Structure-activity relationship (SAR) studies on oxazolidinone antibacterial agents. 3.1) Synthesis and evaluation of 5-thiocarbamate oxazolidinones

Article abstract of DOI:10.1248/cpb.49.361

A series of 5-thiocarbamate oxazolidinones was prepared and tested for in vitro and in vivo antibacterial activities. The results of in vitro antibacterial activity indicated that the 5-thiocarbamate group was a suitable substituent for the activity by the 5-moderate hydrophilicity. The compounds within a favorable log P value range were found to have potent in vitro antibacterial activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Compounds 3a and 4h were superior to linezolid in both in vitro and in vivo potency and were considered to be hopeful compounds. We also discuss the pharmacokinetic properties of several compounds in mice.

Full text of DOI:10.1248/cpb.49.361

April 2001
Chem. Pharm. Bull. 49(4) 361—367 (2001)
361
Structure–Activity Relationship (SAR) Studies on Oxazolidinone
Antibacterial Agents. 3.1) Synthesis and Evaluation of
5-Thiocarbamate Oxazolidinones
Ryukou TOKUYAMA,* Yoshiei TAKAHASHI, Yayoi TOMITA, Masatoshi TSUBOUCHI, Nobuhiko IWASAKI,
Noriyuki KADO, Eiichi OKEZAKI, and Osamu NAGATA
Research and Development Division, Hokuriku Seiyaku Co., Ltd., 37–1–1, Inokuchi, Katsuyama, Fukui 911–8555, Japan.
Received July 26, 2000; accepted December 22, 2000
A series of 5-thiocarbamate oxazolidinones was prepared and tested for in vitro and in vivo antibacterial ac-
tivities. The results of in vitro antibacterial activity indicated that the 5-thiocarbamate group was a suitable sub-
stituent for the activity by the 5-moderate hydrophilicity. The compounds within a favorable log P value range
were found to have potent in vitro antibacterial activity against gram-positive bacteria including methicillin-re-
sistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Compounds 3a and 4h were
superior to linezolid in both in vitro and in vivo potency and were considered to be hopeful compounds. We also
discuss the pharmacokinetic properties of several compounds in mice.
Key words oxazolidinone; antibacterial activity; structure–activity relationship; 5-thiocarbamate oxazolidinone
Several antibiotics have been prescribed and found to the development of 5-thiocarbonyl oxazolidinone antibacter-
be very effective on various infectious disorders. However, ial agents. However, the in vivo activities of 2a and 2b were
the appearance of multi-drug-resistant gram-positive bacte- not sufficient. Thus, we converted the 5-thiourea group into
ria, in particular, methicillin-resistant Staphylococcus aureus 5-thiocarbamate oxazolidinones in order to find candidates
(MRSA) and vancomycin-resistant enterococci (VRE) is with good in vitro and in vivo activities.
causing a serious menace. Moreover, the emergence of van-
In this paper, we describe our SAR study on a series of 5-
comycin-resistant MRSA can be anticipated in the foresee- thiocarbamate oxazolidinones.
able future. For the treatment of these intractable infections, a
new anti-infectious agent is needed in clinical.
Chemistry 5-Thiocarbamate oxazolidinones were pre-
pared as shown in Charts 2 and 3. Compounds 3a—e were
Oxazolidinone antibacterial agents2) are a new class of synthesized from compound 51a) by treatment with the corre-
synthetic antibacterial agents with activity against gram-posi- sponding alcohols as shown in Chart 2.
tive bacteria. Their mode of action has been found to inhibit
(4Ј-Substituted)phenyl-5-thiocarbamate oxazolidinones 4
the protein synthesis in the initial stage.3) Because of this were prepared as shown in Chart 3 from key intermediates 7,
unique mode of action, oxazolidinone is not cross-resistant which were easily derived from 6 by the usual method.1b) The
with other types of antibiotics. Linezolid (1),4) which was intermediates 7 were treated with carbon disulfide followed
discovered by Pharmacia group, is well known as the first by ethyl chloroformate to give isothiocyanates 8. The thio-
promising candidate of oxazolidinone and works effectively carbamate derivatives 4 were prepared from 8 by treatment
against numerous serious gram-positive human pathogens with methanol. The physicochemical data of compounds 3
caused by MRSA and VRE.
and 4 are shown in the experimental section.
In our preceding paper,1) we described that 5-thiourea
compounds 2a and 2b exhibited better in vitro antibacterial Results and Discussion
activities than linezolid. We also indicated that both the cal-
All of the oxazolidinone derivatives were tested for
culated log P value and the balance between 5-hydrophobic antibacterial activity against both standard (Staphylococcus
(or hydrophilic) substituent and hydrophilic (or hydrophobic) aureus SMITH) and clinically isolated strains [S. aureus
substituents on benzene ring would be important factors in HPC1360 (MRSA), S. aureus HPC428 (MRSA), Entero-
coccus faecium HPC1322 and E. casseliflavus HPC1310
(VRE)]. Their minimum inhibitory concentrations (MICs
mg/ml) are shown in Tables 1 and 2. The data of linezolid (1)
and vancomycin were used as reference compounds.
We investigated the influence of side chain at 5-position on
Chart 1
Chart 2
To whom correspondence should be addressed. e-mail: organ-hs@mitene.or.jp
© 2001 Pharmaceutical Society of Japan

362
Vol. 49, No. 4
a) 1) CS2 2) ClCO2Et b) NaH/MeOH
Chart 3
Table 1. In Vitro Antibacterial Activities of 5-Substituted Oxazolidinones
MICs (mg/ml)a)
Clinical isolates
Standard strain
S. aureus
SMITH
S. aureus
S. aureus
E. faecium
HPC1322
E. casseliflavus
No.
R1
Me
Et
n-Pr
HPC1360b)
HPC428b)
HPC1310c)
3a
3b
3c
3d
3e
1.56
3.13
50
Ͼ50
Ͼ50
1.56
3.13
6.25
0.78
3.13
50
Ͼ50
Ͼ50
0.78
1.56
3.13
1.56
6.25
12.5
Ͼ50
Ͼ50
iso-Pr
cycHex
Ͼ50
Ͼ50
12.5
Ͼ50
2a
2b
1
0.78
0.39
6.25
0.78
1.56
0.39
6.25
0.78
0.78
0.39
3.13
0.78
0.78
0.39
3.13
0.78
0.78
0.39
6.25
12.5
Vancomycin
a) Inoculum size, one loopful of 106 CFU/ml. b) MRSA. c) VRE.
5-thiocarbamate derivatives for antibacterial activities. The was 3.10, showed weak activity. It was recently reported that
results of antibacterial activities are summarized in Table 1. the azole analogues at 4Ј-position have interesting levels of
The activity of compound 3a showed 4 times stronger than antibacterial activity in 5-acetamide oxazolidinones.6) Com-
that of linezolid (1). However, the introduction of lengthened pounds 4n and 4p also showed strong in vitro activities. The
alkyl groups or cycloalkyl group at R1 position decreased an- activities of compounds 4b, 4h, 4i, 4n and 4p were 8—16
tibacterial activities. Thus, we focused O-methyl thiocarba- times stronger than that of linezolid (1).
mate group at 5-position, and synthesized some 4Ј-substi-
In Vivo Activity The compounds that exhibited more
tuted oxazolidinones in this series. The antibacterial activi- potent in vitro antibacterial activity than linezolid (1) were
ties and hydrophobic parameter (calculated log P value) of 5- actually tested for in vivo antibacterial activity against gram-
thiocarbamate oxazolidinones are summarized in Table 2.
positive bacteria (S. aureus SMITH). The ED50 (mg/kg) value
In our previous paper,1b) we reported that the balance be- of the oral route was determined based on the survival rates
tween 5-hydrophobic (or hydrophilic) substituent and hy- on day 7 after infection in mice. Among the oxazolidinones,
drophilic (or hydrophobic) substituents on the benzene ring compounds 3a and 4h exhibited higher in vivo activities than
is one of the important factors in antibacterial activity in the linezolid (1) as shown in Table 3. The data showed 5—6 fold
5-thiocarbonyl oxazolidinones. In this series, the prominent increases in oral activity compared with linezolid (1). More-
decrease of antibacterial activity was not observed. We as- over, the thiocarbamate derivative 3a showed stronger in vivo
sume that 5-O-methyl thiocarbamate group would be suitable activity than the corresponding thiourea derivative 2a. To
for various substituents on the benzene ring because of its learn the reason why the activity of 3a was stronger than that
moderate hydrophilic substituent (paϭ0.30) compared with of 2a, we examined their pharmacokinetic profiles. (Table 4)
5-thiourea (paϭϪ0.66) or 5-dithiocarbamate (paϭ0.88)
It was found that the plasma concentration of compound
3a immediately disappeared. The plasma concentrations of
groups.1b)
We described earlier1b) that the favorable calculated log P S-oxide and S,S-dioxide, however, reached the maximum of
value for antibacterial activity in the case of 5-thiocarbonyl 3.48 mg/ml at 1.0 h and 4.92 mg/ml at 6.0 h, respectively, after
oxazolidinones was Ϫ1 to ϩ2. In this series, we also mea- oral dosing of compound 3a. Both of them showed greatly
sured the calculated log P value.5) The compounds within the higher serum concentrations compared to unchanged com-
favorable calculated log P value range provided stable an- pound 3a, suggesting that the metabolites might be responsi-
tibacterial activities as we expected. Among them, com- ble for in vivo activity in the mouse systemic infectious
pounds 4b (calculated log P value: 1.51), 4h (1.01), and 4i model. On the other hand, compound 2a, which had 5-
(0.73) showed stronger in vitro activities than linezolid (1). thiourea moiety, might be similarly metabolized to S-oxide or
On the contrary, compound 4e, whose calculated log P value S,S-dioxide. But the in vitro activity of S-oxide was weak.1b)

April 2001
363
Table 2. In Vitro Antibacterial Activities and Hydrophilic Parameter of 5-Thiocarbamate Oxazolidinones
MICs (mg/ml)a)
Clinical isolates
Hydrophilic
parameter
Standard
strain
Calculated
S. aureus
SMITH
S. aureus
S. aureus
E. faecium
HPC1322
E. casseliflavus
No.
A
log Pb)
HPC1360c)
HPC428c)
HPC1310d)
4a
4b
4c
4d
4e
4f
0.94
1.51
2.07
2.57
3.10
1.05
2.64
3.13
0.39
3.13
3.13
6.25
3.13
3.13
3.13
0.78
3.13
3.13
6.25
1.56
1.56
3.13
0.39
1.56
3.13
6.25
3.13
1.56
1.56
0.39
1.56
1.56
6.25
1.56
1.56
1.56
0.78
3.13
3.13
6.25
3.13
4g
3.13
3a
4h
4i
1.01
Ϫ1.00
Ϫ0.73
0.45
1.56
0.78
0.78
1.56
1.56
1.56
3.13
0.78
1.56
1.56
0.78
0.78
1.56
1.56
1.56
1.56
0.39
1.56
0.78
0.78
0.78
1.56
1.56
1.56
1.56
0.39
0.78
0.78
0.39
0.39
0.78
0.78
0.78
0.78
0.39
0.78
1.56
0.78
0.78
1.56
0.78
1.56
1.56
0.39
0.78
4je)
4k
4l
0.89
1.43
4m
4n
4o
1.96
1.86
0.30
4p
0.76
0.78
0.78
0.39
6.25
0.78
0.78
1.56
0.39
6.25
0.78
0.39
0.78
0.39
3.13
0.78
0.39
0.78
0.39
3.13
0.78
0.39
0.78
0.39
6.25
12.5
2a
2b
1
Vancomycin
a) Inoculum size, one loopful of 106 CFU/ml. b) Ref. 5). c) MRSA. d) VRE. e) Ref. 7).
Table 3. In Vivo Activity in Mouse Systemic Infectious Model
Table 4. Pharmacokinetic Profiles of Unchanged 3a and Its Metabolites in
Serum after a Single Administration to Mice at a Dose of 20 mg/kg
b)
MICa)
(mg/ml)
ED50
Compound
[95% confidence limits]
[0.92—1.91]
(mg/kg/dose)
Cmax
(mg/ml)
Tmax
(h)
AUC0—∞
(mg·h/ml)
T1/2
Compound
(h)
3a
4b
4h
2a
2b
1
1.56
0.39
0.78
0.78
0.39
6.25
1.34
Ͼ5.00
1.15
3a
S,S-Dioxide
S-Oxide
Unchanged
Unchanged
Unchanged
4.92
3.48
0.071
1.10
6.00
1.00
0.25
0.25
0.083
30.8a)
3.9
57.8
1.82
1.14
1.33
1.66
[0.81—1.56]
[8.16—27.0]
14.3c)
Ͼ20.0c)
7.03
0.046b)
2.40
2a
1
[4.90—10.1]
[4.60—10.1]
24.8
50.7
6.80c)
Each value represents the mean of four mice. a) The value of S-dioxide was
AUC 0—8 h b) The value of unchanged 3a was AUC0—4 h
.
.
a) MIC for S. aureus SMITH. b) ED50: 50% effective dose (calculated on day 7 by
Probit method). c) Non-fasted. Animals: male ICR mice, 4-week-old, fasted. Bacter-
ial strain: Staphylococcus aureus SMITH. Treatment: Mice were infected intraperi-
toneally with bacterial suspension. One and four hours after infection, the compounds
were administered orally to animals.

364
Vol. 49, No. 4
Table 5. Physical Data for Compounds 3
Analysis (%)
Calcd (Found)
[a]D20
DMSO
(cϭ0.1)
mp (°C)
(Recryst. Solv.)
No.
Yield (%)a)
Formula
C
H
N
3a
3b
3c
3d
3e
39
78
69
39
32
141.5—143
(EtOH)
103.5—104.5
(iso-PrOH)
124—125
C16H20FN3O3S2
C17H22FN3O3S2
C18H24FN3O3S2
C18H24FN3O3S2
C21H28FN3O3S2
49.85 5.23
(49.58 5.05
51.11 5.55
(51.20 5.67
52.28 5.85
(52.22 5.86
52.28 5.85
(52.06 5.56
55.61 6.22
(55.49 5.97
10.90
10.82)
10.52
10.38)
10.16
10.12)
10.16
10.01)
9.26
Ϫ25.9
Ϫ23.1
Ϫ30.9
Ϫ32.1
Ϫ26.9
(iso-PrOH)
164—166
(iso-Pr2O–iso-PrOH)
150—152
(MeOH)
9.07)
a) Yields were calculated from compounds 5.
Table 6. Physical Data for Compounds 3
No.
1H-NMR (in DMSO-d6)a) d (ppm)
3a
3b
3c
2.73 (4H, t, Jϭ5 Hz), 3.26 (4H, t, Jϭ5 Hz), 3.70—3.85 (3H, m), 3.92 (3H, s), 4.09 (1H, t, Jϭ9 Hz), 4.75—4.93 (1H, m), 7.07 (1H,
t, Jϭ9.5 Hz), 7.17 (1H, dd, Jϭ9.5, 2.5 Hz), 7.40 (1H, dd, Jϭ14.5, 2.5 Hz), 9.10 (1H, br s)
1.26 (3H, t, Jϭ7.5 Hz), 2.73 (4H, t, Jϭ5 Hz), 3.25 (4H, t, Jϭ5 Hz), 3.70—3.90 (3H, m), 4.09 (1H, t, Jϭ9 Hz), 4.43 (2H, q, Jϭ7.5
Hz), 4.75—4.90 (1H, m), 7.07 (1H, t, Jϭ9 Hz), 7.16 (1H, dd, Jϭ9, 2.5 Hz), 7.39 (1H, dd, Jϭ14.5, 2.5 Hz), 9.04 (1H, br s)
0.91 (3H, t, Jϭ7.5 Hz), 1.67 (2H, q, Jϭ7.5 Hz), 2.73 (4H, t, Jϭ5 Hz), 3.25 (4H, t, Jϭ5 Hz), 3.75—3.90 (3H, m), 4.09 (1H, t, Jϭ9
Hz), 4.34 (2H, t, Jϭ7.5 Hz), 4.80—4.90 (1H, m), 7.07 (1H, t, Jϭ8.5 Hz), 7.17 (1H, dd, Jϭ8.5, 2.5 Hz), 7.39 (1H, dd, Jϭ14.5, 2.5
Hz), 9.06 (1H, br s)
3d
3e
1.27 (6H, d, Jϭ6 Hz), 2.73 (4H, t, Jϭ5.5 Hz), 3.25 (4H, t, Jϭ5.5 Hz), 3.60—3.85 (3H, m), 4.09 (1H, t, Jϭ9 Hz), 4.60—4.90 (1H,
m), 5.44 (1H, sep, Jϭ6 Hz), 7.07 (1H, t, Jϭ9.5 Hz), 7.16 (1H, dd, Jϭ9.5, 2.5 Hz), 7.40 (1H, dd, Jϭ14.5, 2.5 Hz), 8.96 (1H, br s)
1.20—1.90 (10H, m), 2.73 (4H, t, Jϭ5 Hz), 3.25 (4H, t, Jϭ5 Hz), 3.70—3.85 (3H, m), 4.09 (1H, t, Jϭ9 Hz), 4.70—4.90 (1H, m),
5.23 (1H, br s), 7.07 (1H, t, Jϭ9 Hz), 7.16 (1H, dd, Jϭ9, 2.5 Hz), 7.39 (1H, dd, Jϭ15, 2.5 Hz), 8.99 (1H, br s)
a) Measured at 100 °C.
zolidine-2-one (7k) A mixture of (R)-5-azidomethyl-3-[3-fluoro-4-(4-
In conclusion, 5-thiocarbamate oxazolidinones which had
both a good balance of hydrophilic parameters (pa, pb) and
favorable calculated log P value (Ϫ1 to ϩ2) were synthe-
sized and their antibacterial activity were evaluated. Among
methyl-1-piperazinyl)phenyl]oxazolidine-2-one (11.2 g, 27.1 mmol), which
was prepared from compound 6 by the usual method,1b) triphenylphosphine
(7.82 g, 29.8 mmol) and H2O (4.8 ml, 271 mmol) in tetrahydrofuran (THF)
(170 ml) was heated at 40 °C for 17 h. After cooling, the reaction mixture
them, compounds 3a and 4h showed good in vitro and in vivo was diluted with water and dilute hydrochloric acid and extracted with
AcOEt. The aqueous layer was made alkaline with aqueous NaOH and ex-
activities compared with linezolid. These compounds are
thus expected to be effective candidates for numerous gram-
positive infections.
tracted with AcOEt. The extract was washed with water, dried and concen-
trated to afford 7k (4.55 g, 54%) as pale yellow amorphous. [a]D20 Ϫ34.0°
(cϭ0.1, DMSO). 1H-NMR (DMSO-d6) d: 1.89 (2H, br s), 2.22 (3H, s), 2.46
(4H, t, Jϭ5 Hz), 2.79 (1H, dd, Jϭ14, 5 Hz), 2.84 (1H, dd, Jϭ14, 5 Hz), 2.98
(4H, t, Jϭ5 Hz), 3.81 (1H, dd, Jϭ9, 6 Hz), 4.01 (1H, t, Jϭ9 Hz), 4.54—4.61
(1H, m), 7.03 (1H, t, Jϭ8.5 Hz), 7.18 (1H, dd, Jϭ8.5, 2 Hz), 7.46 (1H, dd,
Jϭ15.5, 2 Hz).
Experimental
Melting points were measured with a Yanagimoto melting point apparatus
and are uncorrected. Elemental analyses were measured with a Yanagimoto
MT-5 elemental analysis apparatus, and were within Ϯ0.4% of calculated
Compounds 7l—p were respectively prepared from the corresponding 6
in a similar manner.
1
values. H-NMR spectra were measured with a JEOL A-500 (500 MHz) or
JEOL JNM-LA300 (300 MHz) spectrometer using tetramethylsilane as an
internal standard. High-resolution mass spectra were measured on a JEOL
DX-300 mass spectrometer. Specific optical rotations were measured on a
JASCO DIP-370 polarimeter. Column chromatography was carried out with
silica gel [Kieselgel 60 (Merck)]. TLC was conducted on 0.25 mm pre-
coated silica gel plates (60F254, Merck). All extracted solvents were dried
over Na2SO4 and the solvent was evaporated in vacuo.
O-Methyl (S)-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-ox-
azolidinyl]methyl]thiocarbamate (3a) To a solution of NaH (60% in oil,
0.53 g, 13.3 mmol) in MeOH (44 ml), a mixture of 51a) (4.41 g, 12.5 mmol)
was added under ice cooling, followed by stirring at room temperature for
3 h. Then the reaction mixture was poured into ice water and adjusted to pH
7 with dilute hydochloric acid. The precipitates were collected by filtration
and washed with water to afford 3a as pale brown crystals. The physico-
chemical data are listed in Tables 5 and 6.
(S)-5-Aminomethyl-3-[4-(4-ethyl-1-piperazinyl)-3-fluorophenyl]oxazo-
lidine-2-one (7l): Colorless prisms, 87%, mp: 104—105.5 °C (AcOEt–iso-
1
propyl ether (iso-Pr2O)). [a]D20 Ϫ37.0° (cϭ0.1, DMSO). H-NMR (DMSO-
d6) d: 1.02 (3H, t, Jϭ7.5 Hz), 1.52 (2H, br s), 2.38 (2H, q, Jϭ7.5 Hz), 2.51
(4H, t, Jϭ5 Hz), 2.79 (1H, dd, Jϭ13.5, 5 Hz), 2.84 (1H, dd, Jϭ13.5, 5 Hz),
2.98 (4H, t, Jϭ7.5 Hz), 3.81 (1H, dd, Jϭ9, 6.5 Hz), 4.01 (1H, t, Jϭ9 Hz),
4.50—4.60 (1H, m), 7.03 (1H, t, Jϭ9 Hz), 7.18 (1H, dd, Jϭ9, 2.5 Hz), 7.46
(1H, dd, Jϭ15, 2.5 Hz). Anal. Calcd for C16H23FN4O2: C, 59.61; H, 7.19; N,
17.38. Found: C, 59.46; H, 7.17; N, 17.37.
(S)-5-Aminomethyl-3-[3-fluoro-4-(4-propyl-1-piperazinyl)phenyl]oxa-
zolidine-2-one (7m): Pale brown crystals, 89%, mp: 93—95 °C (AcOEt–
iso-Pr2O). [a]D20 Ϫ37.9° (cϭ0.1, DMSO). 1H-NMR (DMSO-d6) d: 0.88 (3H,
t, Jϭ7.5 Hz), 1.46 (2H, sextet, Jϭ7.5 Hz), 1.53 (2H, br s), 2.29 (2H, t,
Jϭ7.5 Hz), 2.50 (4H, t, Jϭ5 Hz), 2.79 (1H, dd, Jϭ14, 5 Hz), 2.85 (1H, dd,
Jϭ14, 5 Hz), 2.98 (4H, t, Jϭ5 Hz), 3.81 (1H, dd, Jϭ9, 6.5 Hz), 4.01 (1H, t,
Jϭ9 Hz), 4.55—4.65 (1H, m), 7.03 (1H, t, Jϭ9 Hz), 7.18 (1H, dd, Jϭ9,
2.5 Hz), 7.46 (1H, dd, Jϭ15, 2.5 Hz). Anal. Calcd for C17H25FN4O2: C,
60.70; H, 7.49; N, 16.65. Found: C, 60.47; H, 7.38; N, 16.55.
Compounds 3b—e were respectively prepared from 5 in a similar manner.
The physicochemical data are listed in Tables 5 and 6.
(S)-5-Aminomethyl-3-[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]oxa-

April 2001
365
(1H, t, Jϭ9 Hz), 4.78—4.85 (1H, m), 6.96 (1H, t, Jϭ9 Hz), 7.11 (1H, dd,
Jϭ9, 2 Hz), 7.42 (1H, dd, Jϭ14, 2 Hz). Anal. Calcd for C16H19FN4O2S: C,
54.84; H, 5.47; N, 15.99. Found: C, 54.83; H, 5.41; N, 15.84.
Compounds 8l—p were respectively prepared from the corresponding 7
in a similar manner.
(R)-[[3-[4-(4-Ethyl-1-piperazinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]-
methyl]isothiocyanate (8l): Colorless prisms, 75%, mp: 86.5—87.5 °C
(AcOEt–iso-Pr2O). [a]D20 Ϫ151.2° (cϭ0.1, DMSO). 1H-NMR (DMSO-d6) d:
1.02 (3H, t, Jϭ7.5 Hz), 2.38 (2H, q, Jϭ7.5 Hz), 2.51 (4H, t, Jϭ5 Hz), 2.99
(4H, t, Jϭ5 Hz), 3.78 (1H, dd, Jϭ9, 5.5 Hz), 4.02 (1H, dd, Jϭ15.5, 5 Hz),
4.10 (1H, dd, Jϭ15.5, 3 Hz), 4.17 (1H, t, Jϭ9 Hz), 4.90—5.00 (1H, m), 7.05
(1H, t, Jϭ9 Hz), 7.18 (1H, dd, Jϭ9, 2.5 Hz), 7.45 (1H, dd, Jϭ15, 2.5 Hz).
Anal. Calcd for C17H21FN4O2S: C, 56.03; H, 5.81; N, 15.37. Found: C,
56.09; H, 5.76; N, 15.46.
(S)-5-Aminomethyl-3-[3-fluoro-4-(1-pyrrolyl)phenyl]oxazolidine-2-
one (7n): Pale brown amorphous, 95%.[a]D20 Ϫ21.9° (cϭ0.1, DMSO). H-
1
NMR (DMSO-d6) d: 1.75 (2H, br s), 2.82 (1H, dd, Jϭ14, 5 Hz), 2.89 (1H,
dd, Jϭ14, 5 Hz), 3.92 (1H, dd, Jϭ9, 6 Hz), 4.11 (1H, t, Jϭ9 Hz), 4.60—4.70
(1H, m), 6.26 (2H, t, Jϭ2 Hz), 7.09 (2H, q, Jϭ2 Hz), 7.43 (1H, dd, Jϭ9,
2.5 Hz), 7.56 (1H, t, Jϭ9 Hz), 7.69 (1H, dd, Jϭ14, 2.5 Hz).
(S)-5-Aminomethyl-3-[3-fluoro-4-(1-pyrazolyl)phenyl]oxazolidine-2-
one (7o): Colorless crystals, 74%, mp: 127—127.5 °C (2-propanol (iso-
PrOH)). [a]D20 Ϫ51.9° (cϭ0.1, DMSO). H-NMR (DMSO-d6) d: 1.54 (2H,
1
br s), 2.83 (1H, dd, Jϭ13.5, 5 Hz), 2.90 (1H, dd, Jϭ13.5, 5 Hz), 3.91 (1H,
dd, Jϭ9, 6 Hz), 4.12 (1H, t, Jϭ9 Hz), 4.60—4.70 (1H, m), 6.55 (1H, t,
Jϭ2.5 Hz), 7.45 (1H, dd, Jϭ9, 2.5 Hz), 7.73 (1H, dd, Jϭ14.5, 2.5 Hz),
7.80—8.00 (2H, m), 8.13 (1H, t, Jϭ2.5 Hz). Anal. Calcd for C13H13FN4O2:
C, 56.52 H, 4.74; N, 20.28. Found: C, 56.51; H, 4.81; N, 20.29.
(R)-[[3-[3-Fluoro-4-(4-propyl-1-piperazinyl)phenyl]-2-oxo-5-oxazo-
lidinyl]methyl]isothiocyanate (8m): Colorless crystals, 76%, mp: 93—94 °C
(AcOEt–iso-Pr2O). [a]D20 Ϫ141.6° (cϭ0.1, DMSO). 1H-NMR (DMSO-d6) d:
0.88 (3H, t, Jϭ7.5 Hz), 1.46 (2H, sextet, Jϭ7.5 Hz), 2.29 (2H, t, Jϭ7.5 Hz),
2.50 (4H, t, Jϭ4.5 Hz), 2.99 (4H, t, Jϭ4.5 Hz), 3.78 (1H, dd, Jϭ9.5, 6 Hz),
4.02 (1H, dd, Jϭ15.5, 5 Hz), 4.10 (1H, dd, Jϭ15.5, 3.5 Hz), 4.17 (1H, t,
Jϭ9.5 Hz), 4.90—5.00 (1H, m), 7.05 (1H, t, Jϭ9 Hz), 7.18 (1H, dd, Jϭ9,
2.5 Hz), 7.45 (1H, dd, Jϭ15.5, 2.5 Hz). Anal. Calcd for C18H23FN4O2S: C,
57.12; H, 6.13; N, 14.80. Found: C, 57.02; H, 6.13; N, 14.75.
(S)-5-Aminomethyl-3-[3-fluoro-4-(1-imidazolyl)phenyl]oxazolidine-2-
one (7p): Colorless oil, 67%, [a]D20 Ϫ44.7° (cϭ0.1, DMSO). 1H-NMR
(DMSO-d6) d: 1.55 (2H, br s), 2.82 (1H, dd, Jϭ14, 5 Hz), 2.89 (1H, dd,
Jϭ14, 5 Hz), 3.90 (1H, dd, Jϭ9, 5.5 Hz), 4.12 (1H, t, Jϭ9 Hz), 4.60—4.70
(1H, m), 7.11 (1H, s), 7.47 (1H, dd, Jϭ9, 2.5 Hz), 7.50 (1H, s), 7.64 (1H, t,
Jϭ9 Hz), 7.74 (1H, dd, Jϭ13.5, 2.5 Hz), 7.96 (1H, s)
(R)-[[3-[3-Fluoro-4-(4-methyl-1-piperazinyl)phenyl]-2-oxo-5-oxazo-
lidinyl]methyl]isothiocyanate (8k) A mixture of 7k (1.00 g, 3.24 mmol),
carbon disulfide (0.40 ml, 6.49 mmol) and Et3N (0.46 ml, 3.24 mmol) in THF
(10 ml) was stirred at 0 °C for 3 h. Ethyl chloroformate (0.31 ml, 3.24 mmol)
was added dropwise to the mixture, and stirred at the same temperature for
1 h. The reaction mixture was extracted with AcOEt. The extract was
washed with brine, dried and concentrated to afford 8k (0.70 g, 62%) as col-
orless crystals. Recrystallization from a mixture of THF and iso-Pr2O af-
forded colorless prisms. mp: 127—127.5 °C. [a]D20 Ϫ159.0° (cϭ0.1,
DMSO). 1H-NMR (CDCl3) d: 2.36 (3H, s), 2.60 (4H, t, Jϭ4.5 Hz), 3.10
(4H, t, Jϭ4.5 Hz), 3.80—3.88 (2H, m), 3.95 (1H, dd, Jϭ14.5, 5.5 Hz), 4.15
(R)-[[3-[3-Fluoro-4-(1-pyrrolyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-
isothiocyanate (8n): Pale brown crystals, 65%. mp: 129—129.5 °C (iso-
1
PrOH). [a]D20 Ϫ168.6° (cϭ0.1, DMSO). H-NMR (DMSO-d6) d: 3.88 (1H,
dd, Jϭ9, 5.5 Hz), 4.06 (1H, dd, Jϭ15, 5.5 Hz), 4.14 (1H, dd, Jϭ15, 3.5 Hz),
4.26 (1H, t, Jϭ9 Hz), 4.95—5.05 (1H, m), 6.27 (2H, t, Jϭ2.5 Hz), 7.11 (2H,
t, Jϭ2.5 Hz), 7.44 (1H, dd, Jϭ9, 2.5 Hz), 7.59 (1H, t, Jϭ9 Hz), 7.69 (1H, dd,
Jϭ14, 2.5 Hz). Anal. Calcd for C15H12FN3O2S: C, 56.77; H, 3.81; N, 13.24.
Found: C, 56.51; H, 3.97; N, 12.92.
Table 7. Physical Data for Compounds 4
Analysis (%)
[a]D20
mp (°C)
(Recryst. Solv.)
Calcd (Found)
No.
Yield (%)a)
Formula
DMSO
(cϭ0.1)
C
H
N
4a
4b
4c
4d
4e
4f
64
48
14
53
46
81
82
57
55
37
36
36
63
83
85
65
Amorphous
C15H18FN3O3S
C16H20FN3O3S
C17H22FN3O3S
C18H24FN3O3S
C19H26FN3O3S
C18H24FN3O4S
C18H24FN3O3S
C16H20FN3O4S2
C16H20FN3O5S2
C16H20FN3O4S
C17H23FN4O3S
C18H25FN4O3S
C19H27FN4O3S
C16H16FN3O3S
C15H15FN4O3S
C15H15FN4O3S
339.10529c)
(339.10536)
Ϫ27.0
Ϫ26.9
Ϫ29.1
Ϫ25.9
Ϫ24.1
Ϫ24.1
Ϫ29.0
Ϫ25.0
Ϫ23.9
Ϫ28.1
Ϫ30.1
Ϫ19.1
Ϫ25.0
Ϫ33.9
Ϫ51.9
Ϫ32.1
147—148.5
(EtOH)
54.38 5.70
(54.27 5.75
55.57 6.03
(55.35 6.24
56.67 6.34
(56.67 6.24
57.70 6.63
(57.70 6.74
54.39 6.09
(54.19 6.21
56.67 6.34
(56.55 6.50
47.87 5.02
(48.04 5.00
11.89
11.91)
11.44
11.33)
11.02
10.91)
10.62
10.53)
10.57
10.47)
11.02
10.82)
10.47
10.51)
117—118
(iso-PrOH)
135—136
(iso-PrOH)
112—114
(iso-PrOH)
112—113.5
(iso-PrOH)
124.5—125.5
(iso-PrOH)
206—207
(CH3CN)
4g
4h
4i
Oil
417.08284c)
(417.08123)
52.02 5.46
(52.10 5.27
53.39 6.06
(53.20 5.94
54.53 6.36
(54.29 6.10
55.59 6.63
(55.36 6.57
55.00 4.62
(54.97 4.68
51.42 4.32
(51.47 4.30
350.08489c)
4j
125—127
(iso-PrOH)
119.5—121.5
(iso-PrOH–iso-Pr2O)
122—123
11.37
11.31)
14.65
14.50)
14.13
14.02)
13.65
13.57)
12.03
11.86)
15.99
16.00)
4k
4l
(iso-PrOH)
128.5—129.5
(iso-PrOH)
141.5—142.5
(iso-PrOH)
127—127.5
4m
4n
4o
4p
(AcOEt–iso-Pr2O)
Amorphous
(350.08382)
a) Yields were calculated from the corresponding compounds 8. b) Elemental analyses were preformed on crystalline samples only. c) High-resolution mass data.

366
Vol. 49, No. 4
Table 8. Physical Data for Compounds 4
No.
1H-NMR (in DMSO-d6)a) d (ppm)
4a
4b
4c
4d
2.29 (2H, quint, Jϭ7.5 Hz), 3.70—3.80 (2H, m), 3.86 (4H, td, Jϭ8.5, 2 Hz), 3.86—3.90 (1H, m), 3.89 (3H, s), 4.07 (1H, t, Jϭ9 Hz),
4.85—4.90 (1H, m), 6.54 (1H, dd, Jϭ9, 9 Hz), 7.09 (1H, dd, Jϭ9, 2.5 Hz), 7.32 (1H, dd, Jϭ14.5, 2.5 Hz), 9.30 (1H, br s)
1.85—1.95 (4H, m), 3.20—3.30 (4H, m), 3.70—3.85 (3H, m), 3.92 (3H, s), 4.05 (1H, t, Jϭ9 Hz), 4.75—4.85 (1H, m), 6.74 (1H, t,
Jϭ9 Hz), 7.07 (1H, dd, Jϭ9, 2.5 Hz), 7.30 (1H, dd, Jϭ15.5, 2.5 Hz), 9.10 (1H, br s)
1.50—1.60 (2H, m), 1.60—1.70 (4H, m), 2.90—3.00 (4H, m), 3.75—3.85 (3H, m), 3.92 (3H, s), 4.08 (1H, t, Jϭ9 Hz), 4.80—4.90
(1H, m), 7.02 (1H, t, Jϭ9 Hz), 7.14 (1H, dd, Jϭ9, 2.5 z), 7.38 (1H, dd, Jϭ14.5, 2.5 Hz), 9.10 (1H, br s)
0.95 (3H, d, Jϭ6.5 Hz), 1.25—1.40 (2H, m), 1.45—1.55 (1H, m), 1.65—1.75 (2H, m), 2.60—2.75 (2H, m), 3.25—3.35 (2H, m),
3.70—3.85 (3H, m), 3.92 (3H, s), 4.08 (1H, t, Jϭ9 Hz), 4.80—4.90 (1H, m), 7.02 (1H, t, Jϭ9 Hz), 7.14 (1H, dd, Jϭ9, 2.5 Hz), 7.37
(1H, dd, Jϭ15, 2.5 Hz), 9.10 (1H, br s)
4e
4f
0.89 (3H, t, Jϭ7.5 Hz), 1.25—1.35 (5H, m), 1.70—1.75 (2H, m), 2.66 (2H, t, Jϭ11.5 Hz), 3.30 (2H, d, Jϭ11.5 Hz), 3.70—3.85 (3H,
m), 3.92 (3H, s), 4.08 (1H, t, Jϭ9 Hz), 4.80–4.90 (1H, m), 7.02 (1H, t, Jϭ9 Hz), 7.14 (1H, dd, Jϭ8, 2.5 Hz), 7.37 (1H, dd, Jϭ15,
2.5 Hz), 9.10 (1H, br s)
1.56—1.65 (2H, m), 1.85—1.95 (2H, m), 2.75—2.85 (2H, m), 3.15—3.25 (2H, m), 3.27 (3H, s), 3.30—3.40 (1H, m), 3.75—3.85 (3H,
m), 3.89 (3H, s), 4.10 (1H, t, Jϭ9 Hz), 4.80—4.90 (1H, m), 7.05 (1H, t, Jϭ9 Hz), 7.14 (1H, dd, Jϭ9, 2.5 Hz), 7.43 (1H, dd, Jϭ14.5,
2.5 Hz), 9.39 (1H, br s)
4g
4h
4i
1.55—1.65 (4H, m), 1.70—1.80 (4H, m), 3.25—3.35 (4H, m), 3.70—3.85 (3H, m), 3.92 (3H, s), 4.06 (1H, t, Jϭ9 Hz), 4.75—4.90
(1H, m), 6.92 (1H, t, Jϭ9 Hz), 7.08 (1H, dd, Jϭ9, 2.5 Hz), 7.31 (1H, dd, Jϭ16, 2.5 Hz), 9.10 (1H, br s)
2.80 (2H, dt, Jϭ14, 3 Hz), 3.20 (2H, td, Jϭ14, 3 Hz), 3.21 (2H, dt, Jϭ14, 4 Hz), 3.60 (2H, t, Jϭ14 Hz), 3.75—3.85 (3H, m), 3.92 (3H,
s), 4.10 (1H, t, Jϭ9 Hz), 4.80—4.90 (1H, m), 7.10—7.20 (2H, m), 7.44 (1H, dd, Jϭ14.5, 2.5 Hz), 9.11 (1H, br s)
3.19 (4H, t, Jϭ5.5 Hz), 3.51 (4H, t, Jϭ5.5 Hz), 3.80—3.90 (3H, m), 3.92 (3H, s), 4.10 (1H, t, Jϭ9 Hz), 4.80—4.90 (1H, m), 7.15—
7.25 (2H, m), 7.43 (1H, dd, Jϭ13.5, 2.5 Hz), 9.10 (1H, br s)
4j
3.00 (4H, t, Jϭ5 Hz), 3.73 (4H, t, Jϭ5 Hz), 3.75—3.85 (3H, m), 3.92 (3H, s), 4.09 (1H, t, Jϭ9 Hz), 4.75-4.95 (1H, m), 7.04 (1H, t,
Jϭ9 Hz), 7.17 (1H, dd, Jϭ9, 3 Hz), 7.41 (1H, dd, Jϭ14.5, 3 Hz), 9.10 (1H, br s)
4k
4l
2.23 (3H, s), 2.47 (4H, t, Jϭ5 Hz), 3.01 (4H, t, Jϭ5 Hz), 3.70—3.85 (3H, m), 3.92 (3H, s), 4.08 (1H, t, Jϭ9 Hz), 4.80—4.90 (1H, m),
7.02 (1H, t, Jϭ9 Hz), 7.15 (1H, dd, Jϭ9, 2.5 Hz), 7.39 (1H, dd, Jϭ15.5, 2.5 Hz), 9.10 (1H, br s)
1.02 (3H, t, Jϭ7 Hz), 2.40 (2H, q, Jϭ7 Hz), 2.52 (4H, t, Jϭ5 Hz), 3.01 (4H, t, Jϭ5 Hz), 3.70—3.85 (3H, m), 3.92 (3H, s), 4.08 (1H, t,
Jϭ9 Hz), 4.80—4.90 (1H, m), 7.02 (1H, t, Jϭ9 Hz), 7.15 (1H, dd, Jϭ9, 2.5 Hz), 7.39 (1H, dd, Jϭ15.5, 2.5 Hz), 9.10 (1H, br s)
0.88 (3H, t, Jϭ7.5 Hz), 1.47 (2H, sextet, Jϭ7.5 Hz), 2.31 (2H, t, Jϭ7.5 Hz), 2.51 (4H, t, Jϭ5 Hz), 3.01 (4H, t, Jϭ5 Hz), 3.70—3.85
(3H, m), 3.92 (3H, s), 4.08 (1H, t, Jϭ9 Hz), 4.80—4.90 (1H, m), 7.02 (1H, t, Jϭ9 Hz), 7.15 (1H, dd, Jϭ9, 2.5 Hz), 7.39 (1H, dd,
Jϭ15, 2.5 Hz), 9.10 (1H, br s)
4m
4n
4o
4p
3.75—3.90 (3H, m), 3.93 (3H, s), 4.18 (1H, t, Jϭ9 Hz), 4.85—4.95 (1H, m), 6.26 (2H, t, Jϭ2.5 Hz), 7.06 (2H, q, Jϭ2.5 Hz), 7.38 (1H,
dd, Jϭ9, 2.5 Hz), 7.54 (1H, t, Jϭ9 Hz), 7.64 (1H, dd, Jϭ14, 2.5 Hz), 9.13 (1H, br s)
3.75—3.90 (3H, m), 3.93 (3H, s), 4.20 (1H, t, Jϭ9 Hz), 4.85—4.95 (1H, m), 6.51 (1H, t, Jϭ2 Hz), 7.43 (1H, dd, Jϭ9, 2 Hz), 7.67 (1H,
dd, Jϭ14, 2 Hz), 7.72 (1H, d, Jϭ2 Hz), 7.77 (1H, t, Jϭ9 Hz), 8.06 (1H, t, Jϭ2 Hz), 9.13 (1H, br s)
3.80—3.90 (3H, m), 3.95 (3H, s), 4.19 (1H, t, Jϭ9 Hz), 4.95—5.00 (1H, m), 7.11 (1H, s), 7.44 (1H, dd, Jϭ9, 2.5 Hz), 7.50 (1H, s),
7.65 (1H, t, Jϭ9 Hz), 7.73 (1H, dd, Jϭ13.5, 2.5 Hz), 7.97 (1H, s), 9.33 (1H, br s)
a) Measured at 100 °C.
to about 5ϫ103 CFU per spot was inoculated on drug-containing agar plates.
The plates were incubated for 18—24 h at 37 °C. The MIC was defined as
the lowest drug concentration that prevented visible growth of bacteria.
In Vivo Antibacterial Test Four week old male ICR mice (18—21 g
body weight) were infected intraperitoneally with bacterial suspension. The
bacterium used for infection was S. aureus Smith (3—7ϫ107). Following in-
fection, graded doses of compounds were administered orally to mice in
groups of 10 each. The ED50, including 95% confidence limits, was calcu-
lated by the probit method9) from the survival rates on day 7 after infection.
(R)-[[3-[3-Fluoro-4-(1-pyrazolyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-
isothiocyanate (8o): Colorless prisms, 81%, mp: 139.5—141 °C (AcOEt).
[a]D20 Ϫ178.4° (cϭ0.1, DMSO). 1H-NMR (DMSO-d6) d: 3.90 (1H, dd, Jϭ9,
6 Hz), 4.06 (1H, dd, Jϭ15.5, 5 Hz), 4.15 (1H, dd, Jϭ15.5, 3 Hz), 4.27 (1H, t,
Jϭ9 Hz), 4.95—5.05 (1H, m), 6.55 (1H, s), 7.48 (1H, dd, Jϭ9, 2.5 Hz), 7.73
(1H, dd, Jϭ14, 2.5 Hz), 7.76 (1H, s), 7.81 (1H, t, Jϭ9 Hz), 8.14 (1H, t,
Jϭ2.5 Hz). Anal. Calcd for C14H11FN4O2S: C, 52.82; H, 3.48; N, 17.60.
Found: C, 52.87; H, 3.53; N, 17.49.
(R)-[[3-[3-Fluoro-4-(1-imidazolyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-
isothiocyanate (8p): Pale yellow oil, 78%. [a]D20 Ϫ144.5° (cϭ0.1, DMSO).
1H-NMR (DMSO-d6) d: 3.89 (1H, dd, Jϭ9.5, 5.5 Hz), 4.06 (1H, dd, Jϭ15,
5.5 Hz), 4.14 (1H, dd, Jϭ15, 3.5 Hz), 4.28 (1H, t, Jϭ9 Hz), 5.00—5.10 (1H,
m), 7.12 (1H, s), 7.49 (1H, dd, Jϭ8.5, 2.5 Hz), 7.63 (1H, s), 7.67 (1H, t,
Jϭ8.5 Hz), 7.74 (1H, dd, Jϭ13.5, 2.5 Hz), 7.97 (1H, s).
Acknowledgement The authors are grateful to Drs. E. Takahara and T.
Mushiroda for pharmacokinetic studies.
References and Notes
1) a) Part 1: Tokuyama R., Takahashi Y., Tomita Y., Suzuki T., Yoshida
T., Iwasaki N., Kado N., Okezaki E., Nagata O., Chem. Pharm. Bull.,
49, 347—352 (2001); b) Part 2: Tokuyama R., Takahashi Y., Tomita
Y., Tsubouchi H., Yoshida T., Iwasaki N., Kado N., Okezaki E., Nagata
O., ibid., 49, 353—360 (2001).
2) Gregory W. A., Brittelli D. R., Wang C.-L. J., Wuonola M. A., McRip-
ley R. J., Eustice D. C., Eberly V. S., Bartholomew P. T., Slee A. M.,
Forbes M., J. Med. Chem., 32, 1673—1681 (1989).
O-Methyl (S)-[[3-[3-Fluoro-4-(4-methyl-1-piperazinyl)phenyl]-2-oxo-
5-oxazolidinyl]methyl]thiocarbamate (4k) To a solution of NaH (60 wt%
in oil, 0.18 g, 7.53 mmol) in MeOH (5 ml), a mixture of 8k (1.32 g, 3.77
mmol) in MeOH (5 ml) was added under ice cooling, followed by stirring at
room temperature for 17 h. Then the reaction mixture was poured into ice
water and adjusted to pH 7 with dilute hydochloric acid. The precipitates
were collected by filtration and washed with water to afford 4k as colorless
crystals. The physicochemical data are listed in Tables 7 and 8.
3) Eustice D. C., Feldman P.A., Zajac I., Slee A. M., Antimicrob. Agents
Chemother., 32, 1218—1222 (1988).
Compounds 4 were respectively prepared from the corresponding 8 in a
similar manner. The physicochemical data are listed in Tables 7 and 8.
In Vitro Antibacterial Test These studies were conducted according to
the method of the Japan Society of Chemotherapy.8) The MICs (mg/ml) were
determined by an agar dilution method with Muller–Hinton agar (MHA,
Difco Laboratories, Detroit, Mich). Bacterial suspensions for inocula were
prepared by diluting overnight cultures of organisms to give a final concen-
tration of 106 CFU/ml, and one loopful (5 ml) of an inoculum, corresponding
4) a) Brickner S. J., Hutchinson D. K., Barbachyn M. R., Garmon S. A.,
Grega K. C., Hendges S. K., Manninen P. R., Toops D. S., Ulanowicz
D. A., Kilburn J. O., Glickman S., Zurenko G. E., Ford C. W., 35th In-
terscience Conference on Antimicrobial Agents and Chemotherapy,
San Francisco, September, 1995, F 208 p. 149; b) Brickner S. J.,
Hutchinson D. K., Barbachyn M. R., Manninen P. R., Ulanowicz D.

April 2001
A., Garmon S. A., Grega K. C., Hendges S. K., Toops D. S., Ford C.
367
J. Med. Chem., 43, 953—970 (2000).
W., Zurenko G. E., J. Med. Chem., 39, 673—679 (1996).
5) Calculated log P values were measured by ACD/Labs log P calcu-
lated., ver. 3.0 (Advanced Chemistry Development, Inc.)
6) Hutchinson D. K., World Intellectual Property Organization 9623788
(1996) [Chem. Abstr., 125, 247827b (1996)]; Genin M. J., Allwine D.
A., Anderson D. J., Barbachyn M. R., Emmert D. E., Garmon S. A.,
Graber D. R., Grega K. C., Hester J. B., Hutchinson D. K., Morris J.,
Reischer R. J., Ford C. W., Zurenko G. E., Hamel J. C., Schaadt, R D.,
7) Some 5-thiocarbonyl oxazolidinones were synthesized at the same
time that we synthesized them: Hester J. B., Nidy E. G., Perricone S.
C., Poel T. J., World Intellectual Property Organization 9854161
(1998) [Chem. Abstr., 130, 38373q (1999)].
8) Goto S., Jo K., Kawakita T., Kosakai N., Mitsuhashi S., Nishino T.,
Ohsawa N., Tanami H., Chemotherapy, 29, 76—79 (1981).
9) Bliss C. I., Method Probit Science, 79, 38—39 (1934).