Discovery of (3S)-amino-(4R)-ethylpiperidinyl quinolones as potent antibacterial agents with a broad spectrum of activity and activity against resistant pathogens

Article abstract of DOI:10.1021/jm030272n

Novel quinolone antibacterial agents bearing (3S)-amino-(4R)-ethylpiperidines were designed by using low energy conformation analysis and synthesized by applying a conventional coupling reaction of the quinolone nuclei with new piperidine side chains. The

Full text of DOI:10.1021/jm030272n

J . Med. Chem. 2003, 46, 3655-3661
3655
Discover y of (3S)-Am in o-(4R)-eth ylp ip er id in yl Qu in olon es a s P oten t
An tiba cter ia l Agen ts w ith a Br oa d Sp ectr u m of Activity a n d Activity a ga in st
Resista n t P a th ogen s
X. Eric Hu,* Nick K. Kim, J effrey L. Gray, J i-In K. Almstead, William L. Seibel, and Benoit Ledoussal
Procter & Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason, Ohio 45040
Received J une 3, 2003
Novel quinolone antibacterial agents bearing (3S)-amino-(4R)-ethylpiperidines were designed
by using low energy conformation analysis and synthesized by applying a conventional coupling
reaction of the quinolone nuclei with new piperidine side chains. These compounds were tested
in MIC assays and found to be highly potent against Gram-positive and Gram-negative
organisms. In particular, the new compounds exhibited high activity against the resistant
pathogens Staphylococcus aureus (MRCR) and Streptococcus pneumoniae (PR). Importantly,
when the (3S)-amino-(4R)-ethylpiperidinyl quinolones were compared with marketed quinolones
sharing the same quinolone nuclei but different side chains at the C-7 position, the new
quinolones showed superior activity against Gram-positive organisms, including resistant
pathogens.
Ta ble 1. Comparison of Relative Antibacterial Activity of
Quinolones Using Qualitative Descriptors
In tr od u ction
Because of increasing threats of bacterial infections,
particularly those such as the clinically important
pathogenic bacteria, methicillin resistant Staphylococ-
cus aureus (MRSA) and methicillin resistant ciprofloxa-
cin resistant S. aureus (MRCRSA),1 drug discovery
efforts have been significantly intensified in the past
years to search for more effective quinolone antibacterial
agents with a broader spectrum of activity and espe-
cially activity against resistant pathogens to fight
infectious diseases.2,3 In our ongoing antiinfective re-
search program, we have recently developed new quin-
olone antibacterial agents derived from a quinolone
nucleus lacking the typical 6-fluoro substituent4 (non-
fluorinated quinolones or NFQs), a similar approach
also reported by others.5 These agents exhibited not only
improved potency, a broad spectrum of activity, and
activity against resistant pathogens but also excellent
in vivo efficacy.6 More importantly, they have demon-
strated ameliorated toxicity profiles, which may warrant
further investigation.7 During the course of this work,
efforts were made to improve these NFQs by generating
new types of side chains.8 Here, we report a finding, the
application of which goes beyond the scope of the NFQs.
The majority of quinolone C7 substituents can be
arranged into three main categories: the piperazinyl,
pyrrolidinyl, and piperidinyl type side chains. Addition-
ally, three subfamilies of side chains were generated
using the pyrrolidine backbone. Table 1 shows these
various families of quinolones, a qualitative descriptor
of their antibacterial spectrum, and some representa-
tives of each family.
Piperazinyl type quinolones such as ciprofloxacin and
levofloxacin display good Gram-negative coverage but
a quite average Gram-positive spectrum. On the other
hand, 3-amino-pyrrolidinyl-based quinolones such as
clinafloxacin and moxifloxacin display a more balanced
spectrum while 3-aminomethyl-pyrrolidinyl-based quin-
olones display good Gram-positive coverage but a rela-
tively weaker Gram-negative spectrum. A very signifi-
cant improvement in both spectrum and potency was
reported upon introduction of a methyl group on the
aminomethyl-pyrrolidine, resulting in aminoethyl-pyr-
rolidinyl side chains.9 The corresponding quinolones
were among the most potent quinolones described to
date. Finally, 3-amino-piperidinyl type side chains led
to quinolones with a spectrum of action quite compa-
* To whom correspondence should be addressed. Tel: (513)622-3859.
Fax: (513)622-1195. E-mail: hu.xe@pg.com.
10.1021/jm030272n CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/22/2003

3656 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17
Hu et al.
F igu r e 2. Three-dimensional superimposition of 3-aminoeth-
yl-pyrrolidine and 3-amino-4-ethyl-piperidine side chains.
F igu r e 1. Energy minimization algorithm of pyrrolidine and
piperidine quinolones.
Ch em istr y
rable to their 3-amino-pyrrolidinyl equivalent.10 It is
worth noting that the number of piperidinyl-based
quinolones reported in the literature is very significantly
lower than that of piperazinyl- and pyrrolidinyl-based
analogues.
Substituted piperidines comprise one of the broadest
subjects of synthetic chemistry due not only to their
application as synthetic building blocks but also to their
unique structural features as important bioactive com-
ponents in pharmaceutical research.13 However, to our
surprise, the 4-alkyl-substituted 3-aminopiperidines
were found to be a much less explored subclass among
piperidine chemistry. Especially rare were asymmetric
synthetic methods for the construction of such relatively
simple piperidine structures. Very recently, the first
asymmetric synthetic method of trans-(3S)-amino-4-
alkyl- and aryl-piperidines was reported by our group.14
Herein, we report a modified procedure based on the
previous method,15 which was utilized in the synthesis
of (3S)-amino-(4R)-ethylpiperidine as outlined in Scheme
1. This synthesis represents a more efficient pathway
with fewer steps, and more importantly, this new
method significantly minimizes potential racemization
of the R-carbon in the amino acid during functional
group transformation.
The synthesis started from commercially available
fully protected (D)-serine ester 1. The methyl ester
underwent double addition with ethyl Grignard reagent
to give a tertiary alcohol (2), which was treated with
methanesulfonyl chloride to afford an elimination in-
termediate (3) in a ratio of 2.4:1 stereoisomers. The
mixed olefin was selectively deprotected, and the pri-
mary alcohol (4) was converted to the diene (5), a
precursor for the ring closure metathesis reaction, via
modified Mitsunobu conditions.16,17 By using a standard
cyclization procedure,18 3-Boc-NH-4-Et-1,2,3,6-tetrahy-
dropyridine (6) was obtained in good yield.19a Stereose-
lective reduction of the double bond resulted in a trans:
cis mixture in a 3:1 ratio, which was separated by flash
chromatography. Desulfonylation of the piperidine (7)
completed asymmetric synthesis of the side chain (8)19b
in 30% overall yield.
During the investigations on quinolones lacking fluo-
rine mentioned above, we noticed that the only two
types of C7 side chains leading to potent analogues were
the 3-aminoalkyl pyrrolidinyl (aminomethyl and ami-
noethyl) as well as the 3-amino-piperidinyl type side
chains.11 Small molecule modeling investigations showed
that these two types of side chains had low energy
conformations positioning the distal nitrogen in the
same area. As mentioned above, the addition of a methyl
on the amino-methyl pyrrolidine side chains boosted
significantly the activity of the resulting quinolone.
Associating this earlier finding with the similar behav-
ior of aminomethyl and piperidinyl type side chains in
our NFQs, we hypothesized that we could obtain the
same positive effects by properly substituting the pi-
peridine ring with hydrophobic groups that would mimic
the additional methyl of the aminoethyl-pyrrolidine type
side chain.
To identify the most promising substitutions, we used
the algorithm outlined in Figure 1. In the first step,
using the aminoethyl-pyrrolidine side chain as the
model to mimic, we identified the most frequently
encountered low energy conformation of this side chain
by using a series of dynamic simulations followed by
reminimizations. Then, we proceeded similarly with a
series of hypothetical substituted (3S)-amino-piperidine
side chains. The (3S)-amino-(4R)-ethylpiperidinyl side
chain was identified as the hypothetical side chain,12
most likely to be able to position a methyl group at the
same position as the beneficial methyl of the amino-
ethyl-pyrrolidine as seen in Figure 2. Three-dimensional
superimposition of the 3-aminoethyl-pyrrolidine and
3-amino-4-ethyl-piperidine side chains illustrates our
working hypothesis. The nitrogen atoms are in blue, the
distal methyl of the 3-amino-4-ethyl-piperidine side
chain is in red, and the corresponding methyl of the
3-aminoethyl-pyrrolidine is in orange. We then em-
barked upon synthesis and testing of quinolones bearing
this type of side chain. Below, we report our findings.
The piperidine side chains (8H,E) were connected to
the substituted quinolone nuclei 9a -d 20 and naphthyri-
dine nucleus 9e21 using conventional coupling conditions
shown in Scheme 2. In the case of the 8-MeO-substi-
tuted quinolones (9b,c), activation of the nuclei was
necessary and accomplished by activating the carboxyl
function with BF3.22 The coupled intermediates 10a -e

(3S)-Amino-(4R)-Ethylpiperidinyl Quinolones
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17 3657
Sch em e 1a
a
Reagents and conditions: (a) 3 equiv of EtMgBr, Et2O, 0 °C, 15 min, 84%. (b) MsCl, Et3N, CH2Cl2, -15 °C room temperature, 1 h,
86%. (c) p-TsOH (0.1 equiv), MeOH, 55 °C, 20 h, 91%. (d) N-Allyl-2,4-dinitro-benzenesulfonamide, Ph3P, DEAD, benzene, <30 °C, 1 h,
66%. (e) Cl2Ru(dCHPh)[(P-(c-Hex)3)]2, CH2Cl2, reflux, 12 h, 86%. (f) H2, 5% Pd/C, MeOH, 86%. (g) i-PrNH2, CH2Cl2, room temperature,
10 min, 93%.
Sch em e 2a
a
Reagents and conditions: (a) Et3N, DMF, room temperature,
1-3 days. (b) When Z ) BF2, 20 equiv of Et3N, EtOH, reflux,
1-2 h or when Z ) Et, 5 equiv of NaOH, water, EtOH, room
temperature, 2-3 h. (c) Concentrated HCl, room temperature,
20 min, overall yield > 65%.
F igu r e 3. Newly synthesized (3S)-amino- and (3S)-amino-
(4R)-piperidinyl quinolones.
underwent sequential deprotections: saponification fol-
lowed by removal of the Boc group. The final quinolone
products 12-17 were collected by crystallization.
clearly seen in most cases that we studied. The anti-
bacterial activity of these new agents is more pro-
nounced for the Gram-positive organisms as exemplified
with 12E-15E vs 12H-15H and found to be 2-15-fold
more active against S. aureus (MRCS); 3-21-fold more
active against S. aureus (MRCR); 3-10-fold more active
against S. pneumoniae (PS); and 2-11-fold more active
against S. pneumoniae (PR). Enhanced activity against
Gram-negative organism E. coli was observed to be 2-7-
fold, but only comparable activity was observed against
P. aeruginosa. Both substituted and unsubstituted pi-
peridinyl quinolone consistently exhibited high potency
and a broad spectrum of activity. Unlike quinolones, the
naphthyridines (16H,E) showed not only modest anti-
bacterial activity but also comparable activity between
nonsubstituted and substituted piperidinyl naphthyri-
dines across the spectrum. This suggests that the
piperidine side chains may elevate antibacterial activity
and a broad spectrum of activity only in certain nuclei.
Resu lts a n d Discu ssion
Five (3S)-aminopiperidinyl quinolones (12H-16H)
and five (3S)-amino-(4R)-ethylpiperidinyl quinolones
(12E-16E) (Figure 3) were synthesized. Their antibac-
terial activity (MIC) is summarized in Table 2 in pairs
in order to compare the in vitro activity of the nonsub-
stituted piperidinyl quinolones with the ethyl-substi-
tuted piperidinyl quinolones. Only representative in
vitro antibacterial data are presented, including four
key Gram-positive organisms of S. aureus (S. a) MRCS,
S. aureus (S. a) MRCR, Streptococcus pneumoniae
(S. p) PS, and S. pneumoniae (S. p) PR, and two key
Gram-negative organisms, Escherichia coli and Pseudo-
monas aeruginosa (P. a). The effect of (4R)-ethyl sub-
stituted over the unsubstituted (3S)-aminopiperidinyl
quinolones in enhancing antibacterial activity was

3658 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17
Hu et al.
Ta ble 3. Inhibitory Effect on E. coli Wild-Type DNA Gyrase/
Ta ble 2. MICs of (3S)-Aminopiperidinyl Quinolones vs
(3S)-Amino-(4R)-Ethylpiperidinyl Quinolones
Quinolone Resistant Gyrase Supercoiling Activity
MIC (µg/mL)a
IC50 (µg/mL)a
Gram-positive
organism
Gram-negative
organism
compd
12H
13H
14H
15H
16H
ciprofloxacin
12E
13E
14E
15E
16E
clinafloxacin
WT gyrase
QR gyrase
3.2
1.6
6.4
3.2
1.6
1.6
0.2
3.2
3.2
1.6
25.6
0.2
25.6
6.4
12.8
S.a
S.a
S. p
S. p
(PR)
compd (MRCS) (MRCR)
(PS)
E. coli
P. a
0.5
12.8
12H
12E
13H
13E
14H
14E
15H
15E
16H
16E
18
0.13
0.006
0.031
0.008
e0.06
e0.004
0.016
e0.004
2
4
0.06
0.023
0.125
0.031
0.03
0.13
0.012
0.063
0.008
e0.008
0.008
0.03
>102.4
102.4
12.8
0.188
0.5
0.125
1
0.006 0.75
0.031
0.016
0.03
0.006
0.03
1
1
0.5
1
0.5
6.4
12.8
3.2
0.25
1
e0.003
0.12
e0.008
>102.4
0.31
e0.004 e0.004 e0.004 0.125
1.0
>4
>4
0.016
4
4
4
2
0.125
0.03
1
4
a
0.25
0.008
0.25
WT gyrase, wild-type DNA gyrase; QR gyrase, quinolone
resistant gyrase (mutation from serine 83 to tryptophane).
0.008
1
0.008
0.5
0.008 0.25
0.125
19
4
4
a
S.a (MRCS), strain MI300; S.a (MRCR), strain MI339; S. p
(PS), strain STP64; S. p (PR), strain STP51; E. coli, strain ES142;
P. a, strain PS96; MRCS, methicillin resistant ciprofloxacin
sensitive; MRCR, methicillin resistant ciprofloxacin resistant; PS,
penicillin sensitive; PR, penicillin resistant.
trans counterpart. These data strongly support that the
design concept of the energy minimization algorithm is
indeed a useful tool in search for new and effective
quinolone side chains. It is believed that the positioning
effect of the terminal methyl group in the amino-ethyl
piperidine in alignment with that of the amino-ethyl
pyrrolidine plays a key role for the observed enhance-
ment of the antibacterial activity.
From the energy minimization algorithm, the inspira-
tion of incorporating the ethyl group to the 3-amino-
piperidinyl side chain led us to discover a very powerful
side chain to enhance the quinolone in vitro potency
significantly. In addition to the interesting structure-
activity relationship (SAR) results for the side chain
modification, we also noticed that the substitution at
the C-6 position did not impose much influence to the
antibacterial activity of the new quinolones. This ob-
servation was evidenced by comparing pairs of 13H,E
with 14H,E, respectively, and they showed identical
MIC activity against most of the pathogens. The sub-
stitution impact at the C-8 position to the MICs varies
depending on the quinolone nuclei. For example, 13H
containing the amino-piperidine exhibited great en-
hancement in antibacterial activity against most of the
Gram-positive pathogens when the 8-F in 12H was
replaced with 8-MeO. On the other hand, 12E and 13E
containing the amino-ethyl-piperidine showed only iden-
tical in vitro activity across the spectrum. It was also
true for 14H,E in comparison with 15H,E, respectively,
when 8-Cl was replaced with 8-MeO. The tolerance
patterns of substitution at the C-6 and C-8 positions
suggest a potential avenue to explore for new quinolone
antibacterial agents with no halogens embedded in the
quinolone nucleus structure, beneficial for reducing
unwanted side effects, such as phototoxicity and geno-
toxicity.
Amino-ethyl pyrrolidinyl quinolone 18 was a model
compound used in our design concept of low energy
conformation minimization algorithm described earlier
to identify new quinolone side chains. As seen in entry
11, this quinolone indeed exhibited remarkable in vitro
antibacterial activity across the board, one of the most
potent quinolone antibacterial agents reported to date
in the literature.4a,9 A powerful feature in superimposing
the substituent of the amino piperidine side chain with
that of the amino-ethyl pyrrolidine was further evident
in the case of (3S)-amino-(4S)-ethylpiperidinyl quinolone
(19), a cis stereoisomer of NFQ 14E.12 A great disad-
vantage for antibacterial activity against the key patho-
gens was shown in the cis isomer as compared to the
In addition to the finding of the increased in vitro
antibacterial activity in (3S)-amino-(4R)-ethylpiperidin-
yl quinolones as compared to the (3S)-amino-piperidin-
yl quinolones, we also evaluated the new piperidinyl
quinolone antibacterial agents against wild-type E. coli
DNA gyrase and quinolone resistant gyrase (Table 3).
Unsubstituted piperidinyl quinolones 12H-15H and
ethyl-substituted quinolones 12E-15E exhibited identi-
cal inhibitory activity against both gyrases, although
slight improvement was seen in the latter cases. In
contrast, naphthyridine 16H was notably less active
against quinolone resistant gyrase and 16E against both
wild-type and quinolone resistant gyrases. This obser-
vation correlates with the impaired MIC data against
key Gram-positive and Gram-negative pathogens dis-
cussed above. On the other hand, the gyrase data of the
new quinolones are comparable to those of the bench-
mark ciprofloxacin and clinafloxacin, which may suggest
that the new quinolones take the same pathways to
intervene in the bacterial infection processes as the
known quinolones.
One of the interesting SAR findings we generated was
the comparison of the side chain effects in the same
quinolone subclasses. Table 4 below summarizes the
antibacterial activity data of (3S)-amino-(4R)-ethylpi-
peridinyl quinolones vs the marketed and clinical quin-
olones. Ciprofloxacin and quinolone 17E share the same
quinolone core structure, and the variation exists only
at the C-7 side chain, piperazine for the former and the
substituted piperidine for the later. The new quinolone
exhibits fairly comparable antibacterial activity to that
of ciprofloxacin across the spectrum, except for activity
against P. aeruginosa pathogen, about 12-fold less active
for 17E. However, in the new piperidinyl quinolones
having C-8 substituted with a methoxy as in 13E and
a chloro group as in 15E, much improved antibacterial
activity is observed against Gram-positive organisms
relative to their counterparts, gatifloxacin and clina-
floxacin, respectively. For example, both new quinolones

(3S)-Amino-(4R)-Ethylpiperidinyl Quinolones
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17 3659
Ta ble 4. MICs of (3S)-Amino-(4R)-ethylpiperidinyl Quinolones
vs Marketed/Clinical Quinolones
Exp er im en ta l Section
Ch em istr y. All reagents were commercial grade and were
used as received without further purification, unless otherwise
specified. Commercially available anhydrous solvents were
used for reactions conducted under inert atmosphere. Reagent
grade solvents were used in all other cases, unless otherwise
specified. Flash chromatography was performed on E. Merck
silica gel 60 (230-400 mesh). Thin-layer chromatography was
performed on E. Merck 60 F-254 precoated silica plates (250
mm layer thickness). The 1H NMR spectra were recorded at
300 MHz. Chemical shifts for 1H NMR spectra are expressed
in parts per million downfield from tetramethylsilane. Splitting
patterns are designated as s, singlet; d, doublet; t, triplet; q,
quartet; p, pentet; m, multiplet; br, broad. Coupling constants
are given in Hertz (Hz). The 13C NMR spectra were recorded
at 75 MHz. The 19F NMR spectra were recorded at 282.7 MHz.
Mass spectra were obtained by electrospray mass spectrometry
utilizing an electrospray ionization (ESI) interface in flow
injection analysis (FIA) mode equipped with an ESI interface.
MIC (µg/mL)a
Gram-positive
organism
Gram-negative
organism
S.a
S.a
S. p
S. p
compd
(MRCS) (MRCR) (PS)
(PR)
E. coli
P. a
ciprofloxacin
17E
gatifloxacin
13E
clinafloxacin
15E
0.25
0.094 >3
0.06
0.008
0.03
e0.004
0.25
16
0.25
0.75
0.12
0.5
0.008 0.12
0.012 1.5
0.015 0.12
0.375
4
NDb
0.125
0.5
0.031 0.008
0.03 0.15
0.016
1
0.015 0.06
0.31 e0.004 e0.004 e0.004 0.125
ND 0.06 0.5
20
8
4
a
S.a (MRCS), strain MI300; S.a (MRCR), strain MI339; S. p
(PS), strain STP64; S. p (PR), strain STP51; E. coli, strain ES142;
P. a, strain PS96. Not determined.
b
show 7.5-fold greater activity against S. aureus (MRCS)
than gatifloxacin and clinafloxacin; 13E is 32-fold more
active against S. aureus (MRCR) than gatifloxacin,
while 15E shows similar activity against S. a (MRCR)
to clinafloxacin; the piperidinyl quinolones are about
7.5-fold more active against penicillin sensitive S.
pneumoniae and 37-fold more active against penicillin
resistant S. pneumoniae. However, again, the new
quinolones are less potent than the marketed drugs
against P. aeruginosa pathogens. In addition, the sub-
stituted piperidinyl quinolone 15E is far more active
than the piperazinyl counterpart 20 across the spectrum
studied. The enhanced activity against Gram-positive
pathogens in the (3S)-amino-(4R)-ethylpiperidinyl quin-
olones (13E and 15E) in comparison to the marketed
drugs and those in clinical studies is believed to be
associated with the presence of both the C-7 and the
C-8 groups in the molecules to exert a synergic effect
for the observed antibacterial activity, whereas these
components are missing in 16H,E and 17E, which show
much less effect on potency.
Melting points were taken on a capillary melting point
apparatus. High-resolution mass spectra were obtained by fast
atom bombardment (FAB) with a p-nitrobenzyl alcohol matrix.
IR spectra were recorded using attenuated total reflectance
spectroscopy with a germanium internal reflection element.
Optical rotations were measured with the use of a 10 cm cell
at 20 °C.
Gen er a l P r oced u r e for th e Syn th esis of Qu in olon e
14E. A solution of (3S)-Boc-amino-(4R)-ethyl piperidine (8E)
(1.201 g, 5.268 mmol), 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-
1,4-dihydro-quinoline-3-carboxylic acid BF2 ester (9c) (1.712
g, 5.268 mmol), and triethylamine (1.47 mL, 10.54 mmol) in
CH3CN (25 mL) was stirred at room temperature for 36 h. The
volatiles were evaporated under reduced pressure, and the
residue was dissolved in EtOAc (50 mL) and then washed with
0.1 N HCl (20 mL). The organic layer was separated, and the
aqueous layer was extracted with EtOAc (20 mL). The
combined organic phase was washed with brine once, dried
over anhydrous MgSO4, and evaporated on a rotary evaporator
to give a yellow solid (2.85 g) as a crude product, which was
used for the next step without purification.
A mixture of the coupled boron ester (10c, when R ) Et)
(2.85 g, 5.35 mmol) in triethylamine (15 mL, excess) and
ethanol (50 mL) was heated at reflux for 1 h, and the solid
was dissolved into the solution when refluxing started. After
the solution was cooled, the volatiles were evaporated on a
rotary evaporator. The residue was dissolved in EtOAc (50 mL)
and washed with 0.1 N HCl twice (20 mL). The organic layer
was separated, dried over anhydrous MgSO4, and evaporated
on a rotary evaporator to give a yellow solid (2.599 g) as a
crude product, which was used for the next step without
purification.
To the t-Boc-protected quinolone (11c, when R ) Et) (2.599
g, 5.359 mmol) in a flask was added concentrated HCl (10 mL),
and the mixture was stirred at room temperature for 30 min.
The solid was dissolved at the end of the reaction time, and
MS analysis showed the complete reaction. The mixture was
washed with CH2Cl2 four times (20 mL each). The aqueous
layer was evaporated under a reduced pressure, and the
residue was azeotroped with ethanol (10 mL) on a rotary
evaporator to produce a yellow solid (2.295 g, 95% for three
steps).
In conclusion, a low energy conformational analysis
approach has been used to effectively assist our design
of new substituted 3-amino piperidinyl side chains and
has led to the discovery of a series of novel (3S)-amino-
(4R)-ethylpiperidinyl quinolones. An efficient method for
the synthesis of trans-(3S)-amino-(4R)-ethylpiperidine
has been developed, and the substituted and unsubsti-
tuted (3S)-piperidines were incorporated into various
quinolone nuclei. The antibacterial activity of (3S)-
amino-(4R)-ethylpiperidinyl quinolones and naphthyri-
dines was evaluated in comparison to pairs with (3S)-
aminopiperidinyl quinolones and naphthyridines. The
data clearly show that the (3S)-amino-(4R)-ethylpiper-
idinyl quinolones are far superior to (3S)-aminopiperi-
dinyl quinolones in potency, spectrum of activity, and
activity against resistant organisms. These new ethyl-
substituted 3-aminopiperidinyl quinolones exhibit only
comparable potency to unsubstituted 3-aminopiperidinyl
quinolones against P. aeruginosa. The new side chains
did not provide significant enhancement of activity in
the naphthyridine series. In addition, activity superior-
ity of the new (3S)-amino-(4R)-ethylpiperidinyl quino-
lones against Gram-positive organisms was also illus-
trated when compared with the marketed and clinical
quinolones in the same nucleus classes, again with only
comparable activity against Gram-negative organisms.
7-((3S)-Am in o-piper idin -1-yl)-1-cyclopr opyl-6,8-diflu or o-
4-oxo-1,4-d ih yd r o-qu in olin e-3-ca r boxylic Acid (12H). 1H
NMR (300 MHz, CD3OD): δ 8.87 (s, 1H), 7.93 (dd, J ) 2.1,
11.7 Hz, 1H), 4.18 (m, 1H), 3.72 (m, 1H), 3.34-3.58 (m, 4H),
2.13-2.23 (m. 1H), 1.98-2.08 (m, 1H), 1.75-1.92 (m, 2H),
1.25-1.36 (m, 4H). 13C NMR (75 MHz, CD3OD): δ 178.9, 169.1,
151.3 (d, J ) 124.0 Hz), 150.7 (d, J ) 124.0 Hz), 142.5, 142.0,
136.3, 122.5, 118.7, 104.5, 60.4,53.3, 50.1, 41.2, 28.4, 23.4, 8.9.
19F NMR (282.7 MHz, CD3OD): δ 42.2 (t, J ) 11.7 Hz, 1F),
37.9 (s, 1F). EIMS m/z: 364 (M + H). Anal. calcd for C18H19
-
FN3O3‚1.9HCl: C, 49.97; H, 4.87; N, 9.71. Found: C, 50.32;
20
H, 4.95; N, 9.64. [R]D +26.1°, c ) 1.74 in CH3OH.

3660 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17
Hu et al.
7-((3S)-Am in o-(4R)-eth yl-p ip er id in -1-yl)-1-cyclop r op yl-
6,8-diflu or o-4-oxo-1,4-dih ydr o-qu in olin e-3-car boxylic Acid
(12E). 1H NMR (300 MHz, CD3OD): δ 8.94 (s, 1H), 7.92 (d,
J ) 11.7 Hz, 1H), 4.22-4.33 (m, 1H), 3.84-3.93 (m, 1H), 3.59-
3.70 (m, 1H), 3.26-3.44 (m, 3H), 2.08-2.18 (m. 1H), 1.71-
1.90 (m, 2H), 1.58-1.69 (m, 1H), 1.30-1.52 (m, 5H), 1.08 (t,
J ) 7.2 Hz, 3H). 13C NMR (75 MHz, CD3OD): δ 177.8, 168.7,
156.7 (d, J ) 124.0 Hz), 148.8 (s, J ) 124.0 Hz), 148.0, 135.1,
130.3, 123.0, 108.4, 108.2, 53.8, 53.0, 51.3, 41.7, 41.6, 41.0, 29.3,
24.7, 10.8, 9.4. 19F NMR (282.7 MHz, CD3OD): δ 43.5 (t, J )
10.7 Hz, 1F), 38.2 (s, 1F). EIMS m/z: 392 (M + H). Anal. calcd
for C20H23F2N3O3‚2HCl: C, 51.37; H, 5.43; N, 9.05. Found: C,
calcd for C18H20ClN3O4‚2HCl: C, 49.73; H, 5.10; N, 9.67.
20
Found: C, 50.01; H, 5.22; N, 9.58. [R]D +24.5°, c ) 2.1 in
CH3OH.
7-((3S)-Am in o-(4R)-eth yl-p ip er id in -1-yl)-8-ch lor o-1-cy-
clop r op yl-4-oxo-1,4-d ih yd r o-qu in olin e-3-ca r boxylic Acid
1
(15E). H NMR (300 MHz, CD3OD): δ 14.80 (s, 1H), 8.88 (s,
1H), 8.27 (d, J ) 8.7 Hz, 1H), 8.23 (br, 2H), 7.45 (d, J ) 8.7
Hz, 1H), 4.45 (m, 1H), 3.77-4.85 (m, 1H), 3.49-3.51 (m, 1H),
3.07-3.20 (br, 1H), 2.28-3.05 (m, 2H), 1.08-2.17 (m, 1H),
1.40-1.72 (m, 1H), 1.54-1.68 (m, 1H), 1.38-1.53 (m, 1H),
1.21-1.35 (m, 3H), 0.95-1.03 (m, 2H), 0.95 (t, J ) 7.2 Hz, 3H).
13C NMR (75 MHz, CD3OD): δ 177.9, 166.2, 156.1, 153.9,
141.9, 126.6, 123.6, 119.9, 115.8, 108.9, 54.3, 51.8, 51.5, 42.5,
40.9, 28.9, 24.1, 11.9, 11.7, 11.1. EIMS m/z: 390 (M + H). Anal.
calcd for C20H24ClN3O3‚2HCl: C, 51.90; H, 5.66; N, 9.08.
20
51.80; H, 5.82; N, 9.01. [R]D +28.5°, c ) 1.85 in CH3OH.
7-((3S)-Am in o-p ip er id in -1-yl)-1-cyclop r op yl-6-flu or o-8-
m eth oxy-4-oxo-1,4-d ih yd r o-qu in olin e-3-ca r boxylic Acid
(13H). 1H NMR (300 MHz, CD3OD): δ 8.88 (s, 1H), 7.82 (d,
J ) 12.0 Hz, 1H), 4.12 (m, 1H), 3.83 (s, 3H), 3.72-3.79 (m,
1H), 3.42-3.60 (m, 2H), 3.21-3.38 (m, 2H), 2.18-2.27 (m. 1H),
1.63-2.07 (m, 3H), 1.02-1.24 (m, 4H). 13C NMR (75 MHz,
CD3OD): δ 179.2, 168.8, 151.5 (d, J ) 124.0 Hz), 146.6, 139.2,
123.1, 122.0, 107.2, 107.0, 106.9, 63.0, 53.7, 51.0, 41.1, 28.1,
23.4, 9.0, 8.8. 19F NMR (282.7 MHz, CD3OD): δ 45.6 (d, J )
20
Found: C, 52.15; H, 5.38; N, 9.18. [R]D +22.5°, c ) 1.20 in
CH3OH.
7-((3S)-Am in o-p ip er id in -1-yl)-1-cyclop r op yl-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
(16H). 1H NMR (300 MHz, DMSO-d6): δ 14.67 (s, 1H), 8.64
(s, 1H), 8.24 (br, 2H), 8.13 (d, J ) 13.2 Hz, 1H), 4.51 (m, 1H),
4.21 (m, 1H), 3.79 (m, 1H), 3.36-3.51 (m, 3H), 2.04-2.13 (m,
1H), 1.82-1.92 (m, 1H), 1.62-1.74 (m, 2H), 1.22-1.29 (m, 2H),
1.08-1.13 (m, 2H). 13C NMR (75 MHz, DMSO-d6): δ 177.0,
166.1, 147.5 (d, J ) 124.0 Hz), 146.9, 145.6, 120.1, 119.8, 113.1,
108.0, 49.2, 47.2, 46.5, 35.4, 28.5, 22.9, 7.3, 7.1. 19F NMR (282.7
MHz, DMSO-d6): δ 35.8 (d, J ) 12.2 Hz, 1F). EIMS m/z: 347
(M + H). Anal. calcd for C17H19FN4O3‚1.9HCl: C, 49.13; H,
11.7 Hz, 1F). EIMS m/z: 376 (M + H). Anal. calcd for C19H22
-
FN3O4‚2HCl: C, 50.79; H, 5.61; N, 9.35. Found: C, 50.42; H,
20
5.61; N, 9.38. [R]D +30.6°, c ) 3.01 in CH3OH.
7-((3S)-Am in o-(4R)-eth yl-p ip er id in -1-yl)-1-cyclop r op yl-
6-flu or o-8-m et h oxy-4-oxo-1,4-d ih yd r o-q u in olin e-3-ca r -
1
boxylic Acid (13E). H NMR (300 MHz, CD3OD): δ 8.82 (s,
20
5.07; N, 13.48. Found: C, 49.18; H, 4.89; N, 13.09. [R]D
+25.4°, c ) 1.57 in CH3OH.
1H), 7.62 (d, J ) 9.3 Hz, 1H), 4.23 (m, 1H), 3.84-3.95 (m, 1H),
3.85 (s, 3H), 3.22-3.37 (m, 4H), 2.05-2.14 (m, 1H), 1.25-1.93
(m, 6H), 1.08-1.15 (m, 2H), 1.07 (t, J ) 7.5 Hz, 3H). 13C NMR
(75 MHz, CD3OD): δ 179.0, 167.9, 151.7 (d, J ) 124.0 Hz),
145.6, 137.5, 124.5, 121.3, 107.8, 107.3, 106.8, 61.6, 53.5, 51.2,
48.7, 42.8, 39.7, 28.9, 24.4, 18.2, 9.3, 9.1. 19F NMR (282.7 MHz,
CD3OD): δ 41.7 (d, J ) 9.0 Hz, 1F). EIMS m/z: 404 (M + H).
Anal. calcd for C21H26NF3O4‚4HCl: C, 48.45; H, 6.20; N, 7.71.
7-((3S)-Am in o-(4S)-eth yl-p ip er id in -1-yl)-1-cyclop r op 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 box-
ylic Acid (16E). 1H NMR (300 MHz, CD3OD): δ 8.70 (s, 1H),
8.01 (d, J ) 12.9 Hz, 1H), 4.70-4.84 (m, 1H), 4.45-4.56 (m,
1H), 3.81 (br, 1H), 3.36-3.50 (m, 3H), 2.07-2.18 (m, 1H),
1.74-1.87 (m, 2H), 1.31-1.64 (m, 4H), 1.01-1.17 (m, 2H), 1.04
(t, J ) 6.9 Hz, 3H). 13C NMR (75 MHz, CD3OD): δ 177.5, 167.8,
150.5, 150.4, 147.3 (d, J ) 124.0 Hz), 147.1, 119.6, 119.4, 113.7,
107.7, 51.3, 46.6, 40.7, 35.1, 27.7, 25.2, 24.9 23.6, 9.6, 6.7. 19F
NMR (282.7 MHz, CD3OD): δ 34.6 (d, J ) 13.8 Hz, 1F). EIMS
m/z: 375 (M + H). Anal. calcd for C19H23FN4O3‚1.5HCl: C,
53.24; H, 5.76; N, 13.07. Found: C, 53.44; H, 5.91; N, 13.07.
20
Found: C, 48.51; H, 6.11; N, 7.75. [R]D +26.1°, c ) 2.6 in
CH3OH.
7-((3S)-Am in o-piper idin -1-yl)-1-cyclopr opyl-8-m eth oxy-
4-oxo-1,4-d ih yd r o-qu in olin e-3-ca r boxylic Acid (14H). 1H
NMR (300 MHz, CD3OD): δ 9.02 (s, 1H), 8.25 (d, J ) 9.3 Hz,
1H), 7.48 (d, J ) 9.3 Hz, 1H), 4.38 (m, 1H), 4.01-4.08 (m, 1H),
3.89 (s, 3H), 3.70-3.81 (m, 1H), 3.50-3.62 (m, 1H), 3.03-3.18
(m. 2H), 2.21-2.36 (m, 1H), 1.86-2.17 (m, 2H), 1.62-1.78 (m,
1H), 1.28-1.33 (m, 2H), 1.08-1.19 (m, 2H). 13C NMR (75 MHz,
CD3OD): δ 178.3, 168.3, 151.3, 150.7, 142.5, 137.6, 122.5,
118.7, 117.8, 106.8, 60.4, 53.3, 50.1, 41.2, 28.3, 23.4, 8.9. EIMS
m/z: 358 (M + H). Anal. calcd for C19H23N3O4‚2.5HCl: C,
20
[R]D +23.1°, c ) 1.80 in CH3OH.
7-((3S)-Am in o-(4S)-eth yl-p ip er id in -1-yl)-1-cyclop r op yl-
6-flu or o-4-oxo-1,4-d ih yd r o-qu in olin e-3-ca r b oxylic Acid
(17E). 1H NMR (300 MHz, CD3OD): δ 8.62 (s, 1H), 7.63 (d,
J ) 12.9 Hz, 1H), 7.60 (s, 1H), 3.71-4.06 (m, 2H), 3.10-3.52
(m, 4H), 2.13-2.28 (m, 1H), 1.77-1.92 (m, 2H), 1.60-1.77 (m,
1H), 1.42-1.60 (m, 3H), 1.08-1.33 (m, 2H), 1.06 (t, J ) 6.9
Hz, 3H). 13C NMR (75 MHz, CD3OD): δ 176.6, 168.3, 148.1
(d, J ) 124.0 Hz), 145.8, 139.4, 197.3, 111.2, 110.9, 106.9,
20
50.88; H, 5.73; N, 9.37. Found: C, 50.50; H, 6.01; N, 9.22. [R]D
+23.5°, c ) 1.48 in CH3OH.
106.5, 57.3, 51.5, 51.3, 39.4, 36.1, 27.1, 23.5, 17.3, 9.9, 7.6. 19
F
7-((3S)-Am in o-(4S)-eth yl-p ip er id in -1-yl)-1-cyclop r op yl-
8-m eth oxy-4-oxo-1,4-dih ydr o-qu in olin e-3-car boxylic Acid
(14E). 1H NMR (300 MHz, CD3OD): δ 9.06 (s, 1H), 8.22 (d,
J ) 8.7 Hz, 1H), 7.53 (d, J ) 8.7 Hz, 1H), 4.41, (m, 1H), 4.23
(dd, J ) 3, 11.7 Hz, 1H), 3.90-3.96 (br, 1H), 3.89 (s, 3H), 3.32
(m, 1H), 3.07 (m, 2H), 2.19 (m, 1H), 1.88 (m, 1H), 1.54-1.74
(br, 2H), 1.42 (m, 1H), 1.32-1.38 (br, 2H), 1.12-1.19 (br, 2H),
1.09 (t, J ) 7.5 Hz, 3H). 13C NMR (75 MHz, CD3OD): δ 175.6,
168.8, 151.7, 151.1, 142.0, 137.6, 122.4, 120.0, 119.9, 105.7,
60.4, 52.5, 52.2, 49.7, 42.2, 40.8, 28.6, 23.7, 17.2, 9.5, 9.0. EIMS
m/z 386 (M + H), 408, (M + Na). Anal. calcd for C21H27N3O4‚
2HCl: C, 55.03; H, 6.38; N, 9.17. Found: C, 55.01; H, 6.45; N,
NMR (282.7 MHz, CD3OD): δ 41.1 (s, 1F). EIMS m/z: 374 g
(M + H). Anal. calcd for C20H24FN4O3‚2HCl: C, 53.82; H, 5.88;
N, 9.41. Found: C, 53.66; H, 6.48; N, 9.36.
7-((3S)-Am in o-(4S)-eth yl-p ip er id in -1-yl)-1-cyclop r op yl-
8-m eth oxy-4-oxo-1,4-dih ydr o-qu in olin e-3-car boxylic Acid
(19). 1H NMR (300 MHz, CD3OD): δ 8.89 (s, 1H), 8.12 (d, J )
8.7 Hz, 1H), 7.41 (d, J ) 8.7 Hz, 1H), 4.27, (m, 1H), 3.82-3.94
(m, 2H), 3.86 (s, 3H), 3.70-3.76 (m, 1H), 3.26-3.36 (m, 1H),
2.96-3.06 (m, 1H), 1.82-2.02 (m, 3H), 1.47-1.60 (m, 2H),
1.20-0.37 (m, 2H), 1.10 (t, J ) 7.5 Hz, 3H), 1.02-1.12 (2H).
13C NMR (75 MHz, CD3OD): δ178.1, 168.3, 151.4, 151.3, 143.1,
137.2, 122.7, 122.5, 119.1, 107.0, 61.4, 53.6, 50.7, 50.3, 40.9,
38.6, 25.7, 24.0, 10.4, 8.9, 8.8. EIMS m/z 386 (M + H), 408,
(M + Na). Anal. calcd for C21H27N3O4‚2HCl: C, 55.03; H, 6.38;
20
9.03. [R]D +23.2°, c ) 2.6 in CH3OH.
7-((3S)-Am in o-p ip er id in -1-yl)-8-ch lor o-1-cyclop r op yl-
4-oxo-1,4-d ih yd r o-qu in olin e-3-ca r boxylic Acid (15H). 1H
NMR (300 MHz, DMSO-d6): δ 14.50 (s, 1H), 9.01 (s, 1H), 8.18
(d, J ) 8.7 Hz, 1H), 7.50 (d, J ) 8.7 Hz, 1H), 7.23 (br, 2H),
4.38, (m, 1H), 4.11-4.25 (m, 1H), 3.78-3.89 (m, 1H), 3.38-
3.43 (m, 1H), 3.10-3.20 (m, 2H), 2.19-2.24 (m, 1H), 1.68-
1.79 (m, 2H), 1.25-1.40 (m, 1H), 1.25-1.30 (m, 2H), 1.10-
1.19 (m, 2H). 13C NMR (75 MHz, CD3OD): δ 174.4, 168.0,
155.9, 153.2, 150.6, 148.0, 140.2, 126.1, 121.6, 107.8, 51.9, 50.7,
41.7, 40.1, 23.6, 11.0, 10.9, 9.6. EIMS m/z 362 (M + H). Anal.
20
N, 9.17. Found: C, 54.96; H, 6.23; N, 9.38. [R]D +21.0°, c )
1.4 in CH3OH.
Ack n ow led gm en t. We thank Dr. P. M. Koenigs,
Mrs. H. D. McKeever, and Mrs. Cindy Wallace for
conducting in vitro antimicrobial assays to generate the
MIC data. We also thank Mrs. Tracy L. Twinem for
conducting in vitro gyrase inhibitory assays.

(3S)-Amino-(4R)-Ethylpiperidinyl Quinolones
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17 3661
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(12) The cis- and trans-3-amino-4-methylpiperidinyl side chains were
also examined in our algorithm model and found that they
displaced superimposition less favorable to that of the 3-ami-
noethyl-pyrrolidinyl side chain. In fact, the hypothesis was
proven by our biological results of new NFQs containing the cis-
(3S)-amino-(4S)-methylpiperidinyl side chain and trans-(3S)-
amino-(4R)-methylpiperidinyl side chain (data not shown here
and
a manuscript describing detail SAR of novel NFQs is
currently in preparation and will be submitted to J . Med. Chem.
as a full paper in the near future).
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Tetrahedron Lett. 1997, 38, 677-680. (b) For a review, see
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(19) (a) Characterization: [R]D +149.6°, c ) 2.1 in CHCl3. (b) 1H
20
NMR (300 MHz, CDCl3): δ 4.37-4.66 (m, 1H), 3.20-3.39 (m,
2H), 3.04 (d, J ) 12.0 Hz, 1H), 2.72 (br, 1H), 2.56 (t, J ) 9.3 Hz,
1H), 2.34 (t, J ) 11.1 Hz, 1H), 1.80-1.92 (m, 1H), 1.62-1.77
(m, 1H), 1.45 (s, 9H), 1.16-1.30 (m, 2H), 0.90 (t, J ) 6.9 Hz,
3H). 13C NMR (75 MHz, CDCl3): δ 155.8, 79.4, 52.4, 51.6, 45.8,
43.2, 30.6, 28.6, 24.9, 11.0. EIMS m/z 229 (M + H): 173, (M-
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