Synthesis and antimicrobial activity of 4H-4-oxoquinolizine derivatives: Consequences of structural modification at the C-8 position

Article abstract of DOI:10.1021/jm990191k

The antibacterial 4H-4-oxoquinolizines were introduced recently to overcome bacterial resistance to fluoroquinolones. They exhibit potent antibacterial activity against Gram-positive, Gram-negative, and anaerobic organisms and are highly active against some quinolone-resistant bacteria including quinolone-resistant MRSA. Preliminary studies indicated that oxoquinolizines possess distinct activity and toxicity profiles as compared with their parent quinolones. In order to develop a potent antibacterial agent with the desired spectrum of activity, good tolerability, and balanced pharmacokinetic profile, we synthesized and evaluated a series of oxoquinolizines with various substituents at the C-8 position. Most compounds tested in this study demonstrated better activity against Gram-positive bacteria than ciprofloxacin and exhibited good susceptibility against ciprofloxacin- and methicillin-resistant S. aureus. While maintaining potent in vitro activity, several compounds showed improved in vivo efficacy over ABT-719 as indicated by the mouse protection test. As an example, the oral ED₅₀ values for the cis-3-amino-4-methylpiperidine analogue 3ss against S. aureus NCTC 10649M, S. pneumoniae ATCC 6303, and E. coli JUHL were 0.8, 2.0, and 1.4 mg/kg, compared to 3.0, 10.0, and 8.3 mg/kg for ABT-719. The current study revealed that the steric and electronic environment conformation, and absolute stereochemistry of the C-8 group are very important to the antibacterial profiles. Structural modifications of the C-8 group provide a useful means to improve the antibacterial activities, physicochemical properties, and pharmacokinetic profiles. Manipulation of the C-8 group also allows us to generate analogues with the desired spectrum of activity, such as analogues that are selective against respiratory pathogens.

Full text of DOI:10.1021/jm990191k

4202
J . Med. Chem. 1999, 42, 4202-4213
Syn th esis a n d An tim icr obia l Activity of 4H-4-Oxoqu in olizin e Der iva tives:
Con sequ en ces of Str u ctu r a l Mod ifica tion a t th e C-8 P osition
Zhenkun Ma,* Daniel T. W. Chu, Curt S. Cooper, Qun Li, Anthony K. L. Fung, Sanyi Wang, Linus L. Shen,
Robert K. Flamm, Angela M. Nilius, J effery D. Alder, J onathan A. Meulbroek, and Yat Sun Or
Infectious Disease Research, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, Illinois 60064-3537
Received April 20, 1999
The antibacterial 4H-4-oxoquinolizines were introduced recently to overcome bacterial resistance
to fluoroquinolones. They exhibit potent antibacterial activity against Gram-positive, Gram-
negative, and anaerobic organisms and are highly active against some quinolone-resistant
bacteria including quinolone-resistant MRSA. Preliminary studies indicated that oxoquinolizines
possess distinct activity and toxicity profiles as compared with their parent quinolones. In
order to develop a potent antibacterial agent with the desired spectrum of activity, good
tolerability, and balanced pharmacokinetic profile, we synthesized and evaluated a series of
oxoquinolizines with various substituents at the C-8 position. Most compounds tested in this
study demonstrated better activity against Gram-positive bacteria than ciprofloxacin and
exhibited good susceptibility against ciprofloxacin- and methicillin-resistant S. aureus. While
maintaining potent in vitro activity, several compounds showed improved in vivo efficacy over
ABT-719 as indicated by the mouse protection test. As an example, the oral ED50 values for
the cis-3-amino-4-methylpiperidine analogue 3ss against S. aureus NCTC 10649M, S. pneu-
moniae ATCC 6303, and E. coli J UHL were 0.8, 2.0, and 1.4 mg/kg, compared to 3.0, 10.0, and
8.3 mg/kg for ABT-719. The current study revealed that the steric and electronic environment,
conformation, and absolute stereochemistry of the C-8 group are very important to the
antibacterial profiles. Structural modifications of the C-8 group provide a useful means to
improve the antibacterial activities, physicochemical properties, and pharmacokinetic profiles.
Manipulation of the C-8 group also allows us to generate analogues with the desired spectrum
of activity, such as analogues that are selective against respiratory pathogens.
In tr od u ction
have low intrinsic activity against a number of clinically
important Gram-positive pathogens, such as: Strepto-
coccus pneumoniae, Streptococcus pyogenes, Staphylo-
coccus aureus, and Enterococcus. Second, extensive
clinical use of fluoroquinolones, especially ciprofloxacin,
has resulted in increasing quinolone resistance among
many pathogens. High-level resistance to ciprofloxacin
and many other antibiotics has developed among me-
thicillin-resistant S. aureus (MRSA).4,5 To address the
deficiencies of the current fluoroquinolones, we directed
our research attention to the core modification of
fluoroquinolones and identified a series of potent anti-
bacterial agents with a 4H-4-oxoquinolizine core struc-
ture.6 Oxoquinolizines exhibit potent activity against
Gram-positive, Gram-negative, and anaerobic organ-
isms. In addition, they show excellent activity against
resistant bacteria such as quinolone-resistant MRSA.6
Oxoquinolizines are bioisosteres of quinolones and pos-
sess the same mechanism of action.7 They exert their
bactericidal effect by inhibiting type II bacterial DNA
topoisomerases, including two highly homologous en-
zymes, topoisomerase II (gyrase) and topoisomerase IV.
The change in the core structure has resulted in
significant enhancement of gyrase and topoisomerase
IV inhibition activities.7 Recent studies suggest that
mutations of the target enzymes in the quinolone
resistance-determining region (QRDR) appear to be the
main factor leading to quinolone resistance.5 Our pre-
liminary study indicated that oxoquinolizines exhibited
The discovery of nalidixic acid in 1962 shed the first
light on a new avenue for the treatment of bacterial
infections by inhibiting bacterial DNA synthesis. To
date many quinolone antibacterial agents have been
introduced into clinical use, and significant improve-
ments in antibacterial spectrum and activity have been
achieved. The prototype quinolone, nalidixic acid, is
active only against Gram-negative organisms and is
indicated primarily for urinary tract infections.1 This
situation did not change until the early 1980s, when the
first fluoroquinolone, norfloxacin, was launched. Intro-
duction of norfloxacin and other fluoroquinolones, such
as: ofloxacin, enoxacin, ciprofloxacin, tosufloxacin, spar-
floxacin, grepafloxacin, and levofloxacin, has changed
the landscape of antimicrobial chemotherapy. Fluoro-
quinolones are active against a wide range of Gram-
negative and Gram-positive pathogens and possess
improved oral absorption and systemic distribution.
Therefore, their clinical applications have been extended
to the treatment of lower respiratory tract infections,
skin and soft tissue infections, sexually transmitted
diseases, and urinary tract infections.2 One of the most
recent fluoroquinolones, trovafloxacin, is reported to
have improved antibacterial activity against Gram-
positive bacteria and anaerobes with improved phar-
macokinetic profiles.3
Despite many advances, the current fluoroquinolones
have shown several deficiencies. First, they generally
10.1021/jm990191k CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/09/1999

Synthesis, Antimicrobial Activity of Oxoquinolizines
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20 4203
Sch em e 1
Sch em e 2a
good inhibition activities to both gyrase and topo-
isomerase IV isolated from resistant bacteria. In con-
trast, quinolones such as ciprofloxacin showed very low-
level inhibition activities against resistant enzymes.
These results suggested that our oxoquinolizines have
the ability to bind to mutated enzymes and thus behave
differently from the fluoroquinolones.8 Although progress
has been made recently on the structure determination
and on the mechanism of DNA topoisomerase,9 we have
very limited knowledge of how the drug, DNA, and
topoisomerase integrate.10 Without a clear picture of
drug-receptor interaction, we pursued a systemic struc-
tural modification of oxoquinolizine in order to optimize
the antibacterial profiles based on this new platform.
Since the discovery of nalidixic acid, thousands of
quinolones have been synthesized and evaluated. One
useful conclusion from the earlier work is that the
structure of the C-7 moiety of quinolones plays an
essential role in their antibacterial activity. This conclu-
sion is consistent with a drug-DNA-gyrase ternary
cooperative binding model suggesting that the quinolone
inserts itself into the complex formed between DNA and
gyrase in such a way that the C-3 carboxylic acid and
the C-4 ketone interact with the cleaved or perturbed
DNA while the C-7 group interacts with DNA gy-
rase.10,11 Due to a different numbering system, the C-8
moiety of oxoquinolizines occupys the same position as
the C-7 group of quinolones. In order to identify an
antibacterial agent with the desired spectrum of activ-
ity, good tolerability and balanced pharmacokinetic
profiles, we carried out an extensive modification of the
C-8 moiety of the oxoquinolizine. Herein, we would like
to discuss in detail the consequences of the structural
variation of the C-8 moiety on the in vitro and in vivo
antibacterial activity.
a
(a) 5, n-BuLi, THF, -78 °C; (b) N-benzyl-N-(methoxymethyl)-
(trimethylsilyl)methylamine (7), 0.1 equiv TFA, toluene; (c) LiOH,
H2O2, THF-H2O, rt; (d) (1) DPPA, Et3N, t-BuOH, 95 °C, (2)
HCO2NH4, 10% Pd-C, MeOH, reflux.
F igu r e 1. X-ray single-crystal structure of compound 10 (R
) cyclopropyl group).
Ch em istr y
The synthesis of the 4H-4-oxoquinolizine core 1 has
been reported earlier6 and served as our key intermedi-
ate. Aromatic nucleophilic substitution of the 8-chloro
group with an appropriate cyclic amine produced the
coupling product 2. Hydrolysis of the 3-ethyl ester
provided the oxoquinolizines 3 with the desired C-8
moiety (Scheme 1). In the cases where diamines were
used, the amino groups were differentiated using a
protecting group prior to coupling. After coupling to the
core and hydrolysis of the ester, the protecting group
was removed to give the desired compounds.
The amines used in this study were obtained from
commercial sources or prepared according to literature
procedures.12 Optically active chiral amines were ob-
tained by chiral HPLC separation or by asymmetric
synthesis. We developed a practical and efficient syn-
thesis as a general route to optically active trans-3-
amino-4-alkyl(aryl)pyrrolidines utilizing an asymmetric
dipolar cycloaddition reaction (Scheme 2).13 The major
diastereomer 10 produced was determined to have the
3R,4R configuration by single-crystal X-ray crystal-
lography (Figure 1). Utilizing this methodology, the
opposite enatiomers of 12 were conveniently obtained
from the chiral auxiliary (5) of opposite stereochemistry.
The structures of the C-8 groups used in this study
are listed in Charts 1 and 2. These amines were selected
with the intention of studying the effects of ring size,
substitution, conformation, and stereochemistry on the
antibacterial activity and efficacy.
Micr obiology
In Vitr o An tiba cter ia l Activity. The C-8-modified
oxoquinolizines used in this study and the reference
agent, ciprofloxacin, were tested against representative
Gram-positive and Gram-negative bacteria from the

4204 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20
Ch a r t 1. Structures of the C-8 Group of Oxoquinolizines 3
Ma et al
Ch a r t 2. Stereochemical Structures of the Selected C-8 Group of Oxoquinolizines 3
Abbott clinical culture collection. The ciprofloxacin-
resistant and less susceptible isolates such as Staphy-
lococcus aureus 1775, Escherichia coli KNK 437,
Pseudomonas cepacia, and Pseudomonas aeruginosa
DPHD-5263 were included in this test in order to
identify potent analogues that could overcome cipro-
floxacin resistance. The in vitro antibacterial activity
is reported as the minimum inhibitory concentrations

Synthesis, Antimicrobial Activity of Oxoquinolizines
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20 4205
Ta ble 1. In Vitro Antibacterial Activity of Compounds 3a -3w w
MIC (µg/mL)
Gram-positive organisma
Gram-negative organismb
S. aureus
S. aureus
E. faecium
S. pyogenes
E. coli
P. cepacia
P. aeruginosa
P. aeruginosa
compd
NCTC 10649M
1775
ATCC 8043
930
KNK 437
2961
5007
DPHP 5263
ciprofloxacin
3a
3d
3e
3f
3g
3i
3j
3k
3l
3m
3o
3p
3q
3s
3t
3u
3v
0.39
0.2
>100
3.1
0.78
>100
3.1
0.39
0.78
0.2
0.78
0.78
0.2
0.2
3.1
0.39
6.2
3.1
6.2
3.1
0.78
6.2
1.56
0.1
0.39
1.56
3.1
3.1
0.39
3.1
0.78
3.1
0.78
0.78
1.56
1.56
1.56
0.39
6.2
3.1
3.1
3.1
3.1
6.2
1.56
3.1
1.56
6.2
3.1
0.39
25
3.1
3.1
3.1
0.78
1.56
3.1
3.1
3.1
0.1
3.1
0.78
6.2
3.1
0.2
0.05
0.2
0.39
1.56
0.39
3.1
1.56
0.78
0.39
0.78
0.39
0.39
1.56
0.1
1.56
0.78
0.78
3.1
0.39
6.2
12.5
>100
>100
>100
>100
6.2
0.02
0.78
0.02
0.005
0.02
0.02
0.05
0.1
3.1
6.2
0.39
0.05
0.02
0.1
0.1
0.39
0.2
0.39
0.39
0.2
0.1
0.1
0.1
0.2
0.2
0.01
0.2
0.39
0.05
0.02
0.05
0.1
0.2
0.2
0.78
1.56
1.56
1.56
0.39
0.78
1.56
1.56
0.39
0.78
0.39
1.56
1.56
0.39
0.39
0.78
0.1
0.2
0.78
3.1
0.39
6.2
0.78
0.78
0.78
6.2
0.02
0.05
0.2
0.2
0.2
1.56
0.39
0.39
0.2
0.1
0.1
0.78
1.56
6.2
0.2
12.5
12.5
>100
12.5
100
12.5
6.2
0.02
0.02
0.05
0.05
0.02
0.01
0.02
0.02
0.05
0.002
0.02
0.05
0.002
0.002
0.005
0.01
0.02
0.05
0.02
0.002
0.05
0.05
0.2
0.05
0.39
0.39
0.2
0.1
0.05
0.1
0.2
0.2
0.002
0.1
6.1
12.5
25
1.56
25
6.2
12.5
50
6.2
6.2
6.2
6.2
3.1
100
25
6.2
100
6.2
3.1
0.2
3x
3y
3z
0.78
0.05
0.39
0.2
0.2
1.56
0.2
0.1
0.2
0.2
0.1
0.78
0.78
0.2
0.78
0.39
0.2
3.1
0.1
0.39
0.39
0.2
3a a
3bb
3d d
3ee
3ff
3gg
3h h
3ii
3jj
3k k
3ll
3m m
3n n
3oo
3p p
3qq
3ss
3tt
0.1
0.02
0.02
0.05
0.05
0.05
0.1
0.1
0.1
0.2
0.2
3.1
0.2
0.1
0.39
0.05
0.2
0.05
0.05
0.05
0.002
0.02
0.02
0.05
0.1
0.05
0.1
0.2
0.05
1.56
0.39
0.2
0.39
1.56
1.56
0.39
3.1
0.78
0.39
3.1
12.5
6.2
6.2
0.78
0.39
1.56
0.39
1.56
1.56
0.05
0.05
0.05
0.01
0.05
0.01
0.01
0.02
0.1
0.2
>100
0.02
0.1
0.02
0.05
0.05
0.2
3.1
12.5
0.78
0.39
0.39
0.39
3u u
3w w
25
6.2
0.2
a
S aureus 1775 is a ciprofloxacin-, erythromycin-, and methicillin-resistant strain, and S. pyogenes 930 is an erythromycin-resistant
b
strain. E. coli KNK 437 is a ciprofloxacin less sensitive strain, and P. cepacia 2961 and P. aeruginosa DPHP 5263 are ciprofloxacin-
resistant strains.
(MICs), which were determined by the agar dilution
method as recommended by the National Committee for
Clinical Laboratory Standards.
optimum. Therefore, we selected 1-cyclopropyl-7-fluoro-
9-methyl-4-oxoquinolizine-3-carboxylic acid as our tem-
plate.15 The structures of the C-8 groups are shown in
Charts 1 and 2. The in vitro activities of the correspond-
ing oxoquinolizines are shown in Tables 1 and 2, and
the in vivo efficacies for selected compounds are shown
in Table 3. A panel of Gram-positive and Gram-negative
bacteria was selected for the in vitro testing to assess
the potency and spectrum of activity. Among the organ-
isms, S. aureus 1775 represents a quinolone-resistant
MRSA. The structures of the C-8 groups were carefully
selected so that the effects of the ring size, functionality,
substitution, conformation, and stereochemistry of the
C-8 moiety could be assessed. In general, most com-
pounds tested demonstrated better activity than cipro-
floxacin against Gram-positive organisms and exhibited
good susceptibility against methicillin- and ciprofloxa-
cin-resistant S. aureus. The activities against Gram-
negative organisms were retained in some cases and
reduced in others depending on the structure of the C-8
substituents.
In Vivo Effica cy. The in vivo efficacies of a selected
group of compounds were assessed by mouse protection
test. The mice were inoculated intravenously with a 100-
fold LD50 of representative organisms. Tested com-
pounds were administered by either subcutaneous
injection or oral gavage at 1 and 5 h post-inoculation.
Mortality rates of the mice were monitored for a period
of 7 days post-inoculation with a 100% mortality rate
for untreated controls. The efficacy of each compound,
based on the survival rates over a dose range, was
reported as the drug dose resulting in a survival of 50%
of treated mice over the duration of the trial (ED50).
Resu lts a n d Discu ssion
The effects of C-114 and C-96 modifications of oxo-
quinolizine on antibacterial activity have been discussed
elsewhere. A cyclopropyl group at the C-1 position and
a methyl group at the C-9 position appear to be

4206 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20
Ma et al
Ta ble 2. In Vitro Antibacterial Activity of Selected Optically Active Compounds
MIC (µg/mL)
Gram-positive organisma
gram-negative organismb
S. aureus
S. aureus
E. faecium
S. pyogenes
E. coli
P. cepacia
P. aeruginosa
P. aeruginosa
compd
NCTC 10649M
1775
ATCC 8043
930
KNK 437
2961
5007
DPHP 5263
ciprofloxacin
(S)-3i
(R)-3i
(S)-3n
(R)-3n
(3S,4R)-3xx
(3R,4S)-3xx
(3S,4R)-3v
(3R,4S)-3v
(3S,4R)-3t
(3R,4S)-3t
(3S,4S)-3s
(3R,4R)-3s
(1S,5S)-3gg
(1R,5R)-3gg
(S)-3u u
0.39
0.01
0.02
0.01
0.02
0.02
0.05
0.01
0.05
0.05
0.02
0.005
0.02
0.05
0.1
>100
0.78
1.56
0.39
0.39
0.78
0.78
0.39
0.78
0.78
0.78
0.39
0.78
3.1
0.39
0.02
0.05
0.1
0.1
0.05
0.2
0.1
0.2
0.1
0.1
0.05
0.1
0.1
0.2
0.1
0.05
0.2
0.39
0.78
0.02
0.05
0.1
0.05
0.05
0.1
0.02
0.1
0.05
0.1
0.2
6.2
0.1
12.5
0.39
1.56
12.5
25
1.56
3.1
3.1
12.5
3.1
12.5
12.5
12.5
3.1
0.02
0.05
0.2
1.56
0.05
0.1
0.05
0.2
0.2
0.2
0.1
0.2
0.1
0.39
0.78
3.1
1.56
0.78
0.78
0.78
0.78
1.56
1.56
0.05
0.05
0.78
1.56
0.2
0.39
0.2
3.1
0.39
0.39
0.39
0.39
0.2
0.39
0.2
0.78
0.78
1.56
0.02
0.1
1.56
0.78
0.78
0.78
6.2
6.2
0.39
3.1
1.56
3.1
0.39
0.05
0.1
0.2
0.78
6.2
3.1
25
0.01
0.01
0.05
0.1
0.02
0.02
0.1
(R)-3u u
(3S,4S)-3ss
(3R,4R)-3ss
1.56
6.2
0.39
12.5
a
S. aureus 1775 is a ciprofloxacin-, erythromycin-, and methicillin-resistant strain, and S. pyogenes 930 is an erythromycin-resistant
b
strain. E. coli KNK 437 is a ciprofloxacin less sensitive strain, and P. cepacia 2961 and P. aeruginosa DPHP 5263 are ciprofloxacin-
resistant strains.
Ta ble 3. In Vivo Efficacy of Selected Compounds
mouse protection test, ED50 (mg/kg)
S. aureus NCTC 10649M
S. pneumoniae ATCC 6303
E. coli J UHL
sc po
0.2 1.3
P. aeruginosa 5007
compd
sca
pob
sc
po
sc
2.4
po
ciprofloxacin
3d
3e
3i
3k
3l
3m
(S)-3n
(R)-3n
3p
3.6
25.0
37.4
>100
20.0
>12
>12
>50
>5
0.8
3.0
7.7
2.6
2.9
10.0
7.9
0.3
8.3
3.0
>10
16.5
17.2
34.1
0.5
>8
>8
>32
>32
>32
2.9
>50
>50
>50
>50
>50
1.0
4.3
3.6
1.1
2.1
6.1
1.5
1.5
3.0
1.3
1.6
1.8
0.7
0.6
1.5
1.2
2.7
6.0
7.0
3.3
1.0
1.2
0.5
0.4
0.8
1.8
1.2
0.6
1.1
5.0
4.9
4.4
2.5
3.7
3.4
1.2
0.5
2.8
25.4
25.0
7.5
9.6
18.1
3.4
>8
23.1
9.9
8.0
30.7
>10
3s
6.6
(3S,4R)-3t
(3R,4S)-3t
3u
3v
3d d
10.9
11.2
8.0
25.0
10.0
>32
>32
>50
>50
>8.0
>50.0
>10
2.7
9.1
6.3
17.7
5.0
1.5
5.0
12.5
4.8
11.5
23.9
0.8
5.0
4.5
13.0
7.6
16.1
>32
6.4
5.0
18.0
6.4
>50
>50
39.1
17.9
>50
58.7
>5
>20
3gg
0.4
0.5
0.8
0.7
2.5
1.1
(1S,5S)-3gg
(1R,5R)-3gg
3h h
3jj
3k k
3m m
3ss
(3S,4R)-3ss
(3R,4S)-3ss
3tt
2.3
1.3
11.2
25.2
10
5.0
>5
>5
4.4
>20
>20
>10
>32
>32
>50
>50
1.0
2.1
8.0
2.0
1.0
5.2
0.6
0.6
2.0
1.7
2.8
1.4
4.3
6.3
1.9
2.1
3.0
12.5
2.3
24.5
>32
>50
>50
3u u
1.0
4.3
2.5
8.0
>32
>32
>32
>50
(S)-3u u
(R)-3u u
3w w
>5
>16
4.1
0.9
5.0
a
b
sc represents subcutaneous injection. po represents oral gavage.
The ring size of the C-8 group appeared to be an
important factor for the antibacterial activity. The
optimum ring sizes are five and six with the five-
membered ring being somewhat more active. This trend
is clearly illustrated by comparing the MICs of com-
pounds 3a , 3d , and 3p p . The antibacterial activity,
especially against Gram-negative organisms, was greatly
enhanced by introducing a hydroxy or an amino group
onto the five- or six-membered ring cyclic amine as
exemplified by compounds 3d , 3g, and 3i or compounds
3p p and 3qq. Moreover, the amino group appeared to
be the key element in giving good in vivo efficacy (Table
3). When an additional heteroatom was integrated into
the ring, as in compounds 3e and 3f, no improvement
in activity was observed.
Manipulation of the C-7/C-8 (C-7 for quinolones and

Synthesis, Antimicrobial Activity of Oxoquinolizines
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20 4207
C-8 for oxoquinolizines) structure has been a useful tool
to achieve the right balance of antibacterial activity,
physiochemical properties, and pharmacokinetics.16 Fur-
thermore, modification of the C-7/C-8 group has been
used to improve the toxicity profiles. It has been
illustrated that introducing substituents on the pipera-
zine ring at the C-7 position of a quinolone increased
the selectivity between bacterial gyrase and mammalian
topoisomerase II.17 In our case, introduction of an alkyl
group to the amino nitrogen of the (3S)-3-aminopyrro-
lidine moiety diminished the in vitro antibacterial
activity. The activities decreased with the increase of
the size of alkyl groups (see MICs for compounds 3i-
3l). However, the in vivo efficacy did not directly
correlate to the size of the alkyl groups (Table 3). The
ethyl-substituted analogue 3k showed comparable or
better efficacy than its unsubstituted parent compound
3i in three of the four organisms tested. Substitutions
on the neighboring carbon of the amino group gave a
series of analogues with excellent antibacterial activi-
ties, especially against Gram-positive bacteria. Although
the configuration of this neighboring alkyl group had
insignificant effects on the in vitro activity as exempli-
fied by cis- and trans-3-amino-4-alkylpyrrolidines (Table
1, 3s and 3t, 3u and 3v), the cis compounds (Table 3,
3s, 3u ) demonstrated better in vivo efficacy than their
trans counterparts (3t, 3v).
negative (E. coli) infections. Compound 3u u , the 3-cy-
clopropylaminopiperidine derivative, demonstrated ex-
cellent activity. The in vitro activities against Gram-
positive bacteria were similar to those of ABT-719, but
the oral efficacies against Gram-positive bacteria (S.
aureus and S. pneumoniae) were much better as il-
lustrated by the mouse protection test.
Chirality also appeared to be an important factor for
antibacterial activity. According to the proposed drug-
DNA-gyrase ternary cooperative binding model, the
C-8 group of oxoquinolizine interacts directly with DNA
gyrase and topoisomerase IV.11 Due to the chiral nature
of gyrase and topoisomerase IV, the chirality of the C-8
moiety would have a direct effect on the binding affinity.
To test this hypothesis, we synthesized a series of
optically pure analogues of selected racemic compounds
by asymmetric synthesis or by chiral separation. The
structures of these chiral derivatives are listed in Chart
2. The absolute stereochemistry of enantiomers of 3i,
3n , 3v, 3t, and 3xx were unambiguously assigned based
on single-crystal X-ray analysis or their chemical sources.
The assignments for the enantiomers of 3s, 3gg, 3u u ,
and 3ss were arbitrary. Nevertheless, the difference in
antibacterial activities and efficacies between enanti-
omers was apparent, ranging from 2 times for some
organisms to 10 times for others (Tables 2 and 3).
Compound (3S,4R)-3v, for example, is on average 5-fold
more active than (3R,4S)-3v against the tested strains.
The activity is inferentially correlated to the stereo-
chemistry of the 3-amino group, suggesting that the
3-amino group may be directly involved in the interac-
tion with a chiral binding site of receptors. For those
compounds with defined stereochemical structure, the
3S isomers always displayed better in vitro activities
and in vivo efficacies than the 3R forms (Table 3).
Among the oxoquinolizine analogues, the 3-(amino-
methyl)pyrrolidine series (3y-3ff) displayed the best
activity against Gram-positive bacteria. For example,
compound 3d d is 10 times more potent than 3x against
Gram-positive bacteria. It is worth noting that the
proper substitution on the amino nitrogen or the ring
can provide analogues with a defined spectrum of
activity. One such compound, 3d d , exhibited excellent
activity against all Gram-positive bacteria but showed
very weak activity against Gram-negative pathogens.
This compound did not show any in vivo efficacy in the
mouse protection model against Gram-negative bacteria.
Such compounds with a defined spectrum of activity
may be advantageous for the treatment of Gram-
positive infections, such as respiratory infections.
Con clu sion
We have demonstrated that the structure of the C-8
moiety of oxoquinolizines is important to the antibacte-
rial profiles. Many factors such as ring size, substitution,
conformation, and stereochemistry influence the in vitro
activity and in vivo efficacy. Oxoquinolizines derived
from five- and six-membered ring cyclic amines with
proper substituents demonstrated the best activity and
efficacy. Many of these compounds showed improved in
vivo efficacy over ABT-719 against Gram-positive bac-
teria. We also observed that the spectrum of antibacte-
rial activity can be altered by controlling the substitu-
tion and configuration of the C-8 group.
In the bicyclic series (3gg-3oo), two 3,4-fused pyr-
rolidine analogues, 2,7-diazobicyclo[3.3.0]octane deriva-
tive 3gg and 2,8-diazobicyclo[4.3.0]nonane derivative
3ii, are among the most potent compounds. In fact,
compound 3gg showed better in vivo efficacies than
ABT-719 (3i) against S. aureus, S. pneumoniae, and E.
coli and was one of the most efficacious compounds in
vivo. Compound 3jj, the oxygen isostere of 3ii, exhibited
excellent Gram-positive activity but had reduced Gram-
negative activity. This compound showed excellent in
vivo efficacy against S. aureus but failed against E. coli
in the mouse protection test. Compound 3k k , the trans
isomer of 3jj, was less active both in vitro and in vivo.
Bicyclic compounds with a 2,3-fused pyrrolidine moiety
such as 3m m -3oo were less active and gave weak
activities against quinolone-resistant MRSA.
Exp er im en ta l Section
The key intermediate, ethyl 8-chloro-1-cyclopropyl-7-fluoro-
9-methyl-4(H)-4-oxoquinolizinecarboxylate (1), was provided
by the Abbott Process Research Department. The synthesis
of this compound has been reported in our previous paper.6
Tetrahydrofuran was distilled from sodium/benzophenone. All
other solvents and reagents were obtained from commercial
sources and used without further purification. All nonaqueous
reactions were carried out under a nitrogen atmosphere using
oven- or flame-dried glassware unless otherwise indicated.
Flash column chromatography was performed on Merck silica
gel 60 (230-400 mesh). Chiral separations were performed on
preparative high-performance liquid chromatography (HPLC)
by the Abbott Process Research Department, and the separa-
tion conditions will be specified in the experimental proce-
dures. Melting points were recorded on a Fisher-J ohns appa-
Several substituted 3-aminopiperidine derivatives
also exhibited excellent activity. trans-3-Amino-4-me-
thylpiperidine derivative 3tt is 5 times more active
against Gram-positive bacteria than its cis counterpart
3ss. Both compounds showed better in vivo efficacy than
ABT- 719 against Gram-positive (S. aureus) and Gram-

4208 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20
Ma et al
ratus and are uncorrected. Optical rotations were measured
at 20 °C with a Perkin-Elmer 241 polarimeter. All elemental
analyses were performed by Robertson Microlite Laboratories,
and the data for carbon, hydrogen, and nitrogen reported are
within 0.4% of theoretical values.
carbonyl)aminomethyl-1-azetidinyl]-1-cyclopropyl-7-fluoro-9-
methyl-4(H)-4-oxoquinolizinecarboxylate (2c) as a yellow solid
(215 mg).
To a solution of the above product (215 mg, 0.45 mmol) in
THF (8 mL) was added a solution of LiOH‚H2O (191 mg, 4.55
mmol) in water (4 mL). The reaction mixture was heated to
80 °C and stirred at this temperature for 4 h. After cooling to
room temperature, the mixture was neutralized to pH 3 with
1 N HCl (4.6 mL) solution followed by addition of water (30
mL). The solid formed was collected by filtration and purified
by flash column eluting with CH2Cl2/MeOH/HOAc (90:5:0.5)
to give 8-[2-(tert-butoxycarbonyl)aminomethyl-1-azetidinyl]-1-
cyclopropyl-7-fluoro-9-methyl-4(H)-4-oxoquinolizinecarboxyl-
ic acid (162 mg) as a yellow solid.
To a solution of the above product (162 mg, 0.37 mmol) in
CH2Cl2 was added a solution of HCl in dioxane (4 N, 2 mL).
The reaction mixture was stirred at room temperature for 4 h
and treated with ethyl ether (20 mL). The precipitate was
collected by filtration, washed with ether, and dissolved in
distilled water. The resulting yellow solution was filtered
through a sintered glass funnel and freeze-dried to give 3c as
a yellow solid (123 mg, 0.32 mmol, 88%): mp 181-183 °C; MS
(DCI/NH3) m/ e 346 (M + H)+; 1H NMR (DMSO) δ 13.8 (1H, s,
COOH), 9.25 (1H, d, J ) 10.0 Hz, H-6), 8.15 (1H, s, H-2), 3.80
(1H, m), 3.64 (1H, m), 3.10-3.40 (3H, m), 2.80 (3H, s, CH3),
2.38 (1H, m), 2.20 (2H, m), 1.05 (2H, m), 0.60 (2H, m). Anal.
(C18H20FN3O3‚HCl‚H2O) C, H, N.
1-Cyclopr opyl-7-flu or o-9-m eth yl-8-(1-pyr r olidin yl)-4(H)-
4-oxoqu in olizin e-3-ca r boxylic Acid (3d ). By following gen-
eral procedure A, starting from 1 (656 mg, 2.00 mmol) and
pyrrolidine (568 mg, 8.00 mmol), 3d was obtained as a yellow
solid (400 mg, 1.21 mmol, 61% in 2 steps): mp 220-221 °C;
MS (DCI/NH3) m/ e 331 (M + H)+; high-resolution MS (APCI)
obsd 331.1465, calcd for C18H20FN2O3 331.1458; 1H NMR
(CDCl3) δ 13.89 (1H, s, COOH), 9.06 (1H, d, J ) 10.5 Hz, H-6),
8.22 (1H, s, H-2), 3.75 (4H, m), 2.61 (3H, s, CH3), 2.17 (1H,
m), 2.06 (4H, m), 0.98 (2H, m), 0.65 (2H, m).
1-Cyclopr opyl-7-flu or o-8-(1-isoxazolin yl)-9-m eth yl-4(H)-
4-oxoqu in olizin e-3-ca r boxylic Acid (3e). By following gen-
eral procedure A, starting from 1 (771 mg, 2.39 mmol) and
isoxazoline hydrochloride19 (1.31 g, 11.95 mmol), 3e was
obtained as a yellow solid (260 mg, 0.78 mmol, 33% in 2
steps): mp 174-175 °C; MS (DCI/NH3) m/ e 333 (M + H)+; 1H
NMR (CDCl3) δ 13.83 (1H, s, COOH), 9.21 (1H, d, J ) 10.5
Hz, H-6), 8.37 (1H, s, H-2), 4.18 (2H, t, J ) 6.3 Hz), 3.78 (2H,
m), 2.88 (3H, s, CH3), 2.50 (2H, m), 2.30 (1H, m), 1.05 (2H,
m), 0.72 (2H, m). Anal. (C17H17FN2O4) C, H, N.
8-(1-Azetid in yl)-1-cyclop r op yl-7-flu or o-9-m eth yl-4(H)-
4-oxoqu in olizin e-3-ca r boxylic Acid (3a ). Gen er a l P r oce-
d u r e A. Azetidine (1.00 g, 17.54 mmol) was added to a stirred
mixture of 1 (1.29 g, 4.00 mmol) and sodium bicarbonate (1.68
g, 20.00 mmol) in acetonitrile (40 mL) under nitrogen. The
reaction mixture was heated with stirring at 60 °C for 20 h.
After cooling to room temperature, the reaction mixture was
taken up in CH2Cl2 (100 mL) and washed with water (50 mL),
1 N HCl (50 mL), water (50 mL), and brine (50 mL). The
resulting solution was dried over Na2SO4 and the solvent was
evaporated. The yellow solid obtained was purified by flash
column chromatography eluting with CH2Cl2/MeOH (95:5) to
give 2a as a yellow solid (1.29 g).
To a solution of the above product 2a (1.29 g, 3.75 mmol) in
THF (100 mL) was added a solution of LiOH‚H2O (1.57 g, 37.5
mmol) in water (40 mL). The reaction mixture was heated to
80 °C and stirred at this temperature for 6 h. After cooling to
room temperature, the mixture was neutralized to pH 3 with
1 N HCl (40 mL) solution and diluted with water (300 mL).
The precipitate was collected by filtration, washed three times
with cold water, and dried in a vacuum desiccator to give a
yellow solid 3a (0.705 g, 2.37 mmol, 60%): mp 245-247 °C;
MS (APCI) m/ e 317 (M + H)+; high-resolution MS (APCI) obsd
1
317.1290, calcd for C17H17FN2O3 317.1301; H NMR (CDCl3)
δ 13.86 (1H, s, COOH), 8.97 (1H, d, J ) 9.3 Hz, H-6), 8.09
(1H, s, H-2), 4.63 (4H, m), 2.62 (3H, s, CH3), 2.53 (2H, m), 2.12
(1H, m), 0.97 (2H, m), 0.69 (2H, m).
1-Cyclop r op yl-7-flu or o-8-(2-h yd r oxym et h yl-1-a zet i-
d in yl)-9-m eth yl-4(H)-4-oxoqu in olizin e-3-ca r boxylic Acid
(3b). Gen er a l P r oced u r e B. To a solution of (()-2-(hy-
droxymethyl)azetidinium trifluoroacetate18 (540 mg, 2.68 mmol)
and 1 (434 mg, 1.34 mmol) in DMF (10 mL) was added
triethylamine (1.00 mL, 7.19 mmol). The reaction mixture was
stirred at 50 °C under a nitrogen atmosphere for 48 h and
cooled to room temperature. The reaction mixture was taken
up in ethyl acetate (50 mL) and washed with water (30 mL),
1 N HCl (30 mL), water (30 mL), and brine (30 mL). The
resulting ethyl acetate solution was dried over Na2SO4 and
evaporated to dryness. Flash column chromatography eluting
with CH2Cl2/MeOH (90:10) provided 2b as a yellow glass (160
mg).
To a solution of the above product 2b (150 mg, 0.40 mmol)
in THF (8 mL) was added a solution of LiOH‚H2O (168 mg,
4.00 mmol) in water (4 mL). The reaction mixture was heated
to 80 °C and stirred at this temperature for 4 h. After cooling
to room temperature, the mixture was neutralized to pH 3 with
1 N HCl solution (5 mL) and diluted with water (30 mL). The
solid formed was collected by filtration and purified by flash
column eluting with CH2Cl2/MeOH/HOAc (90:10:1) to give 3b
(102 mg, 0.29 mmol, 74%) as a yellow solid: mp 235-237 °C;
1-Cyclop r op yl-7-flu or o-9-m eth yl-8-(2-m eth yl-1-p yr a zo-
lid in yl)-4(H)-4-oxoqu in olizin e-3-ca r boxylic Acid (3f). By
following general procedure A, starting from 1 (646 mg, 2.00
mmol) and N-methylpyrazolidine20 (344 mg, 4.00 mmol), 3f
was obtained as a yellow solid (156 mg, 0.45 mmol, 23% in 2
steps): mp 185-187 °C; MS (DCI/NH3) m/ e 346 (M + H)+; 1H
NMR (CDCl3) δ 13.93 (1H, s, COOH), 9.14 (1H, d, J ) 10.2
Hz, H-6), 8.28 (1H, s, H-2), 3.78 (2H, m), 3.14 (2H, t, J ) 6.9
Hz), 2.72 (3H, s, CH3), 2.53 (3H, s), 2.32 (2H, m), 2.25 (1H,
m), 1.02 (2H, m), 0.68 (2H, m).
1
MS (DCI/NH3) m/ e 347 (M + H)+; H NMR (DMSO) δ 13.80
(1H, br s, COOH), 9.04 (1H, d, J ) 10.0 Hz, H-6), 7.86 (1H, s,
H-2), 4.92 (1H, m), 4.68 (1H, m), 4.25 (1H, m), 3.76 (1H, m),
3.63 (1H, m), 3.31 (3H, s, CH3), 2.55 (1H, m), 2.27 (2H, m),
1.05 (1H, m), 0.88 (1H, m), 0.58 (2H, m). Anal. (C18H19FN2O4‚
0.25H2O) C, H, N.
8-(3-Ca r boxy-1-p yr r olid in yl)-1-cyclop r op yl-7-flu or o-9-
m eth yl-4(H)-4-oxoqu in olizin e-3-ca r boxylic Acid (3h ). By
following general procedure A, starting from 1 (323 mg, 1.00
mmol) and 3-carbamoylpyrrolidine (190 mg, 1.75 mmol), 3h
was obtained as a yellow solid (44 mg, 0.12 mmol, 12% in 2
1
8-(2-Am in om eth yl-1-azetidin yl)-1-cyclopr opyl-7-flu or o-
9-m eth yl-4(H)-4-oxoqu in olizin e-3-ca r boxylic Acid Hy-
d r och lor id e (3c). Gen er a l P r oced u r e C. A mixture of 1
(150 mg, 0.46 mmol), (()-2-(tert-butoxycarbonyl)aminomethyl-
azetidine (173 mg, 0.93 mmol), and NaHCO3 (195 mg, 2.32
mmol) in acetonitrile (5 mL) was heated to reflux under
nitrogen for 16 h. The reaction mixture was taken up in ethyl
acetate (50 mL) and sequentially washed with water (30 mL),
1 N HCl (30 mL), water (30 mL), and brine (30 mL). The
resulting ethyl acetate solution was dried over Na2SO4 and
evaporated to dryness. Flash column chromatography eluting
with CH2Cl2/MeOH (90:10) provided ethyl 8-[2-(tert-butoxy-
steps): mp 180 °C dec; MS (DCI/NH3) m/ e 375 (M + H)+; H
NMR (DMSO) δ 9.08 (1H, d, J ) 10.5 Hz, H-6), 7.91 (1H, s,
H-2), 3.90 (2H, m), 3.78 (2H, m), 3.20 (1H, m), 2.61 (3H, s,
CH3), 2.10-2.30 (3H, m), 0.98 (2H, m), 0.62 (2H, m). Anal.
(C19H19FN2O‚0.5H2O) C, H, N.
1-Cyclop r op yl-8-[(3S)-3-eth yla m in o-1-p yr r olid in yl]-7-
flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-ca r boxylic Acid
Hyd r och lor id e (3k ). By following general procedure C,
starting from 1 (535 mg, 1.65 mmol) and (3S)-3-ethyl(tert-
butoxycarbonyl)aminopyrrolidine (708 mg, 3.31 mmol), 3k was
obtained as a yellow solid (412 mg, 1.01 mmol, 61% in 3
1
steps): mp 260 °C dec; MS (DCI/NH3) m/ e 374 (M + H)+; H

Synthesis, Antimicrobial Activity of Oxoquinolizines
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20 4209
NMR (DMSO) δ 13.85 (1H, br s, COOH), 9.12 (1H, d, J ) 10.2
Hz, H-6), 7.95 (1H, s, H-2), 3.90-4.10 (7H, m), 2.64 (3H, s, CH3),
2.33 (2H, m), 2.20 (1H, m), 1.24 (3H, t, J ) 6.9 Hz), 1.00 (2H,
m), 0.62 (2H, m). Anal. (C20H24FN3O3‚HCl‚H2O) C, H, N.
5.00 mmol), 3p was obtained as a yellow solid (272 mg, 0.62
mmol, 25% in 3 steps): mp 204-205 °C; MS (DCI/NH3) m/ e
1
404 (M + H)+; H NMR (DMSO) δ 13.85 (1H, s, COOH), 9.12
(1H, d, J ) 10.5 Hz, H-6), 7.95 (1H, s, H-2), 3.90-4.10 (4H, m),
3.82 (1H, m), 3.65 (2H, t, J ) 4.8 Hz), 3.34 (3H, s, OCH3),
3.24 (2H, m), 2.63 (3H, s, CH3), 2.20-2.40 (3H, m), 1.01 (2H,
m), 0.62 (2H, m). Anal. (C21H26FN3O4‚HCl‚H2O) C, H, N.
1-Cyclopr opyl-7-flu or o-9-m eth yl-8-[(3S)-3-pr opylam in o-
1-p yr r olid in yl]-4(H)-4-oxoqu in olizin e-3-ca r boxylic Acid
Hyd r och lor id e (3l). By following general procedure C, start-
ing from 1 (476 mg, 1.47 mmol) and (3S)-3-propyl(tert-
butoxycarbonyl)aminopyrrolidine (500 mg, 2.21 mmol), 3l was
obtained as a yellow solid (340 mg, 0.80 mmol, 55% in 3
1-Cyclopr opyl-7-flu or o-8-[3-m eth yl(cyclopr opyl)am in o-
1-p yr r olid in yl]-9-m eth yl-4(H)-4-oxoqu in olizin e-3-ca r box-
ylic Acid Hyd r och lor id e (3q). By following general proce-
dure A, starting from 1 (206 mg, 0.64 mmol) and (()-3-
methyl(cyclopropyl)aminopyrrolidine (180 mg, 1.28 mmol), 3q
was obtained as a yellow solid (49 mg, 0.11 mmol, 18% in 3
1
steps): mp 249 °C dec; MS (DCI/NH3) m/ e 388 (M + H)+; H
NMR (DMSO) δ 13.83 (1H, br s, COOH), 9.12 (1H, d, J ) 10.5
Hz, H-6), 7.94 (1H, s, H-2), 3.75-4.05 (5H, m), 2.97 (2H, m),
2.65 (3H, s, CH3), 2.32 (2H, m), 2.25 (1H, m), 1.68 (2H, m),
1.00 (2H, m), 0.95 (3H, t, J ) 8.0 Hz), 0.62 (2H, m). Anal.
(C21H26FN3O3‚HCl‚H2O) C, H, N.
1
steps): mp 192 °C dec; MS (DCI/NH3) m/ e 400 (M + H)+; H
NMR (DMSO) δ 13.85 (1H, s, COOH), 9.13 (1H, d, J ) 10.5
Hz, H-6), 7.95 (1H, s, H-2), 3.90-4.20 (5H, m), 2.85 (1H, m),
2.93 (3H, s, NCH3), 2.64 (3H, s, CH3), 2.20-2.45 (3H, m), 1.25
(1H, m), 0.90-1.10 (4H, m), 0.85 (1H, m), 0.62 (2H, m). Anal.
(C22H26FN3O3‚HCl‚2.25H2O) C, H, N.
1-Cyclop r op yl-8-(3-cyclop r op yla m in o-1-p yr r olid in yl)-
7-flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-car boxylic Acid
Hyd r och lor id e (3m ). (()-3-Cyclopropyl(tert-butoxycarbonyl)-
aminopyrrolidine was obtained in three steps by following the
literature procedure.21 By following general procedure C,
starting from 1 (808 mg, 2.50 mmol) and 3-cyclopropyl(tert-
butoxycarbonyl)aminopyrrolidine (1.13 g, 5.00 mmol), 3m was
obtained as a yellow solid (863 mg, 2.04 mmol, 82% in 3
8-(3-Am in o-3-tr iflu or om eth yl-1-p yr r olid in yl)-1-cyclo-
p r op yl-7-flu or o-9-m et h yl-4(H )-4-oxoq u in olizin e-3-ca r -
boxylic Acid (3r ). By following general procedure C, starting
from 1 (162 mg, 0.50 mmol) and (()-3-(tert-butoxycarbonyl)-
amino-3-trifluoromethylpyrrolidine (254 mg, 1.00 mmol), 3r
was obtained as a yellow solid (79 mg, 0.19 mmol, 38% in 3
1
steps): mp 218 °C dec; MS (DCI/NH3) m/ e 386 (M + H)+; H
1
NMR (DMSO) δ 13.85 (1H, s, COOH), 9.12 (1H, d, J ) 10.5
Hz, H-6), 7.94 (1H, s, H-2), 3.95-4.15 (4H, m), 3.81 (1H, m),
2.85 (1H, m), 2.65 (3H, s, CH3), 2.25-2.45 (3H, m), 0.95-1.05
(4H, m), 0.82 (2H, m), 0.62 (2H, m). Anal. (C21H24FN3O3‚HCl‚
H2O) C, H, N.
steps): mp 150 °C dec; MS (DCI/NH3) m/ e 414 (M + H)+; H
NMR (DMSO) δ 13.85 (1H, s, COOH), 9.12 (1H, d, J ) 10.2
Hz, H-6), 7.97 (1H, s, H-2), 4.15 (2H, m), 3.78 (2H, m), 2.65
(3H, s, CH3), 2.35 (2H, m), 2.19 (1H, m), 1.02 (2H, m), 0.62
(2H, m). Anal. (C19H19F4N3O3) C, H, N.
1-Cyclop r op yl-8-[(3S)-(2-flu or oet h yl)a m in o-1-p yr r o-
lid in yl]-7-flu or o-9-m et h yl-4(H )-4-oxoq u in olizin e-3-ca r -
boxylic Acid Hyd r och lor id e a n d 1-Cyclop r op yl-8-[(3R)-
(2-flu or oeth yl)a m in o-1-p yr r olid in yl]-7-flu or o-9-m eth yl-
4(H)-4-oxoqu in olizin e-3-ca r boxylic Acid Hyd r och lor id e
[(S)-3n a n d (R)-3n ]. The optically pure amines were prepared
from commercially available (S)-3-amino-1-benzylpyrrolidine
and (R)-3-amino-1-benzylpyrrolidine. By following general
procedure C, starting from 1 (808 mg, 2.50 mmol) and (3S)-
(2-fluoroethyl)(tert-butoxycarbonyl)aminopyrrolidine (1.16 g,
5.00 mmol), (S)-3n was obtained as a yellow solid (553 mg,
1.24 mmol, 50% in 3 steps): mp 249 °C dec; MS (DCI/NH3)
m/ e 392 (M + H)+; 1H NMR (DMSO) δ 13.84 (1H, br s, COOH),
9.10 (1H, d, J ) 10.6 Hz, H-6), 7.93 (1H, s, H-2), 4.91 (1H, m),
4.75 (1H, m), 3.93-4.10 (4H, m), 3.82 (1H, m), 3.49 (1H, m),
3.36 (1H, m), 2.64 (3H, s, CH3), 2.25-2.40 (3H, m), 1.00 (2H,
m), 0.62 (2H, m). Anal. (C20H23F2N3O3‚HCl‚H2O) C, H, N.
By following general procedure C, starting from 1 (808 mg,
2.50 mmol) and (3R)-(2-fluoroethyl)(tert-butoxycarbonyl)ami-
nopyrrolidine (1.16 g, 5.00 mmol), (R)-3n was obtained as a
yellow solid (601 mg, 1.33 mmol, 54% in 3 steps): mp 252 °C
dec; MS (DCI/NH3) m/ e 392 (M + H)+; 1H NMR (DMSO) δ
13.85 (1H, br s, COOH), 9.13 (1H, d, J ) 10.6 Hz, H-6), 7.94
(1H, s, H-2), 4.89 (1H, m), 4.73 (1H, m), 3.93-4.10 (4H, m),
3.82 (1H, m), 3.48 (1H, m), 3.36 (1H, m), 2.64 (3H, s, CH3),
2.25-2.40 (3H, m), 1.00 (2H, m), 0.62 (2H, m). Anal.
(C20H23F2N3O3‚HCl‚H2O) C, H, N.
1-Cyclopr opyl-8-[(3S)-(2,2,2-tr iflu or oeth yl)am in o-1-pyr -
r olid in yl]-7-flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-ca r -
boxylic Acid (3o). By following general procedure C, starting
from 1 (646 mg, 2.00 mmol) and (3S)-(2,2,2-trifluoroethyl)(tert-
butoxycarbonyl)aminopyrrolidine (1.07 g, 4.00 mmol), 3o was
obtained as a yellow solid (493 mg, 1.15 mmol, 58% in 3
steps): mp 163-165 °C; MS (DCI/NH3) m/ e 428 (M + H)+; 1H
NMR (DMSO) δ 13.85 (1H, br s, COOH), 9.06 (1H, d, J ) 10.5
Hz, H-6), 7.89 (1H, s, H-2), 3.93 (2H, m), 3.76 (1H, m), 3.55
(2H, m), 2.60 (3H, s, CH3), 2.29 (1H, m), 2.12 (1H, m), 1.93
(1H, m), 0.98 (2H, m), 0.60 (2H, m). Anal. (C20H21F4N3O3‚
0.25H2O) C, H, N.
1-Cyclopr opyl-7-flu or o-8-[(3S)-(2-m eth oxyeth yl)a m in o-
1-p yr r olid in yl]-9-m eth yl-4(H)-4-oxoqu in olizin e-3-ca r box-
ylic Acid Hyd r och lor id e (3p ). By following general proce-
dure C, starting from 1 (810 mg, 2.50 mmol) and (3S)-(2-
methoxyethyl)(tert-butoxycarbonyl)aminopyrrolidine (1.22 g,
8-(cis-3-Am in o-4-cyclop r op yl-1-p yr r olid in yl)-1-cyclo-
p r op yl-7-flu or o-9-m et h yl-4(H )-4-oxoq u in olizin e-3-ca r -
boxylic Acid Hyd r och lor id e (3s). By following general
procedure C, starting from 1 (307 mg, 0.95 mmol) and (()-
cis-3-(tert-butoxycarbonyl)amino-4-cyclopropylpyrrolidine (215
mg, 0.95 mmol), 3s was obtained as a yellow solid (212 mg,
0.50 mmol, 52% in 3 steps): mp 254 °C dec; MS (DCI/NH3)
1
m/ e 386 (M + H)+; H NMR (DMSO) δ 13.85 (1H, s, COOH),
9.10 (1H, d, J ) 10.5 Hz, H-6), 7.95 (1H, s, H-2), 4.20 (1H, m),
3.95 (2H, m), 3.80 (2H, m), 2.64 (3H, s, CH3), 2.35 (1H, m),
1.86 (1H, m), 1.38 (1H, m), 0.90-1.10 (4H, m), 0.60 (2H, m),
0.32 (2H, m). Anal. (C21H24FN3O3‚HCl‚H2O) C, H, N.
8-[(3S,4S)-cis-3-Am in o-4-cyclop r op yl-1-p yr r olid in yl]-1-
cyclop r op yl-7-flu or o-9-m et h yl-4(H)-4-oxoq u in olizin e-3-
ca r boxylic Acid Hyd r och lor id e a n d 8-[(3R,4R)-cis-3-
Am in o-4-cyclop r op yl-1-p yr r olid in yl]-1-cyclop r op yl-7-
flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-ca r boxylic Acid
Hyd r och lor id e [(3S,4S)-3s a n d (3R,4R)-3s]. The optically
pure amines were obtained by a chiral separation of racemic
cis-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-cyclo-
propylpyrrolidine on a Chiralpak column eluting with 90:10
hexane:ethanol. The enantiomer with a longer retention time
was arbitrarily assigned as 3S,4S-isomer. By following general
procedure C, starting from 1 (128 mg, 0.40 mmol) and (3S,4S)-
cis-3-(tert-butoxycarbonyl)amino-4-cyclopropylpyrrolidine (143
mg, 0.40 mmol), (3S,4S)-3s was obtained as a yellow solid (16
mg, 0.04 mmol, 10% in 3 steps): mp 252 °C dec; MS (DCI/
NH3) m/ e 386 (M + H)+; 1H NMR (DMSO) δ 13.85 (1H, s,
COOH), 9.11 (1H, d, J ) 10.8 Hz, H-6), 7.94 (1H, s, H-2), 4.18
(1H, m), 3.95 (2H, m), 3.81 (2H, m), 2.64 (3H, s, CH3), 2.32
(1H, m), 1.87 (1H, m), 1.05 (1H, m), 0.95 (1H, m), 0.82 (1H,
m), 0.59 (3H, m), 0.34 (1H, m), 0.28 (1H, m). Anal. (C21H24
-
FN3O3‚HCl‚H2O) C, H, N.
By following general procedure C, starting from 1 (84 mg,
0.26 mmol) and (3R,4R)-trans-3-(tert-butoxycarbonyl)amino-
4-cyclopropylpyrrolidine (94 mg, 0.26 mmol), (3R,4R)-3s was
obtained as a yellow solid (57 mg, 0.14 mmol, 52% in 3 steps):
1
mp 250 °C dec; MS (DCI/NH3) m/ e 386 (M + H)+; H NMR
(DMSO) δ 13.85 (1H, s, COOH), 9.11 (1H, d, J ) 10.5 Hz, H-6),
7.93 (1H, s, H-2), 4.18 (1H, m), 3.94 (2H, m), 3.81 (2H, m),
2.64 (3H, s, CH3), 2.34 (1H, m), 1.87 (1H, m), 1.05 (1H, m),
0.96 (1H, m), 0.82 (1H, m), 0.59 (3H, m), 0.35 (1H, m), 0.29
(1H, m). Anal. (C21H24FN3O3‚HCl‚0.25H2O) C, H, N.
8-(tr a n s-3-Am in o-4-cyclop r op yl-1-p yr r olid in yl)-1-cy-

4210 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20
Ma et al
clop r op yl-7-flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-ca r -
boxylic Acid Hyd r och lor id e (3t). By following general
procedure C, starting from 1 (533 mg, 1.65 mmol) and (()-
trans-3-(tert-butoxycarbonyl)amino-4-cyclopropylpyrrolidine (745
mg, 3.30 mmol), 3t was obtained as a yellow solid (369 mg,
0.88 mmol, 53% in 3 steps): mp 199 °C dec; MS (DCI/NH3)
(3R,4S)-trans-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-
4-methylpyrrolidines.13 By following general procedure C,
starting from 1 (366 mg, 1.13 mmol) and (3S,4R)-trans-3-(tert-
butoxycarbonyl)methylamino-4-methylpyrrolidine (243 mg,
1.13 mmol), (3S,4R)-3v was obtained as a yellow solid (94 mg,
0.22 mmol, 20% in 3 steps): mp 161-163 °C; MS (DCI/NH3)
1
1
m/ e 386 (M + H)+; H NMR (DMSO) δ 13.85 (1H, s, COOH),
m/ e 374 (M + H)+; H NMR (DMSO) δ 13.82 (1H, s, COOH),
9.12 (1H, d, J ) 10.5 Hz, H-6), 7.95 (1H, s, H-2), 4.16 (1H, m),
4.05 (1H, m), 3.78 (2H, m), 3.64 (1H, m), 2.64 (3H, s, CH3),
2.34 (1H, m), 1.82 (1H, m), 1.00 (2H, m), 0.90 (1H, m), 0.62
9.12 (1H, d, J ) 10.6 Hz, H-6), 7.93 (1H, s, H-2), 4.12 (1H, m),
3.98 (1H, m), 3.84 (2H, m), 3.72 (1H, m), 2.72 (1H, m), 2.68
(3H, s, N-CH3), 2.66 (3H, s, CH3), 2.32 (1H, m), 1.18 (3H, d, J
) 6.6 Hz, CH3), 1.01 (2H, m), 0.63 (2H, m). Anal. (C20H24FN3O3‚
HCl‚H2O) C, H, N.
(2H, m), 0.54 (1H, m), 0.36 (1H, m), 0.24 (1H, m). Anal. (C21H24
-
FN3O3‚HCl‚0.75H2O) C, H, N.
By following general procedure C, starting from 1 (386 mg,
1.19 mmol) and (3R,4S)-trans-3-(tert-butoxycarbonyl)methyl-
amino-4-methylpyrrolidine (255 mg, 1.19 mmol), (3R,4S)-3v
was obtained as a yellow solid (98 mg, 0.23 mmol, 19% in 3
steps): mp 162-164 °C; MS (DCI/NH3) m/ e 374 (M + H)+; 1H
NMR (DMSO) δ 13.82 (1H, s, COOH), 9.12 (1H, d, J ) 10.5
Hz, H-6), 7.93 (1H, s, H-2), 4.10 (1H, m), 3.98 (1H, m), 3.84
(2H, m), 3.73 (1H, m), 2.72 (1H, m), 2.67 (3H, s, N-CH3), 2.64
(3H, s, CH3), 2.30 (1H, m), 1.18 (3H, d, J ) 6.6 Hz, CH3), 1.00
(2H, m), 0.63 (2H, m). Anal. (C20H24FN3O3‚HCl‚H2O) C, H, N.
8-[(3S,4R)-tr a n s-3-Am in o-4-cyclopr opyl-1-pyr r olidin yl]-
1-cyclop r op yl-7-flu or o-9-m et h yl-4(H)-4-oxoq u in olizin e-
3-ca r boxylic Acid Hyd r och lor id e a n d 8-[(3R,4S)-tr a n s-
3-Am in o-4-cyclop r op yl-1-p yr r olid in yl]-1-cyclop r op yl-7-
flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-ca r boxylic Acid
Hyd r och lor id e [(3S,4R)-3t a n d (3R,4S)-3t]. The optically
pure amines were prepared according to the procedure de-
scribed by ref 13. By following general procedure C, starting
from 1 (7.11 g, 22.0 mmol) and (3S,4R)-trans-3-(tert-butoxy-
carbonyl)amino-4-cyclopropylpyrrolidine (5.80 g, 25.6 mmol),
(3S,4R)-3t was obtained as a yellow solid (3.94 g, 9.36 mmol,
43% in 3 steps): mp 220 °C dec; MS (DCI/NH3) m/ e 386 (M +
1-Cyclop r op yl-8-(3-cyclop r op yla m in o-4-m eth yl-1-p yr -
r olid in yl)-7-flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-ca r -
boxylic Acid Hyd r och lor id e (3w ). By following general
procedure C, starting from 1 (241 mg, 0.74 mmol) and 3-(tert-
butoxycarbonyl)cyclopropylamino-4-methylpyrrolidine (269 mg,
1.12 mmol), 3w was obtained as a yellow solid (182 mg, 0.42
mmol, 57% in 3 steps): mp 194 °C dec; MS (DCI/NH3) m/ e
1
H)+; H NMR (DMSO) δ 13.85 (1H, s, COOH), 9.08 (1H, d, J
) 10.5 Hz, H-6), 7.93 (1H, s, H-2), 4.18 (1H, m), 4.07 (1H, m),
3.79 (2H, m), 3.62 (1H, m), 2.62 (3H, s, CH3), 2.33 (1H, m),
1.84 (1H, m), 1.00 (2H, m), 0.90 (1H, m), 0.61 (2H, m), 0.53
(1H, m), 0.38 (1H, m), 0.22 (1H, m). Anal. (C21H24FN3O3‚HCl‚
1.50H2O) C, H, N.
1
400 (M + H)+; H NMR (DMSO) δ 13.85 (1H, s, COOH), 9.13
(1H, d, J ) 10.6 Hz, H-6), 7.95 (1H, s, H-2), 3.90-4.20 (3H,
m), 3.70 (1H, m), 3.49 (1H, m), 2.83 (1H, m), 2.66 (3H, s, CH3),
2.54 (1H, m), 2.38 (1H, m), 1.21 (3H, d, J ) 6.6 Hz, CH3), 1.01
By following general procedure C, starting from 1 (652 mg,
2.02 mmol) and (3R,4S)-trans-3-(tert-butoxycarbonyl)amino-
4-cyclopropylpyrrolidine (640 mg, 2.02 mmol), (3R,4S)-3t was
obtained as a yellow solid (380 mg, 0.90 mmol, 45% in 3
(2H, m), 0.93 (2H, m), 0.82 (2H, m), 0.62 (2H, m). Anal. (C22H26
-
1
steps): mp 218 °C dec; MS (DCI/NH3) m/ e 386 (M + H)+; H
FN3O3‚HCl‚H2O) C, H, N.
NMR (DMSO) δ 13.85 (1H, s, COOH), 9.12 (1H, d, J ) 10.5
Hz, H-6), 7.96 (1H, s, H-2), 4.18 (1H, m), 4.06 (1H, m), 3.78
(2H, m), 3.62 (1H, m), 2.64 (3H, s, CH3), 2.33 (1H, m), 1.82
(1H, m), 1.00 (2H, m), 0.89 (1H, m), 0.61 (2H, m), 0.53 (1H,
m), 0.38 (1H, m), 0.22 (1H, m). Anal. (C21H24FN3O3‚HCl‚
0.25H2O) C, H, N.
1-Cyclop r op yl-7-flu or o-9-m eth yl-8-(cis-4-m eth yl-3-m e-
t h yla m in o-1-p yr r olid in yl)-4(H )-4-oxoq u in olizin e-3-ca r -
boxylic Acid Hyd r och lor id e (3u ). By following general
procedure C, starting from 1 (481 mg, 1.49 mmol) and (()-
cis-3-(tert-butoxyca rbonyl)methyla mino-4-methylpyrroli-
dine22 (637 mg, 2.98 mmol), 3u was obtained as a yellow solid
(378 mg, 0.92 mmol, 62% in 3 steps): mp 227 °C dec; MS (DCI/
NH3) m/ e 374 (M + H)+; 1H NMR (DMSO) δ 13.85 (1H, s,
COOH), 9.13 (1H, d, J ) 10.2 Hz, H-6), 7.94 (1H, s, H-2), 4.08
(2H, m), 3.90 (1H, m), 3.40-3.60 (2H, m), 2.66 (6H, br s, CH3,
N-CH3), 2.56 (1H, m), 2.30 (1H, m), 1.18 (3H, d, J ) 6.6 Hz,
CH3), 1.00 (2H, m), 0.62 (2H, m). Anal. (C20H24FN3O3‚HCl‚H2O)
C, H, N.
1-Cyclop r op yl-7-flu or o-9-m et h yl-8-(tr a n s-4-m et h yl-3-
m et h yla m in o-1-p yr r olid in yl)-4(H )-4-oxoq u in olizin e-3-
ca r boxylic Acid Hyd r och lor id e (3v). By following general
procedure C, starting from 1 (323 mg, 1.00 mmol) and (()-
trans-3-(tert-butoxycarbonyl)methylamino-4-methylpyrroli-
dine22 (320 mg, 1.49 mmol), 3v was obtained as a yellow solid
(218 mg, 0.53 mmol, 53% in 3 steps): mp 160 °C dec; MS (DCI/
NH3) m/ e 374 (M + H)+; 1H NMR (DMSO) δ 13.85 (1H, s,
COOH), 9.12 (1H, d, J ) 10.2 Hz, H-6), 7.92 (1H, s, H-2), 4.11
(1H, m), 4.00 (1H, m), 3.84 (2H, m), 3.72 (1H, m), 2.72 (1H,
m), 2.67 (3H, br s, N-CH3), 2.64 (3H, s, CH3), 2.32 (1H, m),
1.17 (3H, d, J ) 6.6 Hz, CH3), 1.01 (2H, m), 0.63 (2H, m). Anal.
(C20H24FN3O3‚HCl‚1.25H2O) C, H, N.
1-Cyclop r op yl-7-flu or o-9-m et h yl-8-[(3S,4R)-tr a n s-4-
m eth yl-3-m eth yla m in o-1-p yr r olid in yl]-4(H)-4-oxoqu in o-
lizin e-3-car boxylic Acid Hydr och lor ide an d 1-Cyclopr op-
yl-7-flu or o-9-m eth yl-8-[(3R,4S)-tr a n s-4-m eth yl-3-m eth yl-
am in o-1-pyr r olidin yl]-4(H)-4-oxoqu in olizin e-3-car boxylic
Acid Hyd r och lor id e [(3S,4R)-3v a n d (3R,4S)-3v]. Optically
pure amines were obtained by methylation of (3S,4R)- and
8-(cis-1-Am in o-8-a za -8-b icyclo[4.3.0]n on yl)-1-cyclo-
pr opyl-7-flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-car box-
ylic Acid Hyd r och lor id e (3x). By following general proce-
dure C, starting from 1 (317 mg, 0.98 mmol) and cis-1-(tert-
butoxycarbonyl)amino-8-aza-8-bicyclo[4.3.0]nonane (550 mg,
crude), 3x was obtained as a yellow solid (66 mg, 0.15 mmol,
15% in 3 steps): mp 194-196 °C; MS (DCI/NH3) m/ e 400 (M
1
+ H)+; H NMR (DMSO) δ 13.85 (1H, s, COOH), 9.10 (1H, d,
J ) 10.6 Hz, H-6), 7.94 (1H, s, H-2), 4.27 (1H, m), 4.16 (1H,
m), 3.67 (1H, d, J ) 12.0 Hz), 3.56 (1H, d, J ) 12.0 Hz), 2.65
(3H, s, CH3), 2.39 (1H, m), 2.32 (1H, m), 2.07 (1H, m), 1.82
(1H, m), 1.60-1.80 (3H, m), 1.51 (1H, m), 1.20-1.40 (2H, m),
1.01 (2H, m), 0.62 (2H, m). Anal. (C22H26FN3O3‚HCl‚2H2O) C,
H, N.
8-(3-Am in om eth yl-3-tr iflu or om eth yl-1-p yr r olid in yl)-1-
cyclop r op yl-7-flu or o-9-m et h yl-4(H)-4-oxoq u in olizin e-3-
ca r boxylic Acid Hyd r och lor id e (3z). By following general
procedure C, starting from 1 (133 mg, 0.41 mmol) and (()-3-
(tert-butoxycarbonyl)aminomethyl-3-trifluoromethylpyrroli-
dine (222 mg, 0.62 mmol), 3z was obtained as a yellow solid
(47 mg, 0.10 mmol, 25% in 3 steps): mp 181-183 °C; MS (DCI/
NH3) m/ e 428 (M + H)+; 1H NMR (DMSO) δ 13.85 (1H, s,
COOH), 9.16 (1H, d, J ) 10.6 Hz, H-6), 7.99 (1H, s, H-2), 3.98
(2H, m), 3.85 (2H, m), 2.68 (3H, s, CH3), 2.32 (3H, m), 1.02
(2H, m), 0.63 (2H, m). Anal. (C20H21F4N3O3‚HCl‚1.75H2O) C,
H, N.
8-(5-Am in o-2-a za -2-sp ir o[4.4]n on yl)-1-cyclop r op yl-7-
flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-ca r boxylic Acid
Hyd r och lor id e (3a a ). By following general procedure C,
starting from 1 (116 mg, 0.36 mmol) and 5-(tert-butoxycarbon-
yl)amino-2-aza-2-spiro[4.4]nonane (105 mg, 0.44 mmol), 3a a
was obtained as a yellow solid (57 mg, 0.13 mmol, 36% in 3
steps): mp 196-198 °C; MS (DCI/NH3) m/ e 400 (M + H)+; 1H
NMR (DMSO) δ 13.85 (1H, s, COOH), 9.09 (1H, d, J ) 10.6
Hz, H-6), 7.93 (1H, s, H-2), 3.92 (1H, m), 3.81 (2H, m), 3.58
(1H, m), 3.47 (1H, m), 2.63 (3H, s, CH3), 1.65-2.35 (8H, m),
1.00 (2H, m), 0.62 (2H, m). Anal. (C22H26FN3O3‚HCl‚1.50H2O)
C, H, N.
1-Cyclopr opyl-7-flu or o-8-[3-(2-flu or oeth yl)am in om eth yl-

Synthesis, Antimicrobial Activity of Oxoquinolizines
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20 4211
1-p yr r olid in yl]-9-m eth yl-4(H)-4-oxoqu in olizin e-3-ca r box-
ylic Acid Hyd r och lor id e (3bb). By following general pro-
cedure C, starting from 1 (262 mg, 0.81 mmol) and (()-3-(2-
fluoroethyl)(tert-butoxycarbonyl)aminomethylpyrrolidine (200
mg, 0.81 mmol), 3bb was obtained as a yellow solid (85 mg,
0.19 mmol, 23% in 3 steps): mp 229 °C dec; MS (DCI/NH3)
m/ e 406 (M + H)+; 1H NMR (DMSO) δ 13.86 (1H, br s, COOH),
9.08 (1H, d, J ) 10.6 Hz, H-6), 7.92 (1H, s, H-2), 4.89 (1H, m),
4.73 (1H, m), 3.65-3.90 (4H, m), 3.35 (2H, m), 3.16 (2H, m),
2.70 (1H, m), 2.63 (3H, s, CH3), 2.28 (1H, m), 2.20 (1H, m),
1.85 (1H, m), 1.00 (2H, m), 0.60 (2H, m). Anal. (C21H25F2N3O3‚
HCl‚1.25H2O) C, H, N.
2.69 (3H, s, CH3), 2.36 (1H, m), 2.18 (1H, m), 1.97 (1H, m),
1.02 (2H, m), 0.63 (2H, m). Anal. (C20H22FN3O3‚HCl‚H2O) C,
H, N.
1-Cyclop r op yl-8-[(1S,5S)-cis-2,7-d ia za -7-bicyclo[3.3.0]-
octyl]-7-flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-ca r box-
ylic Acid Hyd r och lor id e a n d 1-Cyclop r op yl-8-[(1R,5R)-
cis-2,7-diaza-7-bicyclo[3.3.0]octyl]-7-flu or o-9-m eth yl-4(H)-
4-oxoqu in olizin e-3-car boxylic Acid Hydr och lor ide [(1S,5S)-
3gg a n d (1R,5R)-3gg]. Optically pure amines were obtained
by a chiral separation of racemic 2-benzyloxycarbonyl-7-(tert-
butyloxycarbonyl)-2,7-diazabicyclo[3.3.0]octane on a Chiralpak
column eluting with hexane:ethanol (90:10). The enantiomer
with a longer retention time was arbitrarily assigned as 1S,5S
isomer. By following general procedure C, starting from 1 (438
mg, 1.36 mmol) and 1S,5S)-cis-2-benzyloxycarbonyl-2,7-diaza-
bicyclo[3.3.0]octane (500 mg, 2.03 mmol), (1S,5S)-3gg was
obtained as a yellow solid (263 mg, 0.65 mmol, 48% in 3
1-Cyclop r op yl-7-flu or o-8-[3-(2-im id a zolin -2-yl)-1-p yr -
r olid in yl]-9-m et h yl-4(H )-4-oxoq u in olizin e-3-ca r b oxylic
Acid , Tr iflu or oa cetic Acid Sa lt (3cc). By following general
procedure C, starting from 1 (610 mg, 1.89 mmol) and (()-3-
[1-(tert-butoxycarbonyl)-2-imidazolin-2-yl]pyrrolidine (907 mg,
3.79 mmol), 3cc was obtained as a yellow solid (230 mg, 0.45
mmol, 24% in 3 steps): mp 107-108 °C; MS (DCI/NH3) m/ e
1
steps): mp 194 °C dec; MS (DCI/NH3) m/ e 372 (M + H)+; H
NMR (DMSO) δ 13.84 (1H, br s, COOH), 9.17 (1H, d, J ) 10.5
Hz, H-6), 7.99 (1H, s, H-2), 4.32 (1H, m), 4.05 (1H, m), 3.93
(1H, m), 3.72 (2H, m), 3.28 (2H, m), 3.13 (1H, m), 2.69 (3H, s,
CH3), 2.36 (1H, m), 2.18 (1H, m), 1.97 (1H, m), 1.02 (2H, m),
0.62 (2H, m). Anal. (C20H22FN3O3‚HCl‚1.50H2O) C, H, N.
1
399 (M + H)+; H NMR (DMSO) δ 13.85 (1H, br s, COOH),
10.12 (2H, br s), 9.14 (1H, d, J ) 10.6 Hz, H-6), 7.95 (1H, s,
H-2), 3.80-4.00 (8H, m), 3.45 (2H, m), 2.62 (3H, s, CH3), 2.40
(1H, m), 2.30 (1H, m), 2.19 (1H, m), 1.00 (2H, m), 0.62 (2H,
m). Anal. (C21H23FN4O3‚CF3CO2H‚H2O) C, H, N.
By following general procedure C, starting from 1 (464 mg,
1.44 mmol) and (1R,5R)-cis-2-benzyloxycarbonyl-2,7-diazabi-
cyclo[3.3.0]octane (530 mrg, 2.15 mmol), (1R,5R)-3gg was
obtained as a yellow solid (194 mg, 0.48 mmol, 33% in 3
8-(cis-1-Am in om et h yl-8-a za -8-b icyclo[4.3.0]n on yl)-1-
cyclop r op yl-7-flu or o-9-m et h yl-4(H)-4-oxoq u in olizin e-3-
ca r boxylic Acid Hyd r och lor id e (3d d ). By following general
procedure C, starting from 1 (355 mg, 1.10 mmol) and cis-(()-
1-(ter t-bu t oxyca r bon yl)a m in om et h yl-8-a za bicyclo[4.3.0]-
nonane (560 mg, 2.20 mmol), 3d d was obtained as a yellow
solid (298 mg, 0.66 mmol, 60% in 3 steps): mp 194-196 °C;
1
steps): mp 192 °C dec; MS (DCI/NH3) m/ e 372 (M + H)+; H
NMR (DMSO) δ 13.84 (1H, br s, COOH), 9.18 (1H, d, J ) 10.5
Hz, H-6), 8.01 (1H, s, H-2), 4.32 (1H, m), 4.05 (1H, m), 3.90
(1H, m), 3.72 (2H, m), 3.28 (2H, m), 3.13 (1H, m), 2.70 (3H, s,
CH3), 2.36 (1H, m), 2.18 (1H, m), 1.97 (1H, m), 1.02 (2H, m),
0.62 (2H, m). Anal. (C20H22FN3O3‚HCl‚1.75H2O) C, H, N.
1
MS (DCI/NH3) m/ e 414 (M + H)+; H NMR (DMSO) δ 13.90
(1H, s, COOH), 9.08 (1H, d, J ) 10.5 Hz, H-6), 7.90 (1H, s,
H-2), 3.88 (2H, m), 3.60-3.80 (4H, m), 3.12 (1H, m), 2.93 (1H,
m), 2.63 (3H, s, CH3), 2.28 (1H, m), 2.17 (1H, m), 1.40-1.60
(7H, m), 1.00 (2H, m), 0.62 (2H, m). Anal. (C23H28FN3O3‚HCl‚
1.25H2O) C, H, N.
1-Cyclop r op yl-8-(cis-3,7-d ia za -3-bicyclo[3.3.0]octyl)-7-
flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-ca r boxylic Acid
Hyd r och lor id e (3h h ). By following general procedure C,
starting from 1 (646 mg, 2.00 mmol) and cis-3-(tert-butoxy-
carbonyl)-3,7-diazabicyclo[3.3.0]octane (636 mg, 3.00 mmol),
3h h was obtained as a yellow solid (522 mg, 1.28 mmol, 64%
in 3 steps): mp 220 °C dec; MS (DCI/NH3) m/ e 372 (M + H)+;
1H NMR (DMSO) δ 13.85 (1H, br s, COOH), 9.13 (1H, d, J )
10.5 Hz, H-6), 7.97 (1H, s, H-2), 3.85 (2H, m), 3.72 (2H, m),
3.44 (2H, m), 3.12 (4H, m), 2.68 (3H, s, CH3), 2.35 (1H, m),
1.00 (2H, m), 0.62 (2H, m). Anal. (C20H22FN3O3‚HCl‚H2O) C,
H, N.
1-Cyclop r op yl-8-(cis-5,8-d ia za -2-oxo-8-b icyclo[4.3.0]-
n on yl)-7-flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-car box-
ylic Acid Hyd r och lor id e (3jj). By following general proce-
dure C, starting from 1 (468 mg, 1.45 mmol) and cis-(()-5-
benzyl-5,8-diaza-2-oxobicyclo[4.3.0]nonane (634 mg, 2.91 mmol),
3jj was obtained as a yellow solid (223 mg, 0.53 mmol, 36% in
3 steps): mp 194 °C dec; MS (DCI/NH3) m/ e 388 (M + H)+;
1H NMR (DMSO) δ 13.85 (1H, br s, COOH), 9.12 (1H, d, J )
10.5 Hz, H-6), 7.96 (1H, s, H-2), 4.42(1H, m), 4.26 (2H, m),
4.05 (2H, m), 3.82 (2H, m), 3.58 (1H, m), 3.40 (1H, m), 3.14
(1H, m), 2.64 (3H, s, CH3), 2.33 (1H, m), 1.08 (1H, m), 0.90
(1H, m), 0.62 (2H, m). Anal. (C20H22FN3O4‚HCl‚H2O) C, H, N.
1-Cyclop r op yl-8-(tr a n s-5,8-d ia za -2-oxo-8-bicyclo[4.3.0]-
n on yl)-7-flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-car box-
ylic Acid Hyd r och lor id e (3k k ). By following general pro-
cedure C, starting from 1 (585 mg, 1.81 mmol) and trans-(()-
5-benzyloxycarbonyl-5,8-diaza-2-oxobicyclo[4.3.0]nonane (620
mg, 2.71 mmol), 3k k was obtained as a yellow solid (363 mg,
0.86 mmol, 47% in 3 steps): mp 214 °C dec; MS (DCI/NH3)
m/ e 388 (M + H)+; 1H NMR (DMSO) δ 13.85 (1H, br s, COOH),
9.12 (1H, d, J ) 10.5 Hz, H-6), 7.96 (1H, s, H-2), 4.10-4.30
(4H, m), 3.70-4.00 (5H, m), 3.20 (1H, m), 2.62 (3H, s, CH3),
2.32 (1H, m), 1.09 (1H, m), 0.91 (1H, m), 0.62 (2H, m). Anal.
(C20H22FN3O4‚HCl‚2H2O) C, H, N.
1-Cyclopr opyl-8-(tr a n s-3,8-diaza-8-bicyclo[4.3.0]n on yl)-
7-flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-car boxylic Acid
Hyd r och lor id e (3ll). By following general procedure C,
starting from 1 (323 mg, 1.00 mmol) and trans-(()-3-benzyl-
3,8-diazabicyclo[4.3.0]nonane (380 mg, 1.76 mmol), 3ll was
8-(cis-5-Am in om eth yl-7-aza-2-oxo-7-bicyclo[3.3.0]octyl)-
1-cyclop r op yl-7-flu or o-9-m et h yl-4(H)-4-oxoq u in olizin e-
3-ca r boxylic Acid Hyd r och lor id e (3ee). By following gen-
eral procedure C, starting from 1 (464 mg, 1.43 mmol) and
cis-(()-5-(tert-butoxycarbonyl)aminomethyl-7-aza-2-oxobicyclo-
[3.3.0]octane (978 mg, 4.00 mmol), 3ee was obtained as a
yellow solid (258 mg, 0.59 mmol, 41% in 3 steps): mp 181-
1
184 °C; MS (DCI/NH3) m/ e 402 (M + H)+; H NMR (DMSO)
δ 13.86 (1H, s, COOH), 9.17 (1H, d, J ) 10.5 Hz, H-6), 7.98
(1H, s, H-2), 3.90-4.00 (3H, m), 3.60-3.90 (3H, m), 3.18 (2H,
m), 2.89 (1H, m), 2.68 (3H, s, CH3), 2.35 (1H, m), 2.18 (1H,
m), 1.88 (1H, m), 1.02 (2H, m), 0.63 (2H, m). Anal. (C21H24
-
FN3O4‚HCl‚H2O) C, H, N.
8-(cis-1-Am in om eth yl-7-aza-3-oxo-7-bicyclo[3.3.0]octyl)-
1-cyclop r op yl-7-flu or o-9-m et h yl-4(H)-4-oxoq u in olizin e-
3-ca r boxylic Acid Hyd r och lor id e (3ff). By following gen-
eral procedure C, starting from 1 (172 mg, 0.53 mmol) and
cis-(()-1-(tert-butoxycarbonyl)aminomethyl-7-aza-3-oxobicyclo-
[3.3.0]octane (260 mg, 1.06 mmol), 3ee was obtained as a
yellow solid (87 mg, 0.20 mmol, 37% in 3 steps): mp 214 °C
dec; MS (DCI/NH3) m/ e 402 (M + H)+; 1H NMR (DMSO) δ
13.87 (1H, s, COOH), 9.18 (1H, d, J ) 10.5 Hz, H-6), 8.00 (1H,
s, H-2), 4.02 (1H, m), 3.90 (2H, m), 3.76 (2H, m), 3.50-3.70
(3H, m), 3.14 (2H, m), 2.80 (1H, m), 2.72 (3H, s, CH3), 2.37
(1H, m), 1.02 (2H, m), 0.63 (2H, m). Anal. (C21H24FN3O4‚HCl‚
2.25H2O) C, H, N.
1-Cyclop r op yl-8-(cis-2,7-d ia za -7-bicyclo[3.3.0]octyl)-7-
flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-ca r boxylic Acid
Hyd r och lor id e (3gg). By following general procedure C,
starting from 1 (482 mg, 1.49 mmol) and cis-(()-2-benzyloxy-
carbonyl-2,7-diazabicyclo[3.3.0]octane (550 mg, 2.24 mmol),
3gg was obtained as a yellow solid (336 mg, 0.82 mmol, 55%
in 3 steps): mp 190-192 °C; MS (DCI/NH3) m/ e 372 (M +
H)+; 1H NMR (DMSO) δ 13.85 (1H, br s, COOH), 9.16 (1H, d,
J ) 10.5 Hz, H-6), 8.00 (1H, s, H-2), 4.32 (1H, m), 4.05 (1H,
m), 3.93 (1H, m), 3.72 (2H, m), 3.28 (2H, m), 3.14 (1H, m),

4212 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20
Ma et al
obtained as a yellow solid (20 mg, 0.052 mmol, 5.2% in 3
from 1 (403 mg, 1.25 mmol) and (3S,4S)-cis-3-(tert-butoxycar-
bonyl)amino-4-methylpiperidine (640 mg, 2.50 mmol), (3S,4S)-
3ss was obtained as a yellow solid (332 mg, 0.81 mmol, 65%
in 3 steps): mp 198 °C dec; MS (DCI/NH3) m/ e 374 (M + H)+;
1H NMR (DMSO) δ 13.86 (1H, br s, COOH), 9.24 (1H, d, J )
10.5 Hz, H-6), 8.07 (1H, s, H-2), 3.62 (2H, m), 3.44 (2H, m),
3.24 (1H, m), 2.80 (3H, s, CH3), 2.43 (1H, m), 2.14 (1H, m),
1.82 (1H, m), 1.71 (1H, m), 1.05 (3H, d, J ) 6.0 Hz, CH3), 1.00
(2H, m), 0.65 (2H, m). Anal. (C20H24FN3O3‚HCl‚1.25H2O) C,
H, N.
1
steps): mp 170 °C dec; MS (DCI/NH3) m/ e 386 (M + H)+; H
NMR (DMSO) δ 13.85 (1H, br s, COOH), 9.08 (1H, d, J ) 10.5
Hz, H-6), 7.90 (1H, s, H-2), 3.70-4.00 (4H, m), 3.20 (3H, m),
3.04 (1H, m), 2.62 (3H, s, CH3), 2.50-2.70 (2H, m), 2.30 (1H,
m), 1.90 (1H, m), 1.78 (1H, m), 0.98 (2H, m), 0.62 (2H, m).
1-Cyclop r op yl-8-(cis-3,9-d ia za -9-bicyclo[4.3.0]n on yl)-7-
flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-ca r boxylic Acid
Hyd r och lor id e (3n n ) a n d 1-Cyclop r op yl-8-(cis-3,9-d ia za -
3-bicyclo[4.3.0]n on yl)-7-flu or o-9-m eth yl-4(H)-4-oxoqu in -
olizin e-3-ca r boxylic Acid Hyd r och lor id e (3vv). By follow-
ing general procedure C, starting from 1 (323 mg, 1.00 mmol)
and cis-(()-3,9-diazabicyclo[4.3.0]nonane dihydrochloride (crude),
3n n was obtained as a yellow solid (174 mg, 0.41 mmol, 41%
in 3 steps): mp 176 °C dec; MS (DCI/NIH3) m/ e 386 (M +
H)+; 1H NMR (DMSO) δ 13.83 (1H, br s, COOH), 9.18 (1H, d,
J ) 10.5 Hz, H-6), 8.00 (1H, s, H-2), 3.60-3.80 (3H, m), 3.30-
3.60 (3H, m), 3.23 (1H, m), 2.72 (3H, s, CH3), 2.52 (1H, m),
2.38 (1H, m), 2.04 (1H, m), 1.88 (2H, m), 1.65 (1H, m), 0.97
(2H, m), 0.60 (2H, m). Anal. (C21H24FN3O4‚HCl‚2H2O) C, H,
N.
By following general procedure C, starting from 1 (403 mg,
1.25 mmol) and (3R,4R)-cis-3-(tert-butoxycarbonyl)amino-4-
methylpiperidine (636 mg, 2.50 mmol), (3R,4R)-3ss was
obtained as a yellow solid (391 mg, 0.96 mmol, 76% in 3
1
steps): mp 198 °C dec; MS (DCI/NH3) m/ e 374 (M + H)+; H
NMR (DMSO) δ 13.86 (1H, br s, COOH), 9.24 (1H, d, J ) 10.5
Hz, H-6), 8.07 (1H, s, H-2), 3.63 (2H, m); 3.45 (2H, m), 3.24
(1H, m), 2.80 (3H, s, CH3), 2.43 (1H, m), 2.14 (1H, m), 1.82
(1H, m), 1.71 (1H, m), 1.05 (3H, d, J ) 6.0 Hz, CH3), 1.00 (2H,
m), 0.65 (2H, m). Anal. (C20H24FN3O3‚HCl‚1.75H2O) C, H, N.
8-(t r a n s-3-Am in o-4-m e t h yl-1-p ip e r id in yl)-1-c yc lo-
propyl-7-fluoro-9-methyl-4(H)-4-oxoquinolizine-3-carboxylic
Acid Hyd r och lor id e (3tt). By following general procedure
C, starting from 1 (323 mg, 1.00 mmol) and (()-trans-3-(tert-
butoxycarbonyl)amino-4-methylpiperidine (300 mg, 1.40 mmol),
3tt was obtained as a yellow solid (241 mg, 0.59 mmol, 59%
in 3 steps): mp 205 °C dec; MS (DCI/NH3) m/ e 374 (M + H)+;
1H NMR (DMSO) δ 13.86 (1H, br s, COOH), 9.23 (1H, d, J )
10.5 Hz, H-6), 8.04 (1H, s, H-2), 3.82 (1H, m), 3.48 (2H, m),
3.25 (1H, m), 3.02 (1H, m), 2.78 (3H, s, CH3), 2.40 (1H, m),
1.83 (2H, m), 1.48 (1H, m), 1.10 (3H, d, J ) 6.0 Hz, CH3), 1.02
(2H, m), 0.63 (2H, m). Anal. (C20H24FN3O3‚HCl‚1.50H2O) C,
H, N.
Compound 3vv was obtained as a minor product (34 mg,
0.081 mmol, 8% in 3 steps): mp 180 °C dec; MS (DCI/NH3)
m/ e 386 (M + H)+; 1H NMR (DMSO) δ 13.83 (1H, br s, COOH),
9.16 (1H, d, J ) 10.8 Hz, H-6), 8.00 (1H, s, H-2), 5.21 (1H, m),
4.11 (1H, m), 3.15-3.50 (5H, m), 2.85 (1H, m), 2.68 (3H, s, CH3),
2.56 (1H, m), 2.38 (1H, m), 2.12 (1H, m), 1.84 (2H, m), 1.73
(1H, m), 1.10 (1H, m), 0.91 (1H, m), 0.61 (2H, m). Anal. (C21H24
-
FN3O4‚HCl‚H2O) C, H, N.
1-Cyclopr opyl-7-flu or o-9-m eth yl-8-(1-piper idin yl)-4(H)-
4-oxoqu in olizin e-3-ca r boxylic Acid (3p p ). By following
general procedure A, starting from 1 (1.27 g, 3.94 mmol) and
piperidine (1.60 mL, 16.00 mmol), 3d was obtained as a yellow
solid (831 mg, 2.42 mmol, 61% in 2 steps): mp 260-261 °C;
MS (DCI/NH3) m/ e 345 (M + H)+; high-resolution MS (APCI)
obsd 345.1613, calcd for C19H22FN2O3 345.1614; 1H NMR
(CDCl3) δ 13.89 (1H, s, COOH), 9.17 (1H, d, J ) 10.5 Hz, H-6),
8.32 (1H, s, H-2), 3.41 (4H, m), 2.78 (3H, s, CH3), 2.26 (1H,
m), 1.76 (6H, m), 1.02 (2H, m), 0.68 (2H, m).
8-(5-Am in o-1-a za -3-cycloh exen -1-yl)-1-cyclop r op yl-7-
flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-ca r boxylic Acid
Hyd r och lor id e (3r r ). By following general procedure C,
starting from 1 (323 mg, 1.00 mmol) and (()-5-(tert-butoxy-
carbonyl)amino-1-aza-3-cyclohexene dihydrochloride (crude),
3r r was obtained as a yellow solid (25 mg, 0.070 mmol, 7% in
3 steps): mp 185 °C dec; MS (DCI/NH3) m/ e 358 (M + H)+;
1H NMR (DMSO) δ 13.83 (1H, br s, COOH), 9.25 (1H, d, J )
10.5 Hz, H-6), 8.08 (1H, s, H-2), 6.22 (1H, m), 5.95 (1H, m),
4.05 (2H, m), 3.88 (2H, m), 3.50 (1H, m), 2.78 (3H, s, CH3),
2.42 (1H, m), 1.04 (2H, m), 0.65 (2H, m).
8-(cis-3-Am in o-4-m eth yl-1-p ip er id in yl)-1-cyclop r op yl-
7-flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-car boxylic Acid
Hyd r och lor id e (3ss). By following general procedure C,
starting from 1 (137 mg, 0.42 mmol) and (()-cis-3-(tert-
butoxycarbonyl)amino-4-methylpiperidine (110 mg, 0.51 mmol),
3ss was obtained as a yellow solid (69 mg, 0.17 mmol, 40% in
3 steps): mp 195 °C dec; MS (DCI/NH3) m/ e 374 (M + H)+;
1H NMR (DMSO) δ 13.86 (1H, br s, COOH), 9.22 (1H, d, J )
10.5 Hz, H-6), 8.05 (1H, s, H-2), 3.64 (2H, m), 3.48 (2H, m),
3.24 (1H, m), 2.80 (3H, s, CH3), 2.43 (1H, m), 2.15 (1H, m),
1.82 (1H, m), 1.70 (1H, m), 1.04 (3H, d, J ) 6.0 Hz, CH3), 1.00
(2H, m), 0.65 (2H, m). Anal. (C20H24FN3O3‚HCl‚3H2O) C, H,
N.
8-[(3S,4S)-cis-3-Am in o-4-m eth yl-1-p ip er id in yl]-1-cyclo-
p r op yl-7-flu or o-9-m et h yl-4(H )-4-oxoq u in olizin e-3-ca r -
boxylic Acid Hyd r och lor id e a n d 8-[(3R,4R)-cis-3-Am in o-
4-m eth yl-1-p ip er id in yl]-1-cyclop r op yl-7-flu or o-9-m eth yl-
4(H)-4-oxoqu in olizin e-3-ca r boxylic Acid Hyd r och lor id e
[(3S,4S)-3ss a n d (3R,4R)-3ss]. Optically pure amines were
obtained by a chiral separation of racemic cis-1-benzyloxycar-
bonyl-3-(tert-butoxycarbonyl)amino-4-methylpiperidine on a
Chiralpak column eluting with 90:10 hexane:methanol. The
enantiomer with longer retention time was arbitrarily assigned
as 3S,4S isomer. By following general procedure C, starting
1-Cyclop r op yl-8-(3-cyclop r op yla m in o-1-p ip er id in yl)-7-
flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-ca r boxylic Acid
Hyd r och lor id e (3u u ). By following general procedure C,
starting from 1 (1.01 g, 3.12 mmol) and (()-3-cyclopropyl(tert-
butoxycarbonyl)aminopiperidine (1.50 g, 6.25 mmol), 3u u was
obtained as a yellow solid (630 mg, 1.44 mmol, 46% in 3
1
steps): mp 222 °C dec; MS (DCI/NH3) m/ e 400 (M + H)+; H
NMR (DMSO) δ 13.86 (1H, br s, COOH), 9.22 (1H, d, J ) 10.5
Hz, H-6), 8.04 (1H, s, H-2), 3.90 (1H, m), 3.49 (2H, m), 3.39
(2H, m), 3.25 (1H, m), 2.78 (3H, s, CH3), 2.42 (1H, m), 2.28
(1H, m), 1.94 (1H, m), 1.70 (2H, m), 1.05 (2H, m), 0.90 (2H,
m), 0.82 (2H, m), 0.63 (2H, m). Anal. (C22H26FN3O3‚HCl‚H2O)
C, H, N.
1-Cyclopr opyl-8-[(S)-3-cyclopr opylam in o-1-piper idin yl]-
7-flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-car boxylic Acid
H yd r och lor id e a n d 1-Cyclop r op yl-8-[(R)-3-cyclop r op -
yla m in o-1-p ip e r id in yl]-7-flu or o-9-m e t h yl-4(H )-4-oxo-
qu in olizin e-3-ca r boxylic Acid Hyd r och lor id e [(S)-3u u
a n d (R)-3u u ]. Optically pure amines were obtained by a chiral
separation of racemic 3-(tert-butoxycarbonyl)(cyclopropyl)-
amino-1-benzyloxycarbonylpiperidine on a Chiralpak column
eluting with 90:10 hexane:methanol. The enantiomer with
longer retention time was arbitrarily assigned as R isomer.
By following general procedure C, starting from 1 (646 mg,
2.00 mmol) and (S)-3-cyclopropyl(tert-butoxycarbonyl)amino-
piperidine (1.05 g, 2.78 mmol), (S)-3u u was obtained as a
yellow solid (508 mg, 1.16 mmol, 58% in 3 steps): mp 210 °C
dec; MS (DCI/NH3) m/ e 400 (M + H)+; 1H NMR (DMSO) δ
13.86 (1H, br s, COOH), 9.22 (1H, d, J ) 10.5 Hz, H-6), 8.05
(1H, s, H-2), 3.92 (1H, m), 3.49 (2H, m), 3.40 (2H, m), 3.25
(1H, m), 2.79 (3H, s, CH3), 2.42 (1H, m), 2.29 (1H, m), 1.92
(1H, m), 1.69 (2H, m), 1.03 (2H, m), 0.90 (2H, m), 0.81 (2H,
m), 0.64 (2H, m). Anal. (C22H26FN3O3‚HCl‚H2O) C, H, N.
By following general procedure C, starting from 1 (600 mg,
1.86 mmol) and (R)-3-cyclopropyl(tert-butoxycarbonyl)amino-
piperidine (672 mg, 2.80 mmol), (R)-3u u was obtained as a
yellow solid (514 mg, 1.18 mmol, 63% in 3 steps): mp 208 °C
dec; MS (DCI/NH3) m/ e 400 (M + H)+; 1H NMR (DMSO) δ
13.86 (1H, br s, COOH), 9.24 (1H, d, J ) 10.5 Hz, H-6), 8.06
(1H, s, H-2), 3.92 (1H, m), 3.49 (2H, m), 3.39 (2H, m), 3.25
(1H, m), 2.79 (3H, s, CH3), 2.42 (1H, m), 2.28 (1H, m), 1.94

Synthesis, Antimicrobial Activity of Oxoquinolizines
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20 4213
Hasvold, L.; Fung, A.; Ma, Z.; Tufano, M.; Flamm, R.; Shen, L.
L.; Baranowski, J .; Nilius, A.; Alder, J .; Meulbroek, J .; Marsh,
K.; Crowell, D.; Hui, Y.; Seif, L.; Melcher, L. M.; Henry, R.;
Spanton, S.; Faghih, R.; Klein, L. L.; Tanaka, S. K.; Plattner, J .
J . Synthesis and Structure-Activity Relationships of 2-Pyri-
dones: A Novel Series of Potent DNA Gyrase Inhibitors as
Antibacterial Agents. J . Med. Chem. 1996, 39, 3070-3088.
(7) Shen, L. L.; Chu, D. T. W. Type II DNA Topoisomerase as
Antibacterial Targets. Curr. Pharm. Des. 1996, 2, 195-208.
(8) Shen, L. L.; Tanaka, S. K.; Chu, D. T. W. Quinolones, 2-Pyri-
dones and Resistant Type II DNA Topoisomerases. Curr. Pharm.
Des. 1997, 3, 169-176.
(9) Berger, J . M.; Gamblin, S. J .; Harrison, S. C.; Wang, J . C.
Structure and Mechanism of DNA Topoisomerase II. Nature
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(10) Marians, K. J .; Hiasa, H. Mechanism of Quinolone Action. J .
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(11) Shen, L. L.; Mitscher, L. A.; Sharma, P. N.; O’Donnell, T. J .;
Chu, D. T. W.; Cooper, C. S.; Rosen, T.; Pernet, A. G. Mechanism
(1H, m), 1.70 (2H, m), 1.03 (2H, m), 0.88 (2H, m), 0.82 (2H,
m), 0.65 (2H, m). Anal. (C22H26FN3O3‚HCl‚H2O) C, H, N.
8-(7-Am in o-3-a za -3-bicyclo[4.1.0]h ep tyl)-1-cyclop r op yl-
7-flu or o-9-m eth yl-4(H)-4-oxoqu in olizin e-3-car boxylic Acid
Hyd r och lor id e (3w w ). By following general procedure C,
starting from 1 (426 mg, 1.32 mmol) and (()-7-(tert-butoxy-
carbonyl)amino-3-azabicyclo[4.1.0]heptane (560 mg, 2.64 mmol),
3w w was obtained as a yellow solid (160 mg, 0.39 mmol, 30%
in 3 steps): mp 198 °C dec; MS (DCI/NH3) m/ e 372 (M + H)+;
1H NMR (DMSO) δ 13.86 (1H, br s, COOH), 9.18 (1H, d, J )
10.8 Hz, H-6), 8.04 (1H, s, H-2), 3.85 (1H, m), 3.61 (1H, m),
3.21 (2H, m), 2.72 (3H, s, CH3), 2.55 (1H, m), 2.36 (1H, m),
2.10 (1H, m), 1.92 (1H, m), 1.59 (2H, m), 1.02 (2H, m), 0.65
(2H, m). Anal. (C20H22FN3O3‚HCl‚H2O) C, H, N.
8-[(3S,4R)-tr a n s-3-Am in o-4-m et h yl-1-p yr r olid in yl]-1-
cyclop r op yl-7-flu or o-9-m et h yl-4(H)-4-oxoq u in olizin e-3-
ca r boxylic Acid Hyd r och lor id e a n d 8-[(3R,4S)-tr a n s-3-
Am in o-4-m eth yl-1-p yr r olid in yl]-1-cyclop r op yl-7-flu or o-
9-m eth yl-4(H)-4-oxoqu in olizin e-3-car boxylic Acid Hydr o-
ch lor id e [(3S,4R)-3xx a n d (3R,4S)-3xx]. The optically pure
amines were prepared according to the procedure described
by ref 13. By following general procedure C, starting from 1
(420 mg, 1.30 mmol) and (3S,4R)-trans-3-(tert-butoxycarbonyl)-
amino-4-methylpyrrolidine (350 mg, 1.50 mmol), (3S,4R)-3xx
was obtained as a yellow solid (263 mg, 0.64 mmol, 49% in 3
of Inhibition of DNA Gyrase by Quinolone Antibacterials:
A
Cooperative Drug-DNA Binding Model. Biochemistry 1989, 28,
3886-3894.
(12) See the Experimental Section for preparation procedures and
references of these amines.
(13) Ma, Z.; Wang, S.; Cooper, C. S.; Fung, A. K. L.; Lynch, J . K.;
Plagge, F., Chu, T. W. Asymmetric Dipolar Cycloaddition
Reactions: A Practical, Convergent Synthesis of Chiral Pyrro-
lidines. Tetrahedron: Asymmetry 1997, 8, 883-887.
(14) Klein, L. L.; Degoey, D. A.; Thomas, S. A.; Yeung, C. M.; Leone,
C. L.; Grampovnik, D. J .; Chu, D. T.; Lartey, P. A. Preparation
and Antibacterial Activity of Pyridopyridine Analogs: C-1
Modification. Bioorg. Med. Chem. Lett. 1997, 7, 1167-1170.
(15) See ref 6 for a preliminary study on the effects of the C-8 group
on antibacterial activity.
(16) Mitscher, L. A.; Devasthale, P.; Zavod, R. Structure-Activity
Relationships. In Quinolone Antimicrobial Agents, 2nd ed.;
Hooper, D. C., Wolfson, J . S., Eds.; American Society for
Microbiology: Washington, DC, 1993; pp 3-53.
(17) Gootz, T. D.; McGuirk, P. R.; Moynihan, M. S. Placement of Alkyl
Substituents on the C-7 Piperazine Ring of Fluoroquinolones:
Dramatic Differential Effects on Mammalian Topoisomerase II
and DNA Gyrase. Antimicrob. Agents Chemother. 1994, 38, 130-
133.
(18) Hoshino, J .; Hiraoka, J .; Hata, Y.; Sawada, S.; Yamamoto, Y.
Synthesis of Optically Active Azetidine-2,4-dicarboxylic Acid and
Related Chiral Auxiliaries for Asymmetric Synthesis. J . Chem.
Soc. Perkin Trans. I 1995, 693-697.
1
steps): mp 198 °C dec; MS (DCI/NH3) m/ e 360 (M + H)+; H
NMR (DMSO) δ 13.82 (1H, br s, COOH), 9.07 (1H, d, J ) 10.8
Hz, H-6), 7.93 (1H, s, H-2), 4.02 (2H, m), 3.89 (1H, m), 3.55
(2H, m), 2.63 (3H, s, CH3), 2.52 (1H, m), 2.30 (1H, m), 1.18
(3H, d, J ) 6.3 Hz, CH3), 0.99 (2H, m), 0.60 (2H, m). Anal.
(C19H22FN3O3‚HCl‚H2O) C, H, N.
By following general procedure C, starting from 1 (420 mg,
1.30 mmol) and (3R,4S)-trans-3-(tert-butoxycarbonyl)amino-
4-methylpyrrolidine (541 mg, 2.70 mmol), (3R,4S)-3xx was
obtained as a yellow solid (246 mg, 0.60 mmol, 46% in 3
1
steps): mp 199 °C dec; MS (DCI/NH3) m/ e 360 (M + H)+; H
NMR (DMSO) δ 13.82 (1H, br s, COOH), 9.11 (1H, d, J ) 10.8
Hz, H-6), 7.96 (1H, s, H-2), 4.02 (2H, m), 3.84 (1H, m), 3.55
(2H, m), 2.63 (3H, s, CH3), 2.50 (1H, m), 2.33 (1H, m), 1.19
(3H, d, J ) 6.3 Hz, CH3), 1.00 (2H, m), 0.61 (2H, m). Anal.
(C19H22FN3O3‚HCl‚H2O) C, H, N.
(19) J ohnson, J . E.; Springfield, J . R.; Hwang, J . S.; Hayes, L. J .;
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carbamoyl)pyrazolidines as Potential Anticonvulsant Agents. J .
Pharm. Sci. 1979, 68, 377-378.
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of Chemotheraputic Agents. J . Med. Chem. 1962, 5, 1063-1065.
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J M990191K