Antibacterial oxazolidinone analogues having a N-hydroxyacetyl-substituted seven-membered [1,2,5]triazepane or [1,2,5]oxadiazepane C-ring unit

Article abstract of DOI:10.1016/j.ejmech.2013.03.003

We synthesized a series of oxazolidinone analogues bearing a N-hydroxyacetyl-substituted [1,2,5]triazepane or [1,2,5]oxadiazepane C-ring unit as homologues of an earlier drug candidate, eperezolid. Several of these compounds exhibited potent in vitro antibacterial activities towards not only Gram-positive, but also Gram-negative and linezolid-resistant pathogens. Compounds 21a and 21b, bearing a thiocarbamate side chain, showed high in vivo activity against methicillin-resistant Staphylococcus aureus SR3637, together with a promising safety profile in terms of weak inhibition of monoamine oxidase and cytochrome P450 isozymes.

Full text of DOI:10.1016/j.ejmech.2013.03.003

European Journal of Medicinal Chemistry 63 (2013) 811e825
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Antibacterial oxazolidinone analogues having a N-hydroxyacetyl-
substituted seven-membered [1,2,5]triazepane or [1,2,5]oxadiazepane
C-ring unit
,
a
a
b
b
Hideyuki Suzuki a , Iwao Utsunomiya , Koichi Shudo , Norio Fukuhara , Tsutomu Iwaki ,
*
Tatsuro Yasukata c
a Research Foundation Itsuu Laboratory, 2-28-10 Tamagawa, Setagaya-ku, Tokyo 158-0094, Japan
b Medicinal Research Laboratories, Shionogi & Co., Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan
c Chemical Development Center, CMC Development Laboratories, Shionogi & Co., Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We synthesized a series of oxazolidinone analogues bearing a N-hydroxyacetyl-substituted [1,2,5]tri-
azepane or [1,2,5]oxadiazepane C-ring unit as homologues of an earlier drug candidate, eperezolid.
Several of these compounds exhibited potent in vitro antibacterial activities towards not only Gram-
positive, but also Gram-negative and linezolid-resistant pathogens. Compounds 21a and 21b, bearing
a thiocarbamate side chain, showed high in vivo activity against methicillin-resistant Staphylococcus
aureus SR3637, together with a promising safety profile in terms of weak inhibition of monoamine ox-
idase and cytochrome P450 isozymes.
Received 10 December 2012
Received in revised form
27 February 2013
Accepted 1 March 2013
Available online 14 March 2013
Keywords:
Antibacterial
Ó 2013 Elsevier Masson SAS. All rights reserved.
Oxazolidinone
[1,2,5]Triazepane
[1,2,5]Oxadiazepane
1. Introduction
favourable balance of lipophilicity and hydrophilicity has led to
their utilization as partial structural units for improvement of
Linezolid (1) is a new, completely synthetic class of antibiotic
belonging to the oxazolidinone family, and is used for the treatment
of serious infections caused by Gram-positive bacteria, such as
bioavailability or water-solubility of various lead compounds in
medicinal-chemical research [41]. However, we were interested in
developing a novel scaffold with favourable chemical and phar-
maceutical properties for drug development. This led us to consider
the seven-membered heterocycles [1,2,5]triazepane and [1,2,5]
oxadiazepane as possible substitutes for the six-membered het-
erocycles morpholine in 1 and piperazine in 2. Little work has been
done on the synthesis of derivatives of these seven-membered
heterocycles [42], and their potential as pharmacophores remains
unexplored. Herein we report the synthesis and evaluation of a
series of oxazolidinones in which the piperazine ring of 2 is
replaced with [1,2,5]triazepane or [1,2,5]oxadiazepane [43].
methicillin-resistant
Staphylococcus
aureus
(MRSA)
and
vancomycin-resistant Enterococcus faecalis (VRE) [1,2]. Though
linezolid was the first member of the oxazolidinone family to be
approved by the US Food and Drug Administration (FDA), eper-
ezolid (2) [3] was also a potent drug candidate, developed in par-
allel with 1 (Fig. 1). Indeed, 2 exhibited more potent in vitro
antibacterial activity and a better in vivo therapeutic effect than 1,
but concerns about its safety profile and pharmacokinetics in
humans led to the selection of 1 as the preferred candidate for
clinical application [4]. The oxazolidinone antibacterials 1 and 2
contain a six-membered saturated heterocycle (morpholine or
piperazine, respectively) as the C-ring unit. Morpholine or pipera-
zine moieties have been incorporated in a variety of recently re-
ported pharmacologically active compounds [5e40], and their
2. Results and discussion
2.1. Chemistry
First of all, we planned to synthesize the title oxazolidinone
analogues, in which the C-ring unit was changed to [1,2,5]tri-
azepane or [1,2,5]oxadiazepane bearing a hydroxyacetyl functional
group. The remaining structure was configured as follows, based
* Corresponding author.
E-mail address: hsuzuki@itsuu.or.jp (H. Suzuki).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.03.003

812
H. Suzuki et al. / European Journal of Medicinal Chemistry 63 (2013) 811e825
Compound 1a or 1b was treated with [1,2,5]triazepane-1-
O
F
carboxylic acid tert-butyl ester [43] or [1,2,5]oxadiazepane-2-car
boxylic acid tert-butyl ester [43] in the presence of diisopropyle-
thylamine to afford seven-membered heterocycles 2aec, respec-
tively. Reduction of the nitro group in 2 to an amino group by
catalytic hydrogenation, followed by protection of the amino group
with benzyloxycarbonyl (Cbz) gave compounds 3aec. The carba-
mates 3aec were then subjected to cyclization to obtain oxazoli-
dinones 4aec, respectively. The hydroxyl groups in 4aec were
converted to azide using a standard method, and the azide was
further transformed to amine, affording 6aec. The acetamidation of
[1,2,5]triazepanes 6a and 6b, followed by deprotection of the Cbz
group, afforded the oxazolidinone precursors 7a and 7b bearing the
acetamide side chain unit. Acetamidation of [1,2,5]oxadiazepane
6c, followed by deprotection of tert-butoxycarbonyl (Boc) group,
gave oxazolidinone precursor 7c. Catalytic hydrogenation of 5a and
5b afforded amines 8a and 8b, which were treated with ethyl
dithioacetate in the presence of triethylamine to afford oxazolidi-
none precursors 9a and 9b bearing a thioamide side chain unit. For
the synthesis of the oxazolidinone precursor bearing thio-
carbamate, we changed the protective Cbz group to a trifluoroacetyl
O
H
N
X
N
N
Me
O
Linezolid (1) X = O
Eperazolid (2) X = NC(=O)CH2OH
Fig. 1. Representative oxazolidinone antibacterial agents.
upon abundant related research. Two kinds of aromatic structures,
3-fluorophenyl or 3,5-difluorophenyl were selected as the B-ring
aromatic unit [44]. As the side chain moiety at the C-5 position on
the A-ring, we employed conventional acetamide [45], thio-
acetamide [46], thiocarbamate [47], [1,2,3]triazole [48], or iso-
xazolylaminomethyl [49]. The synthesis of our oxazolidinone
intermediates is outlined in Schemes 1 and 2. Cyclization reaction
to the seven-membered carbocycle was performed at the first stage
of the synthetic process. Commercially available 3,4-
difluoronitrobenzene (1a) or 3,4,5-trifluoronitrobenzene (1b) was
used as a starting material for all our oxazolidinone analogues.
O
F
F
F
F
a
b,c
d
Y
N
Y
N
Y
N
O
F
NO2
N
NO2
N
NHCbz
N
N
OH
Boc
Boc
Boc
X
X
X
X
1a: X = H
1b: X = F
2a: X = H, Y = NH (77%)
2b: X = F, Y = NH (83%)
2c: X = F, Y = O (80%)
3a: X = H, Y = NCbz (95%)
3b: X = F, Y = NCbz (98%)
3c: X = F, Y = O (85%)
4a: X = H, Y = NCbz (93%)
4b: X = F, Y = NCbz (81%)
4c: X = F, Y = O (87%)
O
O
F
X
F
O
F
e,f
g
h,i
Y
N
O
N
Y
N
O
Y
HN
O
H
N
N
N
N
N
N
N
N
N
NH2
Me
Boc
Boc
X
X
O
5a: X = H, Y = NCbz (100%)
5b: X = F, Y = NCbz (100%)
5c: X = F, Y = O (99%)
6a: X = H, Y = NCbz (99%)
6b: X = F, Y = NCbz (99%)
6c: X = F, Y = O (100%)
7a: X = H, Y = NBoc (96%)
7b: X = F, Y = NBoc (97%)
7c: X = F, Y = O (71%)
O
O
F
F
j
k
Y
N
O
Y
HN
O
H
N
5a,5b
8a,8b,6c
N
N
N
NH2
N
Me
Boc
X
X
S
9a: X = H, Y = NBoc (80%)
9b: X = F, Y = NBoc (95%)
9c: X = F, Y = O (71%)
8a: X = H, Y = NH (87%)
8b: X = F, Y = NH (87%)
O
N
F
O
O
F
F
X
l,m
n,o
p
Y
N
O
Y
N
O
Y
N
O
N
N
4a,4b
N
N
N
N
N
NH2
OH
N
Boc
Boc
Boc
X
X
10a: X = H, Y = NC(=O)CF3 (95%)
10b: X = F, Y = NC(=O)CF3 (85%)
11a: X = H, Y = NC(=O)CF3 (99%)
11b: X = F, Y = NC(=O)CF3 (91%)
12a: X = H, Y = NNC(=O)CF3 (92%)
12b: X = F, Y = NNC(=O)CF3 (92%)
O
O
F
F
q,r
s
Y
N
O
Y
HN
O
H
N
H
N
12a,12b,6c
N
N
N
N
OMe
OMe
Boc
X
X
S
S
13a: X = H, Y = NC(=O)CF3 (93%)
13b: X = F, Y = NC(=O)CF3 (90%)
13c: X = F, Y = O (89%)
14a: X = H, Y = NBoc (96%)
14b: X = F, Y = NBoc (94%)
14c: X = F, Y = O (98%)
a
Reagents: (a) [1,2,5]triazepane-1-carboxylic acid t-butylester (for 2a and 2b) or [1,2,5]oxadiazepane-2-carboxylic acid
t-butylester (for 2c), i-Pr2NEt; (b) 10%Pd/C, H2; (c) CbzCl, Na2CO3; (d) n-BuLi, (R)-glycidylbutyrate; (e) MsCl, pyridine;
(f) NaN3; (g) Ph3P, H2O; (h) Ac2O, pyridine; (i) 10%Pd/C, H2 (for 7a and 7b) or CF3CO2H (for 7c); (j) 10%Pd/C, H2; (k)
ethyl dithioacetate, Et3N and CF3CO2H (for 9c); (l) 10%Pd/C, H2; (m) trichloroacetic acid anhydride, Et3N, then NH4OH;
(n) MsCl, pyridine; (o) NaN3; (p) Ph3P, H2O; (q) CS2, Et3N, ClCO2Et; (r) MeONa; (s) LiOH (for 14a and 14b) or CF3CO2H
(for 14c).
Scheme 1.

H. Suzuki et al. / European Journal of Medicinal Chemistry 63 (2013) 811e825
813
O
O
F
F
a
b
Y
N
O
Y
HN
O
5a,5b,5c
N
N
N
N
N
N
N
N
N
N
Boc
X
X
15a: X = H, Y = NCbz (96%)
15b: X = F, Y = NCbz (85%)
15c: X = F, Y = O (89%)
16a: X = H, Y = NBoc (92%)
16b: X = F, Y = NBoc (96%)
16c: X = F, Y = O (94%)
O
O
F
F
c
d
Y
N
O
Boc
N
Y
HN
O
4a,4b,4c
H
N
N
N
N
N
N
N
Boc
O
O
X
X
18a: X = H, Y = NBoc (80%)
18b: X = F, Y = NBoc (81%)
18c: X = F, Y = O (73%)
17a: X = H, Y = NCbz (93%)
17b: X = F, Y = NCbz (93%)
17c: X = F, Y = O (89%)
a
Reagents: (a) 2,5-norbornadiene; (b) 10%Pd/C, H2 (for 11a and 11b) or CF3CO2H (for 11c); (c)
isoxazol-3-yl-carbamic acid t-butyl ester, ADDP, n-Bu3P; (d) 10% Pd/C, H2 (for 18a and 18b) or CF3CO2H (for
18c).
Scheme 2.
group at the N atom on the [1,2,5]triazepane ring. Namely, 4a and
4b were subjected to catalytic hydrogenation, then treated with
trifluoroacetic acid anhydride/triethylamine to afford alcohols 10a
and 10b. Compound 10 was converted to 12 using the same pro-
cedure as described for conversion of 4 to 6. The amines 12a, 12b,
and 6c were converted to thioisocyanates, and then reaction with
sodium methoxide gave thiocarbamates 13aec. Finally, the tri-
fluoroacetyl group on [1,2,5]triazepanes 13a,b was hydrolyzed to
afford oxazolidinone precursors 14a and 14b bearing a thio-
carbamate side chain unit. The Boc group of [1,2,5]oxadiazepane
13c was also deprotected to afford 14c. The azides 5aec were
reacted with 2,5-norbornadiene under reflux to obtain [1,2,3]tri-
azoles 15aec and appropriate deprotection reaction afforded oxa-
zolidinone precursors 16aec, respectively, bearing the [1,2,3]
triazole side chain unit. Mitsunobu reaction of alcohols 4aec with
isoxazol-3-yl-carbamic acid tert-butyl ester gave compounds 17ae
c. The [1,2,5]triazepanes 17a and 17b were subjected to catalytic
hydrogenation to obtain oxazolidinone precursors 18a and 18b
bearing an isoxazol-3-ylamino group side chain unit. The [1,2,5]
oxadiazepane 17c was also deprotected to afford oxazolidinone
precursor 18c. Thus, we completed the preparation of oxazolidi-
none precursors 7aec, 9aec, 14aec, 16aec, and 18aec. As shown in
Scheme 3, we obtained the target oxazolidinone analogues with a
hydroxyacetyl group at a N atom of [1,2,5]triazepane and [1,2,5]
oxadiazepane from the above 7, 9, 14, 16 and 18. Specifically, each
precursor was reacted with acetoxyacetyl chloride in the presence
of pyridine as base to form the acetoxyacetamide, followed by
deacetylation using potassium carbonate; finally, deprotection of
the Boc group at the N atom using trifluoroacetic acid afforded the
desired oxazolidinone analogues 19aec, 20aec, 21aec, 22aec, and
23aec.
2.2. Evaluation of in vitro antibacterial activity
All the synthesized oxazolidinone analogues 19, 20, 21, 22, and
23 were evaluated for in vitro antibacterial activity against Gram-
positive (S. aureus, E. faecalis, Enterococcus faecium, and Strepto-
coccus pneumoniae) bacteria and Gram-negative (Moraxella catar-
rhalis and Haemophilus influenzae) bacteria using a conventional
agar-dilution method. A clinical isolate of linezolid-resistant S.
aureus NRS271 was also examined [50]. In addition, oxazolidinone
precursors 7c, 9c, 14c, 16c, and 18c having a [1,2,5]oxadiazepane
ring as the C-ring unit were included as test compounds because
their structures were considered to be homologous to that of
linezolid (1). The individual minimum inhibitory concentrations
(MICs,
mg/mL) of the tested analogues against the above Gram-
positive and Gram-negative pathogens are listed in Table 1, along
with those of 1 and 2 as reference drugs. The oxazolidinone ana-
logues 19aec bearing an acetamide side chain unit at the C-5 po-
sition on the A-ring exhibited almost the same level of in vitro
O
F
O
F
X
a-c
a,b
7a,7b,9a,9b,
14a,14b,16a,
16b,18a,18b
HN
N
O
7c,9c,14c,
16c,18c
O
N
O
N
N
N
N
R
R
HO
HO
X
O
O
19c: X = F, R = NHC(=O)Me (74%)
20c: X = F, R = NHC(=S)Me (80%)
21c: X = F, R = NHC(=S)OMe (66%)
22c: X = F, R = [1,2,3]triazol-1-yl (92%)
23c: X = F, R = isoxazol-3-ylamino (74%)
19a: X = H, R = NHC(=O)Me (92%)
19b: X = F, R = NHC(=O)Me (90%)
20a: X = H, R = NHC(=S)Me (87%)
20b: X = F, R = NHC(=S)Me (70%)
21a: X = H, R = NHC(=S)OMe (87%)
21b: X = F, R = NHC(=S)OMe (86%)
22a: X = H, R = [1,2,3]triazol-1-yl (88%)
22b: X = F, R = [1,2,3]triazol-1-yl (97%)
23a: X = H, R = isoxazol-3-ylamino (84%)
23b: X = F, R = isoxazol-3-ylamino (90%)
a Reagents: (a) acetoxyacetyl chloride, pyridine; (b) K2CO3; (c) CF3CO2H.
Scheme 3.

814
H. Suzuki et al. / European Journal of Medicinal Chemistry 63 (2013) 811e825
Table 1
In vitro antibacterial activity of synthesized oxazolidinone analogues.
O
O
F
F
F
Y
N
O
O
HN
O
N
N
N
N
R
R
HO
X
O
7c,9c,14c,16c,18c
19a,b,c-23a,b,c
Compound
X
Y
R
Minimum inhibitory concentration (
mg/mL)
ClogPi
S. aureusa S. aureusb S. aureusc E. faecalisd E. faeciume M. catarrhalisf S. pneumoniaeg H. influenzaeh
1
2
e
e
H
F
e
e
e
e
2
1
4
1
2
1
2
1
2
1
2
1
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.5
4
2
2
2
2
32
32
64
16
32
16
8
1
2
4
2
2
2
4
64
16
16
16
64
8
4
1
2
2
4
2
0.5
0.25
0.25
0.25
0.5
0.25
0.5
0.5
4
1
2
2
2
2
2
4
4
2
1
8
8
8
4
8
4
1
0.5
1
1
2
1
1
1
8
4
8
4
1
16
4
16
8
16
16
2
2
4
2
4
4
4
8
16
8
16
8
32
16
16
16
0.5321
0.125
1
0.25
1
ꢀ1.0891
ꢀ0.7353
ꢀ0.5325
0.2818
0.1522
ꢀ0.1886
0.0142
0.8285
0.6989
0.6584
0.8612
1.6755
1.5459
ꢀ0.6366
ꢀ0.4338
0.3805
0.2509
0.5213
0.7241
1.5384
1.4088
19a
19b
19c
7c
20a
20b
20c
9c
21a
21b
21c
14c
22a
22b
22c
16c
23a
23b
23c
18c
NH NHC(]O)Me
NH NHC(]O)Me
O
F
NHC(]O)Me
NHC(]O)Me
e
H
F
e
0.25
ꢁ0.063
0.063
0.063
0.063
0.125
ꢁ0.063
0.125
0.125
1
0.5
1
0.5
0.5
0.125
0.25
0.125
NH NHC(]S)Me
NH NHC(]S)Me
O
0.5
0.125
0.125
0.25
0.25
0.25
0.25
0.25
2
1
1
1
1
0.5
0.125
0.25
0.125
0.25
0.25
0.25
0.25
4
1
2
1
2
F
NHC(]S)Me
NHC(]S)Me
e
H
F
e
NH NHC(]S)OMe
NH NHC(]S)OMe
O
F
NHC(]S)OMe
NHC(]S)OMe
e
H
F
e
NH [1,2,3]Triazol-1-yl
NH [1,2,3]Triazol-1-yl
O
F
[1,2,3]Triazol-1-yl
[1,2,3]Triazol-1-yl
e
H
F
F
e
e
NH Isoxazol-3-ylamino
NH Isoxazol-3-ylamino 0.5
O
e
16
16
4
0.5
0.5
1
0.25
0.5
0.5
1
1
1
Isoxazol-3-ylamino 0.25
Isoxazol-3-ylamino 0.5
8
16
4
a
Staphylococcus aureus SR20549.
Staphylococcus aureus Smith.
Linezolid-resistant Staphylococcus aureus NRS271.
Enterococcus faecalis SR1004.
b
c
d
e
f
Enterococcus faecium SR7940.
Moraxella catarrhalis SR26840.
Streptococcus pneumoniae SR26207.
Haemophilus influenzae SR27914.
g
h
i
ClogP (hydrophobicity) was calculated using ChemDraw Ultra, version 7.0.
antibacterial activity as 1 or 2, and no clear possibilities for further
development were identified. Analogues 22aec with the [1,2,3]
triazole type unit showed similar antibacterial activity to acetamide
19. There seemed to be a tendency that analogues with the 3,5-
difluorophenyl B-ring unit were a little more active than those
with the 3-fluorophenyl B-ring unit (cf. 19a vs 19b and 22a vs 22b).
On the other hand, thioacetamides 20aec and thiocarbamates
21aec showed 4- to 16-fold more potent in vitro antibacterial ac-
tivity than the reference drugs 1 and 2. Moreover, the MIC values
reached clinically useful levels in almost all cases, not only towards
typical Gram-positive bacteria, but also towards Gram-negative
bacteria M. catarrhalis and H. influenzae, as well as linezolid-
2.3. Evaluation of in vivo therapeutic effect
Next, in order to examine the in vivo antibacterial activity of
compounds with potent in vitro activity, selected compounds were
tested for in vivo therapeutic effect in a lethal systemic mouse
infection model with S. aureus SR3637, via both intravenous and
oral routes. The results are shown in Table 2. The control eperezolid
2 exhibited a better in vivo therapeutic effect upon intravenous
Table 2
In vivo antibacterial efficacies (ED50) of selected oxazolidinones in a systemic mouse
infection model.
resistant S. aureus (1e4 mg/mL). The analogues 23aec having an
Compound
MICa
(
mg/mL)
Therapeutic effect ED50 (mg/kg)
Administration route
isoxazol-3-ylamino side chain unit also showed excellent activity
towards Gram-positive pathogens, though their antibacterial
spectra did not extend to linezolid-resistant and Gram-negative
strains. We found no clear correlation between overall lip-
ophilicity of the test molecules and in vitro antibacterial activity,
but ClogP values were all positive for potent analogues (less than
ivb
poc
2
1
1.85 (1: 4.13)
2.95 (1: 1.73)
2.95 (1: 1.73)
0.94 (1: 3.26)
0.77 (1: 2.13)
1.71 (1: 1.73)
2.18 (1: 2.02)
>10 (1: 1.95)
4.76 (1: 4.11)
>10 (1: 2.02e2.83)
9.83 (1: 2.02e2.83)
1.05 (1: 2.10)
2.07 (1: 2.83)
e
20a
20b
21a
21b
22b
23b
23c
0.25
0.125
0.25
0.25
1
0.25 mg/mL MIC against S. aureus SR20549). As regards the B ring
part, the analogues with a 3,5-difluorophenyl group were more
active in vitro than the analogues with the less lipophilic 3-
fluorophenyl group without exception. Thus, it may be necessary
to consider the lipophilicity per partial structure, rather than the
overall molecular lipophilicity to find compounds that are highly
active in vitro.
0.5
0.25
2.83 (1: 4.11)
e
a
Staphylococcus aureus SR3637.
Intravenous.
Oral.
b
c

H. Suzuki et al. / European Journal of Medicinal Chemistry 63 (2013) 811e825
815
Table 3
antibiotics. Compounds 21a and 21b are considered to be promising
antibiotic candidates, and further evaluation is under way.
CYP450 and MAO-A, B inhibition index of potent in vivo active analogues 21a and
21b.
Compound
CYP450 isoform, IC50
(m
M)
MAO inhibition (%)
4. Experimental protocols
1A2
2C9
2D6
3A4
A
B
4.1. Chemistry
1
2
21a
21b
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
61.3
53.6
48.2
12.4
70.4
20.2
10.1
10.6
Melting points were determined with a Yanagimoto micro melting
point apparatus (hot plate) and are uncorrected. Low-resolution mass
spectra (LRMS) were recorded on a Hitachi M-80B spectrometer.
High-resolution mass spectra (HRMS) were recorded on a Hitachi M-
80B spectrometer or a Thermo Fisher Scientific LTQ-Orbitrap. Proton
nuclear magnetic resonance (1H NMR) spectra and carbon nuclear
magnetic resonance (13C NMR) spectra were measured with a Varian
Mercury at 300 MHz and at 75 MHz, respectively. The chemical shifts
administration than did linezolid 1, though it was less effective than
1 in the case of oral administration. In spite of their excellent MIC
profile, thioamides 20a and 20b showed lower in vivo antibacterial
efficacies compared to 1 via intravenous injection, and the thera-
peutic effects upon oral administration were far inferior to that of 1.
Those results may indicate that change of the acetamide side chain
unit to thioacetamide worsened the pharmacokinetic profile or
metabolic stability. Though the analogue 23b with an isoxazol-3-
ylamino side chain unit exhibited moderate in vivo therapeutic
effect via both intravenous and oral routes, the ED50 values were
insufficient. Also, [1,2,5]oxadiazepane 23c did not show in vivo ef-
ficacy, like [1,2,5]triazepane 23b. The reason for this is probably
that the hydroxyacetyl group at the N atom of the [1,2,5]oxadia-
zepane ring is unstable in plasma owing to its chemically active
Weinreb amide-type structure. On the other hand, the analogues
21a and 21b bearing a thiocarbamate side chain unit exhibited
superior in vivo therapeutic efficacy to 1 and 2 via both intravenous
and oral routes. Indeed, 21a displayed a 3-fold greater in vivo
therapeutic effect than 1 via intravenous administration, and a 2-
fold greater effect via oral administration.
are recorded inppm, and coupling constants (J) in Hz.1H NMR and 13
C
NMR chemical shifts were calculated on the basis of tetramethylsilane
(0 ppmfor 1HNMRinCDCl3 orCD3OD/CDCl3)andchloroform(77ppm
for 13C NMR in CDCl3 or CD3OD/CDCl3) as internal standards. Splitting
patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br; broad peak. Column chromatography was
carried out with silica gel [Fuji Davison BW200] as an absorbent. Thin
layer chromatography (TLC) was carried out on Merck Silica gel 60
PF254. Solutions were dried over anhydrous sodium sulphate or
anhydrous magnesium sulphate and the solvent was removed by
rotary evaporation under reduced pressure.
4.1.1. 5-(2-Fluoro-4-nitrophenyl) [1,2,5]triazepane-1-carboxylic
acid tert-butyl ester (2a)
To a solution of [1,2,5]triazepane-1-carboxylic acid tert-butyl
ester 1 (267.6 mg, 1.330 mmol) and 3,4-difluoronitrobenzene
(262.3 mg, 1.649 mmol) in acetonitrile (2 mL) was added iso-
propylethylamine (344.5 mg, 2.666 mmol) at ambient temperature,
the solution was refluxed for 16 h. After cooling, concentration of
the reaction mixture in vacuo followed by silica gel (15 g) column
chromatography using n-hexane/AcOEt (80:20 to 40:60) as the
eluent afforded 2a (348.6 mg, 77%). Yellow prisms (EtOH); mp:
2.4. Evaluation of inhibition of four cytochrome P450 (CYP)
isoforms and monoamine oxidases A and B (MAO-A and -B) by
selected compounds
For further pharmacological and safety evaluation, we examined
the inhibition of four CYP isoforms and MAO-A and -B by the com-
pounds that showed potent in vivo antibacterial activity. The results
are summarized in Table 3. Linezolid (1) is known to be a relatively
potent inhibitorof MAO-A and MAO-B, although there is no report of
any serious clinical side effect resulting from this activity. Never-
theless, it would be desirable to reduce this activity. To our gratifi-
cation, the potentinvivo-active thiocarbamates 21a and 21b showed
improved values of MAO-A, B inhibition index in comparison with
both of the oxazolidinone progenitors 1 and 2. Compounds 21a and
144e145 ꢂC; 1H NMR (CDCl3)
J ¼ 5.5 Hz, eCH2e), 3.66e3.73 (4H, m, eCH2e), 3.86 (2H, br t,
J ¼ 6 Hz, eCH2e), 6.79 (1H, t, J ¼ 9.1 Hz, AreH6), and 7.86e7.95 (2H,
m, AreH3 and H5); EI-LRMS m/z: 340 (Mþ).
d
¼ 1.28 (9H, s, t-C4H9), 3.13 (2H, t,
4.1.2. 5-(2,6-Difluoro-4-nitrophenyl) [1,2,5]triazepane-1-carboxylic
acid tert-butyl ester (2b)
Compound 2b (385.7 mg, 83%) was prepared from 1 (261.3 mg,
1.298 mmol) in the same manner as described for 2a. Yellow
powder (MeOH); mp: 78e79 ꢂC; 1H NMR (CDCl3)
C4H9), 3.12 (2H, t, J ¼ 5.2 Hz, eCH2e), 3.51 (2H, br t, J ¼ 5 Hz, eCH2e
), 3.61e3.72 (4H, m, eCH2e), and 7.77 (2H, d, J ¼ 10.7 Hz, AreH3
and H5); EI-LRMS m/z: 358 (Mþ).
d
¼ 1.54 (9H, s, t-
21b had similar levels of CYP inhibition potential (IC50 > 20 mM for
the four selected isoforms) to 1 and 2, and these levels are satisfac-
tory from a safety point of view. Thus, our oxazolidinone analogues
21a and 21b appear to have pharmacokinetic properties that would
be consistent with clinical application.
4.1.3. 5-(2,6-Difluoro-4-nitrophenyl) [1,2,5]oxadiazepane-2-
carboxylic acid tert-butyl ester (2c)
3. Conclusion
Compound 2c (365.0 mg, 80%) was prepared from 1 (257.0 mg,
1.271 mmol) in the same manner as described for 2a. Yellow nee-
We designed and synthesized new oxazolidinone analogues in
which the six-membered heterocyclic piperazine or morpholine
partial structure is replaced with a seven-membered heterocycle,
[1,2,5]triazepane or [1,2,5]oxadiazepane, as the C-ring. The in vitro
and in vivo antibacterial potentials of these compounds were eval-
uated. Analogues 21a and 21b bearing a thiocarbamate side chain
unit at C-5 of the oxazolidinone ring exhibited particularly potent
in vitro and in vivo antibacterial activities, and a preliminary safety
study indicated that they are not potent inhibitors of MAO-A, B or
four CYP450 isoforms. Thus, our seven-membered heterocyclic units
appeared to be effective partial structures for novel oxazolidinone
dles (n-hexane); mp: 87e88 ꢂC; 1H NMR (CDCl3)
d
¼ 1.51 (9H, s, t-
C4H9), 3.62e3.72 (4H, m, eCH2e), 3.84 (2H, t, J ¼ 6.0 Hz, eCH2e),
4.13 (2H, t, J ¼ 5.1 Hz, eCH2e), and 7.78 (2H, d, J ¼ 10.5 Hz, Are
H3 and H5); EI-LRMS m/z: 359 (Mþ). EI-HRMS m/z: calcd. for
C
15H19F2N3O5 (Mþ): 359.1291; found 359.1278.
4.1.4. 5-(4-Benzyloxycarbonylamino-2-fluorophenyl) [1,2,5]
triazepane-1,2-dicarboxylic acid 1-benzyl ester 2-tert-butyl ester (3a)
A suspension of 2a (346.9 mg, 1.019 mmol) and 10% Pd/C
(70.1 mg) in 95% MeOH (10 mL) was hydrogenated at 1 atm at

816
H. Suzuki et al. / European Journal of Medicinal Chemistry 63 (2013) 811e825
ambient temperature for 2 h, and then filtered through a Celite pad.
The filtrate was concentrated in vacuo. The residue was dissolved in
MeOH (10 mL) and H2O (5 mL). To this solution was added sodium
carbonate (270.1 mg, 2.548 mmol) and benzyl chloroformate
(386.7 mg, 2.267 mmol). Stirring was continued for 30 min, then
water (30 mL) was added and the mixture was extracted with
AcOEt. The organic solution was dried and evaporated. Silica gel
(20 g) column chromatography of the residue using n-hexane/
AcOEt (80:20 to 60:40) as the eluent afforded 3a (558.5 mg, 95%).
OH), 3.04e3.54 (6H, m, eCH2e), 3.75 (1H, br d, J ¼ 12 Hz, eCH2e),
3.88e4.17 (5H, m, eCH2e), 4.69e4.78 (1H, m, oxazolidinone-H5),
5.07e5.32 (2H, m, AreCH2O), 7.12 (2H, d, J ¼ 10.7 Hz, AreH2 and
H6), and 7.28e7.40 (5H, m, AreH); EI-LRMS m/z: 562 (Mþ).
4.1.9. 5(R)-(Hydroxymethyl)-3-(3,5-difluoro-4-(2-(tert-
butoxycarbonyl)[1,2,5]oxadiazepan-5-yl)phenyl)oxazolidin-2-one
(4c)
Compound 4c (291.1 mg, 87%) was prepared from 3c (363.2 mg,
0.784 mmol) in the same manner as described for 4a. Colourless
prisms (benzene/n-hexane); mp: 93e94 ꢂC; 1H NMR (CDCl3)
Amorphous solid; 1H NMR (CDCl3)
d
¼ 1.33e1.48 (9H, m, t-C4H9),
3.12e3.58 (6H, m, eCH2e), 3.95e4.27 (2H, m, eCH2e), 5.05e5.29
(4H, m, AreCH2O), 6.65 (1H, br s, NH), 6.82 (1H, t, J ¼ 9.1 Hz, Are
H6), 6.86e6.94 (1H, m, AreH5), and 7.20e7.42 (11H, m, AreH);
EI-LRMS m/z: 578 (Mþ).
d
¼ 1.51 (9H, s, t-C4H9), 3.33e3.43 (4H, m, eCH2e), 3.71e3.82 (3H,
m, eCH2e), 3.90e4.02 (3H, m, eCH2e), 4.07 (2H, t, J ¼ 5.1 Hz, e
CH2e), 4.70e4.80 (1H, m, oxazolidinone-H5), and 7.02 (2H, d,
J ¼ 10.5 Hz, AreH2 and H6); EI-LRMS m/z: 429 (Mþ). EI-HRMS m/z:
calcd. for C19H25F2N3O6 (Mþ): 429.1710; found 429.1710.
4.1.5. 5-(4-Benzyloxycarbonylamino-2,6-difluorophenyl) [1,2,5]
triazepane-1,2-dicarboxylic acid 1-benzyl ester 2-tert-butyl ester
(3b)
4.1.10. 5(R)-(Azidomethyl)-3-(3-fluoro-4-(1-(benzyloxycarbonyl)-
2-(tert-butoxycarbonyl)[1,2,5]triazepan-5-yl)phenyl) oxazolidin-2-
one (5a)
Compound 3b (410.7 mg, 98%) was prepared from 2b (251.1 mg,
0.701 mmol) in the same manner as described for 3a. Amorphous
solid; 1H NMR (CDCl3)
(6H, m, eCH2e), 3.90e4.17 (2H, m, eCH2e), 5.06e5.32 (4H, m,
AreCH2O), 6.77 (1H, br s, NH), 6.97 (2H, d, J ¼ 10.2 Hz, AreH3 and
H5), and 7.21e7.43 (10H, m, AreH); EI-LRMS m/z: 596 (Mþ).
d
¼ 1.30e1.55 (9H, m, t-C4H9), 3.00e3.53
To a solution of 4a (1.4713 g, 2.702 mmol) and triethylamine
(0.56 mL, 3.985 mmol) in CH2Cl2 (14 mL) was added dropwise
methanesulfonyl chloride (0.26 mL, 3.359 mmol) at 0 ꢂC and the
resulting mixture was stirred for 10 min at ambient temperature.
The reaction mixture was quenched with H2O (10 mL), and
extracted with CHCl3. The organic layer was washed with brine,
dried, and evaporated to afford a residue, which was used without
further purification. To a solution of the residue in N,N-dime-
thylformamide (10 mL) was added sodium azide (0.2641 g,
4.062 mmol), and the mixture was stirred for 4 h within the tem-
perature range of 80e90 ꢂC. The reaction mixture was then cooled
and poured into water (20 mL). The aqueous layer was extracted
with AcOEt and the combined organic layer was washed with
H2O and brine, and dried. Evaporation of the solvent followed by
silica gel (40 g) column chromatography of the residue using n-
hexane/AcOEt (70:30 to 40:60) as the eluent afforded 5a
4.1.6. 5-(4-Benzyloxycarbonylamino-2,6-difluorophenyl) [1,2,5]
oxadiazepane-2-carboxylic acid tert-butyl ester (3c)
Compound 3c (3.1902 g, 85%) was prepared from 2c (2.9011 g,
8.081 mmol) in the same manner as described for 3a. Colourless
prisms (n-hexane); mp: 100e101 ꢂC; 1H NMR (CDCl3)
d
¼ 1.50 (9H,
s, t-C4H9), 3.33 (4H, t, J ¼ 5.1 Hz, eCH2e), 3.75 (2H, t, J ¼ 5.1 Hz, e
CH2e), 4.05 (2H, t, J ¼ 5.1 Hz, eCH2e), 5.06e5.32 (4H, m, AreCH2O),
7.00 (2H, d, J ¼ 10.5 Hz, AreH3 and H5), 7.11 (1H, br s, NH), and
7.28e7.40 (5H, m, AreH); EI-LRMS m/z: 463 (Mþ). EI-HRMS m/z:
calcd. for C23H27F2N3O5 (Mþ): 463.1917; found 463.1904.
4.1.7. 5(R)-(Hydroxymethyl)-3-(3-fluoro-4-(1-
(benzyloxycarbonyl)-2-(tert-butoxycarbonyl)[1,2,5]triazepan-5-yl)
phenyl)oxazolidin-2-one (4a)
(1.5380 g, 100%). Amorphous solid; 1H NMR (CDCl3)
d
¼ 1.31e1.49
(9H, m, t-C4H9), 3.18e3.85 (9H, m, eCH2e), 3.96e4.28 (3H, m, e
CH2e), 4.71e4.82 (1H, m, oxazolidinone-H5), 5.05e5.29 (2H, m,
AreCH2O), 6.88 (1H, t, J ¼ 9.1 Hz, AreH5), 7.01e7.13 (1H, m, AreH6),
and 7.28e7.45 (6H, m, AreH); EI-LRMS m/z: 569 (Mþ).
To a solution of 3a (20.018 g, 34.60 mmol) in tetrahydrofuran
(200 mL) at ꢀ78 ꢂC under an argon atmosphere was added drop-
wise 1.58 M n-butyl lithium/n-hexane (24.0 mL, 37.92 mmol) over
10 min. Further (R)-glycidyl butyrate (5.4847 g, 38.04 mmol) in
tetrahydrofuran (10 mL) was added dropwise to the reaction
mixture over 10 min, followed by stirring for 1 h at the same
temperature. Then the reaction mixture was allowed to come
gradually to ambient temperature. Stirring was continued for 21 h,
then water (300 mL) was added, and the aqueous layer was
extracted with AcOEt. The combined organic layer was washed
with brine, and dried. Evaporation of the solvent followed by silica
gel (250 g) column chromatography of the residue using n-hexane/
AcOEt (1:1 to 0:1) and CHCl3/MeOH (97:3 to 9:1) as eluents affor-
4.1.11. 5(R)-(Azidomethyl)-3-(3,5-difluoro-4-(1-
(benzyloxycarbonyl)-2-(tert-butoxycarbonyl)[1,2,5]triazepan-5-yl)
phenyl)oxazolidin-2-one (5b)
Compound 5b (2.2917 g, 100%) was prepared from 4b (2.2025 g,
3.915 mmol) in the same manner as described for 5a. Amorphous
solid; 1H NMR (CDCl3)
d
¼ 1.35e1.53 (9H, m, t-C4H9), 3.04e3.50 (6H,
m, eCH2e), 3.58 (1H, dd, J ¼ 4.4, 13.2 Hz, eCHHeN3), 3.71 (1H, dd,
J ¼ 4.4, 13.2 Hz, eCHHeN3), 3.78 (1H, dd, J ¼ 6.3, 8.8 Hz,
oxazolidinone-H4), 3.91e4.18 (2H, m, eCH2e), 4.01 (1H, t,
J ¼ 8.8 Hz, oxazolidinone-H4), 4.78 (1H, ddt, J ¼ 6.3, 8.8, 4.4 Hz,
oxazolidinone-H5), 5.07e5.32 (2H, m, AreCH2O), 7.12 (2H, d,
J ¼ 10.7 Hz, AreH2 and H6), and 7.27e7.40 (5H, m, AreH); EI-LRMS
m/z: 587 (Mþ).
ded 4a (17.489 g, 93%). Amorphous solid; 1H NMR (CDCl3)
d
¼ 1.32e
1.52 (9H, m, t-C4H9), 2.46 (1H, br, OH), 3.16e3.60 (6H, m, eCH2e),
3.69e3.80 (1H, m, eCH2e), 3.87e4.27 (5H, m, eCH2e), 4.67e4.77
(1H, m, oxazolidinone-H5), 5.05e5.28 (2H, m, AreCH2O), 6.87
(1H, t, J ¼ 9.1 Hz, AreH5), 7.02e7.13 (1H, m, AreH6), and 7.27e7.46
(6H, m, AreH); EI-LRMS m/z: 544 (Mþ).
4.1.12. 5(R)-(Azidomethyl)-3-(3,5-difluoro-4-(2-(tert-
butoxycarbonyl)[1,2,5]oxadiazepan-5-yl)phenyl)oxazolidin-2-one
(5c)
4.1.8. 5(R)-(Hydroxymethyl)-3-(3,5-difluoro-4-(1-
(benzyloxycarbonyl)-2-(tert-butoxycarbonyl)[1,2,5]triazepan-5-yl)
phenyl)oxazolidin-2-one (4b)
Compound 5c (360.1 mg, 99%) was prepared from 4c (406.0 mg,
0.802 mmol) in the same manner as described for 5a. Colourless
prisms (EtOH); mp: 72e73 ꢂC; 1H NMR (CDCl3)
d
¼ 1.51 (9H, s, t-
Compound 4b (5.5651 g, 81%) was prepared from 3b (7.2419 g,
12.14 mmol) in the same manner as described for 4a. Amorphous
C4H9), 3.34e3.45 (4H, m, eCH2e), 3.59 (1H, dd, J ¼ 4.5, 13.5 Hz, e
CHHeN3), 3.73 (1H, dd, J ¼ 4.5, 13.5 Hz, eCHHeN3), 3.74e3.85
(3H, m, eCH2e and oxazolidinone-H4), 4.03 (1H, t, J ¼ 9.0 Hz,
solid; 1H NMR (CDCl3)
d
¼ 1.35e1.49 (9H, m, t-C4H9), 2.35 (1H, br,

H. Suzuki et al. / European Journal of Medicinal Chemistry 63 (2013) 811e825
817
oxazolidinone-H4), 4.04e4.14 (2H, m, eCH2e), 4.76e4.86 (1H, m,
oxazolidinone-H5), and 7.13 (2H, d, J ¼ 10.8 Hz, AreH2 and H6); EI-
LRMS m/z: 454 (Mþ). EI-HRMS m/z: calcd. for C19H24F2N6O5 (Mþ):
454.1776; found 454.1776.
3.99 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4), 4.70e4.81 (1H, m,
oxazolidinone-H5), 6.37 (1H, br t, J ¼ 6 Hz, eNHeC]O), 6.86 (1H, t,
J ¼ 9.1 Hz, AreH5), 6.99 (1H, dd, J ¼ 2.3, 9.1 Hz, AreH6), and 7.35
(1H, dd, J ¼ 2.3, 15.1 Hz, AreH2); EI-LRMS m/z: 451 (Mþ).
4.1.13. 5(S)-(Aminomethyl)-3-(3-fluoro-4-(1-(benzyloxycarbonyl)-
2-(tert-butoxycarbonyl)[1,2,5]triazepan-5-yl) phenyl)oxazolidin-2-
one (6a)
To a solution of 5a (1.5380 g, 2.700 mmol) and triphenylphos-
phine (0.8661 g, 1.521 mmol) in tetrahydrofuran (14 mL) was added
H2O (0.5 mL, 27.78 mmol) at ambient temperature, and the resulting
mixture was refluxed for 2 h. The reaction mixture was cooled and
concentrated in vacuo. Silica gel (40 g) column chromatography of
the residue using CHCl3/MeOH (98:2 to 85:15) as the eluent afforded
4.1.17. 5(S)-(Acetylaminomethyl)-3-(3,5-difluoro-4-(1-(tert-
butoxycarbonyl) [1,2,5]triazepan-5-yl)phenyl)oxazolidin-2-one (7b)
Compound 7b (1.2867 g, 97%) was prepared from 6b (1.5912 g,
2.833 mmol) in the same manner as described for 7a. Colourless
needles (EtOH); mp: 131e132 ꢂC; 1H NMR (CDCl3)
d
¼ 1.49 (9H, s, t-
C4H9), 2.03 (3H, s, CH3eC]O), 3.04 (2H, t, J ¼ 5.2 Hz, eCH2e), 3.27
(2H, t, J ¼ 5.2 Hz, eCH2e), 3.40 (2H, t, J ¼ 5.8 Hz, eCH2e), 3.60 (2H, t,
J ¼ 5.8 Hz, eCH2e), 3.62e3.68 (2H, m, eCH2e), 3.73 (1H, dd, J ¼ 6.8,
9.1 Hz, oxazolidinone-H4), 3.99 (1H, t, J ¼ 9.1 Hz, oxazolidinone-
H4), 4.72e4.82 (1H, m, oxazolidinone-H5), 6.33 (1H, br t,
J ¼ 6 Hz, eNHeC]O), and 7.07 (2H, d, J ¼ 10.7 Hz, AreH2 and H6);
EI-LRMS m/z: 469 (Mþ).
6a (1.4505 g, 99%). Amorphous solid; 1H NMR (CDCl3)
d
¼ 1.33e1.49
(9H, m, t-C4H9), 2.97 (1H, dd, J ¼ 5.8, 13.7 Hz, eCHHeNH2), 3.10 (1H,
dd, J ¼ 4.1, 13.7 Hz, eCHHeNH2), 3.16e3.60 (6H, m, eCH2e), 3.79
(1H, br t, J ¼ 8 Hz, eCH2e), 3.93e4.27 (3H, m, eCH2e), 4.61e4.72
(1H, m, oxazolidinone-H5), 5.05e5.29 (2H, m, AreCH2O), 6.88 (1H,
t, J ¼ 9.1 Hz, AreH5), 7.03e7.13 (1H, m, AreH6), and 7.25e7.48 (6H,
m, AreH); EI-LRMS m/z: 543 (Mþ).
4.1.18. 5(S)-(Acetylaminomethyl)-3-(3,5-difluoro-4-([1,2,5]
oxadiazepan-5-yl)phenyl)oxazolidin-2-one (7c)
Compound 6c was converted to its acetamide intermediate in the
same manner as described for 7a. The obtained residue was dis-
solved in CHCl3 (10 mL) and to this solution was added trifluoro-
acetic acid (0.5 mL). Stirring was continued for 15 h. The reaction
mixture was neutralized with 10% sodium carbonate, and extracted
with 10% MeOH/CHCl3. The organic layer was dried and evaporated,
followed by preparative TLC of the residue using CHCl3/MeOH (9 : 1)
as the eluent to afford 7c (41.0 mg, 71%). Colourless needles (EtOH);
4.1.14. 5(S)-(Aminomethyl)-3-(3,5-difluoro-4-(1-
(benzyloxycarbonyl)-2-(tert-butoxycarbonyl) [1,2,5]triazepan-5-yl)
phenyl)oxazolidin-2-one (6b)
Compound 6b (1.8095 g, 99%) was prepared from 5b (1.9033 g,
3.239 mmol) in the same manner as described for 6a. Amorphous
solid; 1H NMR (CDCl3)
d
¼ 1.35e1.53 (9H, m, t-C4H9), 2.96 (1H, dd,
J ¼ 5.5, 13.7 Hz, eCHHeNH2), 3.04e3.54 (6H, m, eCH2e), 3.12 (1H,
dd, J ¼ 4.0, 13.7 Hz, eCHHeNH2), 3.80 (1H, br t, J ¼ 8 Hz, eCH2e),
3.90e4.17 (2H, m, eCH2e), 3.96 (1H, t, J ¼ 9.1 Hz, oxazolidinone-
H4), 4.62e4.73 (1H, m, oxazolidinone-H5), 5.08e5.32 (2H, m, Are
CH2O), 7.13 (2H, br d, J ¼ 10.7 Hz, AreH2 and H6), and 7.26e7.40
(5H, m, AreH); EI-LRMS m/z: 561 (Mþ).
mp: 104e105 ꢂC; 1H NMR (CDCl3)
d
¼ 2.03 (3H, s, CH3eC]O), 3.22
(2H, br t, J ¼ 6 Hz, eCH2e), 3.40 (2H, br t, J ¼ 6 Hz, eCH2e), 3.49 (2H,
br t, J ¼ 6 Hz, eCH2e), 3.66 (2H, dd, J ¼ 4.5, 6.3 Hz, eCH2e), 3.75 (1H,
dd, J ¼ 6.3, 9.0 Hz, oxazolidinone-H4), 3.90 (2H, br t, J ¼ 6 Hz, eCH2e
), 4.00 (1H, t, J ¼ 9.0 Hz, oxazolidinone-H4), 4.79 (1H, ddt, J ¼ 6.3, 9.0,
4.5 Hz, oxazolidinone-H5), 6.68 (1H, br t, J ¼ 6 Hz, eNHeC]O), and
7.06 (2H, d, J ¼ 10.8 Hz, AreH2 and H6); 13C NMR (CDCl3)
d
¼ 23.0,
4.1.15. 5(S)-(Aminomethyl)-3-(3,5-difluoro-4-(2-(tert-
butoxycarbonyl) [1,2,5]oxadiazepan-5-yl)phenyl)oxazolidin-2-one
(6c)
Compound 6c (1.6435 g, 100%) was prepared from 5c (1.7502 g,
3.851 mmol) in the same manner as described for 6a. Colourless
prisms (benzene/n-hexane); mp: 73e74 ꢂC; 1H NMR (CDCl3)
41.8, 47.4, 53.6, 55.1, 55.7, 72.0, 72.3, 102.4 (2C, d, J ¼ 30 Hz), 125.6 (t,
J ¼ 14 Hz), 132.3 (t, J ¼ 13 Hz), 154.0,157.5 (2C, dd, J ¼ 9, 244 Hz), and
171.2.; EI-LRMS m/z: 370 (Mþ). EI-HRMS m/z: calcd. for
C
16H20F2N4O4 (Mþ): 370.1451; found 370.1436.
4.1.19. 5(S)-(Aminomethyl)-3-(3-fluoro-4-(1-(tert-butoxy
d
¼ 1.52 (9H, s, t-C4H9), 2.96 (1H, dd, J ¼ 5.5, 13.5 Hz, eCHHeNH2),
carbonyl)[1,2,5]triazepan-5-yl)phenyl)oxazolidin-2-one (8a)
A suspension of 5a (0.6064 g, 1.065 mmol) and 10% Pd/C
(121.5 mg) in 95% MeOH (10 mL) was hydrogenated at 1 atm at
ambient temperature for 42 h, and then filtered through a Celite
pad. Evaporation of the solvent followed by silica gel (15 g) column
chromatography of the residue using CHCl3/MeOH (97:3 to 70:30)
as the eluent afforded 8a (0.3792 g, 87%). Amorphous solid; 1H NMR
3.14 (1H, dd, J ¼ 4.0, 13.5 Hz, eCHHeNH2), 3.39 (4H, br t, J ¼ 5 Hz, e
CH2e), 3.78 (2H, br t, J ¼ 5 Hz, eCH2e), 3.82 (1H, dd, J ¼ 6.5, 9.0 Hz,
oxazolidinone-H4), 3.98 (1H, t, J ¼ 9.0 Hz, oxazolidinone-H4), 4.08
(2H, br t, J ¼ 5 Hz, eCH2e), 4.69 (1H, dddd, J ¼ 4.0, 5.5, 6.5, 9.0 Hz,
oxazolidinone-H5), and 7.13 (2H, d, J ¼ 10.8 Hz, AreH2 and H6); EI-
LRMS m/z: 428 (Mþ).
(CD3OD þ CDCl3) ¼ 1.39 (9H, s, t-C4H9), 3.08e3.74 (10H, m, eCH2e
d
4.1.16. 5(S)-(Acetylaminomethyl)-3-(3-fluoro-4-(1-(tert-
), 3.78 (1H, dd, J ¼ 6.6, 9.1 Hz, oxazolidinone-H4), 4.14 (1H, t,
J ¼ 9.1 Hz, oxazolidinone-H4), 4.92e5.03 (1H, m, oxazolidinone-
H5), 6.89 (1H, t, J ¼ 9.1 Hz, AreH5), 7.04 (1H, dd, J ¼ 2.2, 9.1 Hz,
AreH6), and 7.35 (1H, dd, J ¼ 2.2, 15.3 Hz, AreH2); EI-LRMS m/z:
410 (Mþ).
butoxycarbonyl) [1,2,5]triazepan-5-yl)phenyl)oxazolidin-2-one (7a)
To a solution of 6a (1.2371 g, 2.276 mmol) and pyridine
(0.3669 g, 4.638 mmol) in CH2Cl2 (8 mL) was added acetic anhy-
dride (462.2 mg, 4.527 mmol), and the mixture was stirred for
30 min at ambient temperature. The reaction mixture was then
concentrated in vacuo to afford a residue, which was used without
further purification. A suspension of the above residue and 10% Pd/
C (254.3 mg) in 95% MeOH (12 mL) was hydrogenated at 1 atm at
ambient temperature for 21 h, and then filtered through a Celite
pad. Evaporation of the solvent followed by silica gel (25 g) column
chromatography of the residue using CHCl3/MeOH (98:2 to 90:10)
as the eluent afforded 7a (0.9824 g, 96%). Amorphous solid; 1H
4.1.20. 5(S)-(Aminomethyl)-3-(3,5-difluoro-4-(1-(tert-
butoxycarbonyl) [1,2,5]triazepan-5-yl)phenyl)oxazolidin-2-one (8b)
Compound 8b (0.4265 g, 87%) was prepared from 5b (0.6721 g,
1.144 mmol) in the same manner as described for 8a. Amorphous
solid; 1H NMR (CD3OD þ CDCl3)
¼ 1.49 (9H, s, t-C4H9), 3.05 (2H, t,
d
J ¼ 5.5 Hz, eCH2e), 3.14e3.48 (6H, m, eCH2e), 3.61 (2H, t,
J ¼ 5.5 Hz, eCH2e), 3.80 (1H, dd, J ¼ 6.6, 9.1 Hz, oxazolidinone-H4),
4.18 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4), 5.02e5.13 (1H, m,
oxazolidinone-H5), and 7.11 (2H, d, J ¼ 10.7 Hz, AreH2 and H6); EI-
LRMS m/z: 328 (Mþ-Boc).
NMR (CDCl3)
d
¼ 1.38 (9H, s, t-C4H9), 2.02 (3H, s, CH3eC]O), 3.11
(2H, t, J ¼ 5.3 Hz, eCH2e), 3.43 (2H, t, J ¼ 5.5 Hz, eCH2e), 3.53e3.74
(7H, m, eCH2e), 3.72 (1H, dd, J ¼ 6.6, 9.1 Hz, oxazolidinone-H4),

818
H. Suzuki et al. / European Journal of Medicinal Chemistry 63 (2013) 811e825
4.1.21. 5(S)-(Thioacetylaminomethyl)-3-(3-fluoro-4-(1-(tert-
3.06e3.68 (6H, m, eCH2e), 3.77 (1H, dd, J ¼ 3.9, 12.4 Hz, eCHH-
OH), 3.90e4.35 (5H, m, eCH2e), 4.69e4.79 (1H, m, oxazolidinone-
H5), 6.92 (1H, t, J ¼ 9.1 Hz, AreH6), 7.10 (1H, br d, J ¼ 9 Hz, AreH5),
and 7.43 (1H, br d, J ¼ 15 Hz, AreH2); EI-LRMS m/z: 506 (Mþ).
butoxycarbonyl) [1,2,5]triazepan-5-yl)phenyl)oxazolidin-2-one (9a)
To a solution of 8a (0.2720 g, 0.664 mmol) and triethylamine
(0.1090 g, 1.077 mmol) in THF (6 mL) was added ethyl dithioacetate
(0.1351 g, 1.124 mmol), and the mixture was stirred for 20 h at
ambient temperature. Evaporation of the solvent followed by silica
gel (10 g) column chromatography of the residue using CHCl3/MeOH
(99:1 to 95:5) as the eluent afforded 9a (0.2466 g, 80%). Amorphous
4.1.25. 5(R)-(Hydroxymethyl)-3-(3,4-difluoro-4-(1-(tert-
butoxycarbonyl)-2-(2,2,2-trichloroacetyl) [1,2,5]triazepan-5-yl)
phenyl)oxazolidin-2-one (10b)
solid; 1H NMR (CDCl3)
S), 3.11 (2H, t, J ¼ 5.2 Hz, eCH2e), 3.44 (2H, t, J ¼ 5.2 Hz, eCH2e),
3.54e3.69 (4H, m, eCH2e), 3.79 (1H, dd, 6.9, 9.1 Hz,
d
¼ 1.38 (9H, s, t-C4H9), 2.60 (3H, s, CH3eC]
Compound 10b (1.7092 g, 85%) was prepared from 4b (2.1532 g,
3.828 mmol) in the same manner as described for 10a. Amorphous
J
¼
solid; 1H NMR (CDCl3)
d
¼ 1.46e1.54 (9H, m, t-C4H9), 3.04e3.66
oxazolidinone-H4), 3.99e4.10 (2H, m, eCH2e), 4.24 (1H, ddd, J ¼ 2.7,
6.1, 14.3 Hz, oxazolidinone-H4), 4.92e5.01 (1H, m, oxazolidinone-
H5), 6.86 (1H, t, J ¼ 9.1 Hz, AreH6), 6.98 (1H, dd, J ¼ 2.5, 9.1 Hz,
AreH5), 7.32 (1H, dd, J ¼ 2.5, 15.4 Hz, AreH2), and 8.33 (1H, br t,
J ¼ 6 Hz, eNHeC]S); EI-LRMS m/z: 467 (Mþ).
(6H, m, eCH2e), 3.76 (1H, dd, J ¼ 3.8, 12.6 Hz, eCHH-OH), 3.90e
4.27 (5H, m, eCH2e), 4.70e4.80 (1H, m, oxazolidinone-H5), and
7.15 (2H, d, J ¼ 10.7 Hz, AreH2 and H6); EI-LRMS m/z: 524 (Mþ).
4.1.26. 5(R)-(Azidomethyl)-3-(3-fluoro-4-(1-(tert-butoxycarbonyl)-
2-(2,2,2-trichloroacetyl) [1,2,5]triazepan-5-yl)phenyl) oxazolidin-2-
one (11a)
4.1.22. 5(S)-(Thioacetylaminomethyl)-3-(3,5-difluoro-4-(1-(tert-
butoxycarbonyl) [1,2,5]triazepan-5-yl)phenyl)oxazolidin-2-one (9b)
Compound 9b (0.4074 g, 95%) was prepared from 8b (0.3782 g,
0.885 mmol) in the same manner as described for 9a. Amorphous
To a solution of 10a (1.5342 g, 3.049 mmol) and triethylamine
(0.60 mL, 4.269 mmol) in CH2Cl2 (15 mL) was added dropwise
methanesulfonyl chloride (0.30 mL, 3.876 mmol) at 0 ꢂC, and the
resulting mixture was stirred for 20 min at ambient temperature.
The reaction mixture was quenched with H2O (20 mL), and
extracted with CHCl3. The organic layer was washed with brine,
dried, and evaporated to afford a residue, which was used without
further purification. To a solution of the above residue in N,N-
dimethylformamide (15 mL) was added sodium azide (301.5 mg,
4.638 mmol), and the mixture was stirred for 16 h within the
temperature range of 50e60 ꢂC. The reaction mixture was then
cooled and poured into water (30 mL). The aqueous layer was
extracted with AcOEt and the combined organic layer was
washed with H2O and brine, and dried. Evaporation of the
solvent followed by silica gel (20 g) column chromatography of
the residue using n-hexane/AcOEt (75:25 to 40:60) as the eluent
afforded 11a (1.5859 g, 99%). Amorphous solid; 1H NMR (CDCl3)
solid; 1H NMR (CDCl3)
d
¼ 1.49 (9H, s, t-C4H9), 2.60 (3H, s, CH3eC]
S), 3.04 (2H, t, J ¼ 5.5 Hz, eCH2e), 3.27 (2H, t, J ¼ 5.8 Hz, eCH2e),
3.41 (2H, t, J ¼ 5.8 Hz, eCH2e), 3.60 (2H, t, J ¼ 5.8 Hz, eCH2e),
3.79 (1H, dd, J ¼ 6.9, 9.1 Hz, oxazolidinone-H4), 4.00e4.13 (2H,
m, eCH2e), 4.24 (1H, ddd, J ¼ 2.7, 6.1, 14.3 Hz, oxazolidinone-H4),
4.93e5.03 (1H, m, oxazolidinone-H5), 7.05 (2H, d, J ¼ 10.7 Hz,
AreH2 and H6), and 8.18 (1H, br t, J ¼ 6 Hz, eNHeC]S); EI-LRMS
m/z: 485 (Mþ).
4.1.23. 5(S)-(Thioacetylaminomethyl)-3-(3,5-difluoro-4-([1,2,5]
oxadiazepan-5-yl)phenyl)oxazolidin-2-one (9c)
Compound 9c (0.3269 g, 71%) was prepared from 6c (0.5098 g,
1.190 mmol) in the same manner as described for 9a. Colourless
needles (EtOH); mp: 170e171 ꢂC; 1H NMR (CD3OD þ CDCl3)
d
¼ 2.57 (3H, s, CH3C]S), 3.23 (2H, br t, J ¼ 5 Hz, eCH2e), 3.41 (2H,
d
¼ 1.44e1.52 (9H, m, t-C4H9), 3.06e3.66 (6H, m, eCH2e), 3.60
br t, J ¼ 6 Hz, eCH2e), 3.49 (2H, br t, J ¼ 5 Hz, eCH2e), 3.82 (1H, dd,
J ¼ 6.9, 9.0 Hz, oxazolidinone-H4), 3.92 (2H, br t, J ¼ 6 Hz, eCH2e),
4.00 (1H, dd, J ¼ 6.9, 14.5 Hz, eCHHeNHeC]S), 4.08 (1H, t,
J ¼ 9.0 Hz, oxazolidinone-H4), 4.17 (1H, dd, J ¼ 2.5, 14.5 Hz, eCHHe
NHeC]S), 5.00 (1H, ddt, J ¼ 2.5, 9.0, 6.9 Hz, oxazolidinone-H5),
(1H, dd, J ¼ 4.4, 13.2 Hz, eCHHeN3), 3.70 (1H, dd, J ¼ 4.7, 13.2 Hz, e
CHHeN3), 3.82 (1H, dd, J ¼ 6.1, 9.1 Hz, oxazolidinone-H4), 4.04 (1H,
t, J ¼ 9.1 Hz, oxazolidinone-H4), 4.10e4.36 (2H, m, eCH2e), 4.78
(1H, dddd, J ¼ 4.4, 4.7, 6.1, 9.1 Hz, oxazolidinone-H5), 6.93 (1H, t,
J ¼ 9.1 Hz, AreH6), 7.11 (1H, br d, J ¼ 9 Hz, AreH5), and 7.43 (1H, br
d, J ¼ 15 Hz, AreH2); EI-LRMS m/z: 531 (Mþ).
and 7.10 (2H, d,
J
¼
10.8 Hz, AreH2 and H6); 13C NMR
(CD3OD þ CDCl3)
d
¼ 32.9, 47.6, 47.8, 53.2, 55.0, 55.4, 71.1, 72.3,
102.4 (2C, d, J ¼ 30 Hz),125.5 (t, J ¼ 14 Hz),132.3 (t, J ¼ 13 Hz),154.3,
4.1.27. 5(R)-(Azidomethyl)-3-(3,4-difluoro-4-(1-(tert-
butoxycarbonyl)-2-(2,2,2-trichloroacetyl) [1,2,5]triazepan-5-yl)
phenyl)oxazolidin-2-one (11b)
157.4 (2C, dd, J ¼ 9, 244 Hz), and 203.1; EI-LRMS m/z: 386 (Mþ). EI-
HRMS m/z: calcd. for
C
16H20F2N4O3S (Mþ): 386.1223; found
386.1217.
Compound 11b (1.5026 g, 91%) was prepared from 10b (1.5736 g,
3.001 mmol) in the same manner as described for 11a. Amorphous
4.1.24. 5(R)-(Hydroxymethyl)-3-(3-fluoro-4-(1-(tert-
butoxycarbonyl)-2-(2,2,2-trichloroacetyl) [1,2,5]triazepan-5-yl)-
phenyl)oxazolidin-2-one (10a)
solid; 1H NMR (CDCl3)
d
¼ 1.41e1.54 (9H, m, t-C4H9), 3.05e3.66 (6H,
m, eCH2e), 3.59 (1H, dd, J ¼ 4.1, 13.2 Hz, eCHHeN3), 3.72 (1H, dd,
J ¼ 4.4, 13.2 Hz, eCHHeN3), 3.80 (1H, dd, J ¼ 6.2, 9.1 Hz,
oxazolidinone-H4), 4.02 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4), 4.04e
4.27 (2H, m, eCH2e), 4.79 (1H, dddd, J ¼ 4.1, 4.4, 6.2, 9.1 Hz,
oxazolidinone-H5), and 7.15 (2H, d, J ¼ 10.7 Hz, AreH2 and H6); EI-
LRMS m/z: 549 (Mþ).
A suspension of 4a (1.8671 g, 3.429 mmol) and 10% Pd/C
(95.6 mg) in 95% MeOH (20 mL) was hydrogenated at 1 atm at
ambient temperature for 20 h, and then filtered through a Celite
pad. Evaporation of the solvent afforded a residue, which was used
without further purification. To a solution of the above residue and
triethylamine (1.10 mL, 7.827 mmol) in THF (15 mL) was added
trifluoroacetic anhydride (1.10 mL, 7.924 mmol) at 0 ꢂC, and the
mixture was stirred for 30 min at ambient temperature. The reac-
tion mixture was quenched with 1.4% NH3 aqueous solution. The
resulting mixture was extracted with AcOEt, washed with brine,
and dried. Evaporation of the solvent followed by silica gel (20 g)
column chromatography of the residue using n-hexane/AcOEt
(50:50 to 0:100) as the eluent afforded 10a (1.6569 g, 95%).
4.1.28. 5(S)-(Aminomethyl)-3-(3-fluoro-4-(1-(tert-
butoxycarbonyl)-2-(2,2,2-trichloroacetyl) [1,2,5]triazepan-5-yl)
phenyl) oxazolidin-2-one (12a)
To a solution of 11a (1.4647 g, 2.756 mmol) and triphenyl-
phosphine (1.0730 g, 4.091 mmol) in tetrahydrofuran (14 mL) was
added H2O (0.5 mL, 27.78 mmol) at ambient temperature and the
resulting mixture was refluxed for 2 h. After cooling, the reaction
mixture was concentrated in vacuo followed by silica gel (20 g)
column chromatography of the residue using CHCl3/MeOH (97:3 to
Amorphous solid; 1H NMR (CDCl3)
d
¼ 1.43e1.52 (9H, m, t-C4H9),

H. Suzuki et al. / European Journal of Medicinal Chemistry 63 (2013) 811e825
819
80:20) as the eluent to afford 12a (1.2871 g, 92%). Amorphous solid;
1H NMR (CDCl3)
3.00e4.34 (12H, m, eCH2e), 4.71e4.82 (1H, m, oxazolidinone-H5),
6.90 (1H, t, J ¼ 9.1 Hz, AreH6), 7.09 (1H, br d, J ¼ 8 Hz, AreH5), and
7.40 (1H, br d, J ¼ 15 Hz, AreH2); EI-LRMS m/z: 505 (Mþ).
4.1.33. O-Methyl (S)-N-(3-(4-(1-(tert-butoxycarbonyl) [1,2,5]
triazepan-5-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)-
methylthiocarbamate (14a)
d
¼ 1.35e1.52 (9H, m, t-C4H9), 2.91 (2H, br s, NH2),
To a stirred solution of 13a (1.0483 g, 1.809 mmol) in tetrahy-
drofuran (4 mL) and MeOH (4 mL) and H2O (2 mL) was added
lithium hydroxide monohydrate (116.6 mg, 2.779 mmol) at 0 ꢂC.
Stirring was continued for 1 h at the same temperature, then the
reaction mixture was poured into saturated ammonium chloride
aqueous solution (15 mL), and extracted with AcOEt. The combined
organic layer was washed with brine, dried, and evaporated, fol-
lowed by silica gel (20 g) column chromatography of the residue
using n-hexane/AcOEt (70:30 to 20:80) as the eluent to afford 14a
4.1.29. 5(S)-(Aminomethyl)-3-(3,5-difluoro-4-(1-(tert-
butoxycarbonyl)-2-(2,2,2-trichloroacetyl) [1,2,5]triazepan-5-yl)-
phenyl)oxazolidin-2-one (12b)
Compound 12b (1.1454 g, 92%) was prepared from 11b (1.3080 g,
2.381 mmol) in the same manner as described for 12a. Amorphous
solid; 1H NMR (CDCl3)
NH2), 3.00e4.27 (12H, m, eCH2e), 4.67e4.78 (1H, m,
oxazolidinone-H5), and 7.14 (2H, d, J ¼ 10.7 Hz, AreH2 and H6); EI-
LRMS m/z: 523 (Mþ).
d
¼ 1.45e1.54 (9H, m, t-C4H9), 2.10 (2H, br s,
(0.8433 g, 96%). Amorphous solid; 1H NMR (CDCl3)
d
¼ 1.38 (9H, m,
t-C4H9), 3.11 (2H, t, J ¼ 5.2 Hz, eCH2e), 3.44 (2H, t, J ¼ 5.2 Hz, e
CH2e), 3.54e3.68 (4H, m, eCH2e), 3.80 (1H, dd, J ¼ 6.8, 9.1 Hz,
oxazolidinone-H4), 3.89e4.14 (3H, m, eCH2e), 4.00 (3H, s, OCH3),
4.84e4.95 (1H, m, oxazolidinone-H5), 6.80 (1H, t, J ¼ 6.3 Hz, eNHe
C]S), 6.87 (1H, t, J ¼ 9.1 Hz, AreH6), 7.00 (1H, dd, J ¼ 2.5, 9.1 Hz,
AreH5), and 7.35 (1H, dd, J ¼ 2.5, 15.2 Hz, AreH2); EI-LRMS m/z:
483 (Mþ).
4.1.30. O-Methyl (S)-N-(3-(4-(1-(tert-butoxycarbonyl)-2-(2,2,2-
trichloroacetyl) [1,2,5]triazepan-5-yl)-3-fluorophenyl)-2-
oxooxazolidin-5-yl)methylthiocarbamate (13a)
A mixture of compound 12a (1.2069 g, 2.388 mmol), carbon
disulfide (0.28 mL, 4.634 mmol) and triethylamine (0.34 mL,
2.419 mmol) in tetrahydrofuran (12 mL) was stirred for 30 min at
ambient temperature. Then ethyl chloroformate (0.26 mL,
2.729 mmol) was added dropwise to the reaction mixture at the
same temperature. Stirring was continued for 10 min, then the
reaction mixture was washed with water and extracted with AcOEt.
The extract was washed with brine, dried, and evaporated to afford
a residue, which was used without further purification. To a solu-
tion of NaH (55% in mineral oil, 143.9 mg, 3.298 mmol) in MeOH
(12 mL) was added a solution of the above residue in MeOH (10 mL)
at 0 ꢂC, followed by stirring for 30 min at the same temperature. The
reaction mixture was then poured into saturated ammonium
chloride aqueous solution (15 mL). The aqueous layer was extracted
with AcOEt and the combined organic layer was washed with brine,
and dried. Evaporation of the solvent followed by silica gel (20 g)
column chromatography of the residue using n-hexane/AcOEt
(90:10 to 50:50) as the eluent afforded 13a (1.2809 g, 93%).
4.1.34. O-Methyl (S)-N-(3-(4-(1-(tert-butoxycarbonyl) [1,2,5]
triazepan-5-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)-
methylthiocarbamate (14b)
Compound 14b (1.5184 g, 98%) was prepared from 13b (1.8471 g,
3.091 mmol) in the same manner as described for 14a. Amorphous
solid; 1H NMR (CDCl3)
d
¼ 1.49 (9H, m, t-C4H9), 3.05 (2H, br t,
J ¼ 5 Hz, eCH2e), 3.27 (2H, br t, J ¼ 5 Hz, eCH2e), 3.41 (2H, t,
J ¼ 5.8 Hz, eCH2e), 3.60 (2H, t, J ¼ 5.8 Hz, eCH2e), 3.80 (1H, dd,
J ¼ 7.1, 9.1 Hz, oxazolidinone-H4), 3.93e4.13 (3H, m, eCH2e), 4.01
(3H, s, OCH3), 4.87e4.97 (1H, m, oxazolidinone-H5), 6.77 (1H, t,
J ¼ 6.3 Hz, eNHeC]S), and 7.08 (2H, d, J ¼ 10.8 Hz, AreH2 and H6);
EI-LRMS m/z: 501 (Mþ).
4.1.35. O-Methyl (S)-N-(3-(4-[1,2,5]oxadiazepan-5-yl)-3,5-
difluorophenyl)-2-oxooxazolidin-5-yl)methylthiocarbamate (14c)
To a solution of 13c (36.0 mg, 0.072 mmol) in CHCl3 (5 mL) was
added trifluoroacetic acid (0.3 mL). The mixture was stirred for 15 h
at ambient temperature, then neutralized with 10% sodium car-
bonate aqueous solution, and extracted with 10% MeOH/CHCl3. The
organic solution was dried, and evaporated, followed by prepara-
tive TLC of the residue using CHCl3/MeOH (90:10) as the eluent to
afford 14c (22.0 mg, 76%). Amorphous solid; 1H NMR (CDCl3)
Amorphous solid; 1H NMR (CDCl3)
d
¼ 1.45e1.51 (9H, m, t-C4H9),
3.07e4.35 (12H, m, eCH2e), 4.01 (3H, s, OCH3), 4.86e4.97 (1H, m,
oxazolidinone-H5), 6.74 (1H, t, J ¼ 6.3 Hz, eNHeC]S), 6.92 (1H, t,
J ¼ 9.1 Hz, AreH6), 7.07 (1H, br d, J ¼ 9 Hz, AreH5), and 7.42 (1H, br
d, J ¼ 14 Hz, AreH2); EI-LRMS m/z: 579 (Mþ).
4.1.31. O-Methyl (S)-N-(3-(4-(1-(tert-butoxycarbonyl)-2-(2,2,2-
trichloroacetyl) [1,2,5]triazepan-5-yl)-3,5-difluorophenyl)-2-
oxooxazolidin-5-yl)methylthiocarbamate (13b)
d
¼ 3.22 (2H, br t, J ¼ 5 Hz, eCH2e), 3.40 (2H, br t, J ¼ 5 Hz, eCH2e),
3.44e3.52 (2H, m, eCH2e), 3.81 (1H, dd,
J
¼ 6.9, 9.0 Hz,
oxazolidinone-H4), 3.90 (2H, br t, J ¼ 5 Hz, eCH2e), 3.97e4.10 (3H,
m, eCH2e), 4.00 (3H, s, OCH3), 4.89e4.99 (1H, m, oxazolidinone-
H5), 7.06 (2H, d, J ¼ 10.8 Hz, AreH2 and H6), and 7.30 (1H, br t,
Compound 13b (1.1156 g, 90%) was prepared from 12b (1.0816 g,
2.066 mmol) in the same manner as described for 13a. Amorphous
solid; 1H NMR (CDCl3)
d
¼ 1.46e1.55 (9H, m, t-C4H9), 3.05e4.27
J ¼ 6 Hz, eNHeC]S); 13C NMR (CDCl3)
d
¼ 47.2, 47.4, 53.5, 55.1,
(12H, m, eCH2e), 4.01 (3H, s, OCH3), 4.87e4.98 (1H, m,
oxazolidinone-H5), 6.69 (1H, t, J ¼ 6.3 Hz, eNHeC]S), and 7.12 (2H,
d, J ¼ 10.7 Hz, AreH2 and H6); EI-LRMS m/z: 597 (Mþ).
55.6, 57.6, 71.3, 72.3, 102.4 (2C, d, J ¼ 31 Hz), 125.7 (t, J ¼ 14 Hz),
132.4 (t, J ¼ 14 Hz), 153.9, 157.6 (2C, dd, J ¼ 9, 244 Hz), and 192.8; EI-
LRMS m/z: 402 (Mþ). EI-HRMS m/z: calcd. for C16H20F2N4O4S (Mþ):
402.1171; found 402.1157.
4.1.32. O-Methyl (S)-N-(3-(4-(1-(tert-butoxycarbonyl) [1,2,5]
oxadiazepan-5-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)-
methylthiocarbamate (13c)
Compound 13c (0.9323 g, 89%) was prepared from 6c (0.8893 g,
2.076 mmol) in the same manner as described for 13a. Amorphous
4.1.36. 5(R)-3-(4-(1-(Benzyloxycarbonyl)-2-(tert-butoxycarbonyl)
[1,2,5]triazepan-5-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)
oxazolidin-2-one (15a)
To a solution of 5a (0.8759 g, 1.538 mmol) in 1,4-dioxane (15 mL)
was added 2,5-norbornadiene (0.7088 g, 7.693 mmol) and the
mixture was refluxed for 40 h. Evaporation of the solvent followed
by silica gel (20 g) column chromatography of the residue using n-
hexane/AcOEt (50:50 to 0:100) as the eluent afforded 15a (0.8754 g,
solid; 1H NMR (CDCl3)
d
¼ 1.51 (9H, s, t-C4H9), 3.35e3.44 (4H, m, e
CH2e), 3.78 (2H, br t, J ¼ 6 Hz, eCH2e), 3.83 (1H, dd, J ¼ 7.2, 9.0 Hz,
oxazolidinone-H4), 3.96e4.12 (5H, m, eCH2e), 4.00 (3H, s, OCH3),
4.89e4.99 (1H, m, oxazolidinone-H5), 7.04e7.21 (1H, br, eNHeC]
S), and 7.09 (2H, d, J ¼ 10.8 Hz, AreH2 and H6); EI-LRMS m/z: 502
(Mþ). EI-HRMS m/z: calcd. for C21H28F2N4O6S (Mþ): 502.1696;
found 502.1685.
96%). Amorphous solid; 1H NMR (CDCl3)
d
¼ 1.32e1.49 (9H, m, t-
C4H9), 3.16e3.59 (6H, m, eCH2e), 3.87 (1H, br dd, J ¼ 6, 9 Hz,
oxazolidinone-H4), 3.96e4.26 (3H, m, eCH2e), 4.70e4.84 (2H, m,

820
H. Suzuki et al. / European Journal of Medicinal Chemistry 63 (2013) 811e825
eCH2e, [1,2,3]triazole), 4.98e5.09 (1H, m, oxazolidinone-H5),
5.04e5.29 (2H, m, AreCH2O), 6.83 (1H, t, J ¼ 9.1 Hz, AreH5),
6.86e6.97 (1H, m, AreH6), 7.18e7.38 (6H, m, AreH), 7.74 (1H, s,
[1,2,3]triazole-H), and 7.79 (1H, s, [1,2,3]triazole-H); EI-LRMS m/z:
595 (Mþ).
4.1.41. 5(R)-3-(4-(2-[1,2,5]Oxadiazepan-5-yl)-3,5-difluorophenyl)-
5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (16c)
Compound 16c (0.8097 g, 94%) was prepared from 15c (1.0895 g,
2.268 mmol) in the same manner as described for 14c. Colourless
needles (EtOH); mp: 152e153 ꢂC; 1H NMR (CDCl3)
d
¼ 3.21 (2H, br t,
J ¼ 6 Hz, eCH2e), 3.38 (2H, br t, J ¼ 5 Hz, eCH2e), 3.47 (2H, br t,
J ¼ 6 Hz, eCH2e), 3.84e3.93 (3H, m, eCH2e), 4.13 (1H, t, J ¼ 9.1 Hz,
oxazolidinone-H4), 4.77 (1H, dd, J ¼ 5.0, 15.0 Hz, eCHHe, [1,2,3]
triazole), 4.82 (1H, dd, J ¼ 4.0, 15.0 Hz, eCHHe, [1,2,3]triazole),
5.03e5.12 (1H, m, oxazolidinone-H5), 6.91e7.03 (2H, m, AreH2 and
H6), 7.74 (1H, br s, [1,2,3]triazole-H), and 7.80 (1H, br s, [1,2,3]
4.1.37. 5(R)-3-(4-(1-(Benzyloxycarbonyl)-2-(tert-butoxycarbonyl)
[1,2,5]triazepan-5-yl)-3,5-difluorophenyl)-5-(1,2,3-triazol-1-
ylmethyl)oxazolidin-2-one (15b)
Compound 15b (2.5053 g, 89%) was prepared from 5b (2.6920 g,
4.582 mmol) in the same manner as described for 15a. Amorphous
solid; 1H NMR (CDCl3)
d
¼ 1.34e1.52 (9H, m, t-C4H9), 3.03e3.50 (6H,
triazole-H); 13C NMR (CDCl3)
d
¼ 47.1, 51.9, 53.6, 55.1, 55.6, 70.3,
m, eCH2e), 3.84e4.17 (3H, m, eCH2e), 4.10(1H, t, J ¼ 9.1 Hz,
oxazolidinone-H4), 4.78 (2H, J ¼ 4.1 Hz, eCH2e, [1,2,3]triazole),
5.01e5.11 (1H, m, oxazolidinone-H5), 5.07e5.32 (2H, m, AreCH2O),
6.97 (2H, d, J ¼ 10.7 Hz, AreH2 and H6), 7.27e7.39 (5H, m, AreH),
7.75 (1H, s, [1,2,3]triazole-H), and 7.77 (1H, s, [1,2,3]triazole-H); EI-
LRMS m/z: 613 (Mþ).
72.3, 102.6 (2C, d, J ¼ 30 Hz), 125.0, 125.9 (t, J ¼ 14 Hz), 131.6 (t,
J ¼ 13 Hz),134.4,152.9, and 157.2 (2C, dd, J ¼ 9, 244 Hz); EI-LRMS m/
z: 380 (Mþ). EI-HRMS m/z: calcd. for C16H18F2N6O3 (Mþ): 380.1407;
found 380.1399.
4.1.42. 5(R)-(Isoxazol-3-yl-N-(tert-butoxycarbonyl)aminomethyl)-
3-(3-fluoro-4-(1-(benzyloxycarbonyl)-2-(tert-butoxycarbonyl)
[1,2,5]triazepan-5-yl)phenyl)oxazolidin-2-one (17a)
4.1.38. 5(R)-3-(4-(2-(tert-Butoxycarbonyl) [1,2,5]oxadiazepan-5-
yl)-3,5-difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-
one (15c)
To a solution of compound 4a (383.1 mg, 0.703 mmol) in THF
(3 mL) was added tri-n-butylphosphine (590.1 mg, 2.917 mmol),
ADDP (709.6 mg, 2.812 mmol) and isoxazol-3-yl-carbamic acid tert-
butyl ester (454.3 mg, 2.466 mmol). The mixture was stirred for
21 h at ambient temperature. Evaporation of the solvent followed
by silica gel (20 g) column chromatography of the residue using n-
hexane/AcOEt (80:20 to 40:60) as the eluent afforded 17a
Compound 15c (1.3578 g, 69%) was prepared from 5c (1.8597 g,
4.096 mmol) in the same manner as described for 15a. Amorphous
1
solid; H NMR (CDCl3)
d
¼ 1.51 (9H, s, t-C4H9), 3.35e3.42 (4H, m, e
CH2e), 3.77 (2H, br t, J ¼ 6 Hz, eCH2e), 3.90 (1H, dd, J ¼ 6.0, 9.3 Hz,
oxazolidinone-H4), 4.06 (2H, br t, J ¼ 5 Hz, eCH2e), 4.14 (1H, t,
J ¼ 9.3 Hz, oxazolidinone-H4), 4.81 (2H, d, J ¼ 4.0 Hz, eCH2e, [1,2,3]
triazole), 5.09(1H, ddt, J¼ 6.0,9.3,4.0Hz, oxazolidinone-H5), 6.99(2H,
d, J ¼ 10.8 Hz, AreH2 and H6), 7.74 (1H, d, J ¼ 0.5 Hz, [1,2,3]triazole-H),
and 7.81 (1H, d, J ¼ 0.5 Hz, [1,2,3]triazole-H); EI-LRMS m/z: 480 (Mþ).
(465.1 mg, 93%). Amorphous solid; 1H NMR (CDCl3)
d
¼ 1.33e1.60
(18H, m, t-C4H9 ꢃ2), 3.17e3.60 (6H, m, eCH2e), 3.75 (1H, br dd,
J ¼ 6, 9 Hz, oxazolidinone-H4), 3.97e4.28 (3H, m, eCH2e), 4.11 (1H,
dd, J ¼ 4.9, 14.6 Hz, eCHHeNBoc-isozazole), 4.36 (1H, dd, J ¼ 7.7,
14.6 Hz, eCHHeNBoc-isoxazole), 5.00e5.10 (1H, m, oxazolidinone-
H5), 5.05e5.29 (2H, m, AreCH2O), 6.88 (1H, t, J ¼ 9.1 Hz, AreH5),
6.91 (1H, br s, isoxazole-H), 7.01e7.11 (1H, m, AreH6), 7.28e7.44
(6H, m, AreH), and 8.25 (1H, d, J ¼ 1.9 Hz, isoxazole-H); EI-LRMS
m/z: 610 (Mþ-Boc).
4.1.39. 5(R)-3-(4-(1-(tert-Butoxycarbonyl) [1,2,5]triazepan-5-yl)-
3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazoli din-2-one
(16a)
A suspension of 15a (0.6789 g, 1.140 mmol) and 10% Pd/C
(136.2 mg) in 95% MeOH (10 mL) was hydrogenated at 1 atm at
ambient temperature for 24 h, and then filtered through a Celite
pad. Evaporation of the solvent followed by silica gel (15 g) column
chromatography of the residue using CHCl3/MeOH (98:2 to 90:10)
as the eluent afforded 16a (0.4838 g, 92%). Amorphous solid; 1H
4.1.43. 5(R)-(Isoxazol-3-yl-N-(tert-butoxycarbonyl)aminomethyl)-
3-(3,5-difluoro-4-(1-(benzyloxycarbonyl)-2-(tert-butoxycarbonyl)
[1,2,5]triazepan-5-yl)phenyl)oxazolidin-2-one (17b)
Compound 17b (463.3 mg, 93%) was prepared from 4b
(385.4 mg, 0.685 mmol) in the same manner as described for 17a.
NMR (CDCl3)
d
¼ 1.37 (9H, s, t-C4H9), 3.10 (2H, t, J ¼ 5.5 Hz, eCH2e),
3.43 (2H, t, J ¼ 5.5 Hz, eCH2e), 3.52e3.59 (2H, m, eCH2e), 3.60e
3.68 (2H, m, eCH2e), 3.86 (1H, dd, J ¼ 6.1, 9.1 Hz, oxazolidinone-
H4), 4.10 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4), 4.76 (1H, dd,
J ¼ 4.7, 14.9 Hz, eCHHe, [1,2,3]triazole), 4.80 (1H, dd, J ¼ 3.9,
14.9 Hz, eCHHe, [1,2,3]triazole), 5.03 (1H, dddd, J ¼ 3.9, 4.7, 6.1,
9.1 Hz, oxazolidinone-H5), 6.83 (1H, t, J ¼ 9.1 Hz, AreH5), 6.88 (1H,
dd, J ¼ 2.5, 9.1 Hz, AreH6), 7.21 (1H, dd, J ¼ 2.5, 15.2 Hz, AreH2),
7.75 (1H, br s, [1,2,3]triazole-H), and 7.79 (1H, br s, [1,2,3]triazole-
H); EI-LRMS m/z: 461 (Mþ).
Amorphous solid; 1H NMR (CDCl3)
d
¼ 1.35e1.61 (18H, m, t-
C4H9 ꢃ2), 3.05e3.55 (6H, m, eCH2e), 3.76 (1H, br dd, J ¼ 6, 9 Hz,
oxazolidinone-H4), 3.97e4.19 (3H, m, eCH2e), 4.12 (1H, dd,
J ¼ 4.9, 14.6 Hz, eCHHeNBoc-isoxazole), 4.35 (1H, dd, J ¼ 7.5,
14.6
Hz,
eCHHeNBoc-isoxazole),
5.01e5.12
(1H,
m,
oxazolidinone-H5), 5.05e5.32 (2H, m, AreCH2O), 6.90 (1H, br s,
isoxazole-H), 7.11 (2H, d, J ¼ 10.7 Hz, AreH2 and H6), 7.28e7.40
(5H, m, AreH), and 8.26 (1H, d, J ¼ 1.9 Hz, isoxazole-H); EI-
LRMS m/z: 728 (Mþ).
4.1.40. 5(R)-3-(4-(1-(tert-Butoxycarbonyl) [1,2,5]triazepan-5-yl)-
3,5-difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one
(16b)
4.1.44. 5(R)-(Isoxazol-3-yl-N-(tert-butoxycarbonyl)aminomethyl)-
3-(3,5-difluoro-4-(2-(tert-butoxycarbonyl) [1,2,5]oxadiazepan-5-yl)
phenyl)oxazolidin-2-one (17c)
Compound 16b (0.4778 g, 96%) was prepared from 15b
(0.6342 g, 1.034 mmol) in the same manner as described for 15a.
Compound 17c (839.8 mg, 89%) was prepared from 4c (650.1 mg,
1.093 mmol) in the same manner as described for 17a. Amorphous
Colourless prisms (EtOH); mp 158e159 ꢂC; 1H NMR (CDCl3)
d
¼ 1.49
solid; 1H NMR (CDCl3)
d
¼ 1.51 (9H, s, t-C4H9), 1.59 (9H, s, t-C4H9),
(9H, s, t-C4H9), 3.03 (2H, t, J ¼ 5.2 Hz, eCH2e), 3.25 (2H, t, J ¼ 5.2 Hz,
eCH2e), 3.39 (2H, t, J ¼ 5.7 Hz, eCH2e), 3.59 (2H, t, J ¼ 5.7 Hz, e
CH2e), 3.88 (1H, dd, J ¼ 6.1, 9.1 Hz, oxazolidinone-H4), 4.10 (1H, t,
J ¼ 9.1 Hz, oxazolidinone-H4), 4.78 (2H, d, J ¼ 4.1 Hz, eCH2e, [1,2,3]
triazole), 5.05 (1H, ddt, J ¼ 6.1, 9.1, 4.1 Hz, oxazolidinone-H5), 6.88
(2H, d, J ¼ 10.7 Hz, AreH2 and H6), 7.75 (1H, br s, [1,2,3]triazole-H),
and 7.77 (1H, br s, [1,2,3]triazole-H); EI-LRMS m/z: 479 (Mþ).
3.33e3.44 (4H, m, eCH2e), 3.74e3.82 (3H, m, eCH2e), 4.06 (1H, t,
J ¼ 9.0 Hz, oxazolidinone-H4), 4.08 (2H, br t, J ¼ 5 Hz, eCH2e), 4.12
(1H, dd, J ¼ 4.5, 14.7 Hz, eCHHeNBoc-isoxazole), 4.36 (1H, dd t,
J ¼ 7.5, 14.7 Hz, eCHHeNBoc-isoxazole), 5.02e5.12 (1H, m,
oxazolidinone-H5), 6.90 (1H, br s, isoxazole-H), 7.12 (2H, d,
J ¼ 11.1 Hz, AreH2 and H6), and 8.27 (1H, d, J ¼ 1.8 Hz, isoxazole-H);
EI-LRMS m/z: 595 (Mþ).

H. Suzuki et al. / European Journal of Medicinal Chemistry 63 (2013) 811e825
821
4.1.45. 5(R)-(Isoxazol-3-yl-N-(tert-butoxycarbonyl)aminomethyl)-
3-(3-fluoro-4-(1-(tert-butoxycarbonyl) [1,2,5]triazepan-5-yl)
phenyl)oxazolidin-2-one (18a)
mixture was stirred for 10 min at ambient temperature. The reac-
tion mixture was diluted by the addition of H2O (10 mL), and
extracted with 5% MeOH/CHCl3. The organic solution was dried and
evaporated to afford a residue, which was used without further
purification. To a stirred solution of the residue in CH2Cl2 (4 mL)
was added trifluoroacetic acid (0.5 mL) and stirring was continued
for 3 h at ambient temperature. The reaction mixture was
neutralized by the addition of 10% sodium carbonate aqueous so-
lution, and the mixture was extracted with 10% MeOH/CHCl3. The
organic solution was dried and evaporated, followed by silica gel
(8 g) column chromatography of the residue using CHCl3/MeOH
(97:3 to 90:10) as the eluent to afford 19a (192.5 mg, 92%). Amor-
A suspension of 17a (465.1 mg, 0.654 mmol) and 10% Pd/C
(93.1 mg) in 95% MeOH (7 mL) was hydrogenated at 1 atm at
ambient temperature for 4 h, and then filtered through a Celite pad.
Evaporation of the solvent followed by silica gel (15 g) column
chromatography of the residue using n-hexane/AcOEt (70:30 to
20:80) as the eluent afforded 18a (301.0 mg, 80%). Amorphous
solid; 1H NMR (CDCl3)
d
¼ 1.38 (9H, s, t-C4H9), 1.56 (9H, s, t-C4H9),
3.12 (2H, t, J ¼ 5.5 Hz, eCH2e), 3.44 (2H, t, J ¼ 5.5 Hz, eCH2e), 3.57
(2H, t, J ¼ 5.2 Hz, eCH2e), 3.65 (2H, t, J ¼ 5.2 Hz, eCH2e), 3.75 (1H,
dd, J ¼ 5.2, 9.1 Hz, oxazolidinone-H4), 4.05 (1H, t, J ¼ 9.1 Hz,
oxazolidinone-H4), 4.11 (1H, dd, J ¼ 4.9, 14.6 Hz, eCHHeNBoc-
isoxazole), 4.36 (1H, dd, J ¼ 7.7, 14.6 Hz, eCHHeNBoc-isoxazole),
5.04 (1H, dddd, J ¼ 4.9, 5.2, 7.7, 9.1 Hz, oxazolidinone-H5), 6.88
(1H, t, J ¼ 9.1 Hz, AreH5), 6.91 (1H, br s, isoxazole-H), 7.03 (1H, dd,
J ¼ 2.7, 9.1 Hz, AreH6), 7.37 (1H, dd, J ¼ 2.7, 15.4 Hz, AreH2), and
8.26 (1H, d, J ¼ 1.7 Hz, isoxazole-H); EI-LRMS m/z: 576 (Mþ).
phous solid; 1H NMR (CDCl3)
d
¼ 2.02 (3H, s, CH3C]O), 3.12e3.78
(9H, m, eCH2e), 3.91e4.05 (3H, m, eCH2e), 4.37 (2H, br s, eCH2e
OH), 4.72e4.81 (1H, m, oxazolidinone-H5), 6.27 (1H, br t, J ¼ 6 Hz, e
NHeC]O), 6.89 (1H, t, J ¼ 9.1 Hz, AreH5), 6.98e7.06 (1H, m, Are
H6), and 7.37e7.46 (1H, m, AreH2); 13C NMR (CD3OD þ CDCl3)
d
¼ 22.3, 41.8, 47.7, 49.9, 50.7 (2C), 53.8, 60.2, 71.9, 107.6 (d,
J ¼ 27 Hz), 114.0, 118.8, 131.4 (d, J ¼ 10 Hz), 136.0 (d, J ¼ 9 Hz), 154.0
(d, J ¼ 242 Hz), 154.7, 172.0, and 174.0.; EI-LRMS m/z: 409 (Mþ). EI-
HRMS m/z: calcd. for C18H24FN5O5 (Mþ): 409.1761; found 409.1769.
4.1.46. 5(R)-(Isoxazol-3-yl-N-(tert-butoxycarbonyl)aminomethyl)-
3-(3,5-difluoro-4-(1-(tert-butoxycarbonyl) [1,2,5]triaze-pan-5-yl)
phenyl)oxazolidin-2-one (18b)
4.1.49. (S)-N-((3-(3,5-Difluoro-4-(1-(hydroxyacetyl) [1,2,5]
triazepan-5-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)acetamide
(19b)
Compound 19b (193.7 mg, 90%) was prepared from 7b
(236.5 mg, 0.504 mmol) in the same manner as described for 19a.
Compound 18b (305.6 mg, 81%) was prepared from 17b
(463.3 mg, 0.636 mmol) in the same manner as described for 18a.
Amorphous solid; 1H NMR (CDCl3)
d
¼ 1.49 (9H, s, t-C4H9), 1.56 (9H,
s, t-C4H9), 3.05 (2H, t, J ¼ 5.2 Hz, eCH2e), 3.27 (2H, t, J ¼ 5.2 Hz, e
CH2e), 3.41 (2H, t, J ¼ 5.7 Hz, eCH2e), 3.60 (2H, t, J ¼ 5.7 Hz, eCH2e
), 3.76 (1H, dd, J ¼ 5.5, 9.1 Hz, oxazolidinone-H4), 4.04 (1H, t,
J ¼ 9.1 Hz, oxazolidinone-H4), 4.12 (1H, dd, J ¼ 4.9, 14.7 Hz, eCHHe
NBoc-isoxazole), 4.36 (1H, dd, J ¼ 7.5, 14.7 Hz, eCHHeNBoc-
isoxazole), 5.04 (1H, dddd, J ¼ 4.9, 5.5, 7.3, 9.1 Hz, oxazolidinone-
H5), 6.90 (1H, br s, isoxazole-H), 7.10 (2H, d, J ¼ 10.7 Hz, AreH2
and H6), and 8.26 (1H, d, J ¼ 1.9 Hz, isoxazole-H); EI-LRMS m/z:
594 (Mþ).
Amorphous solid; 1H NMR (CDCl3)
d
¼ 2.03 (3H, s, CH3eC]O),
3.10e3.22 (2H, m, eCH2e), 3.25e3.31 (2H, m, eCH2e), 3.34e3.42
(2H, m, eCH2e), 3.63e3.70 (2H, m, eCH2e), 3.75 (1H, dd, J ¼ 6.6,
9.1 Hz, oxazolidinone-H4), 3.88e3.93 (2H, m, eCH2e), 4.01 (1H, t,
J ¼ 9.1 Hz, oxazolidinone-H4), 4.39 (2H, s, eCH2eOH), 4.75e4.85
(1H, m, oxazolidinone-H5), 6.77 (1H, t, J ¼ 6.1 Hz, eNHeC]O),
and 7.09 (2H, d, J ¼ 10.7 Hz, AreH2 and H6); 13C NMR (CDCl3)
d
¼ 23.0, 41.8, 51.2, 51.9, 52.4, 55.5, 60.6, 72.0, 102.2 (2C, d,
J ¼ 29 Hz), 124.7 (t, J ¼ 14 Hz), 134.1 (t, J ¼ 13 Hz), 153.9, 158.3 (2C,
dd, J ¼ 9, 244 Hz), 171.3, and 174.2.; ESI-LRMS m/z: 428 (Mþ þ H).
ESI-HRMS m/z: calcd. for C18H24F2N5O5 (Mþ þ H): 428.1740; found
428.1739.
4.1.47. 5(S)-(Isoxazol-3-yl-aminomethyl)-3-(3,5-difluoro-4-([1,2,5]
oxadiazepan-5-yl)phenyl)oxazolidin-2-one (18c)
Compound 18c (180.6 mg, 73%) was prepared from 17c
(372.0 mg, 0.625 mmol) in the same manner as described for 14c.
Colourless prisms (EtOH); mp: 139e140 ꢂC; 1H NMR (CDCl3)
4.1.50. (S)-N-((3-(3,5-Difluoro-4-(2-(hydroxyacetyl) [1,2,5]
oxadiazepan-5-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)acetamide
(19c)
d
¼ 3.21 (2H, br t, J ¼ 6 Hz, eCH2e), 3.38 (2H, br t, J ¼ 6 Hz, eCH2e),
3.48 (2H, br t, J ¼ 6 Hz, eCH2e), 3.61 (1H, dt, J ¼ 14.7, 6.0 Hz, eCHHe
NH-isoxazole), 3.71 (1H, ddd, J ¼ 3.6, 6.0, 14.7 Hz, eCHHeNH-
isoxazole), 3.81 (1H, dd, J ¼ 6.6, 9.0 Hz, oxazolidinone-H4), 3.89
(2H, br t, J ¼ 6 Hz, eCH2e), 4.03 (1H, t, J ¼ 9.0 Hz, oxazolidinone-
H4), 4.92 (1H, br t, J ¼ 6 Hz, eCH2e), 4.93 (1H, dddd, J ¼ 3.6, 6.0,
6.6, 9.0 Hz, oxazolidinone-H5), 5.82 (1H, br s, NH), 5.90 (1H, d,
J ¼ 2.1 Hz, isoxazole-H), 7.06 (2H, d, J ¼ 11.1 Hz, AreH2 and H6), and
To a solution of compound 7c (129.8 mg, 0.433 mmol) and Et3N
(0.80 mL, 5.692 mmol) in CH2Cl2 (10 mL) was added acetoxyacetyl
chloride (0.20 mL, 1.860 mmol) at 0 ꢂC. The mixture was stirred for
1 h at the same temperature, and then extracted with CHCl3. The
organic solution was dried and evaporated to afford a residue,
which was used without further purification. To a solution of the
residue in MeOH (10 mL) was added potassium carbonate
(112.9 mg, 0.817 mmol). The mixture was stirred for 30 min at
ambient temperature, diluted by the addition of H2O (5 mL),
extracted with 5% MeOH/CHCl3, and dried. Evaporation of the sol-
vent followed by preparative TLC of the residue using CHCl3/MeOH
(9:1) as the eluent afforded 19c (111.2 mg, 74%). Colourless needles
8.05 (1H, d, J ¼ 2.1 Hz, isoxazole-H); 13C NMR (CDCl3)
¼ 46.4, 47.5,
d
53.6, 55.1, 55.7, 71.4, 72.3, 96.4, 102.3 (2C, d, J ¼ 30 Hz), 125.5 (t,
J ¼ 14 Hz), 132.5 (t, J ¼ 13 Hz), 154.0, 157.5 (2C, dd, J ¼ 9, 244 Hz),
158.1, and 163.4; EI-LRMS m/z: 395 (Mþ). EI-HRMS m/z: calcd. for
C
17H19F2N5O4 (Mþ): 395.1404; found 395.1399.
4.1.48. (S)-N-((3-(3-Fluoro-4-(1-(hydroxyacetyl) [1,2,5]triazepan-
5-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)acetamide (19a)
(EtOH); mp: 145e146 ꢂC; 1H NMR (CD3OD þ CDCl3)
¼ 2.03 (3H, s,
d
CH3eC]O), 3.42 (2H, br t, J ¼ 5 Hz, eCH2e), 3.47 (2H, br t, J ¼ 5 Hz,
eCH2e), 3.51e3.67 (2H, m, eCH2e), 3.74 (1H, dd, J ¼ 6.6, 9.0 Hz,
oxazolidinone-H4), 3.94 (2H, br t, J ¼ 5 Hz, eCH2e), 4.04 (1H, t,
J ¼ 9.0 Hz, oxazolidinone-H4), 4.14 (2H, br t, J ¼ 5 Hz, eCH2e), 4.38
(2H, s, eCH2eOH), 4.74e4.84 (1H, m, oxazolidinone-H5), 7.14 (2H,
d, J ¼ 10.8 Hz, AreH2 and H6), and 7.91 (1H, br t, J ¼ 6 Hz, eNHeC]
To a solution of compound 7a (229.7 mg, 0.509 mmol) and
pyridine (61.0 mg, 0.771 mmol) in CH2Cl2 (3 mL) was added ace-
toxyacetyl chloride (84.1 mg, 0.616 mmol). The mixture was stirred
for 10 min, and then 10% citric acid aqueous solution (10 mL) was
added. The mixture was extracted with CHCl3 and dried. Evapora-
tion of the solvent afforded a residue, which was used without
further purification. To a solution of the residue in MeOH (3 mL)
was added potassium carbonate (138.1 mg, 0.999 mmol), and the
O); 13C NMR (CD3OD þ CDCl3)
d
¼ 22.3, 41.7, 47.4, 50.2, 51.9, 54.4,
59.5, 71.9, 77.7, 102.2 (2C, d, J ¼ 30 Hz), 124.1 (t, J ¼ 14 Hz), 133.9 (t,
J ¼ 14 Hz), 154.2, 157.9 (2C, dd, J ¼ 8, 244 Hz), 172.0, and 172.1.; EI-

822
H. Suzuki et al. / European Journal of Medicinal Chemistry 63 (2013) 811e825
LRMS m/z: 380 (Mþ). HRMS-EI (m/z): calcd. for C18H22F2N4O6 (Mþ):
428.1506; found 428.1520.
J ¼ 26 Hz), 114.1, 118.8 (d, J ¼ 4 Hz), 131.4 (d, J ¼ 11 Hz), 136.1 (d,
J ¼ 9 Hz), 154.0 (d, J ¼ 242 Hz), 154.7, 174.0, and 192.5; ESI-LRMS m/
z: 442 (Mþ þ H). ESI-HRMS m/z: calcd. for C18H25FN5O5S (Mþ þ H):
442.1555; found 442.1561.
4.1.51. (S)-N-((3-(3-Fluoro-4-(1-(hydroxyacetyl) [1,2,5]triazepan-
5-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)thioacetamide (20a)
Compound 20a (120.1 mg, 87%) was prepared from 9a (151.0 mg,
0.323 mmol) in the same manner as described for 19a. Colourless
4.1.55. (S)-N-((3-(3,5-Difluoro-4-(1-(hydroxyacetyl) [1,2,5]
triazepan-5-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-O-
methylthiocarbamate (21b) [43]
Compound 21b (201.7 mg, 86%) was prepared from 14b
(257.5 mg, 0.513 mmol) in the same manner as described for 19a.
prisms (EtOH); mp 158e159 ꢂC; 1H NMR (CD3OD þ CDCl3)
¼ 2.57
d
(3H, s, CH3eC]S), 3.12e3.21 (2H, m, eCH2e), 3.32e3.39 (2H, m, e
CH2e), 3.41e3.47 (2H, m, eCH2e), 3.84 (1H, dd, J ¼ 6.9, 9.1 Hz,
oxazolidinone-H4), 3.88e4.20 (5H, m, eCH2e), 4.38 (2H, s, eCH2e
OH), 4.94e5.04 (1H, m, oxazolidinone-H5), 6.93 (1H, t, J ¼ 9.1 Hz,
AreH5), 7.05 (1H, dd, J ¼ 2.5, 9.1 Hz, AreH6), and 7.40 (1H, dd,
J ¼ 2.5,14.5 Hz, AreH2); ESI-LRMS m/z: 426 (Mþ þ H). ESI-HRMS m/
z: calcd. for C18H25FN5O4S (Mþ þ H): 426.1606; found 426.1602.
4.1.56. (S)-N-((3-(3,5-Difluoro-4-(2-(hydroxyacetyl) [1,2,5]
oxadiazepan-5-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-O-
methylthiocarbamate (21c) [43]
Compound 21c (87.2 mg, 66%) was prepared from 14c (115.8 mg,
0.288 mmol) in the same manner as described for 19c.
4.1.52. (S)-N-((3-(3,5-Difluoro-4-(1-(hydroxyacetyl) [1,2,5]
triazepan-5-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)thioacetamide
(20b)
Compound 20b (102.7 mg, 70%) was prepared from 9b
(160.3 mg, 0.330 mmol) in the same manner as described for 19a.
White powder (EtOH); mp 136e137 ꢂC; 1H NMR (CD3OD þ CDCl3),
4.1.57. 5(R)-3-(4-(1-(Hydroxyacetyl) [1,2,5]triazepan-5-yl)-3-
fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (22a)
Compound 22a (212.0 mg, 88%) was prepared from 16a
(266.3 mg, 0.577 mmol) in the same manner as described for 19a.
White powder (EtOH); mp 138.5e139.5 ꢂC; 1H NMR (CDCl3)
d
¼ 2.56 (3H, s, CH3eC]S), 3.09e3.16 (2H, m, eCH2e), 3.25e3.33
d
¼ 3.11e4.00 (9H, m, eCH2e), 4.12 (1H, t, J ¼ 9.1 Hz, oxazolidinone-
(2H, m, eCH2e), 3.34e3.43 (2H, m, eCH2e), 3.80e3.88 (3H, m, e
CH2e), 3.96e4.21 (3H, m, eCH2e), 4.41 (2H, s, eCH2eOH), 4.95e
5.05 (1H, m, oxazolidinone-H5), and 7.13 (2H, d, J ¼ 10.7 Hz, Are
H4), 4.36 (2H, d, J ¼ 4.3 Hz, eCH2eOH), 4.78 (2H, d, J ¼ 4.1 Hz, e
CH2e, [1,2,3]triazole), 5.00e5.10 (1H, m, oxazolidinone-H5), 6.85
(1H, t, J ¼ 9.1 Hz, AreH5), 6.92 (1H, dd, J ¼ 2.5, 9.1 Hz, AreH6), 7.26
(1H, dd, J ¼ 2.5, 14.3 Hz, AreH2), 7.75 (1H, s, [1,2,3]triazole-H), and
H2 and H6); 13C NMR (CD3OD þ CDCl3)
d
¼ 31.9, 46.3, 46.8, 49.6,
50.8 (2C), 54.3, 59.2, 69.4, 101.0 (2C, dd, J ¼ 9, 30 Hz), 123.4 (t,
J ¼ 14 Hz), 133.0 (t, J ¼ 11 Hz), 152.5, 156.9 (2C, dd, J ¼ 9, 244 Hz),
172.7, and 201.1; ESI-LRMS m/z: 444 (Mþ þ H). ESI-HRMS m/z:
calcd. for C18H24F2N5O4S (Mþ þ H): 444.1512; found 444.1511.
7.79 (1H, s, [1,2,3]triazole-H); 13C NMR (CD3OD þ CDCl3)
d
¼ 47.3,
49.9, 50.6 (2C), 51.9, 53.7, 60.2, 70.4, 107.9 (d, J ¼ 26 Hz), 114.3, 118.6,
125.2, 130.6 (d, J ¼ 10 Hz), 133.8, 136.2 (d, J ¼ 9 Hz), 153.5, 153.8 (d,
J ¼ 242 Hz), and 174.0; ESI-LRMS m/z: 420 (Mþ þ H). ESI-HRMS m/z:
calcd. for C18H23FN7O4 (Mþ þ H): 420.1790; found 420.1795.
4.1.53. (S)-N-((3-(3,5-Difluoro-4-(2-(hydroxyacetyl) [1,2,5]
oxadiazepan-5-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)
thioacetamide (20c)
4.1.58. 5(R)-3-(4-(1-(Hydroxyacetyl) [1,2,5]triazepan-5-yl)-3,5-
difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (22b)
Compound 22b (147.3 mg, 97%) was prepared from 16b
(167.4 mg, 0.349 mmol) in the same manner as described for 19a.
Compound 20c (57.1 mg, 80%) was prepared from 9c (61.9 mg,
0.160 mmol) in the same manner as described for 19c. Colourless
needles (EtOH); mp: 137e138 ꢂC; 1H NMR (CD3OD þ CDCl3)
White powder (EtOH); mp 155e156 ꢂC; 1H NMR (CDCl3)
d
¼ 3.01e
4.18 (10H, m, eCH2e), 4.38 (2H, d, J ¼ 4.5 Hz, eCH2eOH), 4.79 (2H,
d, 4.1 Hz, eCH2e, [1,2,3]triazole), 5.02e5.12 (1H, m,
d
¼ 2.57 (3H, s, CH3eC]S), 3.42 (2H, br t, J ¼ 5 Hz, eCH2e), 3.48
(2H, br t, J ¼ 6 Hz, eCH2e), 3.83 (1H, dd, J ¼ 6.9, 9.0 Hz,
oxazolidinone-H4), 3.94 (2H, br t, J ¼ 6 Hz, eCH2e), 4.02 (1H, dd,
J ¼ 6.6, 14.4 Hz, eCHHeNHeC]S), 4.07 (1H, t, J ¼ 9.0 Hz,
oxazolidinone-H4), 4.13 (2H, br t, J ¼ 5 Hz, eCH2e), 4.18 (1H, dd,
J ¼ 3.0, 14.4 Hz, eCHHeNHeC]S), 4.38 (2H, s, eCH2eOH), 4.99
(1H, dddd, J ¼ 3.0, 6.6, 6.9, 9.0 Hz, oxazolidinone-H5), and 7.14
(2H, d, J ¼ 10.8 Hz, AreH2 and H6); 13C NMR (CD3OD þ CDCl3)
J
¼
oxazolidinone-H5), 6.98 (2H, d, J ¼ 10.7 Hz, AreH2 and H6), 7.75
(1H, s, [1,2,3]triazole-H), and 7.78 (1H, s, [1,2,3]triazole-H).; 13C
NMR (CD3OD þ CDCl3) ¼ 47.0, 51.0, 51.6, 51.8, 52.1, 55.3, 60.3, 70.4,
d
102.4 (2C, dd, J ¼ 6, 30 Hz), 125.0 (t, J ¼ 14 Hz), 125.2, 133.3 (t,
J ¼ 13 Hz), 133.9, 153.1, 158.1 (2C, dd, J ¼ 9, 244 Hz), and 174.0; ESI-
LRMS m/z: 438 (Mþ þ H). ESI-HRMS m/z: calcd. for C18H22F2N7O4
(Mþ þ H): 438.1696; found 438.1700.
d
¼ 33.1, 47.6, 47.8, 50.3, 52.0, 54.5, 59.6, 71.3, 77.8, 102.4 (2C, d,
J ¼ 30 Hz), 124.4 (t, J ¼ 14 Hz), 133.7 (t, J ¼ 13 Hz), 154.3, 157.9 (2C,
dd, J ¼ 8, 244 Hz), 172.2, and 203.3; EI-LRMS m/z: 444 (Mþ). EI-
HRMS m/z: calcd. for C18H22F2N4O5S (Mþ): 444.1279; found
444.1272.
4.1.59. 5(R)-3-(4-(2-(Hydroxyacetyl) [1,2,5]oxadiazepan-5-yl)-3,5-
difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (22c)
Compound 22c (53.2 mg, 92%) was prepared from 16c (50.1 mg,
0.131 mmol) in the same manner as described for 19c. Colourless
4.1.54. (S)-N-((3-[3-Fluoro-4-(1-(hydroxyacetyl) [1,2,5]triazepan-
5-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-O-
methylthiocarbamate) (21a)
prisms (EtOH); mp: 136e137 ꢂC; 1H NMR (CD3OD þ CDCl3)
¼ 3.40
d
(2H, br t, J ¼ 5 Hz, eCH2e), 3.46 (2H, br t, J ¼ 6 Hz, eCH2e), 3.85e
3.96 (3H, m, eCH2e), 4.13 (2H, br t, J ¼ 5 Hz, eCH2e), 4.17 (1H, t,
J ¼ 9.3 Hz, oxazolidinone-H4), 4.37 (2H, s, eCH2eOH), 4.81 (1H, dd,
J ¼ 4.5, 14.7 Hz, eCHHe, [1,2,3]triazole), 4.85 (1H, dd, J ¼ 3.9,
14.7 Hz, eCHHe, [1,2,3]triazole), 5.07e5.17 (1H, m, oxazolidinone-
H5), 7.04 (2H, d, J ¼ 10.5 Hz, AreH2 and H6), 7.74 (1H, d, J ¼ 0.9 Hz,
Compound 21a (221.1 mg, 87%) was prepared from 14a
(279.1 mg, 0.577 mmol) in the same manner as described for 19a.
White powder (EtOH); mp: 116e119 ꢂC; 1H NMR (CDCl3)
d
¼ 3.12e
3.48 (6H, m, eCH2e), 3.62e3.76 (2H, m, eCH2e), 3.82 (1H, dd,
J ¼ 6.9, 9.1 Hz, oxazolidinone-H4), 3.90e4.14 (3H, m, eCH2e), 4.00
(3H, s, OCH3), 4.37 (2H, br s, eCH2eOH), 4.85e4.96 (1H, m,
oxazolidinone-H5), 6.87 (1H, br t, J ¼ 6 Hz, eNHeC]S), 6.89 (1H, t,
J ¼ 9.1 Hz, AreH5), 7.05 (1H, dd, J ¼ 2.5, 9.1 Hz, AreH6), and 7.41
(1H, dd, J ¼ 2.5, 14.6 Hz, AreH2); 13C NMR (CD3OD þ CDCl3)
[1,2,3]triazole-H), and 7.89 (1H, d, J ¼ 0.9 Hz, [1,2,3]triazole-H); 13
C
NMR (CD3OD þ CDCl3) ¼ 46.9, 50.2, 51.7 (2C), 54.4, 59.5, 70.5, 77.7,
d
102.4 (2C, d, J ¼ 29 Hz), 124.4 (t, J ¼ 14 Hz),125.2,133.2 (t, J ¼ 13 Hz),
133.8, 153.1, 157.8 (2C, dd, J ¼ 9, 244 Hz), and 172.1; EI-LRMS m/z:
438 (Mþ). EI-HRMS m/z: calcd. for C18H20F2N6O5 (Mþ): 438.1462;
found 438.1469.
d
¼ 47.3, 47.7, 49.9, 50.7, 51.3, 53.9, 57.2, 60.2, 71.5, 107.7 (d,

H. Suzuki et al. / European Journal of Medicinal Chemistry 63 (2013) 811e825
823
4.1.60. 5(S)-(Isoxazol-3-yl-aminomethyl)-3-(3-fluoro-4-(1-
(hydroxyacetyl) [1,2,5]triazepan-5-yl)phenyl)oxazolidin-2-one
(23a)
Compound 23a (123.2 mg, 84%) was prepared from 18a
(194.3 mg, 0.337 mmol) in the same manner as described for 19a.
SR26207, E. faecalis SR1004 and E. faecium SR7940. S. aureus Smith
and S. aureus resistant to linezolid NRS271 (NARSA) were also used.
Gram-negative bacteria used in the study were clinical isolates of
M. catarrhalis SR26840 and H. influenzae SR27914.
Amorphous solid; 1H NMR (CDCl3)
d
¼ 3.11e3.76 (9H, m, eCH2e),
4.3. In vivo antibacterial efficacy
3.81 (1H, dd, J ¼ 6.9, 9.1 Hz, oxazolidinone-H4), 3.89e3.95 (1H,
m, eCH2e), 4.04 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4), 4.36 (2H, s, e
CH2-OH), 4.73 (1H, br s, J ¼ 6 Hz, NH), 4.87e4.98 (1H, m,
oxazolidinone-H5), 5.89 (1H, d, J ¼ 1.9 Hz, isoxazole-H), 6.87 (1H, t,
J ¼ 9.1 Hz, AreH5), 7.03 (1H, br d, J ¼ 9 Hz, AreH6), 7.39 (1H, dd,
The data on in vivo efficacy of the compounds are summarized in
Table 2. Five-week-old male JCL/ICR mice (body weight 20e25 g)
from Clea Japan, Inc. (Tokyo) were used in systemic infection
models (five mice per group). All studies with animals were
approved by the Animal Care and Use Committee of Shionogi Co.,
Ltd. The test strain was methicillin-resistant S. aureus SR3637 [51].
Mice were injected intraperitoneally with 0.5 or 1.0 mL of bacterial
suspension (approximately 100 times the 50% lethal dose). Test and
reference compounds were administered intravenously or orally
1 h after infection. Mortality was recorded over 7 days to estimate
the 50% effective dose (ED50), and 95% confidence limits, which
were determined by the logit method.
J ¼ 2.5,14.6 Hz, AreH2), and 8.05 (1H, d, J ¼ 1.9 Hz, isoxazole-H); 13
C
NMR (CDCl3)
d
¼ 46.6, 47.8, 50.3, 51.0, 51.1, 54.1, 60.6, 71.3, 96.4,
107.7 (d, J ¼ 26 Hz), 114.0, 119.0, 131.9 (d, J ¼ 10 Hz), 136.0 (d,
J ¼ 9 Hz), 154.3 (d, J ¼ 242 Hz), 154.3, 158.1, 163.4, and 174.3; ESI-
LRMS m/z: 435 (Mþ þ H). ESI-HRMS m/z: calcd. for C19H24FN6O5
(Mþ þ H): 435.1787; found 435.1794.
4.1.61. 5(S)-(Isoxazol-3-yl-aminomethyl)-3-(3,5-difluoro-4-(1-
(hydroxyacetyl) [1,2,5]triazepan-5-yl)phenyl)oxazolidin-2-one
(23b)
4.4. In vitro inhibition assay for CYP450 isoforms
Compound 23b (379.2 mg, 90%) was prepared from 18b
(555.5 mg, 0.934 mmol) in the same manner as described for 19a.
The inhibitory effects of the compounds on selected CYP450
isoforms are summarized in Table 3. Human CYP450 activities were
measured using the following reactions: ethoxyresorufin O-dee-
thylation for CYP1A2, tolbutamide hydroxylation for CYP2C9, dex-
tromethorphan O-demethylation for CYP2D6, and terfenadine
hydroxylation for CYP3A4. The incubation mixture consisted of
1 mM NADPH, 50 mM HEPES buffer (pH 7.4) including 10 mM MgCl2
and 0.1 mM EDTA, human liver microsomes (0.2 mg protein/mL) and
Amorphous solid; 1H NMR (CDCl3)
d
¼ 3.01e3.89 (11H, m, eCH2e),
4.04 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4), 4.38 (2H, br s, eCH2eOH),
4.67 (1H, br t, J ¼ 6 Hz, NH), 4.90e5.00 (1H, m, oxazolidinone-H5),
5.89 (1H, d, J ¼ 1.9 Hz, isoxazole-H), 7.11 (2H, d, J ¼ 10.7 Hz, AreH2
and H6), and 8.05 (1H, d, J ¼ 1.9 Hz, isoxazole-H); 13C NMR (CDCl3)
d
¼ 46.5, 47.5, 51.3, 51.9, 52.4, 55.5, 60.6, 71.4, 96.4, 102.2 (2C, d,
J ¼ 30 Hz), 124.8 (t, J ¼ 15 Hz), 134.2 (t, J ¼ 13 Hz), 153.9, 158.4 (2C,
dd, J ¼ 9, 244 Hz), 158.5, 163.4, and 174.2; ESI-LRMS m/z: 453
(Mþ þ H). ESI-HRMS m/z: calcd. for C19H22F2N6O5 (Mþ þ H):
453.1693; found 453.1693.
a cocktail of the 4 substrates (0.375
tolbutamide, 5 M dextromethorphan and 1
presence or absence of test compound in a final volume of 500
solution of test compound in DMSO (final 0.5%) was added to give a
final concentration of 0, 1, 5, 10 and 20 M. Reactions were initiated
m
M ethoxyresorufin, 100
M terfenadine) in the
l. A
mM
m
m
m
4.1.62. 5(S)-(Isoxazol-3-yl-aminomethyl)-3-(3,5-difluoro-4-(2-
(hydroxyacetyl) [1,2,5]oxadiazepan-5-yl)phenyl)oxazolidin-2-one
(23c)
m
by adding NADPH. After incubation for 20 min at 37 ꢂC, reactions
were terminated by the addition of an equivalent volume of aceto-
nitrile/methanol (1/1, v/v). A standard curvewas prepared byadding
authentic metabolite cocktail to the same reaction components
without incubation. After centrifugation, the supernatants were
evaluated with a fluorescence plate reader (for CYP1A2) or an LC/
MS/MS system (for CYP2C9, 2D6 and 3A4).
Compound 23c (38.1 mg, 74%) was prepared from 18c (55.9 mg,
0.141 mmol) in the same manner as described for 19c. Colourless
needles (EtOH); mp: 154.5e155.5 ꢂC; 1H NMR (CD3OD þ CDCl3)
d
¼ 3.41 (2H, br t, J ¼ 5 Hz, eCH2e), 3.47 (2H, br t, J ¼ 5 Hz, eCH2e),
3.57 (1H, dd, J ¼ 5.7, 14.4 Hz, eCHHeNH-isoxazole), 3.64 (1H, dd,
J ¼ 3.9, 14.4 Hz, eCHHeNH-isoxazole), 3.83 (1H, dd, J ¼ 6.6, 9.0 Hz,
oxazolidinone-H4), 3.93 (2H, br t, J ¼ 5 Hz, eCH2e), 4.07 (1H, t,
J ¼ 9.0 Hz, oxazolidinone-H4), 4.14 (2H, br t, J ¼ 5 Hz, eCH2e), 4.38
(2H, s, eCH2eOH), 4.94 (1H, dddd, J ¼ 3.9, 5.7, 6.6, 9.0 Hz,
oxazolidinone-H5), 5.93 (1H, d, J ¼ 1.5 Hz, isoxazole-H), 7.14 (2H, d,
J ¼ 10.8 Hz, AreH2 and H6), and 8.07 (1H, d, J ¼ 1.5 Hz, isoxazole-
4.5. In vitro inhibition assay for MAO-A and MAO-B
The inhibitory effects of test compounds on MAO-A and MAO-B
activities are summarized in Table 3. MAO-A and MAO-B activities
were measured by a slight modification of the method of Curet et al.
[52]. Rat forebrains were homogenized in 20 volumes of buffer
(0.25 M sucrose, 10 mM sodium phosphate buffer, pH 7.4) at 4 ꢂC
H); 13C NMR (CD3OD þ CDCl3)
d
¼ 46.0, 47.4, 50.2, 51.9, 54.5, 59.5,
71.6, 77.7, 96.2, 102.2 (2C, d, J ¼ 29 Hz), 124.0 (t, J ¼ 14 Hz), 134.0 (t,
J ¼ 13 Hz),154.3,157.9, 157.9 (2C, dd, J ¼ 9, 244 Hz),163.4, and 172.1;
EI-LRMS m/z: 453 (Mþ). EI-HRMS m/z: calcd. for C19H21F2N5O6
(Mþ): 453.1458; found 453.1459.
(final concentration: 500
mogenate was preincubated for 20 min at 37 ꢂC with or without
test compound (final concentration of 30 M) in a total volume of
400 l. After this preincubation, the reaction was started by the
addition of [14C]5-HT as a specific MAO-A substrate (final concen-
tration 500 M, specific activity 1 Ci/
mol) or [14C]PEA as a specific
MAO-B substrate (final concentration 125 M, specific activity
0.1 Ci/ mol). The final volume of incubation buffer (0.25 M su-
crose, 10 mM sodium phosphate buffer, pH 7.4) was 500 l and the
incubation times were 5 min for MAO-A and 10 min for MAO-B. The
reaction was stopped by adding 200 l of 4 M HCl and 5 mL of
mg of tissue/assay). Briefly, 100 ml of ho-
m
m
4.2. In vitro antibacterial activity
m
m
m
The in vitro antibacterial activities of the compounds shown in
Table 1 were determined by the broth microdilution method rec-
ommended by the Clinical Laboratory Standards Institute (CLSI).
Cation-adjusted Mueller-Hinton broth (CAMHB) (Difco) was used
except for S. pneumoniae and H. influenzae. For S. pneumoniae,
CAMHB supplemented with 5% lysed horse blood was used. For
H. influenzae, Haemophilus test medium (Nissui Pharmaceutical
Co., Ltd., Japan) was used. The tested Gram-positive organisms
included clinical isolate of S. aureus SR20549, S. pneumoniae
m
m
m
m
m
extraction solvent (toluene/ethyl acetate vol/vol). After vigorous
shaking and centrifugation (1000 rpm, 5 min) of the mixture, the
radioactivity of the organic layer was measured with a liquid
scintillation counter.

824
H. Suzuki et al. / European Journal of Medicinal Chemistry 63 (2013) 811e825
nitroxides and their precursors from myocardial ischemiaereperfusion injury,
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We are grateful to various medicinal chemists and biologists of
Shionogi & Co., Ltd. Discovery Laboratory for their contributions to
this work: Masakatsu Tsuji and Rio Nakamura (infectious diseases
section), Kenji Morimoto, Toshiaki Aoki, Mikito Asai, and Keisuke
Miyazaki (medicinal chemistry section), Kyoko Kadono (pharma-
cokinetics section) and Megumi Kimura (safety section). Linezolid-
resistant strain NRS271 was kindly provided by the network on
antimicrobial resistance in Staphylococcus aureus (http://www.
narsa.net/content/default.jsp).
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