Synthesis and structure-activity studies of novel benzocycloheptanone oxazolidinone antibacterial agents

Article abstract of DOI:10.1016/j.bmcl.2006.07.064

We describe a novel class of benzocycloheptanone derived oxazolidinone antibacterial agents. The synthesis and antibacterial activities with structure variation is discussed.

Full text of DOI:10.1016/j.bmcl.2006.07.064

Bioorganic & Medicinal Chemistry Letters 16 (2006) 5392–5397
Synthesis and structure–activity studies of novel
benzocycloheptanone oxazolidinone antibacterial agents
J. V. N. Vara Prasad,a,* Frederick E. Boyer,a Lou Chupak,b Michael Dermyer,a
Qizhu Ding,c K. Gavardinas,b Susan E. Hagen,a Michael D. Huband,a Wenhua Jiao,b
Takushi Kaneko,b Samarendra N. Maiti,a Michael Melnick,a Karina Romero,b
M. Pattersonb and Xiujuan Wuc
aPfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA
bPfizer Global Research and Development, Groton, CT 06340, USA
cNaeja Pharmaceutical Inc., Edmonton, Alberta, Canada T6E 5V2
Received 26 June 2006; revised 18 July 2006; accepted 20 July 2006
Available online 9 August 2006
Abstract—We describe a novel class of benzocycloheptanone derived oxazolidinone antibacterial agents. The synthesis and antibac-
terial activities with structure variation is discussed.
Ó 2006 Elsevier Ltd. All rights reserved.
Oxazolidinones are a new class of totally synthetic
antibiotics with excellent activity against Gram-positive
organisms including methicillin-resistant Staphylococcus
aureus (MRSA), Staphylococcus epidermidis (MRSE),
and vancomycin-resistant enterococci (VRE).1 This class
of compounds (e.g., 1, Dup-721) was initially discovered
at E.I. du Pont Nemours & Company in the 1980s.2
Later, extensive structure–activity relationship (SAR)
efforts at Pharmacia and Upjohn led to eperezolid (2)
and linezolid (3) as clinical candidates.3 Subsequently,
the food and drug administration (FDA) approved
linezolid (ZYVOXÒ) for the treatment of community-
acquired and nosocomial pneumonia, complicated and
uncomplicated skin and soft-tissue infections, and
infections caused by MRSA and VRE.
O
Z
F
C N
O
O
NA O
B
N
O
O
O
N
N
1
H
H
Dup-721
2: Z = N-C(O)CH2OH eperezolid
3: Z = O linezolid
ring and also substitutions on the phenyl ring. Nota-
bly, these compounds lack the typical C-ring as pres-
ent in linezolid.
O
O
Previous SAR studies at Du Pont and Pharmacia
also led to the indanone analog (PNU-82965, 4)4 pos-
sessing Gram-positive antibacterial activity. Herein,
we report the synthesis and antibacterial activities
of ketone analogs of various ring sizes, including
benzocycloheptane analogs possessing functional
groups at various positions on the seven-membered
N
O
O
N
4
H
PNU-82965
The oxazolidinone containing a tetralone moiety (5)
was synthesized in two steps as shown in Scheme 1.
The first step is a copper catalyzed coupling5 of oxazo-
lidinone fragment 7 with 7-bromo-3,4-dihydro-2H-
naphthalene-1-one 6, followed by deprotection of the
dimethoxybenzyl group in 8 to afford the oxazolidi-
none 5.
Keywords: Oxazolidinones; Antibacterial agents; Gram-negative
activity.
*
Corresponding author. Tel.: +1 734 622 2866; fax: +1 734 622
2265; e-mail: Josyula.VaraPrasad@Pfizer.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.07.064

J. V. N. Vara Prasad et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5392–5397
5393
O
Benzoheptanone oxazolidinones (9) were synthesized in
a multi-step procedure as shown in Scheme 4.6 The
intermediates required for Sonogashira coupling were
synthesized as shown in Schemes 2 and 3. The remaining
nitro compounds are commercially available.
O
O
a
O
HN
O
O
+
75%
N
O
O
Br
N
N
8
6
7
OMe
MeO
OMe
MeO
4-Pentynoic acid (16) on treatment with methanol in
the presence of acid gave its methyl ester 17. Coupling
with the corresponding 1-iodo- or 1-bromo-3-nitroben-
zene under Sonogashira coupling conditions7 afforded
compound 18. The nitro group in 18 was reduced to
the amine moiety (19), followed by reaction with ethyl
chloroformate to afford the corresponding ethyl carba-
mate 20. The ester group in 20 was saponified to the
corresponding acid 21. Intramolecular cyclization of
21 under acidic conditions furnished benzocyclohepta-
none 22. Next, the C-5 acetamidomethyl oxazolidi-
none side chain in 9 was installed in a single step
by using (1S)-2-(acetylamino)-1-(chloromethyl)ethyl
acetate.8 Some of these intermediates (22) were synthe-
sized in multi-gram (20–200 g) quantities without any
scale-up issues.
O
b
O
78%
N
O
O
5
N
H
Scheme 1. Reagents: (a) trans-1,2-diaminocyclohexane, CuI, potassi-
um carbonate; (b) trifluoroacetic acid.
a
b
73%
96%
O2N
COOH
O2N
Br
O2N
Br
Cl
Cl
F
12
10
11
Scheme 2. Reagents and condition: (a) Br2, HgO, CCl4, light; (b) KF/
CsF, DMF.
An oxazolidinone possessing a benzooctanone moiety
(23) was synthesized using hex-5-ynoic acid 24 as the
starting material (Scheme 5). The methyl ester of 25,
on coupling with 1-iodo-3-bromobenzene, afforded the
compound 26. Triple bond reduction in 26, then sapon-
ification of the ester group in 27 followed by conversion
of the acid to the acid chloride afforded compound 28.
Intramolecular cyclization of 28 in the presence of
aluminum chloride under high dilution conditions, as
described by Allinger et al., gave 29.9 Coupling of 29
F
F
F
F
a
b
72%
38%
COOH
O2N
COOH
O2N
Br
F
F
15
13
14
Scheme 3. Reagents: (a) nitric acid, sulfuric acid; (b) Br2, HgO, CCl4,
light.
P
P
R
R
O
O
a
NO2
X
NO2
MeO
OH
OMe
Q
Q
75%
17
16
O
18
b
65 - 83%
P
P
R
R
d
O
c
MeO
MeO
O
NH2
N
H
O
92 - 98%
89 - 95%
O
Q
Q
19
20
P
O
P
R
R
O
O
f
e
O
HO
N
H
N
94 - 98%
O
65 - 87%
H
O
Q
Q
22
21
O
Cl
P
R
OAc
NHAc
O
O
N
g
H
N
Q
54 - 78%
9
O
9a:P= Q= R = H
9b: P = F, Q = R =H
9c: P =R = H, Q =F
9d:P= Q= H, R = F
9e: P = Q = F, R=H
Scheme 4. Reagents: (a) sulfuric acid, MeOH; (b) appropriately substituted 1-iodo- or 1-bromo-3-nitrobenzene, Pd(OAc)2, triphenylphosphine, CuI,
diethylamine, DMF; (c) 10% Pd/C, H2, MeOH; (d) ethyl chloroformate, diisopropylamine, CH2Cl2; (e) 2 N LiOH, MeOH, THF; (f) P = Q = R = H:
polyphosphoric acid, toluene, Celite; others: phosphorus pentoxide, methanesulfonic acid; (g) lithium tert-butoxide in hexanes, DMF.

5394
J. V. N. Vara Prasad et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5392–5397
I
Br
MeO
O
O
O
a
Br
b
OH
OMe
70%
72%
24
26
25
f
O
d, e
O
c
Cl
Br
43%
MeO
Br
78%
85%
28
27
O
O
O
7
h
O
O
g
O
N
82%
O
O
N
O
Br
67%
NH
23
29
N
30
OMe
MeO
Scheme 5. Reagents: (a) sulfuric acid, MeOH; (b) Pd(PPh3)2Cl2, CuI, Et3N, DMF; (c) Raney nickel, H2, MeOH; (d) NaOH, MeOH; (e) oxalyl
chloride, benzene, catalytic amount of DMF; (f) AlCl3, CS2; (g) trans-1,2-diaminocyclohexane, CuI, potassium carbonate; (h) trifluoroacetic acid.
with 7 yielded 30, followed by deprotection, giving the
final oxazolidinone 23.
under basic conditions by treating 40 with (1S)-2-
(acetylamino)-1-(chloromethyl)ethyl acetate. Deprotec-
tion of the THP ether (41) to the corresponding
alcohol (42), followed by oxidation, furnished the final
ketone 31.
Pyridylbenzoheptanone analog (31) was synthesized as
shown in Scheme 6 starting from N-methylpyridone
(32). The first step was nitration to 33. Condensation
with heptanone yielded 34,10 which on further treat-
ment with MCPBA afforded the corresponding N-oxide
(35). Pummerer-like rearrangement of 35 gave 36.11
Reduction of the nitro group, followed by amino group
protection, yielded the corresponding ethyl carbamate
38. Saponification of the acetate group and protection
of the alcohol group as a THP ether gave 40. Oxazolid-
inone ring formation was accomplished in one step
Oxazolidinones containing a substituted benzocyclohep-
tane moiety were synthesized as shown in Scheme 7.
These novel oxazolidinone analogs were tested against
a panel of Gram-positive and fastidious Gram-nega-
tive bacteria.12 Minimum inhibitory concentration
(MIC) of the test compounds was determined by
micro broth methodology according to the Clinical
O2N
O
NO2
N
c
77%
a
b
30%
91%
O
N
N
NO2
32
O-
N+
33
OCOCH3
34
OCOCH3
N
d
f
e
N
86%
66%
(2 steps)
NO2
NO2
NH2
36
35
37
THP
N
OH
O
OCOCH3
N
N
g
h
O
O
O
62%
99%
N
OEt
OH
N
OEt
H
N
H
OEt
THP
39
H
40
38
O
N
j
N
k
O
i
O
66%
71%
99%
N
O
O
N
O
O
42
41
NH
O
NH
N
O
N
O
O
31
NH
Scheme 6. Reagents: (a) nitric acid, sulfuric acid; (b) cycloheptanone, ammonia, MeOH; (c) MCPBA, CH2Cl2; (d) Ac2O; (e) SnCl2, EtOAc; (f) ethyl
chloroformate, pyridine; (g) K2CO3, MeOH, H2O; (h) dihydropyran, PTS; (i) LiO-t-Bu, MeOH, DMF; (j) PTS, MeOH; (k) oxalyl chloride, DMSO,
CH2Cl2.

J. V. N. Vara Prasad et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5392–5397
5395
O
X
OH
X
X
a
b
O
O
O
80 - 85%
O
89 - 95%
O
N
N
O
N
O
O
O
44
45
43
NH
X
NH
NH
c
O
98%
N
O
O
NH
46
O
Ar
d
O
43
42 - 87%
N
O
O
47
Ar =
NH
47a : Phenyl
47b: para-fluorophenyl
47c: para-hydroxyphenyl
47d: para-(2-hydroxylethyl)phenyl
47e: para-(dimethylaminopropyloxy)phenyl
47f: para-(dimethylaminoethoxy)phenyl
47g: para-(sulfonylmethyl)phenyl
47h: meta-cyanophenyl
47i: benzodioxinyl
47j: 2-(N-methyl)-pyrrole
47k: 3-thiophenyl
47l: thioazolyl
47m: 4-pyridyl
Scheme 7. Reagents: (a) NaBH4; (b) PPTS; (c) Pd/C, H2; (d) ArCHO, piperidine.
and Laboratory Standards Institute Guidelines (For-
merly, National Committee for Clinical Laboratory
Standards, NCCLS). The Escherichia coli in vitro
transcription and translation (TnT) assay was per-
formed in 96-well microtiter plates using a luciferase
reporter system.13
Table 1 shows the effect of ring size on antibacterial
activities. Analogs possessing a seven-membered ring
system, for example, 9a showed better antibacterial
activities than their five (4), six (5), and eight (23) mem-
bered ring congeners. Compound 9a also showed better
antibacterial activities compared to the acyclic system
Table 1. Minimum inhibitory concentrations (MICs) for ketones possessing various ring sizes
Compound
EC TnT IC50 (lM)
S. a. MIC (lg/mL)
S. p. MIC (lg/mL)
S. py. MIC (lg/mL)
E. f. MIC (lg/mL)
3 linezolid
1 (Dup-721)
3.3 0.46
7.5 0.83
21 2.9
2
2
2
1
1
2
2
2
4
8
2
2
8
5
4
0.29
32
1
8
16
0.5
2
16
0.5
8
9a
23
3.9 0.18
5.9 0.72
0.5
4
4
Strains: S. a., Staphylococcus aureus UC-76 SA-1; S. p., Streptococcus pneumoniae SVI SP-3; S. py., Streptococcus pyogenes C-203, SP1-1; E. f.,
Enterococcus faecalis MGH-2 EF1-1.
Table 2. Minimum inhibitory concentrations (MICs) for ketones possessing various substitutions on the phenyl ring
Compound
EC TnT IC50 (lM)
S. a. MIC (lg/mL)
S. p. MIC (lg/mL)
S. py. MIC (lg/mL)
E. f. MIC (lg/mL)
3 linezolid
3.3 0.46
3.9 0.18
9.4 1.2
8.9 0.73
90 5.5
2
1
2
0.5
2
1
0.5
2
2
2
9a
9b
9c
9d
9e
31
8
4
16
64
32
8
4
8
8
32
8
32
16
4
64
16
8
14 1.5
13 1.2
16
Strains: S. a., Staphylococcus aureus UC-76 SA-1; S. p., Streptococcus pneumoniae SVI SP-3; S. py., Streptococcus pyogenes C-203, SP1-1; E. f.,
Enterococcus faecalis MGH-2 EF1-1.

5396
J. V. N. Vara Prasad et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5392–5397
Table 3. Minimum inhibitory concentrations (MICs) for Benzocycloheptane analogs
Compound
EC TnT IC50 (lM)
S. a. MIC (lg/mL)
S. p. MIC (lg/mL)
S. py. MIC (lg/mL)
E. f. MIC (lg/mL)
3 linezolid
45 (X = H)
45 (X = F)
46 (X = H)
3.3 0.46
1.3 0.07
9.3 0.59
2
1
2
1
2
0.5
1
0.5
1
1
2
64
2
>64
8
0.33
8
2
Strains: S. a., Staphylococcus aureus UC-76 SA-1; S. p., Streptococcus pneumoniae SVI SP-3; S. py., Streptococcus pyogenes C-203, SP1-1; E. f.,
Enterococcus faecalis MGH-2 EF1-1.
Table 4. Minimum inhibitory concentrations (MICs) for a,b-unsaturated ketones
Compound EC TnT IC50 (lM) S. a. MIC (lg/mL) S. p. MIC (lg/mL) E. f. MIC (lg/mL) H.i. MIC (lg/mL) M. c. MIC (lg/mL)
3 linezolid
47a
47b
3.3 0.46
2.7 0.4
2
2
1
16
16
2
8
4
2
2
4
4
8
4
2
1
4
1
4
8
1
0.25
0.25
0.125
0.25
0.125
0.25
0.25
0.25
0.25
0.25
0.125
0.25
0.5
0.5
0.5
0.5
0.5
0.5
2
2.7 0.13
0.95 0.13
2.6 0.4
0.5
0.5
1
47c
47d
8
16
16
32
16
32
8
47e
47f
1.2 0.11
1.5 0.07
2.8 0.24
1.7 0.1
1
2
47g
47h
1
0.5
0.25
0.25
0.5
0.5
0.5
1
0.5
0.5
1
47i
47j
1.6 0.08
1.6 0.27
1.1 0.22
1.1 0.16
1.7 0.2
16
2
47k
47l
2
1
16
16
47m
1
Strains: S. a., Staphylococcus aureus UC-76 SA-1; S. p., Streptococcus pneumoniae SVI SP-3; E. f., Enterococcus faecalis MGH-2 EF1-1; H.i.
Haemophilus influenzae HI-3542; M. c., Moraxella catarrhalis BC-3531.
(1) as well as linezolid (3). These analogs did not show
fastidious Gram-negative activity when tested up to
the maximum concentration of 64 lg/mL.
fastidious Gram-negative activities. The improved
spectrum of antibacterial activities and novel analogs
such as 47b and 47k represent promising new leads in
the oxazolidinone area.
The phenyl ring of 9 was substituted with fluorine atoms
at various positions, because such substitutions have
showed enhanced activities in other series.1,5 Various
fluoro substitutions on the phenyl ring (series 9), as well
as replacing the phenyl ring with a pyridyl ring (31), did
not enhance antibacterial activities (Table 2). Among
the various benzocycloheptane analogs tested, com-
pound 45 showed antibacterial activities similar to 9a
(Table 3).
References and notes
1. For recent reviews, see: (a) Wilcox, M. H. Expert Opin.
Pharmacother. 2005, 6, 2315; (b) Mukhtar, T. A.; Wright,
G. D. Chem. Rev. 2005, 105, 529; (c) Hutchinson, D. K.
Expert Opin. Ther. Patents 2004, 14, 1309; (d) Nilus, A. M.
Curr. Opin. Invest. Drugs 2003, 4, 149.
2. Park, C.-H.; Brittelli, D. R.; Wang, C. L.-J.; Marsh, F. D.;
Gregory, W. A.; Wuonola, M. A.; McRipley, R. J.;
Eberly, V. S.; Slee, A. M.; Forbes, M. J. Med. Chem. 1992,
35, 1156, and references therein.
3. Brickner, S. J.; Hutchinson, D. K.; Barbachyn, M. R.;
Manninen, P. R.; Ulanowicz, D. A.; Garmon, S. A.;
Grega, K. C.; Hendges, S. K.; Toops, D. S.; Ford, C. W.;
Zurenko, G. E. J. Med. Chem 1996, 39, 673.
4. Barbachyn, M. R.; Ford, C. W. Angew. Chem., Int. Ed.
2003, 42, 2010.
5. (a) Mallesham, B.; Rajesh, B. M.; Reddy, P. R.; Srinivas,
D.; Trehan, S. Org. Lett. 2003, 5, 963; (b) Madar, D. J.;
Kopecka, H. K.; Pireh, D.; Pease, J.; Pliushchev, M.;
Sciotti, R. J.; Wiedeman, P. E.; Djuric, S. W. Tetrahedron
Lett. 2001, 42, 3681.
6. Chupak, L. S.; Kaneko, T.; Vara Prasad, J. V. N.;
Peterson, M.; Lall, M.; Hagen, S. E.; Boyer, F. E. WO
2004/069244.
Various analogs of 47 showed improved Gram-positive
activities compared to linezolid. More significantly,
47b and 47k showed surprisingly potent activity against
the fastidious Gram-negative organisms (Table 4). These
results are a major improvement compared to the activ-
ities of linezolid versus fastidious Gram-negative bacte-
ria. All of these analogs in Table 4 showed activities
similar to or better than linezolid in the translation as-
say, thereby confirming the mechanism of action, that
is, similar to linezolid.
In summary, novel oxazolidinones possessing various
benzocycloalkyl rings were prepared and evaluated for
antimicrobial activity. The analog possessing a benzocy-
cloheptanone ring (9a) showed better antibacterial activ-
ities compared to other cycloketone analogs. More
importantly, oxazolidinones of structure 47 also showed
7. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4467; (b) Mio, M. J.; Kopel, L. C.; Braun, J.

J. V. N. Vara Prasad et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5392–5397
5397
B.; Gadzikwa, T. L.; Hull, K. L.; Brisbois, R. G.;
Markworth, C. J.; Grieco, P. A. Org. Lett. 2002, 4, 3199.
8. Perrault, W. R.; Pearlman, B. A.; Godrej, D. B.; Jegan-
nathan, A.; Yamagata, K.; Chen, J. J.; Lu, C. V.;
Herrinton, P. M.; Gadwood, R. C.; Chan, L.; Lyster, M.
A.; Maloney, M. T.; Moeslein, J. A.; Greene, M. L.;
Barbachyn, M. R. Org. Process Res. Dev. 2003, 7, 533.
9. Allinger, N. L.; Jones, E. S. J. Org. Chem 1962, 27, 70.
10. (a) Tohda, Y.; Eiraku, M.; Nakagawa, T.; Usami, Y.;
Ariga, M.; Kawashima, T.; Tani, K.; Watanbe, H.; Mori,
Y. Bull. Chem. Soc. Jpn 1990, 63, 2820; (b) Takada, S.;
Sasatani, T.; Chomei, N.; Adachi, M.; Fujishita, T.;
Eigyo, M.; Murata, S.; Kawasaki, K.; Matsushita, A. J.
Med. Chem. 1996, 39, 2844; (c) Chupak, L. S.; Kaneko, T.;
Vara Prasad, J. V. N.; Kim, J. -Y.; Choy, A. L.; Hagen, S.
E.; Boyer, F. E. WO 2004/069832.
11. (a) Traynelis, V. J.; Pacini, P. L. J. Am. Chem. Soc. 1964,
86, 4917, and references therein; (b) Basha, F. Z.; Hibino,
S.; Kim, D.; Pye, W. E.; Wu, Tai-Teh; Weinreb, S. M. J.
Am. Chem. Soc. 1980, 102, 3964; (c) Weinreb, S. M.;
Basha, F. Z.; Hibino, S.; Khatri, N. A.; Kim, D.; Pye, W.
E.; Wu, Tai-Teh J. Am. Chem. Soc. 1982, 104, 536.
12. Clinical and Laboratory Standards Institute (Formerly,
National Committee for Clinical Laboratory Stan-
dards). Methods for dilution antimicrobial susceptibility
tests for bacteria that grow aerobically; 6th ed.;
Approved Standard. NCCLS Document M7-A6, Vol.
23, No. 2.
13. (a) Zubay, G. Annu. Rev. Genet. 1973, 7, 267; (b)
Murray, R. W.; Melchior, E. P.; Hagadorn, J. C.;
Marotti, K. R. Antimicrob. Agents Chemother. 2001, 45,
1900.