Conformationally constrained analogues of N′-(4-tert-butylbenzyl)-N-(4-methylsulfonylaminobenzyl)thiourea as TRPV1 antagonists

Article abstract of DOI:10.1016/j.ejmech.2008.02.026

A series of bicyclic analogues having indan and tetrahydronaphthalene templates in the A-region were designed as conformationally constrained analogues of our previously reported potent TRPV1 antagonists (1, 3). The activities for rat TRPV1 of the conformationally restricted analogues were moderately or markedly diminished, particularly in the case of the tetrahydronaphthalene analogues. The analysis indicated that steric constraints at the benzylic position in the bicyclic analogues may be an important factor for their unfavorable interaction with the receptor.

Full text of DOI:10.1016/j.ejmech.2008.02.026

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European Journal of Medicinal Chemistry 44 (2009) 322e331
http://www.elsevier.com/locate/ejmech
Original article
Conformationally constrained analogues of N0-(4-tert-butylbenzyl)-N-
(4-methylsulfonylaminobenzyl)thiourea as TRPV1 antagonists
Ju-Ok Lim a, Mi-Kyoung Jin a, HyungChul Ryu a, Dong Wook Kang a, Jeewoo Lee a,
Larry V. Pearce b, Richard Tran b, Attila Toth b, Peter M. Blumberg b
*
,
a Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-Dong,
Kwanak-Ku, Seoul 151-742, Republic of Korea
b Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Received 31 October 2007; received in revised form 14 January 2008; accepted 24 February 2008
Available online 7 March 2008
Abstract
A series of bicyclic analogues having indan and tetrahydronaphthalene templates in the A-region were designed as conformationally con-
strained analogues of our previously reported potent TRPV1 antagonists (1, 3). The activities for rat TRPV1 of the conformationally restricted
analogues were moderately or markedly diminished, particularly in the case of the tetrahydronaphthalene analogues. The analysis indicated that
steric constraints at the benzylic position in the bicyclic analogues may be an important factor for their unfavorable interaction with the receptor.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords: TRPV1 antagonists; Analgesic; Conformationally constrained analogues
1. Introduction
reported continues to increase and some of them have entered
clinical trials [9,10].
The transient receptor potential V1 (TRPV1) receptor [1] is
a molecular integrator of nociceptive stimuli, including pro-
tons [2], heat [3], inflammatory mediators such as anandamide
[4] and lipoxygenase products [5], and vanilloids such as cap-
saicin (CAP) [6] and resiniferatoxin (RTX) [7]. The receptor
functions as a non-selective cation channel with high Ca2þ
permeability and its activation leads to an increase in intracel-
lular Ca2þ that results in excitation of primary sensory neurons
and ultimately the central perception of pain.
TRPV1 antagonists have attracted much attention as prom-
ising drug candidates for inhibiting the transmission of noci-
ceptive signaling from the periphery to the CNS and for
blocking other pathological states associated with this recep-
tor. They have thus emerged as novel and promising analgesic
and anti-inflammatory agents, particularly for chronic pain and
inflammatory hyperalgesia [8]. The number of antagonists
Previously, we have demonstrated that a series of N-4-(meth-
ylsulfonylaminobenzyl)thiourea analogues were effective
antagonists of the action of capsaicin on rat TRPV1 [11e14].
A prototype antagonist (1) showed high binding affinity and po-
tent antagonism (Ki ¼ 63 nM and Ki(ant) ¼ 54 nM in rTRPV1/
CHO) [11]. We further found that 3-substituents of the 4-(meth-
ylsulfonylamino)phenyl group in the A-region affected the
extent of agonism/antagonism. Thus, the 3-fluoro derivative 2
(Ki ¼ 53.5 nM, Ki(ant) ¼ 9.2 nM in rTRPV1/CHO) was a potent
antagonist not only of capsaicin stimulation of rTRPV1 but also
of stimulation by temperature and pH [11]. Conversely, the 3-
methoxy derivative 3 showed a shift to partial agonism
(Ki ¼ 51 nM, 17% agonism and 84% antagonism in rTRPV1/
CHO) while the binding affinity remained unaffected [12]. In
order to optimize the in vitro activities of 4-methylsulfonamide
TRPV1 antagonists, we have investigated extensively their
structureeactivity relationships as a function of the structural
regions designated as the A, B and C-regions [15e17].
As part of our continuing effort to further optimize the
receptor potency and antagonist efficacy of lead antagonists,
* Corresponding author. Tel.: þ82 2 880 7846; fax: þ82 2 888 0649.
E-mail address: jeewoo@snu.ac.kr (J. Lee).
0223-5234/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.02.026

J.-O. Lim et al. / European Journal of Medicinal Chemistry 44 (2009) 322e331
323
(CH2)n
S
R
N
H
N
H
A
NHSO2CH3
S
R
Type A
N
H
N
H
NHSO2CH3
B
(CH2)n
S
1 R = H
2 R = F
N
N
H
H
3 R = OCH3
NHSO2CH3
R
Type B
Fig. 1.
we have investigated conformationally constrained analogues
of the lead antagonists with the goal of stabilizing a favorable
‘‘bioactive conformation’’. The target compounds were de-
signed to impose conformational restriction between the ben-
zylic position and the phenyl ring through incorporation of
a carbon linker as shown in Fig. 1, providing indan and tetra-
hydronaphthalene templates. In the interest of synthetic acces-
sibility, parent compounds 1 and 3 were chosen to evaluate the
effect of the conformational constraint.
tetrahydro-1-naphthyl moieties in the A-region are outlined
in Scheme 1. Benzylic oxidation of N-Boc substituted bicycles
(6, 7), prepared from commercially available 5-aminoindan (4)
or tetrahydronaphthalene, by pyridinium chlorochromate pro-
vided 1-indanone (8) and 5-oxo-tetrahydronaphthalene (9)
templates. After deprotection and mesylation, ketones of 12
and 13 were converted to the corresponding amines (16, 17)
via oximes, which were condensed with 4-tert-butylbenzyl
isothiocyanate to afford the final thiourea compounds (18, 19).
The syntheses of methoxy substituted analogues of 18 and 19
are shown in Schemes 2 and 3. Nitration [18] of commercially
available 4-methoxy-1-indanone (20) and 5-methoxy-1-
tetralone (21) provided the key intermediates, 4-methoxy-5-
nitro-1-indanone (22) and 5-methoxy-6-nitro-1-tetralone (23),
respectively. As by-products, para-nitration isomers, 7-nitro-
1-indanone and 8-nitro-1-tetralone, were also isolated, respec-
tively. The structures of isomers were assigned based on the
comparison of chemical shifts and NOE enhancement of pro-
tons adjacent to the methoxy group. For example, the H7 and
H8 protons of 5-methoxy-6-nitro-1-tetralone (23) shifted down-
field compared to the H6 and H7 protons of 5-methoxy-8-nitro-
1-tetralone (23
2. Chemistry
The synthetic strategy for preparation of the target com-
pounds is shown in Fig. 2. The target thioureas were synthe-
sized by the coupling of 4-tert-butylbenzyl isothiocyanate
with the bicyclic amines of the A-region moieties, which
were obtained from the corresponding ketones via oxime inter-
mediates. The ketones were prepared either by benzylic oxida-
tion of N-Boc substituted indan or by nitration of appropriately
substituted 1-indanone/a-tetralone.
The syntheses of the target compounds having 5-(methyl-
sulfonylamino)indanyl and 6-(methylsulfonylamino)-1,2,3,4-
0). Whereas only one NOE enhancement by
(CH2)n
(CH2)n
R1
S
R1
N
H
H2N
N
H
NHSO2CH3
R2
NHSO2CH3
R2
(CH2)n
(CH2)n
R1
(CH2)n
R1
O
O
NHBoc
NHSO2CH3
R2
R2
Fig. 2.

324
J.-O. Lim et al. / European Journal of Medicinal Chemistry 44 (2009) 322e331
O
O
a, b
c, d
(CH2)n
(CH2)n
R=H
(CH2)n
R=H
NHR
NHBoc
NHR
R=Ms
R=Boc
8
n=1
n=2
10 n=1
11 n=2
12 n=1
13 n=2
4
n=1
6
n=1
n=2
9
5
n=2
7
e
HO
N
(CH2)n
NH2
S
N
H
N
H
g
f
(CH2)n
(CH2)n
NHMs
NHMs
NHMs
18 n=1
19 n=2
16 n=1
17 n=2
14 n=1
15 n=2
Scheme 1. Reagents and conditions: (a) (Boc)2O, NEt3, CH2Cl2; (b) PCC, CH2Cl2; (c) TFA, CH2Cl2; (d) MsCl, pyridine; (e) NH2OHeHCl, pyridine; (f) 10% Pde
C, H2, concd. HCl, MeOH; (g) 4-t-BuPhCH2NCS, DMF.
OCH3 irradiation of 23 (6-nitro isomer) was observed, the two
enhancements in 230 (8-nitro isomer) were found (see
Ref. [19]). Nitro groups of 22 and 23 were converted to the cor-
responding methylsulfonylamino groups (26 and 27) in two
steps. The final 4-methoxy-1-indanyl (32) and 5-methoxy-1-
naphthyl (33) compounds were prepared from 26 and 27 by
the protocol described in Scheme 1.
starting from 6-methoxy-1-indanone (20) and 7-methoxy-1-
tetralone (21). The structures of the geometric isomers result-
ing from nitration of 34 and 35 were readily confirmed by the
values of the ortho or para coupling constants.
3. Result and discussion
The syntheses of 6-methoxy-1-indanyl (46) and 7-methoxy-
1-naphthyl (47) compounds as shown in Scheme 3 were car-
ried out by a strategy similar to that described in Scheme 2,
The binding affinities and potencies as agonists/antagonists
of the synthesized TRPV1 ligands were assessed in vitro by
a binding competition assay with [3H]RTX and by a functional
O
(CH2)n
O
O
a
b, c
(CH2)n
(CH2)n
NO2
NHR
OCH3
OCH3
OCH3
R=Ms
R=H
20 n=1
22 n=1
23 n=2
24 n=1
25 n=2
26 n=1
27 n=2
21 n=2
d
HO
(CH2)n
OCH3
H2N
(CH2)n
N
S
f
e
N
H
N
(CH2)n
H
NHMs
NHMs
NHMs
OCH3
OCH3
n=1
n=1
n=2
n=1
32
33
30
28
29
31 n=2
n=2
Scheme 2. Reagents and conditions: (a) Cu(NO3)2, Ac2Oeether (1:2); (b) 10% PdeC, H2, MeOH; (c) MsCl, pyridine; (d) NH2OHeHCl, pyridine; (e) 10% PdeC,
H2, concd. HCl, MeOH; (f) 4-t-BuPhCH2NCS, DMF.

J.-O. Lim et al. / European Journal of Medicinal Chemistry 44 (2009) 322e331
325
O
O
O
OCH3
NO2
OCH3
OCH3
NHR
a
b, c
(CH2)n
(CH2)n
(CH2)n
R=H
R=Ms
34 n=1
36 n=1
37 n=2
38 n=1
39 n=2
40 n=1
41 n=2
35 n=2
d
(CH2)n
S
HO
H2N
N
OCH3
OCH3
NHMs
N
H
N
f
e
H
(CH2)n
(CH2)n
NHMs
NHMs
OCH3
46 n=1
47 n=2
44 n=1
45 n=2
42 n=1
43 n=2
Scheme 3. Reagents and conditions: (a) Cu(NO3)2, Ac2Oeether (1:2); (b) 10% PdeC, H2, MeOH; (c) MsCl, pyridine; (d) NH2OHeHCl, pyridine; (e) 10% PdeC,
H2, concd. HCl, MeOH; (f) 4-t-BuPhCH2NCS, DMF.
45Ca2þ uptake assay using rat TRPV1 heterologously expressed
in Chinese hamster ovary (CHO) cells, as previously described
[13]. The results are summarized in Table 1, together with the
potencies of the previously reported antagonists 1 and 3 [15].
The conformational restriction of the parent thiourea 1 by
bridging between the benzylic position in the B-region and
the phenyl in the A-region with a two (or three) carbon linker
provided the two bicycles, indan (18) and tetrahydronaphtha-
lene (19), respectively. These compounds revealed that the
constraint led to the moderate loss of receptor activity
compared to the parent antagonist. The binding affinities of
18 and 19 were reduced by 10-fold and 25-fold compared to
1; their potencies as antagonists decreased by a similar extent,
14-fold and 50-fold, respectively. The reduction in activity for
the tetrahydronaphthalene analogue (19) was greater than that
for the indan analogue (18).
Although conformational restriction might shift the confor-
mations of the bicylic compounds away from the ‘‘bioactive
conformation’’, the steric environment at the benzylic position
appears to be dominant for favorable interaction with the
receptor. We previously reported that incorporation of a methyl
group, particularly with an (R)-configuration, at the benzylic
position of the A-region in compound 1 enhanced specific
binding to the receptor [17]. For example, the (R)-a-methyl
Table 1
S
analogue of compound
1 showed high potency with
N
H
NH
a Ki ¼ 41 nM for receptor binding and Ki(ant) ¼ 4.5 nM for
antagonism of capsaicin stimulated calcium uptake. However,
more bulky substituents such as ethyl, isopropyl, phenyl and
benzyl groups resulted in modest to dramatic decreases in
binding affinities and antagonistic potencies, with the antago-
nist potencies diminishing as the size of the substituents
increased, Et > i-Pr > Bn > Ph. Our current findings, that the
sterically more demanding tetrahydronaphthalene analogue
(19) caused greater reduction in receptor activity compared
to indan (18), are consistent with these observations.
To further investigate the conformationally constrained
bicycles, we synthesized the conformationally constrained an-
alogues of the parent compound 3 with a 3-methoxy group in
the A-region. Depending upon the direction of cyclization and
the length of the linker, there are four possible bicyclic ana-
logues, as shown in Fig. 1.
R2
(CH2)n
NHSO2CH3
R1
EC50 (nM)
n
R1
R2
Ki (nM)
binding affinityc agonismc
Ki (nM)
antagonismc
1
63 (ꢀ10)
660 (ꢀ190)
1590 (ꢀ270)
50 (ꢀ17)
NE
NE
53.9 (ꢀ8.7)
740 (ꢀ320)
2640 (ꢀ720)
3.4 (ꢀ1.0)b
1690 (ꢀ750)
4700 (ꢀ2600)
25000 (ꢀ6300)
NE
18
19
3
1
2
H
H
H
H
NE
32.4 (ꢀ5.3)a
32
33
46
47
1
2
1
2
OCH3
OCH3
H
H
H
1820 (ꢀ260)
1750 (ꢀ200)
NE
NE
OCH3 3370 (ꢀ580)
NE
WEa
H
OCH3 6900 (ꢀ2200)
NE, no effect. WE, weak effect (quantitation of fractional agonism/antagonism
is from 1 to 3 experiments).
a
Only fractional calcium uptake compared with that induced by 300 nM
capsaicin: 3, 17%; 47, 14%.
The indan analogues representing the 4-isomer(32) and the 6-
isomer (46) were prepared. As with the analogues described
above, their activities were reduced compared to that of the
b
Only fractional antagonism: 3, 88%.
Values represent mean ꢀ SEM from three or more experiments.
c

326
J.-O. Lim et al. / European Journal of Medicinal Chemistry 44 (2009) 322e331
parent compound. The binding affinities of the 4-isomer (32) and
the 6-isomer (46) decreased by 36-fold and 67-fold, respectively,
and their potencies as antagonists were markedly reduced. The
two tetrahydronaphthalene analogues, the 5-isomer (33) and
the 7-isomer (47), similarly showed a reduction in receptor activ-
ities. The binding affinities of the 5-isomer (33) and the 7-isomer
(47) decreased by 35-fold and 137-fold, respectively, and their
potencies as antagonists were again markedly diminished, or,
for compound 47, undetectable over the range of concentrations
that were tested. As observed with compounds 18 and 19, the re-
ceptor activities of the tetrahydronaphthalenes were reduced
more than those of the indans and this may be attributed to the
more sterically demanding tetrahydronaphthalene ring. Interest-
ingly, the 4- or 5-isomers were found to be more potent than their
corresponding 6- or 7-isomers in the bicyclic analogues, and this
positional effect of substitution is currently under investigation.
It should be noted that, at high (10e30 mM) ligand concen-
trations, interpretation of inhibitory responses on TRPV1 is
somewhat less straightforward because of the possibility of
superimposed specific and non-specific mechanisms of antag-
onism. However, for this series of ligands no change in the na-
ture of the responses from antagonist to agonist was observed,
as evidenced by the agonism assays. In any case, we believe
that the ligand binding assays, because they circumvent issues
of calcium processing, desensitization, and rates of ligand pen-
etration into the cells, provide the most robust measure of the
structureeactivity relations for receptoreligand recognition.
performed on an EA 1110 Automatic Elemental Analyzer,
CE Instruments.
5.1.1. 5,6,7,8-Tetrahydro-2-naphthylamine (5)
1,2,3,4-Tetrahydronaphthalene (3.965 g, 30 mmol) was
added to a stirred suspension of copper(II) nitrate hydrate
(5.62 g, 30 mmol) and acetic anhydride (10 mL) in diethyl
ether (20 mL). The reaction mixture was stirred at room tem-
perature until consumption of the starting material was com-
pleted, as monitored by TLC (ca. 3 h). The mixture was
filtered through celite by washing with additional ether and
the filtrate was concentrated in vacuo. The residue was purified
by flash column chromatography on silica gel using EtOA-
c:hexanes (1:10) as eluant to give a mixture of mono-nitrated
products as a yellow oil (2.55 g, 48%). The compound (2.55 g,
57.6 mmol) in MeOH (50 mL) was treated with 10% palla-
dium on carbon (0.3 g) and hydrogenated under a balloon of
hydrogen for 1 h. The reaction mixture was filtered through
celite and the filtrate was concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel us-
ing EtOAc:hexanes (1:5) as eluant to provide 2-naphthylamine
(5) as a white solid (1.144 g, 54%) along with its isomer, 1-
naphthylamine (50) as a red oil (0.657 g, 31%).
5,6,7,8-Tetrahydro-2-naphthylamine
(5).
Rf ¼ 0.250
(EtOAc:hexanes ¼ 1:5), mp ¼ 29e33 ꢁC. 1H NMR (CDCl3)
d 6.85 (d, 1H, J ¼ 7.8 Hz, H-4), 6.47 (dd, 1H, J ¼ 7.8,
2.4 Hz, H-3), 6.41 (d, 1H, J ¼ 2.4 Hz, H-1), 3.47 (br s, 2H,
NH2), 2.62e2.68 (m, 4H, H-5 and H-8), 1.70e80 (m, 4H,
H-6 and H-7).
4. Conclusion
5,6,7,8-Tetrahydro-1-naphthylamine
(50).
Rf ¼ 0.375
(EtOAc:hexanes ¼ 1:5). 1H NMR (CDCl3) d 6.93 (t, 1H,
J ¼ 7.6 Hz, H-3), 6.50e6.54 (m, 2H, H-2 and H-4), 3.55 (br
s, 2H, NH2), 2.73 (t, 2H, J ¼ 6.1 Hz, H-5), 2.45 (t, 2H,
J ¼ 6.1 Hz, H-8), 1.71e1.92 (m, 4H, H-6 and H-7).
We have investigated conformationally constrained ana-
logues of the potent TRPV1 antagonists (1, 3), designed
with the intention of stabilizing the bioactive conformation,
and have analyzed their structureeactivity relationships. The
six bicyclic analogues, representing indan and tetrahydronaph-
thalene templates, were designed and synthesized employing
regioselective nitration and reductive amination of benzylic
ketones. Unfortunately, the synthesized bicyclic analogues
showed moderate or weak receptor activities compared to par-
ent compounds. The SAR analysis, together with our previous
findings, suggests that the loss in activity may be attributed to
steric restrictions at the benzylic position of the bicyclic ana-
logues resulting in unfavorable interactions with the receptor.
5.1.2. tert-Butyl N-(indan-5-yl)carbamate (6)
A solution of 5-aminoindan (4) (3 g, 30 mmol) in CH2Cl2
(50 mL) was treated with triethylamine (8.36 mL, 60 mmol)
and di-tert-butyl dicarbonate (7.857 g, 36 mmol), and stirred
at room temperature for 3 h. The reaction mixture was diluted
with H2O and extracted with EtOAc several times. The com-
bined organic layers were washed with H2O and brine, dried
over MgSO4, filtered, and the filtrate was concentrated in va-
cuo. The residue was purified by flash column chromatography
on silica gel using EtOAc:hexanes (1:10) as eluant to provide
1
6 as a white solid (7.0 g, 100%): mp ¼ 70e72
ꢁC. H NMR
5. Experimental
(CDCl3) d 7.33 (br s, 1H, H-4), 7.11 (d, 1H, J ¼ 8.0 Hz, H-
7), 6.99 (dd, 1H, J ¼ 1.7, 8.0 Hz, H-6), 6.41 (br s, 1H,
NHCO), 2.81e2.89 (m, 4H, H-1 and H-3), 2.00e2.10 (m,
2H, H-2), 1.51 (s, 9H, C(CH3)3).
5.1. General
All chemical reagents were commercially available. Melt-
ing points were determined on a melting point Buchi B-540
apparatus and are uncorrected. Silica gel column chromatogra-
phy was performed on silica gel 60, 230e400 mesh, Merck.
Proton NMR spectra were recorded on a JEOL JNM-LA
300 at 300 MHz. Chemical shifts are reported in ppm units
with Me4Si as a reference standard. Mass spectra were re-
corded on a VG Trio-2 GCeMS. Combustion analyses were
5.1.3. tert-Butyl N-(5,6,7,8-tetrahydro-2-naphthyl)
carbamate (7)
This compound was obtained from 5 by following the pro-
cedure described above to afford a white solid with a quantita-
tive yield: mp ¼ 85e87 ꢁC. 1H NMR (CDCl3) d 7.14 (br s, 1H,
H-1), 6.96e7.00 (m, 2H, H-3 and H-4), 6.33 (br s, 1H, NH),

J.-O. Lim et al. / European Journal of Medicinal Chemistry 44 (2009) 322e331
327
2.66e2.73 (m, 4H, H-5 and H-8), 1.72e1.78 (m, 4H, H-6 and
H-7), 1.50 (s, 9H, C(CH3)3).
The reaction mixture was diluted with H2O and extracted
with EtOAc several times. The combined organic layers
were washed with H2O and brine, dried over MgSO4, filtered,
and the filtrate was concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel using
EtOAc:hexanes (2:1) as eluant to give 12 as a brown solid
5.1.4. tert-Butyl N-(1-indanone-5-yl)carbamate (8)
To a suspension of pyridinium chlorochromate (8.622 g,
˚
40 mmol) and 4 A molecular sieve (10 g) in CH2Cl2
1
(200 mL) was added 6 (4.666 g, 20 mmol) portionwise. The
reaction mixture was refluxed for 24 h, cooled and diluted
with ether. After stirring for 1 h, the mixture was filtered
through celite and the filtrate was concentrated in vacuo.
The residue was purified by flash column chromatography
on silica gel using EtOAc:hexanes (1:3) as eluant to provide
8 as a white solid (3.46 g, 70%): mp ¼ 175e176 ꢁC. 1H
NMR (CDCl3) d 7.76 (br s, 1H, H-4), 7.67 (d, 1H,
J ¼ 8.3 Hz, H-7), 7.13 (dd, 1H, J ¼ 1.7, 8.3 Hz, H-6), 6.81
(br s, 1H, NHCO), 3.09 (t, 2H, J ¼ 5.6 Hz, H-3), 2.65e2.67
(m, 2H, H-2), 1.54 (s, 9H, C(CH3)3).
(0.8 g, 88%): mp ¼ 222e223 ꢁC. H NMR (CDCl3) d 7.75
(d, 1H, J ¼ 8.3 Hz, H-7), 7.36 (d, 1H, J ¼ 1.7 Hz, H-4), 7.09
(dd, 1H, J ¼ 1.7, 8.3 Hz, H-6), 6.87 (s, 1H, NHSO2), 3.12e
3.15 (m, 5H, H-3 and SO2CH3), 2.69e2.73 (m, 2H, H-2).
5.1.9. 6-(Methylsulfonylamino)-1-tetralone (13)
This compound was obtained from 11 by following the pro-
cedure described above to afford a white solid in 93% yield:
mp ¼ 170e172 ꢁC. 1H NMR (CDCl3) d 8.04 (d, 1H,
J ¼ 8.5 Hz, H-8), 7.09 (d, 1H, J ¼ 2.2 Hz, H-5), 7.04 (dd,
1H, J ¼ 8.5, 2.2 Hz, H-7), 6.69 (s, 1H, NHSO2), 3.11 (s, 3H,
SO2CH3), 2.96 (t, 2H, J ¼ 6.1 Hz, H-4), 2.64 (t, 2H,
J ¼ 6.1 Hz, H-2), 2.12e2.16 (m, 2H, H-3).
5.1.5. tert-Butyl N-(5-oxo-5,6,7,8-tetrahydro-2-naphthyl)
carbamate (9)
This compound was obtained from 7 by following the pro-
cedure described above to afford a yellow solid in 65% yield:
mp ¼ 133e135 ꢁC. 1H NMR (CDCl3) d 7.97 (d, 1H,
J ¼ 8.6 Hz, H-4), 7.49 (br s, 1H, H-1), 7.10 (dd, 1H,
J ¼ 2.2 Hz, H-3), 6.76 (br s, 1H, NHCO), 2.93 (t, 2H,
J ¼ 6.1 Hz, H-8), 2.61 (t, 2H, J ¼ 6.1 Hz, H-6), 2.10e2.14
(m, 2H, H-7), 1.53 (s, 9H, C(CH3)3); IR (KBr) 3311 (s),
5.1.10. 5-(Methylsulfonylamino)-1-indanone oxime (14)
A mixture of 12 (0.675 g, 3 mmol) and hydroxylamine hy-
drochloride (0.417 g, 6 mmol) in pyridine (3 mL) was heated
at 70 ꢁC for 3 h. The reaction mixture was cooled to room tem-
perature, diluted with H2O, and extracted with EtOAc several
times. The combined organic layers were washed with H2O
and brine, dried over MgSO4, filtered, and the filtrate was con-
centrated in vacuo. The residue was purified by flash column
chromatography on silica gel using EtOAc:hexanes (1:1) as el-
uant to give 14 as a white solid (0.684 g, 95%): mp ¼ 186e
1729 (m), 1662 (s), 1604 (s), 1585 (m), 1529 (m) cmꢂ1
.
5.1.6. 5-Amino-1-indanone (10)
A cooled solution of 8 (3.46 g, 14 mmol) in CH2Cl2
(30 mL) at 0 ꢁC was treated with trifluoroacetic acid
(6 mL) and stirred at room temperature for 1 h. The mixture
was removed in vacuo, neutralized with saturated NaHCO3
solution, and extracted with EtOAc several times. The com-
bined organic layers were washed with H2O and brine, dried
over MgSO4, filtered, and the filtrate was concentrated in
vacuo. The residue was purified by flash column chromato-
graphy on silica gel using EtOAc:hexanes (1:1) as eluant to
give 10 as a yellow solid (1.852 g, 90%): mp ¼ 188e
1
188 ꢁC. H NMR (CDCl3) d 7.62 (d, 1H, J ¼ 8.3 Hz, H-7),
7.23 (d, 1H, J ¼ 1.7 Hz, H-4), 7.03 (dd, 1H, J ¼ 1.7, 8.3 Hz,
H-6), 6.42 (s, 1H, NHSO2), 3.02e3.08 (m, 5H, H-3 and
SO2CH3), 2.94e2.99 (m, 2H, H-2).
5.1.11. 6-(Methylsulfonylamino)-1-tetralone oxime (15)
This compound was obtained from 13 by following the pro-
cedure described above to afford a white solid in 93% yield:
mp ¼ 191e192 ꢁC. 1H NMR (CDCl3) d 7.90 (d, 1H,
J ¼ 8.5 Hz, H-8), 7.02 (d, 1H, J ¼ 2.2 Hz, H-5), 6.99 (dd,
1H, J ¼ 8.5, 2.2 Hz, H-7), 6.33 (s, 1H, NHSO2), 3.04 (s, 3H,
SO2CH3), 2.79 (t, 2H, J ¼ 6.1 Hz, H-4), 2.75 (t, 2H,
J ¼ 6.1 Hz, H-2), 1.82e1.89 (m, 2H, H-3).
1
190 ꢁC. H NMR (CDCl3) d 7.58 (d, 1H, J ¼ 9.0 Hz, H-7),
6.58e6.61 (m, 2H, H-4 and H-6), 4.21 (br s, 2H, NH2),
3.00 (t, 2H, J ¼ 5.8 Hz, H-3), 2.60e2.64 (m, 2H, H-2).
5.1.7. 6-Amino-1-tetralone (11)
This compound was obtained from 9 by following the pro-
cedure described above to afford a yellow solid in 92% yield:
mp ¼ 130e132 ꢁC. 1H NMR (CDCl3) d 7.89 (d, 1H,
J ¼ 8.6 Hz, H-8), 6.54 (dd, 1H, J ¼ 8.6, 2.2 Hz, H-7), 6.42
(d, 1H, J ¼ 2.2 Hz, H-5), 4.10 (br s, 2H, NH2), 2.83 (t, 2H,
J ¼ 6.1 Hz, H-4), 2.57 (t, 2H, J ¼ 6.1 Hz, H-2), 2.06e2.10
(m, 2H, H-3).
5.1.12. 5-(Methylsulfonylamino)-1-indanylamine (16)
A suspension of 14 (0.48 g, 2 mmol) and 10% palladium on
carbon (100 mg) in MeOH (20 mL) was treated with concen-
trated hydrochloric acid (10 drops) and hydrogenated under
a balloon of hydrogen for 6 h. The reaction mixture was neu-
tralized with solid NaHCO3, filtered and the filtrate was con-
centrated in vacuo. The residue was purified by flash column
chromatography on silica gel using CH2Cl2:MeOH (5:1) as el-
uant to give 16 as a brown solid (0.443 g, 98%): mp ¼ 146e
5.1.8. 5-(Methylsulfonylamino)-1-indanone (12)
1
A cooled solution of 10 (0.59 g, 4 mmol) in pyridine
(4 mL) at 0 ꢁC was treated with methanesulfonyl chloride
(0.62 mL, 8 mmol) and stirred at room temperature for 2 h.
148 ꢁC. H NMR (CDCl3) d 7.28 (d, 1H, J ¼ 8.3 Hz, H-7),
7.10 (br s, 1H, H-4), 7.04 (dd, 1H, J ¼ 1.7, 8.3 Hz, H-6),
4.36 (t, 1H, J ¼ 7.1 Hz, H-1), 3.32 (br s, 2H, NH2), 2.98 (s,

328
J.-O. Lim et al. / European Journal of Medicinal Chemistry 44 (2009) 322e331
3H, SO2CH3), 2.90e2.94 (m, 1H, H-3a), 2.73e2.83 (m, 1H,
H-3b), 2.45e2.56 (m, 1H, H-2a), 1.66e1.78 (m, 1H, H-2b).
monitored by TLC (ca. 3 h). The mixture was filtered through
celite by washing with additional ether and the filtrate was
concentrated in vacuo. The residue was purified by flash col-
umn chromatography on silica gel using EtOAc:hexanes
(1:2) as eluant to give the 5-nitro isomer (22) as a yellow solid
(0.973 g, 47%) along with its 7-nitro isomer (220) as a yellow
solid (0.787 g, 38%).
5.1.13. 6-(Methylsulfonylamino)-1,2,3,4-tetrahydro-1-
naphthylamine (17)
This compound was obtained from 13 by following the pro-
cedure described above to afford a white solid in 98% yield:
1
mp ¼ 197e199 ꢁC. H NMR (DMSO-d6) d 8.25 (br s, 3H,
5-Nitro (22). Rf ¼ 0.29 (EtOAc:hexanes ¼ 1:2), mp ¼ 85e
1
NH2 and NHSO2), 7.46 (d, 1H, J ¼ 8.5 Hz, H-8), 7.05 (dd,
1H, J ¼ 8.5, 2.2 Hz, H-7), 6.97 (d, 1H, J ¼ 2.2 Hz, H-5),
4.28 (t, 1H, J ¼ 5.6 Hz, H-1), 2.97 (s, 3H, SO2CH3), 2.65e
2.75 (m, 2H, H-4), 1.62e2.10 (m, 4H, H-2 and H-3).
86 ꢁC. H NMR (CDCl3) d 7.75 (d, 1H, J ¼ 8.3 Hz, H-6),
7.56 (d, 1H, J ¼ 8.3 Hz, H-7), 4.05 (s, 3H, OCH3), 3.27 (t,
2H, J ¼ 6.1 Hz, H-3), 2.78e2.82 (m, 2H, H-2).
7-Nitro
(220).
Rf ¼ 0.23
(EtOAc:hexanes ¼ 1:2),
mp ¼ 140e143 ꢁC. 1H NMR (CDCl3) d 7.82 (d, 1H,
J ¼ 8.5 Hz, H-6), 7.01 (d, 1H, J ¼ 8.5 Hz, H-5), 4.00 (s, 3H,
OCH3), 3.04 (t, 2H, J ¼ 6.1 Hz, H-3), 2.77e2.82 (m, 2H, H-2).
5.1.14. N-(4-tert-Butylbenzyl)-N0-[5-(methylsulfonylamino)-
1-indanyl]thiourea (18)
A mixture of 16 (0.226 g, 1 mmol) and 4-tert-butylbenzyl
isothiocyanate (0.205 g, 1 mmol) in DMF (4 mL) was stirred
at room temperature for 2 h. The reaction mixture was diluted
with H2O and extracted with EtOAc several times. The com-
bined organic layers were washed with H2O and brine, dried
over MgSO4, filtered, and the filtrate was concentrated in va-
cuo. The residue was purified by flash column chromatography
on silica gel with EtOAc:hexanes (1:1) as eluant to give 18 as
5.1.17. 5-Methoxy-6-nitro-1-tetralone (23)
This compound, along with its 8-nitro isomer (230), was
obtained from 5-methoxy-1-tetralone (21) by following the
procedure described above.
6-Nitro (23). Yield 46%, Rf ¼ 0.50 (EtOAc:hexanes ¼ 1:2),
1
yellow solid, mp ¼ 75e76 ꢁC. H NMR (CDCl3) d 7.91 (d,
1H, J ¼ 8.5 Hz, H-8), 7.67 (d, 1H, J ¼ 8.5 Hz, H-7), 3.94 (s,
3H, OCH3), 3.05 (t, 2H, J ¼ 6.1 Hz, H-4), 2.71 (t, 2H,
J ¼ 6.1 Hz, H-2), 2.13e2.21 (m, 2H, H-3).
1
a white solid (0.363 g, 84%): mp ¼ 170e172 ꢁC. H NMR
(CDCl3) d 7.38 (d, 2H, J ¼ 8.3 Hz, t-BuPh), 7.25 (d, 2H,
J ¼ 8.3 Hz, t-BuPh), 7.11e7.15 (m, 2H, H-7 and H-4), 6.95
(dd, 1H, J ¼ 1.7, 8.3 Hz, H-6), 6.48 (s, 1H, NHSO2), 6.22
(br s, 1H, NH), 5.77 (br s, 2H, NH and H-1), 4.55 (br s, 2H,
CH2NHCS), 2.99 (s, 3H, SO2CH3), 2.75e2.94 (m, 2H, H-3),
2.62e2.66 (m, 1H, H-2a), 1.82e1.84 (m, 1H, H-2b), 1.32 (s,
9H, C(CH3)3); IR (KBr) 3433 (s), 2961 (w), 1628 (s), 1545
(s), 1489 (w), 1322 (m), 1148 (s) cmꢂ1; MS m/z 432 (MHþ).
Anal. Calcd for C22H29N3O2S2: C, 61.22; H, 6.77; N, 9.74;
S, 14.86. Found: C, 61.43; H, 6.80; N, 9.70; S, 14.81.
8-Nitro (230). Yield 42%, Rf ¼ 0.39 (EtOAc:hexanes ¼ 1:2),
1
yellow solid, mp ¼ 104e106 ꢁC. H NMR (CDCl3) d 7.41 (d,
1H, J ¼ 8.8 Hz, H-7), 6.96 (d, 1H, J ¼ 8.8 Hz, H-6), 3.87 (s,
3H, OCH3), 2.90 (t, 2H, J ¼ 6.1 Hz, H-4), 2.71 (t, 2H,
J ¼ 6.1 Hz, H-2), 2.11e2.19 (m, 2H, H-3).
5.1.18. 5-Amino-4-methoxy-1-indanone (24)
A suspension of 22 (1.035 g, 5 mmol) and 10% palladium
on carbon (150 mg) in MeOH (50 mL) was hydrogenated un-
der a balloon of hydrogen for 1 h. The reaction mixture was
filtered through celite and the filtrate was concentrated in va-
cuo. The residue was purified by flash column chromatography
on silica gel using EtOAc:hexanes (1:1) as eluant to give 24 as
5.1.15. N-(4-tert-Butylbenzyl)-N0-[6-(methylsulfonylamino)-
1,2,3,4-tetrahydro-1-naphthyl]thiourea (19)
This compound was obtained from 17 by following the pro-
cedure described above to afford a white solid in 86% yield:
mp ¼ 130e131 ꢁC. 1H NMR (CDCl3) d 7.38 (d, 2H,
J ¼ 8.3 Hz, t-BuPh), 7.21e7.25 (m, 3H, t-BuPh, H-8), 6.90e
6.95 (m, 2H, H-5 and H-7), 6.38 (s, 1H, NHSO2), 6.18 (br s,
1H, NH), 5.71 (br s, 1H, NH), 5.50 (br s, 1H, H-1), 4.51 (br
s, 2H, CH2NHCS), 3.00 (s, 3H, SO2CH3), 2.70e2.74 (m,
2H, H-4), 2.02e2.08 (m, 1H, H-2a), 1.71e1.92 (m, 3H, H-3
and H-2b), 1.31 (s, 9H, C(CH3)3); IR (KBr) 3430 (s), 2961
(w), 1616 (m), 1548 (s), 1505 (m), 1394 (s), 1311 (s), 1150
1
a yellow solid (0.78 g, 88%): mp ¼ 147e148 ꢁC. H NMR
(CDCl3) d 7.39 (d, 1H, J ¼ 8.1 Hz, H-7), 6.71 (d, 1H,
J ¼ 8.1 Hz, H-6), 4.39 (br s, 2H, NH2), 3.89 (s, 3H, OCH3),
3.11 (t, 2H, J ¼ 6.1 Hz, H-3), 2.62e2.66 (m, 2H, H-2).
5.1.19. 6-Amino-5-methoxy-1-tetralone (25)
This compound was obtained from 23 by following the pro-
cedure described above to afford a white solid in 93% yield:
1
mp ¼ 144 ꢁC. H NMR (CDCl3) d 7.74 (d, 1H, J ¼ 8.5 Hz,
(m) cmꢂ1
;
MS m/z 446 (MHþ). Anal. Calcd for
H-8), 6.64 (d, 1H, J ¼ 8.5 Hz, H-7), 4.28 (br s, 2H, NH2),
3.75 (s, 3H, OCH3), 2.93 (t, 2H, J ¼ 6.8 Hz, H-4), 2.56 (t,
2H, J ¼ 6.8 Hz, H-2), 2.08 (m, 2H, H-3).
C23H31N3O2S2: C, 61.99; H, 7.01; N, 9.43; S, 14.39. Found:
C, 61.78; H, 7.03; N, 9.39; S, 14.34.
5.1.16. 4-Methoxy-5-nitro-1-indanone (22)
5.1.20. 4-Methoxy-5-(methylsulfonylamino)-1-
indanone (26)
This compound was obtained from 24 by following the pro-
cedure described for the synthesis of 12 to afford a yellow
solid in 95% yield: mp ¼ 185e186 ꢁC. 1H NMR (CDCl3)
d 7.61 (d, 1H, J ¼ 8.3 Hz, H-6), 7.54 (d, 1H, J ¼ 8.3 Hz,
4-Methoxy-1-indanone (20) (1.62 g, 10 mmol) was added
to a stirred suspension of copper(II) nitrate hydrate (1.88 g,
10 mmol) and acetic anhydride (10 mL) in diethyl ether
(20 mL). The reaction mixture was stirred at room temperature
until consumption of the starting material was completed, as

J.-O. Lim et al. / European Journal of Medicinal Chemistry 44 (2009) 322e331
329
H-7), 7.31 (s, 1H, NHSO2), 4.01 (s, 3H, OCH3), 3.24 (t, 2H,
J ¼ 6.1 Hz, H-3), 3.10 (s, 3H, SO2CH3), 2.69e2.74 (m, 2H,
H-2).
2H, J ¼ 8.3 Hz, t-BuPh), 7.34 (d, 1H, J ¼ 8.3 Hz, H-6), 7.25
(d, 2H, J ¼ 8.3 Hz, t-BuPh), 6.82e6.85 (m, 1H, H-7 and
NHSO2), 6.17 (br s, 1H, NH), 5.72 (br s, 2H, NH and H-1),
4.55 (br s, 2H, CH2NHCS), 3.88 (s, 3H, OCH3), 2.85e3.15
(m, 5H, SO2CH3 and H-3), 2.68e2.73 (m, 1H, H-2a), 1.81e
1.89 (m, 1H, H-2b), 1.32 (s, 9H, C(CH3)3); IR (KBr) 3433
(s), 2961 (w), 1635 (s), 1540 (s), 1483 (w), 1312 (m), 1155
5.1.21. 5-Methoxy-6-(methylsulfonylamino)-1-tetralone (27)
This compound was obtained from 25 by following the pro-
cedure described for the synthesis of 12 to afford a white solid
in 93% yield: mp ¼ 178e179 ꢁC. 1H NMR (CDCl3) d 7.89 (d,
1H, J ¼ 8.8 Hz, H-7), 7.51 (d, 1H, J ¼ 8.8 Hz, H-8), 7.25 (s,
1H, NHSO2), 3.80 (s, 3H, OCH3), 3.11 (s, 3H, SO2CH3),
2.97 (t, 2H, J ¼ 6.1 Hz, H-4), 2.64 (t, 2H, J ¼ 6.1 Hz, H-2),
2.08e2.16 (m, 2H, H-3).
(s) cmꢂ1
;
MS m/z 462 (MHþ). Anal. Calcd for
C23H31N3O3S2: C, 59.84; H, 6.77; N, 9.10; S, 13.89. Found:
C, 60.00; H, 6.81; N, 9.05; S, 13.86.
5.1.27. N-(4-tert-Butylbenzyl)-N0-[5-methoxy-6-
(methylsulfonylamino)-1,2,3,4-tetrahydro-1-
naphthyl]thiourea (33)
5.1.22. 4-Methoxy-5-(methylsulfonylamino)-1-
indanone oxime (28)
This compound was obtained from 31 by following the pro-
cedure described for the synthesis of 18 to afford a white solid
in 65% yield: mp ¼ 169e172 ꢁC. 1H NMR (CDCl3) d 7.40 (d,
2H, J ¼ 8.0 Hz, t-BuPh), 7.34 (d, 1H, J ¼ 8.4 Hz, H-7), 7.25
(d, 2H, J ¼ 8.0 Hz, t-BuPh), 7.05 (d, 1H, J ¼ 8.4 Hz, H-8),
6.86 (s, 1H, NHSO2), 6.15 (br s, 1H, NH), 5.71 (br s, 1H,
NH), 5.52 (br s, 1H, H-1), 4.53 (s, 2H, CH2NHCS), 3.76 (s,
3H, OCH3), 3.06 (s, 3H, SO2CH3), 2.70e2.74 (m, 2H, H-4),
2.07e2.11 (m, 1H, H-2a), 1.80e1.84 (m, 2H, H-3), 1.68e
1.72 (m, 1H, H-2b), 1.34 (s, 9H, C(CH3)3); IR (KBr) 3434
(s), 2952 (w), 1635 (m), 1555 (s), 1487 (m), 1315 (s), 1152
This compound was obtained from 26 by following the pro-
cedure described for the synthesis of 14 to afford a white solid
in 90% yield: mp ¼ 207e209 ꢁC. 1H NMR (CDCl3) d 7.50 (d,
1H, J ¼ 8.3 Hz, H-6), 7.40 (d, 1H, J ¼ 8.3 Hz, H-7), 7.28 (s,
1H, NHSO2), 7.01 (s, 1H, OH), 3.94 (s, 3H, OCH3), 3.18 (t,
2H, J ¼ 6.1 Hz, H-3), 2.95e3.05 (m, 5H, SO2CH3 and H-2).
5.1.23. 5-Methoxy-6-(methylsulfonylamino)-1-
tetralone oxime (29)
This compound was obtained from 27 by following the pro-
cedure described for the synthesis of 14 to afford a white solid
in 99% yield: mp ¼ 187e189 ꢁC. 1H NMR (CDCl3) d 7.73 (d,
1H, J ¼ 8.8 Hz, H-7), 7.42 (d, 1H, J ¼ 8.8 Hz, H-8), 7.37 (br s,
1H, OH), 6.99 (s, 1H, NHSO2), 3.76 (s, 3H, OCH3), 3.06 (s,
3H, SO2CH3), 2.76e2.80 (m, 4H, H-4 and H-2), 1.83e1.87
(m, 2H, H-3).
(s) cmꢂ1
;
MS m/z 476 (MHþ). Anal. Calcd for
C24H33N3O3S2: C, 60.60; H, 6.99; N, 8.83; S, 13.48. Found:
C, 60.82; H, 7.02; N, 8.79; S, 13.42.
5.1.28. 6-Methoxy-5-nitro-1-indanone (36)
This compound, along with its 7-nitro isomer (360), was
obtained from 6-methoxy-1-indanone (34) by following the
procedure described for the synthesis of 22.
5.1.24. 4-Methoxy-5-(methylsulfonylamino)-1-indanamine
(30)
5-Nitro (36). Rf ¼ 0.29 (EtOAc:hexanes ¼ 1:2), 22% yield,
yellow solid, mp ¼ 172e174 ꢁC. 1H NMR (CDCl3) d 7.81
(s, 1H, H-4), 7.40 (s, 1H, H-7), 3.98 (s, 3H, OCH3), 3.16 (t,
2H, J ¼ 6.1 Hz, H-3), 2.77e2.81 (m, 2H, H-2).
This compound was obtained from 28 by following the pro-
cedure described for the synthesis of 16 to afford a white solid
in 98% yield: mp ¼ 217e218 ꢁC. 1H NMR (CDCl3) d 7.42 (d,
1H, J ¼ 8.0 Hz, H-6), 7.04 (d, 1H, J ¼ 8.0 Hz, H-7), 4.33 (t,
1H, J ¼ 7.3 Hz, H-1), 3.90 (s, 3H, OCH3), 3.06e3.15 (m,
1H, H-3a), 2.98 (s, 3H, SO2CH3), 2.82e2.93 (m, 1H, H-3b),
2.46e2.57 (m, 1H, H-2a), 1.66e1.78 (m, 1H, H-2b).
7-Nitro (360). Rf ¼ 0.13 (EtOAc:hexanes ¼ 1:2), 64% yield,
1
yellow solid, mp ¼ 154e157 ꢁC. H NMR (CDCl3) d 7.55 (d,
1H, J ¼ 8.5 Hz, H-4), 7.33 (d, 1H, J ¼ 8.5 Hz, H-5), 3.94 (s,
3H, OCH3), 3.13 (t, 2H, J ¼ 6.1 Hz, H-3), 2.76e2.80 (m,
2H, H-2).
5.1.25. 5-Methoxy-6-(methylsulfonylamino)-
1,2,3,4-tetrahydro-1-naphthylamine (31)
5.1.29. 7-Methoxy-6-nitro-1-tetralone (37)
This compound was obtained from 29 by following the pro-
cedure described for the synthesis of 16 to afford a white solid
in 98% yield: mp ¼ 129e132 ꢁC. 1H NMR (CDCl3) d 7.39 (d,
1H, J ¼ 8.5 Hz, H-7), 7.26 (d, 1H, J ¼ 8.5 Hz, H-8), 4.88 (br s,
2H, NH2), 4.08e4.15 (m, 1H, H-1), 3.75 (s, 3H, OCH3), 3.04
(s, 3H, SO2CH3), 2.81e2.88 (m, 2H, H-4), 1.92e2.04 (m, 2H,
H-2), 1.79e1.84 (m, 2H, H-3).
This compound, along with its 8-nitro isomer (370), was
obtained from 7-methoxy-1-tetralone (35) by following the
procedure described for the synthesis of 22.
6-Nitro (37). Rf ¼ 0.47 (EtOAc:hexanes ¼ 1:2), 20% yield,
yellow solid, mp ¼ 115e116 ꢁC. 1H NMR (CDCl3) d 7.72
(s, 1H, H-5), 7.67 (s, 1H, H-8), 3.98 (s, 3H, OCH3), 2.96 (t,
2H, J ¼ 6.1 Hz, H-4), 2.71 (t, 2H, J ¼ 6.1 Hz, H-2), 2.17e
2.21 (m, 2H, H-3).
5.1.26. N-(4-tert-Butylbenzyl)-N0-[4-methoxy-5-
(methylsulfonylamino)-1-indanyl] thiourea (32)
8-Nitro (370). Rf ¼ 0.22 (EtOAc:hexanes ¼ 1:2), 76% yield,
1
yellow solid, mp ¼ 120e121 ꢁC. H NMR (CDCl3) d 7.35 (d,
This compound was obtained from 30 by following the pro-
cedure described for the synthesis of 18 to afford a white solid
1H, J ¼ 8.5 Hz, H-5), 7.20 (d, 1H, J ¼ 8.5 Hz, H-6), 3.89 (s,
3H, OCH3), 2.95 (t, 2H, J ¼ 6.1 Hz, H-4), 2.67 (t, 2H,
J ¼ 6.1 Hz, H-2), 2.09e2.17 (m, 2H, H-3).
1
in 90% yield: mp ¼ 92e96 ꢁC. H NMR (CDCl3) d 7.39 (d,

330
J.-O. Lim et al. / European Journal of Medicinal Chemistry 44 (2009) 322e331
5.1.30. 5-Amino-6-methoxy-1-indanone (38)
3H, OCH3), 2.93 (s, 3H, SO2CH3), 2.70e2.95 (m, 2H, H-3),
2.48e2.56 (m, 1H, H-2a), 1.62e1.74 (m, 1H, H-2b).
This compound was obtained from 36 by following the pro-
cedure described for the synthesis of 24 to afford a white solid
in 86% yield: mp ¼ 187e188 ꢁC. 1H NMR (CDCl3) d 7.10 (s,
1H, H-7), 6.65 (s, 1H, H-4), 4.44 (br s, 2H, NH2), 3.88 (s, 3H,
OCH3), 2.96 (t, 2H, J ¼ 6.1 Hz, H-3), 2.61e2.64 (m, 2H, H-2).
5.1.37. 7-Methoxy-6-(methylsulfonylamino)-
1,2,3,4-tetahydro-1-naphthylamine (45)
This compound was obtained from 43 by following the pro-
cedure described for the synthesis of 16 to afford a white solid
in 93% yield: mp ¼ 136e138 ꢁC. 1H NMR (CDCl3) d 7.21 (s,
1H, H-5), 7.02 (s, 1H, H-8), 3.92e3.94 (m, 1H, H-1), 3.87 (s,
3H, OCH3), 2.94 (s, 3H, SO2CH3), 2.69e2.76 (m, 2H, H-4),
1.64e2.06 (m, 4H, H-2 and H-3).
5.1.31. 6-Amino-7-methoxy-1-tetralone (39)
This compound was obtained from 37 by following the pro-
cedure described for the synthesis of 24 to afford a brown solid
in 90% yield: mp ¼ 152e155 ꢁC. 1H NMR (CDCl3) d 7.44 (s,
1H, H-8), 6.45 (s, 1H, H-5), 4.30 (br s, 2H, NH2), 3.88 (s, 3H,
OCH3), 2.79 (t, 2H, J ¼ 6.1 Hz, H-4), 2.56 (t, 2H, J ¼ 6.1 Hz,
H-2), 2.02e2.10 (m, 2H, H-3).
5.1.38. N-(4-tert-Butylbenzyl)-N0-[6-methoxy-5-
(methylsulfonylamino)-1-indanyl]thiourea (46)
This compound was obtained from 44 by following the pro-
cedure described for the synthesis of 18 to afford a white solid
in 84% yield: mp ¼ 101e104 ꢁC. 1H NMR (CDCl3) d 7.38 (d,
2H, J ¼ 8.3 Hz, t-BuPh), 7.37 (s, 1H, H-4), 7.25 (d, 1H,
J ¼ 8.3 Hz, t-BuPh), 6.91 (s, 1H, H-7), 6.75 (s, 1H, NHSO2),
6.11 (br s, 1H, NH), 5.80 (br s, 2H, NH and H-1), 4.58 (br
s, 2H, CH2NHCS), 3.83 (s, 3H, OCH3), 2.95 (s, 3H,
SO2CH3), 2.70e2.95 (m, 2H, H-3), 2.60e2.63 (m, 1H, H-
2a), 1.80e1.84 (m, 1H, H-2b), 1.30 (s, 9H, C(CH3)3); IR
(KBr) 3430 (s), 2960 (w), 1617 (m), 1540 (s), 1494 (s),
1336 (s), 1147(s) cmꢂ1; MS m/z 462 (MHþ). Anal. Calcd
for C23H31N3O3S2: C, 59.84; H, 6.77; N, 9.10; S, 13.89.
Found: C, 60.02; H, 6.80; N, 9.06; S, 13.85.
5.1.32. 6-Methoxy-5-(methylsulfonylamino)-1-
indanone (40)
This compound was obtained from 38 by following the pro-
cedure described for the synthesis of 12 to afford a yellow
solid in 93% yield: mp ¼ 190e192 ꢁC; 1H NMR (CDCl3)
d 7.63 (s, 1H, H-4), 7.25 (s, 1H, NHSO2), 7.23 (s, 1H, H-7),
3.93 (s, 3H, OCH3), 3.07e3.10 (m, 5H, H-3 and SO2CH3),
2.68e2.72 (m, 2H, H-2).
5.1.33. 7-Methoxy-6-(methylsulfonylamino)-1-tetralone (41)
This compound was obtained from 39 by following the pro-
cedure described for the synthesis of 12 to afford a white solid
in 94% yield: mp ¼ 165e167 ꢁC. 1H NMR (CDCl3) d 7.55 (s,
1H, H-5), 7.40 (s, 1H, H-8), 7.14 (s, 1H, NHSO2), 3.92 (s, 3H,
OCH3), 3.06 (s, 3H, SO2CH3), 2.91 (t, 2H, J ¼ 6.1 Hz, H-4),
2.63 (t, 2H, J ¼ 6.1 Hz, H-2), 2.04e2.16 (m, 2H, H-3).
5.1.39. N-(4-tert-Butylbenzyl)-N0-[7-methoxy-6-
(methylsulfonylamino)-1,2,3,4-tetrahydro-1-
naphthyl]thiourea (47)
This compound was obtained from 45 by following the pro-
cedure described for the synthesis of 18 to afford a white solid
in 82% yield: mp ¼ 100e102 ꢁC. 1H NMR (CDCl3) d 7.38 (d,
2H, J ¼ 8.3 Hz, t-BuPh), 7.25 (d, 2H, J ¼ 8.3 Hz, t-BuPh),
7.22 (s, 1H, H-5), 6.90 (s, 1H, H-8), 6.73 (s, 1H, NHSO2),
6.18 (br s, 1H, NH), 5.79 (br s, 1H, NH), 5.53 (br s, 1H, H-
1), 4.53 (s, 2H, CH2NHCS), 3.82 (s, 3H, OCH3), 2.96 (s,
3H, SO2CH3), 2.66e2.70 (m, 2H, H-4), 2.02e2.04 (m, 1H,
H-2a), 1.74e1.92 (m, 3H, H-3 and H-2b), 1.32 (s, 9H,
C(CH3)3); IR (KBr) 3433 (s), 2959 (w), 1635 (m), 1540 (s),
1457 (s), 1338 (m), 1153 (s) cmꢂ1; MS m/z 476 (MHþ).
Anal. Calcd for C24H33N3O3S2: C, 60.60; H, 6.99; N, 8.83;
S, 13.48. Found: C, 60.84; H, 7.03; N, 8.80; S, 13.41.
5.1.34. 6-Methoxy-5-(methylsulfonylamino)-1-
indanone oxime (42)
This compound was obtained from 40 by following the pro-
cedure described for the synthesis of 14 to afford a white solid
in 90% yield: mp ¼ 236e238 ꢁC. 1H NMR (CDCl3) d 7.49 (s,
1H, H-4), 7.15 (s, 1H, H-7), 7.06 (s, 1H, NHSO2), 6.95 (s, 1H,
OH), 3.90 (s, 3H, OCH3), 2.95e3.05 (m, 7H, H-2, H-3 and
SO2CH3).
5.1.35. 7-Methoxy-6-(methylsulfonylamino)-1-
tetralone oxime (43)
This compound was obtained from 41 by following the pro-
cedure described for the synthesis of 14 to afford a white solid
in 98% yield: mp ¼ 186e188 ꢁC. 1H NMR (CDCl3) d 7.42 (s,
1H, H-5), 7.31 (s, 1H, H-8), 6.95 (s, 1H, NHSO2), 3.86 (s, 3H,
OCH3), 3.00 (s, 3H, SO2CH3), 2.78 (t, 2H, J ¼ 6.1 Hz, H-4),
2.71 (t, 2H, J ¼ 6.1 Hz, H-2), 1.81e1.90 (m, 2H, H-3).
Acknowledgement
This work was supported by the ERC program of MOST/
KOSEF (R11-2007-107-02001-0) and in part by the intramural
research program of the NIH, National Cancer Institute,
Center for Cancer Research.
5.1.36. 6-Methoxy-5-(methylsulfonylamino)-1-
indanamine (44)
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1H, H-4), 6.93 (s, 1H, H-7), 4.30e4.35 (m, 1H, H-1), 3.88 (s,
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O
NO2
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7.67
8
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7.41
7
6
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6
[19]
6.96
5
5
NO2
NOE
NOE
OCH3
OCH3
NOE
23 (6-nitro)
23' (8-nitro)