane mixture was added, and the precipitated crystals were filtered. 3.89 of compound (8) is obtained.

'H NMR (CDCI3) δ: 2-16 (2H.
q, J. 6.8Hz); 2.50 (2H, t, J=6
．． 8Hz); 2.58 (3H, s); 3.22 (2
H, t, J = 6.8 Hz); 6.63 (1B, d, J
= 3.4Hz); 7.04 (IH, d, J = 3.4H
z) (b) Compound (8) 4.01? Dissolve PtO. in vinegar @80mQ. l. h and perform catalytic reduction at 6 atm.

The catalyst is filtered and the acetic acid is removed under reduced pressure. K, Go, in the remaining liquid
was added, extracted with ethyl acetate, and the solvent was distilled off.

Ethyl acetate is added to the residue, insoluble matter is filtered off, and the filtrate is concentrated under reduced pressure. Diethyl ether was added to the residue and the precipitated crystals were collected by filtration to obtain 1.8 g of compound (9).

凰H-NMR (CDC13) δ: 0.94-2.1
8 (8H, m); 2.01 (9/5H.s); 2.0
7 (6/5H, s); 2.54 (IH, m); 3.
37-3.64 (2H, m); 3.75 (2/5H,
m); 3.97 (LH, m); 4.16 (3/5
H, m) (c) DMSO in 200lllIl of methylene chloride
Add 13 Jm(l), cool to -78°C, and dropwise add 9.5ml of oxalyl chloride while keeping the internal temperature below -60°C. Add 10.0g of compound (9) to methylene chloride/l.
It is dissolved in OOmQ and added dropwise to the reaction mixture while keeping the internal temperature below -65°C. After stirring at the same temperature for 30 minutes, 55 mQ of triethylamine was added dropwise to the reaction mixture. Return to room temperature while stirring. Water was added to separate the layers, the organic layer was washed with saturated saline, and Na. Dry with SO. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.

Elute with ethyl acetate - 10% methanol-ethyl acetate,
Fractions containing the target product were collected and the solvent was distilled off to obtain 8.1 g of compound (10) as an oil.

' H N M R ( C D C l s ) δ
: l. 45-2.45 (8H, m); 2.04 (2H
,s); 2.13(IH,s); 2.87(2/3
H, m); 2.99 (1/3 H, m); 3.39~
3.70 (2H.m); 4.08 (1/3H, m)
;4.41 (2/3H, m) (d) Methylamine hydrochloride 4.0 in 70 mQ of methanol
4.5 g of a 20% KOH-methanol solution was added with stirring, and a solution of 7.1 g of compound (10) dissolved in 7 mQ of methanol was further added. Stir for 15 minutes at room temperature, add a solution of 5.0 g of sodium cyanoborohydride dissolved in 35 m of methanol (2), and stir for 3 hours.
Stir for a minute. 20% KOH-methanol solution 15.5m
After adding 12 liters of water and stirring, insoluble matter was filtered off and the filtrate
Concentrate to /3. Methylene chloride and saturated brine are added to the concentrated solution, stirred, and allowed to separate. The organic layer is dried over Na2SO4, and the solvent is distilled off. The residue was subjected to silica gel column chromatography 7E. 5% methanol methylene chloride ~l%
Elute with NH3-10% methanol-methylene chloride, collect fractions containing the target product, and distill off the solvent.
Compound (11) as an oil 6. get h.

'H-NMR (CDCI3) δ: 0.92-2.65
(8H, m); 2.00 (9/5H, s); 2.08
(6/5H, s); 2.45 (9/5H, s); 2
-46 (6/5H, s); 2-73 (IH, m);
3.35-3.65 (2H, m); 3.71 (2/5
H, m); 4.14 (3/5H, m) (e) Compound (
11) 6. Add 30 mQ of 2N hydrochloric acid to h, and stir and reflux for 12 hours. After cooling to room temperature, ethyl acetate was added to the reaction solution, stirred, and allowed to separate. The aqueous layer was concentrated under reduced pressure for 19 hours, an ethanol-benzene mixture was added to the residue, and the solvent was distilled off again under reduced pressure. Ethanol-ethyl acetate was added to the residue, the precipitated crystals were collected by filtration, and compound (I
[+-2) 4.817 is obtained.

'H-NMR (D20) δ: l. 34-1.56 (3
H, m); l. 95-4 (IH, m); 3.39
~3.67 (3H, m); 3.94 (LH, m) Reference Example 3 (lR*6R*7s*)-7-(N-acetyl N-methylamino)-3-azabishikuchi [4.4 .0] Decane hydrochloride (I[I-3) (II[-3) (a) 5--1-troisoquinoline (12) 6.0g
was dissolved in 120 mQ of acetic acid, PtO23. Add Og and perform catalytic reduction at 6 atm. The catalyst is filtered and the acetic acid is distilled off under reduced pressure. Toluene was added to the residue, and the solvent was distilled off again under reduced pressure.

A 10% hydrochloric acid-methanol solution was added to the residue, and the solvent was distilled off under reduced pressure. Toluene was added to the residue, and the solvent was distilled off again under reduced pressure. An ethanol-ethyl acetate mixture is added to the residue, and the precipitated crystals are collected by filtration to obtain 2.99% of compound (13).

' H N M R (D 2 0) δ: 1.
40-2.16 (9H, m); 2.35 (LH, m)
; 3.00 (IH, dt, J=12.7Hz.J=2
．． 9Hz); 3.19(dd.J42.7Hz, J=
3.9Hz, IH); 3-31 (LH, d.J=12
．． 7Hz); 3.45 (LH, m); 3.54 (I
H, m) (b) Compound (13) 3. The hg is suspended in 100 ml of methylene chloride and excess ammonia gas is introduced. The generated NH4CQ was filtered off, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was mixed with 6 m4 of methanol and 6 m of water.
1. After cooling to 0°C, di-t-butyl dicarbonate (Boc20) 2. h to meta/-r 311
112 is added dropwise. Stir overnight at room temperature;
The solvent is removed under reduced pressure. Add methylene chloride to the residue,
Wash with saturated brine, dry over Na2SOa, and remove the solvent under reduced pressure. Dissolve the residue in pyridine, add acetic anhydride,
Stir for 15 minutes at room temperature. The solvent was distilled off under reduced pressure, methylene chloride and saturated brine were added to the residue, stirred and allowed to stand for liquid separation, and the organic layer was diluted with Na, So. Dry with. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
Compound (14) 1.99% is obtained as crystals.

'H-NMR (CDCI3) δ: 1.21-1.82
(9H, m); 1.44 (9H.s); 1.99 (3
H. s); 2.16 (IH, m); 2.62 (18
, m); 2.85 (LH, m); 3.97 (2H,
m); 4.28 (IH, m); 5.32 (IH.b
rs) (c) Compound (14) 1.0g was dried DMF2
Dissolve in 0mQ, add 60% NaH170+++g (oil dispersion), and gradually heat until the internal temperature reaches 75°C.

After foaming has stopped, the mixture is cooled to 20°C under an argon atmosphere, 260 μα of methyl iodide is added, and the mixture is stirred at room temperature overnight. Add methylene chloride and water to the reaction mixture, stir, and separate the liquid by standing still.
The organic layer is washed with saturated brine and dried over Na2SO4.

The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: ethyl acetate 10-hexane).
The eluate containing the target product is collected and the solvent is distilled off under reduced pressure. Diethyl ether 101 hexane was added to the residue, the precipitated crystals were filtered off, and the filtrate was concentrated to dryness to give compound (15) 0.
get h.

'H-NMR (CDCI,) δ: l. 20-1.95 (
9H, m); 1.44 (9H, s); 2.10 (9/
4H,s); 2.15 (3/4H,s); 2.20
(IH, m); 2.57 (IH, m); 2.84 (
3/4H, s); 2.85 (IH, m); 2.88
(9/4H, s); 3.68 (1/4H, dt, J=
13.7Hz, J=3.5Hz); 3.91(IH,
m); 4.25 (LH, m); 4.39 (3/4H
, dt, J43.7Hz, J=3.5Hz) (d) Compound (15) 1.3g was added with 10% hydrochloric acid monomethanol solution 2
Add 0 mQ and stir at 50'O for 15 minutes. Further l
Add 0% hydrochloric acid methanol solution lOmQ and incubate at 50°C for 3
After stirring for 0 minutes, the solvent was distilled off under reduced pressure, a mixture of ethanol and ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration to obtain the desired product (I).
I[-3) 0.9b is obtained.

'H-NMR (D20) δ: l. 40-2.32 (
IOH, m); 2.13 (2H, s); 2.19 (I
H, s); 2.84 (IH, s); 2.90 (IH
, m); 2.97 (2H, s); 3.11 (LH,
m); 3.25 (LH, m); 3.45 (IH, m
); 3.92 (1/3H, dt, J=12.9Hz,
J=3.7Hz); 4.25(2/31,dt,
J=12.9Hz, J=3.7Hz)23 Reference example 4 (l S*.6R*)-2-oxo8-azabicyclo[4.3.0]nonane hydrochloride (■ 4) (a) 2- 4.5 g of cyclohexen-1-one was dissolved in 155+ u4 of dry toluene, 15.5 g of 3-trityl-5-oxazolidinone (2) was added, and the mixture was heated under reflux for 64 hours. Toluene was distilled off, and the residue was separated using silica gel column chromatography (n-hexane:ethyl acetate = 5:1 v/v) to obtain compound (16).
Obtain 8.5 g.

'H NMR (CDCIs) δ: 1.20 to -2.
05 (48,m); 2.20-2.70 (7H.m)
; 2.90-3.07 (LH.m); 7.08-7
．． 53 (15H, m) I R (C H C 13): 1710. 91
0cm-'(b) Compound (16) 5.0g of CF,C
Add 20 m4 of O*H and 20 ml of water, and stir at 90°C for 2 minutes. After cooling, CF. CO, H and water are distilled off, ethyl acetate is added to the residue, and the solvent is distilled off again. Add concentrated hydrochloric acid to the residue 10+++
12 and 50 mQ of water were added, and ethyl acetate was poured in for extraction. The layers are separated, the aqueous layer is collected, concentrated to dryness under reduced pressure, an ethanol-ethyl acetate mixture is added to the residue, and the precipitated crystals are collected by filtration to obtain 2.1 g of compound (n[-4).

'H-NMR(D20)δ: 1
．． 68 to 1.92 (2H.m); l. 97-2.1
5 (2H, m); 2.38-2.63 (2H, m);
2.89 (IH, m); 3.05 (IH, m);
3.22-3.43 (3H, m); 3.89 (IH,
m) Reference Example 5 (IR*, 23*, 63*)-2-methylamino 7-azabisic [4.3. O]nonane hydrochloride (I[I-5) (a) Add 4-oxo-4,5.6.7-tetrahydride (7XJ) to 25 mg of dry dimethylformamide.
．． Org. Chem. Vol. 43, No. l
8 (1978) 3541) Melt 5g and cool on ice for 60 minutes.
%NaHl. Add 8g (oil dispersion) and stir for 5 minutes. Subsequently, penzoyl chloride 629 is added dropwise and reacted for 10 minutes at room temperature. The mixture is poured into ice water, extracted with ether, washed with water, dried over Na2SO4, and the solvent is distilled off.

The residue was washed with ethyl acetate-isobrobyl ether to obtain compound (17) 6 as crystals with a melting point of 121-122°C.
．． Obtain 5 g (73%).

IR (Nujoor): 1690. 1650cm-
''H NMR (CDClx): l. 90-2.60
(4H.m); 3.15-3.27 (2H, m); 6
．． 58 (IH, d, J = 4.5Hz); 6.87 (L
H, d, J = 4.5 Hz); 7.40-7.80 (5
H, m) (b) 5 g of compound (17) was dissolved in 50 rnQ of acetic acid.
201 g of PtO2.H was added, and catalytic reduction was performed at 5 atm.

The catalyst is filtered and the acetic acid is removed under reduced pressure. NaHCO to the residue
, extracted with methylene chloride, washed with water, NaSO,
Dry with. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.

Elute with ethyl acetate to 5% methanol-ethyl acetate, collect fractions containing the desired product, and evaporate the solvent to obtain 6.3 g of compound (18) as an oil.

IR (Film): 3370. 1650, 14
35. 790cm-'' H N M R (C
D C Is) δ: 0.90 to 2.70 (9H, m)
; 3.20-4.50 (5H.m); 7.30-7.
50(5H,m)(c) 5.5 g of compound (18) was dissolved in 40 mQ of dry methylene chloride, 3.3 g of Et3N was added, and 3.3 g of methanesulfonyl chloride was dissolved in a colander under ice-cooling.
Add 76g and react for 15 minutes. N a H C
Add an Os aqueous solution and extract with methylene chloride. The organic layer was washed with water and diluted with Na2So. and evaporate the solvent. The residual liquid was subjected to column chromatography 7E using silica gel and eluted with methylene chloride to a 3% methanol-methylene chloride mixture to obtain compound (19) 5.
9 g are obtained as an oil.

IR (Film): 1520. 1420. 13
45. 1170. 790cm"''H-NMR (CDCl,) δ: 0.90-2.40
(9H, m); 2.60-2.90 (IH, m); 3
．． 04 (3H, s); 3.30-3-80 (2H.m
); 4.80-5.05 (IH, m); 7.35-
7.50(5H,m)(d) Compound (19) 5. Dissolve b in D M F 59, add water 5.9+++12 and N
Add 1.75 g of aN3 and react by heating at 120°C for 20 minutes. DMF was distilled off, ice water was added to the residue, extracted with ether, washed with water, dried over Na2So, and the solvent was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane=1:2 (v/v).
Elute with ~ethyl acetate 101 hexane = 1:1 (v/v) to obtain 1.3 g of compound (20) as an oil.

IR (Film): 2075. 1620. 14
10. 780 cm-'=28'H-NMR (CDCl3) δ: l. 20-2.40
(9H, m); 3.30-4. OO(4H,m); 7
．． 30-7.50(5H,m)(e) Compound (20)
Dissolve 1.39 in methanol 3Q++IQ, lO%P
Add 800 mg of d-C and perform catalytic reduction.

The catalyst was filtered off and the filtrate was concentrated under reduced pressure to obtain the compound (2 l
) is obtained as an oil.

(f) Add acetic anhydride 20+IlQ to compound (2l),
Warm on water bath for IO minutes. Acetic anhydride was distilled off, NaHCO3 was added to the residue, extracted with methylene chloride, washed with water, Na,
S.O. Dry with. The solvent was distilled off, and the residue was subjected to silica gel column chromatography and eluted with 10% methanol-ethyl acetate to obtain the target compound (22) as an oil.
Obtain 540 mg.

IR (C H C Qs): 1415. 161
5. 1665cm-''H NMR (CDCIs)
:l. 33-2.20 (9B, m); l. 94 (3H
, s); 3.60 to 3.78 (LH, m); 4.0
4-4.20 (2H, m); 4.40 (IH, brs
); 6.01 (IH, brs); 7.35-7.5
9(58,m) (g) Compound (22) 2g was dried D M F 40m
560 mg of 60% sodium hydride (oil dispersion) was added, and the mixture was stirred at 60 to 70°C for 1 hour and 30 minutes.

After cooling to room temperature, methyl iodide 1. Add 99 g dropwise and stir overnight. Ice water was added to the reaction solution, extracted with methylene chloride, washed with water, and extracted with Na2SO. and evaporate the solvent. The residue is subjected to silica gel column chromatography.

Extract with 5% methanol-ethyl acetate to 7% methanol-ethyl acetate, collect 7 fractions containing the N-methyl compound, and distill off the solvent to obtain 0.8 N-methyl compound as an oil.
Get hg. 3QmQ of concentrated hydrochloric acid to 0.80g of N-methyl compound
The mixture was stirred and refluxed at 130°C for 11 hours. After cooling, ethyl acetate and water are added to the reaction mixture, stirred, and allowed to stand still for separation. The aqueous layer is concentrated to dryness under reduced pressure, sodium carbonate is added to the residue, and extracted with methanol and methylene chloride. The extract is dried under reduced pressure, acetonitrile is added to the residue, the precipitated crystals are separated by filtration, and the filtrate is concentrated. By doing this, 0.25 g of the target product (nl-5) was obtained as an oily substance.

'H-NMR (D20) δ: 1.18-2.00 (9
H, m); 2.11 (3H, s); 2.19-2
．． 29 (2H, m); 2.83-2.95 (2H, m
) Reference Example 6 (IR*, 2S*, 6S*) 2-methylamino-8-azabishikuchi [4.3. O] monononane hydrochloride (27
) Me Me (a) Under water cooling, compound -31- compound (23) (35 g, 9.17 mmo (1) was added to trifluoroacetic acid (20 m4),
Water (20 ml2) was added to the resulting solution and stirred at room temperature for 5 minutes. After the reaction, excess water was added and the aqueous layer was washed with ethyl acetate. Sodium carbonate (30 g,
284 mm off), benzyl chlorocarbonate (1.72 g
,lo. lmmoQ) was added thereto, and the mixture was stirred at room temperature for 50 minutes.

The reaction solution was extracted with ether, the ether layer was washed with water, dried (MgSO*), the ether was distilled off under reduced pressure, and the by-product benzyl alcohol was further distilled off at 80°C under reduced pressure (kmHg). Crude product of compound (24) (1.6
7 g, 67%).

'H-NMR (CDCI,) δ: 1.58-1.82
(2H, m); 1.82 to 2.02 (2H, m); 2
．． 24-2.52 (2H, m); 2.73-2.95
(2H, m); 3.11-3.26 (LH, m);
3.31-3.57 (2H, m); 3.93-4.0
6 (LH, m); 5.03-5.21 (2H, m);
7.26-7.48 (15H, m) (b) Compound (24) (1.67g, 6.1mmol
) in anhydrous THF (17 mff) was cooled to -78°C and added to it L-selectride (LM in THF, 9 mff).
．． 2mQ, 9.2mmo+) was added at -70°C or lower. The mixture was further stirred at -78°C for 332 θ minutes, then returned to room temperature, and further stirred for 2 hours. To this reaction solution were added ice-cooled water (b++71) and 30% hydrogen peroxide (4 m (2)) at below 30°C. Then, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water and extracted with ether. This ether layer was washed with water, dried (MgSOs), and the ether was distilled off under reduced pressure.The residue was subjected to silica gel chromatography, and 1.4 g of the fraction eluted with toluene-ethyl acetate (2 + 13 v/v) was Compound (25) was obtained (83%).

'H-NMR (CDCIs) δ: l. 02~1.74(
7H, ■); 2.06-2.26 (LH.m); 2.
51-2-72 (lH.m); 3.28-3.63 (
4H, m); 3.90-4.05 (IH, m); 5
．． 04-5.23 (2H, m); 7.44 (5B, m
) (c) Compound (25) (1.40g, 51mmol)
, triethylamine (617+++g, 6.1 mmol
) under water cooling, methanesulfonyl chloride (641 mg, 5.6 mmol) was added to a methylene chloride solution (28 ml2), and the mixture was stirred at room temperature for 40 minutes.

This reaction solution was washed with an aqueous sodium hydrogen carbonate solution and water, and the methylene chloride layer was dried (Na2SO4).
Thereafter, methylene chloride was distilled off under reduced pressure to obtain 1.75 g of compound (26) as crystals (97%). mpl00-1
04°C0'H NMR (CDCIs) δ: 1.0
5-200 (6H, m); 2.20-2.30 (IH,
m); 2.75-2.90 (IH, m); 2.99
(3H, s); 3.30-3.65 (4H, m);
4.90-5.08 (IH, m); 5.14 (2H,
s); 7.03-7.40 (5H.m) (d) Compound (26) (1.4g, 5.9mmol), sodium azide (773mg, 11.9mmo+), DM
A mixture of F (20 ml2) and water (2 m4) was added to 12
The mixture was stirred at 0°C for 1 hour.

After the reaction, it was poured into ice water and extracted with ether. After washing the ether layer with water and drying (MgS O a), the ether was distilled off under reduced pressure. This residue was subjected to silica gel chromatography and eluted with toluene-ethyl acetate.
9+++g of compound (27) (35%) and 608
mg of compound (28) (51%) was obtained.

Compound (28): IR(neat)' 2090,
1695. 1410cm-''H-NMR (CDC
I. ) δ: l. 40-1.70 (5H, m); 1.9
0-2.10 (2H, m); 2.40-2.55 (l
H. m); 3.15-3.65 (51, m); 5.
09 (IH, d, J = lOHz); 5.18 (LH,
d. J=lOHz); 7.30-7.40(5H, m
)(e) Compound (28) (608mg, 2.02mm
ol), triphenylphosphine (637mg, 24m
mol), tetrahydrofuran (30+n4) and water (
A mixture of 3 ml2) was heated and stirred at 60° C. for 4 hours. After the reaction, tetrahydrofuran was distilled off under reduced pressure, diluted hydrochloric acid was added thereto, the aqueous layer was washed with ether, made alkaline by adding potassium carbonate, and extracted with ether.

After washing the ether layer with water and drying (MgSOa), the ether was distilled off under reduced pressure to obtain compound (29) (44h9, 80%)
I got it.

' H N M R ( C D C 1 s ) δ
: 1.03-1.78 (8H, m); 2.32-2.
45 (2B, m); 3.12-3.69 (5H, m)
; 5.11(l}I, d, J=13Hz); 5.1
5 (IH, d, J=13Hz); 7.24-7.74
(5H, ■) (f) Compound (29) C440my, 1. 6 mm
di-t-butyl dicarbonate (BOC20X422m9,
1.76 mmol) was added and left to stand at room temperature for 15 hours.

This was subjected to silica gel column chromatography (toluene:ethyl acetate = 4:1) to obtain compound (30).
(387+++9, 64%) was obtained.

'H-NMR (CDCl3) δ: l. 09-1.38
(IH, m); 35 1.44 (9H, s); 1.48-1.68 (4H,
m); 1.80-2.06 (2H, m); 2.30
~2.54 (LH, m); 3.18 ~ 3.63 (5H
, m); 4.30-4.48 (IH, m); 5.0
2-5.23 (2H.m); 7.15-7.43 (5
H, m) (g) Compound (30) (380m9, 1.0mmol
) in dimethylformamide (10 m(2) solution, 60
% sodium hydride (45 mg, 1.1 mmol) and methyl iodide (158 mg, 1.1 mmol) were added, and the mixture was heated and stirred at 60°C for 1 hour. After the reaction, this solution was poured into ice water and extracted with ether. This ether layer was washed with water, dried (MgSO,), and then the ether was distilled off under reduced pressure. This residue was purified by silica gel column chromatography (toluene:ethyl acetate = 1:1 v/v) to obtain compound (31) (381 mg.97%).

'H NMR (CDCa): 1.27-1.78 (
15H, m); 2.02 to 2-28 (IH, m); 2
．． 46-2.70 (4H, m); 3.17-3.58
(4B, m); 3.67-4.00 (IH, m);
4.99-5.27 (2H, m); 7.13-7.5
7(5H,m) (h) Compound (31) (375mg, 0.97mmo
l) in methanol (30 ml) with 10% Pd-C (
200+119) Hydrogenation was carried out at room temperature and pressure using a catalyst. After removing the catalyst, the solvent was distilled off under reduced pressure to obtain compound (In-6) (226+++g, 9
2%).

'H NMR (CDC(23)δ: 1.22-1.
74 (14H, m); l. 87-2.60 (4H, m
); 2.67-3.01 (7H, m), . 3.86
~4.06 (LH, m) [Example] Example 1 7-[(lR*.5s*)-1-methylaminomethyl-
3-Azabicyclo [3.3. O]octane-3yl]-
1-cyclopyl-6-fluoro1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (I-1) (II-1) (1-1) (I-1
) ■-Cyclopropyl-6,7-difluoro l,4-
Dihydro-4-oxo-3-quinolinecarboxylic acid (I
[l) 500 mg and (IR*.5S*)-
t-Methylaminomethyl-3-azabicyclo [3.3.
0] octane hydrochloride (I[[ − 1 ) 72011
19 was suspended in 10 mQ of acetonitrile, 1.3 ml2 of DBU was added while stirring, and the mixture was heated under reflux for 2 hours. After cooling, the precipitated crystals were collected by filtration and recrystallized from an ethanol-chloroform mixed solvent to obtain the compound (1-
1) Obtain 530111 g (yield 61%). Melting point=
229~231'C! .

Elemental analysis (%) C 22H 26F N 30 3'
1/5C 2H soH-1/2CO2・3/2H
．． Calculated value as O: C, 60.10; H. 6.
61; F. 4.16i N, 9.19 Actual value: C. 60.21;H. 6.33; F
．． 4.24; N, 9. 12 Examples 2 to 4 Reactions were carried out in the same manner as in Example 1 to obtain the compounds shown in Table 1.

39-l10 Example 5 ■-Cyclopropyl-6,8-difluoro-7-[(l
R*. 6R*,7S*]-7-methylamino 3-azabicyclo[4.4.0]decan-3-yl]1,4-dihydro-4-oxo-3-quinolinecarponylic acid hydrochloride (
I-5) (n-2) (m-3) (lR*.6R
*7s*)-7-(N-acetyl N-methylamino)-
3-Azabisic [4.4.0]decane hydrochloride (I[[
-3) 900mg and 1-cycloprovir-6.
7.8-1 Refluoro-1.4-dihydro-4-oxo-3-quinolinecarboxylic acid (I[-2) 1.09 was suspended in acetonitrile l OmQ, and DBU was added with stirring.
Add 1.2 g and heat under reflux for 12 hours.

The acetonitrile is distilled off under reduced pressure and the residue is dissolved in methylene chloride. Wash the organic layer with IN hydrochloric acid and saturated saline,
Dry and concentrate over Na2SOa. The residue was crystallized from ethyl acetate, the crystals were collected by filtration, and recrystallized from a methylene chloride-ethanol mixed solvent to obtain the acetyl form (I-5).
a) Obtain 860 mg.

Acetyl body (I-5 a) 860+++g 6
Add to rm17mQ of N salt and reflux overnight. After distilling off the solvent,
A mixed solvent of ethanol and toluene is added to the residue, and the solvent is distilled off again. The residue is crystallized from ethanol-ethyl acetate, the crystals are collected by filtration, and recrystallized from ethanol to obtain 93 mg of crystals of compound (I-5). Melting point: 280-28
2°C (decomposition).

Elemental analysis (%) CzsH*aCI2F2N, Calculated value as Os: c, 59.03; H, 6.03; N
．． 8.98; F, 8.12 Actual value: C, 58.91; H, 6.16; N
．． 8.93; F, 7.86 Examples 6 to 7 The reaction was carried out in the same manner as in Example 1 to obtain the compounds shown in Table 2.

=43 44-Example 8 7-[(lR*.2s*.6s*)-2-methylamino-8-azabisic[4.3.0]nonane-8yl1-
1-Cycloprobyl-6,8-difluoro-1,4-dihydro-4-oxo 3-quinolinecarponate hydrochloride (
1-8) Quinolone carboxylic acid (n2X163mg, 0
-58mmo1), amino form (m-6 X22
0mg, 0.86mmol), DBU (145mg,
0.95mtool) and acetonitrile (4ml2)
The mixture was heated to reflux for 2 hours. After the reaction, the solvent was distilled off, and the residue was subjected to silica gel chromatography and eluted with 5% methanol-methylene chloride.

The solvent of this fraction was distilled off under reduced pressure, and the residue was washed with isopropyl ether and collected by filtration to obtain 24511
Compound 9 (I-8a) was obtained (82%).

Compound (I 8 aX235+ng, 0.45mm
A methanol solution of hydrochloric acid (ol) was stirred at 80°C for 5 minutes. After the reaction, the solvent was distilled off under reduced pressure, and the residue was recrystallized from methanol-ethanol to obtain 182 mg of compound (1-8). Melting point = 290°C (decomposed).

Elemental analysis (%) C 2 2H 2 6 C Q F
Calculated value as N s O s·l/3H20: C. 57.45;H. 5.84.
(1. 7.7l; F, 8.26; N. 9.14 Actual value: C. 57.46; H, 5.72; C
Q. 8.10. F, 8.24; N. 9.15 Example 9 7-[(l R*,55*)-1-methylaminomethyl-3-azabicyclo[3.3.0]octan-3-yl 1-1-cycloprobyl-6-chloro- 1.4-dihydro-4-oxo-3-quinolinecarboxylic acid (I 9) ■ (n-3) (m-1) (r-
9) l-Cycloprobyl-6.7-dichloro-1.4dihydro-4-oxo-3-quinolinecarboxylic acid (I[-
3) Suspend 6.1 g and (l R*.5S*)-1-methylaminomethyl-3-azabicyclo[3.3.0]octane hydrochloride (I[[-1) 7.09 in acetonitrile 61rnQ D B U 13 while stirring.
Add 2 ml and heat to reflux for 64 hours. After cooling, the precipitated crystals were collected by filtration and washed with acetonitrile to obtain the desired product (1
-9) Obtain 5.8 g (yield 68%).

'H-NMR (CDCl3) δ: 1.16-1-86
(IOH, m); 2.58 (IH, m); 2.49
(3H.s); 2.67(2H,s); 3.29(
IH, dd, J=IO. lHz, 4.9Hz); 3.
36 (IH, d, J = 9.9Hz); 3.50 (IH
, m); 3.60 (LH, d, J=9.9Hz);
3.73(LH,dd,.l'10.1Hz.7.9H
z); 7.21 (1B, s); 8.37 (IH, s
); 8.76(IH,s) 47 Example 10 7-[(lR*.5s*)-1-methyltrialoacetylaminomethyl-3-azabisic[3.3.01
Octane-3-yl 1-1-cyclopropyl-6.8-
Dichloro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1-9a) 7-[(1.R*,5S*)
-1-methylaminomethyl-3-azabishikuchi [3.3
．． 0]octan-3-yl]-1-cyclopill-6
-Chloro=1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1-9) l. hg to dichloromethane lO
ml2 of the suspension, add 0.5 mQ of triethylamine and 0.5 mQ of anhydrous triflic acetic acid, and stir at room temperature for 45 minutes. The reaction mixture was cooled to θ°C, and 3.8 mQ of IM sulfuryl chloride dichloromethane solution was added dropwise and stirred for 5 minutes. cormorant. After adding ice water to the reaction solution and stirring vigorously, the lower layer is separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off.

The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain compound (1-9a) 270m
y (yield 2l%) is obtained.

'H NMR (CDCIs) δ: 0.88-1.8
8 (lOH.m); 2.54 (LH, m); 3.0
7 (1B, dd, J=9.8Hz, 5.2Hz); 3
．． 22 (3H, brs); 3.40 (IH, d, J=
9.8Hz); 3.48(IH, d, J■9.8Hz
); 3.58 (lH.d.J=13.9Hz); 3
．． 82 (1B, d.J43.9Hz); 4.07 (1
B, dd, J=9.8Hz, 8.2Hz); 4.30
(LH, m); 8.36 (IH, s); 8.91 (
IH,s) Example 11 7-[(IR*,53*)-1-methylaminomethyl-
3-azabicyclo[3.3.0]octane-3-yl]
-1-cycloprobyl-6,8-dichloro-1,4-dihydro-4-oxo-3-quinolinecarboxylic hydrochloride (
I-10) 7-[(l R*,5S*)-1-methyltripleoacetylaminomethyl-3-azabicyclo[3.3.
O]octan-3-yl]-1-cyclopropyl-6-
7 Luol 1,4-dihydro-4-oxo 3-quinolinecarboxylic acid (1-9a) 270mg, potassium carbonate 200mg, water 14raQ, methanol 7m
Dissolve in the solution of Q and stir at room temperature for 45 minutes and then at 50°C for 2 hours. Distill off methanol and dilute with 1N hydrochloric acid.
is set to 8, and pu is set to 7 with acetic acid, and the resulting precipitate is collected by filtration and washed with water and ethanol. The obtained crystals are suspended in 10 ml of ethanol, 10 mQ of IN hydrochloric acid is added to dissolve them completely, and the solvent is distilled off. The residue was dissolved in ethanol, diethyl ether was added, and the resulting precipitate was collected by filtration to obtain 120 mg of the desired product (Process 10).
yield of 50%). Melting point: 220℃ (min?) (recrystallized from aqueous ethanol) Elemental analysis (%) cg H 2 a C Q s N s
Calculated value as Os・79/50H20: C, 51.28; H, 5.70; C
Q. 20.64; N, 8.15 Actual value: C, 51.56; H, 5.46; C
4, 20.38; N, 8.42 Example 12 7-[(lR*.5s*)-1-(N-methyl-N trifluoroacetylaminomethyl)-3-azabishikuchi[
3.3.0]octan-3-yl]-1cyclopropyl-8-chloro-6-fluoro1,4-dihydro-4-oxoquinolinecarboxylic acid (I-18) (■ la) -51-7 -[(IR*,5S*)-1-methylaminomethyl-
3-Azabicyclo[3.3.0]octan-3yl]-1-cyclopropyl-6-7fluoro-■,4-dihydro-4-oxo-3-quinolinecarboxylic acid (I-1)
l. h in 50 ml of dichloromethane, add 0.72 mQ of triethylamine, and cool to -78°C. A solution of 0.71 mQ of anhydrous trifluoroacetic acid in dichloromethane 5++IQ was added dropwise to this, and the mixture was gradually warmed to room temperature. After stirring at room temperature for 30 minutes, it was cooled again to -78°C and 0.2 mQ of sulfuryl chloride in dichloromethane 5+n
Add Q solution dropwise, warm to room temperature, and stir for 10 minutes.

After adding ice water to the reaction solution and stirring vigorously, the lower layer is separated, washed sequentially with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off.

The residue was purified by silica gel TLC (developing solvent ethyl acetate:hexane = 2:L elution solvent ethyl acetate) to obtain the target product (I-1a) 360+n9 (yield 27%)
get.

' H N M R ( C D C 1 3 ) δ
: 0.91-1.89 (IOH, m); 2.50 (
IH, m); 3.20 (LH.m); 3.22 (3
H, bs); 3.50 (252 H, bs); 3.66 (2H, bs); 3.98 (
LH, t, J=8.5Hz); 4.31 (IH, m)
; 8.00 (IH, d, J=12.5}1z); 8
．． 91 (IH, s); 14. 52(IH,s) Example 13 7-[(IR*,5S*)-1-methylaminomethyl-
3-Azabisic [3.3.0]octane-3-yl]-1-cyclopropyl-8-chloro 67 1,4
-dihydro-4-oxo3=quinolinecarponohydrochloride (I-11) 7-[(IR*,53*)-1-(N-
Methyl-N trifluoroacetylaminomethyl)-3-
Azabishikuku [3.3.0]octane-3-yl]-1
- cyclopkubiru-8-chloro-6-7ru ro 1.4
-dihydro-4-oxo-3-quinolinecarboxylic acid (
1-1 a) 460111g to 48% potassium carbonate
0 mg, dissolved in a solution of 18 mQ of methanol and 18 mQ of water, and stirred at 50°C for 2 hours. Distilling off methanol,
Adjust the pH to 7 with IN monohydrochloric acid, collect the resulting precipitate by filtration, and wash with water and ethanol. The obtained precipitate was diluted with 10m ethanol.
After complete dissolution by adding 10 ml of IN hydrochloric acid, the solvent is distilled off. The residue is dissolved in ethanol, ethyl acetate is added, and the resulting crystals are collected by filtration.

This was recrystallized from aqueous ethanol to obtain the desired product (I-
1 1) 310+++9 (yield 76%) is obtained. Melting point: 233-235°C (decomposed).

Elemental analysis (%) C 22H zacQ2FO 3N s
' l/4C 2H. OH・2/5H. Calculated value as O: C, 55.25; H, 5.83; C
Q. 14.50; F, 3.88; N. 8.
59 actual measurement value: C. 54.98;H. 5.83;
CQ. 14.25;F, 3.86. N. 8
．． 96 Examples 14 to 18 Compound Nos. 1-12, I-13, I-14, and ■-16 were prepared using the method described in Japanese Patent Application No. 1-106948. -15 compound is patent application Hei-12669.
Produced by the method described in No. 5. Table 2 shows the structural formula, melting point, molecular formula, and coordination.

The reaction was carried out in the same manner as in Example 1, and the results are shown in Table 3. The compound shown is obtained.

Example 19 7-[(IR*,5S*)-1-methylaminomethyl-
3-Azabicyclo[3.3.0]octan-3yl]-5-amino-l-cyclopropyl-6.8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarponide hydrochloride (1 -1 7) ■-Amino-l-cyclopropyl-6.7.8 triple oro-1,4-dihydro-4
-Oxo-3-quinolinecarboxylic acid (II-4) 1.5g
and (IR*,5S*)-1-methylaminomethyl-3azabicic[3.3.0]octane hydrochloride (I[[-1
) was suspended in 15 ml of acetonitrile, 3.0 mQ of DBU was added with stirring, and the mixture was heated under reflux for 2 hours.

After cooling, 1.7 g of the resulting precipitate was suspended in ethanol,
After adding an excess amount of IN hydrochloric acid to completely dissolve the mixture, the solvent was distilled off under reduced pressure. Ethanol is added to the residue, and the resulting crystals are collected by filtration to obtain 1.7 g of the target product (I-17). Melting point: 260-262°C (decomposed).

Elemental analysis (%) C22H2yCQF2NaOs・H20
Calculated as: C, 54.26; H, 6.00; C
Q, 7.28; F. 7.80;N. 11.51
; Actual value: C. 54.38;H. 5.94; C
I2. 7.05; F, 7.27; N. 11.4
5 Example 20 7-[(IR*.5 S*)-1-methylaminomethyl-3-azabicyclo[3.3.0]octane-3iJ
L,]-1-cycloprobyl-6-7fluoro=1.4-
Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride (I-18) (II-5) (I[[-1) H (1-18) 7-chloro-1-cycloprobyl- 6-7 fluoro-1.
4-dihydro-4-oxo1,8-natiridine-3-
Carboxylic acid (I[-5) 1.0g and (IR*,5S*)
-1-methylaminomethyl-3=azabishikuchou [3.3
．． 0] Octane hydrochloride (I[I-I) 1.2 g was suspended in acetonitrile QrnQ, and D B
Add 2.29 U and heat to reflux for 2.5 hours.

After cooling, 1.1 g of the resulting precipitate was suspended in ethanol,
After adding an excess amount of IN hydrochloric acid to completely dissolve the mixture, the solvent was distilled off under reduced pressure. An ethanol-diethyl ether solution was added to the residual solution, the resulting crystals were collected by filtration, and the desired product (I-1
8) l. Get h. Melting point: 250-253°C Elemental analysis (%) C2+H2aC (2FNaps・l/2H20
Calculated value: C, 56.56; H. 6.10;.
CQ. 7.95;F. 4.26;N. 12.5
7 Actual measurement value: C. 56.61; H, 5.93. (
1, 7.99; F, 3.72; N. 12.5
6 Example 2l 7-[(lR*.5s*)-1-methylaminomethyl-
3-Azabishikuku [3.3.0]octane-3yl]-
1-ethyl-6.8-difluoro-1.4dihydro-4
-Oxo-3-quinolinecarponate hydrochloride (I-19) (II-6) (II1-1)
(1-19)l-ethyl-6.7.8-trifluoro-1.4-dihydro-4-oxo-3-quinolinecarboxylic acid (I[-6)1.09 and (IR*,5S*) -1-
Methylaminomethyl-3-azabicyclo[3.3.0]
Octane hydrochloride (In-1) 1.39 was suspended in 10 mQ of acetonitrile, stirred, and DBU6.
Add 5ml2 and heat under reflux for 3 hours. After cooling, add 10 mQ of acetonitrile and neutralize with acetic acid,
1.1 g of the resulting precipitate was suspended in methanol, and an excess amount of 1O% hydrochloric acid-methanol solution was added to completely dissolve it, and then the solvent was distilled off under reduced pressure. Dissolve the residue in methanol, add ethyl acetate, and recrystallize the resulting crystal 1.19 from methanol-ethyl acetate to obtain the desired product (■1 9).
Gets 710mp. Melting point: 238-240°C.

'H-NMR (D20) δ: 1.51 (3H, t, J
=6.8Hz);1.60-2.00(6H,m);
2.50 (1B, m); 2.81 (2H, s); 3
．． 36 (IH); 3.58 (IH, d, J = 10.7
Hz); 3.71 (IH, d, J=IO.7Hz);
3.95 (lH.m); 4.56 (2H, m);
7.82 (IH, d, J=12.7Hz); 8.72
(lH.s) Example 22 *10-[(IR,5S*)-1-methylaminomethyl-3-azabisic[3.3.0]octan-3-yl]-9-fluoro-3-methyl-7 -Oxo2,3-
dihydro-7H-pyrido[1.2.3de]-1.4-
Penzoxazine-6-carboxylic acid hydrochloride (■-20) (■ 7) (III-1) (I 20) 62 The compound shown is obtained.

9,IO-difluoro-3-methyl-7-oxo2.
3-dihydro-7H-pyrido [1,2.3del-1.
4-penzoxazine-6-carboxylic acid (If-7
) 1.0 g and (lR*.5S*)-1-methylaminomethyl-3-azabisic[3.3.0]octane hydrochloride (III-1) 1.29 in acetonitrile 20
Suspend in mQ and add D B U2. while stirring. Add OmQ and heat to reflux for 24 hours. After cooling, the resulting crystals 1.
After suspending 29 in methanol and completely dissolving it by adding an excess amount of 10% hydrochloric acid-methanol solution, the solvent was distilled off under reduced pressure. The residue was dissolved in methanol, ethyl acetate was added, and 1.1 g of the resulting crystals were recrystallized from methanol-ethyl acetate to obtain 560 mg of the desired product (I-20).

Melting point: 222-223°C (decomposed).

'H-NMR (CF.C02D) δ:l. 86-2.2
8 (9H, m); 3.07 (38, s); 3.07
(lH.m); 3.40 (IH,m); 3.78-
4.09 (3H, m); 4.51-4.92 (4H,
m); 5.22 (1B, m); 8.14 (IH, d,
J=lO. 7Hz); 9.39(IH,s)-63 [Applications and Formulation 1 The novel quinolone 3-carboxylic acid derivative represented by the general formula (1) of the present invention and its pharmaceutically acceptable salt are suitable for use in Durham-positive bacteria. It has broad antibacterial activity against , Durham-negative bacteria, and mycoplasma, and is effective against chewing mammals (e.g., cows, pigs, horses, sheep, goats, mink, mice, rats, hamsters, rabbits, guinea pigs, etc.), birds (e.g., chickens, turkeys, guinea fowl, quail, etc.), amphibians (e.g. frogs, newts,
It is used as a preventive or therapeutic agent for infectious diseases that occur in salamanders, etc.) and fish (e.g., crucian crucians, goldfish, medaka, etc.).

To give a more specific example, the compound (I) of the present invention is:
In poultry (chicken, turkey, guinea fowl, quail, etc.), mycoplasmosis, E. coli infection, chronic respiratory disease,
Salmofilosis, contagious avian influenza, Basullerella infection, etc.; in pigs, for example, E. coli diarrhea,
Hemo7 viral pleuropneumonia, sepsis, dysentery, salmonellosis, arthritis, atrophic rhinitis, mycoplasmal pneumonia, myometritis, mastitis, erysipelas, etc.: In ruminants (cows, sheep, goats, etc.), For example, Escherichia coli diarrhea, sepsis, bronchopneumonia,
Salmonellosis, hemorrhagic septicemia in cattle, Pasteurella infection, mycoplasmosis (bovine pneumonia, etc.), mastitis, etc.: In horses, for example, bronchopneumonia, calf elbow arthritis, salmonellosis; in amphibians, it is thought to be caused by bacteria. In fish, it is effective against nodules, vibriosis, streptococcosis, and fin red disease.

The antibacterial agent for animals containing the compound (1) of the present invention as an active ingredient may be used alone or together with a suitable carrier normally used for this type of drug, and optionally a disintegrant, a lubricant, a stabilizer, a flavoring agent. , colorants, preservatives, fragrances, etc. are added to powders, granules,
It can be used in the form of solutions, suspensions, premixes, capsules, emulsions, tablets, etc. As carriers, those commonly used for livestock drugs can be used, such as water, gum arabic, lactose, sucrose, talc, colloidal silica, soybean oil cake, starch, yeast, wheat, and defatted beans. , corn, bran, and other commercially available feeds.

Compound (I) of the present invention can be mixed with other veterinary drugs and used as a mixture.

The anti-mycoplasma agent containing the compound (I) of the present invention is
It is effective by any administration method such as oral, intramuscular injection, intravenous injection, or subcutaneous injection, but in the case of oral administration, the active ingredient is 0.
．． It is effective at 1-100 mg/kg/day, and can be effectively administered by dissolving or mixing it in drinking water or feed at a concentration of 5 to 1000 ppm.

For intramuscular injection, active ingredient 0.1-100m9/7
Effective at 2g/day.

Preparation Preparation Example 1 1000 ml of water21 Compound of Example 1 (I 1
) 500mg, 400mg, 200+++g, 100
+119 and 50m9 dissolved, 0.05% each
, 0.04%, 0.02%, 0.01% and 0.00
A 5% aqueous solution for drinking water administration is obtained.

Formulation Example 2 Compound (I2) of Example 2 in 1000g of feed 5
Mix 00+++g, 400mz, 200■, 100mg and 50+ng, respectively 500ppm, 40
0ppm, 200ppm, 100ppm and 50
Feed containing ppm of active ingredients.

As feed, commercially available feed may be used.

An example of a specific feed is corn 41.00% Milo as shown below.
25.00% soybean meal
l9. 10% fishmeal
8.0θ% oil 4
．． 00% sodium carbonate 1.40
%calcium phosphate 0.85%*)
Vitamin inorganic salt mixture 0.26% Methionine 0.10% Sodium chloride 0.29% *) Vitamin inorganic salt mixture: Vitamin A1 Vitamin D3, Vitamin E1 Vitamin B1, Vitamin B2, Vitamin B6, Vitamin B
12. Calcium pantothenate, nicotinamide, vitamin K, choline chloride, magnesium sulfate, iron sulfate, copper sulfate, zinc sulfate, cobalt sulfate, potassium iodide Formulation Example 3 Add the compound of Example 6 (1 -6) is dissolved in 500 mg, 250 +++ g or 125 mg to prepare a sample for oral administration at a concentration of 20, 10 or 5 yng/mQ, respectively.

b C = 3% gum arabic = 5% gum arabic: 3% gum arabic + 20rng/mQ Sodium citrate d: 20% ethanol e: 20m97mQ Sodium citrate f: Sodium carboxymethyl cellulose 109, Tween 8
08g, benzyl alcohol 18g, sodium chloride 1
8g, distilled water 2Ilg = 20% DMSO h: Distilled water 71- The antibacterial test results of the compounds of the present invention are shown below.

Experimental Example 1 In Vitro Susceptibility Test Results A liquid dilution method or an agar dilution method was used to test the susceptibility of each strain of bacteria. Among these, Mycoplasma gallisebuticum (Mycoplasma gallise
-pticumX PPLO medium supplemented with 12% horse serum), Mycoplasma
ynoviaeXl 2% pig serum, 0. Frey medium supplemented with βNAD), Mycoplasma hyopneumoniae
iaeX 0.5% lactalbumin added Hanks, 10
% horse serum, 0.5% yeast extract (25%)) was determined after culturing at 37°C for 7 days using the broth dilution method. Haemophilus balagarinarum
lus paragal linarum
moniae) (10% sheep defibrinated blood, 0.05% β
NAD addition heart infusionagar),
Salmonella typhimurium
typhimurium), E. typhimurium (E.
scher ic-72 hia coli), Staphylococcus aureus, Bordeitella proticepti (B ordetel
la bronchiseptica) (Muel
ler H inton agar(Difco)
), the agar dilution method was used. H.paragalinarum
and Haemophilus plulopneumoniae (H. pl
europneu+noniae), the determination was made by culturing at 37° C. for 20 hours under 10% carbon dioxide gas.

The four bacterial species using Mueller-Hinton medium were incubated at 37°C for 20
Judgment was made after culturing for ~24 hours. Pasteurella piscicid derived from fish
aXl. 5% salt addition heart infusion
agar) and Staphylococcus spp.
ococcus sp. ) (susceptible disk medium) is determined after culturing at 25°C for 40 to 48 hours.

The results of measuring the susceptibility of various compounds of the present invention to animal-derived bacteria are shown in Table-3.

The bacterial species used in the test were 11 bacterial species and 15 strains, including 4 bacterial strains of chicken origin, Mycoplasma gallisepticum (
M. gallisepticum) (MG), Mycoplasma synoviae (M.
S), Haemophilus balagarinarum (H. pa
ragallinarum) (H. pg), Escherichia coli (E. coli), and three pig-derived bacterial species (Mycoplasma hyopneumo-j- (M. hyop).
H. pneumoniae (Mh), H. pleuropneumon
iae) (H.pp), Pordetella bronchiseptica (B.b)
), two fish-derived bacterial species Basturella viscicida (P.p.
iscicida), Streptococcus (S tre
ptococcus sp), and three other bacterial species (E. colt, S. typhimurium)
, Staphylococcus aureus (S. aureus)
us)).

The compound (1) of the present invention was subjected to an in vitro susceptibility test. As control drugs, enrofloxacin (ERFX1 Bayer AG) and commercially available antibacterial agents such as tylosin (TS), chlortetracycline hydrochloride (CTC), and doxycycline (DOXY) were used, respectively.

The experimental results are shown in Table-5.

Compound (I) of the present invention all showed superior sensitivity compared to commercially available antibacterial agents. Especially mycoplasma (MG, Mh)
) showed higher activity than the control drug ERFX.

75 JP-A-3 218312 (22) JP-A-3 218312 (23) Experimental Example 2 MG, H. pg, and H. in viv for pp
o Experimental results Using each compound of the present invention, MG, H. pg and H. p
Experimentally, H.p.
After infecting p), forcible oral administration of each compound of the present invention,
Feed addition method and intramuscular injection were used.

M.G. and H. The chicks used in the experiments in [)g were Specif produced by Shionogi Pharmaceuticals (Aburi Laboratories).
IC pathology free (SPF) chicks were used.

Among them, 9 to IO day old chicks were used in the MG experiment, and 4 to 7 chicks were used in each group.
Using each feather (no sexing), a fresh culture of a field-isolated tylosin (TS) resistant strain of MG (cultured at 37°C for 1 to 2 days and diluted with a medium) was added to the right air of the chick. Approximately 10"IO' colony forming
It(CFU) was inoculated. Dosing was performed immediately after infection, and chicks were necropsied 5 to 6 days after infection.

H. pg (Haemo7ilus balagarinarum)
mophi1us paragallinarum):
Regarding infectious coryza causative bacteria), 28-day-old chicks (
Freshly cultured bacteria (bacterial solution diluted with medium) was inoculated into the nasal cavities of 4XlO'CFU/chicks (7 birds/group), and the compound was immediately administered by feed addition for 3 days. Necropsy of the chicks was performed 10 days after infection.

For MG, the effectiveness evaluation method is based on the degree of appearance of air sac lesions or {. PG was determined from the degree of nasal discharge and facial swelling during the administration period. Chicks used in the experiment (M
G1H. pg) were housed in cages and kept at 25°C±
The mice were kept at a temperature of 2°C until the end of the experiment.

H. pp [Haemophilus brulopneumonia (Ha
emophilus pleuropneumoni
ae), also known as Actinobacillus plulopneumoniae (Actinobacillus pluropneumoniae)
leuropneumoniae)]: the causative agent of swine haemophynolytic pleuropneumonia).
4 to 5 animals/group), and the infection method was H. pp(M-
1 strain) fresh culture (approximately 10'cFU/elvish) was added to
Immediately after, the compounds of the present invention (I-6, I-6,
ERFX) was administered once into the abdominal muscles at a dose of 10 mg/kg.

A necropsy was performed on piglet 1791 on the 6th day after infection. Efficacy criteria were determined based on respiratory symptoms during the test period, number of deaths, and degree of lung nodules at autopsy.

(1) Effect of the oral administration method of the compound of the present invention on MG (Tables 6 to 9) The compound of the present invention exhibited a superior effect to the control drug ERFX I; -12.

All of these compounds showed about twice or more efficacy than ERFX. Compounds that showed approximately the same efficacy as ERFX were I-13, 1-1, I-11 and I-14.
Met. In addition, other compounds such as commercially available antibacterial agents such as DO
It showed a better effect than XY.

JP-A-3 218312 (25) JP-A-3 218312 (26) JP-A-3-218312 (27) JP-A-3 218312 (28) Table-9A M. Effect test of I-19, ■-23 and I-16 by oral administration on chicks experimentally infected with G. gallisepticum Chicks = 9 days old SPF (no sex identification, 5 birds/group), used Strain: Mycoplasma gallisepticum (M
．． ga11isepticum) (field isolated, tylosin-resistant strain), inoculum amount: 3.5 x 103 CFU/chick, experimental method: Immediately after inoculating the bacteria into the right air sac of the chick, the drug was forcibly administered orally. A clinical examination of chick 85 was performed 5 days after infection.

Table-98 M. Effect test of I-19, ■-23, and Il6 by feed addition method on experimental intrapneumococcal infection of M. gallisepticum Chicks: Highline W36 male, 9 days old, strain used: Mycoplasma gallisepticum (M.gal) I
isept icum) (field isolated, tylosin-resistant strain), Inoculum amount: 6.6Xl03CFU/chick, Chemicals used: I-19, ■-23, ■-16, 86-ERFX1 Experimental method: Inside the right air pouch of the chick Immediately after inoculation of the bacteria, the drug was added to the feed for 3 days. The chick was examined at 6 days after infection.
Go on the first day.

(2) Effect of the feed addition method of the compounds of the present invention on MG (Table 10) The compounds of the present invention used in the experiment were I-14, Il5, ■-
16, I-6, Il9, ■-23, ■-16, ERFX as a control drug, and commercially available antibacterial agents Tylosin Premix (TSP) and CTC were used. I-6 is ER
It was about twice as effective as FX (15.6 ppm).

Other I-1 4, ■l5, I-19, ■-16 are ERF
It was almost the same as X (31.3 ppm). In addition, commercially available antibacterial agents (TSP, CTC) are llooppm (T
Even at 880 ppm (S P ) and 880 ppm (CTC), air sac lesions caused by MG could not be inhibited at all.

(3) Effects of injection of 114, I-15, I-16 and ERFX on MG (Table-11) I-14, ■-
Both I-15 and I-16 were able to completely inhibit air pouch lesions with a single intramuscular injection of 1,56+Ilg/kg. However, ERFX required 3.13 mg/h9 or more.

88 (4) H. I-6 against pg (chicken coryza)
Effects of feed addition method of and ERFX (Table-12) I-6
is 15.6 ppm, and ERFX is 7.8 ppm}l. The symptoms caused by pg could be prevented.

Table-12 1-6 and ERFX}{. Efficacy test use for pg During administration period (3 days) Number of positive birds/E R
F X 7.8ppmX tt
O/7 infection control 7/
7 Non-infected control 0/7 Bacterial strain used: 22l strain, inoculum amount: 4XlO'CFU/chick (
(intranasal inoculation), test chicks = 28-day-old SPF chicks (no sexing) (5) H. I- against pp (Porcine pleuropneumoniae)
Effects of intramuscular injection of 6, I-16, ■-23 and ERFX (Table 13) 5m9/kg or lOrny/J2gX One injection}{. No symptoms due to pp were observed in I-6 and I-16.

90 Table-13 I-6, ■-16 and ■-23 and ERF
X's H. H. pleu
ropneumoniae Intramuscular injection 5 m97 kg Compounds were injected intramuscularly (thigh muscle) at the same time as infection.

6) Toxicity Acute toxicity value (LD..) Compound ■ 6

Claims (6)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is lower alkyl, halo-lower alkyl, lower cycloalkyl, or optionally substituted phenyl; R^2 and R^3 are each Hydrogen, hydroxy, lower alkoxy, halogen or CH_2N(R^5)R^6;R^4
is hydrogen, oxo, hydroxy, lower alkoxy, halogen or CH_2N(R^7)R^8; R^5 and R
^6 is hydrogen, lower alkyl, lower alkenyl or hydroxy (lower) alkyl, respectively; R^7 and R^8
are hydrogen or lower alkyl, respectively;
Q is hydrogen or halogen; R^9 is hydrogen or lower alkyl; Z is hydrogen or NH_2; l is an integer of 1 or 2; m
is an integer of 0 or 1; n is an integer of 1 or 2] An agent for preventing or treating bacterial infections for animals, which contains a compound represented by the following or a salt thereof as an active ingredient. (2) The prophylactic or therapeutic agent according to claim 1, wherein the bacterial infection of animals is mycoplasma infection of poultry. (3) The prophylactic or therapeutic agent according to claim 1, wherein the bacterial infection of animals is an infectious coryza infection of poultry. (4) The prophylactic or therapeutic agent according to claim 1, wherein the bacterial infection of animals is mycoplasma infection of pigs. (5) The prophylactic or therapeutic agent according to claim 1, wherein the bacterial infection of animals is porcine haemophilus pleuropneumonia. (6) The prophylactic or therapeutic agent according to claim 1, wherein the bacterial infection of animals is bovine mycoplasmal pneumonia.