JPH013181A - Pyridonecarboxylic acid derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION OBJECTS OF THE INVENTION The present invention relates to novel pyridonecarboxylic acid derivatives that exhibit strong antibacterial activity, and thereby provides compounds useful as pharmaceuticals for treating bacterial infections. be.

Constitution of the Invention The pyridonecarboxylic acid derivative of the present invention is a pyridonecarboxylic acid derivative having the general formula and a salt or ester thereof.

In the above formula, R1 is a lower alkyl group, a halogeno-lower alkyl group, a cycloalkyl group, a lower alkoxy group, a lower alkylamino group, or has at least one Z of a lower alkyl group, a hydroxyl group, a lower alkoxy group, or a halogen atom as a substituent. R2 represents a lower alkyl group, R3 and R4 are the same or different and represent a lower alkyl group spanning hydrogen atoms, R5 represents a hydrogen atom or a lower alkyl group, and A represents a nitrogen atom. or represents a formula C-R6 group (in the formula, R6 represents a hydrogen atom, a methyl group, or a halogen atom), and when X---Y is a single bond, Y represents a methylene group, and represents a methylene group, a carbonyl group, an oxygen atom or a sulfur atom,
When x = y is a double bond, X and Y together form a cis-vinylene group.

In the general formula (Ia) (Ib), R1 is preferably a linear or branched alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, and isopropyl. , for example, a halogenoalkyl group having 1 to 2 carbon atoms such as difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, and 1 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. cycloalkyl groups, such as methoxy, ethoxy, n
- 1 to 3 carbon atoms such as propoxy and isopropoxy
linear or branched alkoxy groups having carbon atoms, such as alkylamino groups having 1 to 3 carbon atoms such as methylamino, ethylamino, n-propylamino, and isopropylamino, or phenyl groups, such as (09
m or p-)tolyl, (09m or p-)ethylphenyl, (0゜m or p-)propylphenyl, (O
smt or p-)hydroxyphenyl, (0,mtp-)methoxyphenyl, (Ot mt?,,: is p-
) ethoxyphenyl, (0, m or p-=) isopropoxyphenyl, (Q, mf or p-) chlorphenyl, (0, mi or p) fluorophenyl, (2,3
-, 2,4-, 2,5-, 2,6- or 3.4-) difluorophenyl, phenyl group having a C1-C3 alkyl group, hydroxyl group, 01-C3 alkoxy group or halogen atom as a substituent , R2 represents an alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, and R3 and R4 are the same or different and represent a hydrogen atom or, for example, methyl, ethyl, n-propyl. , is an alkyl group having 1 to 3 carbon atoms such as isopropyl, and R5 is a hydrogen atom or an alkyl group having 1 to 2 carbon atoms such as methyl or ethyl.
alkyl group, A is a nitrogen atom or a formula C-R6
group (in the formula, R6 represents a hydrogen atom, a methyl group, or, for example, fluorine, chlorine, or bromine) or a rogene atom. ), and when x---y is a single bond, Y represents a methylene group, X represents a methylene group, carbonyl group, oxygen atom, or sulfur atom, and when x---y is a single bond, In the case of a double bond, X and Y together form a cis-vinylene group.6 Preferred compounds in the general formula (Ia) or (Ib) include R1 in which R1 is an ethyl group, a fluoroethyl group, or a cyclopropyl group. group, 4-fluorophenyl group or 2,4-difluorophenyl group, R2 represents a methyl group, ethyl group, n-propyl group or isopropyl group, and the formula R4
>N- group represents an amino group, methylamine group, ethylamino group, or dimethylamino group, R5 represents a methyl group, A is a nitrogen atom or a C-R6 group (wherein, R6 is a hydrogen atom, a fluorine atom or a chlorine atom),
Formula x-y is ethylene group, formula -0-CH2- group 1 formula -〇-
C) Compounds having a T2-group or a cis-vinylene group can be mentioned.

Said general formula (I)? The compound can be converted into a pharmacologically acceptable salt or ester if necessary.

Such salts include acid addition salts of mineral acids such as hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, methanesulfonates, ethanesulfonates, benzenesulfonates. acid addition salts or sodium salts, potassium salts of organic acids, such as acid salts, p-toluenesulfonates, oxalates, maleates, fumarates, tartrates, citrates;
Examples include alkali metal salts or alkaline earth metal salts of carboxylic acids such as calcium salts. Examples of ester-forming groups include lower alkyl groups such as methyl, ethyl, n-propyl, inpropyl, n-butyl, and isobutyl, aralkyl groups such as benzyl, and acetoxymethyl and pivaloyloquinemethyl. lower aliphatic acyloxyalkyl groups such as 1-(ethoxycarbonyloxy)ethyl, lower alkoxycarbonyloxyalkyl groups such as 1-(isopropoxycarbonyloxy)ethyl, phthalidyl groups or (5-methyl-2
-Oxo-1,3-dioxolen-4-yl)methyl group, which can be easily converted into a carboxy group in vivo. In addition, the compound (Ia) or (Ib) of the present invention
) can also exist as a hydrate.

Examples of the compound having the general formula Da) or (Ib) of the present invention include the compounds shown in the table below and their pharmacologically acceptable salts.

Table I
CH3) 211s C2H5NH2 12N1 (CH3 13// NHC2H5 15 # n-C3
H7NH21s
1so-C3H7NH217-(!H2CH2F
CH3N)T218t
t C2H5NH219s -NH
CH5CH3NH22g
C2H5NH221-ocHy,
CHr, N)T222
C2H5NH224#
NHCH325NH
O2) 15 26 N
(CH3) 227
C2H5zu 22B
NHCH32g
NT(C
2T(53ON(CH3)2 31 〃n C3)! 7NH2
34 #tt
// NHCH335[C2H5 36〃#N(CH3)2 37 # #
C2H5NH238NHCH3 3g # #
NHCH335, N(CH3)2 41” n-C3H7N)T242
tt #l5CI”
3H7NH243C-HCH3C)T3
NH244s C2H5N
H245iy C2H5CH3NT (246
s C2H5NH247〃
Enter CH5NH2481/
II NHCH34B
NHC2H
550C-H△ CH3N)TC3H7n51
z'NH
C3H7152N(CH3)2 53 C2
H5NH2541/
NHCH355NHCH3 56# N(
CH3) 257 #
n-C3H7NH258# 1so-C5
H7NH259II -CH2CH2F
CH5NH21iQ
C2H5NH261・-NHCH3CH
3NH2 62C2H5hm2 63 # -0CH3CH3N
H264C2H5NH2 66NHCH3 67NHC2H5 69 # # C
2H5NH270, s s
NHCH37i 〃
s l state C2H572#
s〃N(CH3)273.
11 #n-C3H7NH
2I4 〃1so-C3H7
NH275##
NHC) T! .

77
NHCH335s N
// N(CH3)279
s s C2H5
NH280s
NHCH381# I'
NHCH363
s // n-C3H7N
R1R2〃iso C3H7NR2 R5C-F CH3CH3NH2g5C-
FCTha C2H5NH287C2H5CH
5NH2 88C2H5NH2 90NHCH3 91# #
NHCH335N NHC3H7n 93 〃N)TC3H71 94N(CH3)2 95 1' C
2H5NH296# N)IC)(3
97'NHC2H5 98#
N(CH3)299 l
nC3H7NH4I 00 #
#1so-C3H7NH2I01
-CH2CH2F CHy,
NH4I g 2
C2H5NH2103N
-NHCH3CH3NH2104 C-
F -NHCH3C2H5NH2105-0C
H3CH3[2 106// C2H5NH2107〃-◇
XF CH3NH2 toa tt
tt NHCH.

109 tt
NHC2H5110tt
// // N(C
H3) 2111' 〃C2
I (5Nr smell 112,,
tt pi 'MH
CH31131/NHC2H5114
/l tt N(CH3)2
115 7'n
C3H7NH4I 18 1/
＃ ＃NHCH
3119〃 〃 〃
NHC2H5120tt
〃N(CH3)2121
N C2H5NH2i 23
rl
lT(C2H5124#7/
s N(CH3)2125
n-C3H7NH21261so-
C3H7NH4 I 27 C-Cl CH3CH3NH
2128II C2H5NI (2129#
C2H5CH3NH2130〃C2H5NH
2 132〃 Abon CH3133NHCH3 134N(CH3)2 135 y C2H
5NI (2136NHCH3 137” C2H5, 3a
N (CH3) 2139 tt -C
H2CH2F CH3zu 2140 C-
Cl-42CH2F C2H5NT141
N-NHCH3CH3NH4I
42 C2
H5NH2143-0CH5CH3NH4 I 44
C2H5NH4I 45 5-GPC) 13NH2 146NHCH3 147s NHCH3 14B
N(cHs)2149
C2H5NH4I 50

NHCI(5151NHC21(5 152N(CH3)2 154
NHCH3tss
#NHC
H31ss z s
#N(CH3)2157
C2H5NH2159#
NHCH3 160# N(CH3)2 1 B I C-Br C2H5CH
3NH2162at C2H5NH216
3 people 4 N) 12 164
NHCH,.

165 # #
# NHCH3166C2I (5NH
2 167NHCH3 168n NBC21 (5169'
Q(2CH2F CH3NH2170C2H
51 笥2 1 ryo 1 -NHcH3CH3NH
2172C2) Is 2 173+FCH3 2 174
NT(C1(3175tt)
NHC2H51
76 CBr -◇XF C2H5NH2177
II #NH
CH3180# # #
NHCH3181#s
# NHCH3182at
C2H5NH21g 3 //
sNHCH3
184NHC2H5 185C-CH3C2H5CH5NH2186#
# C2H5NH2187〃
Enter CH5NH2188〃at
NHCH3189II
#NHCH3190#
C2H5NH2191'
II NHCH3192n
s NHC2
H5193# -CH2CH2F CH3N
H2194 C-CH3-CH2CH2F
C2H5NH2195-0CH3CH3NH2 196C2H5NH2 198#
N) TCH3199# NHCH3 100C2TT5 NH2201NHCH
3 202#
NHCH3104NHCHv.

205
NHCH3207#s
NHCH3208#
N.H.
CH3 second coat 2 # N NHCH33NHCH3 4N(CH3)2 5 s C2H5NH2 6# // NHCH3 7II NHCH3 1N(CH3)2 g s n-C3H7NH2 10〃1SO-C3H7NH2 11tt C2) I5 CH3 old 213
tt C2H5NH414%, -CH3CH3NH2 15#
NHC) I316
NHCH31y
s N
(CH5') 218 s
C2H5NH21g
HHCH-
.

20
NHCH31tt N(CH3
)2 22 # C2H5 port 3
NH224tt C2H5NH2 25CH3CH3NH2 26tt 〃'NHCH
327NHCH3 29 a C2
H5NH230NHCH 31# #NHC2H5
33 s s n
-C3H7NH234#s
1scr-C5H7NH2υ 37 # #
NHCH338##
II NHCH338#
#N (CH3)
240/l
C2H5NH241# #
l/NHCH342#
s NHC
H338 # # #
N(CJ)2 The novel compound having the general formula (Ia) or (Ib) of the present invention can be produced, for example, according to the reaction formula shown below.

(Ia) )OH base In the above formula, B1. R2, R5, R4, R5, R6, X
and Y has the same meaning as defined above, R7 represents a hydrogen atom or a lower alkyl group such as methyl or ethyl, and 2 represents a nitrogen atom such as fluorine or chlorine.

That is, the novel compound (Ia) of the present invention is the compound (I
t) or boron fluoride chelate compound (V) derived from (N) and an amine compound (I[[
) in the presence or absence of a deoxidizing agent and in the presence or absence of a solvent.

The solvents used in this reaction are dimethyl sulfoxide, dimethyl formamide, hexamethyl phosphoric triamide, dimethyl acetate (25).
Aprotic polar solvents such as 'waxed amide are preferred, but other solvents include ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether, tetrahydrofuran and dioxane, esters such as ethyl acetate, methanol, ethanol, n-propyl ether, etc. Alcohols such as tool, isopropanol, butanol, and nitriles such as acetonitrile can also be used. Examples of the deoxidizing agent include tertiary amines such as triethylamine, tributylamine, pyridine, picoline, lutidine, and collidine, and inorganic bases such as sodium carbonate and potassium carbonate. The amount of the deoxidizing agent used is preferably equimolar to 5 times the molar amount of compound (TI) or (V), but
In the case of the amines (I[), it can be used in large excess as a solvent. Furthermore, since the excess amine (I[[) acts as a deoxidizing agent, the reaction proceeds smoothly even when no other deoxidizing agent is added. The reaction is carried out at a temperature ranging from room temperature to 200°C.

After completion of the reaction, the target compound of this reaction can be obtained by treating the reaction mixture according to a conventional method, and if necessary, it can be further purified using a conventional purification method such as recrystallization method or column chromatography. can.

When an ester derivative of compound (1) is used in this reaction, an ester derivative of the target compound can be obtained, which can be easily converted into the target compound (Ia) by a conventional hydrolysis method.
be guided by.

When using the chelated compound (V), the target chelate compound (■) is first obtained, but this compound can be obtained by treating it with a basic hydrous alcohol (in some cases, after treatment with a hydrous alcohol). By treating the BF3 adduct obtained with a base), the target compound (Ia) can be easily obtained.
be guided by.

Bases used in this treatment include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, or tertiary amines such as triethylamine and 4-dimethylaminopyridine. can be given.

Similarly to this reaction, the target compound (Ib) is produced by reacting a chelate compound of compound (VIA) with an amine (fir).

Compound (Ia) or (Ib) thus obtained
is converted into the desired salt according to conventional methods, if necessary.

In addition, boron fluoride chelate compound (
The conversion reaction to V) is carried out by reacting fluoroboric acid, for example, according to the method described in JP-A-59-67290.

The general formula (1,) or (
Ib) The compound having Y has optical isomers or geometric (cis, trans) isomers based on the asymmetric carbon atom of the side chain amine moiety in its structure, but if desired,
Optically resolved or separated raw material amine compound (II[)
By carrying out the above reaction using
Each stereoisomer can be obtained by subjecting the optical isomer or geometric isomer mixture of l)) to a conventional optical resolution or separation method.

Effects of the Invention The target compound of the present invention having the general formula (1,) or (Ib) and its pharmacologically acceptable salts exhibit excellent antibacterial activity. When its antibacterial activity was measured using an agar plate dilution method, it was found that Gram-negative bacteria such as Staphylococcus aureus and Enterococcus, Escherichia coli, Shigella, Klebsiella pneumoniae, Protozoa, Serratia, Enterobacter, Salmonella, and Pseudomonas aeruginosa. It showed strong antibacterial activity against a wide range of pathogenic bacteria, including Gram-negative bacteria such as Bacteria and their resistant bacteria. The test results are shown in the third column using norfloxacin as a control compound.

Therefore, the compound (Ia) or (Ib) of the present invention is useful as an antibacterial agent for treating bacterial infections caused by these pathogens. Examples of dosage forms for this purpose include oral administration in the form of tablets, capsules, granules, powders, syrups, etc., and parenteral administration in the form of intravenous injections, intramuscular injections, full injections, etc. The dosage varies depending on age, body weight, symptoms, dosage form and number of administrations, but it is usually about 100 to 100 mg per day for adults.
000■ is administered orally in one or several divided doses.

Next, reference examples and examples are given to demonstrate the present invention [Reference Example 1
] Cis-3-amino-4-methoxy(1) 6.91 f (0.1 mol) of 3-pyrroline was dissolved in 100 g of dichloromethane.
21.81 (0.1 mol) of di-tert-butyl dicarbonate was added in portions under water cooling. After stirring at room temperature for 7 hours, the solvent was distilled off under reduced pressure to obtain 17.0II of 1-tert-butoxycarbonyl-3-pyrroline as a pale yellow oil.

MS spectrum (cX): m/e 100 (M++
1) IR spectrum (capillary, sima, at
t') :2990.2870.1710~169
0,1625,1400゜1170.1120 (211-tert-butoxycarbonyl-3-pyrroline 1.691 (0.01 mol) chloroform 10g
Dissolved in / under water cooling, 70% m-chloroperbenzoic acid 2.9
69 (0,012 mol) was added thereto, and the mixture was stirred for 8 hours under water cooling and then for 15 hours under water cooling.

After the reaction is completed, extraction is performed with toluene, and the toluene layer is extracted with an aqueous solution of sodium bicarbonate, 0.1N sodium thiosulfate,
and water, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: a mixture of 15 ethyl acetate and 5 toluene) to obtain 1-tert-butoxycarbonyl. -3,
1.099 of 4-epoxypyrrolidine was obtained as a colorless oil.

MS spectrum (CI): m/e 18B (M+
+1) IR spectrum (capillary, maxff
i-1):2990.2880.1710-1690,
1420,1390°1180.1120 (311-tert-butoxycarbonyl-3,4-epoxypyrrolidine 1.02 f (0,0055 mol)
was dissolved in anhydrous methanol 2 (ly+/), 0.301 (0,0055 mol) of sodium methoxide was added, and 1
The mixture was heated under reflux for 0 hours. The reaction mixture was diluted with water, extracted with chloroform, the chloroform layer was washed with water, dried, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: a mixture of 1 ethyl acetate and 2 toluene),
1-tert-butoxycarbonyl-3-hydroxy-
0.73 g of 4-methoxypyrrolidine was obtained as a colorless oil.

MS spectrum: m/e 217 (M+L 57(
C4H9”) NMR spectrum (CDC13, δ):
1.46 (9I(,S.

(411-tert-butoxycarbonyl-3-hydroxy-4-methoxypyrrolidine 130y (0.06 mol) dissolved in 100 g of pyridine, cooled with water, dropwise added methanesulfonyl chloride 11.51 (0.1 mol), cooled with water The reaction mixture was poured into 800 ml of water, extracted with diethyl ether, the diethyl ether layer was washed with water, dried, and the solvent was distilled off under reduced pressure to give 1-tert-butoxycarbonyl-3-hydroxy-4-methanesulfonyl. Oxypyrrolidine 12.9F was obtained as a brown oil.

Put this into a 100g/volume stainless steel autoclave and add 50*1 liquid ammonia! was added and stirred at 140° C. for 8 hours under pressure. Excess ammonia was removed and the residue was subjected to silica gel column chromatography (solvent: ethanol) to obtain cis-3-amino-1-tert-butoxycarbonyl-4-methoxypyrrolidine 8,0g as a brown oil. .

MS spectrum (cr): m/e 217 (M
”+1) *201(M+-CH5), 184
(M+-CH30H).

161 (M+-〇'1-r2=c(CH5)2)SI
R spectrum (capillary, Simaxa-1): 34
00s 2990s 2950e 1680,1
41L1170.11l1 00N spectrum (cDcJ5. δ): 1.4
6 (9H, S.

Goods.

3.4G (3H, S, -0CH3), 340-3.60
(5) cis-3-amino-1-tcrt-butoxycarbonyl-4-methoxypyrrolidine 4.161 (0,
019 mol) was dissolved in 200 ml of ethanol, 64 ml of 6N hydrochloric acid was added, and after heating under reflux for 1 hour, it was completely dried under reduced pressure to give 3.41 F of cis-3-amino-4-methoxypyrrolidine dihydrochloride a brown color. Obtained as a powder.

Melting point 220-226℃ 130 NMR spectrum (D20*8) 47.9 (
C2) 50.6 (c5) 53.3 (C3) 59,s (-0CH3) 79.7 (C4) Cis-3-amino-4-methoxypyrrolidine dihydrochloride obtained as above3. Dissolve 41 f in water 201,
After adding 1.9 T da (0,037 mol) of sodium methoxide, the solvent was distilled off, and the residue was diluted with ethanol-ethyl acetate 1:
1 mixed solution, and the washed solution was concentrated under reduced pressure to give cis-3-
2.06f of amino-4-methoxypyrrolidine was obtained as a brown oil.

MS spectrum: m/e 116 (M+), 99 (
M+-NH3).

84 (M+-CH30H) The following cis-3-amino-4 was prepared by the same method as above.
-Alkoxypyrrolidines were synthesized.

Cis-3-amino-4-ethoxypyrrolidine 2-hydrochloride cis-3-methylamino-4-methoxypyrrolidine 2
Hydrochloride (1) 1-tert-butoxycarbonyl-3,4-epoxypyrrolidine 3.71 (0,
0.02 mol) was dissolved in 15 ml of ethanol, 7.881 (0.04 mol) of dibenzylamine was added, and the mixture was heated under reflux for 10 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: ethyl acetate 12-toluene 8B mixture) to obtain 1-tert.
-Butoxycarbonyl-3-dibenzylamino-4-hydroxypyrrolidine 1.211 was obtained as a pale yellow oil.

M8 spectrum (CI): m/e 383 (M+
+1) IR spectrum (capillary, simaxα
-1):3420.1690,1670,1420,1
175(2) 1-tert-butoxycarbonyl-3-dibenzylamino-4-hydroxypyrrolidine 1
．． 21 (0,0031 mol) in tetrahydrofuran 1
Dissolved in 0ml of 60% sodium hydride 0.19g (0
,0047 mol), methyl iodide 0.89Q (0,0
063 mol) and stirred at room temperature for 5 hours.

Water was added to the reaction mixture, extracted with ethyl acetate, the ethyl acetate layer was washed with water, dried, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: ethyl acetate 5-
95% of toluene) to obtain 0.991x of 1-tert-butoxycarbonyl-3-dibenzylamino-4-methoxypyrrolidine as a colorless oil.

MS spectrum: m76396 (M+)340 (M
+-CH2=C(CH5)2).

305 (M+-cH2ph) 296 (M+-CO2-CH2=C(04)2)IR
Spectrum (capillary, νmaX'')'16
90.1390-1410. 1170. 1100f
31 1-tcrt-butoxycarbonyl-3-dibenzylamino-4-methoxypyrrolidine 0.99f (
0,0025 mol) in 15 ml of ethanol, 20
% palladium-carbon powder was added thereto, and the mixture was vigorously stirred at 50° C. for 4 hours while blowing hydrogen gas under normal pressure.

After removing the catalyst from the reaction solution, the solvent was distilled off under reduced pressure to obtain 044 g of 3-amino-1-tert-butoxycarbonyl-4-methoxypyrrolidine as a colorless oil.

MS spectrum (CI): m/e 217 (M+
+1) (EI): m/e 184 (M”-CH3
0H).

16o (M+-cl(2=c(CI(3)2) IR spectrum (capillary 1 'maX-') "3
370.3300.1660-1690,1400.1
160°(4) 3-amino-1-tert-butoxycarbonyl-4-methoxypyrrolidine 0.41 (0,0
019 mol) in 20 tons of ethanol, 6N @ acid 6
．． After adding 3 ml of 1k and heating under reflux for 1.5 hours, the solvent was distilled off under reduced pressure, and the residue was washed with a 1:9 mixture of ethanol and ethyl acetate to obtain trans-3-amino-4-methoxypyrrolidine dihydrochloride 034f as a colorless powder. obtained as.

Melting point 248-258℃ (decomposition) MS, (vector (CI): m/e 117 (M
++1) (EI): 99 (M+-NH3) 84 (M+-CH50H) i3CNMR spectrum (D20.δ): 50.1 (
C2) sl,t (05) 56°O(C3) 60.0 (-oCH3) 84.2 (c4) Copyru-6-fluoro-1,4-dihydro-4-·hydrochloride cis-3-amino-4 -Methoxypyrrolidine dihydrochloride 0.649 (0,0034 mol) in ethanol 20
1.13 g of triethylamine (0.01
12 mol) was added to form a solution. This solution contains 7-
Chlor-1-cyclopropyl-6-fluoro-1,4-
Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (Reference: JP-A-60-17
No. 2981) [1,BB Q (0,0 (12Q mol)!) was added and stirred at 30°C for 3 hours.

Reaction mixture? After concentration under reduced pressure, 10 ml of 6N hydrochloric acid was added to the residue, heated under reflux for 2 hours, and dried under reduced pressure.

5 ssl'l of water was added to the residue to remove insoluble matter, the pH of solution F was adjusted to 8-9 with sodium hydroxide, and the precipitated crystals were collected and washed with ethanol.

The obtained crystals were suspended in 20*l of ethanol, and concentrated hydrochloric acid 05
After adding 100 g of amine, it was concentrated under reduced pressure and the residue was washed with ethanol to give γ-(cis-3-amino-4-methoxy-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4
-dihydro-4-oxo-1,8-naphthyridine-3-
028 g of carboxylic acid hydrochloride was obtained as colorless powdery crystals.

Melting point 200-201℃ Elemental analysis value (%) C17H2QCIFN404-H
CHN as 2O Theoretical value 48.9B 5.32 13.44 Measured value 48,72 5.05 13.34 [Example
2-4] The following compound (Ia) was synthesized from compound (11) in the same manner as in Example 1.

(I[) 1-cyclopropyl-6,7,8-)refluoro-1,
4-dihydro-4-oxoquinoline-3=carboxylic acid ethyl ester (Reference: JP-A-60-126271) 2. To Of (0,0064 mol) was added 50 dew of 42 ql fluoroboric acid, and the mixture was stirred at 110°C for 3 hours. The reaction mixture was poured into 200 l/ml of water, and the precipitated crystals were collected to give 1-cyclopropyl-6゜7.8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. BF2 chelate 1.751 was obtained as colorless powdery crystals.

1.1411 (0,006 mol) of cis-3-amino-4-methoxypyrrolidine dihydrochloride was suspended in 5 ml of dimethyl sulfoxide, and 0.65 ml of sodium methoxide was suspended.
After adding 1 (0,012 mol), the mixture was stirred at room temperature for 30 minutes.

To this mixture, chelate compound 1 obtained as above,
Of (0,003 mol) and triethylamine 0.9
2 g (0°009 mol) was added and stirred overnight at room temperature. The reaction mixture 7 was poured into 50 d of water, and the precipitated yellow crystals were collected. This was dissolved in a mixture of 150 g of 80% aqueous methanol and 2 ml of triethylamine, and heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethanol. The yellowish brown crystals obtained were suspended in 100 ml of water. 1N caustic soda was added to adjust the pH to 9-10, and insoluble materials were removed. 1N hydrochloric acid was added to solution f to adjust the pH to 8. ~Adjust to 9,
The precipitated crystals (integrated with the target object) were collected.

The crystals were suspended in ethanol Sow/concentrated hydrochloric acid 111
1"l: was added, concentrated under reduced pressure, and the residue was washed with ethanol to give 7-(cis-3-amino-4-methoxy-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-4-oxo. Quinoline-3-carboxylic acid hydrochloride 0.2
4f was obtained as pale yellow powdery crystals.

Melting point 171-178℃ Elemental analysis value (%) 018H2oCIF2N304・H2
CHN as O Theoretical value 49,84 5,11 9.69 Measured value 49,66 4.83 9.30 (4B) [Example 14] -6-carboxylic acid 9.10-difluoro-3-methyl-7- Oxo-2,
3-dihydro-7H-pyrido [1,2,3-de)
[1,4]]Benzoxazine-6-carboxylic acid ethyl ester Reference document: JP-A-57-46986) 0.
849 (0,003 mol) in the same manner as in Example 5, 10-(cis-3-amino-4-methoxy-1
-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-
de]C1,4]]he7zoxazine-6-carboxylic acid 030 f'f Obtained as yellow powdery crystals.

Melting point 213-217 t (decomposition) Elemental analysis value (%') C)T N as Cl8H20FN505

Claims (1)

[Scope of Claims] A pyridonecarboxylic acid derivative and its salt or ester having the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I a) or the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I b) In the above formula, R^1 is a lower alkyl group, a halogeno lower alkyl group, a cycloalkyl group, a lower alkoxy group, a lower alkylamino group, or a lower alkyl group as a substituent,
Indicates a phenyl group that may have at least one of a hydroxyl group, a lower alkoxy group, or a halogen atom, and R^
2 represents a lower alkyl group, R^3 and R^4 are the same or different and represent a hydrogen atom or a lower alkyl group,
R^5 represents a hydrogen atom or a lower alkyl group, A represents a nitrogen atom or a group of the formula C-R^6 (wherein R^6 represents a hydrogen atom, a methyl group, or a halogen atom), and X■
When there is a single bond between Y, Y represents a methylene group, and
represents a methylene group, a carbonyl group, an oxygen atom or a sulfur atom, and when there is a double bond between X and Y,
together form a cis-vinylene group.