Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles

Article abstract of DOI:10.1021/jm060957y

In an effort to develop potent new antituberculosis agents that would be effective against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis, we prepared a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxaz

Full text of DOI:10.1021/jm060957y

7854
J. Med. Chem. 2006, 49, 7854-7860
Synthesis and Antituberculosis Activity of a Novel Series of Optically Active
6-Nitro-2,3-dihydroimidazo[2,1-b]oxazoles
Hirofumi Sasaki,† Yoshikazu Haraguchi,† Motohiro Itotani,† Hideaki Kuroda,† Hiroyuki Hashizume,‡ Tatsuo Tomishige,‡
Masanori Kawasaki,‡ Makoto Matsumoto,‡ Makoto Komatsu,† and Hidetsugu Tsubouchi*,†
Medicinal Chemistry Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan,
and Microbiological Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan
ReceiVed August 8, 2006
In an effort to develop potent new antituberculosis agents that would be effective against both drug-susceptible
and drug-resistant strains of Mycobacterium tuberculosis, we prepared a novel series of optically active
6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles substituted at the 2-position with various phenoxymethyl groups
and a methyl group and investigated the in Vitro and in ViVo activity of these compounds. Several of these
derivatives showed potent in Vitro and in ViVo activity, and compound 19 (OPC-67683) in particular displayed
excellent in Vitro activity against both drug-susceptible and drug-resistant strains of M. tuberculosis H37Rv
(MIC ) 0.006 µg/mL) and dose-dependent and significant in ViVo efficacy at lower oral doses than rifampicin
in mouse models infected with M. tuberculosis Kurono. The synthesis and structure-activity relationships
of these new compounds are presented.
Introduction
Recognizing this serious situation, we initiated a program to
screen for new antituberculosis agents. We synthesized and
screened various compounds, including a number of dihydro-
phenazines,13 indoles, and ureas.14 One group of compounds
on which we focused our attention was 6-nitro-2,3-dihydroimi-
dazo[2,1-b]oxazoles because of their inhibitory activity against
mycolic acid biosynthesis,14 which plays an important role in
mycobacteria.15 Nitroimidazoles, such as the nitroimidazole
antibiotic metronidazole, are widely used for the treatment of
anaerobic bacteria and protozoan infections, but they have had
poor potency against M. tuberculosis.16 In 1989, researchers at
Ciba-Geigy reported the discovery of a bicyclic nitroimida-
zooxazole, 1 (CGI 17341)17 (Figure 1), possessing favorable in
Vitro activity and in ViVo efficacy. However, further investigation
of 1 as an antituberculosis agent had to be discontinued due to
the compound’s mutagenicity.18 Later, a research group at
PathoGenesis Corporation developed a bicyclic nitroimidazopy-
ran, 2 (PA-824),19 that exhibited potent bactericidal activity
against MDR M. tuberculosis and promising oral activity in
animal infection models. We speculated that changing the
substituents at the 2-position of 6-nitro-2,3-dihydroimidazo[2,1-
b]oxazoles, which have a structure similar to 1, might enhance
antituberculosis activity and eliminate mutagenicity. In our early
experiments, however, no decrease in mutagenicity was achieved
by introducing other alkyl substituents into the 2-position. After
various experiments with different substituents, we succeeded
in discovering a number of derivatives that did not exert
mutagenicity from among compounds with heteroatoms in the
side chains at the 2-position.20 Therefore, to identify agents that
display increased antituberculosis activity, we prepared a series
of novel optically active 6-nitro-2,3-dihydroimidazo[2,1-b]-
oxazoles having various phenoxymethyl groups and a methyl
group at the 2-position. As a result of extensive evaluation, we
found a potent, orally active compound that is a promising
candidate for the treatment of tuberculosis. We describe herein
the synthesis and biological activity of these novel agents.
Tuberculosis (TB),a an airborne lung infection, still remains
a major public health problem worldwide. It is estimated that
about 32% of the world population is infected with TB bacillus,
and of those, approximately 8.9 million people develop active
TB and 1.7 million die as a result annually according to 2004
figures.1 Human immunodeficiency virus (HIV) infection has
been a major contributing factor in the current resurgence of
TB.2,3 HIV-associated TB is widespread, especially in sub-
Saharan Africa, and such an infectious process may further
accelerate the resurgence of TB. Moreover, the recent emergence
of multidrug-resistant (MDR) strains of Mycobacterium tuber-
culosis that are resistant to two major effective drugs, isonico-
tinic acid hydrazide (INH)4 and rifampicin (RFP),5 has further
complicated the world situation.6 The World Health Organiza-
tion (WHO) has estimated that if the present conditions remain
unchanged, more than 30 million lives will be claimed by TB
between 2000 and 2020.7 As for subsequent drug development,
not a single new effective compound has been launched as an
antituberculosis agent since the introduction of RFP in 1965,
despite the great advances that have been made in drug
development technologies.3 Although many effective vaccine
candidates have been developed, more potent vaccines will not
become immediately available. The current therapy consists of
an intensive phase with four drugs, INH, RFP, pyrazinamide
(PZA),8 and streptomycin (SM)9 or ethambutol (EB),10 admin-
istered for 2 months followed by a continuous phase with INH
and RFP for 4 months.11 Thus, there exists an urgent need for
the development of potent new antituberculosis agents with low-
toxicity profiles that are effective against both drug-susceptible
and drug-resistant strains of M. tuberculosis and that are capable
of shortening the current duration of therapy.12
* To whom correspondence should be addressed. Phone: +81-88-665-
2126. Fax: +81-88-665-6031. E-mail: h_tsubouchi@research.otsuka.co.jp.
† Medicinal Chemistry Research Institute.
‡ Microbiological Research Institute.
a Abbreviations: TB, tuberculosis; HIV, human immunodeficiency virus;
MDR, multidrug-resistant; INH, isonicotinic acid hydrazide; RFP, rifampi-
cin; PZA, pyrazinamide; SM, streptomycin; EB, ethambutol; MIC, minimum
inhibitory concentration; CFU, colony forming unit; DMSO, dimethylsul-
foxide.
Chemistry
The first objective of this investigation was to immediately
synthesize a variety of (R)-form derivatives and evaluate their
10.1021/jm060957y CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/06/2006

Synthesis and Antituberculosis ActiVity
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 26 7855
Scheme 1a
Figure 1. Metronidazole and bicyclic nitroimidazole derivatives 1
and 2.
a Reagents: (a) Et3N, AcOEt, 60-65 °C, 6 h; (b) K2CO3, MeOH, rt, 2
h; (c) MsCl, pyridine, <15 °C, 2 h; (d) DBU, AcOEt, rt, 2 h; (e) 28, NaH,
DMF, 50 °C, 2 h.
Table 1. In Vitro MIC Values of 3a-g
The (S)-form 3g was similarly prepared by using the (S)-
form epoxide 29 instead of 27 essentially according to the same
method. Compound 12 was synthesized by oxidation of 11 with
m-chloroperbenzoic acid in dichloromethane (Scheme 2). Among
the phenol compounds 28, 4-(piperidin-1-yl)phenol for 9,
4-(morpholin-4-yl)phenol for 10, and 4-(thiomorpholin-4-yl)-
phenol for 11 were obtained according to the previously reported
methods.25 The synthesis method for the phenol compounds
28a-i for preparing 13-21 was as follows: 2-(4-bromophe-
noxy)tetrahydropyran (30)26 was reacted with various 4-phe-
noxypiperidine derivatives 3127 by the Buchwald palladium-
catalyzed amination method28 to afford 32. The thus-obtained
32 was deprotected with pyridinium p-toluenesulfonate in
ethanol to give the desired phenols 28a-i (Scheme 3). All
synthesized (R)-form compounds are displayed in Tables 2 and
3, and each compound was chemically characterized by melting
point and nuclear magnetic resonance (1H NMR), as well as by
elemental microanalysis.
compd
R1
R2
configuration
MIC (µg/mL)a
3a
3b
3c
3d
3e
3f
H
H
H
H
Me
Me
Me
OPh
racemic
racemic
racemic
racemic
racemic
(R)
0.78
3.13
1.56
12.5
0.1
OCH2Ph
O(CH2)2Ph
OCH2CHdCHPh
OPh
OPh
OPh
0.05
3.13
3g
(S)
a MIC against M. tuberculosis H37Rv. MIC of RFP ) 0.1-0.39 µg/mL.
in Vitro and in ViVo activity. Second, through screening, we
intended to identify a potent agent having no mutagenicity as a
candidate for the treatment of tuberculosis.
We first synthesized the four racemic compounds 3a-d
essentially according to previously reported methods (Table
1).17,21 Their minimum inhibitory concentration (MIC) values
against M. tuberculosis H37Rv22 were, respectively, 0.78, 3.13,
1.56, and 12.5 µg/mL, with 3a, which has a phenoxymethyl
group at the 2-position, providing the best result. We then
prepared compound 3e, which has a methyl group at the
2-position of 3a. Compared with 3a, 3e showed increased
inhibitory activity (MIC ) 0.1 µg/mL). Furthermore, comparison
of (R)-form 3f (MIC ) 0.05 µg/mL) with (S)-form 3g (MIC )
3.13 µg/mL) showed the (R)-form to be the more active form.
The synthesis method for these two optically active compounds
will be described later. Accordingly, we decided to develop (R)-
derivatives with various substituted-phenoxymethyl groups and
a methyl group at the 2-position to obtain a more potent
compound.
Results and Discussion
All compounds 3f and 4-21 prepared in this investigation
were tested for in Vitro antituberculosis activity against both
drug-susceptible and drug-resistant strains of M. tuberculosis
H37Rv22 and for short-term in ViVo efficacy at an oral dose of
50 mg/kg for 10 days in mice infected with M. tuberculosis
Kurono11 as the primary screening model. The results are
summarized in Tables 2 and 3. Among the compounds 3f and
4-8 (Table 2), 3f (H), 4 (Cl), and 5 (Me) showed high in Vitro
activity and significant in ViVo efficacy. However, the in ViVo
efficacy of 6 (MeO) was found to be inferior to that of 3f despite
its high in Vitro activity. Although 7 (CF3) and 8 (OCF3) showed
only moderate MIC values, they exhibited more potent in ViVo
efficacy than 3f. Compounds 9-12 (Table 2), designed to
improve bioavailability by the introduction of hydrophilic
substituents into the 4-position of the benzene ring of 3f, also
had moderate MIC values, except for 12, but unexpectedly their
in ViVo efficacy was generally poor in comparison with 3f.
Because 9 (piperidino) showed the most potent in ViVo efficacy,
(1.9 log CFU reduction in mouse lung) among these four
compounds having hydrophilic substituents, we prepared com-
pounds 13-21 (Table 3) by introducing lipophilic phenoxy
groups to the 4-position of the piperidine ring of 9 to search
for more potent agents. Among compounds 13-17, 14 (p-Cl)
exhibited high in Vitro activity and 13 (H), 14, and 15 (p-F)
showed increased in ViVo efficacy in comparison with 9.
However, 16 (p-Me) and 17 (p-MeO) did not show efficacy in
in ViVo screening, contrary to our expectations. In particular,
18 (p-CF3) and 19 (p-OCF3) both showed similar excellent in
Our synthesis strategy for preparation of the optically active
6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles with substituted-phe-
noxymethyl groups 3f and 4-21 ((R)-form) involved the
utilization of the key intermediate (R)-form 27, an optically
active epoxide easily derived from 2-chloro-4-nitro-1H-imida-
zole (22)23 and (R)-2-methyl-2,3-epoxypropyl 4-nitrobenzoate
(23)24 (Scheme 1). Namely, compound 22 was reacted with the
epoxide 23 in the presence of triethylamine in ethyl acetate to
afford 24, followed by de-esterification with methanol and a
catalytic amount of potassium carbonate to give the diol 25.
The thus obtained diol was allowed to react with methanesulfo-
nyl chloride in pyridine to afford the mesylate 26, which was
easily converted into the (R)-form epoxide 27 with 1,8-
diazabicyclo[5.4.0]-7-undecene in ethyl acetate. Finally, the
target compounds were synthesized by coupling 27 with various
phenol compounds 28, followed by ring closure in the presence
of sodium hydride in N,N-dimethylformamide.

7856 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 26
Sasaki et al.
Scheme 2
Scheme 3a
a Reagents: (a) Pd(OAc)2, rac-BINAP, Cs2CO3, toluene, reflux, 30 min; (b) pyridinium p-toluenesulfonate, EtOH, 70 °C, 24 h.
Table 2. In Vitro and in ViVo Activity of Synthesized Compounds 3f and 4-12
a MIC of RFP against M. tuberculosis H37Rv ) 0.1-0.39 µg/mL. b log CFU reduction in mouse lung relative to untreated controls by once-daily oral
administration at 50 mg/kg for 10 days (n ) 2) starting on the day after intravenous infection with 104 CFU of M. tuberculosis Kurono. c ND ) not
determined.
OCF3), synthesized by converting the positions of a trifluo-
romethoxy group of 19 into ortho or meta, were found to have
less potent in Vitro activity than 19; the in ViVo efficacy of 21
was found to be similar to that of 19.
Next, the compounds 8, which showed potent in ViVo efficacy,
and 19, which demonstrated the highest in Vitro activity among
all of the synthesized compounds, were then evaluated in ViVo
at oral doses of 0.5 and 10 mg/kg for 10 days (Table 4). In this
in ViVo test, RFP at 5 mg/kg was used as a reference compound.
Compounds 8 and 19 both showed a significant decrease in
bacterial load in this evaluation. The oral activity of 8 at a dose
of 0.5 mg/kg was similar to that of RFP at 5 mg/kg, and even
more notably, oral administration of 19 at a dose of 0.5 mg/kg
produced a much better result than RFP at 5 mg/kg. Conse-
quently, based on these evaluation results, compound 19 was
selected for further scrutiny.
Figure 2. In ViVo efficacy of compound 19 against M. tuberculosis
Kurono. Mice were orally dosed once daily for 28 days (n ) 6) starting
on the day after intravenous infection with 104 CFU of mycobacteria.
Finally, 19 was tested for in ViVo efficacy at lower oral doses
of 0.078-2.5 mg/kg once daily for 28 days in mice infected
with M. tuberculosis Kurono (Figure 2) as a model system. The
results for RFP at a dose of 5 mg/kg as a reference drug are
Vitro activity, but 19 was superior to 18 regarding in ViVo
potency (>3.8 log CFU reduction). The excellent in Vitro
activity of 19 was mirrored by its significant in ViVo efficacy
in the mouse acute model. Although 20 (o-OCF3) and 21 (m-

Synthesis and Antituberculosis ActiVity
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 26 7857
Table 3. In Vitro and in ViVo Activity of Synthesized Compounds
13-21
JASCO DPI-370 digital polarimeter. Satisfactory spectral data were
obtained for all of the new compounds. Satisfactory elemental
analyses ((0.4%) were obtained for all crystalline derivatives.
Chromatographic separations were performed on silica gel columns
by gravity column (Kieselgel 60, 0.063-0.200 mm; Merck)
chromatography.
Racemic compounds 3b-e were essentially prepared according
to the previously reported methods.17,21 Compound 3a has been
previously reported.17
2-Benzyloxymethyl-6-nitro-2,3-dihydroimidazo[2,1-b]ox-
azole (3b). Mp 125-126 °C. 1H NMR (CDCl3) δ 3.76 (1H, dd, J
) 3.5 Hz, 11.2 Hz), 3.87 (1H, dd, J ) 4.1 Hz, 11.2 Hz), 4.23-
4.34 (2H, m), 4.59 (2H, s), 5.34-5.43 (1H, m), 7.23-7.41 (5H,
m), 7.52 (1H, s). MS (DI) m/z 276 (M+ + 1). Anal. (C13H13N3O4)
C, H, N.
6-Nitro-2-phenethyloxymethyl-2,3-dihydroimidazo[2,1-b]ox-
azole (3c). Mp 115-116 °C. 1H NMR (CDCl3) δ 2.84 (2H, t, J )
6.6 Hz), 3.64-3.86 (4H, m), 4.09 (1H, dd, J ) 6.2 Hz, 10.0 Hz),
4.21 (1H, dd, J ) 8.6 Hz, 10.0 Hz), 5.25-5.41 (1H, m), 7.07-
7.32 (5H, m), 7.46 (1H, s). MS (DI) m/z 289 (M+). Anal.
(C14H15N3O4) C, H, N.
MIC (µg/mL) against
M. tuberculosis strains
H37Rv
H37Rv
log CFU
compd
R6
H37Rva INH-resistant RFP-resistant reductionb
13
14
15
16
17
18
19
20
21
H
0.39
0.05
0.39
0.78
0.39
0.012
0.006
0.39
0.39
0.05
0.39
0.39
0.39
0.012
0.006
0.39
0.024
0.2
0.024
0.2
0.39
0.2
0.006
0.006
0.2
2.8
2.2
2.2
0.6
0.1
2.2
>3.8
3.0
p-Cl
p-F
p-Me
p-MeO
p-CF3
p-OCF3
o-OCF3
m-OCF3 0.024
0.024
>4.4
a MIC of RFP against M. tuberculosis H37Rv ) 0.1-0.39 µg/mL. b log
CFU reduction in mouse lung relative to untreated controls by once-daily
oral administration at 50 mg/kg for 10 days (n ) 2) starting on the day
after intravenous infection with 104 CFU of M. tuberculosis Kurono.
2-Cinnamyloxymethyl-6-nitro-2,3-dihydroimidazo[2,1-b]ox-
azole (3d). Mp 145-147 °C. 1H NMR (CDCl3) δ 3.80 (1H, dd, J
) 3.6 Hz, 11.3 Hz), 3.90 (1H, dd, J ) 4.0 Hz, 11.3 Hz), 4.20-
4.34 (4H, m), 5.34-5.50 (1H, m), 6.22 (1H, ddd, J ) 6.2 Hz, 12.4
Hz, 16.0 Hz), 6.57 (1H, d, J ) 16.0 Hz), 7.20-7.39 (5H, m), 7.54
(1H, s). MS (DI) m/z 302 (M+). Anal. (C15H15N3O4) C, H, N.
2-Methyl-6-nitro-2-phenoxymethyl-2,3-dihydroimidazo[2,1-
Table 4. In ViVo Efficacy of Compounds 8 and 19 as Compared with
RFP
compd
19
8
RFP
5
0.5
dose (mg/kg)
0.5
2.5
10
>4.4
0.5
0.4
10
3.0
log CFU reductiona
1
b]oxazole (3e). Mp 117-119 °C. H NMR (CDCl3) δ 1.79 (3H,
a 10-day treatment of mouse model infection with M. tuberculosis Kurono
s), 4.03 (1H, d, J ) 10.2 Hz), 4.09 (1H, d, J ) 10.2 Hz), 4.24 (1H,
d, J ) 10.1 Hz), 4.50 (1H, d, J ) 10.1 Hz), 6.84 (2H, dd, J ) 2.0
Hz, 8.6 Hz), 7.01 (1H, t, J ) 7.4 Hz), 7.20-7.31 (2H, m), 7.56
(1H, s). MS (DI) m/z 275 (M+). Anal. (C13H13N3O4) C, H, N.
(R)-2-Chloro-1-[2-hydroxy-2-methyl-3-(4-nitrobenzoyloxy)]-
propyl-4-nitroimidazole (24). A solution of 2-chloro-4-nitro-1H-
imidazole (22)23 (3 g, 20.34 mmol), (R)-form epoxide 2324 (5.31
g, 22.37 mmol), and triethylamine (0.57 mL, 4.07 mmol) in ethyl
acetate (10 mL) was heated at 60-65 °C for 6 h. The reaction
mixture was allowed to cool to room temperature and concentrated
under reduced pressure. To the residue was added ethyl acetate (3
mL) and toluene (30 mL). The resulting precipitates were collected
by filtration and recrystallized from ethyl acetate-isopropylether
to give 24 (6.82 g, 87%) as colorless needles. Mp 122-123 °C. 1H
NMR (DMSO-d6) δ 1.23 (3H, s), 4.11-4.33 (4H, m), 5.61 (1H,
s), 8.25 (2H, d, J ) 8.9 Hz), 8.31-8.45 (3H, m). [R]2D6 54.0° (c
1.04, CH3CN). MS (DI) m/z 384 (M+). Anal. (C14H13ClN4O7) C,
H, N.
(R)-2-Chloro-1-(2,3-dihydroxy-2-methyl)propyl-4-nitroimida-
zole (25). To a solution of 24 (6.80 g, 17.67 mmol) in methanol
(68 mL) was added potassium carbonate (122 mg, 0.88 mmol).
After the solution was stirred at room temperature for 2 h, 6 M
hydrochloric acid (0.3 mL) and magnesium sulfate (3 g) were added
at 0 °C, and the resulting mixture was stirred for 1 h. The insoluble
materials were filtered off through Celite, and the filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (dichloromethane/methanol )
20/1) and recrystallized from ethyl acetate-isopropylether to give
25 (4.09 g, 97%) as colorless needles. Mp 110-111 °C. 1H NMR
(DMSO-d6) δ 1.01 (3H, s), 3.25 (2H, d, J ) 5.3 Hz), 4.05 (2H, s),
5.01 (1H, s), 5.11 (1H, t, J ) 5.4 Hz), 8.32(1H, s). [R]2D7 17.4° (c
1.03, DMSO). MS (DI) m/z 235 (M+). Anal. (C7H10ClN3O4) C, H,
N.
similar to Tables 1 and 2.
also presented. Compound 19 showed a dose-dependent and
significant decrease in mouse pulmonary M. tuberculosis
bacterial counts. In particular, the efficacy of 19 at 0.313 mg/
kg was comparable to that of RFP at 5 mg/kg. This potent
compound 19 had none of the mutagenicity previously associ-
ated with 1.20 Therefore, based on the screening results, we
selected compound 19 as an orally active candidate for the
treatment of tuberculosis.
Conclusions
Screening of this novel series of (R)-form optically active
6-nitro-2,3-dihydroimidazo[2,1-b]oxazole derivatives for in Vitro
antituberculosis activity and in ViVo oral efficacy indicated that
compounds with substituted phenoxymethyl groups and a methyl
group at the 2-position are a new class of agents endowed with
highly potent antituberculosis activity. Due to its excellent in
Vitro antituberculosis activity against both drug-susceptible and
drug-resistant strains of M. tuberculosis H37Rv and its potent
in ViVo efficacy in mice infected with M. tuberculosis Kurono
as a model system, compound 19 was concluded to be a
promising orally active candidate for the treatment of tubercu-
losis. Most notably, compound 19 at an oral dose of 0.313 mg/
kg for 28 days showed in ViVo efficacy comparable to that of
RFP at 5 mg/kg. Still more detailed biological data will be
presented in a separate paper.20 Compound 19 (OPC-67683)20
is now under intensive development.
Experimental Section
General Methods. Reagents were used as supplied unless
otherwise noted. All melting points were determined on a Yanaco
MP-500D apparatus and are uncorrected. Proton nuclear magnetic
resonance (1H NMR) spectra were recorded on a Bruker DPX250
instrument operating at 250 MHz. Chemical shifts are shown in
parts per million (ppm) on the δ scale downfield relative to
tetramethylsilane as an internal standard, and coupling constants
are shown in hertz (Hz). Optical rotations were measured on a
(R)-2-Chloro-1-(2-methyl-2,3-epoxypropyl)-4-nitroimida-
zole (27). To a solution of 25 (10 g, 42.44 mmol) in pyridine (20
mL) was added methanesulfonyl chloride (7.29 g, 63.66 mmol) at
below 15 °C dropwise over 30 min. After the solution was stirred
for 2 h, 6 M hydrochloric acid (63 mL) was added to the reaction
mixture at below 30 °C. The resulting mixture was extracted with
ethyl acetate (75 mL × 2), and the combined organic layer was
washed with brine, dried over magnesium sulfate, and filtered. The

7858 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 26
Sasaki et al.
filtrate was concentrated under reduced pressure, and to the residue
was added toluene (75 mL). The resulting precipitates were
collected by filtration to afford crude 26. To a solution of this crude
26 in ethyl acetate (100 mL) was added 1,8-diazabicyclo[5.4.0]-
7-undecene (7.10 g, 46.68 mmol), and the mixture was stirred at
room temperature for 2 h. The reaction mixture was washed with
brine, dried over magnesium sulfate, and filtered. The filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethy acetate/hexane ) 1/1) to
give the (R)-form epoxide 27 (6.93 g, 75%) as colorless needles.
Mp 72-73 °C. 1H NMR (CDCl3) δ 1.38 (3H, s), 2.62 (1H, d, J )
4.0 Hz), 2.78 (1H, d, J ) 4.0 Hz), 4.00 (1H, d, J ) 14.9 Hz), 4.38
(1H, d, J ) 14.9 Hz), 7.87 (1H, s). [R]2D6 31.1° (c 2.02, CHCl3).
MS (DI) m/z 217 (M+). Anal. (C7H8ClN3O3) C, H, N.
(S)-2-Chloro-1-(2-methyl-2,3-epoxypropyl)-4-nitroimida-
zole (29). This compound was obtained by the same procedure as
described for 27 from 2-chloro-4-nitro-1H-imidazole (22) and (S)-
2-methyl-2,3-epoxypropyl 4-nitrobenzoate.24 Mp 72-73 °C. 1H
NMR (CDCl3) δ 1.39 (3H, s), 2.63 (1H, d, J ) 4.0 Hz), 2.79 (1H,
d, J ) 4.0 Hz), 4.00 (1H, d, J ) 14.9 Hz), 4.38 (1H, d, J ) 14.9
Hz), 7.88 (1H, s). [R]2D7 -29.2° (c 1.18, CHCl3). MS (DI) m/z 217
(M+). Anal. (C7H8ClN3O3) C, H, N.
1-[4-(Tetrahydropyran-2-yloxy)phenyl]-4-(4-trifluoromethox-
yphenoxy)piperidine (32g). A mixture of 2-(4-bromophenoxy)-
tetrahydropyran (30)26 (30 g, 116.67 mmol) and 4-(4-trifluo-
romethoxyphenoxy)piperidine (31g)27 (30.30 g, 115.60 mmol) in
the presence of palladium acetate (1 g, 4.64 mmol), rac-2,2′-bis-
(diphenylphosphino)-1,1′-binaphthyl (4.30 g, 6.96 mmol), and
cesium carbonate (49 g, 150.39 mmol) in toluene (300 mL) was
refluxed under a nitrogen atmosphere for 30 min. The reaction
mixture was allowed to cool to room temperature, and ethyl acetate
(300 mL) and water (200 mL) were added. The thus-obtained
mixture was filtered through Celite. The organic layer was
separated, washed with brine, dried over magnesium sulfate, and
filtered. The filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethy
acetate/hexane ) 1/20) to give 32g (32.60 g, 64%) as a yellow
crystalline powder. 1H NMR (CDCl3) δ 1.55-1.75 (3H, m), 1.81-
2.20 (7H, m), 2.95-3.04 (2H, m), 3.38-3.42 (2H, m), 3.55-3.66
(1H, m), 3.87-3.99 (1H, m), 3.56-4.45 (1H, m), 5.29-5.32 (1H,
m), 6.89-7.01 (6H, m), 7.11-7.16 (2H, m).
m), 3.30-3.40 (2H, m), 4.29-4.39 (1H, m), 4.72 (1H, s), 6.71-
6.78 (2H, m), 6.83-7.01 (6H, m).
4-[4-(4-Methylphenoxy)piperidin-1-yl]phenol (28d). 1H NMR
(CDCl3) δ 1.87-2.01 (2H, m), 2.04-2.16 (2H, m), 2.29 (3H, s),
2.90-3.00 (2H, m), 3.30-3.40 (2H, m), 4.33-4.43 (1H, m), 4.85
(1H, s), 6.71-6.78 (2H, m), 6.80-6.92 (4H, m), 7.06-7.10 (2H,
m).
4-[4-(4-Methoxyphenoxy)piperidin-1-yl]phenol (28e). 1H NMR
(CDCl3) δ 1.86-2.00 (2H, m), 2.05-2.13 (2H, m), 2.88-2.99 (2H,
m), 3.31-3.41 (2H, m), 3.77 (3H, s), 4.25-4.35 (1H, m), 4.72
(1H, s), 6.72-6.77 (2H, m), 6.80-6.92 (6H, m).
4-[4-(4-Trifluoromethylphenoxy)piperidin-1-yl]phenol (28f).
1H NMR (CDCl3) δ 1.90-2.05 (2H, m), 2.08-2.20 (2H, m), 2.94-
3.05 (2H, m), 3.30-3.40 (2H, m), 4.46-4.56 (1H, m), 4.64 (1H,
s), 6.72-6.80 (2H, m), 6.86-6.93 (2H, m), 6.96-7.00 (2H, m),
7.52-7.56 (2H, m).
4-[4-(2-Trifluoromethoxyphenoxy)piperidin-1-yl]phenol (28h).
1H NMR (CDCl3) δ 1.91-2.16 (4H, m), 2.91-3.07 (2H, m), 3.25-
3.40 (2H, m), 4.40-4.53 (1H, m), 4.70 (1H, s), 6.76 (2H, dd, J )
2.3 Hz, 6.7 Hz), 6.81-7.05 (4H, m), 7.12-7.28 (2H, m).
4-[4-(3-Trifluoromethoxyphenoxy)piperidin-1-yl]phenol (28i).
1H NMR (CDCl3) δ 1.89-2.18 (4H, m), 2.94-3.06 (2H, m), 3.27-
3.41 (2H, m), 4.35-4.51 (1H, m), 4.71 (1H, s), 6.71-6.96 (7H,
m), 7.25-7.35 (1H, m).
(R)-2-Methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)pi-
peridin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]ox-
azole (19). To a mixture of 27 (127.56 g, 586.56 mmol) and 4-[4-
(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenol (28g) (165.70 g,
468.95 mmol) in N,N-dimethylformamide (1600 mL) was added
60% sodium hydride (22.51 g, 562.74 mmol) at 0 °C portionwise.
After the mixture was stirred at 50 °C for 2 h under a nitrogen
atmosphere, the reaction mixture was cooled in an ice bath and
carefully quenched with ethyl acetate (230 mL) and ice water (50
mL). The thus-obtained mixture was poured into water (3000 mL)
and stirred for 30 min. The resulting precipitates were collected
by filtration, washed with water, and dried at 60 °C overnight. This
crude product was purified by silica gel column chromatography
using a dichloromethane and ethyl acetate mixture (5/1) as solvent.
The appropriate fractions were combined and evaporated under
reduced pressure. The residue was recrystallized from ethyl acetate
(1300 mL)-isopropyl alcohol (150 mL) to afford 19 (119.11 g,
1
48%) as a pale yellow crystalline powder. Mp 195-196 °C. H
NMR (CDCl3) δ 1.77 (3H, s), 1.87-2.16 (4H, m), 2.95-3.05 (2H,
m), 3.32-3.41 (2H, m), 4.02 (1H, d, J ) 10.2 Hz), 4.04 (1H, d, J
) 10.2 Hz), 4.18 (1H, J ) 10.2 Hz), 4.36-4.45 (1H, m), 4.49
(1H, d, J ) 10.2 Hz), 6.76 (2H, d, J ) 6.7 Hz), 6.87-6.94 (4H,
m), 7.14 (2H, d, J ) 8.6 Hz), 7.55 (1H, s). [R]2D8 -9.9° (c 1.01,
CHCl3). MS (DI) m/z 535 (M+ + 1). Anal. (C25H25F3N4O6) C, H,
N.
4-[4-(4-Trifluoromethoxyphenoxy)piperidin-1-yl]phenol (28g).
A mixture of 32g (30.10 g, 68.81 mmol) and pyridinium p-
toluenesulfonate (5.20 g, 20.69 mmol) in ethanol (450 mL) was
heated at 70 °C for 24 h. The reaction mixture was allowed to cool
to room temperature and concentrated under reduced pressure.
Saturated sodium hydrogen carbonate aqueous solution (100 mL)
was added to the residue, which was extracted with dichloromethane
(200 mL). The organic layer was washed with brine, dried over
magnesium sulfate, and filtered. The filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (dichloromethane/ethyl acetate ) 10/1) to give 28g
(22.90 g, 94%) as a pale yellow crystalline powder. 1H NMR
(CDCl3) δ 1.88-2.02 (2H, m), 2.06-2.16 (2H, m), 2.92-3.02 (2H,
m), 3.30-3.39 (2H, m), 4.36-4.44 (1H, m), 4.74 (1H, s), 6.71-
6.78 (2H, m), 6.85-6.94 (4H, m), 7.10-7.16 (2H, m).
Other phenol derivatives 28a-f and 28h,i were synthesized by
the same procedure as described for 28g. Compounds 28a-i were
immediately used for the next reaction.
4-(4-Phenoxypiperidin-1-yl)phenol (28a). 1H NMR (CDCl3) δ
1.89-2.03 (2H, m), 2.04-2.18 (2H, m), 2.92-3.02 (2H, m), 3.31-
3.41 (2H, m), 4.39-4.49 (1H, m), 4.92 (1H, s), 6.70-6.78 (2H,
m), 6.84-6.98 (5H, m), 7.24-7.33 (2H, m).
Compounds 3f, 4-11, 13-18, 20, and 21 were prepared by the
same procedure as described for 19.
(R)-2-Methyl-6-nitro-2-phenoxymethyl-2,3-dihydroimidazo-
1
[2,1-b]oxazole (3f). Mp 151-153 °C. H NMR (CDCl3) δ 1.79
(3H, s), 4.03 (1H, d, J ) 10.2 Hz), 4.09 (1H, d, J ) 10.2 Hz), 4.24
(1H, d, J ) 10.1 Hz), 4.50 (1H, d, J ) 10.1 Hz), 6.84 (2H, dd, J
) 1.8 Hz, 8.5 Hz), 7.01 (1H, t, J ) 7.2 Hz), 7.21-7.31 (2H, m),
7.55 (1H, s). MS (DI) m/z 275 (M+). Anal. (C13H13N3O4) C, H, N.
(R)-2-(4-Chlorophenoxymethyl)-2-methyl-6-nitro-2,3-dihy-
droimidazo[2,1-b]oxazole (4). Mp 185-187 °C. 1H NMR (CDCl3)
δ 1.78 (3H, s), 4.04 (1H, d, J ) 3.2 Hz), 4.08 (1H, d, J ) 3.2 Hz),
4.21 (1H, d, J ) 10.1 Hz), 4.49 (1H, d, J ) 10.1 Hz), 6.78 (2H, d,
J ) 9.0 Hz), 7.19-7.29 (2H, m), 7.56 (1H, s). MS (DI) m/z 309
(M+). Anal. (C13H12ClN3O4) C, H, N.
(R)-2-Methyl-2-(4-methylphenoxymethyl)-6-nitro-2,3-dihy-
droimidazo[2,1-b]oxazole (5). Mp 177-179 °C. 1H NMR (CDCl3)
δ 1.78 (3H, s), 2.28 (3H, s), 4.02 (1H, d, J ) 7.2 Hz), 4.06 (1H,
d, J ) 7.2 Hz), 4.20 (1H, d, J ) 10.1 Hz), 4.49 (1H, d, J ) 10.1
Hz), 6.74 (2H, d, J ) 8.3 Hz), 7.08 (2H, d, J ) 8.3 Hz), 7.55 (1H,
s). MS (DI) m/z 289 (M+). Anal. (C14H15N3O4) C, H, N.
4-[4-(4-Chlorophenoxy)piperidin-1-yl]phenol (28b). 1H NMR
(CDCl3) δ 1.87-2.01 (2H, m), 2.04-2.16 (2H, m), 2.91-3.02 (2H,
m), 3.29-3.39 (2H, m), 4.34-4.44 (1H, m), 4.85 (1H, s), 6.71-
6.78 (2H, m), 6.82-6.92 (4H, m), 7.20-7.26 (2H, m).
4-[4-(4-Fluorophenoxy)piperidin-1-yl]phenol (28c). 1H NMR
(CDCl3) δ 1.86-2.00 (2H, m), 2.04-2.16 (2H, m), 2.90-3.00 (2H,
(R)-2-(4-Methoxyphenoxymethyl)-2-methyl-6-nitro-2,3-dihy-
droimidazo[2,1-b]oxazole (6). Mp 179-180 °C. 1H NMR (CDCl3)

Synthesis and Antituberculosis ActiVity
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 26 7859
δ 1.77 (3H, s), 3.76 (3H, s), 4.02 (1H, d, J ) 2.6 Hz), 4.06 (1H,
d, J ) 2.6 Hz), 4.17 (1H, d, J ) 10.2 Hz), 4.50 (1H, d, J ) 10.2
Hz), 6.71-6.86 (4H, m), 7.55 (1H, s). MS (DI) m/z 305 (M+).
Anal. (C14H15N3O5) C, H, N.
J ) 6.2 Hz), 4.04 (1H, d, J ) 6.2 Hz), 4.18 (1H, d, J ) 10.1 Hz),
4.22-4.35 (1H, m), 4.49 (1H, d, J ) 10.1 Hz), 6.71-6.92 (8H,
m), 7.55 (1H, s). MS (DI) m/z 480 (M+). Anal. (C25H28N4O6) C,
H, N.
(R)-2-Methyl-6-nitro-2-(4-trifluoromethylphenoxymethyl)-2,3-
dihydroimidazo[2,1-b]oxazole (7). Mp 188-190 °C. 1H NMR
(CDCl3) δ 1.81 (3H, s), 4.08 (1H, d, J ) 10.3 Hz), 4.18 (1H, d, J
) 10.3 Hz), 4.29 (1H, d, J ) 10.3 Hz), 4.50 (1H, d, J ) 10.3 Hz),
6.93 (2H, d, J ) 8.7 Hz), 7.50-7.59 (3H, m). MS (DI) m/z 343
(M+). Anal. (C14H12F3N3O4) C, H, N.
(R)-2-Methyl-6-nitro-2-(4-trifluoromethoxyphenoxymethyl)-
2,3-dihydroimidazo[2,1-b]oxazole (8). Mp 176-178 °C. 1H NMR
(CDCl3) δ 1.79 (3H, s), 4.06 (1H, d, J ) 6.8 Hz), 4.10 (1H, d, J
) 6.8 Hz), 4.23 (1H, d, J ) 10.1 Hz), 4.49 (1H, d, J ) 10.1 Hz),
6.84 (2H, d, J ) 9.0 Hz), 7.13 (2H, d, J ) 9.0 Hz), 7.56 (1H, s).
MS (DI) m/z 359 (M+). Anal. (C14H12F3N3O5) C, H, N.
(R)-2-Methyl-6-nitro-2-[4-(piperidin-1-yl)phenoxymethyl]-2,3-
dihydroimidazo[2,1-b]oxazole (9). Mp 217-219 °C. 1H NMR
(CDCl3) δ 1.45-1.57 (5H, m), 1.61-1.78 (4H, m), 2.94-3.08 (4H,
m), 4.00 (1H, d, J ) 7.4 Hz), 4.04 (1H, d, J ) 7.4 Hz), 4.17 (1H,
d, J ) 10.1 Hz), 4.49 (1H, d, J ) 10.1 Hz), 6.75 (2H, d, J ) 6.8
Hz), 6.89 (2H, d, J ) 6.8 Hz), 7.54 (1H, s). MS (DI) m/z 358
(M+). Anal. (C18H22N4O4) C, H, N.
(R)-2-Methyl-6-nitro-2-{4-[4-(4-trifluoromethylphenoxy)pip-
eridin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (18).
Mp 179-181 °C. H NMR (CDCl3) δ 1.77 (3H, s), 1.88-2.20
(4H, m), 2.92-3.10 (2H, m), 3.27-3.43 (2H, m), 4.01 (1H, d, J )
5.8 Hz), 4.05 (1H, d, J ) 5.8 Hz), 4.18 (1H, d, J ) 10.2 Hz),
4.43-4.57 (2H, m), 6.78 (2H, d, J ) 6.8 Hz), 6.90 (2H, d, J ) 6.8
Hz), 6.98 (2H, d, J ) 8.6 Hz), 7.47-7.60 (3H, m). MS (DI) m/z
518 (M+). Anal. (C25H25F3N4O5) C, H, N.
1
(R)-2-Methyl-6-nitro-2-{4-[4-(2-trifluoromethoxyphenoxy)pi-
peridin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]ox-
1
azole (20). Mp 152-153 °C. H NMR (CDCl3) δ 1.77 (3H, s),
1.86-2.19 (4H, m), 2.95-3.12 (2H, m), 3.28-3.44 (2H, m), 4.10
(1H, d, J ) 10.2 Hz), 4.04 (1H, d, J ) 10.2 Hz), 4.18 (1H, d, J )
10.2 Hz), 4.42-4.56 (2H, m), 6.78 (2H, dd, J ) 2.3 Hz, 6.9 Hz),
6.83-7.07 (4H, m), 7.14-7.28 (2H, m), 7.55 (1H, s). MS (DI)
m/z 534 (M+). Anal. (C25H25F3N4O6) C, H, N.
(R)-2-Methyl-6-nitro-2-{4-[4-(3-trifluoromethoxyphenoxy)pi-
peridin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]ox-
1
azole (21). Mp 184-186 °C. H NMR (CDCl3) δ 1.77 (3H, s),
(R)-2-Methyl-2-[4-(morpholin-4-yl)phenoxymethyl]-6-nitro-
2,3-dihydroimidazo[2,1-b]oxazole (10). Mp 233-235 °C. 1H NMR
(DMSO-d6) δ 1.67 (3H, s), 2.92-3.00 (4H, m), 3.61-3.71 (4H,
m), 4.08-4.22 (3H, m), 4.36 (1H, d, J ) 10.9 Hz), 6.80 (2H, d, J
) 6.8 Hz), 6.88 (2H, d, J ) 6.8 Hz), 8.15 (1H, s). MS (DI) m/z
360 (M+). Anal. (C17H20N4O5) C, H, N.
(R)-2-Methyl-6-nitro-2-[4-(thiomorpholin-4-yl)phenoxymethyl]-
2,3-dihydroimidazo[2,1-b]oxazole (11). Mp 227-229 °C. 1H NMR
(CDCl3) δ 1.77 (3H, s), 2.69-2.80 (4H, m), 3.31-3.71 (4H, m),
4.01 (1H, d, J ) 5.5 Hz), 4.05 (1H, d, J ) 5.5 Hz), 4.18 (1H, d,
J ) 10.1 Hz), 4.49 (1H, d, J ) 10.1 Hz), 6.77 (2H, d, J ) 6.7 Hz),
6.86 (2H, d, J ) 6.7 Hz), 7.55 (1H, s). MS (DI) m/z 376 (M+).
Anal. (C17H20N4O4S) C, H, N.
1.88-2.17 (4H, m), 2.96-3.06 (2H, m), 3.31-3.41 (2H, m), 4.02
(1H, d, J ) 10.2 Hz), 4.04 (1H, d, J ) 10.2 Hz), 4.18 (1H, d, J )
10.2 Hz), 4.40-4.48 (1H, m), 4.50 (1H, d, J ) 10.2 Hz), 6.74-
6.94 (7H, m), 7.24-7.31 (1H, m), 7.55 (1H, s). MS (DI) m/z 534
(M+). Anal. (C25H25F3N4O6) C, H, N.
(S)-2-Methyl-6-nitro-2-phenoxymethyl-2,3-dihydroimidazo-
[2,1-b]oxazole (3g). This compound was obtained by the same
procedure as described for 19 using (S)-form epoxide 29 instead
1
of 27. Mp 153-155 °C. H NMR (CDCl3) δ 1.79 (3H, s), 4.04
(1H, d, J ) 10.2 Hz), 4.09 (1H, d, J ) 10.2 Hz), 4.24 (1H, d, J )
10.1 Hz), 4.50 (1H, d, J ) 10.1 Hz), 6.83 (2H, dd, J ) 2.0 Hz, 8.6
Hz), 7.01 (1H, t, J ) 7.4 Hz), 7.20-7.31 (2H, m), 7.56 (1H, s).
MS (DI) m/z 275 (M+). Anal. (C13H13N3O4) C, H, N.
(R)-2-Methyl-6-nitro-2-[4-(4-phenoxypiperidin-1-yl)phenoxym-
ethyl]-2,3-dihydroimidazo[2,1-b]oxazole (13). Mp 195-197 °C.
1H NMR (CDCl3) δ 1.77 (3H, s), 1.86-2.18 (4H, m), 2.92-3.08
(2H, m), 3.31-3.47 (2H, m), 4.01 (1H, d, J ) 5.8 Hz), 4.05 (1H,
d, J ) 5.8 Hz), 4.18 (1H, d, J ) 10.2 Hz), 4.37-4.55 (2H, m),
6.78 (2H, dd, J ) 2.2 Hz, 6.8 Hz), 6.84-7.00 (5H, m), 7.20-7.33
(2H, m), 7.55 (1H, s). MS (DI) m/z 450 (M+). Anal. (C24H26N4O5)
C, H, N.
(R)-2-Methyl-6-nitro-2-{4-[(1-oxo-thiomorpholin)-4-yl]phe-
noxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (12). To a solu-
tion of 11 (85 mg, 0.23 mmol) in dichloromethane (5 mL) was
added 70% m-chloroperbenzoic acid (59 mg, 0.24 mmol), and the
resulting mixture was stirred at room temperature for 20 min.
Sodium thiosulfate aqueous solution (10%, 15 mL) was added to
the reaction mixture, which was extracted with dichloromethane
(20 mL). The organic layer was washed with saturated sodium
hydrogen carbonate aqueous solution (15 mL) and brine, dried over
magnesium sulfate, and filtered. The filtrate was concentrated under
reduced pressure. The residue was recrystallized from methanol-
isopropylether to afford 12 (59 mg, 67%) as a colorless crystalline
powder. Mp 198-200 °C. 1H NMR (CDCl3) δ 1.77 (3H, s), 2.82-
2.96 (4H, m), 3.33-3.45 (2H, m), 3.78-3.90 (2H, m), 4.02 (1H,
d, J ) 5.5 Hz), 4.06 (1H, d, J ) 5.5 Hz), 4.20 (1H, d, J ) 10.2
Hz), 4.49 (1H, d, J ) 10.2 Hz), 6.80 (2H, d, J ) 6.8 Hz), 6.91
(2H, d, J ) 6.8 Hz), 7.56 (1H, s). MS (DI) m/z 392 (M+). Anal.
(C17H20N4O5S) C, H, N.
In Vitro Antituberculosis Activity. MICs of test agents against
both drug-susceptible and drug-resistant strains of M. tuberculosis
H37Rv were determined essentially according to the previously
reported method.22 Test drugs were each dissolved in dimethyl
sulfoxide (DMSO), and the solutions were diluted serially with
DMSO in 2-fold dilutions to the desired concentrations. All strains
were grown in Middlebrook 7H9 broth. Stock cultures stored frozen
at -80 °C were diluted and adjusted to approximately 106 CFU/
mL. The bacterial suspension containing about 106 CFU/mL was
spotted onto 7H11 agar plates containing test drugs using a
multipoint inoculator (Sakuma Seisakusho). After cultivation at 37
°C for 14 days, MICs were determined as the minimum concentra-
tions of drugs completely inhibiting visible growth of organism.
In ViWo Efficacy for 10 Days. The basic therapeutic efficacy of
test agents was determined in mouse models of acute bacterial
infection with M. tuberculosis Kurono.10 In brief, the designated
compound was suspended in 5% gum arabic. ICR male mice (Japan
(R)-2-{4-[4-(4-Chlorophenoxy)piperidin-1-yl]phenoxymethyl}-
2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (14). Mp 183-
1
184 °C. H NMR (CDCl3) δ 1.77 (3H, s), 1.84-2.14 (4H, m),
2.92-3.04 (2H, m), 3.29-3.43 (2H, m), 4.01 (1H, d, J ) 6.5 Hz),
4.05 (1H, d, J ) 6.5 Hz), 4.18 (1H, d, J ) 10.2 Hz), 4.33-4.45
(1H, m), 4.49 (1H, d, J ) 10.2 Hz), 6.71-6.92 (6H, m), 7.16-
7.27 (2H, m), 7.55 (1H, s). MS (DI) m/z 484 (M+). Anal. (C24H25-
ClN4O5) C, H, N.
(R)-2-{4-[4-(4-Fluorophenoxy)piperidin-1-yl]phenoxymethyl}-
2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (15). Mp 191-
1
193 °C. H NMR (DMSO-d6) δ 1.59-1.76 (5H, m), 1.92-2.10
(2H, m), 2.80-2.98 (2H, m), 3.24-3.41 (2H, m), 4.10-4.20 (3H,
m), 4.37-4.51 (2H, m), 6.78 (2H, d, J ) 8.6 Hz), 6.90 (2H, d, J
) 8.6 Hz), 6.92-7.12 (4H, m), 8.16 (1H, s). MS (DI) m/z 468
(M+). Anal. (C24H25FN4O5) C, H, N.
(R)-2-Methyl-2-{4-[4-(4-methylphenoxy)piperidin-1-yl]phe-
noxymethyl}-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (16). Mp
1
199-201 °C (decomp.). H NMR (CDCl3) δ 1.77 (3H, s), 1.86-
2.14 (4H, m), 2.29 (3H, s), 2.88-3.04 (2H, m), 3.29-3.45 (2H,
m), 4.00 (1H, d, J ) 6.3 Hz), 4.04 (1H, d, J ) 6.3 Hz), 4.17 (1H,
d, J ) 10.1 Hz), 4.33-4.43 (1H, m), 4.49 (1H, d, J ) 10.1 Hz),
6.71-6.92 (6H, m), 7.08 (2H, d, J ) 8.4 Hz), 7.55 (1H, s). MS
(DI) m/z 464 (M+). Anal. (C25H28N4O5) C, H, N.
(R)-2-{4-[4-(4-Methoxyphenoxy)piperidin-1-yl]phenoxymethyl}-
2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (17). Mp 193-
1
195 °C. H NMR (CDCl3) δ 1.77 (3H, s), 1.82-2.14 (4H, m),
2.86-3.02 (2H, m), 3.31-3.45 (2H, m), 3.77 (3H, s), 4.00 (1H, d,

7860 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 26
Sasaki et al.
SLC) weighing 20-25 g were infected intravenously with 104 CFU
of mycobacteria through a caudal tail vein and treated once daily
at oral doses of 0.5-50 mg/kg for 10 days (n ) 2) starting on the
day after infection. Animals were sacrificed on day 11, ap-
proximately 24 h after administration of the final drug dose. Lungs
were aseptically removed and ground in a contained tissue
homogenizer. The number of viable organisms was determined by
dilution plating on 7H11 agar plate and incubating at 37 °C for 14
days prior to counting. Mean log colony forming units (CFU)
reduction values were calculated from mycobacterial counts of test
groups relative to untreated controls.
In ViWo Efficacy for 28 Days. The designated compound was
suspended in 5% gum arabic. ICR male mice (Japan SLC) weighing
20-25 g were infected intravenously with 104 CFU of mycobacteria
through a caudal tail vein and treated once daily at various oral
doses for 28 days (n ) 6) starting on the day after infection. Animals
were sacrificed on day 29, approximately 24 h after administration
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