Synthesis and antibacterial evaluation of novel 2-[N-Imidoylpyrrolidinyl] carbapenems

Article abstract of DOI:10.1016/S0960-894X(01)00753-3

The synthesis, antibacterial activity and DHP-susceptibility of a series of novel carbapenems, directly linked with heterocyclic moiety are described. Especially, the compounds linked pyrrolidine-carbapenem exhibited to have a good antibacterial activity against Staphylococcus aureus (MRSA) as well as Pseudomonas aeruginosa to maintain a good stability towards DHP-I.

Full text of DOI:10.1016/S0960-894X(01)00753-3

Bioorganic & Medicinal Chemistry Letters 12 (2002) 383–386
Synthesis and Antibacterial Evaluation of Novel
2
-[N-Imidoylpyrrolidinyl] Carbapenems
Kouji Hattori,* Akira Yamada, Satoru Kuroda, Toshiyuki Chiba,
Masayoshi Murata and Kazuo Sakane
Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co. Ltd,
1
-6, Kashima 2-Chome, Yodogawa-Ku, Osaka, Japan
Received 17September 2001; accepted 9 November 2001
Abstract—The synthesis, antibacterial activity and DHP-susceptibility of a series of novel carbapenems, directly linked with het-
erocyclic moiety are described. Especially, the compounds linked pyrrolidine-carbapenem exhibited to have a good antibacterial
activity against Staphylococcus aureus (MRSA) as well as Pseudomonas aeruginosa to maintain a good stability towards DHP-I.
#
2002 Elsevier Science Ltd. All rights reserved.
Introduction
Chemistry
Since the discovery of (+)-thienamycin in the early
1
The synthetic route to the target carbapenems was out-
lined in Scheme 1. Acetyl-azetizine, pyrrolidine, and
piperidine derivatives were prepared from correspond-
ing carboxylic acid derivatives 5 using Meldrum’s acid
1
980s, the carbapenems have attracted considerable
attention as the most promising b-lactam antibiotics
due to their chemical and metabolic stability as well as
2
7
their potent antimicrobial activities. The earliest car-
3
by standard method. The trimethylsilyl enol ether of
bapenems to become available, namely Imipenem 1
4
ketones were formed with trimethylsilyl trifluoro-
methanesulfonate, followed trifrate mediated aldol con-
densation with the acetoxyazetidinone afforded in
and Panipenem 2, possess a non-1-substituted carba-
penem skeleton, as in the original, phenotype carba-
penem, thienamycin. Whilst these compounds have a
broad, potent spectra of antibacterial activity, they are
unstable to the renal enzyme dehydropeptidase-I (DHP-I)
and have a low urinary recovery. Effort to improve the
intrinsic DHP-I stability of the carbapenem skeleton by
introduction of a 1b-methyl substitution has been
8
moderate good yield and regioselectivity. Mono-
bactams 7 were then performed cyclization via the
oxalimides to give 8. Desilylation, followed by a palla-
dium-catalyzed deprotection of both the AOC and allyl
ester produced 9 after purification by HP-20 column
chromatography and lypophilization.
5
exhibited, such as Meropenem. On the other hand, we
have reported the discovery of 2-vinyl carbapenem
derivatives that are remarkably stable toward renal
0
best balance of antibacterial activity. As a continuation
DHP-I, particularly; the 1 -methyl compound 3 had the
6
of these studies, we have carried out the chemical mod-
ification of side chain of 3 to increase antibacterial activ-
ity, especially against methicillin-resistant Staphylococcus
aureus (MRSA). In this paper, we report the novel car-
bapenems 4, directly linked with heterocyclic moiety,
have significantly improved antibacterial activity while
maintaining good stability toward DHP-I (Fig. 1).
*Corresponding author. Tel.:+81-6-390-1220; fax:+81-6-304-5435;
e-mail: kouji_hattori@po.fujisawa.co.jp
Figure 1.
0
960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00753-3

384
K. Hattori et al. / Bioorg. Med. Chem. Lett. 12 (2002) 383–386
Scheme 1.
Scheme 2 was shown the synthetic route to the optically
pure pyrrolidine substituted carbapenem. Dynamic
kinetic resolution in Ru–BINAP catalysed hydrogena-
tion developed by Noyori to give hydroxyethyl pyrroli-
titatively afforded the reductive product 12, which was
converted protection group and subsequent Swern oxi-
dation to give desired ketone 6. The optically pure
ketone 6 was corresponding carbapenem 9 in the same
method. Furthermore, 9 was introduced several kind of
imidoyl group to the pyrrolidine using corresponding
iminoether by standard method.
9
done 11. Purification by recyclization from toluene
provided the optically pure adduct 11 in 76% yield and
ꢀ
9
8% ee. Reduction of 11 with NaBH -BF Et O quan-
4
3
2
Table 1. Biological evaluation of novel N-containing heterocycle carbapenems
Compd
R
1
Staphylococcus Staphylococcus Escherichia coli Proteus vulgaris Ps. auruginosa DHP-I stabilityb
Urinary
recoveryc
(%)
aureus
09P JC-1
aureus 3004a
NIHJ JC-2
IAM 1025
26
human, swern
2
9a
9b
9c
9d
9e
9f
0.050
<0.025
<0.025
<0.025
<0.025
0.050
>100
1.56
12.5
0.78
NT, 0.18
43
59
42
37
46
45
50
100
50
0.39
0.39
0.20
0.39
1.56
25
1.56
0.78
0.39
0.78
1.56
NT, 0.044
0.58, 0.13
0.48, 0.088
0.78, 0.16
NT, 0.020
12.5
6.25
6.25
3.13
100
100
3
1
2
<0.025
<0.025
0.025
50
100
50
0.39
0.78
0.20
1.56
3.1
1.56
3.13
0.78
0.39
0.45, 0.043
1.0, 1.0
NT, NT
61
29
25
: Imipenem
: Panipenem
a
Methicillin-resistant S. aureus (MRSA).
DHP-I susceptibility is given relative to imipenem (IMP).
Recovery (%) in mice after sc administration (20 mg/kg).
b
c

K. Hattori et al. / Bioorg. Med. Chem. Lett. 12 (2002) 383–386
385
Scheme 2.
Biological Activity
nems.10 In spite of this type carbapenem 9a–f not
having a 1b-methyl substituent, it exhibits high sta-
bility to DHP-I and urinary recovery superior to
imipenem. Generally, these compounds in this initial
series were more active against Pseudomonas aeruginosa
Table 1 was shown the vitro antibacterial activity, the
urinary recovery of mice, and stability to human and
swine renal DHP-I of a variety of azetidinyl, pyrroli-
dinyl, and piperidinyl directly substituted carbape-
Table 2. Biological evaluation of novel N-imidoylpyrrolidinyl carbapenems
Compd
R
2
S. aureus
09P JC-1
S. aureus
3004a
E. coli
NIHJ JC-2
P. vulgaris
IAM 1025
Ps. aeruginosa
26
DHP-I stabilityb,
human, swern
Urinary
c
2
recovery (%)
4
4
4
4
4
4
4
4
a
a
b
c
d
e
f
<0.025
25
0.10
0.20
0.20
0.20
0.39
0.10
0.20
0.39
1.56
1.56
0.78
1.56
3.13
1.56
3.13
1.56
0.20
0.78
0.39
0.39
0.78
0.78
0.39
0.39
0.39, 0.15
0.34, 0.084
0.91, 0.078
0.28, 0.084
NT, 0.13
41
44
48
50
52
42
47
43
<0.025
<0.025
<0.025
<0.025
<0.025
<0.025
<0.025
6.25
3.13
12.5
25
6.25
25
0.13, NT
g
h
0.20, NT
6.25
0.14, 0.13
Methicillin-resistant S. aureus (MRSA).
b
c
DHP-I susceptibility is given relative to imipenem (IMP).
Recovery (%) in mice after sc administration (20 mg/kg).

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K. Hattori et al. / Bioorg. Med. Chem. Lett. 12 (2002) 383–386
than the our previous reported compound 3, but were
less active against Proteus vulgaris than 3 and imipenem
References and Notes
(
IMP) 1. Amongst these compounds, pyrrolidinyl car-
1
. Kahan, J. S.; Kahan, F. M.; Goegelman, R.; Currie, S. A.;
bapenems had the best balance of antibacterial activity
and (S)-isomer 9d of the chiral center at C-3 of pyrroli-
dine was slightly improved activity compared to (R)-
isomer 9e.
Jackson, M.; Stapley, E. O.; Miller, A. K.; Hendlin, D.;
Mochales, S.; Hernandez, S.; Woodruff, H. B.; Birnbaum, J. J.
Antibiot. 1979, 32, 1.
2. (a) Clissold, S. P.; Todd, P. A.; Campoli-Richards, D. M.
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2
3
001, 10, 245.
. Miyadera, T.; Sugimura, Y.; Hashimoto, T.; Tanaka, T.;
Introduction of amidine unit was dramatically effect on
antibacterial activity in shown Table 2. All of these
compounds were increased activity against both MRSA
and P. vulgaris and 4a, 4c, 4d, 4g, and 4h were more
active against Ps. aeruginosa than original compound
Iino, K.; Shibata, T.; Sugawara, S. J. Antibiot. 1983, 36, 1034.
. Coulton, S; Hunt, E. In Progress in Medicinal Chemistry;
4
Ellis, G. P., Luscombe, D. K., Eds.; Elsevier: 1996; Vol. 33,
p 99.
5
H. M. Drugs 1995, 50, 7 3.
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mura, T.; Sakane, K. Bioorg. Med. Chem. Lett. 1996, 6, 2705.
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9
d. Especially, best compound 4c was 30-fold more
. Wiseman, L. R.; Wagstaff, A. J.; Brogden, R. N.; Bryson,
active than IMP against MRSA and 4-fold more active
against P. vulgaris. And also these compounds were less
susceptible to DHP-I than IMP and a good stable urin-
ary recovery.
8
. The regio-isomer was produced with less than 5%, which
was easily removed by column chromatograpy.
. (a) Kitamura, M.; Tokunaga, M.; Noyori, R. Tetrahedron:
9
Conclusion
Asymmetry 1990, 1, 1. (b) Yuwasa, Y.; Sotoguchi, T.; Seido,
N. EP Patent 855390, 1998.
In this communication, we have reported directly linked
pyrrolidine-carbapenem was synthesized and found to
have a good antimicrobial spectrum showing activity
against MRSA as well as Ps. aeruginosa, and to main-
tain a good stability toward DHP-I.
1
heart infusion agar incubation at 37 C for 20 h with an
inoculum size of of 10 cfu/mL. DHP-I stability was deter-
mined as the relative rate of hydrolysis compared to the con-
trol compound, imipenem.
0. MICS were determined by the agar dilution method using
ꢁ
6