Synthesis and SAR study of novel 7-(pyridinium-3-yl)-carbonyl imidazo[5,1-b]thiazol-2-yl carbapenems

Article abstract of DOI:10.1016/j.bmc.2006.09.049

A new series of 1β-methyl carbapenems, possessing a 7-substituted imidazo[5,1-b]thiazol-2-yl group directly attached to the C-2 position of the carbapenem nucleus, was synthesized and evaluated for antibacterial activity. These compounds showed potent act

Full text of DOI:10.1016/j.bmc.2006.09.049

Bioorganic & Medicinal Chemistry 15 (2007) 392–402
Synthesis and SAR study of novel 7-(pyridinium-3-yl)-
carbonyl imidazo[5,1-b]thiazol-2-yl carbapenems
Takahisa Maruyama,* Yuko Kano, Yasuo Yamamoto, Mizuyo Kurazono,
Katsuyoshi Iwamatsu, Kunio Atsumi and Eiki Shitara
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd, 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan
Received 9 August 2006; revised 21 September 2006; accepted 22 September 2006
Available online 20 October 2006
Abstract—A new series of 1b-methyl carbapenems, possessing a 7-substituted imidazo[5,1-b]thiazol-2-yl group directly attached to
the C-2 position of the carbapenem nucleus, was synthesized and evaluated for antibacterial activity. These compounds showed
potent activities against Gram-positive bacteria, in particular methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-
resistant Streptococcus pneumoniae (PRSP). They also exhibited potent activity against b-lactamase-negative ampicillin-resistant
Haemophilus influenzae (BLNAR).
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
potent activity against MRSA. In our search for more
potent carbapenems against MRSA, we have synthe-
sized various derivatives of CP5068 with a 7-heterocyclic
carbonyl imidazo[5,1-b]thiazol-2-yl group. Among
them, we found 7-(pyridinium-3-yl)carbonyl imi-
dazo[5,1-b]thiazol-2-yl carbapenems with improved
anti-MRSA activity. Furthermore, they exhibited potent
activity against PRSP and BLNAR, which often cause
serious respiratory tract infections. Herein, we report
the synthesis and structure–activity relationships of
these compounds (Fig. 2).
Recently, the emergence of various types of resistant
bacterial strains has become a serious clinical problem.
In particular, methicillin-resistant Staphylococcus aureus
(MRSA)1 is one of the most serious pathogens causing
nosocomial infections. Only a few drugs such as arbek-
acin, vancomycin (VCM), teicoplanin, linezolid, and
daptomycin are available for MRSA infections and
many types of resistant strains have already been report-
ed against these drugs.2 To overcome this problem, new
anti-MRSA agents are required.
b-Lactams have good bactericidal activity and safety
profiles, but generally they are insufficient against
MRSA due to their low affinity for PBP2a. Nevertheless,
in the last decade, potent anti-MRSA b-lactams with
improved affinity for PBP2a such as cephalosporins3
and carbapenems4 have been found. We have already
reported various anti-MRSA b-lactams such as
CP0467,3a CP6679,5 CP0569,6 and CP50687 (Fig. 1).
Among them, CP5068 possesses a 6,7-disubstituted imi-
dazo[5,1-b]thiazolium-2-yl group directly attached to the
C-2 position of the carbapenem nucleus, and it shows
2. Chemistry
First, we introduced various heterocyclic carbonyl
groups at the C-7 position of the imidazo[5,1-b]thiazole
ring. The synthesis of 7g possessing 3-pyridyl ketone is
illustrated in Scheme 1 as an example. Selective
iodination at the C-7 position of imidazo[5,1-b]thiazole
1 gave compound 2. Grignard reaction of 2 with
3-pyridinecarboxyaldehyde followed by oxidation with
manganese (IV) oxide afforded 7-(3-pyridylcarbon-
yl)imidazo[5,1-b]thiazole 3. A tri-n-butyl stannyl group
was introduced at the C-2 position of 3 by n-Bu3SnCl
and LHMDS. The Stille coupling reaction of 4 and a tri-
fluoromethanesulfonate of 5 afforded the key intermedi-
ate 6. After removal of the 4-nitrobenzyl group of 6,
compound 7g was obtained as a lyophilized amorphous
powder. Related compounds 7a–j were prepared
Keywords: Carbapenem; Imidazo[5,1-b]thiazole; 7-Heterocyclic car-
bonyl imidazo[5,1-b]thiazol-2-yl group; Anti-MRSA activity; MRSA;
PRSP; BLNAR.
*
Corresponding author. Tel.: +81 455412521; fax: +81 455410667;
e-mail: takahisa_maruyama@meiji.co.jp
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.09.049

T. Maruyama et al. / Bioorg. Med. Chem. 15 (2007) 392–402
393
Figure 1. Our previous compounds.
Figure 2. Our strategy for anti-MRSA carbapenems.
Scheme 1. Synthesis of 7g. Reagents and conditions: (a) NIS, CH2Cl2, rt, 70%; (b) i—MeMgBr, 3-pyridinecarboxyaldehyde, THF, 0 ꢁC; ii—MnO2,
CH2Cl2, rt, 74%; (c) n-Bu3SnCl, LHMDS, THF, À40 ꢁC, 65%; (d) i—DIPEA, Tf2O, CH3CN, À35 ꢁC; ii—4, Pd2(dba)3, P(2-furyl)3, ZnCl2, NMP,
50 ꢁC, 78%; (e) H2, 10% Pd/C, THF–1/15 M phosphate buffer, rt, 40%.
similarly from 2 and the corresponding heterocyclic
aldehydes (Fig. 3).
the desired compound 9b. The other quaternary salts
9a and 9c–j were obtained similarly (Fig. 4).
Synthesis of 9b from the key intermediate 6 is shown in
Scheme 2. Reaction with iodoacetamide converted 6 to a
quaternary pyridinium salt 8 without quaternization at
the C-6 position of imidazo[5,1-b]thiazole. Finally,
deprotection of the 4-nitrobenzyl group of 8 afforded
We also introduced various substituents at the C-5 posi-
tion of the imidazo[5,1-b]thiazole ring of 9b. Synthesis of
14a–g is illustrated in Scheme 3. These substituents were
introduced by acylation of aminomethylthiazole 10 with
the corresponding acid anhydride or acyl chloride,
Figure 3. Structures of compounds 7a–f, 7h–j.

394
T. Maruyama et al. / Bioorg. Med. Chem. 15 (2007) 392–402
Scheme 2. Synthesis of 9b. Reagents and conditions: (a) ICH2CONH2, acetone, 35 ꢁC, 93%; (b) H2, 10% Pd/C, THF–H2O, rt, 43%.
Figure 4. Structures of compound 9a, 9c–j.
Scheme 3. Synthesis of 14a–g. Reagents and conditions: (a) i—(R2CO)2O or R2COCl, Et3N, CH2Cl2, 0 ꢁC; ii—POCl3, toluene, 100 ꢁC; (b) NIS,
CH2Cl2, rt; (c) NCS, ClCH2CH2Cl, rt; (d) EtMgBr, CH3SSO2CH3, THF, 0 ꢁC.
followed by cyclization with POCl3. Iodination of 11a–e
proceeded readily with N-iodosuccinimide. A chlorine
atom (12f) was introduced by the reaction of 7-iodoim-
idazo[5,1-b]thiazole 2 and N-chlorosuccinimide. Grig-
nard reaction of 5,7-diiodoimidazo[5,1-b]thiazole 13
and methyl methanethiosulfonate resulted in selective
methylsulfanylation at the C-5 position (12g). 5-Substi-
tuted-7-iodoimidazo[5,1-b]thiazoles 12a–g were convert-
ed to the desired compounds 14a–g, respectively, by the
same method as employed for 9b.
3. Biological activity
Table 1 shows the antibacterial activities of the novel
7-heterocyclic carbonyl imidazo[5,1-b]thiazolyl carba-

T. Maruyama et al. / Bioorg. Med. Chem. 15 (2007) 392–402
Table 1. Antibacterial activities of 7a–j, CP5068, and VCM (MIC; lg/mL)
395
Test organism
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
CP5068 VCM
S. aureus 209P JC-1
S. aureus M-126a
50.008 0.016 0.016 0.008 50.008 50.008 50.008 50.008 50.008 0.008 0.008
0.5
1
1
4
1
4
1
4
1
4
0.031
4
0.031
4
1
0.063
4
0.016
2
0.031
8
1
4
S. aureus M-126HRb
4
2
0.5
S. pneumoniae KK133c 0.063
0.063 0.125 0.063 0.125
0.031
1
0.031
1
0.031
2
0.031
4
0.125 0.031
E. coli NIHJ JC-2
K. pneumoniae GN69
M. catarrhlis W-0500
H. influenzae 870d
0.125
0.125
0.031
0.125
0.063 0.125 0.063
0.125 0.25 0.125
2
4
4
8
0.016
0.031
>128
>128
64
2
2
2
8
0.031 0.063 0.031 0.016
0.125 0.25
0.016
0.063
0.016
0.031
0.031
0.031
0.031
0.125
0.016 0.031
0.125 0.5
0.063 0.125
>128
a MRSA.
b Carbapenem-resistant MRSA.
c PRSP.
d BLNAR.
Table 2. Antibacterial activities of 9a–j (MIC; lg/mL)
Test organism
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
7g
S. aureus 209P JC-1
S. aureus M-126a
50.008
1
50.008
0.5
50.008
1
50.008
0.5
0.031
2
0.016
2
0.016
1
0.016
1
50.008
1
50.008
1
50.008
1
S. aureus M-126HRb
S. pneumoniae KK133c
E. coli NIHJ JC-2
K. pneumoniae GN69
M. catarrhlis W-0500
H. influenzae 870d
4
2
2
4
8
8
4
4
4
4
4
0.031
0.063
0.063
0.031
0.063
0.031
0.031
0.063
0.016
0.063
0.031
0.031
0.063
0.016
0.063
0.016
0.5
0.063
0.031
0.063
0.031
0.063
0.063
0.031
0.063
0.031
0.063
0.063
0.125
0.25
0.031
0.063
0.063
0.125
0.25
0.031
0.063
0.031
0.5
0.5
0.031
0.125
0.25
0.031
0.063
0.031
1
1
2
0.063
0.063
0.016
0.063
0.016
0.031
a MRSA.
b Carbapenem-resistant MRSA.
c PRSP.
d BLNAR.
penems 7a–j. All these compounds had strong anti-
MRSA, and they could be divided into two groups
according to their antibacterial activity spectra. Com-
pounds 7a–d, possessing a pyrrolidine or piperidine ring,
showed potent antibacterial activities against both
Gram-positive and Gram-negative bacteria. The other
group, 7e–j possessing an aromatic heterocycle, showed
excellent anti-G(+) activities, but insufficient activities
against G(À)-bacteria such as Escherichia coli and K.
pneumoniae. The activities against G(À)-bacteria ap-
peared to be dependent on the lipophilicity and the size
of the heterocycle; compounds with larger substituents
(7i and 7j) showed weaker activities. Among them, 7i
showed the best anti-MRSA activity, however, we were
not satisfied with its activities against G(À)-bacteria,
especially BLNAR. Anti-MRSA and anti-PRSP activity
of 7g was as strong as CP5068 and its anti-BLNAR
activity was clearly stronger than CP5068. Considering
the balance of the activities against not only MRSA
but also PRSP and BLNAR, we chose 7g for further
derivatization.
The antibacterial activities of the quaternary pyridinium
salts 9a–j are shown in Table 2. Introduction of carbox-
ylic acid (9e) and its ethyl ester (9f) weakened the MRSA
activity compared with 7g. A carbonyl group (9g, 9h),
sulfonyl group (9i), and basic moiety (9j) also failed to
improve anti-MRSA activity, however, amide moieties
(9b and 9c) strengthened the anti-MRSA activity. Fur-
thermore, all quaternized derivatives showed improved
Table 3. Antibacterial activities of 14a–g (MIC; lg/mL)
Test organism
14a
14b
14c
14d
14e
0.031
14f
14g
9b
S. aureus 209P JC-1
S. aureus M-126a
0.016
1
0.016
1
0.016
0.5
0.031
2
0.008
0.5
0.008
0.5
50.008
0.5
2
S. aureus M-126HRb
S. pneumoniae KK133c
E. coli NIHJ JC-2
K. pneumoniae GN69
M. catarrhlis W-0500
H. influenzae 870d
4
4
2
4
8
0.063
2
1
2
0.031
0.25
0.5
0.031
2
0.031
4
0.063
8
0.031
1
0.016
4
0.031
0.031
0.063
0.016
0.063
16
16
0.063
0.125
4
4
4
2
4
0.008
0.063
0.031
0.063
0.016
0.031
0.031
0.063
0.016
0.063
0.016
0.031
a MRSA.
b Carbapenem-resistant MRSA.
c PRSP.
d BLNAR.

396
T. Maruyama et al. / Bioorg. Med. Chem. 15 (2007) 392–402
activity against G(À)-bacteria such as E. coli and
K. pneumoniae compared to 7g. Among them, we fo-
cused on 9b because it showed the strongest anti-MRSA
activity.
Disk Agar-N (Nissui) supplemented with hemin
(5 lg/ml), NAD (15 lg/ml), and horse blood (5%). The
final inoculum was adjusted to approximately 104
CFU per spot. After incubation for 18 h at 35 ꢁC, the
MIC was defined as the lowest drug concentration that
prevented viable growth.
In order to examine the SAR of 9b, we further synthe-
sized various derivatives. Table 3 shows the antibacterial
activities of 14a–g, which have various substituents at
the C-5 position of the imidazo[5,1-b]thiazole ring. Sub-
stitution at this position weakened the antibacterial
activities against G(À)-bacteria, especially E. coli and
K. pneumoniae, possibly because of increased lipophilic-
ity. A similar tendency was seen in 7e–7j. Compounds
14a–f did not exhibit improved anti-MRSA activity
compared to 9b, either. Introduction of a methylthio
group (14g) decreased water solubility, however, in-
creased anti-MRSA activity. It was interesting informa-
tion for the SAR study of anti-MRSA carbapenems,
because the anti-MRSA activity of our former com-
pound CP5068 was also strengthened by the introduc-
5.3. 7-Iodoimidazo[5,1-b]thiazole (2)
To a solution of 31.0 g of imidazo[5,1-b]thiazole (1)
in 550 ml of 1,2-dichloroethane, 56.3 g of N-iodosuc-
cinimide was added at 5 ꢁC, and the mixture was
stirred at room temperature for 17 h. The solution
was washed with aqueous Na2S2O3 and water, dried
over anhydrous magnesium sulfate, and then concen-
trated under reduced pressure. The residue was puri-
fied by silica gel column chromatography (CH2Cl2/
hexane/AcOEt = 1:1:1) to give 39.9 g of the title
compound.
tion of
a
methylthio group to the imidazo[5,1-
NMR (CDCl3) d: 6.89 (1 H, d, J = 4.2 Hz), 7.50 (1H, d,
J = 4.2 Hz), 7.96 (1H, s); FABHRMS calcd for
C5H4N2SI [(M+H)+]: 250.9140, found: 250.9138.
b]thiazole ring.7
4. Conclusion
5.4. 7-[(Pyridin-3-yl)carbonyl]imidazo[5,1-b]thiazole (3)
In order to find a novel b-lactam with potent anti-
MRSA activity, we introduced various heterocycles at
the C-7 position of the imidazo[5,1-b]thiazole ring
directly attached to the C-2 position of the carbapenem
nucleus. Among them, we focused on 7g with the pyri-
dine ring because of its balanced antibacterial activity
and prepared various derivatives of 7g. As a result, we
successfully found several compounds such as 9b and
14g, which showed potent anti-MRSA activity superior
to that of VCM, and also exhibited strong activities
against PRSP and BLNAR.8
A solution of 2.50 g of 7-iodoimidazo[5,1-b]thiazole
(2) in 50 ml of dry THF was cooled in an ice bath,
and 11.3 ml of a 0.93 M methylmagnesium bromide/
THF solution was added to the cooled solution.
Twenty
min
later,
3-pyridine-carboxaldehyde
(1.04 ml) was added thereto, and the mixture was stir-
red at that temperature for 40 min and then at room
temperature for 4 h. Water was added to the reaction
solution, and the whole was extracted with CH2Cl2
five times. The organic layer was dried over anhy-
drous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel
column chromatography (CH2Cl2/MeOH = 20:1) to
give 1.93 g of 7-[(pyridin-3-yl)hydroxymethyl]imi-
dazo[5,1-b]thiazole. Manganese dioxide (1.0 g) was
added to a solution of 1.02 g of 7-[(pyridin-3-yl)hy-
5. Experimental
5.1. General methods
droxymethyl]imidazo[5,1-b]thiazole
in
40 ml
of
1H NMR spectra were measured with a JEOL JNM-
LA400 NMR spectrometer at 400 MHz in CDCl3,
DMSO-d6, or D2O. TMS (0 ppm) in CDCl3 and
DMSO-d6 or HDO (4.80 ppm) in D2O were used as
internal reference standards. Mass spectra were ob-
tained on a JEOL JMS-700 mass spectrometer for FAB-
MS and FABHRMS. Purity of final compounds was
evaluated by HPLC analysis on a HITACHI L-7000
HPLC system (Column: Nacalai tesque Cosmosil
5C18-PREP) 4.6 · 150 mm, detection UV: 315 nm, flow
rate: 1.0 ml/min, eluent: 1/15 M phosphate buffer (pH
6.8)/methanol = 70:30 or 60:40. Silica gel flash column
chromatography was performed on Wako-gel C-300
and reversed-phase column chromatography was per-
formed on Nacalai tesque Cosmosil 40 C18-PREP.
CH2Cl2, and the mixture was stirred at room temper-
ature for 5 h. The reaction solution was filtered and
washed with CH2Cl2. The filtrate was concentrated
under reduced pressure to give 1.10 g of 7-[(pyridin-
3-yl)carbonyl]imidazo[5,1-b]thiazole (3) as a yellow
solid.
NMR (CDCl3) d: 7.20 (1 H, d, J = 4.2 Hz), 7.4–7.5 (1H,
m), 7.63 (1H, d, J = 4.2 Hz), 8.10 (1H, s), 8.75–8.85 (2H,
m), 9.7–9.75 (1H, m); FABHRMS calcd for C11H8N3OS
[(M+H)+]: 230.0388, found: 230.0387.
5.5. 7-(Pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imi-
dazo[5,1-b]thiazole (4)
Tri-n-butylstannyl chloride (0.841 ml) and 2.95 ml of a
1.0 N lithium bis(trimethylsilyl)amide/THF solution
were added to a solution of 520 mg of 3 in 25 ml THF
at À60 ꢁC, and the mixture was stirred for 20 min. The
temperature of the mixture was raised to À50 ꢁC, and
5.2. Antimicrobal activity in vitro
Minimum inhibitory concentration (MIC) was deter-
mined by the agar dilution method using Sensitivity

T. Maruyama et al. / Bioorg. Med. Chem. 15 (2007) 392–402
397
1.0 ml of a 1.0 N lithium bis(trimethylsilyl)amide/THF
solution was added thereto. The mixture was stirred
for 30 min. The temperature of the mixture was raised
to À40 ꢁC, and 0.5 ml of a 1.0 N lithium bis(trimethylsi-
lyl)amide/THF solution was added thereto. The mixture
was stirred for 30 min. Aqueous NH4Cl was added to
the reaction solution, and the whole was extracted with
AcOEt, followed by washing with brine. The organic
layer was dried over anhydrous magnesium sulfate.
The solvent was then removed by evaporation, and the
residue was purified by short column chromatography
on silica gel (hexane/AcOEt = 2:1 to AcOEt only) to
give 712 mg of the title compound. Compound 4 was
employed for the next Stille coupling reaction immedi-
ately due to its instability.
5.7. (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-
(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carba-
pen-2-em-3-carboxylic acid (7g)
Compound 6 (129 mg) was dissolved in 6.7 ml THF and
6.7 ml of 1/15 M sodium phosphate buffer (pH 6.8), and
130 mg of 10% Pd–C was added to the solution. The air
in the reaction vessel was replaced with hydrogen, and
the mixture was stirred at room temperature for 2 h.
The catalyst was removed by filtration, followed by
washing with water. The filtrate was washed with AcOEt
and then concentrated under reduced pressure to a vol-
ume of about 2 ml. The concentrate was purified by col-
umn chromatography on Cosmosil 40 C18-PREP (5%
aqueous MeOH solution) to give 41 mg of the title
compound.
NMR (CDCl3) d: 0.92 (9H, t, J = 7.2 Hz), 1.2–1.3 (6H,
m), 1.3–1.45 (6H, m), 1.55–1.65 (6H, m), 7.36 (1H, s),
7.4–7.45 (1H, m), 8.03 (1H, s), 8.75–8.85 (2H, m),
9.65–9.7 (1H, m).
NMR (D2O) d: 1.15 (3H, d, J = 7.2 Hz), 1.33 (3H, d,
J = 6.3 Hz), 3.45–3.6 (2H, m), 4.2–4.35 (2H, m), 7.35–
7.45 (1H, m), 7.91 (1H, s), 8.07 (1H, s), 8.25–8.3 (1H,
m), 8.5–8.55 (1H, m), 8.85–8.9 (1H, m); FABHRMS
calcd for C21H19N4O5S [(M+H)+]: 439.1076, found:
439.1073; HPLC analysis: 96.8% (Area %).
5.6. 4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-
methyl-2-[7-(pyridin-3-yl)carbonyl imidazo[5,1-b]thiazol-
2-yl]-1-carbapen-2-em-3-carboxylate (6)
5.8. (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-
((2S)-pyrrolidin-2-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-
1-carbapen-2-em-3-carboxylic acid (7a)
Under an argon atmosphere at À30 ꢁC, N,N-diisopro-
pylethylamine (0.343 ml) was added dropwise to a
solution of 474 mg of compound 5 in 13 ml of dry
CH3CN, and 0.218 ml of anhydrous trifluoromethane-
sulfonic acid was then added dropwise thereto. The
mixture was stirred at the same temperature for
30 min. AcOEt (30 ml) was then added thereto, fol-
lowed by washing with brine, a mixed solution com-
posed of brine and 1 N HCl, a mixed solution
composed of brine and saturated aqueous NaHCO3,
and brine. The organic layer was dried over anhy-
drous magnesium sulfate and removed by evaporation.
The residue was dissolved in 6 ml of dry N-meth-
ylpyrrolidinone. Tri-2-furylphosphine (37 mg), 343 mg
of zinc chloride, 37 mg of tris (dibenzylideneacetone)
dipalladium (0), and 712 mg of 4 were added to the
above solution, and the mixture was stirred at 5 ꢁC
for 2 h. AcOEt (30 ml) and 15 ml of aqueous NaH-
CO3 were added to the reaction solution, and the mix-
ture was stirred. Insolubles were removed by filtration.
The organic layer was washed three times with 20 ml
of semisaturated brine and dried over anhydrous mag-
nesium sulfate. The solvent was removed by evapora-
tion, and the residue was purified by silica gel column
chromatography (CH2Cl2/MeOH = 20:1–10:1) to give
388 mg of the title compound 6.
The title compound (7a) was obtained in 13% yield from
7-iodoimidazo[5,1-b]thiazole (2) and (S)-2-formyl-1-(4-
nitrobenzyloxycarbonyl)pyrrolidine by a procedure
similar to that employed for the preparation of 3–7g.
NMR (D2O) d: 1.24 (3H, d, J = 6.9 Hz), 1.35 (3H, d,
J = 6.3 Hz), 2.5–2.2 (3H, m), 2.6–2.75 (1H, m), 3.4–
3.65 (4H, m), 4.2–4.4 (2H, m), 5.05–5.2 (1H, m), 8.05
(1H, s), 8.17 (1H, s); FABHRMS calcd for
C20H23N4O5S [(M+H)+]: 431.1389, found: 431.1385;
HPLC analysis: 98.9% (Area %).
5.9. (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-2-[7-((2S,4R)-
4-hydroxypyrrolidin-2-yl)carbonylimidazo[5,1-b]thiazol-
2-yl]-1-methyl-1-carbapen-2-em-3-carboxylic acid (7b)
The title compound (7b) was obtained in 10% yield from
7-iodoimidazo[5,1-b]thiazole (2) and (2S,4R)-2-formyl-
4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbon-
yl)pyrrolidine by a procedure similar to that employed
for the preparation of 3–7g.
NMR (D2O) d: 1.24 (3H, d, J = 6.9 Hz), 1.32 (3H, d,
J = 6.3 Hz), 2.1–2.25 (1H, m), 2.65–2.75 (1H, m), 3.4–
3.6 (4H, m), 4.2–4.35 (2H, m), 4.7–4.8 (1H, m), 5.2–5.3
(1H, m), 8.00 (1H, s), 8.08 (1H, s); FABHRMS calcd
for C20H23N4O6S [(M+H)+]: 447.1338, found:
447.1335; HPLC analysis: 98.0% (Area %).
NMR (DMSO-d6) d: 1.19 (3 H, d, J = 6.0 Hz), 1.24 (3H,
d, J = 7.5 Hz), 3.45 (1H, dd, J1 = 6.3 Hz, J2 = 3.0 Hz),
3.7–3.85 (1H, m), 4.0–4.1 (1H, m), 4.68 (1H, dd,
J1 = 9.9 Hz, J2 = 3.0 Hz), 5.17 (1H, d, J = 5.4 Hz), 5.41
(1H, d, J = 13.8 Hz), 5.55 (1H, d, J = 13.7 Hz), 7.55–
7.65 (1H, m), 7.74 (2H, d, J = 9.0 Hz), 8.22 (2H, d,
J = 9.0 Hz), 8.47 (1H, s), 8.64 (1H, s), 8.65–8.75 (1H,
m), 8.75–8.8 (1H, m), 9.55–9.6 (1H, m); FABHRMS
calcd for C28H24N5O7S [(M+H)+]: 574.1396, found:
574.1395.
5.10. (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-
(piperidin-2-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-car-
bapen-2-em-3-carboxylic acid (7c)
The title compound (7c) was obtained in 0.6% yield
from 7-iodoimidazo[5,1-b]thiazole (2) and 1-(4-nitroben-

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T. Maruyama et al. / Bioorg. Med. Chem. 15 (2007) 392–402
zyloxycarbonyl)piperidine-2-carboxaldehyde by a pro-
cedure similar to that employed for the preparation of
3–7g.
5.14. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-
methyl-2-[7-(pyridin-4- yl)carbonylimidazo[5,1-b]thiazol-
2-yl]-1-carbapen-2-em-3-carboxylate (7h)
NMR (DMSO-d6) d: 1.13 (3H, d, J = 6.9 Hz), 1.17
(3H, d, J = 6.3 Hz), 1.36–1.92 (6H, m), 2.3–2.45
(1H, m), 2.91–3.16 (2H, m), 3.32–3.48 (1H, m),
3.88–4.02 (1H, m), 4.02–4.16 (1H, m), 4.52–4.66
(1H, m), 5.03 (1H, m), 8.19 (1H, s), 8.23 (1H, s);
FABHRMS calcd for C21H25N4O5S [(M+H)+]:
445.1546, found: 445.1548; HPLC analysis: 97.3%
(Area %).
The title compound (7h) was obtained in 11% yield from
7-iodoimidazo[5,1-b]thiazole (2) and pyridine-4-carbox-
aldehyde by a procedure similar to that employed for
the preparation of 3–7g.
NMR (D2O) d: 1.16 (3H, d, J = 6.3 Hz), 1.34 (3H, d,
J = 6.3 Hz), 3.4–3.6 (2H, m), 4.2–4.35 (2H, m), 7.7–7.8
(2H, m), 7.96 (1H, s), 8.11 (1H, s), 8.5–8.6 (2H, m);
FABHRMS calcd for C21H18N4NaO5S [(M+H)+]:
461.0896, found: 461.0893; HPLC analysis: 97.2%
(Area %).
5.11. (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-
(piperidin-4-yl)carbonylimidazo[5,1-b] thiazol-2-yl]-1-car-
bapen-2-em-3-carboxylic acid (7d)
5.15. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-
methyl-2-[7-(quinolin-3- yl)carbonylimidazo[5,1-b]thiazol-
2-yl]-1-carbapen-2-em-3-carboxylate (7i)
The title compound (7d) was obtained in 15% yield from
7-iodoimidazo[5,1-b]thiazole (2) and 1-(4-nitrobenzyl-
oxycarbonyl)piperidine-4-carboxaldehyde by a proce-
dure similar to that employed for the preparation
of 3–7g.
The title compound (7i) was obtained in 1.5% yield from
7-iodoimidazo[5,1-b]thiazole (2) and quinoline-3-alde-
hyde by a procedure similar to that employed for the
preparation of 3–7g.
NMR (D2O) d: 1.21 (3H, d, J = 6.9 Hz), 1.33 (3H, d,
J = 6.3 Hz), 1.8–2.0 (2H, m), 2.05–2.2 (2H, m), 3.1–
3.25 (2H, m), 3.25–3.6 (5H, m), 4.2–4.35 (2H, m), 7.92
(1H, s), 8.02 (1H, s); FABHRMS calcd for
C21H25N4O5S [(M+H)+]: 445.1546, found: 445.1538;
HPLC analysis: 99.6% (Area %).
NMR (DMSO-d6) d: 1.09 (3H, d, J = 7.3 Hz), 1.11 (3H,
d, J = 6.4 Hz), 3.14 (1H, m), 3.47 (1H, m), 3.95 (1H, m),
4.09 (1H, dd, J1 = 9.8 Hz, J2 = 2.9 Hz), 5.02 (1 H, br s),
7.71 (1H, t, J = 6.8 Hz), 7.90 (1H, t, J = 8.5 Hz), 8.11
(1H, d, J = 9.0 Hz), 8.21 (1H, d, J = 7.8 Hz), 8.31 (1H,
s), 8.37 (1H, s), 9.47 (1H, s), 9.73 (1H, s); FABHRMS
calcd for C25H20N4NaO5S [(M+H)+]: 511.1052, found:
511.1047; HPLC analysis: 97.7% (Area %).
5.12. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-
methyl-2-[7-(thiophen-2-yl)carbonylimidazo[5,1-b]thiazol-
2-yl]-1-carbapen-2-em-3-carboxylate (7e)
The title compound (7e) was obtained in 26% yield from
7-iodoimidazo[5,1-b]thiazole (2) and thiophene-2-car-
boxaldehyde by a procedure similar to that employed
for the preparation of 3–7g.
5.16. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-
methyl-2-[7-(1-methylindol-3- yl)carbonylimidazo[5,1-
b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (7j)
The title compound (7j) was obtained in 20% yield from
7-iodoimidazo[5,1-b]thiazole (2) and 1-methylindole-3-
formyl by a procedure similar to that employed for the
preparation of 3–7g.
NMR (D2O) d: 1.16 (3H, d, J = 7.3 Hz), 1.36 (3H, d,
J = 6.3 Hz), 3.42–3.51 (2H, m), 4.21–4.33 (2H, m), 7.08
(1H, m), 7.75 (1H, m), 7.83 (1H, s), 7.89 (1H, s), 8.02
(1H, m); FABHRMS calcd for C20H17N3NaO5S2
[(M+H)+]: 466.0507, found: 466.0510; HPLC analysis:
97.7% (Area %).
NMR (DMSO-d6) d: 1.09 (3H, d, J = 7.2 Hz), 1.12 (3H,
d, J = 6.4 Hz), 3.03–3.08 (1H, m), 3.31–3.37 (1H, m),
3.79–3.94 (4H, m), 3.98–4.03 (1H, m), 4.94 (1H, d,
J = 5.2 Hz), 7.14–7.24 (2H, m), 7.48 (1H, m), 8.20 (2H,
s), 8.36 (1H, m), 9.05 (1H, s); FABHRMS calcd for
C25H22N4NaO5S [(M+H)+]: 513.1209, found: 513.1205;
HPLC analysis: 99.2% (Area %).
5.13. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-
methyl-2-[7-(thiazol-5- yl)carbonylimidazo[5,1-b]thiazol-
2-yl]-1-carbapen-2-em-3-carboxylate (7f)
The title compound (7f) was obtained in 19% yield from
7-iodoimidazo[5,1-b]thiazole (2) and thiazole-5-carbox-
aldehyde by a procedure similar to that employed for
the preparation of 3–7g.
5.17. 4-Nitrobenzyl (1S,5R,6S)-2-[7-(1-carbamoylmethyl-
pyridinium-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-
((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-car-
boxylate iodide (8)
NMR (D2O) d: 1.21 (3H, d, J = 7.3 Hz), 1.37
(3H, d, J = 6.3 Hz), 3.52 (1H, dd, J1 = 6.1 Hz,
J2 = 2.9 Hz), 3.58 (1H, m), 4.29–4.37 (2H, m),
7.92 (1H, s), 8.05 (1H, s), 8.60 (1H, s), 9.03
(1H, s); FABHRMS calcd for C19H16N4NaO5S2
[(M+H)+]: 467.0460, found: 467.0541; HPLC anal-
ysis: 97.9% (Area %).
Compound 6 (105.5 mg) was suspended in 2 ml of aceto-
nitrile to prepare
(340 mg) was added to the suspension, and the mixture
was stirred at 50 ꢁC for 6 h. The reaction solution was
concentrated under reduced pressure, and 5 ml of ethyl
acetate was added to the concentrate. Insolubles were
a suspension. 2-Iodoacetamide

T. Maruyama et al. / Bioorg. Med. Chem. 15 (2007) 392–402
399
collected by filtration to give 157 mg of the title com-
pound 8.
m), 9.52 (1H, s), 9.78 (1H, s); FABHRMS calcd for
C23H25N6O7S2 [(M+H)+]: 561.1221, found: 561.1223;
HPLC analysis: 96.0% (Area %).
NMR (DMSO-d6) d: 1.20 (3H, d, J = 6.3 Hz), 1.25 (3H,
d, J = 7.2 Hz), 3.47 (1H, dd, J1 = 6.0 Hz, J2 = 3.3 Hz),
3.75–3.85 (1H, m), 4.0–4.1 (1H, m), 4.38 (1H, dd,
J1 = 10.2 Hz, J2 = 3.3 Hz), 5.42 (1H, d, J = 13.8 Hz),
5.5–5.6 (3H, m), 7.7–7.8 (3H, m), 8.08 (1H, br s), 8.22
(2H, d, J = 8.7 Hz), 8.3–8.4 (1H, m), 8.57 (1H, s), 8.69
(1H, s), 9.15–9.2 (1H, m), 9.55–9.6 (1H, m), 9.76 (1H,
s); FABHRMS calcd for C38H27N6O8S [(MÀI)+]:
631.1611, found: 631.1600.
5.21. (1S,5R,6S)-2-[7-(1-Benzylpyridinium-3-yl)carbony-
limidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-
methyl-1-carbapen-2-em-3-carboxylate (intramolecular
salt) (9d)
The title compound (9d) was obtained in 7.8% yield
from compound 6 and benzyl bromide by a procedure
similar to that employed for the preparation of 8–9b.
5.18. (1S,5R,6S)-2-[7-(1-Carbamoylmethylpyridinium-
3-yl)-carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-
hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
(intramolecular salt) (9b)
NMR (D2O) d: 1.0–1.15 (3H, m), 1.30 (3H, d,
J = 6.0 Hz), 3.35–3.5 (2H, m), 4.1–4.3 (2H, m), 5.86
(2H, s), 7.4–7.6 (5H, m), 7.85–8.1 (3H, m), 8.8–9.0
(2H, m), 9.6–9.7 (1H, m); FABHRMS calcd for
C28H25N4O5S [(M+H)+]: 529.1540, found: 529.1544;
HPLC analysis: 94.3% (Area %).
The title compound (9b) (1.62 g) was obtained from
4.43 g of compound 8 by a procedure similar to that em-
ployed for the preparation of 7g.
5.22. (1S,5R,6S)-2-[7-(1-Carboxymethyl-pyridinium-3-
yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxy-
ethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (intra-
molecular salt) (9e)
NMR (D2O) d: 1.16 (3H, d, J = 7.5 Hz), 1.33 (3H, d,
J = 6.0 Hz), 3.4–3.55 (2H, m), 4.15–4.35 (2H, m), 5.65
(2H, s), 7.89 (1H, s), 8.03 (1H, s), 8.1–8.2 (1H, m),
8.85–8.95 (1H, m), 9.15–9.2 (1H, m), 9.58 (1H, s); FAB-
HRMS calcd for C23H22N5O6S [(M+H)+]: 496.1285,
found: 496.1277; HPLC analysis: 97.6% (Area %).
The title compound (9e) was obtained in 16% yield from
compound 6 and 4-nitrobenzyloxycarbonylmethyl triflu-
oromethanesulfonate by a procedure similar to that em-
ployed for the preparation of 8–9b.
5.19. (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-
(1-methylpyridinium-3-yl)carbonylimidazo[5,1-b]-thiazol-
2-yl]-1-carbapen-2-em-3-carboxylate (intramolecular salt)
(9a)
NMR (D2O) d: 1.18 (3H, d, J = 7.3 Hz), 1.35 (3H, d,
J = 6.3 Hz), 3.55 (1H, m), 3.64 (1H, m), 4.27–4.37 (2H,
m), 5.39 (2H, s), 8.15 (1H, s), 8.24 (1H, m), 8.29 (1H,
s), 8.97 (1H, m), 9.25 (1H, m), 9.67 (1H, s); FABHRMS
calcd for C23H21N4O7S [(M+H)+]: 497.1125, found:
497.1129; HPLC analysis: 97.3% (Area %).
The title compound (9a) was obtained in 19% yield from
compound 6 and methyl trifluoromethanesulfonate by a
procedure similar to that employed for the preparation
of 8–9b.
5.23. (1S,5R,6S)-2-[7-(1-Ethoxycarbonylmethyl-pyridin-
ium-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-
hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
(intramolecular salt) (9f)
NMR (D2O) d: 1.13 (3H, d, J = 7.1 Hz), 1.35 (3H, d,
J = 6.3 Hz), 3.48–3.56 (2H, m), 4.23 (1H, dd,
J1 = 9.3 Hz, J2 = 2.7 Hz), 4.29 (1H, m), 4.55 (3H, s),
8.02 (1H, s), 8.15 (1H, s), 8.18 (1H, s), 8.98 (1H, s),
9.17 (1H, s), 9.66 (1H, s); FABHRMS calcd for
C22H21N4O5S [(M+H)+]: 453.1227, found: 453.1232;
HPLC analysis: 95.4% (Area %).
The title compound (9f) was obtained in 13% yield from
compound 6 and ethoxycarbonylmethyl bromide by a
procedure similar to that employed for the preparation
of 8–9b.
5.20. (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-
[1-(2- sulfamoylaminoethyl)pyridinium-3-yl]carbonylimi-
dazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate
(intramolecular salt) (9c)
NMR (DMSO-d6) d: 1.03–1.25 (9H, m), 3.02–3.10 (1H,
m), 3.33–3.48 (1H, m), 3.82–3.94 (1H, m), 3.95–4.05
(1H, m), 4.19 (2H, t, J = 7.6 Hz), 4.95 (1H, m), 5.71
(2H, s), 8.22 (1H, s), 8.30–8.36 (2H, m), 9.11 (1H, m),
9.59 (1H, m), 9.75 (1H, s); FABHRMS calcd for
C25H25N4O7S [(M+H)+]: 525.1438, found: 525.1439;
HPLC analysis: 97.6% (Area %).
The title compound (9c) was obtained in 28% yield from
compound 6 and 2-(4-nitrobenzyloxycarbonyl-amin-
osulfonyl)aminoethyl trifluoromethanesulfonate by a
procedure similar to that employed for the preparation
of 8–9b.
5.24. (1S,5R,6S)-2-[7-(1-Acetoxymethyl-pyridinium-3-
yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxy-
ethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (intra-
molecular salt) (9g)
NMR (DMSO-d6) d: 1.14–1.21 (6H, m), 3.16 (1H, dd,
J1 = 6.0 Hz, J2 = 2.6 Hz), 3.42–3.57 (3H, m), 3.95 (1H,
m), 4.09 (1H, dd, J1 = 9.5 Hz, J2 = 2.7 Hz), 4.84 (2H,
m), 5.07 (1H, d, J = 4.2 Hz), 6.80 (2H, s), 7.29 (1H, br
s), 8.27 (1H, s), 8.32 (1H, m), 8.35 (1H, s), 9.14 (1H,
The title compound (9g) was obtained in 30% yield from
compound 6 and dichloroacetone by a procedure similar
to that employed for the preparation of 8–9b.

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T. Maruyama et al. / Bioorg. Med. Chem. 15 (2007) 392–402
NMR (D2O) d: 1.05–1.38 (6H, m), 2.44 (3H, s), 3.31–3.50
(1H, m), 4.02–4.28 (2H, m), 5.83 (2H, m), 7.87 (1H, s),
7.95–8.05 (2H, m), 8.90 (1H, m), 9.14 (1H, m), 9.58 (1H,
s); FABHRMS calcd for C24H23N4O6S [(M+H)+]:
495.1333, found: 495.1339; HPLC analysis: 96.1% (Area %).
room temperature. The mixture was stirred for 1 h, then
washed with aqueous NaHCO3, dried over anhydrous
magnesium sulfate, and concentrated under reduced
pressure. To the residue, 50 ml of toluene and 23.0 ml
POCl3 were added and the mixture was stirred at
100 ꢁC for 1 h. After having been quenched with aque-
ous K2CO3, the mixture was extracted with CH2Cl2
three times. The organic layer was washed with aqueous
NaCl, dried over anhydrous magnesium sulfate, and
evaporated to give 6.00 g of the title compound.
5.25. (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-
(1- trifluoroacetoxymethyl-pyridinium-3-yl)carbonylimi-
dazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate
(intramolecular salt) (9h)
The title compound (9h) was obtained in 17% yield from
compound 6 and 3-bromo-1,1,1-trifluoroacetone by a
procedure similar to that employed for the preparation
of 8–9b; HPLC analysis: 97.4% (Area %).
NMR (CDCl3) d: 2.57 (3 H, s), 6.77 (1H, d, J = 4.2 Hz),
6.94 (1H, s), 7.20 (1H, d, J = 4.2 Hz), MS (EI) m/z :138
(M+).
5.29. 7-Iodo-5-methylimidazo[5,1-b]thiazole (12a)
NMR (DMSO-d6) d: 1.10–1.28 (6H, m), 3.35–3.50 (1H,
m), 3.60–3.76 (1H, m), 3.90–4.08 (1H, m), 4.20–4.30
(1H, m), 5.04–5.11 (2H, m), 6.89 (1H, s), 7.97 (1H, m),
8.48 (1H, s), 8.81 (1H, m), 9.72 (1H, m), 10.61 (1H, s);
FABHRMS calcd for C24H20F3N4O6S [(M+H)+]:
549.1050, found: 549.1043.
To a solution of 1.41 g of 5-methylimidazo[5,1-b]thia-
zole (11a) in 40 ml of 1,2-dichloroethane, 2.30 g of
N-iodosuccinimide was added, and the mixture was stir-
red at room temperature for 3.5 h. The solution was
washed with aqueous Na2S2O3 and water, dried over
anhydrous magnesium sulfate, and then concentrated
under the reduced pressure. The obtained residue was
employed for the next step without further purification.
5.26. (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-2-[7-[1-[2-
(methanesulfonyl)ethyl]pyridinium-3-yl]carbonylimi-
dazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-
carboxylate (intramolecular salt) (9i)
NMR (CDCl3) d: 2.59 (3H, s), 6.92 (1H, d, J = 4.2 Hz),
7.30 (1H, d, J = 4.2 Hz).
The title compound (9i) was obtained in 32% yield from
compound 6 and 2-(methanesulfonyl)ethyl trifluorome-
thanesulfonate by a procedure similar to that employed
for the preparation of 8–9b.
The other 5-substituted-7-iodoimidazo[5,1-b]thiazoles
(12b–e) were prepared by a procedure similar to that em-
ployed for the synthesis of 11a and 12a.
NMR (D2O)
d
(HOD = 4.65 ppm): 1.19 (3H, d,
5.30. 5-Ethyl-7-iodoimidazo[5,1-b]thiazole (12b)
J = 7.3 Hz), 1.32 (3H, d, J = 6.4 Hz), 3.29 (3H, s), 3.43–
3.54 (2H, m), 4.16–4.31 (4H, m), 5.34 (2H, t, J = 6.1 Hz),
7.98 (1H, s), 8.02 (1H, s), 8.17–8.24 (1H, m), 9.12–9.17
(1H, m), 9.21–9.27 (1H, m), 9.80 (1H, s); FABHRMS
calcd for C24H25N4O7S2 [(M+H)+]: 545.1159, found:
545.1155; HPLC analysis: 95.2% (Area %).
The title compound (12b) was obtained in 41% yield
from compound 10.
NMR (CDCl3) d: 1.36 (3H, t, J = 7.7 Hz), 2.91 (2H, q,
J = 7.7 Hz), 6.83 (1H, d, J = 4.1 Hz), 7.32 (1H, d,
J = 4.1 Hz).
5.27. (1S,5R,6S)-2-[7-[1-[2-(N,N-Dimethylamino)eth-
yl]pyridinium-3-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-6-
((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-car-
boxylate (intramolecular salt) (9j)
5.31. 5-Cyclopropyl-7-iodoimidazo[5,1-b]thiazole (12c)
The title compound (12c) was obtained in 28% yield
from compound 10.
The title compound (9j) was obtained in 17% yield from
compound 6 and 2-(N,N-dimethylamino)ethyl trifluo-
romethanesulfonate by a procedure similar to that em-
ployed for the preparation of 8–9b.
NMR (CDCl3) d: 1.09–1.25 (4H, m), 2.05–2.12 (4H, m),
6.82 (1H, d, J = 4.2 Hz), 7.35 (1H, d, J = 4.2 Hz).
5.32. 7-Iodo-5-methoxymethylimidazo[5,1-b]thiazole
(12d)
NMR (DMSO-d6) d: 1.10–1.25 (6H, m), 2.21 (6H, s),
2.77–2.84 (2H, m), 3.10–3.22 (1H, m), 3.42–3.53 (1H,
m), 3.88–4.01 (1H, m), 4.05–4.16 (1H, m), 4.76–4.88
(2H, m), 5.02 (1H, m), 8.25–8.35 (2H, m), 8.39 (1H, s),
9.12 (1H, m), 9.48 (1H, m), 9.80 (1H, s); FABHRMS
calcd for C25H28N5O5S [(M+H)+]: 510.1806, found:
510.1810; HPLC analysis: 71.7% (Area %).
The title compound (12d) was obtained in 12% yield
from compound 10.
NMR (CDCl3) d: 3.35 (3H, s), 4.71 (2H, s), 6.87 (1H, d,
J = 4.1 Hz), 7.59 (1H, d, J = 4.1 Hz).
5.28. 5-Methylimidazo[5,1-b]thiazole (11a)
5.33. 7-Iodo-5-(morpholin-1-yl)imidazo[5,1-b]thiazole (12e)
To a solution of 5.70 g of 2-aminomethylthiazole (10) in
60 ml CH2Cl2, 7.10 ml of acetic anhydride was added at
The title compound (12e) was obtained in 15% yield
from compound 10.

T. Maruyama et al. / Bioorg. Med. Chem. 15 (2007) 392–402
401
NMR (CDCl3) d: 3.18 (4H, m), 3.84 (4H, m), 6.74 (1H,
d, J = 4.2 Hz), 7.25 (1H, d, J = 4.2 Hz).
5.37. (1S,5R,6S)-2-[7-(1-Carbamoylmethylpyridinium-3-
yl)carbonyl-5-ethylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-
hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
(intramolecular salt) (14b)
5.34. 5-Chloro-7-iodoimidazo[5,1-b]thiazole (12f)
To a solution of 1.49 g of 7-iodoimidazo[5,1-b]thiazole
(2) in 30 ml of 1,2-dichloroethane, 801 mg of N-chlo-
rosuccinimide was added at room temperature, and
the mixture was stirred at room temperature for
18 h. Further N-chlorosuccinimide (795 mg) was added
and the mixture was stirred for another 3 days. The
solution was washed with aqueous NaCl twice, dried
over anhydrous magnesium sulfate, and then concen-
trated under reduced pressure. The residue was puri-
fied by silica gel short chromatography (AcOEt) to
give 1.53 g of the title compound. The obtained title
compound was employed for the next step without
further purification.
The title compound (14b) was obtained in 7.5% yield
from compound 12b.
NMR (D2O) d: 1.10 (3H, d, J = 6.9 Hz), 1.24 (3H, t,
J = 7.7 Hz), 1.32 (3H, d, J = 6.3 Hz), 2.71–2.77 (2H,
m), 3.40–3.45 (2H, m), 4.14–4.30 (2H, m), 5.62 (2H, s),
7.74 (1H, s), 8.06–8.13 (1H, m), 8.88 (1H, d,
J = 6.0 Hz), 9.23 (1H, d, J = 8.2 Hz), 9.53 (1H, s); FAB-
HRMS calcd for C25H26N5O6S [(M+H)+]: 524.1598,
found: 524.1593; HPLC analysis: 87.4% (Area %).
5.38. (1S,5R,6S)-2-[7-(1-Carbamoylmethylpyridinium-3-
yl)carbonyl-5-cyclopropylimidazo[5,1-b]thiazol-2-yl]-6-
((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-car-
boxylate (intramolecular salt) (14c)
NMR (CDCl3) d: 6.93 (1H, d, J = 4.2 Hz), 7.38 (1H, d,
J = 4.2 Hz).
The title compound (14c) was obtained in 28% yield
from compound 12c.
5.35. 7-Iodo-5-methylthioimidazo[5,1-b]thiazole (12g)
A solution of 2.05 g of 5,7-diiodoimidazo[5,1-b]thia-
zole (13) in 30 ml of dry THF was cooled in ice
bath, and 6.43 ml of a 0.89 M ethylmagnesium bro-
mide/THF solution was added. Fifteen min later,
methylthiomethanesulfonate (0.617 ml) was added
thereto, and the mixture was stirred at room tem-
perature for 30 min. Further methylthiomethanesulf-
onate (0.150 ml) was added and the mixture was
stirred for 1 h. Aqueous NH4Cl and AcOEt were
added to the reaction solution. The organic layer
was washed with aqueous NaCl, dried over anhy-
drous magnesium sulfate, and then concentrated un-
der reduced pressure. Recrystallization of the residue
(CH2Cl2/hexane) gave 1.54 g of the title compound
(12g).
NMR (DMSO-d6) d: 0.95–1.18 (10H, m), 3.05–3.12 (1H,
m), 3.42–3.58 (1H, m), 3.82–3.94 (1H, m), 3.98–4.08
(1H, m), 4.98 (1H, m), 5.47 (2H, s), 7.69 (1H, br s),
8.06 (1H, br s), 8.21–8.26 (1H, m), 8.33 (1H, s), 9.01
(1H, m), 9.44 (1H, m), 9.63 (1H, s); FABHRMS calcd
for C26H26N5O6S [(M+H)+]: 536.1598, found:536.1602;
HPLC analysis: 98.0% (Area %).
5.39. (1S,5R,6S)-2-[7-(1-Carbamoylmethylpyridinium-3-
yl)carbonyl-5-methoxymethylimidazo[5,1-b]thiazol-2-yl]-
6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-
carboxylate (intramolecular salt) (14d)
The title compound (14d) was obtained in 6.5% yield
from compound 12d.
NMR (CDCl3) d: 2.55 (3H, s), 6.89 (1H, d, J = 4.2 Hz),
7.50 (1H, d, J = 4.2 Hz), MS (EI) m/z: 296 (M+).
NMR (D2O) d: 1.23 (3H, d, J = 7.1 Hz), 1.34 (3H, d,
J = 6.3 Hz), 3.47 (3H, s), 3.50–3.62 (2H, m), 4.26–4.32
(2H, m), 4.76 (2H, s), 5.67 (2H, s), 8.01 (1H, s), 8.20–
8.25 (1H, m), 8.97 (1H, d, J = 5.8 Hz), 9.32 (1H, d,
J = 8.0 Hz), 9.66 (1 H, s); FABHRMS calcd for
C25H26N5O7S [(M+H)+]: 540.1547, found: 540.1545;
HPLC analysis: 97.1% (Area %).
Compounds 14a–g were obtained from the correspond-
ing 5-substituted-7-iodoimidazo[5,1-b]thiazoles 12a–g
by a similar procedure to that adopted in the prepara-
tion of 3–6 and 8–9b.
5.36. (1S,5R,6S)-2-[7-(1-Carbamoylmethylpyridinium-3-
yl)carbonyl-5-methylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-
1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxyl-
ate (intramolecular salt) (14a)
5.40. (1S,5R,6S)-2-[7-(1-Carbamoylmethylpyridinium-3-
yl)carbonyl-5-(morpholin-1-yl)imidazo[5,1-b]thiazol-2-yl]-
6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-
carboxylate (intramolecular salt) (14e)
The title compound (14a) was obtained in 25% yield
from compound 12a.
The title compound (14e) was obtained in 10% yield
from compound 12e.
NMR (D2O) d: 1.17 (3H, d, J = 7.1 Hz), 1.32 (3H, d,
J = 6.3 Hz), 2.53 (3H, s), 3.42–3.52 (2H, m), 4.19–4.32
(2H, m), 5.65 (2H, s), 7.83 (1H, s), 8.14–8.20 (1H, m),
8.91-8.96 (1H, m), 9.19–9.25 (1H, m), 9.54 (1H, s);
FABHRMS calcd for C24H24N5O6S [(M+H)+]:
510.1442, found: 510.1443; HPLC analysis: 96.4%
(Area %).
NMR (DMSO-d6) d: 1.09 (3H, d, J = 7.2 Hz), 1.16 (3H,
d, J = 6.4 Hz), 3.09–3.18 (1H, m), 3.18–3.31 (4H, m),
3.62–3.88 (5H, m), 3.90–4.01 (1H, m), 4.03–4.12 (1H,
m), 5.03 (1H, d, J = 5.2 Hz), 5.55 (1H, d, J = 15.8 Hz),
5.71 (1H, d, J = 15.8 Hz), 7.72 (1H, s), 8.07 (1H, s),
8.26–8.34 (2H, m), 9.08 (1H, m), 9.44 (1H, m), 9.82
(1H, s); FABHRMS calcd for C27H29N6O7S

402
T. Maruyama et al. / Bioorg. Med. Chem. 15 (2007) 392–402
[(M+H)+]: 581.1813, found: 581.1816; HPLC analysis:
97.1% (Area %).
2. (a) Woodford, N. Clin. Microbiol. Infect. 2005, 11, 2; (b)
Mangili, A.; Bica, I.; Snydman, D. R.; Hamer, D. H. Infect.
Dis. 2005, 40, 1058.
3. (a) Tsushima, M.; Iwamatsu, K.; Tamura, A.; Shibahara, S.
Bioorg. Med. Chem. 1998, 6, 1009; (b) Spronger, D. M.;
Luh, B.; Bronson, J. J. Bioorg. Med. Chem. Lett. 2001, 11,
797.
5.41. (1S,5R,6S)-2-[7-(1-Carbamoylmethylpyridinium-3-
yl)carbonyl-5-chloroimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-
hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
(intramolecular salt) (14f)
4. (a) Ratcliffe, R. W.; Wilkening, R. R.; Wildonger, K. J.;
Waddell, S. T.; Santorelli, G. M.; Parker, D. L., Jr.;
Morgan, J. D.; Blizzard, T. A.; Hammond, M. L.; Heck, J.
V.; Huber, J.; Kohler, J.; Dorso, K. L.; St. Rose, E.;
Sundelhof, J. G.; May, W. J.; Hammond, G. G. Bioorg.
Med. Chem. Lett. 1999, 9, 679; (b) Ohtake, N.; Imamura,
H.; Jona, H.; Kiyonaga, H.; Shimizu, A.; Moriya, M.; Sato,
H.; Nakano, M.; Ushijima, R.; Nakagawa, S. Bioorg. Med.
Chem. 1997, 5, 1089; (c) Shinagawa, H.; Yamaga, H.;
Houchigai, H.; Sumita, Y.; Sunagawa, M. Bioorg. Med.
Chem. 1998, 6, 601.
5. (a) Atsumi, K.; Iwamatsu, K.; Umemura, K.; Kudo, T.;
Tsushima, M.; Sato, Y.; Shiokawa, S.; Takizawa, H.,
Kano, Y.; Tamura, A.; Omoto, S. Abstract of Papers, 35th
Interscience Conference on Antimicrobial Agents and
Chemotherapy, San Fransisco CA; American Society for
Microbiology: Washington, DC, 1995; Abstract F2272; (b)
Tsushima, M.; Iwamatsu, K.; Umemura, E.; Kudo, K.;
Sato, Y.; Shiokawa, S.; Takizawa, H.; Kano, Y.; Kobay-
ashi, K.; Ida, T.; Tamura, A.; Atsumi, K. S. Bioorg. Med.
Chem. 2000, 8, 2781.
The title compound (14f) was obtained in 10% yield
from compound 12f.
NMR (D2O) d: 1.04 (3H, d, J = 6.5 Hz), 1.28 (3H, d,
J = 6.1 Hz), 3.20–3.38 (2H, m), 4.06 (1H, m), 4.20 (1H,
m), 5.54 (2H, s), 7.57 (1H, s), 7.97 (1H, m), 8.81 (1H,
m), 9.06 (1H, m), 9.29 (1H, s); FABHRMS calcd for
C23H21ClN5O6S [(M+H)+]: 530.0896, found: 530.0905;
HPLC analysis: 97.5% (Area %).
5.42. (1S,5R,6S)-2-[7-(1-Carbamoylmethylpyridinium-3-
yl)-carbonyl-5-methylthioimidazo[5,1-b]thiazol-2-yl]-6-
((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-car-
boxylate (intramolecular salt) (14g)
The title compound (14g) was obtained in 3.7% yield
from compound 12g.
6. Aihara, K.; Kano, Y.; Shiokawa, S.; Sasaki, T.; Setsu, F.;
Sambongi, Y.; Ishii, M.; Tohyama, K.; Ida, T.; Tamura, A.;
Atsumi, K.; Iwamatsu, K. Bioorg. Med. Chem. 2003, 11,
3475.
7. Shitara, E.; Sasaki, T.; Yamamoto, Y.; Kano, Y.;
Maruyama, T.; Kitagawa, H.; Toyooka, Y.; Aihara,
K.; Atsumi, K.; Yamada, K.; Tohyama, K.; Matsuh-
isa, E.; Hiranuma, T.; Iwamatsu. K, Abstract of
Papers, 40th Interscience Conference on Antimicrobial
Agents and Chemotherapy, Toronto Canada; American
Society for Microbiology: Washington, DC, 2000;
Abstract F1236.
NMR (DMSO-d6) d: 1.13 (3H, d, J = 6.8 Hz), 1.19 (3H,
d, J = 6.1 Hz), 2.67 (3H, s), 3.15 (1H, dd, J1 = 6.8 Hz,
J2 = 2.7 Hz), 3.66 (1H, m), 3.97 (1H, m), 4.10 (1H, dd,
J1 = 9.3 Hz, J2 = 2.7 Hz), 5.07 (1H, d, J = 5.1 Hz), 5.60
(1H, d, J = 15.7 Hz), 5.83 (1H, d, J = 15.7 Hz), 7.20
(1H, s), 7.74 (1H, s), 8.34 (1H, m), 8.45 (1H, s), 9.14
(1H, m), 9.50 (1H, m), 9.87 (1H, s); FABHRMS calcd
for C24H24N5O6S2 [(M+H)+]: 542.1163, found:
542.1159; HPLC analysis: 95.6% (Area %).
8. We performed detailed in vitro and in vivo evaluations
of 9b. For an in vitro antibacterial property of 9b, see:
Kurazono, M.; Ida, T.; Yamada, K.; Hirai, Y.; Maruy-
ama, T.; Shitara, E.; Yonezawa, M. Antimicrob. Agents
Chemother. 2004, 48, 2831; For a therapeutic effect of 9b
on Endocarditis caused by MRSA, see: Nagura, J.;
Kijima, K.; Kurazono, M.; Takahata, S.; Sugano, T.;
Tanaka, Y.; Hirai, Y.; Yamada, K.; Shitara, E.;
Yonezawa, M. Antimicrob. Agents Chemother. 2004, 48,
2831.
Acknowledgments
We are grateful to Dr. Ida for the biological study and
to Miss Miki for measurement of mass spectra.
References and notes
1. Jovens, M. P. Br. Med. J. 1961, 1, 124.