A novel antibacterial 8-chloroquinolone with a distorted orientation of the N1-(5-amino-2,4-difluorophenyl) group

Article abstract of DOI:10.1021/jm0205090

Fluoroquinolones represent a major class of antibacterial agents with great therapeutic potential. In this study, we designed m-aminophenyl groups as novel N-1 substituents of naphthyridones and quinolones. Among newly synthesized compounds, 7-(3-aminoazetidin-1-yl)-1-(5-amino-2,4-difluorophenyl)-8-chloro-6- fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4) has extremely potent antibacterial activities against Gram (+) as well as Gram (-) bacteria. This compound is significantly more potent than trovafloxacin against clinical isolates: 30 times against Streptococcus pneumoniae and 128 times against methicillin resistant Staphylococcus aureus. The structure-activity relationship (SAR) study revealed that a limited combination of 1-(5-amino-2,4-difluorophenyl) group, 7-(azetidin-1-yl) group, and 8-Cl atom (or Br atom or Me group) gave potent antibacterial activity. An X-ray crystallographic study of a 7-(3-ethylaminoazetidin-1-yl)-8-chloro derivative demonstrated that the N-1 aromatic group was remarkably distorted out of the core quinolone plane by steric repulsion between the C-8 Cl atom and the N-1 substituent. Furthermore, a molecular modeling study of 4 and its analogues demonstrated that a highly distorted orientation was induced by a steric hindrance of the C-8 substituent, such as Cl, Br, or a methyl group. Thus, their highly strained conformation should be a key factor for the potent antibacterial activity.

Full text of DOI:10.1021/jm0205090

J . Med. Chem. 2003, 46, 1905-1917
1905
A Novel An tiba cter ia l 8-Ch lor oqu in olon e w ith a Distor ted Or ien ta tion of th e
N1-(5-Am in o-2,4-d iflu or op h en yl) Gr ou p
Yasuhiro Kuramoto,*,†,‡ Yoshihiro Ohshita,‡ J iro Yoshida,‡ Akira Yazaki,‡ Motoo Shiro,§ and Tohru Koike†
Division of Medicinal Chemistry, Graduated School of Biomedical Science, Hiroshima University, Kasumi 1-2-3, Minamiku,
Hiroshima 734-8551, J apan, Institute for Medical Research, Wakunaga Pharmaceutical Co., Ltd., 1624 Shimokotachi
Kodacho, Takata-gun, Hiroshima 739-1195, J apan, and Rigaku Cooporation X-ray Research Laboratory, Matsubaracho 3-9-12,
Akishima, Tokyo 196-8666, J apan
Received November 8, 2002
Fluoroquinolones represent a major class of antibacterial agents with great therapeutic
potential. In this study, we designed m-aminophenyl groups as novel N-1 substituents of
naphthyridones and quinolones. Among newly synthesized compounds, 7-(3-aminoazetidin-1-
yl)-1-(5-amino-2,4-difluorophenyl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
(4) has extremely potent antibacterial activities against Gram (+) as well as Gram (-) bacteria.
This compound is significantly more potent than trovafloxacin against clinical isolates: 30
times against Streptococcus pneumoniae and 128 times against methicillin resistant Staphy-
lococcus aureus. The structure-activity relationship (SAR) study revealed that a limited
combination of 1-(5-amino-2,4-difluorophenyl) group, 7-(azetidin-1-yl) group, and 8-Cl atom
(or Br atom or Me group) gave potent antibacterial activity. An X-ray crystallographic study
of a 7-(3-ethylaminoazetidin-1-yl)-8-chloro derivative demonstrated that the N-1 aromatic group
was remarkably distorted out of the core quinolone plane by steric repulsion between the C-8
Cl atom and the N-1 substituent. Furthermore, a molecular modeling study of 4 and its
analogues demonstrated that a highly distorted orientation was induced by a steric hindrance
of the C-8 substituent, such as Cl, Br, or a methyl group. Thus, their highly strained
conformation should be a key factor for the potent antibacterial activity.
In tr od u ction
rine atom was introduced to the N1-cyclopropyl group
to enhance the activity.14
Norfloxacin, the first “new quinolone”, opened a new
era in the treatment of infectious diseases in 1980.1 A
number of new compounds with successful chemical
modifications, such as ciprofloxacin (1),2 tosufloxacin
(2),3 and ofloxacin,4 had been brought into clinical use.
These compounds offered novel N-1 substituents, such
as cyclopropyl, 2,4-difluorophenyl, and 1,8-bridged groups.
For further improvement, the cyclopropyl group was
widely used as an N-1 substituent because 1-cyclopropyl
compounds generally gave superior antibacterial activ-
ity.5,6 Various structural modifications have been con-
ducted, and a number of structure-activity relation-
On the other hand, the structural modifications of N-1
aryl compounds have not been fully studied. Chu et al.
reported the SAR of N-1 aryl quinolones carrying the
fluorophenyl, hydroxyphenyl, or methoxyphenyl groups.15
This study indicated that a 2,4-difluorophenyl group
was the most preferable N-1 aryl substituent; therefore,
many 1-(2,4-difluorophenyl)naphthyridones and quino-
lones were synthesized. By contrast, little is known
about N-1 phenyl groups with other substituents, such
as an amino group. Thus, we focused our effort on the
structural modification of the N-1 phenyl group and
synthesized novel N-1 phenyl groups that have an
amino group and fluorine atoms. We found that the 1-(5-
amino-2,4-difluorophenyl) analogue 3 gave slightly su-
perior activity to 2. Although compound 3 had a closely
related structure to 2, there was an unexpected dis-
crepancy in phototoxicity between the two compounds.
Compound 2, a typical N-1 aryl naphthylidone, demon-
strated moderate phototoxicity in a mouse model at an
intravenous dose of 40 mg/kg. On the contrary, com-
pound 3 showed no phototoxicity in the same mouse
model.16 This fact enabled us to continue to synthesize
the 1-(5-amino-2,4-difluorophenyl) derivatives.
ships (SARs) have been accumulated as follows:
combination of the C-7 pyrrolidinyl group and the C-8
chlorine atom remarkably enhances the activity,5,7
a
a
methoxy group or a trifluoromethyl group at the C-8
position reduces the phototoxicity,8,9 and a replacement
of the 1-cyclopropylquinolone core structure with a novel
scaffold, 4H-4-oxoquinolidine, gives excellent activity.10
These SARs provided a great deal of useful information
to obtain improved compounds with enhanced activity
and good safety profiles. Several novel 1-cyclopropy-
lquinolones have been developed to overcome the critical
problems related to resistant strains,11 phototoxicity,12
and cardiac dysrhythmia.13 However, these problems
have not been satisfactorily resolved. Recently, a fluo-
In this study, we synthesized a novel antibacterial
quinolone, 7-(3-aminoazetidin-1-yl)-1-(5-amino-2,4-dif-
luorophenyl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquino-
line-3-carboxylic acid (4), and its derivatives, which
contain a 1,8-naphthyridone or quinolone core structure.
A SAR study on the novel compounds was carried out
to determine the effects of (i) the substitution pattern
* To whom correspondence should be addressed. Tel: 81-826-45-
2331. Fax: 81-826-45-4351. E-mail: kuramoto_y@wakunaga.co.jp.
† Hiroshima University.
‡ Wakunaga Pharmaceutical Co., Ltd..
§ Rigaku Cooporation X-ray Research Laboratory.
10.1021/jm0205090 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/09/2003

1906 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Kuramoto et al.
Sch em e 2
Sch em e 3
on the N-1 phenyl ring and (ii) the combination of C-7
and C-8 substituents. Furthermore, we were able to
describe a novel correlation between the activity and
the distorted orientation of the N-1 aromatic group
based on X-ray crystallographic and molecular modeling
studies.
Ch em istr y
Novel 1,8-naphthyridone and quinolone derivatives
were synthesized according to Schemes 1-5. Scheme 1
shows the preparation of N-1 substituents, tert-butyl
aminophenylcarbamates 7a -e. The intermediates, m-
nitrobenzoic acids, were prepared by nitration of the
corresponding benzoic acids 5a -e with KNO3 in con-
centrated H2SO4 and then converted to the nitrophe-
nylcarbamate derivatives 6a -e by Curtius rearrange-
ment. Catalytic hydrogenation of the nitro group gave
7a -e. The reaction of 8 or 11a -e with triethyl ortho-
formate, following substitution with 7a -e and cycliza-
tion, gave the corresponding naphthyridone-3-carboxy-
lates 9a -e or quinolone-3-carboxylates 12a -e (see
Schemes 2 and 3). Deprotection was achieved in a
mixture of an aqueous solution of HCl and acetic acid
to obtain 10a -e and 13a -e.
Sch em e 4
Aromatic nucleophilic substitution of the 7-halogeno
group (on 10 and 13) with selected cyclic amines (i.e.,
Sch em e 1

Antibacterial 8-Chloroquinolone
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 1907
Ta ble 1. In Vitro Antibacterial Activities
GM-MICs (µg/mL)
Sch em e 5
compd no.
Gram (+)
Gram (-)
7-(3-aminopyrrolidinyl)
14 (naphthyridone)
15 (naphthyridone)
16 (naphthyridone)
17 (naphthyridone)
3 (naphthyridone)
20 (8-H)
1.99
0.45
3.22
1.61
0.26
0.22
0.34
1.16
0.86
0.14
1.81
0.32
0.10
0.14
0.22
1.21
21 (8-F)
22 (8-Cl)
7-(piperazin-1-yl)
18 (naphthyridone)
23 (8-H)
24 (8-F)
5.81
1.05
2.60
1.61
1.72
0.15
0.39
0.52
25 (8-Cl)
7-(3-aminoazetidinyl)
19 (naphthyridone)
0.65
0.49
0.42
0.07
0.07
0.09
0.08
0.12
0.12
0.10
0.15
0.12
0.08
0.03
0.04
0.03
0.04
0.08
0.22
0.06
26 (8-H)
27 (8-F)
4 (8-Cl)
28 (8-Br)
29 (8-CH3)
30 (8-Cl)
31 (8-Cl)
32 (8-Cl)
33 (8-Cl)
reference compds
1
2
0.99
0.44
0.29
0.13
0.04
0.12
0.30
0.06
34
35 (8-Cl)
reaction condition at 60 °C for 2 h in DMSO gave ca.
80% yield (see Experimental Section). The catalytic
effect of the Li+ ion is possibly due to its chelation with
3-carboxylic acid and 4-carbonyl groups.
Resu lts a n d Discu ssion
SAR. Compounds 3, 4, and 14-33 were evaluated for
their in vitro antibacterial activities against a variety
of Gram (+) bacteria (13 strains) and Gram (-) bacteria
(14 strains). The geometric means of minimum inhibi-
tory concentrations (GM-MICs) for the Gram (+) and
Gram (-) bacteria were calculated to facilitate a com-
parison of their activities (Table 1). The activities of four
reference compounds, 1 (a standard compound for Gram
(-) bacteria), 2, trovafloxacin (34)20 (a standard com-
pound for Gram (+) bacteria), and 3517 (the desamino
analogue of 4), against those bacteria were also exam-
ined. The MICs of 1, 4, 34, and 35 against four clinical
isolates (Streptococcus pneumoniae, methicillin resistant
Staphylococcus aureus (MRSA), Pseudomonas aerugi-
nosa, and Escherichia coli) are summarized in Table 2.
pyrrolidine, piperazine, and azetidine) gave compounds
3, 4, and 14-33 (see Scheme 4 for 1,8-naphthyridone
derivatives and Scheme 5 for quinolone derivatives). The
requisite 3-aminoazetidine and derivatives were syn-
thesized according to a method similar to established
procedures.17,18 The substitution reaction of 10a -e and
13a -c was completed within a few hours in the pres-
ence of Et3N at 80 °C in dimethyl formamide (DMF),
dimethyl sulfoxide (DMSO), or MeCN. On the other
hand, a longer reaction time (ca. 1 day) and a higher
temperature (>100 °C) were required to complete the
reaction of the less reactive 8-Br (13d ) and 8-Me (13e)
derivatives. Such conditions resulted in low yields
(<20%) because of the competitive decarboxylation at
the 3-position. Previously, an analogous nucleophilic
substitution of an 8-Br quinolone derivative without
decarboxylation by derivatizing to its boron difluoride
intermediate was accomplished.19 Applying this method
to the reaction of 13d ,e with 3-aminoazetidine did not
improve the yield. After the examination of many
additives (organic bases and inorganic salts) and reac-
tion conditions (temperature and solvent), Li+ ion was
identified as a novel accelerator for the C-7 substitution
reaction. In the presence of 4.5 equiv of LiCl, a moderate
To elucidate the effect of the substitution pattern of
the N-1 phenyl ring on the activity, the activities of

1908 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Kuramoto et al.
Ta ble 2. In Vitro Antibacterial Activities against Clinical
Gram (-) bacteria (see compound 4). The chlorine
derivative 4 was more active than the 8-F derivative
27: ca. six times against Gram (+) and three times
against Gram (-) bacteria. The naphthyridone analogue
19 and the 8-H analogue 26 were slightly less active
than the fluorine derivative 27. In the 7-(3-aminoaze-
tidin-1-yl) analogues, the order of activity imparted by
the C-8 substituent was Cl . F g H g naphthyridone.
This order of activity is opposite to that of 7-(3-
aminopyrrolidin-1-yl) analogues (naphthyridone g H g
F . Cl) as shown above. It is worth noting that the C-8
chlorine atom makes a dramatic difference in the
antibacterial activity of the pyrrolidine and azetidine
series. One possible cause for such a discrepancy in the
activity is the bulkiness of the chlorine atom. To test
this assumption, two 7-(3-aminoazetidin-1-yl) deriva-
tives with a large C-8 substituent, the 8-bromo analogue
28 and the 8-methyl analogue 29, were synthesized.
Both compounds were almost as active as 4 and exhib-
ited remarkably potent activity superior to that of the
8-F analogue 27. These results demonstrate that a
larger C-8 substituent is required for the potent activity
in 7-(3-aminoazetidin-1-yl) derivatives.
Isolatesa
MICs (µg/mL)
compd no.
sp
MRSA
pa
ec
4
1
34
35
0.008
1
0.25
0.03
1
128
128
8
1
8
16
16
1
128
>128
32
a
sp, S. pneumoniae W1466; MRSA, MRSA W9501; pa, P.
aeruginosa W348; ec, E. coli W9523.
compounds 3 and 14-17, which varied in the N-1
substituent for a same 7-[(3S)-3-aminopyrrolidin-1-yl]-
1,8-naphthyridone skeleton, were evaluated. The result
clearly shows that the antibacterial activity of these
analogues is very sensitive to the precise substitution
pattern on the N-1 phenyl ring. Among the compounds,
the 5-amino-2,4-difluorophenyl analogue 3 has the
strongest activity. Removal of a fluorine atom from the
N-1 phenyl group of 3 reduced the activity against Gram
(+) and Gram (-) bacteria. The activities of 14 (5-amino-
2-fluorophenyl) and 15 (3-amino-4-fluorophenyl) were
reduced to one-eighth and ca. one-half, respectively, as
compared with that of 3. Regarding the position of the
m-amino group, the 5-amino-2,4-difluorophenyl deriva-
tive 3 is more active than its regio isomer 17 (3-amino-
2,4-difluorophenyl analogue): six times against Gram
(+) bacteria and three times against Gram (-) bacteria.
The addition of a m-fluorine atom to 3 significantly
reduced the activity to 1/12 against Gram (+) bacteria
and 1/18 against Gram (-) bacteria (see the 5-amino-
2,3,4-trifluorophenyl analogue 16). Because the activity
of 5-amino-2,4-difluorophenyl derivative 3 was markedly
higher than those of the other N-1 derivatives, we
further investigated the effects of the substituents at
C-7 and C-8 positions of 1-(5-amino-2,4-difluorophenyl)
derivatives in the next step.
Several quinolones (H, F, or Cl atom at the C-8
position) and naphthyridones carrying a 7-(3-aminopy-
rrolidin-1-yl), 7-(piperazin-1-yl), or 7-(3-aminoazetidin-
1-yl) group were synthesized (3, 4, and 18-33). The
activities of these 1-(5-amino-2,4-difluorophenyl) deriva-
tives strongly depend on a combination of C-7 and C-8
substituents (see Table 1). All piperazine analogues (18
and 23-25) were less active than the aminopyrrolidinyl
derivative 3. Among them, 8-H derivative 23 was the
most active against Gram (+) and Gram (-) bacteria.
The naphthyridone analogue 18 was significantly less
active than the quinolone derivatives 23-25, especially
against Gram (-) bacteria.
Significantly enhanced activity was obtained only
when an azetidinyl group was introduced to the C-7
position of 8-chloroquinolone containing the 1-(5-amino-
2,4-difluorophenyl) group. The azetidine analogue 4 was
at least 15 times more potent than the piperazine
analogue 25 and the pyrrolidine analogue 22. Such a
dramatic enhancement of the activity, however, was not
observed in the other C-8 series of compounds (8-H, -F
quinolone, or naphthyridone). A limited combination,
the 7-azetidinyl group and the 8-Cl (or Br) atom,
enhances the activity synergistically. Thus, the best
combination of the 7-(3-aminoazetidin-1-yl) group and
the 8-Cl atom (see compound 4) gave extremely low GM-
MICs of 0.07 µg/mL against Gram (+) bacteria and 0.03
µg/mL against Gram (-) bacteria.
Frigola et al. already reported the desamino com-
pound 3517 with the same C-7 and C-8 substituents as
compound 4. Compound 35 gave almost half the activity
of compound 4. However, against clinical isolates,
compound 4 was remarkably more potent than 35
(Table 2): four times more active against S. pneumoniae
and 8-32 times more active against ciprofloxacin re-
sistant strains (MRSA, P. aeruginosa, and E. coli). The
m-amino group on the N-1 phenyl ring enhanced the
activity, especially against quinolone resistant strains.
The mechanism for enhancing the activity is unclear;
however, there might be two possible reasons for it: (i)
the electrostatic effect of the amino group and (ii) the
hydrogen bond formation at the binding site.
Among the 7-(3-aminopyrrolidin-1-yl) derivatives (3
and 20-22), the naphthyridone analogue 3 and the 8-H
quinolone derivative 20 showed comparable activity
against Gram (+) and Gram (-) bacteria. The activity
of the 8-F quinolone derivative 21 was reduced to ca.
one-half for that of 3 against Gram (+) and Gram (-)
bacteria. Notably, there was a remarkable difference
between the activities of 8-F and 8-Cl derivatives. The
introduction of a chlorine atom to the C-8 position (22)
significantly reduced the activity as compared with 3:
ca. one-fifth against Gram (+) bacteria and 1/12 against
Gram (-) bacteria.
For further improvement of the activity, various alkyl
groups were introduced to the 3-aminoazetidine moiety
of 4 (compounds 30-33). Unfortunately, this attempt
resulted in reduced activity against Gram (-) bacteria.
The methylamino derivative 30 was as active as 4, and
the 3-amino-3-methyl derivative 33 exhibited slightly
reduced activity. The introduction of the ethyl group to
the 3-amino group (31) reduced the activity to ca. one-
half of that of 4 against Gram (+) and Gram (-)
bacteria. The activity of the dimethylamino analogue
32 against Gram (-) bacteria was reduced to one-
seventh of that of 4. The reason for the decreased
By contrast, in the series of the 7-(3-aminoazetidin-
1-yl) derivatives, the C-8 chlorine atom gave greatly
enhanced antibacterial activity against Gram (+) and

Antibacterial 8-Chloroquinolone
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 1909
even smaller than that of 124.0(2)° for C9-N1-C11,
indicating a shift of the N-1 aromatic group toward the
C-2 hydrogen atom. This strained conformation is
possibly due to the steric repulsion of the N-1 aromatic
substituent and the C-8 Cl atom. As was reported for
X-ray crystal structures of nalidixic acid and its deriva-
tives,22,23 a π-π ring stacking interaction in a pair of
31 molecules was observed. The intermolecular distance
of two quinolone planes is ca. 3.6 Å, where each N-1
aromatic group is directed toward the opposite sides.
The protonated ethylamino nitrogen H+‚N21 makes an
ion pair with a tosylate O40 anion with a distance of
2.863(2) Å. The m-amino nitrogen atom on the N-1
aromatic group is positioned to interact by hydrogen
bonds with the EtOH oxygen atom (N32H‚‚‚O, N-O
distance of 3.032(3) Å) and the carbonyl oxygen atom
(N32H‚‚‚O27, N-O distance of 3.013(2) Å). The observa-
tion of these hydrogen bonds suggests that the m-amino
group might be an effective electron acceptor in the
quinolone binding site.
F igu r e 1. X-ray crystal structure of 31‚TsOH‚EtOH. Atoms
are drawn with 50% probability ellipsoids.
activity against Gram (-) bacteria might be an in-
creased lipophilicity.
The activity of 4 was compared with those of 1 and
34. The GM-MIC of 4 against Gram (+) bacteria was
ca. four times superior to that of 34 and that against
Gram (-) bacteria was almost equal to that of 1.
Moreover, compound 4 was significantly more potent
than 1 and 34 against clinical isolates. Typical MIC
values (µg/mL) of compounds 4, 1, and 34 against
clinical isolates are listed in Table 2. Compound 4
exhibited 8-128 times superior activity to those of 1
and 34 against ciprofloxacin resistant MRSA, P. aerugi-
nosa, and E. coli. Furthermore, compound 4 gave an
excellent activity against S. pneumoniae, i.e., 30 times
more potent than 34. Compound 4 had the extremely
potent activity against Gram (+) bacteria as well as
Gram (-) bacteria, including quinolone resistant clinical
isolates.
Phototoxicity is one of the most noticeable side effects
induced by “new quinolones”. Especially, quinolone
compounds containing a fluorine or chlorine atom at the
C-8 position have been reported to have a critical
problem in phototoxicity.5,21 The 1-(5-amino-2,4-difluo-
rophenyl) derivatives with a halogen atom (F, Cl, or Br)
at C-8, however, showed none or very low phototoxicity,
which is similar to that of ofloxacin in a mouse model
(data not shown).16
Followingly, to determine a more detailed role of a
C-8 substituent and an m-aminophenyl group of 4 and
its derivatives in the biological activities, an X-ray
crystallographic study, molecular modeling, and mea-
surements of pKa values and dissociation constants with
Mg2+ ions were carried out.
X-r ay Cr ystal Str u ctu r e of 31‚TsOH‚EtOH. Among
all of the attempts to isolate an appropriate crystal of
the quinolones for X-ray crystal analysis, a p-TsOH salt
of 3-ethylaminoazetidinyl derivative 31 was crystallized
as colorless prisms from a DMSO/EtOH solution. The
1H NMR data were compatible with a structural formula
of 31‚TsOH‚EtOH. The X-ray crystal structure is shown
in Figure 1. The carbonyl oxygen, carboxylic acid, and
C-6 F atom are almost in a quinolone core ring plane.
On the other hand, the N-1 aromatic group is remark-
ably distorted out of the plane. The strain of the N1-
C11 bond from the plane is evaluated as a torsion angle
of 155.2(2)° for C10-C9-N1-C11 (cf. 180° for strain free).
Furthermore, the angle of 114.6(2)° for C2-N1-C11 is
Molecu la r Mod elin g Stu d y. To rationalize the
correlation between the antibacterial activity and the
strained conformation, we attempted to obtain the X-ray
crystal structures of other C-8 derivatives. However,
appropriate crystals for X-ray analysis have not been
obtained because this series of compounds had a marked
tendency to give very small crystals. Therefore, we
calculated the minimum energy conformations for C-8
derivatives 4 and 26-29. The calculations of these
compounds were performed as their zwitterionic species,
since the deprotonation constants (pKa) of 3-carboxylic
acid and the 3-amino group in the azetidine moiety for
4 were 5.4 and >9, respectively (see Experimental
Section). Typical calculated structures are shown as side
and top views in Figure 2. The obtained conformation
for 4 (see Figure 2a) is evidently distorted, being almost
the same as the X-ray crystal structure of its ethyl
derivative 31. The N-1 aromatic group is located above
the quinolone core ring plane. Here again, we evaluate
the structural strain of the N-1 aromatic group as a
torsion angle for C10-C9-N1-C11 and the angles around
the N1 atom. The torsion angle of 159.7° for C10-C9-
N1-C11, the angle of 115.4° for C2-N1-C11, and the
angle of 123.8° for C9-N1-C11 in 4 are similar to the
crystal data of 31 (155.2, 114.6, and 124.0°, respec-
tively). Larger substituents, C-8 Br atom of 28 and the
methyl group of 29, induced slightly more strained
conformations, as shown by the smaller torsion angles
of 155.3 and 149.5°, respectively. By contrast, the
smaller substituents, C-8 F and H groups, gave less
strain to the N-1 aromatic group (see Figure 2b for 27
and c for 26): torsion angles of -178.6 and -178.0° for
C10-C9-N1-C11 and angles of 114.9 and 118.2° for C2-
N1-C11. These torsion angles demonstrate that the N1-
C11 bonds of 27 and 26 are not distorted from the
quinolone core ring plane.
The three-dimensional orientation of the N-1 aromatic
1
group of 4 was also confirmed by an upfield shift of H
NMR for the C-2 hydrogen atom, which would be caused
by the shielding effect of the N-1 phenyl group: δ 8.42
for 4 and δ 8.64 for 26 in a DMSO solution. These
results obviously demonstrate that steric repulsion of
the C-8 substituent causes the distoted orientation of
the N-1 phenyl group. The highly distorted compounds

1910 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Kuramoto et al.
Con clu sion s
We have synthesized a series of antibacterial naph-
thyridones and quinolones appended with a novel
5-amino-2,4-difluorophenyl group at the N-1 position.
The antibacterial activities of these compounds strongly
depend on the combination of C-7 and C-8 substituents.
The SAR study showed that a limited combination,
3-aminoazetidin-1-yl group at the C-7 and Cl (or Br)
atom at the C-8 on the quinolone ring (i.e., 4 or 28), gave
potent activity. Compound 4 had extremely stronger
activity than clinically used compounds, including 1, 2,
and 34. The amino group on the N-1 phenyl ring
enhanced the activity, especially against quinolone
resistant strains. An X-ray crystallographic analysis and
a molecular modeling study revealed that the distorted
orientation of the N-1 phenyl group was a key factor
for the potent activity. These findings should be useful
for the design of newer quinolones. We conclude that
compound 4 may be promising as a new class of
quinolone antibacterial compounds. Further modifica-
tion of the N-1 aromatic group in 4 is now under
consideration.
Exp er im en ta l Section
Gen er a l Meth od s. All chemicals used were of reagent
grade. Column chromatography was performed using silica gel
60 (60-200 mesh). Reactions were monitored by thin-layer
chromatography on silica gel (Merck 60F254) plates using UV
light (254 nm) for detection. Melting points were determined
with a Yanagimoto melting point apparatus and were not
corrected. Infrared (IR) spectra were determined in KBr on a
J ASCO FT/IR-5300. NMR spectra were recorded with a J EOL
J NM-ECP 500 at 500 MHz (1H NMR) and at 125 MHz (proton
decoupling 13C NMR). Chemical shifts are expressed in ppm
(δ) relative to internal tetramethylsilane, and coupling con-
stants (J values) are in hertz. Mass spectra were obtained with
a J EOL J MS-GC mate in fast-atom bombardment (FAB) mode
(with 1:1 glycerol/DMSO matrix). Elemental analytical data
(C, H, N) within 0.4% were obtained on a Perkin-Elmer 2400
CHN analyzer. UV spectra were recorded on a Hitachi U-3500
spectrophotometer equipped with a thermoelectric cell tem-
perature controller at 35.0 ( 0.1 °C. Before pH measurement
at 35.0 ( 0.1 °C with I ) 0.10 (NaCl), the pH electrode system
(DKK Corporation Multi Channel Ion Meter IOL-40 with a
Ross Combination pH Electrode 8102BN) was calibrated with
standard pH solutions (pH 4.02 and 6.84) under the nitrogen
atmosphere (>99.999% purity) at 35.0 ( 0.1 °C.
F igu r e 2. Minimum energy structures of twitterionic spe-
cies: side and top views for (a) 4, (b) 27, and (c) 26.
4, 28, and 29 have significantly stronger antibacterial
activity than the less-strained analogues 26 and 27, as
mentioned above. Therefore, the distorted orientation
of the N-1 pheny group is a key factor for the stronger
activity. The other combination with 7-(3-aminopyrro-
lidin-1-yl) group and the same N-1 aromatic group,
however, shows an inverse relationship between the
antibacterial activity and the degree of distorted orien-
tation (see the activity-order of 20 (C-8 H) > 21 (F) .
22 (Cl) in Table 1).
ter t-Bu tyl 2,4-Diflu or o-5-n itr op h en ylca r ba m a te (6a ).
To a solution of 2,4-difluorobenzoic acid (5a ) (158.0 g, 1.0 mol)
in concentrated sulfuric acid (500 mL) was added portionwise
potassium nitrate (111.0 g, 1.1 mol) with ice-cooling and
stirring. The reaction mixture was stirred at room temperature
for 24 h. The solution was poured into 2 L of ice water and
allowed to stand overnight. The precipitated solid was collected
by filtration, washed with water, and dried over P2O5 to give
2,4-difluoro-5-nitrobenzoic acid (141.0 g, 70%). 1H NMR (DMSO-
d6): δ 8.60 (1H, dd, J ) 8.7, 7.3 Hz), 7.86 (1H, t, J ) 11.0 Hz).
To a solution of 2,4-difluoro-5-nitrobenzoic acid (122.0 g, 0.60
mol) in CH2Cl2 (500 mL) and DMF (1.0 mL) at room temper-
ature was added dropwise oxalyl chloride (105 mL, 1.2 mol).
The reaction mixture was stirred at room temperature for 18
h, and the solvent was evaporated under reduced pressure.
The residue was dissolved in CH2Cl2 (120 mL) and DMF (150
mL). To the solution was added portionwise sodium azide (47.8
g, 0.66 mol) with ice cooling. After the reaction mixture was
stirred at room temperature for 20 min, 2-methyl-2-propanol
(300 mL) was added. After the reaction mixture was heated
to reflux for 2 h, the solvent was evaporated. The residue was
extracted with ethyl acetate (600 mL), and the obtained extract
was washed with aqueous 2% (w/v) sodium bicarbonate. After
Recently, an X-ray crystal structure of the 1:1 Mg2+
complex with norfloxacin was reported, in which the
oxygen atoms of quinolone carbonyl and carboxylate
anion coordinate to a Mg2+ ion bidentately.24 The
antibacterial activity of quinolone is proposed to be
achieved via binding to the gyrase-DNA complex in the
presence of Mg2+ ion.25 Because these reports suggest
that the Mg2+-quinolone complex is important for
biological activity, we determined the pKa values and
dissociation constants with Mg2+ ions for 4 and 27.
Compounds 4 and 27 have almost the same pKa values
of 5.4 ( 0.1 and Mg2+ dissociation constants of 2.0 (
0.2 mM (see Experimental Section). Although the steric
repulsion of the C-8 Cl atom and the N-1 phenyl group
induces the distorted conformation, it does not affect the
physicochemical properties of quinolone carboxylic acid.
Therefore, we conclude that the shape of 1-(5-amino-
2,4-difluorophenyl)-8-chloroquinolone should be very
important for an interaction at the target site.

Antibacterial 8-Chloroquinolone
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 1911
the organic layer was dried over MgSO4, the solvent was
evaporated. Purification by silica gel column chromatography
(CH2Cl2) gave 6a as a yellowish powder (149 g, 93% yield);
20 Hz), 109.3 (s), 109.2 (s), 78.9 (s), 28.0 (s). IR: 3362, 1720,
1248, 1165 cm-1. MS m/z: 227 (M + H)+. Anal. (C11H15FN2O2)
C, H, N.
1
mp 82-83 °C. H NMR (CDCl3): δ 8.95 (1H, s), 7.04 (1H, t, J
ter t-Bu tyl 3-Am in o-4-flu or op h en ylca r ba m a te (7c). Yel-
lowish solid (47% yield) purified by silica gel column chroma-
tography (20:1 CH2Cl2/ethyl acetate); mp 125-126 °C. 1H NMR
(CDCl3): δ 7.04 (1H, brs), 6.86 (1H, dd, J ) 10.6, 8.7 Hz), 6.44
(1H, ddd, J ) 8.7, 6.4, 2.8 Hz), 6.34 (1H, brs), 3.72 (2H, brs),
1.50 (9H, s). 13C NMR (DMSO-d6): δ 152.7 (s), 146.3 (d, J )
232 Hz), 136.1 (d, J ) 14 Hz), 135.8 (s), 114.3 (d, J ) 19 Hz),
106.2 (s), 105.8 (s), 78.5 (s), 28.1 (s). IR: 3312, 1697, 1305,
1163 cm-1. MS m/z: 227 (M + H)+. Anal. (C11H15FN2O2) C, H,
N.
) 10.1 Hz), 6.69 (1H, s), 1.53 (9H, s). 13C NMR (CDCl3): δ
154.0 (dd, J ) 257, 11 Hz), 151.6 (s), 150.7 (dd, J ) 264, 13
Hz), 133.7 (s), 124.2 (dd, J ) 12, 4 Hz), 117.0 (s), 105.8 (dt, J
) 25, 4 Hz), 82.4 (s), 28.1 (s). IR: 1705, 1547, 1344, 1151, 891,
858 cm-1. MS m/z: 275 (M + H)+.
ter t-Bu t yl 2-F lu or o-5-n it r op h en ylca r b a m a t e (6b ). 2-
Fluoro-5-nitrobenzoic acid (yellowish solid, 85% yield). 1H NMR
(DMSO-d6): δ 8.61 (1H, dd, J ) 6.4, 3.2 Hz), 8.49 (1H, dt, J )
9.2, 3.2 Hz), 7.63 (1H, t, J ) 9.2 Hz). The nitrophenylcarbam-
ate derivative 6b (yellow solid 75% yield); mp 98-99 °C. 1H
NMR (CDCl3): δ 9.09 (1H, s), 7.95-7.88 (1H, m), 7.20 (1H,
dd, J ) 9.6, 6,9 Hz), 6.83 (1H, s), 1.56 (9H, s). 13C NMR (DMSO-
d6): δ 152.6 (s), 149.6 (d, J ) 257 Hz), 136.4 (s), 136.3 (d, J )
11 Hz), 125.2 (d, J ) 8 Hz), 118.7 (d, J ) 22 Hz), 113.9 (s),
ter t-Bu tyl 5-Am in o-2,3,4-tr iflu or oph en ylcar bam ate (7d).
Pale brown solid (26% yield) purified by silica gel column
chromatography (40:1 CH2Cl2/ethyl acetate); mp 123-124 °C.
1H NMR (CDCl3): δ 7.35 (1H, brs), 6.53 (1H, s), 3.67 (2H, brs),
1.52 (9H, s). 13C NMR (DMSO-d6): δ 152.9 (s), 139.9 (ddd, J
) 242, 15, 13 Hz), 135.4 (dd, J ) 227, 7 Hz), 134.6 (dd, J )
236, 12 Hz), 133.1 (d, J ) 21 Hz), 123.0 (d, J ) 9 Hz), 104.5
(s), 79.3 (s), 27.9 (s). IR: 3364, 1734, 1267, 1155 cm-1. MS
m/z: 263 (M + H)+. Anal. (C11H13F3N2O2) C, H, N.
80.0 (s), 27.9 (s). IR: 1707, 1535, 1346, 1157, 877, 828 cm-1
.
MS m/z: 257 (M + H)+.
ter t-Bu tyl 4-Flu or o-3-n itr oph en ylcar bam ate (6c). 4-Flu-
1
oro-3-nitrobenzoic acid (yellowish solid, 88% yield). H NMR
ter t-Bu tyl 3-Am in o-2,6-d iflu or op h en ylca r ba m a te (7e).
Pale brown solid (38% yield) purified by silica gel column
chromatography (20:1 CH2Cl2/ethyl acetate); mp 103-104 °C.
1H NMR (CDCl3): δ 6.72 (1H, dt, J ) 9.2, 1.8 Hz), 6.56 (1H,
dt, J ) 9.2, 5.1 Hz), 5.90 (1H, brs), 3.58 (2H, brs), 1.49 (9H, s).
13C NMR (DMSO-d6): δ 153.2 (s), 149.0 (dd, J ) 235, 2 Hz),
145.9 (dd, J ) 242, 3 Hz), 133.2 (dd, J ) 13, 2 Hz), 114.7 (dd,
J ) 17, 15 Hz), 112.3 (s), 110.1 (d, J ) 21 Hz), 78.9 (s), 27.9
(s). IR: 3213, 1705, 1282, 1167 cm-1. MS m/z: 245 (M + H)+.
Anal. (C11H14F2N2O2) C, H, N.
(DMSO-d6): δ 8.57 (1H, dd, J ) 7.3, 1.9 Hz), 8.31 (1H, ddd, J
) 8.7, 4.2, 1.9 Hz), 7.72 (1H, dd, J ) 11.4, 8.7 Hz). The
nitrophenylcarbamate derivative 6c (yellow solid, 70% yield);
mp 117-118 °C. 1H NMR (CDCl3): δ 8.14 (1H, dd, J ) 6.4,
2.7 Hz), 7.60 (1H, brs), 7.21 (1H, t, J ) 9.7 Hz), 6.64 (1H, brs),
1.53 (9H, s). 13C NMR (DMSO-d6): δ 156.4 (d, J ) 247 Hz),
152.6 (s), 143.7 (s), 127.9 (d, J ) 14 Hz), 119.4 (d, J ) 10 Hz),
117.4 (s), 116.5 (d, J ) 23 Hz), 80.4 (s), 27.9 (s). IR: 1709,
1547, 1348, 1159, 873 cm-1. MS m/z: 257 (M + H)+.
ter t-Bu tyl 5-Nitr o-2,3,4-tr iflu or oph en ylcar bam ate (6d).
5-Nitro-2,3,4-trifluorobenzoic acid (yellowish solid, 85% yield).
1H NMR (DMSO-d6): δ 8.43 (1H, dt, J ) 6.4, 2.1 Hz). The
nitrophenylcarbamate derivative 6d (yellowish solid, 61%
yield); mp 100-102 °C. 1H NMR (CDCl3): δ 8.78 (1H, brs),
6.74 (1H, s), 1.55 (9H, s). 13C NMR (DMSO-d6): δ 152.5 (s),
145.8 (dd, J ) 260, 12 Hz), 141.4 (dd, J ) 261, 12 Hz), 140.2
(dd, J ) 250, 5 Hz), 132.9 (s), 124.3 (d, J ) 7 Hz), 112.9 (s),
Eth yl
1-(5-ter t-Bu toxyca r bon yla m in o-2,4-d iflu or o-
ph en yl)-7-ch lor o-6-flu or o-4-oxo-1,4-dih ydr o-1,8-n aph th yr i-
d in e-3-ca r boxyla te (9a ). To a solution of acetic anhydride
(2.8 mL, 30 mmol) and triethyl orthoformate (2.6 mL, 15 mmol)
was added ethyl 2,6-dichloro-5-fluoronicotinoyl acetate (8, 2.8
g, 10 mmol). The mixture was heated at 140 °C for 6 h. After
the solvent was evaporated, the residue was dissolved in CH2-
Cl2 (10 mL). To a resulting solution was added dropwise a
solution of 7a (2.43 g, 10 mmol) in CH2Cl2 (10 mL), followed
by stirring at room temperature for 1 h. After the solvent was
evaporated, DMF (8 mL) and K2CO3 (1.39 g, 10 mmol) were
added to the residue followed by stirring at 80 °C for 30 min.
The solution was poured into water (400 mL), and the
precipitate was collected by filtration. The solid was purified
by silica gel column chromatography (20:1 CH2Cl2/ethyl ac-
etate) to give 9a as a yellowish solid (4.6 g, 93% yield); mp
80.8 (s), 27.8 (s). IR: 1720, 1547, 1342, 1165, 879, 808 cm-1
.
MS m/z: 293 (M + H)+.
ter t-Bu tyl 2,6-Diflu or o-3-n itr otr iflu or op h en ylca r ba m -
a te (6e). 2,6-Difluoro-3-nitrobenzoic acid (yellowish solid, 87%
1
yield). H NMR (DMSO-d6): δ 8.39 (1H, dt, J ) 9.2, 5.5 Hz),
7.48 (1H, dt, J ) 9.2, 1.4 Hz). The nitrophenylcarbamate
derivative 6e (yellowish solid, 73% yield); mp 113-114 °C. 1H
NMR (CDCl3): δ 8.00 (1H, ddd, J ) 9.7, 8.3, 5.5 Hz), 7.08 (1H,
dt, J ) 8.3, 2.3 Hz), 6.07 (1H, s), 1.52 (9H, s). 13C NMR (DMSO-
d6): δ 160.7 (dd, J ) 259, 4 Hz), 152.6 (s), 151.5 (dd, J ) 261,
6 Hz), 134.2 (s), 124.3 (d, J ) 11 Hz), 117.3 (dd, J ) 19, 17
Hz), 112.1 (dd, J ) 23, 3 Hz), 80.2 (s), 27.8 (s). IR: 1705, 1545,
1346, 1157, 866, 821 cm-1. MS m/z: 275 (M + H)+.
1
191-192 °C. H NMR (CDCl3): δ 8.56 (1H, s), 8.48 (1H, d, J
) 7.3 Hz), 8.35 (1H, brs), 7.12 (1H, dd, J ) 10.6, 8.9 Hz), 6.81
(1H,s), 4.41 (2H, q, J ) 7.1 Hz), 1.52 (9H, s), 1.41 (3H, t, J )
7.1 Hz). 13C NMR (CDCl3): δ 173.4 (s), 164.1 (s), 152.7 (d, J )
251 Hz), 152.2 (dd, J ) 252, 13 Hz), 152.0 (s), 151.7 (dd, J )
250, 11 Hz), 149.3 (s), 144.7 (s), 142.8 (d, J ) 23 Hz), 124.6
(dd, J ) 11, 3 Hz), 123.3 (d, J ) 10 Hz), 123.2 (d, J ) 2 Hz),
123.1 (d, J ) 21 Hz), 119.2 (s), 113.3 (s), 104.7 (dt, J ) 25, 3
Hz), 82.0 (s), 61.4 (s), 28.1 (s), 14.3 (s). IR: 3315, 1738, 1718,
1631, 1543, 1161 cm-1. MS m/z: 498 and 500 for Cl isotopic
peaks of (M + H)+.
ter t-Bu tyl 5-Am in o-2,4-d iflu or op h en ylca r ba m a te (7a ).
Under hydrogen atmosphere, a solution of 6a (48.0 g, 176
mmol) and palladium black (0.5 g) in MeOH (400 mL) was
stirred at room temperature for 3 days. After the catalyst was
filtered, the filtrate was concentrated under reduced pressure.
Purification by silica gel column chromatography (20:1 CH2-
Cl2/ethyl acetate) gave the phenylcarbamate 7a as a colorless
Eth yl 1-(5-ter t-Bu toxyca r bon yla m in o-2-flu or op h en yl)-
7-ch lor o-6-flu or o-4-oxo-1,4-d ih yd r o-1,8-n a p h th yr id in e-3-
ca r boxyla te (9b). Colorless solid (90% yield); mp 237-238
°C. 1H NMR (DMSO-d6): δ 9.74 (1H, brs), 8.74 (1H, s), 8.53
(1H, d, J ) 7.7 Hz), 7.88 (1H, brs), 7.55-7.51 (1H, m), 7.43
(1H, t, J ) 9.1 Hz), 4.24 (2H, q, J ) 7.4 Hz), 1.47 (9H, s), 1.27
(3H, t, J ) 7.4 Hz). 13C NMR (DMSO-d6): δ 172.5 (s), 163.2
(s), 152.7 (s), 152.1 (d, J ) 246 Hz), 151.9 (d, J ) 258 Hz),
149.2 (s), 144.8 (s), 140.9 (d, J ) 22 Hz), 136.7 (s), 126.6 (d, J
) 15 Hz), 123.4 (d, J ) 21 Hz), 122.8 (d, J ) 2 Hz), 120.9 (d,
J ) 6 Hz), 118.4 (s), 116.5 (d, J ) 20 Hz), 112.7 (s), 79.6 (s),
60.4 (s), 28.0 (s), 14.1 (s). IR: 3281, 1736, 1705, 1608, 1406,
1182 cm-1. MS m/z: 480 and 482 for Cl isotopic peaks of (M +
H)+.
1
powder (32 g, 75% yield); mp 120-121 °C. H NMR (CDCl3):
δ 7.57 (1H, brs), 6.77 (1H, t, J ) 10.1 Hz), 6.52 (1H, s), 3.57
(2H, s), 1.50 (9H, s). 13C NMR (DMSO-d6): δ 153.1 (s), 145.9
(dd, J ) 227, 11 Hz), 145.1 (dd, J ) 235, 10 Hz), 132.3 (dd, J
) 14, 2 Hz), 122.0 (dd, J ) 13, 3 Hz), 111.5 (s), 103.3 (dt, J )
24, 3 Hz), 78.9 (s), 28.0 (s). IR: 3364, 1728, 1319, 1163 cm-1
.
MS m/z: 245 (M + H)+. Anal. (C11H14F2N2O2) C, H, N.
ter t-Bu tyl 5-Am in o-2-flu or op h en ylca r ba m a te (7b). Col-
orless needles from hexane in 85% yield; mp 95-96 °C. 1H
NMR (CDCl3): δ 7.49 (1H, brs), 6.82 (1H, dd, J ) 11.0, 8.7
Hz), 6.66 (1H, s), 6.23 (1H, ddd, J ) 8.7, 3.7, 2.8 Hz), 3.55
(2H, s), 1.53 (9H, s). 13C NMR (DMSO-d6): δ 152.9 (s), 146.2
(d, J ) 231 Hz), 144.9 (s), 126.1 (d, J ) 13 Hz), 115.0 (d, J )

1912 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Kuramoto et al.
Eth yl 1-(3-ter t-Bu toxyca r bon yla m in o-4-flu or op h en yl)-
7-ch lor o-6-flu or o-4-oxo-1,4-d ih yd r o-1,8-n a p h th yr id in e-3-
ca r boxyla te (9c). Colorless powder (71% yield); mp 214-215
8.2 Hz), 8.33 (1H, s), 7.06 (1H, dd, J ) 10.5, 8.9 Hz), 6.80 (1H,
brs), 4.39 (2H, q, J ) 7.3 Hz), 1.51 (9H, s), 1.39 (3H, t, J ) 7.3
Hz). 13C NMR (CDCl3): δ 171.9 (s), 164.2 (s), 152.3 (dd, J )
241, 12 Hz), 152.0 (s), 151.8 (s), 151.7 (dd, J ) 252, 10 Hz),
151.1 (dd, J ) 255, 17 Hz), 148.6 (dd, J ) 254, 14 Hz), 133.9
(s), 126.4 (dd, J ) 14, 5 Hz), 126.2 (d, J ) 3 Hz), 124.7 (dd, J
) 11, 3 Hz), 119.0 (s), 113.8 (d, J ) 12 Hz), 112.2 (d, J ) 19
Hz), 111.9 (s), 104.5 (dt, J ) 24, 3 Hz), 82.2 (s), 61.4 (s), 28.2
1
°C. H NMR (CDCl3): δ 8.63 (1H, s), 8.48 (1H, d, J ) 7.3 Hz),
8.28 (1H, brs), 7.26 (1H, dd, J ) 11.1, 8.7 Hz), 7.00 (1H, ddd,
J ) 8.7, 4.5, 2.8 Hz), 6.90 (1H, s), 4.40 (2H, q, J ) 7.3 Hz),
1.52 (9H, s), 1.41 (3H, t, J ) 7.3 Hz). 13C NMR (CDCl3): δ
173.3 (s), 164.3 (s), 152.6 (d, J ) 262 Hz), 151.9 (s), 151.5 (d,
J ) 246 Hz), 149.4 (s), 145.2 (s), 142.5 (d, J ) 22 Hz), 135.9
(d, J ) 3 Hz), 128.5 (d, J ) 12 Hz), 123.4 (d, J ) 2 Hz), 123.1
(dd, J ) 21, 2 Hz), 121.4 (d, J ) 8 Hz), 118.5 (s), 115.6 (d, J )
21 Hz), 112.7 (s), 81.9 (s), 61.3 (s), 28.2 (s), 14.3 (s). IR: 3254,
1728, 1612, 1539, 1406, 1159 cm-1. MS m/z: 480 and 482 for
Cl isotopic peaks of (M + H)+.
(s), 14.3 (s). IR: 3250, 1739, 1712, 1612, 1529, 1172, 1070 cm-1
.
MS m/z: 515 and 517 for Cl isotopic peaks of (M + H)+.
Eth yl 8-Br om o-1-(5-ter t-bu toxyca r bon yla m in o-2,4-d i-
flu or op h en yl)-6,7-d iflu or o-4-oxo-1,4-d ih yd r oqu in olin e-3-
ca r boxyla te (12d ). Colorless solid (44% yield); mp 202-203
1
°C. H NMR (CDCl3): δ 8.39 (1H, t, J ) 9.4 Hz), 8.37 (1H, s),
Ethyl 1-(5-tert-Butoxycarbonylamino-2,3,4-trifluorophen-
yl)-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
ca r boxyla te (9d ). Colorless needles (92% yield); mp 208-
8.32 (1H, s), 7.06 (1H, t, J ) 9.7 Hz), 6.78 (1H, brs), 4.38 (2H,
q, J ) 7.3 Hz), 1.51 (9H, s), 1.39 (3H, t, J ) 7.3 Hz). 13C NMR
(CDCl3): δ 172.0 (s), 164.2 (s), 152.4 (dd, J ) 251, 12 Hz), 152.2
(s), 151.9 (dd, J ) 253, 16 Hz), 151.8 (s), 151.8 (dd, J ) 251,
10 Hz), 148.4 (dd, J ) 256, 16 Hz), 135.0 (s), 126.8 (d, J ) 3
Hz), 126.0 (dd, J ) 14, 4 Hz), 124.9 (dd, J ) 11, 4 Hz), 119.4
(s), 114.7 (d, J ) 19 Hz), 111.9 (s), 104.6 (dt, J ) 24, 3 Hz),
99.9 (d, J ) 12 Hz), 82.2 (s), 61.4 (s), 28.1 (s), 14.3 (s). IR: 3219,
1738, 1714, 1610, 1527, 1167 cm-1. MS m/z: 559 and 561 for
Br isotopic peaks of (M + H)+.
1
209 °C. H NMR (CDCl3): δ 8.54 (1H, s), 8.48 (1H, d, J ) 6.8
Hz), 8.16 (1H, brs), 6.82 (1H, s), 4.41 (2H, q, J ) 7.4 Hz), 1.52
(9H, s), 1.41 (3H, t, J ) 7.4 Hz). 13C NMR (DMSO-d6): δ 172.6
(s), 163.2 (s), 152.6 (s), 152.0 (d, J ) 258 Hz), 149.4 (s), 144.7
(s), 143.6 (dd, J ) 253, 10 Hz), 142.8 (dd, J ) 251, 12 Hz),
140.9 (d, J ) 22 Hz), 139.4 (dt, J ) 259, 13 Hz), 124.4 (d, J )
9 Hz), 123.5 (d, J ) 21 Hz), 123.2 (d, J ) 11 Hz), 122.8 (d, J
) 3 Hz), 118.1 (s), 112.8 (s), 80.3 (s), 60.4 (s), 27.8 (s), 14.1 (s).
IR: 3304, 1738, 1726, 1608, 1548, 1471, 1163 cm-1. MS m/z:
516 and 518 for Cl isotopic peaks of (M + H)+.
Eth yl 1-(3-ter t-Bu toxycar bon ylam in o-2,4-diflu or oph en -
yl)-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
ca r boxyla te (9e). Colorless solid (67% yield); mp 128-131
°C. 1H NMR (DMSO-d6): δ 9.16 (1H, brs), 8.75 (1H, s), 8.56
(1H, d, J ) 7.8 Hz), 7.68 (1H, ddd, J ) 8.2, 5.5, 2.7 Hz), 7.40
(1H, t, J ) 9.2 Hz), 4.24 (2H, q, J ) 7.4 Hz), 1.43 (9H, s), 1.28
(3H, t, J ) 7.4 Hz). 13C NMR (DMSO-d6): δ 172.6 (s), 163.1
(s), 158.0 (d, J ) 249 Hz), 153.3 (dd, J ) 249, 6 Hz), 152.7 (s),
151.9 (d, J ) 258 Hz), 149.4 (s), 144.9 (s), 141.0 (d, J ) 22
Hz), 127.3 (d, J ) 10 Hz), 123.7 (d, J ) 13 Hz), 123.4 (d, J )
20 Hz), 122.8 (d, J ) 3 Hz), 116.1 (t, J ) 17 Hz), 112.8 (s),
112.0 (d, J ) 22 Hz), 79.8 (s), 60.4 (s), 27.8 (s), 14.1 (s). IR:
3304, 1730, 1612, 1527, 1406, 1178 cm-1. MS m/z: 498 and
500 for Cl isotopic peaks of (M + H)+.
Eth yl
1-(5-ter t-Bu toxyca r bon yla m in o-2,4-d iflu or o-
phenyl)-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-
ca r boxyla te (12e). Slightly yellow solid (59% yield); mp 191-
192 °C. 1H NMR (CDCl3): δ 8.34 (1H, s), 8.32 (1H, s), 8.24
(1H, t, J ) 9.6 Hz), 7.10 (1H, dd, J ) 10.4, 8.7 Hz), 6.79 (1H,
brs), 4.40 (2H, q, J ) 7.3 Hz), 1.82 (3H, d, J ) 2.7 Hz), 1.52
(9H, s), 1.41 (3H, t, J ) 7.3 Hz). 13C NMR (CDCl3): δ 172.7
(s), 164.7 (s), 158.3 (dd, J ) 258, 12 Hz), 155.4 (dd, J ) 256,
12 Hz), 153.7 (s), 152.6 (dd, J ) 242, 15 Hz), 151.5 (s), 148.9
(dd, J ) 252, 16 Hz), 136.2 (d, J ) 4 Hz), 129.3 (d, J ) 16 Hz),
128.8 (s), 127.4 (dd, J ) 14, 4 Hz), 126.3 (d, J ) 3 Hz), 116.5
(d, J ) 19 Hz), 112.7 (d, J ) 19 Hz), 111.7 (s), 106.1 (dt, J )
26, 3 Hz), 81.6 (s), 61.3 (s), 28.1 (s), 14.3 (s), 11.5 (d, J ) 7
Hz). IR: 3049, 1736, 1714, 1616, 1520, 1159 cm-1. MS m/z:
495 (M + H)+.
1-(5-Am in o-2,4-diflu or oph en yl)-7-ch lor o-6-flu or o-4-oxo-
1,4-d ih yd r o-1,8-n a p h th yr id in e-3-ca r boxylic a cid (10a ).
The naphthyridine-3-carboxylate derivative 9a (1.9 g, 3.82
mmol) was added to a mixture of acetic acid (10 mL) and
aqueous 6 M HCl (5 mL). The reaction mixture was heated to
reflux for 6 h, and then, H2O (50 mL) was added. After it was
cooled, the precipitate was collected by filtration and washed
with H2O, EtOH, and Et2O to give 10a as yellow needles (1.17
g, 84%); mp >270 °C. 1H NMR (DMSO-d6): δ 8.98 (1H, s), 8.76
(1H, d, J ) 7.4 Hz), 7.43 (1H, t, J ) 10.6 Hz), 7.02 (1H, dd, J
) 8.8, 7.7 Hz), 5.46 (2H, s). 13C NMR (DMSO-d6): δ 177.4 (s),
164.4 (s), 152.2 (d, J ) 259 Hz), 150.6 (s), 150.0 (dd, J ) 244,
11 Hz), 147.1 (dd, J ) 240, 11 Hz), 144.9 (s), 142.7 (d, J ) 23
Hz), 134.0 (d, J ) 15 Hz), 123.0 (d, J ) 20 Hz), 122.5 (dd, J )
15, 4 Hz), 121.4 (d, J ) 3 Hz), 114.7 (s), 110.3 (s), 104.5 (t, J
Eth yl
1-(5-ter t-Bu toxyca r bon yla m in o-2,4-d iflu or o-
p h en yl)-6,7-d iflu or o-4-oxo-1,4-d ih yd r oq u in olin e-3-ca r -
boxyla te (12a ). Colorless solid (76% yield); mp 235-236 °C.
1H NMR (DMSO-d6): δ 9.42 (1H, brs), 8.59 (1H, s), 8.14 (1H,
dd, J ) 10.1, 8.7 Hz), 8.10 (1H, t, J ) 8.0 Hz), 7.71 (1H, t, J )
10.1 Hz), 7.22 (1H, dd, J ) 11.2, 6.2 Hz), 4.22 (2H, q, J ) 7.3
Hz), 1.45 (9H, s), 1.27 (3H, t, J ) 7.3 Hz). 13C NMR (DMSO-
d6): δ 171.5 (s), 163.6 (s), 154.2 (dd, J ) 250, 8 Hz), 152.9 (dd,
J ) 249, 13 Hz), 152.8 (s), 152.5 (dd, J ) 254, 15 Hz), 149.3
(s), 147.7 (dd, J ) 248, 14 Hz), 137.5 (d, J ) 10 Hz), 124.6 (d,
J ) 3 Hz), 124.5 (d, J ) 20 Hz), 124.4 (d, J ) 16 Hz), 122.6
(dd, J ) 15, 4 Hz), 113.9 (d, J ) 18 Hz), 111.3 (s), 106.9 (d, J
) 21 Hz), 106.0 (t, J ) 26 Hz), 79.9 (s), 60.1 (s), 27.9 (s), 14.1
(s). IR: 3269, 1722, 1616, 1533, 1163 cm-1. MS m/z: 481 (M
+ H)+.
) 24 Hz). IR: 3472, 1741, 1612, 1525, 1406, 1255, 1147 cm-1
MS m/z: 370 (M + H)+. Anal. (C15H7ClF3N3O3) C, H, N.
.
E t h yl
1-(5-ter t-Bu t oxyca r b on yla m in o-2,4-d iflu or o-
1-(5-Am in o-2-flu or op h en yl)-7-ch lor o-6-flu or o-4-oxo-
1,4-d ih yd r o-1,8-n a p h th yr id in e-3-ca r boxylic Acid (10b).
Yellow solid (82% yield); mp >290 °C. 1H NMR (DMSO-d6): δ
8.91 (1H, s), 8.75 (1H, d, J ) 7.8 Hz), 7.19 (1H, t, J ) 9.6 Hz),
6.81-6.79 (2H, m), 5.57 (2H, s). 13C NMR (DMSO-d6): δ 177.4
(s), 164.4 (s), 152.2 (d, J ) 260 Hz), 150.4 (s), 144.9 (s), 143.8
(d, J ) 255 Hz), 142.7 (d, J ) 22 Hz), 126.6 (d, J ) 14 Hz),
123.0 (d, J ) 20 Hz), 121.4 (d, J ) 4 Hz), 116.6 (d, J ) 21 Hz),
116.5 (d, J ) 20 Hz), 114.4 (s), 113.9 (s), 110.3 (s). IR: 3474,
1743, 1618, 1518, 1404, 1251, 1049 cm-1. MS m/z: 352 (M +
H)+. Anal. (C15H8ClF2N3O3) C, H, N.
1-(3-Am in o-4-flu or op h en yl)-7-ch lor o-6-flu or o-4-oxo-
1,4-d ih yd r o-1,8-n a p h th yr id in e-3-ca r boxylic Acid (10c).
Yellow solid (94% yield); mp >270 °C. 1H NMR (DMSO-d6): δ
8.79 (1H, s), 8.76 (1H, d, J ) 7.4 Hz), 7.22 (1H, dd, J ) 11.0,
8.7 Hz), 6.95 (1H, dd, J ) 7.8, 2.7 Hz), 6.74 (1H, ddd, J ) 8.7,
4.1, 2.7 Hz), 5.62 (2H, s). 13C NMR (DMSO-d6): δ 177.5 (s),
164.6 (s), 152.0 (d, J ) 260 Hz), 150.6 (d, J ) 241 Hz), 150.2
p h en yl)-4-oxo-6,7,8-tr iflu or o-1,4-d ih yd r oqu in olin e-3-ca r -
boxyla te (12b). Colorless powder (50% yield); mp 181-183
1
°C. H NMR (CDCl3): δ 8.44 (1H, brs), 8.31 (1H, s), 8.17 (1H,
t, J ) 10.1 Hz), 7.09 (1H, dd, J ) 10.5, 8.9 Hz), 6.80 (1H, brs),
4.39 (2H, q, J ) 7.3 Hz), 1.52 (9H, s), 1.39 (3H, t, J ) 7.3 Hz).
13C NMR (CDCl3): δ 171.4 (s), 164.3 (s), 151.9 (s), 151.5 (dd,
J ) 250, 10 Hz), 150.8 (s), 148.6 (dd, J ) 254, 11 Hz), 143.5
(dd, J ) 269, 16 Hz),143.2 (dd, J ) 259, 15 Hz), 141.4 (dd, J
) 256, 15 Hz), 126.9 (s), 126.2 (d, J ) 14 Hz), 124.7 (dd, J )
11, 3 Hz), 124.5 (d, J ) 4 Hz), 118.4 (s), 111.7 (s), 109.6 (d, J
) 19 Hz), 104.5 (dt, J ) 24, 3 Hz), 82.2 (s), 61.4 (s), 28.2 (s),
14.3 (s). IR: 1722, 1608, 1533, 1161 cm-1. MS m/z: 499 (M +
H)+.
Eth yl
1-(5-ter t-Bu toxyca r bon yla m in o-2,4-d iflu or o-
phenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-
ca r boxyla te (12c). Colorless solid (67% yield); mp 185-187
1
°C. H NMR (CDCl3): δ 8.35 (1H, s), 8.34 (1H, dd, J ) 10.1,

Antibacterial 8-Chloroquinolone
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 1913
(s), 145.5 (s), 142.4 (d, J ) 23 Hz), 137.4 (d, J ) 15 Hz), 135.9
(s), 122.6 (d, J ) 21 Hz), 121.5 (d, J ) 5 Hz), 115.5 (d, J ) 20
Hz), 114.4 (s), 114.3 (d, J ) 7 Hz), 109.4 (s). IR: 3481, 3377,
1741, 1616, 1516, 1404, 1249, 1049 cm-1. MS m/z: 352 (M +
H)+. Anal. (C15H8ClF2N3O3) C, H, N.
1-(5-Am in o-2,3,4-tr iflu or op h en yl)-7-ch lor o-6-flu or o-4-
oxo-1,4-d ih yd r o-1,8-n a p h t h yr id in e-3-ca r b oxylic Acid
(10d ). Colorless solid (96% yield); mp >242 °C (decomposed).
1H NMR (DMSO-d6): δ 9.04 (1H, s), 8.77 (1H, d, J ) 7.3 Hz),
6.87 (1H, dt, J ) 8.2, 1.6 Hz), 5.84 (2H, s). 13C NMR (DMSO-
d6): δ 177.4 (s), 164.3 (s), 152.3 (d, J ) 260 Hz), 150.6 (s), 144.8
(s), 142.7 (d, J ) 22 Hz), 139.8 (dt, J ) 235, 14 Hz), 139.4 (dd,
J ) 244, 11 Hz), 137.2 (dd, J ) 241, 12 Hz), 134.5 (d, J ) 11
Hz), 123.2 (s), 123.1 (d, J ) 20 Hz), 121.4 (d, J ) 4 Hz), 110.5
(s), 108.8 (s). IR: 3472, 3379, 1743, 1616, 1523, 1257, 1155
cm-1. MS m/z: 388 (M + H)+. Anal. (C15H6ClF4N3O3) C, H, N.
) 239, 10 Hz), 148.0 (dd, J ) 254, 17 Hz), 135.7 (s), 133.3 (d,
J ) 15 Hz), 125.1 (d, J ) 14 Hz), 124.4 (d, J ) 6 Hz), 115.2
(s), 113.2 (d, J ) 18 Hz), 109.1 (s), 104.7 (t, J ) 25 Hz), 101.3
(d, J ) 23 Hz). IR: 3333, 1716, 1620, 1512, 1271, 1151 cm-1
.
MS m/z: 431 and 433 for Br isotopic peaks of (M + H)+. Anal.
(C16H7BrF4N2O3) C, H, N.
1-(5-Am in o-2,4-d iflu or op h en yl)-6,7-d iflu or o-8-m eth yl-
4-oxo-1,4-d ih yd r oqu in olin e-3-ca r boxylic Acid (13e). Col-
orless solid (96% yield); mp 264-267 °C. 1H NMR (DMSO-
d6): δ 8.68 (1H, s), 8.24 (1H, t, J ) 9.6 Hz), 7.45 (1H, t, J )
10.5 Hz), 7.10 (1H, dd, J ) 8.7, 7.8 Hz), 5.45 (2H, brs), 1.86
(3H, d, J ) 2.7 Hz). 13C NMR (DMSO-d6): δ 176.8 (s), 164.7
(s), 152.4 (dd, J ) 251, 14 Hz), 152.4 (s), 150.2 (dd, J ) 246,
11 Hz), 148.3 (dd, J ) 251, 16 Hz), 147.2 (dd, J ) 237, 11 Hz),
137.2 (d, J ) 5 Hz), 134.2 (d, J ) 14 Hz), 126.5 (dd, J ) 14, 4
Hz), 123.3 (d, J ) 5 Hz), 118.3 (d, J ) 17 Hz), 114.2 (s), 110.8
(d, J ) 18 Hz), 108.2 (s), 104.9 (t, J ) 25 Hz), 10.8 (d, J ) 8
Hz). IR: 3337, 1724, 1620, 1527, 1280, 1143 cm-1. MS m/z:
367 (M + H)+. Anal. (C17H10F4N2O3) C, H, N.
1-(3-Am in o-2,4-diflu or oph en yl)-7-ch lor o-6-flu or o-4-oxo-
1,4-d ih yd r o-1,8-n a p h th yr id in e-3-ca r boxylic Acid (10e).
Yellowish solid (66% yield); mp 244-248 °C. 1H NMR (DMSO-
d6): δ 8.96 (1H, s), 8.76 (1H, d, J ) 7.3 Hz), 7.14 (1H, dd, J )
9.1, 8.2 Hz), 7.02 (1H, dt, J ) 8.2, 5.5 Hz), 5.69 (2H, s). 13C
NMR (DMSO-d6): δ 177.3 (s), 164.4 (s), 152.3 (d, J ) 259 Hz),
151.5 (dd, J ) 242, 8 Hz), 150.8 (s), 146.0 (dd, J ) 235, 10
Hz), 144.9 (s), 142.8 (d, J ) 23 Hz), 126.6 (dd, J ) 18, 15 Hz),
123.5 (dd, J ) 11, 3 Hz), 123.0 (d, J ) 21 Hz), 121.3 (d, J ) 4
Hz), 113.3 (d, J ) 8 Hz), 111.1 (d, J ) 20 Hz), 110.2 (s). IR:
1-(5-Am in o-2,4-d iflu or op h en yl)-7-[(3S)-3-a m in iop yr r o-
lid in -1-yl]-6-flu or o-4-oxo-1,4-d ih yd r o-1,8-n a p h th yr id in e-
3-ca r boxylic Acid (3). The 1,8-naphthyridine-3-carboxylic
acid derivative 10a (1.3 g, 3.52 mmol), (3S)-aminopyrrolidine
(0.60 g, 6.97 mmol), and Et3N (0.60 g, 5.94 mmol) were
dissolved in DMF (7.0 mL). The solution was stirred at 90 °C
for 1 h. After addition of EtOH (25 mL), the solution was
heated at 90 °C for 10 min and allowed to cool. The precipitate
was collected by filtration and washed with EtOH and Et2O.
The crude solid was purified by reprecipitaiton from its DMF
solution with EtOH to obtain 1.4 g of 3 as a colorless solid
3344, 3072, 1734, 1616, 1568, 1402, 1253, 1170, 1053 cm-1
.
MS m/z: 370 and 372 for Cl isotopic peaks of (M + H)+. Anal.
(C15H7ClF3N3O3) C, H, N.
1-(5-Am in o-2,4-d iflu or op h en yl)-6,7-d iflu or o-4-oxo-1,4-
d ih yd r oqu in olin e-3-ca r boxylic Acid (13a ). Colorless solid
(95% yield); mp >270 °C. 1H NMR (DMSO-d6): δ 8.87 (1H, s),
8.34 (1H, dd, J ) 10.1, 8.7 Hz), 7.50 (1H, t, J ) 10.5 Hz), 7.45
(1H, dd, J ) 11.5, 6.4 Hz), 7.04 (1H, t, J ) 8.2 Hz), 5.54 (2H,
s). 13C NMR (DMSO-d6): δ 176.8 (s), 164.9 (s), 153.6 (dd, J )
266, 15 Hz), 150.5 (dd, J ) 246, 12 Hz), 150.3 (s), 148.4 (dd, J
) 252, 14 Hz), 146.9 (dd, J ) 241, 12 Hz), 138.2 (d, J ) 11
Hz), 134.8 (d, J ) 15 Hz), 122.6 (d, J ) 11 Hz), 122.3 (d, J )
6 Hz), 114.0(s), 113.5 (d, J ) 18 Hz), 108.7 (s), 107.8 (d, J )
24 Hz), 105.3 (t, J ) 25 Hz). IR: 3371, 1705, 1616, 1529, 1284,
1138 cm-1. MS m/z: 353 (M + H)+. Anal. (C16H8F4N2O3) C, H,
N.
1-(5-Am in o-2,4-d iflu or op h en yl)-4-oxo-6,7,8-t r iflu or o-
1,4-d ih yd r oqu in olin e-3-ca r boxylic Acid (13b). Colorless
solid (94% yield); mp 256-261 °C. 1H NMR (DMSO-d6): δ 8.72
(1H, s), 8.24 (1H, t, J ) 8.7 Hz), 7.44 (1H, t, J ) 10.6 Hz), 7.13
(1H, t, J ) 8.5 Hz). 13C NMR (DMSO-d6): δ 175.6 (s), 164.5
(s), 152.0 (s), 150.2 (dd, J ) 245, 11 Hz), 148.2 (dd, J ) 255,
10 Hz), 147.3 (dd, J ) 240, 11 Hz), 143.4 (dd, J ) 275, 14 Hz),
141.4 (dd, J ) 275, 17 Hz), 133.6 (dd, J ) 15, 2 Hz), 127.9 (s),
125.0 (dd, J ) 14, 4 Hz), 122.1 (d, J ) 6 Hz), 114.1 (s), 108.9
(s), 108.3 (d, J ) 21 Hz), 104.4 (t, J ) 25 Hz). IR: 3356, 1726,
1620, 1521, 1234, 1145 cm-1. MS m/z: 371 (M + H)+. Anal.
(C16H7F5N2O3‚1/3H2O) C, H, N.
1
(95% yield); mp 260-266 °C (decomposed). H NMR (DMSO-
d6): δ 8.66 (1H, s), 8.01 (1H, d, J ) 12.8 Hz), 7.35 (1H, t, J )
9.7 Hz), 6.97 (1H, t, J ) 8.3 Hz), 5.34 (2H, s), 4.01-3.30 (5H,
m), 1.92 (1H, brs), 1.64 (1H, brs). 13C NMR (DMSO-d6 with 1
equiv TFA-d): δ 176.9 (d, J ) 3 Hz), 165.3 (s), 149.6 (dd, J )
244, 11 Hz), 149.2 (d, J ) 14 Hz), 147.6 (s), 147.1 (dd, J )
240, 12 Hz), 146.1 (d, J ) 259 Hz), 146.1 (s), 133.7 (d, J ) 15
Hz), 123.3 (d, J ) 14 Hz), 117.8 (d, J ) 21 Hz), 114.5 (s), 110.7
(s), 108.8 (s), 104.1 (t, J ) 24 Hz), 52.3 (s), 46.4 (s). IR: 1633,
1523, 1469, 1271, 823 cm-1. MS m/z: 420 (M + H)+. Anal.
(C19H16F3N5O3‚2.25H2O) C, H, N.
1-(5-Am in o-2-flu or oph en yl)-7-[(3S)-3-am in iopyr r olidin -
1-yl]-6-flu or o-4-oxo-1,4-d ih yd r o-1,8-n a p h th yr id in e-3-ca r -
boxylic Acid (14). Colorless solid (85% yield); mp 217-219
1
°C. H NMR (DMSO-d6): δ 8.61 (1H, s), 8.01 (1H, d, J ) 12.4
Hz), 7.11 (1H, t, J ) 9.7 Hz), 6.74-6.70 (2H, m), 5.29 (2H, s),
3.95-3.20 (5H, m), 1.89 (1H, brs), 1.59 (1H, brs). 13C NMR
(DMSO-d6 with 1 equiv TFA-d): δ 176.9 (d, J ) 3 Hz), 165.3
(s), 148.7 (d, J ) 237 Hz), 148.6 (d, J ) 12 Hz), 147.3 (s), 146.1
(d, J ) 259 Hz), 146.0 (s), 144.7 (s), 127.3 (d, J ) 15 Hz), 117.7
(d, J ) 22 Hz), 116.4 (s), 116.2 (d, J ) 20 Hz), 113.5(s), 110.7
(s), 108.7 (s), 51.7 (s), 48.4 (s), 46.0 (s). IR: 1633, 1512, 1456,
1269, 821 cm-1. MS m/z: 402 (M + H)+. Anal. (C19H17F2N5O3‚
2H2O) C, H, N.
1-(3-Am in o-4-flu or oph en yl)-7-[(3S)-3-am in iopyr r olidin -
1-yl]-6-flu or o-4-oxo-1,4-d ih yd r o-1,8-n a p h th yr id in e-3-ca r -
boxylic Acid (15). Colorless powder (87% yield); mp 262-
1-(5-Am in o-2,4-d iflu or op h en yl)-8-ch lor o-6,7-d iflu or o-
4-oxo-1,4-d ih yd r oqu in olin e-3-ca r boxylic Acid (13c). Col-
orless solid (85% yield); mp 225-227 °C. 1H NMR (DMSO-
d6): δ 8.69 (1H, s), 8.40 (1H, dd, J ) 9.7, 8.7 Hz), 7.42 (1H,
dd, J ) 11.0, 10.1 Hz), 7.08 (1H, dd, J ) 8.7, 7.8 Hz). 13C NMR
(DMSO-d6): δ 175.9 (s), 164.4 (s), 152.9 (s), 151.2 (dd, J ) 254,
7 Hz), 151.0 (dd, J ) 246, 12 Hz), 148.6 (dd, J ) 241, 12 Hz),
148.1 (dd, J ) 243, 15 Hz), 134.4 (s), 132.2 (d, J ) 14 Hz),
125.5 (dd, J ) 10, 4 Hz), 124.0 (d, J ) 7 Hz), 115.6 (s), 112.6
(d, J ) 18 Hz), 112.4 (d, J ) 19 Hz), 109.1 (s), 104.7 (t, J ) 25
Hz). IR: 3346, 1722, 1614, 1514, 1273, 1165, 1109 cm-1. MS
m/z: 387 and 389 for Cl isotopic peaks of (M + H)+. Anal.
(C16H7ClF4N2O3) C, H, N.
1-(5-Am in o-2,4-d iflu or op h en yl)-8-br om o-6,7-d iflu or o-
4-oxo-1,4-d ih yd r oqu in olin e-3-ca r boxylic Acid (13d ). Col-
orless solid (87% yield); mp 228-232 °C. 1H NMR (DMSO-
d6): δ 8.68 (1H, s), 8.40 (1H, dd, J ) 9.6, 8.7 Hz), 7.42 (1H,
dd, J ) 11.0, 10.0 Hz), 7.08 (1H, t, J ) 8.2 Hz), 5.94 (2H, brs).
13C NMR (DMSO-d6): δ 176.1 (s), 164.4 (s), 153.0 (s), 152.0
(dd, J ) 251, 16 Hz), 150.8 (dd, J ) 246, 11 Hz), 148.3 (dd, J
1
265 °C. H NMR (DMSO-d6 with 1 equiv TFA-d): δ 8.57 (1H,
s), 8.12 (1H, d, J ) 12.4 Hz), 8.02 (3H, brs), 7.17 (1H, dd, J )
11.5, 8.3 Hz), 6.91 (1H, dd, J ) 8.3, 2.7 Hz), 6.73-6.68 (1H,
m), 5.51 (2H, s), 3.95-3.20 (5H, m), 2.12 (1H, brs), 2.02 (1H,
brs). 13C NMR (DMSO-d6 with 1 equiv TFA-d): δ 176.7 (d, J
) 3 Hz), 165.6 (s), 150.1 (d, J ) 239 Hz), 148.4 (d, J ) 13 Hz),
147.2 (s), 146.4 (s), 145.9 (d, J ) 259 Hz), 137.1 (d, J ) 15
Hz), 136.5 (s), 117.7 (d, J ) 19 Hz), 115.1 (d, J ) 19 Hz), 114.5-
(s), 114.4 (d, J ) 7 Hz), 111.1 (d, J ) 3 Hz), 108.1 (s), 51.7 (s),
46.1 (s). IR: 1712, 1635, 1512, 1265, 1207, 808 cm-1. MS m/z:
402 (M + H)+. Anal. (C19H17F2N5O3‚2H2O) C, H, N.
7-[(3S)-3-Am in iop yr r olid in -1-yl]-1-(5-Am in o-2,3,4-t r i-
fluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
ca r boxylic Acid (16). Colorless solid (69% yield); mp >268
°C (decomposed). 1H NMR (DMSO-d6): δ 8.76 (1H, s), 8.09 (1H,
d, J ) 12.9 Hz), 6.81 (1H, brs), 5.74 (2H, s), 4.05-3.41 (5H,
m), 2.14 (1H, brs), 1.91 (1H, brs). 13C NMR (DMSO-d6 with 1

1914 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Kuramoto et al.
equiv TFA-d): δ 177.0 (d, J ) 2 Hz), 165.7 (s), 148.6 (d, J )
14 Hz), 147.1 (s), 146.1 (d, J ) 258 Hz), 145.9 (d, J ) 3 Hz),
139.7 (ddd, J ) 245, 17, 14 Hz), 139.0 (dd, J ) 243, 12 Hz),
137.1 (dd, J ) 242, 11 Hz), 134.3 (d, J ) 10 Hz), 124.0 (d, J )
8 Hz), 117.9 (d, J ) 21 Hz), 110.6(s), 108.9 (s), 108.6 (s), 52.3
(s), 46.7 (s). IR: 1635, 1510, 1464, 1219, 821 cm-1. MS m/z:
438 (M + H)+. Anal. (C19H17F2N5O3‚2.75H2O) C, H, N.
in DMSO (1.5 mL). The solution was stirred at 70 °C for 1 h.
After addition of EtOH (25 mL), the solution was heated at
90 °C for 10 min and allowed to cool. The precipitate was
collected by filtration and washed with EtOH and Et2O. The
crude solid was dissolved in aqueous 10% (v/v) HCl (10 mL).
After the solvent was evaporated, the residue was purified by
reprecipitaiton from its DMF solution with EtOH to obtain
183 mg of 18 as a yellow solid (74% yield); mp 197-199 °C.
1H NMR (DMSO-d6): δ 9.50 (2H, s), 8.82 (1H, s), 8.24 (1H, d,
J ) 12.8 Hz), 7.42 (1H, t, J ) 10.5 Hz), 7.08 (1H, t, J ) 8.2
Hz), 3.80 (4H, t, J ) 5.1 Hz), 3.15 and 3.13 (4H, t, J ) 5.1
Hz). 13C NMR (DMSO-d6 with 1 equiv TFA-d): δ 177.1 (s),
165.1 (s), 150.6 (dd, J ) 246, 11 Hz), 149.7 (d, J ) 10 Hz),
148.3 (dd, J ) 242, 11 Hz), 148.2 (s), 147.2 (d, J ) 265 Hz),
145.2 (s), 131.4 (dd, J ) 12, 3 Hz), 123.0 (dd, J ) 14, 4 Hz),
119.8 (d, J ) 22 Hz), 116.3(s), 112.8 (d, J ) 3 Hz), 109.0 (s),
104.5 (t, J ) 25 Hz), 43.3 (d, J ) 8 Hz), 41.9 (s). IR: 1726,
1631, 1452, 1277, 1033, 810 cm-1. MS m/z: 420 (M + H)+.
Anal. (C19H16F3N5O3‚2HCl‚0.5H2O) C, H, N.
1-(3-Am in o-2,4-d iflu or op h en yl)-7-[(3S)-3-a m in iop yr r o-
lid in -1-yl]-6-flu or o-4-oxo-1,4-d ih yd r o-1,8-n a p h th yr id in e-
3-ca r boxylic Acid (17). Yellowish solid (76% yield); mp >268
1
°C (decomposed). H NMR (DMSO-d6 with 1 equiv TFA-d): δ
8.70 (1H, s), 8.13 (2H, s), 8.12 (1H, d, J ) 12.3 Hz), 7.10 (1H,
t, J ) 9.6 Hz), 6.83 (1H, dd, J ) 13.8, 8.2 Hz), 4.10-3.35 (5H,
m), 2.20 (1H, brs), 2.03 (1H, brs). 13C NMR (DMSO-d6 with 1
equiv TFA-d): δ 176.9 (s), 165.3 (s), 151.1 (dd, J ) 242, 8 Hz),
148.6 (d, J ) 12 Hz), 147.7 (s), 146.2 (d, J ) 10 Hz), 146.1 (d,
J ) 257 Hz), 146.0 (dd, J ) 247, 12 Hz), 126.3 (dd, J ) 17, 16
Hz), 124.1 (dd, J ) 11, 2 Hz), 117.7 (d, J ) 20 Hz), 113.3 (s),
110.8 (s), 110.7 (s), 108.7 (s), 51.7 (s), 46.0 (s). IR: 1728, 1639,
1550, 1467, 1271, 1176, 815 cm-1. MS m/z: 420 (M + H)+.
Anal. (C19H16F3N5O3‚2.25H2O) C, H, N.
1-(5-Am in o-2,4-d iflu or op h en yl)-6-flu or o-4-oxo-7-(p ip -
er a zin -1-yl)-1,4-d ih yd r oqu in olin e-3-ca r boxylic Acid (23).
The quinolone-3-carboxylic acid derivative 13a (190 mg, 0.50
mmol), piperazine (85 mg, 1.0 mmol), and Et3N (100 mg, 1.0
mmol) were dissolved in DMSO (1.5 mL). The solution was
stirred at 70 °C for 1 h. After EtOH (25 mL) was added, the
solution was heated at 90 °C for 10 min and allowed to cool.
The precipitate was collected by filtration and washed with
EtOH and Et2O. The residue was purified by reprecipitaiton
from its DMF solution with EtOH to obtain 70 mg of 23 as a
1-(5-Am in o-2,4-d iflu or op h en yl)-7-[(3S)-3-a m in iop yr r o-
lid in -1-yl]-6-flu or o-4-oxo-1,4-d ih yd r oqu in olin e-3-ca r box-
ylic Acid (20). Colorless solid (97% yield); mp 213-221 °C
(decomposed). 1H NMR (DMSO-d6 with 1 equiv TFA-d): δ 8.67
(1H, s), 8.03 (2H, s), 7.93 (1H, d, J ) 13.8 Hz), 7.51 (1H, t, J
) 9.7 Hz), 7.03 (1H, dd, J ) 14.7, 7.8 Hz), 5.96 (1H, d, J ) 7.4
Hz), 3.90 (1H, s), 3.73 (1H,s), 3.58-3.42 (3H, m), 2.28-2.20
(1H, m), 2.04 (1H, brs). 13C NMR (DMSO-d6 with 1 equiv TFA-
d): δ 176.3 (s), 165.6 (s), 150.1 (dd, J ) 245, 11 Hz), 149.9
(dd, J ) 248, 4 Hz), 148.4 (s), 146.9 (dd, J ) 239, 10 Hz), 141.4
(dd, J ) 12, 4 Hz), 139.4 (d, J ) 6 Hz), 134.8 (d, J ) 14 Hz),
122.9 (dd, J ) 14, 3 Hz), 114.8 (d, J ) 7 Hz), 114.1 (t, J ) 3
Hz), 111.1 (d, J ) 23 Hz), 107.5(s), 105.2 (t, J ) 24 Hz), 100.2
(s), 53.0 (d, J ) 8 Hz), 49.4 (s), 47.3 (s), 28.6 (s). IR: 3470,
1716, 1631, 1520, 1147, 819 cm-1. MS m/z: 419 (M + H)+.
Anal. (C20H17F3N4O3‚2.75H2O) C, H, N.
1
colorless solid (63% yield); mp 167-171 °C. H NMR (DMSO-
d6): δ 8.73 (1H, s), 7.97 (1H, d, J ) 13.3 Hz), 7.52 (1H, t, J )
10.5 Hz), 7.07 (1H, t, J ) 8.2 Hz), 6.43 (1H, d, J ) 6.9 Hz),
5.56 (2H, s), 3.02 (4H, s), 2.81 (4H, s). 13C NMR (DMSO-d6
with 1 equiv TFA-d): δ 176.7 (s), 165.3 (s), 152.8 (d, J ) 251
Hz), 150.2 (dd, J ) 245, 11 Hz), 149.3 (s), 146.8 (dd, J ) 241,
11 Hz), 144.7 (d, J ) 11 Hz), 138.5 (s), 134.8 (dd, J ) 15, 2
Hz), 122.8 (dd, J ) 14, 3 Hz), 119.2 (d, J ) 7 Hz), 114.1(s),
111.5 (d, J ) 24 Hz), 108.1 (s), 106.1 (s), 105.2 (t, J ) 24 Hz),
46.2 (s), 42.5 (s), 40.4 (s). IR: 3308, 1720, 1618, 1520, 1271,
1145, 823 cm-1. MS m/z: 419 (M + H)+. Anal. (C20H17F3N4O3‚
H2O) C, H, N.
1-(5-Am in o-2,4-d iflu or op h en yl)-7-[(3S)-3-a m in iop yr r o-
lid in -1-yl]-6,8-d iflu or o-4-oxo-1,4-d ih yd r oqu in olin e-3-ca r -
boxylic Acid (21). Colorless solid (95% yield); mp 204-210
1
°C (decomposed). H NMR (DMSO-d6 with 1 equiv TFA-d): δ
1-(5-Am in o-2,4-d iflu or op h en yl)-6,8-d iflu or o-4-oxo-7-
(p ip er a zin -1-yl)-1,4-d ih yd r oqu in olin e-3-ca r boxylic Acid
(24). Colorless solid (85% yield); mp 262-265 °C. 1H NMR
(DMSO-d6): δ 8.54 (1H, s), 7.88 (1H, d, J ) 11.9 Hz), 7.40 (1H,
t, J ) 10.6 Hz), 7.09 (1H, t, J ) 8.3 Hz), 5.45 (2H, s), 3.14 (4H,
s), 2.83-2.77 (4H, m). 13C NMR (DMSO-d6 with 1 equiv TFA-
d): δ 175.9 (s), 164.7 (s), 154.6 (dd, J ) 250, 5 Hz), 151.4 (s),
149.8 (dd, J ) 244, 11 Hz), 146.9 (dd, J ) 246, 8 Hz), 145.8
(dd, J ) 253, 7 Hz), 133.8 (d, J ) 15 Hz), 132.8 (dd, J ) 15, 13
Hz), 128.0 (d, J ) 5 Hz), 126.5 (d, J ) 14 Hz), 120.8 (d, J ) 9
Hz), 113.8(s), 108.0 (s), 107.2 (d, J ) 23 Hz), 104.4 (t, J ) 24
Hz), 47.3 (s), 43.3 (d, J ) 9 Hz). IR: 1722, 1628, 1525, 1273,
1141 cm-1. MS m/z: 437 (M + H)+. Anal. (C20H16F4N4O3‚H2O)
C, H, N.
1-(5-Am in o-2,4-diflu or oph en yl)-8-ch lor o-6-flu or o-4-oxo-
7-(piper azin -1-yl)-1,4-dih ydr oqu in olin e-3-car boxylic Acid
(25). Colorless solid (65% yield); mp >232 °C (decomposed).
1H NMR (DMSO-d6): δ 8.53 (1H, s), 8.06 (1H, d, J ) 11.9 Hz),
7.36 (1H, t, J ) 10.5 Hz), 6.96 (1H, t, J ) 8.7 Hz), 5.40 (2H, s),
3.14 (4H, s), 2.82-2.78 (4H, m). 13C NMR (DMSO-d6 with 1
equiv TFA-d): δ 176.2 (d, J ) 2 Hz), 164.5 (s), 156.2 (d, J )
252 Hz), 152.7 (s), 149.8 (dd, J ) 245, 11 Hz), 147.1 (dd, J )
249, 11 Hz), 142.6 (d, J ) 16 Hz), 135.4 (s), 134.2 (dd, J ) 15,
2 Hz), 126.7 (dd, J ) 14, 4 Hz), 123.9 (d, J ) 9 Hz), 120.5 (d,
J ) 5 Hz), 113.7(s), 111.2 (d, J ) 24 Hz), 108.3 (s), 104.4 (t, J
) 24 Hz), 47.4 (s), 43.4 (s). IR: 1725, 1620, 1525, 1263, 1113
cm-1. MS m/z: 453 and 455 for Cl isotopic peaks of (M + H)+.
Anal. (C20H16ClF3N4O3‚H2O) C, H, N.
8.53 (1H, s), 8.04 (2H, s), 7.85 (1H, d, J ) 13.7 Hz), 7.39 (1H,
t, J ) 10.1 Hz), 7.10 (1H, t, J ) 8.2 Hz), 3.90-3.55 (5H, br),
2.19-2.14 (1H, m), 1.99-1.95 (1H, m). 13C NMR (DMSO-d6
with 1 equiv TFA-d): δ 175.7 (s), 165.0 (s), 151.4 (dd, J ) 250,
6 Hz), 150.9 (s), 149.7 (dd, J ) 244, 11 Hz), 146.9 (dd, J )
239, 11 Hz), 140.8 (dd, J ) 247, 8 Hz), 133.8 (d, J ) 15 Hz),
131.6 (dd, J ) 14, 11 Hz), 128.6 (s), 126.9 (d, J ) 15 Hz), 115.6
(d, J ) 9 Hz), 113.6 (s), 107.4 (s), 107.0 (d, J ) 24 Hz), 104.2
(dt, J ) 25, 4 Hz), 54.6 (s), 49.2 (s), 40.4 (s), 29.0 (s). IR: 3319,
1732, 1624, 1523, 1253, 1155, 819 cm-1. MS m/z: 437 (M +
H)+. Anal. (C20H16F4N4O3‚H2O) C, H, N.
1-(5-Am in o-2,4-d iflu or op h en yl)-7-[(3S)-3-a m in iop yr r o-
lid in -1-yl]-8-ch lor o-6-flu or o-4-oxo-1,4-d ih yd r oqu in olin e-
3-ca r boxylic Acid (22). Colorless solid (93% yield); mp >205
1
°C (decomposed). H NMR (DMSO-d6 with 1 equiv TFA-d): δ
8.58 (1H, s), 8.07 (2H, s), 8.04 (1H, d, J ) 13.2 Hz), 7.39 and
7.38 (1H, t, J ) 10.5 Hz), 7.02 and 6.98 (1H, t, J ) 8.3 Hz),
3.90-3.45 (5H, br), 2.29-2.21 (1H, m), 1.99-1.91 (1H, m). 13
C
NMR (DMSO-d6 with 1 equiv TFA-d): δ 176.1 (s), 164.7 (s),
155.8 and 154.7 (d, J ) 253 Hz), 152.3 (s), 149.8 and 149.7
(dd, J ) 245, 11 Hz), 146.8 and 146.7 (dd, J ) 239, 12 Hz),
141.2 and 141.1 (d, J ) 14 Hz), 136.5 and 136.4 (s), 134.3 and
134.1 (d, J ) 15 Hz), 126.9 (dd, J ) 13, 4 Hz), 121.3 (d, J ) 6
Hz), 115.3 (d, J ) 4 Hz), 113.3(s), 110.5 (d, J ) 22 Hz), 108.4
(s), 104.5 and 104.4(t, J ) 24 Hz), 54.5 (s), 49.2 (s), 40.4 (s),
29.6 (s). IR: 1716, 1635, 1452, 1261, 1109 cm-1. MS m/z: 453
and 455 for Cl isotopic peaks of (M + H)+. Anal. (C20H16
ClF3N4O3‚4H2O) C, H, N.
-
1-(5-Am in o-2,4-d iflu or op h en yl)-6-flu or o-4-oxo-7-(p ip -
er a zin -1-yl)-1,4-d ih yd r o-1,8-n a p h t h yr id in e-3-ca r b oxyl-
ic Acid Dih yd r oclor id e (18). The 1,8-naphthyridine-3-
carboxylic acid derivative 10a (185 mg, 0.50 mmol), piperazine
(86 mg, 1.0 mmol), and Et3N (100 mg, 1.0 mmol) were dissolved
7-(3-Am in oazetidin -1-yl)-1-(5-am in o-2,4-diflu or oph en yl)-
6-flu or o-4-oxo-1,4-d ih yd r o-1,8-n a p h th yr id in e-3-ca r boxy-
lic Acid (19). The 1,8-naphthyridine-3-carboxylic acid deriva-
tive 10a (556 mg, 1.5 mmol), 3-aminoazetidine dihydrochloride
(320 mg, 2.2 mmol), and Et3N (1.04 g, 8.0 mmol) were dissolved

Antibacterial 8-Chloroquinolone
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 1915
in MeCN (200 mL). The solution was stirred at 80 °C for 15 h.
After EtOH (25 mL) was added, the solution was heated at 90
°C for 10 min and allowed to cool. The precipitate was collected
by filtration and washed with EtOH and Et2O. The crude solid
was purified by reprecipitaiton from its DMF solution with
EtOH to obtain 720 mg of 19 as a colorless solid (91% yield);
mp 168-171 °C. 1H NMR (DMSO-d6): δ 8.68 (1H, s), 8.02 (1H,
d, J ) 11.5 Hz), 7.35 (1H, t, J ) 10.5 Hz), 6.94 (1H, dd, J )
10.8, 7.6 Hz), 5.34 (2H, brs), 4.60-3.96 (4H, br), 3.85-3.83
(1H, m). 13C NMR (DMSO-d6 with 1 equiv TFA-d): δ 177.1
(s), 165.2 (s), 150.2 (d, J ) 15), 149.7 (dd, J ) 243, 11 Hz),
147.7 (s),147.3 (dd, J ) 240, 12 Hz), 146.4 (s), 146.3 (d, J )
257 Hz), 133.6 (dd, J ) 15, 2 Hz), 123.1 (dd, J ) 14, 4 Hz),
117.4 (d, J ) 18 Hz), 114.7(s), 111.4 (s), 108.9 (s), 104.0 (t, J
) 24 Hz), 55.0 (br), 41.2 (s). IR: 3072, 1651, 1525, 1255, 1141,
891 cm-1. MS m/z: 406 (M + H)+. Anal. (C18H14F3N5O3‚1.5H2O)
C, H, N.
7-(3-Am in oazetidin -1-yl)-1-(5-am in o-2,4-diflu or oph en yl)-
6-flu or o-4-oxo-1,4-d ih yd r oq u in olin e-3-ca r b oxylic Acid
(26). Colorless solid (74% yield); mp >183 °C (decomposed).
1H NMR (DMSO-d6): δ 8.64 (1H, s), 7.86 (1H, d, J ) 12.8 Hz),
7.51 (1H, t, J ) 10.6 Hz), 7.02 (1H, t, J ) 8.3 Hz), 5.74 (1H, d,
J ) 7.3 Hz), 5.54 (2H, s), 4.28-4.16 (2H, m), 3.83-3.78 (1H,
m), 3.67-3.58 (2H, m). 13C NMR (DMSO-d6): δ 176.4 (s), 165.5
(s), 150.1 (dd, J ) 246, 10 Hz), 150.0 (d, J ) 246 Hz), 148.5
(s), 146.9 (dd, J ) 240, 11 Hz), 143.5 (d, J ) 14 Hz), 139.2 (s),
134.8 (d, J ) 15 Hz), 122.8 (dd, J ) 14, 4 Hz), 115.5 (d, J ) 6
Hz), 114.1 (s), 110.6 (d, J ) 20 Hz), 107.5(s), 105.2 (t, J ) 24
Hz), 98.7 (d, J ) 4 Hz), 57.3 (d, J ) 10 Hz), 40.8 (s). IR: 3036,
1711, 1630, 1525, 1240, 1143, 825 cm-1. MS m/z: 405 (M +
H)+. Anal. (C19H15F3N4O3‚0.4H2O) C, H, N.
7-(3-Am in oazetidin -1-yl)-1-(5-am in o-2,4-diflu or oph en yl)-
6,8-diflu or o-4-oxo-1,4-dih ydr oqu in olin e-3-car boxylic Acid
(27). Colorless solid (74% yield); mp >203 °C (decomposed).
1H NMR (DMSO-d6): δ 8.45 (1H, s), 7.77 (1H, d, J ) 12.4 Hz),
7.38 (1H, t, J ) 10.6 Hz), 7.07 (1H, t, J ) 8.3 Hz), 5.44 (2H, s),
4.42 (2H, brs), 3.91 (2H, brs), 3.77-3.73 (1H, m). 13C NMR
(DMSO-d6 with 1 equiv TFA-d): δ 175.7 (s), 165.0 (s), 150.7
(s), 149.9 (dd, J ) 246, 8 Hz), 149.6 (dd, J ) 244, 10 Hz), 146.9
(dd, J ) 239, 12 Hz), 139.0 (dd, J ) 245, 7 Hz), 133.9 (d, J )
15 Hz), 132.6 (dd, J ) 15, 12 Hz), 128.1 (d, J ) 3 Hz), 126.6
(d, J ) 15 Hz), 114.9 (s), 113.6(s), 107.4 (s), 106.9 (d, J ) 21
Hz), 104.5 (t, J ) 25 Hz), 59.5 (s), 42.1 (s). IR: 2980, 1622,
1527, 1257, 1145, 825 cm-1. MS m/z: 423 (M + H)+. Anal.
(C19H14F4N4O3‚0.75H2O) C, H, N.
Hz), 5.39 (2H, s), 4.65 (2H, s), 4.00 (2H, s), 3.75-3.66 (1H, m).
13C NMR (DMSO-d6 with 1 equiv TFA-d): δ 175.9 (s), 164.8
(s), 152.0 (s), 150.3 (d, J ) 251 Hz), 149.7 (dd, J ) 244, 11
Hz), 146.7 (dd, J ) 239, 12 Hz), 144.4 (d, J ) 11 Hz), 138.3
(s), 134.5 (d, J ) 14 Hz), 126.6 (dd, J ) 13, 4 Hz), 118.3 (d, J
) 8 Hz), 113.3 (s), 110.4 (d, J ) 24 Hz), 108.3 (s), 104.6 (t, J
) 25 Hz), 92.4 (d, J ) 4 Hz), 61.0 (s), 60.8 (s), 41.0 (s). IR:
3072, 1718, 1620, 1523, 1143, 869 cm-1. MS m/z: 483 and 485
for Br isotopic peaks of (M + H)+. Anal. (C19H14BrF3N4O3‚
1.5H2O) C, H, N.
7-(3-Am in oazetidin -1-yl)-1-(5-am in o-2,4-diflu or oph en yl)-
6-flu or o-8-m eth yl-4-oxo-1,4-d ih yd r oqu in olin e-3-ca r boxy-
1
lic Acid (29). Colorless solid (69% yield); mp 203-205 °C. H
NMR (DMSO-d6): δ 8.46 (1H, s), 7.76 (1H, d, J ) 13.7 Hz),
7.40 (1H, t, J ) 10.6 Hz), 7.02 (1H, t, J ) 8.1 Hz), 5.46 (2H, s),
4.46-4.35 (2H, m), 3.86 (1H, m), 3.75-3.67 (2H, m), 1.63 (3H,
s). 13C NMR (DMSO-d6 with 1 equiv TFA-d): δ 176.5 (s), 165.3
(s), 151.4 (s), 150.8 (d, J ) 257 Hz), 149.4 (dd, J ) 245, 11
Hz), 146.1 (dd, J ) 240, 12 Hz), 145.7 (d, J ) 10 Hz), 139.3
(s), 134.7 (d, J ) 14 Hz), 127.6 (dd, J ) 13, 3 Hz), 118.1 (d, J
) 8 Hz), 113.1 (d, J ) 4 Hz), 113.0 (s), 108.7 (d, J ) 23 Hz),
107.5 (s), 104.7 (t, J ) 24 Hz), 60.4 (s), 60.2 (s), 41.1 (s), 17.1
(s). IR: 3094, 1718, 1628, 1523, 1248, 1145, 821 cm-1. MS
m/z: 419 (M + H)+. Anal. (C20H17F3N4O3‚1.5H2O) C, H, N.
1-(5-Am in o-2,4-d iflu or op h en yl)-8-ch lor o-6-flu or o-7-(3-
m eth yla m in oa zetid in -1-yl)-4-oxo-1,4-d ih yd r oqu in olin e-
3-ca r boxylic Acid (30). Colorless solid (52% yield); mp 220-
1
224 °C. H NMR (DMSO-d6): δ 8.44 (1H, s), 7.87 (1H, d, J )
13.8 Hz), 7.36 (1H, t, J ) 10.5 Hz), 6.95 (1H, t, J ) 8.7 Hz),
5.41 (2H, s), 4.67-4.55 (2H, m), 4.15-4.06 (2H, m), 3.48-3.41
(1H, m), 2.20 (3H, s). 13C NMR (DMSO-d6 with 1 equiv TFA-
d): δ 175.8 (s), 164.8 (s), 151.9 (s), 150.1 (d, J ) 249 Hz), 149.7
(dd, J ) 244, 10 Hz), 146.9 (dd, J ) 239, 12 Hz), 141.9 (d, J )
12 Hz), 136.5 (s), 134.2 (d, J ) 15 Hz), 126.8 (dd, J ) 13, 4
Hz), 117.6 (d, J ) 8 Hz), 113.3 (s), 110.1 (d, J ) 22 Hz), 108.1
(s), 105.0 (d, J ) 6 Hz), 104.4 (t, J ) 24 Hz), 59.4 (s), 48.8 (s),
30.2 (s). IR: 3335, 1718, 1622, 1525, 1263, 883 cm-1. MS m/z:
453 and 455 for Cl isotopic peaks of (M + H)+. Anal. (C20H16
ClF3N4O3‚1.5H2O) C, H, N.
-
1-(5-Am in o-2,4-d iflu or op h en yl)-8-ch lor o-7-(3-eth yla m i-
n oa zet id in -1-yl)-6-flu or o-4-oxo-1,4-d ih yd r oq u in olin e-3-
ca r boxylic Acid (31). Colorless solid (71% yield); mp 208-
1
209 °C. H NMR (DMSO-d6): δ 8.43 (1H, s), 7.86 (1H, d, J )
14.2 Hz), 7.36 (1H, t, J ) 10.6 Hz), 6.96 (1H, t, J ) 8.5 Hz),
5.42 (2H, s), 4.68-4.60 (2H, m), 4.15-4.08 (2H, m), 3.58-3.50
(1H, m), 2.47 (2H, q, J ) 6.9 Hz), 0.97 (3H, t, J ) 6.9 Hz). 13C
NMR (DMSO-d6 with 1 equiv TFA-d): δ 175.8 (s), 164.8 (s),
151.9 (s), 150.1 (d, J ) 249 Hz), 149.7 (dd, J ) 245, 11 Hz),
146.9 (dd, J ) 238, 12 Hz), 141.9 (d, J ) 12 Hz), 136.5 (s),
134.2 (d, J ) 16 Hz), 126.8 (dd, J ) 13, 4 Hz), 117.6 (d, J ) 7
Hz), 113.3 (t, J ) 6 Hz), 110.1 (d, J ) 23 Hz), 108.1 (s), 105.0
(d, J ) 6 Hz), 104.4 (t, J ) 25 Hz), 59.6 (s), 47.2 (s), 11.0 (s).
IR: 1622, 1525, 1263, 1147, 817 cm-1. MS m/z: 467 (M + H)+.
Anal. (C21H18ClF3N4O3‚0.5H2O) C, H, N.
7-(3-Am in oazetidin -1-yl)-1-(5-am in o-2,4-diflu or oph en yl)-
8-ch lor o-6-flu or o-4-oxo-1,4-d ih yd r oqu in olin e-3-ca r boxy-
lic Acid (4). Colorless solid (70% yield); mp >270 °C (decom-
1
posed). H NMR (DMSO-d6): δ 8.42 (1H, s), 7.87 (1H, d, J )
13.8 Hz), 7.32 (1H, t, J ) 10.7 Hz), 6.96 (1H, t, J ) 8.2 Hz),
5.32 (s, 1H), 4.69-4.63 (2H, m), 4.10-4.03 (2H, m), 3.75 (1H,
brs). 13C NMR (DMSO-d6 with 1 equiv TFA-d): δ 175.8 (s),
164.7 (s), 151.8 (s), 150.2 (d, J ) 249 Hz), 149.0 (dd, J ) 244,
10 Hz), 146.9 (dd, J ) 239, 12 Hz), 142.0 (d, J ) 12 Hz), 136.6
(s), 134.2 (d, J ) 14 Hz), 126.9 (dd, J ) 15, 2 Hz), 117.7 (d, J
) 8 Hz), 113.4 (d, J ) 6 Hz), 110.0 (d, J ) 23 Hz), 108.1 (s),
104.5 (d, J ) 7 Hz), 104.3 (t, J ) 24 Hz), 60.8 (d, J ) 6 Hz),
60.7 (d, J ) 8 Hz), 41.4 (d, J ) 5 Hz). IR: 3331, 1718, 1618,
1521, 1452, 1255, 1143, 891 cm-1. MS m/z: 439 (M + H)+.
Anal. (C19H14ClF3N4O3‚0.75H2O) C, H, N.
1-(5-Am in o-2,4-d iflu or op h en yl)-8-ch lor o-7-(3-d im et h -
ylam in oazetidin -1-yl)-6-flu or o-4-oxo-1,4-dih ydr oqu in olin e-
3-ca r boxylic Acid (32). Yellowish solid (63% yield); mp >256
°C (decomposed). 1H NMR (DMSO-d6): δ 8.45 (1H, s), 7.87 (1H,
d, J ) 13.6 Hz), 7.37 (1H, t, J ) 10.6 Hz), 6.95 (1H, t, J ) 8.3
Hz), 5.40 (2H, s), 4.57-4.51 (2H, m), 4.25-4.17 (2H, m), 3.05-
2.96 (1H, m), 2.07 (6H, s). 13C NMR (DMSO-d6 with 1 equiv
TFA-d): δ 175.8 (s), 164.8 (s), 151.9 (s), 150.2 (d, J ) 249 Hz),
149.8 (dd, J ) 245, 11 Hz), 147.0 (dd, J ) 239, 11 Hz), 141.8
(d, J ) 12 Hz), 136.4 (s), 134.2 (d, J ) 16 Hz), 126.8 (dd, J )
14, 4 Hz), 117.8 (d, J ) 8 Hz), 113.4 (s), 110.1 (d, J ) 23 Hz),
108.0 (s), 105.4 (d, J ) 6 Hz), 104.4 (t, J ) 25 Hz), 58.3 (s),
55.8 (d, J ) 5 Hz). IR: 3391, 1718, 1624, 1529, 1446, 1226,
1157 cm-1. MS m/z: 467 and 469 for Cl isotopic peaks of (M +
H)+. Anal. (C21H18ClF3N4O3) C, H, N.
7-(3-Am in oazetidin -1-yl)-1-(5-am in o-2,4-diflu or oph en yl)-
8-br om o-6-flu or o-4-oxo-1,4-d ih yd r oqu in olin e-3-ca r boxy-
lic Acid (28). The quinoline-3-carboxylic acid derivative 13d
(120 mg, 0.27 mmol), 3-aminoazetidine dihydrochloride (73 mg,
0.5 mmol), LiCl (50 mg, 1.2 mmol), and Et3N (300 mg, 3.0
mmol) were dissolved in DMSO (0.6 mL). The solution was
stirred at 60 °C for 2 h. After addition of Et2O (15 mL), the
supernatant was removed by decantation. To the residue was
added H2O (3 mL). The precipitate was collected by filtration
and washed with EtOH and Et2O. The crude solid was purified
by reprecipitaiton from its DMF solution with EtOH to obtain
110 mg of 28 as a yellow solid (82% yield); mp >206 °C
1-(5-Am in o-2,4-d iflu or op h en yl)-7-(3-a m in io-3-m eth yl-
a zetid in -1-yl)-8-ch lor o-6-flu or o-4-oxo-1,4-d ih yd r oqu in o-
lin e-3-ca r boxylic Acid (33). Colorless solid (96% yield); mp
1
1
(decomposed). H NMR (DMSO-d6): δ 8.43 (1H, s), 7.86 (1H,
252-257 °C. H NMR (DMSO-d6): δ 8.43 (1H, s), 7.86 (1H, d,
d, J ) 13.2 Hz), 7.36 (1H, t, J ) 10.6 Hz), 6.89 (1H, t, J ) 8.7
J ) 13.7 Hz), 7.36 (1H, t, J ) 10.5 Hz), 6.95 (1H, t, J ) 8.7

1916 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Kuramoto et al.
Hz), 5.42 (2H, s), 4.33-4.27 (2H, m), 4.21-4.14 (2H, m), 1.34
(3H, s). 13C NMR (DMSO-d6 with 1 equiv TFA-d): δ 175.8 (s),
164.8 (s), 151.9 (s), 150.3 (d, J ) 250 Hz), 149.7 (dd, J ) 244,
10 Hz), 146.9 (dd, J ) 239, 12 Hz), 142.1 (d, J ) 12 Hz), 134.2
(d, J ) 14 Hz), 126.9 (dd, J ) 14, 3 Hz), 117.5 (d, J ) 8 Hz),
115.6 (s), 110.0 (d, J ) 23 Hz), 108.0 (s), 105.1 (d, J ) 6 Hz),
104.3 (t, J ) 24 Hz), 65.9 (d, J ) 7 Hz), 50.1 (s), 22.0 (s). IR:
1730, 1624, 1523, 1452, 885 cm-1. MS m/z: 453 and 455 for
Cl isotopic peaks of (M + H)+. Anal. (C20H16ClF3N4O3‚0.5H2O)
C, H, N.
In Vitr o An tiba cter ia l Activity. Newly synthesized com-
pounds (3, 4, and 14-33) and reference compounds (1, 2, 34,
and 35) were evaluated for their in vitro antibacterial activity
against representative organisms; Gram (+) organisms includ-
ing S. aureus 209P, S. aureus smith, MRSA W200, Staphylo-
coccus epidermidis IFO12293, Enterococcus faecalis IFO12580,
E. faecalis ATCC19433, E. faecium W1140, Micrococcus luteus
IFO12708, Bacillus subtilis ATCC6633, E. faecium (VanA)
ATCC51559, Enterococcus casseliflavus (VanC) ATCC51559,
E. faecalis (VanB) ATCC51299, and Enterococcus gallinarum
(VanC) ATCC49573, and Gram (-) organisms including E. coli
NIHJ -J C2, E. coli NIHJ , Citrobacter freundii IFO1268, Kleb-
siella pneumoniae KC-1, K. pneumoniae DT-S, Salmonella
typhimurium IFO13245, Enterobacter cloacae IFO13535, Pro-
teus vulgaris IFO3167, Serratia marcescens IFO3736, Mor-
ganella morganii W1026, Providencia rettgeri W1008, P.
aeruginosa IFO3445, P. aeruginosa E-2, and P. aeruginosa
15846. The antibacterial activities of compounds 1, 4, 34, and
35 were determined against quinolone susceptible S. pneu-
moniae W1466 and three quinolone resistant isolates including
MRSA W9501, P. aeruginosa W348, and E. coli W9523. The
minimum inhibitory concentrations (MICs) were determined
using standard agar dilution method as described by the
National Committee for Clinical Laboratory Standards.26 Two-
fold dilution of the test compound in the range of 128-0.002
µg/mL was carried out in Muller Hinton Medium (Difco). For
S. pneumoniae, 10% horse blood was added to Muller Hinton
Medium. The plate was inoculated with approximately 104
organisms and then incubated at 37 °C for 18 h. The MIC was
the lowest concentration of the test compound that yielded no
visible growth on the plate.
F igu r e 3. UV-pH profile for 10 µM 4 at 35 °C with I ) 0.10
(NaCl) in aqueous solution: (a) at pH 7.4, λmax ) 282 (ꢀ ) 3.6
× 104) and 340 nm (ꢀ ) 1.6 × 104); (b) at pH 5.2; (c) at pH 3.4,
λmax ) 290 (ꢀ ) 4.4 × 104) and 337 nm (ꢀ ) 1.2 × 104).
F igu r e 4. UV absorption spectra for 10 µM 4 at 35 °C and
pH 7.4 with I ) 0.10 (NaCl) in aqueous solution: (a) in the
absence of Mg2+ ion; (b) in the presence of 20 mM Mg2+ ion,
λmax ) 285 (ꢀ ) 4.0 × 104) and 337 nm (ꢀ ) 1.4 × 104).
Cr ysta llogr a p h ic Stu d y of 31‚TsOH‚EtOH. A crystal
suitable for X-ray crystallographic analysis was obtained from
a DMSO solution containing an equimolar TsOH by using the
vapor diffusion method with EtOH. Colorless prisms of 31‚
TsOH‚EtOH (C30H32ClF3N4O7S, Mr ) 685.11) with approxi-
mate dimensions of 0.25 mm × 0.10 mm × 0.10 mm was
mounted in a loop and used for data collection. All measure-
ments were made on a Rigaku RAXIS-RAPID Imaging Plate
diffract meter with graphite monochronomated Mo KR radia-
tion. Indexing was performed from three oscillations, which
were exposed for 0.6 min. The camera radius was 127.40 mm.
Readout was performed in the 0.100 mm pixel mode. The data
were collected at a temperature of -180 ( 1 °C to a maximum
2θ value of 59.9°. A total of 44 images, corresponding to 220.0°
oscillation angles, were collected with two different goniometer
settings. Exposure time was 4.00 min per degree. The struc-
ture was solved by the direct methods (SIR 97) and expanded
using Fourier techniques (DIRDIF 94). All calculations were
performed using the PROCESS-AUTO program package.
Crystal data for 31‚TsOH‚EtOH: monoclinic, space group P21/c
(no. 14), a ) 15.502 (1) Å, b ) 8.5274(5) Å, c ) 23.390(1) Å, â
) 106.599(2)°, V ) 2963.1(3) Å3, Z ) 4, Dcalcd ) 1.536 g/cm3,
2θmax ) 59.9°, total no. of reflections ) 33 174. The nonhydro-
gen atoms were refined anisotropically. Hydrogen atoms were
included but not refined. The final cycle of full-matrix least-
squares refinement was based on 8378 observed reflections (I
> -3.00σ(I), 2θ < 59.94°) and 415 variable parameters and
Molecular Limited). The X-ray crystallographic data of 31 were
used as starting geometries of the quinolones 4 and 26-29.
By concerning their main species at physiological pH, calcula-
tions were performed as their zwitterionic species. The struc-
tures of the these compounds are refined by performing a
preoptimization calculation in Mechanics using Augmented
MM3, followed by an optimized geometry calculation in a
molecular orbital package (MOPAC 2002) using a Hamilto-
nian, PM3 parameters, and including solvent effects of water
simulated by Conductor-like Screening model (COSMO).
Mea su r em en ts of p Ka Va lu es a n d Dissocia tion Con -
sta n ts of 4 a n d 27 in Aqu eou s Solu tion . Deprotonation
constants (pKa) of monoprotonated species for 4 and 27 were
estimated by using pKalc 5.0 (PALLAS version 3.0, Compu-
Drug International Inc.). Almost the same values were ob-
tained for 3-carboxylic acid, and protonated aminoazetidine
is ca. 5.6 and 9.7, respectively. To define the protonation of
the 3-carboxylate, spectrophotometric pH titrations with 10
µM ligand (4 and 27) were conducted at 35 °C with I ) 0.10
(NaCl) in aqueous solution. With decreasing pH, the UV
absorption band at ca. 340 nm decreased while another band
at ca. 280 nm increased (see Figure 3 for 4). The UV-pH
profile for 4 gave a pKa value of 5.4 ( 0.1, which is almost the
same as the calculated value for the carboxylic acid. The pKa
value for the carboxylic acid of 27 was similarly determined
to be 5.4 ( 0.1.
converged (largest parameter shift was 0.00 times its esd) with
2
unweighted and weighted agreement factors of R () ∑(Fo
-
Fc2)/∑Fo2) ) 0.088, Rw () (∑w(Fo - Fc2)2/∑w(Fo2)2)0.5) ) 0.107,
and R1 ) ∑||Fo| - |Fc||/∑|Fo| ) 0.051 for I > 2.0σ(I).
2
In the presence of excess amounts of Mg2+ ion at 35 °C and
pH 7.4 with I ) 0.10 (NaCl), the ligands 4 and 27 showed
similar UV spectral changes as shown for the carboxylate
protonation (see Figure 4). The addition of MgCl2 (0.2, 0.6, 1.4,
Molecu la r Mod elin g Stu d y. All calculations were per-
formed using the CAChe WorkSystem Version 5.0 (Oxford

Antibacterial 8-Chloroquinolone
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 1917
S.; Shen, L. L.; Flamm, R. K.; Nilius, A. M.; Alder, J . D.;
Meulbroek, J . A.; Or, Y. S. Synthesis and Antimicrobial Activity
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3.0, 6.0, 10.0, and 20.0 mM) did not change the solution pH of
7.4 for the 10 µM ligands, indicating that the Mg2+ complex-
ation occurs without protonation and deprotonation (e.g.,
-NH3+ to -NH2). A typical UV absorption spectrum for 4 with
20 mM Mg2+ ion is shown in Figure 2b. A well-known double
reciprocal plot of the absorbances at 340 nm against concen-
trations of Mg2+ ion gave a line, from which a Mg2+ dissociation
constant of 2.0 ( 0.2 mM is estimated as -1/x-intercept.
Compound 27 gave almost the same dissociation constants of
2.1 ( 0.2 mM.
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