Synthesis and antibacterial activity of the 4-quinolone-3-carboxylic acid derivatives having a trifluoromethyl group as a novel n-1 substituent

Article abstract of DOI:10.1021/jm040204g

Novel 1-trifluoromethyl-4-quinolone derivatives (8a,b) were synthesized, and the antibacterial activity of each was evaluated. An oxidative desulfurization-fluorination reaction was employed to introduce a trifluoromethyl group at the N-1 position as a ke

Full text of DOI:10.1021/jm040204g

J. Med. Chem. 2005, 48, 3443-3446
3443
Synthesis and Antibacterial Activity of the 4-Quinolone-3-carboxylic Acid
Derivatives Having a Trifluoromethyl Group as a Novel N-1 Substituent
Yoshikazu Asahina,* Ichiro Araya, Kazuhiko Iwase, Fujio Iinuma, Masaki Hosaka, and Takayoshi Ishizaki
Discovery Research Laboratories, Kyorin Pharmaceutical Co. Ltd., 2399-1, Nogi, Nogi-Machi, Shimotsuga-Gun,
Tochigi, 329-0114, Japan
Received November 23, 2004
Novel 1-trifluoromethyl-4-quinolone derivatives (8a,b) were synthesized, and the antibacterial
activity of each was evaluated. An oxidative desulfurization-fluorination reaction was employed
to introduce a trifluoromethyl group at the N-1 position as a key step. Among the derivatives,
8a was found to exhibit antibacterial activity comparable to that of norfloxacin (1) against
Staphylococcus aureus Smith, Streptococcus pneumoniae IID1210, and Escherichia coli NIHJ
JC-2.
Introduction
Since the development of norfloxacin (1),1 the first
quinolone (fluoroquinolone) in which a fluorine atom is
at the C-6 position, other fluoroquinolones, e.g., cipro-
floxacin (2)2 and levofloxacin (3),3 have been developed
and clinically used for the treatment of various infec-
tious diseases (Figure 1). Among the synthetic studies
of the fluoroquinolones 4-7,4-7 2-fluoroethyl, 2,4-di-
fluorophenyl, 2-fluorocyclopropyl, and tert-butyl groups
were established as novel N-1 substituents capable of
improving antibacterial activity and/or pharmacokinetic
properties. In light of these structural characteristics,
we designed and synthesized the fluoroquinolone 8,
which carries a trifluoromethyl group as a novel N-1
substituent. Our next study established the trifluoro-
methyl group as a novel N-1 substituent of the fluoro-
Figure 1.
iodomethane gave 23. After much experimentation,11 it
was finally found that the treatment of 15, derived from
23 with a hydrogen fluoride-pyridine complex and
N-bromosuccimide, afforded the 1-trifluoromethyl-
tetrahydroquinolone 16 in excellent yield. Ethoxycar-
bonylation of 16 with diethyl (ethoxycarbonyl)phospho-
nate using sodium hydride gave the 3-ethoxycarbonyl-
1-trifluoromethylquinolone derivative 24. Oxidation of
24 to 1-trifluoromethylquinolone 25 with 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ),12 followed by hy-
drolysis under acidic conditions, gave 1-trifluoromethyl-
quinolonecarboxylic acid 17. With the desired 1-trifluo-
romethylquinolonecarboxylic acid (17) in hand, our next
attempt was the introduction of cyclic amines to the C-7
position of 17. Unfortunately, the reaction of 17 with
1-methylpiperazine by heating the mixture in dimethyl
sulfoxide (DMSO) failed to give the 7-(4-methylpiper-
azinyl) derivative 8a. The introduction of the cyclic
amines to 3-ethoxycarbonyl-1-trifluoromethyltetrahyd-
roquinolone 24 was then attempted. As shown in
Scheme 2, it was found that the reaction of 24 with
cyclic amines (1-methylpiperazine and 3-Boc-aminopy-
rrolidine) in acetonitrile proceeded smoothly to give the
7-cyclic amino derivatives 26a,b. Treatment of 26a,b
with DDQ, followed by the removal of an ester group
and a Boc group under acidic conditions, gave the
desired 7-cyclic amino-1-trifluoromethyl-4-quinolone-3-
carboxylic acid derivatives 8a,b.
quinolone by comparison of the in vitro antibacterial
activity of 8 and fluoroquinolones 9-14 carrying known
N-1 substituents (Figure 2).
In this paper, we report the synthesis and antibacte-
rial activity of the 7-substituted 1-trifluoromethyl-4-
quinolone-3-carboxylic acids 8a,b, which both bear a
trifluoromethyl group as a novel N-1 substituent.
Results and Discussion
Chemistry. The synthetic strategy of the 7-substi-
tuted-1-trifluoromethyl-4-quinolone-3-carboxylic acids
8a,b by way of trifluoromethylquinolone carboxylic acid
17 is shown in Scheme 1. We employed an oxidative
desulfurization-fluorination reaction8 as the key step
in the introduction of a trifluoromethyl group to the N-1
position of 17. Thus, treatment of the 1-benzyl deriva-
tive 19, derived from ester 189 with sodium borohydride
in the presence of a catalytic amount of p-toluene-
sulfonic acid in methanol,10 provided tetrahydroqui-
nolone 20. Protection of a carbonyl group of 20 with an
ethylenedioxy group and removal of a benzyl group gave
ethylenedioxy ketal 22. Reaction of 22 with carbon
disulfide smoothly proceeded using lithium bis(trimeth-
ylsilyl)amide as a base; subsequent treatment with
* To whom correspondence should be addressed. Phone: 81 (0)280
56 2201. Fax: 81 (0)280 57 1293. E-mail: yoshikazu.asahina@
mb.kyorin-pharm.co.jp.
10.1021/jm040204g CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/13/2005

3444 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9
Brief Articles
Figure 2.
Scheme 1
Table 1. In Vitro Antibacterial Activity of
1-Trifluoromethylquinolones (8a,b) and 1-Subutituted
7-(4-Methyl-1-piperazinylquinolones (9-14)
Table 2. In Vitro Antibacterial Activity of 1-Subutituted
7-(4-Methyl-1-piperazinyl)quinolones (8a, 9-14)
MIC (µg/mL)
MIC (µg/mL)
Gram-positive bacteria
Gram-negative bacteria
Gram-positive bacteria
Gram-negative bacteria
S. aureus St. pneumoniae
E. coli
NIHJ JC-2
P. aeruginosa
IID1210
S. aureus St. pneumoniae
E. coli
NIHJ JC-2
P. aeruginosa
IID1210
compd
Smith
type III
compd
Smith
type III
8a
9
10
11
12
13
14
0.78
0.20
0.39
0.20
0.20
0.10
0.10
3.13
0.78
6.25
3.13
1.56
0.39
0.39
0.05
0.025
0.05
0.025
0.0125
e0.0063
0.10
6.25
1.56
1.56
1.56
1.56
0.78
3.13
8a
8b
1
0.78
1.56
0.39
3.13
12.5
3.13
0.05
0.39
0.05
6.25
>12.5
1.56
Antibacterial Activity. With the 7-cyclic amino-1-
trifluoromethyl-4-quinolone-3-carboxylic acid deriva-
tives 8a,b in hand, the in vitro antibacterial activity of
each against Gram-positive (Staphylococcus aureus
Smith and Streptococcus pneumoniae type III) and
Gram-negative (Escherichia coli NIHJ JC-2 and Pseudo-
monas aeruginosa IID1210) bacteria was evaluated. The
minimum inhibitory concentration (MIC, µg/mL) of each
derivative is shown in Table 1 along with that of 1. The
antibacterial activity of 8a was comparable to that of 1
except against P. aeruginosa IID1210.
Conclusion
As described above, we have successfully designed,
synthesized, and evaluated the 4-quinolone-3-carboxylic
acids 8a,b carrying a trifluoromethyl group as a novel
N-1 substituent. The synthesis of these compounds was
achieved in nine steps from 18 by a method featuring
an oxidative desulfurization-fluorination reaction as
the key step. Of the two derivatives 8a and 8b, 8a was
found to exhibit antibacterial activity comparable to that
of 1. In addition, the properties of a trifluoromethyl
group as the N-1 substituent of fluoroquinolone were
more similar to those of a methyl group than to that of
a tert-butyl group, as determined by comparing the
antibacterial activity of 8a with that of 7-(4-methyl-1-
piperazinyl)quinolones 9-14 carrying various known
N-1 substituents. Further investigation of the 1-tri-
fluoromethyl-4-quinolone-3-carboxylic acid derivatives
is in progress.
Next, we compared the in vitro antibacterial activity
of the 7-(4-methyl-1-piperazinyl) derivative 8a to that
of the 7-(4-methyl-1-piperazinyl)quinolone derivatives
9-14, which respectively carry a tert-butyl, methyl,
ethyl, 2-fluoroethyl, cyclopropyl, and 2,4-difluorophenyl
group as the N-1 substituent.13 As shown in Table 2,
8a showed weaker antibacterial activity than the tert-
butyl derivative 9, which was expected to have the same
steric hindrance for the N-1 substituent as that of 8a,
against both Gram-positive and -negative bacteria. The
antibacterial activity of 8a was close to that of the
1-methyl derivative 10 rather than to that of the tert-
butyl derivative 9.
Experimental Section
Melting points were determined with a Yanagimoto mi-
cromelting point apparatus and are uncorrected. Elemental
analyses are within (0.4% of theoretical values and were

Brief Articles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9 3445
Scheme 2a
of saturated NaHSO3 solution (60 mL) and saturated NaHCO3
solution (60 mL), and the resulting mixture was stirred at
room temperature for 15 min. The organic layer was separated,
washed with 1 M HCl and water, dried over anhydrous Na2-
SO4, filtered, and then concentrated in vacuo. Flash chroma-
tography (hexane/AcOEt ) 4:1) of the residue gave 16 (483
mg, 96%) as a colorless powder. Mp: 47-48 °C (petroleum
1
ether). H NMR (CDCl3): δ 2.82-2.85 (m, 2H, C3-H), 3.82-
3.85 (m, 2H, C2-H), 7.18 (m, 1H, C8-H), 7.84 (dd, J ) 10.3,
8.8 Hz, 1H, C5-H). MS (EI) m/z: 251 (M+). HRMS (EI) for
C10H6F5NO (M+): calcd, 251.0370; found, 251.0402.
Ethyl 6,7-Difluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-
4-oxo-3-quinolonecarboxylate (24). A solution of 16 (314
mg, 1.25 mmol) in anhydrous THF (2 mL) was added to a
suspension of NaH (60% dispersion in mineral oil, 115 mg,
2.88 mmol) in anhydrous THF (4.3 mL) at -78 °C. Diethyl
ethoxycarbonylphoshonate (0.30 mL, 1.63 mmol) was added
to the above mixture at -78 °C, and the mixture was heated
under reflux for 30 min. After the reaction was quenched by
adding acetic acid (0.4 mL) under conditions of cooling with
ice, the mixture was diluted with AcOEt and washed with
saturated NaHCO3 solution and water, dried over anhydrous
Na2SO4, filtered, and then concentrated in vacuo. Flash
chromatography (hexane/AcOEt ) 20:1) of the residue gave
24 (316 mg, 78%) as a colorless powder. Mp: 79-80 °C
(petroleum ether). 1H NMR (CDCl3): δ 1.36 (t, J ) 7.3 Hz,
3H, CH3), 4.26 (s, 2H, C2-H), 4.32 (q, J ) 7.3 Hz, 2H,
COOCH2), 7.04 (m, 1H, C8-H), 7.59 (dd, J ) 10.3, 8.8 Hz, 1H,
C5-H), 12.1 (br s, 1H, OH). MS (EI) m/z: 323 (M+). Anal.
(C13H10F5NO3) C, H, N.
Ethyl 6-Fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-7-
(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylate
(26a). A solution of 24 (129 mg, 0.399 mmol), 1-methyl-
piperazine (49 µL, 0.440 mmol), and triethylamine (0.11 mL,
0.800 mmol) in anhydrous MeCN (3 mL) was heated at 50 °C
for 18 h and then concentrated in vacuo. Flash chromatogra-
phy (CH2Cl2/acetone ) 5:1) of the residue gave 26a (146 mg,
91%) as a pale-yellow powder. Mp: 77-78 °C (petroleum
a Reagents: (a) H2SO4, AcOH, H2O, 97%; (b) NaBH4, p-tolu-
enesulfonic acid, MeOH, 68%; (c) HOCH2CH2OH, p-toluenesulfonic
acid, toluene, 60%; (d) HCOONH4, Pd-C, MeOH, 80%; (e) (i) CS2,
lithium bis(trimethylsilyl)amide, THF; (ii) MeI; (f) 3 M HCl, 96%
(from 22); (g) HF-pyridine, CH2Cl2, 96%; (h) (EtO)2P(dO)COOEt,
NaH, THF, 78%; (i) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone,
dioxane, 98%; (j) 1-methylpiperazine, Et3N, DMSO; (k) 1-meth-
ylpiperazine or 3-Boc-aminopyrrolidine, Et3N, MeCN 91% (for
26a), 85% (for 26b); (l) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone,
dioxane, 93% (for 27a), 83% (for 27b); (m) 1 M HCl, dioxane, 87%
(for 8a), 86% (for 8b).
1
ether). H NMR (CDCl3): δ 1.29 (t, J ) 7.3 Hz, 1.5H, CH3),
1.35 (t, J ) 7.3 Hz, 1.5H, CH3), 2.37 (s, 1.5H, NCH3), 2.40 (s,
1.5H, NCH3), 2.60-2.65 (m, 4H, CH2 × 2), 3.23-3.31 (m, 4H,
CH2 × 2), 3.70 (q, J ) 4.4 Hz, 0.5H, C3-H), 3.93 (dd, J ) 13.2
Hz, 3.9 Hz, 0.5H, C2-H), 4.10 (dd, J ) 9.3, 8.3 Hz, 0.5H, C2-
H), 4.22 (s, 1H, C2-H), 4.29 (q, J ) 7.3 Hz, 2H, COOCH2),
6.62 (m, 0.5H, C8-H), 6.71 (m, 0.5H, C8-H), 7.42 (d, J ) 12.7
Hz, 0.5H, C5-H), 7.65 (d, J ) 13.2 Hz, 0.5H, C5-H), 12.1 (br
s, 0.5H, OH). MS (EI) m/z: 403 (M+). Anal. (C18H21F4N3O3) C,
H, N.
Ethyl 7-(3-tert-Butoxycarbonyamino-1-pyrrolidinyl)-
6-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-4-oxo-3-
quinolinecarboxylate (26b). The compound 26b (165 mg,
85%) was prepared from 24 (129 mg 0.399 mmol) in the same
manner as that described for 26a. Mp: 109-110 °C (hexane).
1H NMR (CDCl3): δ 1.29 (t, J ) 6.9 Hz, 1.5H, CH3), 1.34 (t, J
) 7.3 Hz, 1.5H, CH3), 1.45 (s, 4.5H, C4H9), 1.56 (s, 4.5H, C4H9),
1.93-1.96 (m, 1H, CH2), 2.21-2.25 (m, 1H, CH2), 3.35-4.28
(m, 8.5H, C3-H, CH2 × 3, COOCH2), 4.33 (brs, 1H, C2-H),
4.69 (brs, 1H, C2-H), 6.26-6.27 (m, 0.5H, C8-H), 6.28-6.39
(m, 0.5H, C8-H), 7.37 (d, J ) 12.2 Hz, 0.5H, C5-H), 7.61 (d,
J ) 14.2 Hz, 0.5H, C5-H), 12.1 (br s, 0.5H, OH). MS (FAB+)
m/z: 490 (M+ + H). Anal. (C22H27F4N3O5) C, H, N.
Ethyl 6-Fluoro-1-trifluoromethyl-1,4-dihydro-7-(4-meth-
yl-1-piperazinyl)-4-oxo-3-quinolinecarboxylate (27a). A
solution of 26a (121 mg, 0.300 mmol) and DDQ (71.7 mg, 0.300
mmol) in anhydrous dioxane (3 mL) was heated under reflux
for 1.5 h, and the mixture was concentrated in vacuo. Flash
chromatography (CH2Cl2/MeOH ) 20:1) of the residue gave
27a (111 mg, 93%) as a pale-yellow powder. Mp: 129-130 °C
(cyclohexane). 1H NMR (CDCl3): δ 1.40 (t, J ) 6.9 Hz, 3H,
CH3), 2.38 (s, 3H, NCH3), 2.61-2.64 (m, 4H, CH2 × 2), 3.29-
3.31 (m, 4H, CH2 × 2), 4.41 (q, J ) 6.9 Hz, 2H, COOCH2),
6.93-6.96 (m, 1H, C8-H), 8.03 (d, J ) 13.2 Hz, 1H, C5-H),
8.68 (s, 1H, C2-H). MS (EI) m/z: 401 (M+). Anal. (C18H19F4N3O3)
C, H, N.
determined by a Yanaco CHN corder MT-5. Infrared spectra
were recorded with a JASCO FT/IR-5300 spectrometer. Mass
spectrometry (MS) and high-resolution MS (HRMS) were
performed with a JEOL JMS SX-102A mass spectrometer.
Proton nuclear magnetic resonance (1H NMR) spectra were
obtained with a JEOL FX-90 (90 MHz) or a JEOL JMN-EX400
(400 MHz) spectrometer. The chemical shifts are expressed
in parts per million (δ) downfield from tetramethylsilane, using
tetramethylsilane (δ ) 0) and/or residual solvents such as
chloroform (δ ) 7.26) as an internal standard. Splitting
patterns are indicated as follows: s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; br, broad peak. Column
chromatography was carried out with silica gel [silica gel 60
(Kanto)] as an absorbent. Merck precoated thin-layer chro-
matography (TLC) plates (silica gel 60 F254, 0.25 mm, Art 5715)
were used for TLC analysis. Solutions were dried over sodium
sulfate, and the solvent was removed by rotary evaporation
under reduced pressure.
6,7-Difluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-4-
oxoquinoline (16). Pyridinium poly(hydrogen fluoride) (2.86
mL, 10.0 mmol) was added to a solution of 15 (547 mg, 2.00
mmol) in anhydrous CH2Cl2 (12 mL) at -78 °C. N-Bromosuc-
cimide (1.42 g, 8.00 mmol) was added portionwise to the above
solution at -78 °C, and the whole mixture was stirred at the
same temperature for 1 h and then further stirred at room
temperature for 1 h. The mixture was poured into a solution

3446 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9
Brief Articles
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Cesare, P.; Essiz, M.; Jacquet, J. P.; Kiechel, J. R.; Ledoussal,
B.; Kessler, R. E.; Fung-Tome, J. Fluoronaphthyridine and
Quinolones as Antibacterial Agents. 3. Synthesis and Structure-
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(11) For example, reaction of 23 with tetrabutylammonium dihydro-
gen trifluoride and 1,3-dibromo-5,5-dimethylhydantoin (DBH)
gave only undesired complex products, and reaction of 15 with
HF-pyridine complex and DBH gave a mixture of 16 and the
3-bromo derivative of 16.
Ethyl 7-(3-tert-Butoxycarbonyamino-1-pyrrolidinyl)-
6-fluoro-1-trifluoromethyl-1,4-dihydro-4-oxo-3-quinolin-
ecarboxylate (27b). The compound 27b (116 mg, 83%) was
prepared from 26b (139 mg 0.285 mmol) in the same manner
as that described for 27a. 1H NMR (CDCl3): δ 1.41 (t, J ) 7.3
Hz, 3H, CH3), 1.59 (s, 9H, C4H9), 1.96-2.20 (m, 1H, CH2),
2.24-2.33 (m, 1H, CH2), 3.42-3.46 (m, 1H, CH2), 3.58-3.63
(m, 1H, CH2), 3.64-3.71 (m, 1H, CH2), 3.72-3.85 (m, 1H, CH2),
4.40 (q, J ) 7.3 Hz, 2H, COOCH2), 4.74 (br s, 1H, CH), 6.53-
6.55 (m, 1H, C8-H), 7.98 (d, J ) 13.7 Hz, 1H, C5-H), 8.69 (s,
1H, C2-H). MS (FAB+) m/z: 488 (M+ + H). Anal. (C22H25-
F4N3O3) C, H, N.
6-Fluoro-1-trifluoromethyl-1,4-dihydro-7-(4-methyl-1-
piperazinyl)-4-oxo-3-quinolinecarboxylic Acid Hydro-
chloride (8a). A solution of 27a (90.3 mg, 0.225 mmol) in 1
M HCl (2.5 mL) and dioxane (3.5 mL) was heated under reflux
for 1.5 h. The mixture was concentrated, and the residue was
triturated with EtOH. The resulting precipitates were collected
by filtration, washed with EtOH, and then dried in air to give
8a (80 mg, 87%) as a colorless powder. Mp: >300 °C. 1H NMR
(DMSO-d6 + CF3COOD): δ 2.91 (s, 3H, NCH3), 3.23 (m, 4H,
CH2x2), 3.60 (m, 4H, CH2 × 2), 7.07 (m, 1H, C8-H), 8.06 (d, J
) 12.7 Hz, 1H, C5-H), 8.90 (s, 1H, C2-H). MS (FAB+) m/z:
374 (M+ + H). Anal. (C16H15F4N3O3‚HCl) C, H, N.
7-(3-Amino-1-pyrrolidinyl)-6-fluoro-1-trifluoromethyl-
1,4-dihydro-4-oxo-3-quinolinecarboxylic Acid (8b). A so-
lution of 27b (63.4 mg, 0.130 mmol) in 1 M HCl (2.5 mL) and
dioxane (2.5 mL) was heated under reflux for 4 h. The mixture
was concentrated, and the residue was dissolved in water. The
aqueous solution was adjusted to pH 7 by addition of 0.01 M
NaOH solution. The resulting precipitates were collected by
filtration, washed with water, exposed with CH2Cl2, and then
again washed with water to give 8b (40 mg, 86%) as pale-
brown powder. Mp: >300 °C. 1H NMR (DMSO-d6 + CF3-
COOD): δ 2.15-2.17 (m, 1H, CH2), 2.29-2.38 (m, 1H, CH2),
3.63-3.81 (m, 3H, CH2 × 2), 3.93-3.99 (m, 2H, CH, CH2),
6.60-6.62 (m, 1H, C8-H), 7.95 (d, J ) 13.7 Hz, 1H, C5-H),
8.82 (S, 1H, C2-H). MS (FAB+) m/z: 360 (M+ + H). Anal.
(C15H13F4N3O3‚H2O) C, H, N.
In Vitro Antibacterial Activity. The MIC (µg/mL) was
determined by the agar dilution method14 with Muller-Hinton
agar (Difco Laboratories, Detroit, MI). The MIC was defined
as the lowest concentration of an antibacterial agent that
inhibited visible growth after incubation at 35 °C for 18 h.
Acknowledgment. We thank Dr. Keiji Hirai,
Kyorin Pharmaceutical Co. Ltd., for his encouragement
and support of this project. We are also grateful to Dr.
Yasumichi Fukuda, Kyorin Pharmaceutical Co. Ltd.,
and Drs. James V. Heck and Milton L. Hammond,
Merck Research Laboratories, for their close reading of
this manuscript and for their helpful comments on the
study. We also thank Ms. Hinako Gomori, Kyorin
Pharmaceutical Co. Ltd., for providing the antibacterial
data.
Supporting Information Available: Purity data for
compounds 8, 15, 17, 20-27, experimental details and spec-
troscopic characterization of compounds 15, 17, 19-23, 25, and
13C NMR data for compounds 8, 16, 24, 26, 27. This material
is available free of charge via the Internet at http://
pubs.acs.org.
(12) Miyamoto, T.; Egawa, H.; Matsumoto, J. Pyridonecarboxylic
Acids as Antibacterial Agents. VIII. An Alternative Synthesis
of Enoxacin via Fluoronicotinic Acid Derivatives. Chem. Pharm.
Bull. 1987, 35, 2280-2285.
(13) Compounds 9-14 were prepared by following literature proce-
dures in refs 1, 2b, 5, and 7b.
(14) Japan Society of Chemotherapy. Chemotherapy 1981, 29, 76.
References
(1) Koga, H.; Itoh, A.; Murayama, S.; Suzue, S.; Irikura, T. Structure-
Activity Relationships of Antibacterial 6,7- and 7.8-Disubstituted
1-Alkyl-1,4-dihydro-4-oxoquinolone-3-carboxylic Acids. J. Med.
Chem. 1980, 23, 1358-1363.
JM040204G