JPS61243081A - Pyridonecarboxylic acid derivative, and ester and salt thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (X1 and X2 are halogen; R1 is lower alkyl, lower alkenyl or cycloalkyl; R2 and R3 are H, lower alkyl or cycloalkyl; k is 3-5; m and n are 0-2), its ester and its salt. EXAMPLE:7-( cis-3-Aminomethyl-4-chloro-1-pyrrolidinyl )-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride. USE:Medicinal drug for man and animal. It exhibits extremely excellent antibacterial activity, and is used as an antibacterial agent, medicine for fish, agricultural chemicals, food preservative, etc. PREPARATION:The compound of formula I can be produced by reacting the carboxylic acid of formula II (Z is functional group substitutable with cyclic amine derivative of formula III) or its ester, preferably a lower alkyl ester, with the cyclic amine derivative of formula III in an inert solvent, optionally in the presence of an acid acceptor at 10-180 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel pyrido/carboyflJ derivative, its ester, and its salt, which exhibit extremely excellent antibacterial activity.

More specifically, the compound of the present invention has the following general formula (wherein X
t, X2 are the same or different and mean a halogen atom,
RIcIc means an alkyl group, lower alkenyl group or cycloalkyl group, and R2+ and R3 are the same or different and are hydrogen atoms.

means lower alkyl IIh or cycloalkyl group,
k means an integer 3, 4 or 5, m and n are integers 0, 1
Or it means 2. ) Pyridonecarboxylic acid derivatives, esters thereof, and salts thereof.

In this Specification 4, the halogen atom means fluorine.

It means chlorine, bromine or iodine, lower alkyl group means an alkyl group having 1 to 6 carbon atoms, and lower alkenyl group means an alkenyl group having 2 to 5 carbon atoms. Furthermore, the term cycloalkyl group means a cycloalkyl group having 3 to 6 carbon atoms.

Salts of the compounds of the present invention include acetic acid, lactic acid, and succinic acid.

Methanesulfo/acid, maleic acid, malon i! 1. Salts with organic acids such as glucoheptacid, salts with amino acids such as aspartic acid and glutamic acid, or salts with inorganic acids such as hydrochloric acid and phosphoric acid, or sodium, potassium, zinc, and al. metal salts such as, or salts with organic bases.

The ester of the compound of formula [I] refers to the compound [! Lower alkyl esters such as methyl esters and ethyl esters, or known esters that are easily eliminated by hydrolysis or in vivo to form compound [I], such as acetoxymethyl esters and pivaloyloxy Methyl ester, ethoxycarbonyloxyethyl ester,
coli/Nisder, dimethylaminoethyl ester and 1-
It means 7minoethyl esters such as Pibe IJ-7nyledylester, 5-indanyl ester, 7talidyl ester, and the like.

Compounds of the invention may also exist as hydrates. Therefore, such forms are naturally included in the compounds of the present invention.

Since the compound of the present invention has an asymmetric carbon atom in its 7-position substituent, it can exist as an optically active form. Therefore, these optically active substances are included in the compounds of the present invention.

Furthermore, since the compound of the present invention has two asymmetric carbon atoms in its 7-position substituent, it can exist as different stereoisomers (cis type, trans type).

These stereoisomers and mixtures thereof are also included in the compounds of the present invention.

The method for producing the compound of the present invention will be explained below.

The compound of the present invention is a carbo/acid or its ester (preferably (lower alkyl ester) and the following general formula (in the formula N
It can be produced by reacting a cyclic amine derivative represented by (1R3+ k + m and n are the same as above) and isolating the product by a conventional method.

The reactive functional group represented by 2 in formula [■] includes halogen Q, arylsulfonyl, arylsulfinyl, lower alkylsulfonyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, arylsulfonyloxy, lower alkylsulfonyloxy, etc. Can be mentioned.

This reaction consists of ethanol, acetonitrile, dioxa/,
in an inert solvent such as dimethylformamide, toluene, xylem, 10-180°C, preferably it 20-15
This can be carried out by mixing and stirring the starting compound [■] or its ester and [I] at 0°C for 5 to 120 minutes, usually for 20 to 00 minutes.

The amount of starting compound [■] to be used relative to starting compound [11] or its ester is one equivalent or one excess. Depending on the type of Z functional group in the starting compound [■] or its ester, a substance such as hydrochloric acid may be produced as a by-product as a result of the reaction, so in such cases it is common to use an acid acceptor; 111] may be used in excess to serve as an acid acceptor.

Further, the starting compound [11] used in this reaction may be used in a protected form, and after the completion of the reaction, the protecting group may be removed by a conventional method.

The raw material compound [rl] or its ester can be produced by the method described in Reference Example 1, No. 32, or a method analogous thereto, or by the method described in the following literature, or a method analogous thereto.

2Hs starting compound [111] can be produced by the method described in Examples 2 and 10 or a method analogous thereto.

When the compound of the present invention obtained by the above method is an ester, it can be converted to the compound of formula [I] by hydrolyzing the ester moiety by a conventional method.

Furthermore, if necessary, the compound of formula [1] may be esterified by a Japanese method to lead to an ester of the compound of formula [■].

The compound of the present invention produced in this manner is isolated and purified according to conventional methods. Isolation, purification, salt form,
Although it is obtained in the form of a free carboxylic acid or a free amine, these can be mutually converted depending on the purpose to produce the compound of the present invention in the desired form.

Stereoisomers (cis, trans) of the compounds of the invention can be separated from each other by conventional methods, such as fractional crystallization, chromatographic separation, and the like. In addition, a raw material compound having a cis or trans configuration [111]
It is also possible to produce compounds of the present invention which have a cis or trans configuration, respectively, by using the above method.

Optically active forms of the compounds of the present invention can be separated by applying known methods.

The compound [■] thus obtained, its ester, and its salt are all new IT compounds. Especially compound [I]
and its salts exhibit extremely excellent antibacterial activity and are therefore valuable as antibacterial agents.

Compound [I] or a salt thereof can be used not only as a medicine for the human body and animals, but also as a medicine for fish diseases, a Q medicine, a food preservative, and the like. Moreover, the ester form of compound [1] is of course valuable as a raw material for the synthesis of compound [I], but in addition, when this compound is easily converted into compound [1] in vivo, compound [I] ]
It is an excellent compound as an antibacterial agent because it can exert the same effect as that of .

Next, data regarding the antibacterial activity of the compounds of the present invention are listed below.

(Left below) Antibacterial action ゛1 Experimental conditions table
(1), 7B (+981) t i own * % j; tF zhang τ
i'l set h most I to ζE171 stop chin next (+tc:l
＾）/-ntne completed.

S, a,: λtafilokov hλ-y ureus 20
9P JC-1 (S, aureus 209P J
C-1>.

S, py,: Streptococcus biodenes ^
65 (S, pyogenes AG5>.

E, c,: X: tx Riki T. Cori N1 old JC-
'1 (E, coll Ni1 (J JC-2)
.

P, a,: Pseudominus 71 Lugineau fNa1
2 (P, aerug+nosa hk 12>.

"Means the compound of Example 1-(2) (the same applies hereinafter)."

When the compound of the present invention is used as an antibacterial agent in humans, the dosage is determined according to age, body weight, symptoms, and route of administration.

Although it varies depending on the number of administrations, etc., it is recommended to administer 5n to 5g per day in one or several divided doses. The route of administration may be either oral or parenteral.

Although the compound of the present invention may be administered as a bulk powder, it is usually administered in a prepared form together with a pharmaceutical carrier. Good examples are tablets, capsules, and granules.

Examples include fine granules, powders, syrups, and injections. These formulations are prepared according to conventional methods. Examples of carriers for oral preparations include De/Pun and Mannitol.

Substances commonly used in the pharmaceutical field, such as cellulose and CMCNa, which do not react with the compound of the present invention are used. Injectable carriers include water, physiological saline,
Examples include carriers commonly used in the field of injections such as glucose solutions and infusions.

Next, the method for producing the compound of the present invention will be explained in more detail with reference to Examples and Reference Examples.

Reference example 1 7-chloro-1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-1,8-naphthyridine-3
-Carbo/ethyl acid: (1) 60 g of a known compound, 2,6-dichloro-5-fluorodicodinonitrile, is heated in O sulfuric acid at 65-75°C for 1 hour. Add water and further heat at 100 to 110°C for 2 hours to obtain 2,6-dichloro-5-fluoronicotinic acid 5.
Obtain 9.8 g. m, 9. 155-150℃■
45.2 g of this compound was treated with thionyl chloride, 2.
6-dichloro-5-fluoronicotinic acid chloride 47.
5 g are obtained as an oil.

(3) 47.5 g of this compound was reacted with diethyl ethoxymagnesium malonate in anhydrous ether, and 2
．． 6-dichloro-5-fluoronicotinoyl malo/diedyl acid is obtained as an oil. Add water and catalyst amount p-)
Add luensulfo/a and heat at 140°C for 2 hours.
40 g of ethyl 2.6-dichloro-5-fluorodicodinoyl acetate is obtained.

m, P, 09-70°C (4) 12 g of this compound was treated with ethyl orthoformate and acetic anhydride to obtain a 2-(2,8-dichloro-5-fluoronicotinoyl)-3-ethoxyacrylic layer, This compound was then reacted with cyclopropylamine and triethylamine in ethanol under chamber 4 to form 3-
Cyclopropylamino-2-(2,6-dichloro-5-
12.7 g of edyl fluoronicotinoyl acrylate are obtained.

m, 9. 129-130°C (5) 12 g of this compound was reacted with potassium t-butoxide in anhydrous dioxane to give 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-
10 g of ethyl oxo-1,8-naphthyridine-3-carboxylate are obtained. m, f), 170-178°C Reference Example 2 3-acedelaminomethyl-4-chloropyrrolidi/: (■) After reacting 3-azidomethyl-1-benzyl-4-hydroxypyrrolidine with thionyl chloride in chloroform, Separation and purification by column chromatography yields the following product.

Cis-3-azidomethyl-1-be/giru-4-chloropyrrolidine. IR spectrum (liquid film) am-': 2800
, 2100.740.700. mass spectrum m
/z:250 (M”), +58.91.NMR
Spectrum (CDC13) δ: 2.0 (I H, m
, Ca-H), 2.5-3.0 (2H.

m, C2-II), 24-3.4 (2H, m,
Cs-1-1) +3.3 to 3.7 (2) Iris, m, CH
2N5), 3.73 (2H.

s, Cll2Ph), 4.5(IH,m,
C4-H), 7.34 (5H, S, CaHs)
.

trans-3-azidomethyl-1-benzyl-4-chloropyrrolidine. IR spectrum (liquid 112) am-':
2800.2100.740.700. Mass spectrum m/z: 250 (M+), 158.9
1. NMR spectrum (CDC13) δ: 2.5
g (1)1, m, C3-II), 2.4
5-2.8 (2Il, m, C2-H), 2.8
~3.2 (2II.

m, Cs1l), 3.44(2H,m, C11
2N3), 3.00(211,br s, C
Tl2Ph), 4.05 (I II, m, Ca1-
1), 7.34 (51-1, s,
CeHs).

■ After converting the above compound (cis form) with sodium bis(2-methoxyethoxy)aluminum hydride,
By treatment with acetic anhydride and aqueous caustic soda solution, oily cis-3-acetylaminomethyl-1-be/di-4-chloropyrrolidine is obtained. IR spectrum (liquid film) cs-': 3300°2800, 1050.
700. Mass spectrum m/z: 200 (M”)
, 231.171.158.91. NMR spectrum (CDCl2) δ: 1.97 (3H, s,
C0CHa), 2.5-2.9 (2H, m, C
2-H), 2.72 (IH, m, C3-H), 2.
8-3.3 (2H, m, C5-H), 3.3
~3.7 (2N, m, CH2NHCOC
H3), 3.71 (2H, s.

CH2Ph), 4.48 (I H, m, C4-
H), 7.33 (5H,s, CaHs).

Similarly, from the above compound (trans form), oily trans-3-acetylaminomethyl-1-benzyl-4-
I got Chloropyrrolysine. IRX vector (liquid film) c
m-': 3300.2800.1G50.700°Mass spectrum m/z: 20[i (M”),
231.158°9+, NMR spectrum (CDC
l2) δ: 1.97 (311°s, COCl13
), 2.3-2.8 (3H, m, C2-H.

C3II), '3.05-3.75 (4H, m,
C112NIICOCII3゜Cs-1-1)
, 3.0 (21-1, s, Mountain Ph),
4.1 (11-1.

m, C4dl), 7.3 (5H,s,
C61-Is).

(3) The above compound (cis form) is hydrogenolyzed in ethanol in the presence of acetic acid and 5% palladium-carbon. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give an oily cis-3
-acetylaminomethyl-4-chloropyrrolidine is obtained.

Similarly, trans-3-acetylaminomethyl-4-chloropyrrolidine is obtained from the above compound (trans form).

Reference Example 3 Cis-4-fluoro-3-(N-methyltrifluoroacetylaminomethyl)pyrrolidine: (1) Cis-3-
Azidomethyl-1-benzyl-4-fluoropyrrolidine was reduced with sodium bis(2-methoxyethoxy)aluminum hydride and then formylated with formic acid-acetic anhydride to produce cis-1-be/zi-4-fluoro-3-formylamino. Obtain methylpyrrolidine.

(2) This compound was reduced with sodium bis(2-methoxyethoxy)aluminum hydride and then treated with trifluoroacetic anhydride to form an oily cis-1-benzyl-4-fluoro-3-(N-methyltrifluoro acetylaminomethyl)pyrrolidine is obtained. IR spectrum (liquid film) cxa-': 1G90°1+90. Mass spectrum m/z: 318 (M”), 241
゜158, 91. NMR spectrum (CDC1a)
δ: 3.08 (2H, s, CH2Ph), 5
．． 00(I H,br d, J =511-1z+
Ca-1-1), 7.30 (5H,s, C
oHs).

(3) This compound is treated in the same manner as in Reference Example 2-(3) to obtain cis-4-fluororl-3-(N-ethyltrifluoroacetylamitumedel)pyrrolidine.

Reference Example 4 4-Fluoro-3-(N-ethyltrifluoroacetylamitumedel)pyrrolidine: cis-3-acetylaminomethyl-endyl-4
- Fluoropyrrolidine was treated in the same manner as in Reference Example 3-■ to form an oily cis-1-benzyl-4-fluoro-3-(N
-ethyltrifluoroacedelaminomethyl)pyrrolidine is obtained. IR spectrum (liquid film) am-': 1
690. 1140. Mass spectrum m/z:
332 (M”), 255, 158. 91.
NMR spectrum (CDC13) δ: 5.10 (
I II, br d, J”00 11z,
Ca-1-1), 7.33(5H, S,
Cal1g).

Similarly, oily trans-
1-be/gi-4-fluoro-3-(N-ethyltrifluoroacetylaminomethyl)pyrrolidine is obtained. IR
Spectrum (liquid film) cs-': 1090. 119
0. 1+45. Mass spectrum m/z: 332
(M”), 255, 235. 9+. NMR
Spectrum (CI) CI+>δ: 1.20 (3H.t,
J=71-1z), 4. ,90(I II, br
d. J”52 11z. Ca-II),
7.34 (5tl.

s, Calls) - (2) The above compound (cis form) was treated in the same manner as in Reference Example 2-(3) to form cis-4-ful, 4-c+-3-(N
-ethyltrifluoroacetylaminomethyl)pyrrolidine is obtained.

Similarly, trans-4-fluoro-3-(N-ethyltrifluoroacetylaminomethyl)pyrrolidi/ is obtained from the above compound (trans form).

Reference example 5 trans-3-(acetyl-N-ethylaminomethyl)
-4-Fluoropyrrolidine: (trans-3-acetylaminomethyl-1-be/di-4-fluoropyrrolidine) in sodium bis(2-
After reduction with methoxyethoxy)aluminum hydride, acetylation was performed with acetic anhydride, and 41)
-(acetyl-N-ethylaminomethyl)-1-benzyl-4-fluoropyrrolidine is obtained. IR spectrum (
a112) cs-':1030, +450.
1420. Cis spectrum m/z: 278 (M”
), 258.158.91. NMR spectrum (CDC13) δ: 1.18 (3H, t
, J = 7 Hz, C]ItCI-■
3) 12.10 (311,s, COCl13)
, 3.01 (21!, s, C112r”h)
, 4.88 (III, brd, J = 5
0 11z, C4-1-1).

7.30 (5II, s, Ce1ls)
.

■This compound was treated in the same manner as in Reference Example 2-(3),
trans-3-(acetyl-N-ethylaminomethyl)
-4-fluoropyrrolidi/ is obtained.

Reference Example 6 4-Fluoro-2-trifluoroacetylamide/methylpyrrolidine: (I) 1-benzoyl-4-hydroxy-thi-proline methyl ester was mixed with hexafluoropropene-diethylamide/mixed reagent in the presence of propylene oxide. The reaction yields 1-benzoyl-4-fluoro-proline methyl ester.

m, 9.01-63°C.

■ Treat this compound with methanolic ammonia to
1-benzoyl-4-fluoro-prolinamide is obtained. m, 9.175-177°C.

(3) Reaction of this compound with sodium borohydride and acetic acid followed by treatment with trifluoroacetic anhydride yields 1-be/zi-4-fluoro-2-trifluoroacetylaminomethylpyrrolidine. Recrystallize from ether-n-hexa/.

m, 9.05-66°C.

(4) This compound was treated in the same manner as in Reference Example 2-(3) to produce 4-fluoro-2-trifluoroacetylamine/
Obtain methylpyrrolidine.

Reference Example 7 5-Fluoro-3-trifluoroacetylaminopiperid 7: (1) 4-Hydroxy-thi-proline methyl ester hydrochloride is benzylated with benzyl chloride in the presence of potassium iodide and sodium hydrogen carbonate.

After treatment of this compound with triethylamine and methanesulfonyl chloride, reaction with sodium azide yields oily 4-azido-1-benozyl-1-proline methyl ester.

(2) This compound is reduced with sodium bis(2-methoxyethoxy)aluminum hydride and then treated with trifluoroacetic anhydride to obtain 1-benzyl-2-hydroxymethyl-4-trifluoroacetylaminopyrrolidine.

(3) This compound was treated with diethylaminosulf-1 trifluoride to produce 1-benzyl-5-fluoro-3
- trifluoroacetylaminopiperidine is obtained. n-
Recrystallize from hexane.

m, f), 70°C.

(4) This compound is treated in the same manner as in Reference Example 2-(31) to obtain 5-fluoro-3-trifluoroacetylamide/piperidine.

Reference Example 8 3-acedelamino-4-fluoromethylpyrrolidine: (1) 1-be/di-3-hydroxy-4-hydroxymethylpyrrolidine was benzoylated with benzoyl chloride in the presence of triethylamine, and then reacted with diethylaminosulfur trifluoride. This gives 3-benzoyloxy-1-benzyl-4-fluoromethylpyrrolidine.

(21 Hydrolyze this compound with an aqueous solution of caustic soda.

Next, after treatment with methanesulfonyl chloride to bring about the presence of triethylamine, sodium azide is reacted to obtain 3-azido-1-benzyl-4-fluoromethylpyrrolidine.

(3) This compound is treated in the same manner as in Reference Example 5-0) to obtain 3-7cetylamino-1-benzyl-4-fluoromethylpyrrolidine. Recrystallize from ether-〇-hexa/. m, p, 92-94°C.

(4) This compound is treated in the same manner as in Reference Example 2-■ to obtain 3-acetylamino-4-fluoromethylpyrrolidine.

Reference Example 9 3-acetylaminomethyl-3-fluoropyrrolidine: (1) Reacting 1-benzyl-3-oxopyrrolidine with oxin sulfonylide to produce 5-benzyl-5-aza-1-oxaspiro[2,4 ] Obtain hebutane. b,
9.130-135℃/3.5mmHg, this compound was treated with 70% 0% fluoric acid to form 1-benzyl-3
-Fluoro-3-hydroxymethyl bi'1 to obtain lysine. b, p, 133~b S Spect Jl/m/
z: 209 (M”), 132.118.9.

(21 After treating this compound with methanesulfonyl chloride, reacting with sodium azide, 3-azidomethyl-
1-benzyl-3-fluoropyrrolidi/ is obtained.

(3) This compound was treated in the same manner as in Reference Example 5-(1) to obtain 3-acetylaminomethyl-1-benzyl-3
- Obtain fluoropyrrolidine. IR spectrum (liquid film) low': 3150.2800.1850.1550.
Mass spectrum m/z: 250 (M”)
, 249.230.172.9 Wataru.

NMR spectrum (CDCl3) δ: 1.75-2.
6 (2H.

m, C4-1-1), 1.98 (3H,s,
C0CIh), 2.35-3.08 (4H, m,
Ca-tl, C5-H), 3.54 (2II.

Q, J = 22 11z,
O)Iz, 'CIbNlIC0CI■3)
, 3.0G(21-1,s, Cl-1aP
h), 8.95 (I II, N11), 7.
3(51-1, s, CaHs) - (4) This compound is treated in the same manner as in Reference Example 2-(3) to obtain 3-acetylaminomethyl-3-fluoropyrrolidine.

Reference Example 10 3-dimethylaminomethyl-3-fluoropyrrolidine = (+) 3-Aminomethyl-1-benzyl-3-fluoropyrrolidine was reacted with a 37% formaldehyde aqueous solution and formic acid to form l-benzyl-3-dimethyl. Aminomethyl-3-fluoropyrrolidine is obtained. b, p, 12
4.5-1211.5℃/1mm1g, IR spectrum (liquid film) low': 28G0.1450.1
040.740.700°mass spectrum m/z:
21 (1,172,9+, NMR spectrum (CD
Cl5) δ: 1.75-2.85 (4H, m.

Ca-H,C5-)1), 2.3 (6H,s,
, NMez) , 2.36 (2H, d, J=251
iz), 2.78 (2H, d, J=24 Hz),
3.08(2H,s, CH2Ph), 7.3(5
)1°s, CaHs).

(2) This compound is treated in the same manner as in Reference Example 2-(3) to obtain 3-dimethylaminomethyl-3-fluoropyrrolidine.

Example 1 7-(3-Aminomethyl-4-chloro-1-bi1lidinyl)-1-cyclopropyl-6-fluoro'J-1,4-
Dihydro-4-oxo-1,8-naphthyridine-3-carbo/W1: (1) Cis-3-acetylaminomethyl-1-benzyl-4-chloropyrrolidi:/3.5g in ethanol 40
-1 dissolved in acetic acid 21 and 5% palladium-carbon 0
．． Add 3g and perform hydrolysis. After the calculated amount of hydrogen has been absorbed, the catalyst is filtered off. The filtrate was concentrated under reduced pressure, and the obtained cis-3-acetylaminomethyl-4-chloropyrrolidine was not dissolved in acetonitrile 501. To this, 7-chloro-1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-1,8-naphthyridine-3
- Carbo/ethyl acid 3.3g and triethylamine 8 1
was added and heated under reflux for 1 x 1 j. -After leaving it at room temperature overnight, filter out the precipitated crystals! ■Do. After dissolving the crystals in a mixture of water and chloroform and shaking, the chloroform layer is separated, dried, and the chloroform is distilled off. The residue was recrystallized from acetonitrile to give 7-(cis-3-acedelamizmedel-
4-chloro-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,
4.6 g of ethyl 8-naphthyridine-3-carboxylate are obtained.

m, p, 213-214°C.

(21 Add 20% hydrochloric acid 201 to 2.0 g of this compound and heat under reflux for 2 hours. The hydrochloric acid is distilled off under reduced pressure, and ethanol is added to the residue. The precipitated crystals are collected by filtration, and the 7-(cis-
3-aminomethyl-4-chloro-1-pyrrolidinyl)-
1.55 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbo/hydrochloride are obtained. m, 9. 243～
248°C (decomposition).

(3) Dissolve 1.0 g of this compound in water, add saturated aqueous sodium bicarbonate solution to 1) 117.5 to 8.
Cool to 0. The crystals were collected by filtration and recrystallized from a chloroform-methanol mixture to give 7-(cis-3-aminomethyl-4-chloro-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-
0.1 g of 1,8-naphthyridine-3-J Rubone a is obtained. m, 9.174-177°C.

Compounds of Examples 2 to 11 are obtained in the same manner as in Example 1.

Example 2 (117-() lance-3-acetylaminomethyl-4
-'/rollo-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,
Ethyl 8-naphthyridine-3-carboxylate, m, p
, 203-206℃.

(2) 7-(trans-3-aminomethyl-4-chloro-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carvone acid.

m, p, 222-224°C (decomposition).

Example 3 (1) 1-Cyclopropyl-6-fluoro-7-[cis-4-fluoro-3-(N-methyltrifluoroacetylaminomethyl)-1-pyrrolidinyl]-1. /1-dihydro-4-okine-1,8-leifthyridine-3-carboxylic acid ethyl.

m, l), 177-179°C.

■ 1-Cyclopropyl-6-fluoro-7-(cis-
4-Fluoro-3-methylaminomethyl-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyrinph-3-carbo/acid.

m, p, 230-240°C.

Example 4 (1) 1-cyclopropyl-7-[? /Susu--(N-
Ethyl trifluoroacetylaminomethyl)-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-ly-phthyridine-3-carboxylate.

m, p, 198-200°C.

1-Cyclopropyl-7-(cis-3-ethylaminomethyl-4-fluoro-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-omon-1,8-naphdilydi/-3- Carbo/acid diacid salt, m, 9.27
5-280℃.

Example 5 (1) 1-cyclopropyl-7-[trans-3-(N
-edyltrifluoroacedylaminomethyl)-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-
Ethyl dihydro-4-oxo-1,8-naphthyridine-3-carboxylate.

m, p, 150-153°C.

(2) 1-cyclopropyl-7-(trans-3-ethylaminomethyl-4-fluoro-1-pyrrolidinyl)-
6-fluoro-1,4-dihydro-4-oxo-1,8
-naphthyridine-3-carboxylic hydrochloride, m, 9.
208-270℃.

Example 6 (1) 1-cyclopropyl-7-[trans-3-(N
-ethylacetylaminomethyl)-4-fluoro-1-
pyrrolidinyl]-6-fluoro-1゜4-dihydro-4
-oxo-1+8-rifthyridine-3-carbo/ethyl acid, m, p, 105-107°C.

(2) 1-cyclopropyl-7-(trans-3-
ethylaminomethyl-4-fluoro-1-bi'I-lysinyl)13-fluoro-1,4-dihydro-4-oxo-
1,8-naphthyridine-3-carboxylic hydrochloride, m,
p, 2G8-270°C.

Example 7 (1) 1-cyclopropyl-6-fluoro-7-(4-
Fluoro-2-trifluoroacetylamide/methyl-l
-pyrrolidinyl)-1,4-dihydro-4-oxo-1
, ethyl 8-naphthyridine-3-carboxylate, m,
p, 203-204°C.

(2) 7-(2-aminomethyl-4-fluoro-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1
, 4-dihydro-4-oxo-1,8-lyphthyridine-3-carboxylic hydrochloride.

m, 9.218-229°C, (3) 7-(2-aminomethyl-4-fluoro-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1
,4-dihydro-4-oxo-1,8-naphthyridine-
3-Carvone 1g1I.

m, p, 268-275°C.

Example 8 (1) 1-cyclopropyl-6-fluoro-7-(5
-fluoro-3-trifluoroacetylamino-1-piperidinyl)-1,4-dihydro-4-oxo-1,8
-Ethyl naphthyridine-3-carboxylate, m, p,
205-206°C.

(2) 7-(3-ami/-5-fluoro-1-piperidinyl)-1-cyclopropyl-6-fluoro-1,4-
Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride.

m, p, 209-276°C.

Example 1) (1) 7-(3-acetylamino-4-fluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-o-1,8- Ethyl naphthyridine-3-carboxylate.

m, p, 270-274°C.

(2) 7-(3-amino-4-fluoromethyl-1-pyrrolidinyl)-! -cyclopropyl-fluoro-1
,4-dihydro-4-oxo-1,8-naphthyridine-
3-carboxylic hydrochloride.

m, p, 227-230°C.

Example 10 (1) 7-(3-acetylaminomethyl-3-fluoro-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3 -Ethyl carboxylate.

m, p, 214-215°C.

[2) 7-(3-Aminomethyl-3-fluoro-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro1
．． 4-dihydro-4-oxo-1,8-naphthyridine-
3-carboxylic hydrochloride.

m, p, 272-279°C.

(3) 7-(3-aminomethyl-3-fluoro-1-pyrrolidinyl)-1-cyclopropyl-〇-fluoro 1
,4-dihydroa-4-okine-1.8-su7chiridi/-
3-carbo/acid.

m, I), 229-232°C.

Example 11 (1) 1-cyclopropyl-7-(3-dimethylaminomethyl-3-fluoro-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3 -ethyl carboxylate, m, p, 17
9-180℃.

(2) 1-7 cloprobyl-7-(3-dimethylaminomethyl-3-fluoro-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

m, p, 174-177°C.

Claims (2)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, X_1 and X_2 are the same or different and mean a halogen atom, R_1 means a lower alkyl group, lower alkenyl group or cycloalkyl group, R_2 and R_3 are the same or different and mean a hydrogen atom, a lower alkyl group or a cycloalkyl group, k means an integer 3, 4 or 5, m and n mean an integer 0, 1 or 2). Pyridonecarboxylic acid derivatives, esters thereof and salts thereof. (2) The pyridonecarboxylic acid derivative, its ester, and its salt according to claim 1, wherein X_1 is a fluorine atom and k is 4.