Silicon switch approach in TRPV1 antagonist MK-056 and its analogues

Article abstract of DOI:10.1016/j.bmc.2009.11.014

In searching for opportunities to exploit the benefits of silicon in TRPV1 research, we tried to investigate the pharmacological effects of sila-substitution (C/Si exchange) of tert-butyl group in the MK-056 series. Compound 13a, with a 4-positioned trime

Full text of DOI:10.1016/j.bmc.2009.11.014

Bioorganic & Medicinal Chemistry 18 (2010) 111–116
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Silicon switch approach in TRPV1 antagonist MK-056 and its analogues
Minsun Chang b, Seol-Rin Park a, Juhyun Kim a, Mijung Jang a, Jeong Hyun Park a, Ji Eun Park a,
Hyeung-Geun Park c, Young-Ger Suh c, Yeon Su Jeong d, Young-Ho Park d, Hee-Doo Kim a,
*
a College of Pharmacy, Sookmyung Women’s University, Yongsan-gu, Seoul 140-742, Republic of Korea
b Department of Biological Science, Sookmyung Women’s University, Yongsan-gu, Seoul 140-742, Republic of Korea
c College of Pharmacy, Seoul National University, Kwanak-gu, Seoul 151-742, Republic of Korea
d AmorePacific R&D Center 314-1, Giheung-gu, Youngin-Si, Kyounggi-do 446-729, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
In searching for opportunities to exploit the benefits of silicon in TRPV1 research, we tried to investigate
the pharmacological effects of sila-substitution (C/Si exchange) of tert-butyl group in the MK-056 series.
Compound 13a, with a 4-positioned trimethylsilanyl group on the B ring in place of tert-butyl group,
exhibited the most potent antagonist activity with IC50 values of 0.15 lM, which is almost equipotent
with that of MK-056. This is the first example that tert-butyl group on MK-056 series can be replaced
Received 15 October 2009
Revised 3 November 2009
Accepted 5 November 2009
Available online 10 November 2009
to the other substituent without loss of activity.
Key Words:
Ó 2009 Elsevier Ltd. All rights reserved.
Silicon switch
TRPV1
Antagonist
1,3-Dibenzylthiourea
1. Introduction
We have also reported the dibenzylthiourea analogues including
MK-056 (1),3a SC-0030 (2),3b and ATC-120 (3),3c which exhibit
Silicon and carbon are members of group IV of Periodic Table of
the Element and share some similarities in several aspects. Due to
these similarities, in general, the silicon-substituted derivatives
share the same pharmacological mode of action as the correspond-
ing carbon analogues. However, these two elements also have
some subtle differences in molecular size, shape, electronegativity,
and lipophilicity. These differences can lead to marked alterations
in the physicochemical and biological properties of silicon-con-
taining analogues.1 Thus, incorporation of silicon into biologically
pre-validated drug scaffolds represents an excellent tetrahedral
isostere of carbon. This silicon switch approach for safe marketed
drugs is cost-effective and of lower developmental risk because
known drugs have recognized pharmacology and toxicity profiles,
proven safety in humans, and established manufacturing and for-
mulation methods.2
Recently, we have reported the synthesis and biological evalua-
tion of 1,3-dibenzylthioureas as novel TRPV1 antagonist (Fig. 1).3
TRPV1 is a ligand-gated nonselective cation channel vanilloid
receptor 1 (VR1) with high Ca2+ permeability,4 emerging as a novel
target for the treatment of pain.5 Based on the premise that direct
blockage of TRPV1 by its antagonists could be a promising way of
silencing pain signaling pathways,6 extensive works have been
done to develop new TRPV1 antagonists during the past decade.7
highly potent competitive TRPV1 antagonist effects, as well as their
structure–activity relationship (SAR).8 From the SAR study, it re-
vealed that 4-tert-butyl group of MK-056 derivatives is essential
for potency. All attempts to replace tert-butyl groups of MK-056
series to other alkyl groups resulted in weakening their potencies.9
In searching for opportunities to exploit the benefits of silicon in
TRPV1 (transient receptor potential vanilloid subfamily 1) re-
search, we tried silicon switch approach to search for new TRPV1
antagonist that have beneficial pharmacodynamic or pharmacoki-
netic properties and novel IP position. In this context, we decided
to investigate the pharmacological effects of sila-substitution
(C/Si exchange) of tert-butyl group in the MK-056 series.
2. Results and discussion
2.1. Chemistry
Trimethylsilanyl, ethyldimethylsilanyl, and triethylsilanyl
groups were chosen as bioisosteres of t-butyl group. MK-056 (1),
SC-0030 (2) and ATC-120 (3) were also chosen as reference com-
pounds in order to clarify the sila-substitution effect. It is because
that these three compounds represent the most important scaf-
folds in 1,3-dibenzylthioureas with high antagonist activity. Thus,
target compounds in this study were the trialkylsilanyl derivatives
of MK-056 (1), SC-0030 (2) and ATC-120 (3). These targets were
synthesized via the route outlined in Schemes 1 and 2. 4-Trialkyls-
* Corresponding author. Tel.: +82 2 710 9567; fax: +82 2 703 0736.
E-mail addresses: hdkim@sm.ac.kr, hdkim@sookmyung.ac.kr (H.-D. Kim).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.11.014

112
M. Chang et al. / Bioorg. Med. Chem. 18 (2010) 111–116
S
CH3
S
Y
O
S
N
N
O
S
N
N
H
H
H
H
N
H
N
O
O
H
1: Y=H: MK-056
2: Y=F: SC-0030
3: ATC-120
R1
S
Y
O
N
N
B
A
H
H
R2
S
N
Si
O
H
R2
R3
Target Molecule
Figure 1. Structures of 1,3-dibenzylthioureas.
I
X
c
b
X
a
Br
H3C
H3C
6a: X=SiMe3
6b: X=SiMe2Et
6c: X=SiEt3
5a: X=SiMe3
5b: X=SiMe2Et
5c: X=SiEt3
4
X
X
X
d
e
W
H2N
SCN
9a: X=SiMe3
8a: X=SiMe3
8b: X=SiMe2Et
8c: X=SiEt3
7a: X=SiMe3, W=N3
7b: X=SiMe2Et, W=N3
7c: X=SiEt3, W=N-phthalimide
9b: X=SiMe2Et
9c: X=SiEt3
Scheme 1. Reagents and conditions: (a) t-BuLi, THF, ꢀ78 °C, then R3SiCl, 59–73%; (b) NBS, AIBN, CCl4, reflux; (c) NaN3, CH3CN, reflux, 37–76% (two steps)/or phthalimide,
Cs2CO3, acetone, reflux, 35% (two steps); (d) H2, Pd on carbon/or SnCl2, EtOH/or NH2NH2, ethanol, 98–100%; (e) 1,1-thiocarbonyl di-2(1H)-pyridone, DCM, 43–80%.
S
13a: X=SiMe3
a
NH2
+
N
H
N
H
13b: X=SiMe2Et
13c: X=SiEt3
MsHN
MsHN
MsHN
MsHN
X
10
SCN
X
CH3
S
Me
9a~c
14a: X=SiMe3
14b: X=SiMe2Et
14c: X=SiEt3
a
N
H
N
H
NH2
X
11
12
S
F
F
a
SCN
+
NH2
N
H
N
H
MsHN
Si
MsHN
Si
9a
15
Scheme 2. Reagents and conditions: (a) Triethylamine, DCM, rt, 46–74%.
ilanylbenzylisothiocyanates were synthesized via the route out-
lined in Scheme 1. Halogen-metal exchange of 4-iodotoluene (4)
by t-butyllithium, followed by quenching with three kinds of chlo-
rotrialkylsilanes gave the corresponding 4-trialkylsilanyltoluenes
5a–c.10 4-Trialkylsilanyltoluenes 5a–c were treated with N-bromo-
succinimide in CCl4 in the presence of AIBN under reflux to give the
corresponding benzyl bromides 6a–c.11 Nucleophilic substitution
of benzyl bromide 6a–c to azide 7a–b or N-phthalimide 7c, fol-
lowed by reduction or hydrolysis gave the corresponding benzyl-
amines 8a–c.12 Treatment of benzylamines 8a–c with 1,1-
thiocarbonyl di-2(1H)-pyridone gave the corresponding 4-trialk-
ylsilanylbenzylisothiocyanates 9a–c. The requisite 4-metha-
nesulfonamidobenzylamines 10–12 were prepared according to
the previously reported method.3c,8,13 Finally, 4-methanesulfo-

M. Chang et al. / Bioorg. Med. Chem. 18 (2010) 111–116
113
namidobenzylamines 10–12 were treated with the appropriate 4-
3. Conclusion
trialkylsilanylbenzylisothiocyanates 9a–c and triethylamine in
dry dichloromethane to give the compounds trialkysilanyl-1,3-dib-
enzylthioureas 13–15 as target compounds.
In summary, we have designed and synthesized a series of sili-
con analogues of the MK-056 by silicon switch approach to search
for new TRPV1 antagonist. The synthesized seven silicon-substi-
tuted 1,3-dibenzylthioureas 13a–c, 14a–c and 15 were tested for
their antagonist activities on TRPV1 by 45Ca2+-influx assay using
neonatal rat cultured spinal sensory neurons. Compound 13a, with
a 4-positioned trimethylsilanyl group on the B ring in place of tert-
butyl group, exhibited the most potent antagonist activity with
2.2. Biological evaluation
The synthesized silicon-substituted 1,3-dibenzylthioureas 13a–
c, 14a–c and 15 were tested for their antagonist activities on
TRPV1 by 45Ca2+-influx assay using neonatal rat cultured spinal
sensory neurons.14 The results are summarized in Table 1. MK-
056 (1), SC-0030 (2), and ATC-120 (3) were used as reference com-
pounds. Among the three trialkylsilanyl analogues of MK-056, not
unexpectedly, the most potent is trimethylsilanyl analogue 13a,
and the worst is triethylsilanyl analogue 13c. As shown in Table
1, compound 13a, with a 4-positioned trimethylsilanyl group on
the B ring in place of tert-butyl group, exhibited the most potent
IC50 values of 0.15 lM, which is almost equipotent with that of
MK-056. This is the first example that tert-butyl group on MK-
056 series can be replaced to the other substituent without loss
of activity. The results emphasize the great potential of the car-
bon/silicon switch strategy for drug design.
4. Experimental section
4.1. General method
antagonist activity with IC50 values of 0.15 lM, which is almost
equipotent with that of MK-056. This is the first example that
tert-butyl group on MK-056 series can be replaced to the other
substituent without loss of activity. However, replacing tert-butyl
group with dimethylethylsilanyl group, compound 13b showed a
drastic loss of activities. Small difference made by one methyl
group in 13b led to the drop in potency by one order of magnitude
in comparison with 13a. This result is consistent with previous re-
sults that 4-positioned tert-butyl group on the B ring is very reluc-
tant to permit chemical modification.8 Substitution at 4-position
on the B ring with a triethylsilanyl group, 13c, was not tolerated
and showed a 20-fold decrease in antagonist activity compared
to 13a, indicating that increasing bulk at the 4-position on the B
The melting points were obtained using Büchi 535 melting
point apparatus and were uncorrected. Optical rotations were
measured on a JASCO DIP 1000 digital polarimeter. 1H NMR and
13C NMR spectra were obtained on a Varian Inova 400 spectrome-
ter and the chemical shifts are reported as values in parts per mil-
lion (d) relative to tetramethylsilane (TMS) as an internal standard.
The infrared spectra (IR) were recorded on a JASCO FT/IR-430 spec-
trophotometer. Low resolution mass spectra were obtained on VG
Trio-2 GC–MS. High resolution mass spectra were obtained on a
JEOL JMS-AX 505wA and JEOL JMS-HX/HX 110A spectrometer. Thin
layer chromatography (TLC) was carried out on 0.25 mm E. Merck
precoated silica gel glass plates (60F254). Column chromatography
was performed using the forced flow of indicated solvent on Merck
Kieselgel 60 (230–400 mesh). Unless otherwise noted, the materi-
als were obtained from commercially available sources and were
used without further purification. THF was freshly distiled from so-
dium benzophenone ketyl under an argon atmosphere. Benzene,
DCM, DMF, triethylamine (TEA) and toluene were freshly distiled
under a nitrogen atmosphere with calcium hydride.
ring beyond
a trimethylsilanyl was detrimental for receptor
binding. Next, we also investigated the sila-substitution effect of
SC-0030 (2) and ATC-120 (3) analogues. The similar trend was ob-
served in ATC-120 series (14a–c), indicating that trimethylsilanyl
group is the best bioisostere of tert-butyl group. While 13a was
equipotent with that of parent MK-056, 14a and 15 were about
fourfold less potent than parent carbon compounds (2, 3), but
retaining the antagonist activities with IC50 values in the range of
submicromole. As mentioned above, one of the goals for silicon
switch is to search for new TRPV1 antagonist having beneficial
pharmacodynamic or pharmacokinetic properties and novel IP
position. Compound 13a comes closest to achieving this goal in
that its IC50 values are very near that of MK-056.
4.1.1. Trimethyl p-tolyl silane (5a)
To a solution of 4-iodotoluene (4, 700 mg, 3.21 mmol) in anhy-
drous THF (16 mL, 0.2 M) was added dropwise tert-BuLi (1.7 M
Table 1
45Ca2+-Uptake inhibition by MK-056 analogues
R
S
Y
N
N
H
H
MsHN
X
Compound
X
R
Y
45Ca2+ influx activitya
Agonist (EC50
(lM)
)
Antagonist (IC50)
13a
13b
13c
1 (MK-056)
14a
14b
14c
3 (ATC-120)
15
2 (SC-0030)
Trimethylsilanyl
Ethyldimethylsilanyl
Triethylsilanyl
tert-Butyl
Trimethylsilanyl
Ethyldimethylsilanyl
Triethylsilanyl
tert-Butyl
H
H
H
H
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
F
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
0.15
1.20
3.10
0.11
0.21
0.67
1.50
0.05
0.16
0.04
Trimethylsilanyl
tert-Butyl
H
F
a
EC50 (the concentration of derivatives necessary to produce 50% of the maximal response) and IC50 values (the concentration of derivatives necessary to reduce the
response to 0.5 M capsaicin by 50%) were estimated with at least three replicates at each concentration. Each compound was tested in two independent experiments.
Antagonist data were fitted with a sigmoidal function.
l

114
M. Chang et al. / Bioorg. Med. Chem. 18 (2010) 111–116
solution in hexane, 3.77 mL, 6.42 mmol) at ꢀ78 °C. The mixture
was stirred for 20 min at ꢀ78 °C, and chlorotrimethylsilane
7.28 (d, 2H, J = 8.0 Hz), 4.31 (s, 2H), 0.25(s, 9H); IR (NaCl, neat)
cmꢀ1 3018, 2956, 2099.
(698 lL, 6.42 mmol) was added. After being stirred for an hour at
the same temperature, the reaction mixture was quenched with
aqueous NH4Cl and diluted with ethyl acetate (30 mL). The layers
were separated, and the aqueous layer was extracted twice with
ethyl acetate (20 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, and concentrated in va-
cuo. The residue was purified by column chromatography (silica
gel, n-hexane) to afford the title compound 5a as a colourless liquid
(359 mg, 68%). 1H NMR (400 MHz, CDCl3) d 7.37 (d, 2H, J = 8.0 Hz),
7.12 (d, 2H, J = 8.0 Hz), 2.29 (s, 3H), 0.19(s, 9H); IR (NaCl, neat)
cmꢀ1 3011, 2995, 1247, 1106.
4.1.8. (4-Azidomethylphenyl)ethyldimethylsilane (7b)
By the same procedure described above, the product was ob-
tained from 6b as syrup in 76% yield (two steps). 1H NMR
(400 MHz, CDCl3) d 7.45 (d, 2H, J = 7.6 Hz), 7.22 (d, 2H, J = 7.6 Hz),
4.25 (s, 2H), 0.87 (t, 3H, J = 8.0 Hz), 0.86 (s, 3H), 0.65 (q, 2H,
J = 8.0 Hz), 0.17 (s, 3H); IR (NaCl, neat) cmꢀ1 3422, 2955, 2099.
4.1.9. 2-(4-Triethylsilanylbenzyl)isoindole-1,3-dione (7c)
To a solution of the crude bromide 6c (155.0 mg, 0.55 mmol) in
acetone (11 mL) were added phthalimide (96.4 mg, 0.66 mmol)
and cesium carbonate (213.5 mg, 0.66 mmol) at room temperature.
The reaction mixture was stirred at refluxing temperature for 12 h,
and then cooled to room temperature. The reaction mixture was
concentrated in vacuo, and then diluted with ethyl acetate
(30 mL). The organic layer was washed with water and brine, dried
over anhydrous Na2SO4, and concentrated in vacuo to afford the ti-
tle compound 7c as solid (67.4 mg, 35%, two steps). Mp, 85–86 °C;
1H NMR (400 MHz, CDCl3) d 7.67 (dd, 2H, J = 3.2, 5.6 Hz), 7.53 (dd,
2H, J = 3.2, 5.6 Hz), 7.26 (d, 2H, J = 8.0 Hz), 7.22 (d, 2H, J = 8.0 Hz),
4.68 (s, 2H), 0.75 (t, 9H, J = 8.0 Hz), 0.58 (q, 6H, J = 8.0 Hz); IR
(KBr) cmꢀ1 2951, 2909, 1713.
4.1.2. Ethyldimethyl(p-tolyl)silane (5b)
By the same procedure described above, the product was ob-
tained from 4 as syrup in 59% yield. 1H NMR (400 MHz, CDCl3) d
7.40 (d, 2H, J = 8.0 Hz), 7.16 (d, 2H, J = 8.0 Hz), 2.34 (s, 3H), 0.94
(t, 3H, J = 8.0 Hz), 0.70 (q, 2H, J = 8.0 Hz), 0.22 (s, 6H); IR (NaCl,
neat) cmꢀ1 3011, 2954.
4.1.3. Triethyl (p-tolyl)silane (5c)
By the same procedure described above, the product was ob-
tained from 4 as syrup in 73% yield. 1H NMR (400 MHz, CDCl3) d
7.48 (d, 2H, J = 7.6 Hz), 7.25 (d, 2H, J = 7.6 Hz), 2.42 (s, 3H), 1.05
(t, 9H, J = 7.6 Hz), 0.87 (q, 6H, J = 7.6 Hz); IR (NaCl, neat) cmꢀ1
3011, 2954.
4.1.10. 4-Trimethylsilanylbenzylamine (8a)
To a stirred solution of benzyl azide 7a (180.8 mg, 0.88 mmol)
in methanol (10 mL) was added 10% Pd/C (36.0 mg, 20 wt% of start-
ing material). The solution was stirred under H2 balloon condition
for 1 h at room temperature. The reaction mixture was filtered
through a pad of Celite and concentrated in vacuo to afford benzyl-
amine 8a as syrup (153.5 mg, 98%). 1H NMR (400 MHz, CDCl3) d
7.42 (m, 2H), 7.25 (m, 2H), 3.42 (s, 2H), 0.19 (s, 9H); IR (NaCl, neat)
cmꢀ1 3352, 3017, 2954.
4.1.4. (4-Bromomethylphenyl)trimethylsilane (6a)
To
a solution of p-tolyl trimethylsilane (5a, 359.0 mg,
2.18 mmol) in carbon tetrachloride (22 mL, 0.1 M) were added N-
bromosuccinimde (427.7 mg, 2.40 mmol) and AIBN (5 mg) at room
temperature. The reaction mixture was stirred at refluxing temper-
ature for 2 h and then cooled to room temperature. n-Hexane
(30 mL) was added to the solution, and the resulting turbid suspen-
sion was filtered through a pad of Celite to obtain the filtrate as a
transparent liquid. The filter cake was rinsed twice with hexane
(20 mL). The combined filtrates were concentrated in vacuo to af-
ford the title compound (582 mg, 110%) as yellow oil. This crude
product was directly used for the next step without further purifi-
cation. 1H NMR (400 MHz, CDCl3) d 7.46 (d, 2H, J = 8.0 Hz), 7.33 (d,
2H, J = 8.0 Hz), 4.46 (s, 2H), 0.23 (s, 9H); IR (NaCl, neat) cmꢀ1 3015,
2955, 1393, 1248.
4.1.11. 4-(Ethyldimethylsilanyl)benzylamine (8b)
To a solution of the azide 7b (313.1 mg, 1.43 mmol) in ethanol
(15 mL) was added SnCl2 (813.4 mg, 4.29 mmol) at room tempera-
ture. After being stirred at room temperature for 5 h, the reaction
mixture was concentrated in vacuo, and then diluted with ethyl
acetate (50 mL). The organic layer was washed with water and
brine, dried over anhydrous Na2SO4, and concentrated in vacuo
to afford the title compound 8b as syrup (276.0 mg, 100%). 1H
NMR (400 MHz, CDCl3) d 7.56 (d, 2H, J = 8.0 Hz), 7.41 (d, 2H,
J = 8.0 Hz), 4.08 (s, 2H), 0.90 (t, 3H, J = 7.6 Hz), 0.72 (q, 2H,
J = 8.0 Hz), 0.22 (s, 6H); IR (NaCl, neat) cmꢀ1 3378, 3017, 2955.
4.1.5. (4-Bromomethylphenyl)ethyldimethylsilane (6b)
By the same procedure described above, the crude product was
obtained from 5b as syrup. This crude product was directly used
for the next step without further purification. Rf = 0.62 (silica gel,
n-hexane).
4.1.12. 4-Triethylsilanylbenzylamine (8c)
To a solution of the phthalimide 7c (30 mg, 0.085 mmol) in eth-
anol (6 mL) were added hydrazine (5.13 mg, 0.1 mmol) at room
temperature. The reaction mixture was stirred at refluxing temper-
ature for 12 h and then cooled to room temperature. The reaction
mixture was concentrated in vacuo, and then diluted with ethyl
acetate (30 mL). The organic layer was washed with water and
brine, dried over anhydrous Na2SO4, and concentrated in vacuo
to afford the title compound 8c as syrup (19 mg, 99%). 1H NMR
(400 MHz, CDCl3) d 7.40 (d, 2H, J = 7.6 Hz), 7.23 (d, 2H, J = 7.6 Hz),
3.91 (s, 2H), 0.89 (t, 9H, J = 7.6 Hz), 0.71 (q, 6H, J = 7.6 Hz); IR (NaCl,
neat) cmꢀ1 3374, 3299, 3011, 2955.
4.1.6. (4-Bromomethylphenyl)triethylsilane (6c)
By the same procedure described above, the crude product was
obtained from 5c as syrup. This crude product was directly used for
the next step without further purification. Rf = 0.42 (silica gel, n-
hexane).
4.1.7. (4-Azidomethylphenyl)trimethylsilane (7a)
To a solution of the crude bromide 6a (582 mg) in acetonitrile
(22 mL) were added sodium azide (233.4 mg, 3.59 mmol) in one
portion at room temperature. The reaction mixture was stirred at
refluxing temperature for 2 h and then cooled to room tempera-
ture. The reaction mixture was concentrated in vacuo. The residue
was purified by column chromatography (silica gel, n-hexane) to
afford the title compound 7a as colourless liquid (181 mg, 37%,
two steps). 1H NMR (400 MHz, CDCl3) d 7.52 (d, 2H, J = 8.0 Hz),
4.1.13. (4-Isothiocyanatomethylphenyl)trimethylsilane (9a)
To a solution of the benzylamine 8a (153.5 mg, 0.86 mmol) in
dichloromethane (17 mL) was added 1,1-thiocarbonyl di-2(1H)-
pyridone (219.0 mg, 0.94 mmol) in one portion at room tempera-
ture. After being stirred for 12 h at the same temperature, the reac-
tion mixture was quenched with H2O (5 mL) and diluted with

M. Chang et al. / Bioorg. Med. Chem. 18 (2010) 111–116
115
dichloromethane (30 mL). The organic layer was washed with
4.1.18. N-{4-[3-(4-Triethylsilanylbenzyl)thioureidomethyl]-
brine, dried over anhydrous Na2SO4, and concentrated in vacuo.
The residue was purified by column chromatography (silica gel,
n-hexane) to afford the title compound 9a as colourless solid
(152.4 mg, 80%). Mp, 69–70 °C; 1H NMR (400 MHz, CDCl3) d 7.52
(d, 2H, J = 8.2 Hz), 7.23 (d, 2H, J = 8.2 Hz), 4.69 (s, 2H), 0.25 (s,
9H); 13C NMR (100 MHz, CDCl3) d 140.9, 134.6, 133.9, 126.1,
48.6, ꢀ1.2; IR (KBr) cmꢀ1 2954, 2927, 2180, 2112; MS (EI) m/z (rel-
ative intensity) 221 (M+, 100), 206 (100), 191 (50), 174 (100));
HRMS (EI) calcd for C11H15NSSi (M+) 221.0694, found 221.0692.
phenyl}methanesulfonamide (13c)
By the same procedure described above, the product was ob-
tained from 10 and 9c as solid in 60% yield. Mp 139–140 °C; 1H
NMR (400 MHz, CDCl3) d 7.44 (d, 2H, J = 8.0 Hz), 7.41 (br s, 1H),
7.23 (d, 2H, J = 8.0 Hz), 7.17 (d, 2H, J = 8.4 Hz), 7.11 (d, 2H,
J = 8.4 Hz), 6.50 (br s, 2H), 4.60 (s, 4H), 2.91 (s, 3H), 0.93 (t, 9H,
J = 7.6 Hz), 0.76 (q, 6H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) d
182.1, 137.4, 137.0, 136.2, 134.7, 134.2, 128.8, 126.7, 121.0, 48.3,
47.8, 39.4, 7.3, 3.2; IR (KBr) cmꢀ1 3363, 3263, 3066, 2953, 2873,
1152; LRMS (FAB+) m/z (rel intensity) 464 [84, (M+H)], 384 (14),
281 (37), 220 (37), 184 (100); HRMS (FAB+) calcd for C22H34N3O2S2-
Si (M+H) 464.1862, found 464.1865.
4.1.14. Ethyl(4-isothiocyanatomethylphenyl)dimethylsilane
(9b)
By the same procedure described above, the product was ob-
tained from 8b as syrup in 43% yield. 1H NMR (400 MHz, CDCl3)
d 7.45 (d, 2H, J = 7.6 Hz), 7.21 (d, 2H, J = 7.6 Hz), 4.61 (s, 2H), 0.86
(t, 3H, J = 7.6 Hz) 0.65 (q, 2H, J = 7.6 Hz), 0.17 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 139.9, 134.6, 134.2, 126.0, 48.6, 7.3, 7.2,
ꢀ3.6; IR (KBr) cmꢀ1 3018, 2954, 2175, 2092; MS (EI) m/z (relative
intensity) 235 (M+, 8), 206 (48), 177 (25), 147 (36), 83 (100); HRMS
(EI) calcd for C12H17NSSi (M+) 235.0851, found 235.0848.
4.1.19. (R)-N-(4-{1-[3-(4-Trimethylsilanylbenzyl)thioureido]-
ethyl}phenyl)methanesulfonamide (14a)
By the same procedure described above, the product was ob-
tained from N-[4-[(1R)-1-aminoethyl]phenyl]methanesulfonamide
(11) and 9a as solid in 61% yield. Mp 96–98 °C; ½a D20
ꢀ10.18 (c 2.29,
ꢁ
CHCl3); 1H NMR (400 MHz, CDCl3) d 7.63 (s, 1H), 7.41 (d, 2H,
J = 8.0 Hz), 7.17 (d, 2H, J = 8.4 Hz), 7.13 (d, 2H, J = 8.4 Hz), 7.09 (d,
2H, J = 6.8 Hz), 5.01 (br s, 1H), 4.58 (s, 2H), 2.92 (s, 3H), 1.42 (d,
3H, J = 6.8 Hz), 0.20 (s, 9H); 13C NMR (100 MHz, CDCl3) d 181.0,
139.7, 137.8, 136.5, 134.0, 127.4, 126.8, 121.5, 53.6, 48.7, 39.6,
23.2, ꢀ0.92; IR (KBr) cmꢀ1 3351, 3262, 3024, 2955, 1544, 1325;
LRMS (FAB+) m/z (rel intensity) 436 [11, (M+H)], 281 (11), 198
(37), 147 (70), 73 (100); HRMS (FAB+) calcd for C20H30 N3O2S2Si
(M+H) 436.1549, found 436.1554.
4.1.15. Triethyl(4-isothiocyanatomethylphenyl)silane (9c)
By the same procedure described above, the product was ob-
tained from 8c as oil in 72% yield. 1H NMR (400 MHz, CDCl3) d
7.47 (d, 2H, J = 7.6 Hz), 7.25 (d, 2H, J = 7.6 Hz), 4.66 (s, 2H), 0.92
(t, 9H, J = 7.6 Hz) 0.75 (q, 6H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3)
d 138.1, 135.0, 134.8, 126.2, 48.8, 7.5, 3.5; IR (NaCl, neat) cmꢀ1
2953, 2910, 2092, 1633, 1105; MS (EI) m/z (relative intensity)
263 (M+, 100), 235 (100), 177 (100), 147 (100), 86 (100); HRMS
(EI) calcd for C14H21NSSi (M+) 263.1164, found 263.1164.
4.1.20. (R)-N-[4-(1-{3-[4-(Ethyldimethylsilanyl)benzyl]thio-
ureido}ethyl)phenyl]methanesulfonamide (14b)
By the same procedure described above, the product was ob-
4.1.16. N-{4-[3-(4-Trimethylsilanylbenzyl)thioureidomethyl]-
phenyl}methanesulfonamide (13a)
tained from 11 and 9b as solid in 70% yield. Mp 85–87 °C; ½a D20
ꢁ
ꢀ8.35 (c 2.03, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.55 (s, 1H),
7.40 (d, 2H, J = 7.6 Hz), 7.17 (d, 2H, J = 8.0 Hz), 7.13 (d, 2H,
J = 7.6 Hz), 7.08 (d, 2H, J = 7.6 Hz), 5.00 (br s, 1H), 4.57 (s, 2H),
2.93 (s, 3H), 1.42 (d, 3H, J = 7.0 Hz), 0.89 (t, 3H, J = 7.6 Hz), 0.66
(q, 2H, J = 7.0 Hz), 0.19 (s, 6H); 13C NMR (100 MHz, CDCl3) d
181.0, 139.6, 139.3, 137.6, 136.5, 134.3, 127.4, 126.8, 121.5, 53.5,
48.8, 39.6, 23.2, 7.6, 7.5, ꢀ3.3; IR (KBr) cmꢀ1 3350, 3026, 2955,
1613, 1324; LRMS (FAB+) m/z (rel intensity) 450 [20, (M+H)], 370
(6), 253 (23), 198 (100); HRMS (FAB+) calcd for C21H32N3O2S2Si
(M+H) 450.1705, found 450.1716.
To a solution of the N-(4-aminomethylphenyl)methanesulfon-
amide (10, 44.4 mg, 0.22 mmol) in dichloromethane (5 mL) were
added isothiocyanate 9a (44.6 mg, 0.20 mmol) and triethylamine
(89 mg, 0.66 mmol) at room temperature. After being stirred for
12 h at room temperature, the reaction mixture was quenched
with H2O (1 mL) and diluted with dichloromethane (30 mL). The
organic layer was washed with brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was purified by
column chromatography (silica gel; 17% ethyl acetate in n-hexane)
to afford the title compound 13a as liquid (39.4 mg, 46%). 1H NMR
(400 MHz, CD3OD) d 7.44 (d, 2H, J = 8.0 Hz), 7.24 (d, 2H, J = 8.0 Hz),
7.23 (d, 2H, J = 8.4 Hz), 7.16 (d, 2H, J = 8.4 Hz), 4.77 (s, 2H), 4.66 (s,
2H), 2.87 (s, 3H), 0.21 (s, 9H); 13C NMR (100 MHz, CDCl3+DMSO-d6)
d 182.9, 138.7, 136.7, 134.4, 133.0, 128.2, 126.6, 120.2, 47.8, 47.2,
38.5, ꢀ1.5; (NaCl, neat) cmꢀ1 3299, 3063, 2952, 1573, 1158; LRMS
(FAB+) m/z (rel intensity) 422 [100, (M+H)], 342 (17), 239 (39), 199
(24), 184 (100); HRMS (FAB+) calcd for C19H28N3O2S2Si (M+H)
422.1392, found 422.1398.
4.1.21. (R)-N-(4-{1-[3-(4-Triethylsilanylbenzyl)thioureido]-
ethyl}phenyl)methanesulfonamide (14c)
By the same procedure described above, the product was ob-
tained from 11 and 9c as solid in 72% yield. Mp 89–91 °C; ½a D20
ꢁ
ꢀ10.29 (c 2.54, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.44 (s, 1H),
7.39 (d, 2H, J = 7.6 Hz), 7.18 (d, 2H, J = 8.4 Hz), 7.14 (d, 2H,
J = 8.4 Hz), 7.10 (d, 2H, J = 6.8 Hz), 5.10 (br s, 1H), 4.58 (s, 2H),
2.93 (s, 3H), 1.42 (d, 3H, J = 6.8 Hz), 0.90 (d, 9H, J = 8.0 Hz), 0.73
(q, 6H, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) d 181.0, 139.8,
137.6, 137.2, 136.5, 134.0, 127.4, 126.8, 121.5, 53.6, 48.7, 39.6,
23.2, ꢀ0.92; IR (KBr) cmꢀ1 3356, 3262, 3025, 2953, 1542, 1325;
LRMS (FAB+) m/z (rel intensity) 478 [19, (M+H)], 281 (29), 220
(20), 198 (100); HRMS (FAB+) calcd for C23H36N3O2S2Si (M+H)
478.2018, found 478.2023.
4.1.17. N-{4-[3-(4-Ethyldimethylsilanylbenzyl)thioureidometh-
yl]phenyl}methanesulfonamide (13b)
By the same procedure described above, the product was ob-
tained from 10 and 9b as solid in 74% yield. Mp 86–88 °C; 1H
NMR (400 MHz, CDCl3) d 7.42 (d, 2H, J = 8.0 Hz), 7.37 (br s, 1H),
7.20 (d, 2H, J = 8.0 Hz), 7.13 (d, 2H, J = 8.0 Hz), 7.08 (d, 2H,
J = 8.0 Hz), 6.47 (br s, 2H), 4.57 (s, 4H), 2.88 (s, 3H), 0.89 (t, 3H,
J = 8.0 Hz), 0.67 (q, 2H, J = 8.0 Hz), 0.18 (s, 6H); 13C NMR
(100 MHz, CDCl3) d 181.9, 140.7, 139.2, 136.2, 134.3, 134.1,
128.8, 126.8, 121.1, 47.7, 39.3, 7.3, 7.2, ꢀ3.5; IR (KBr) cmꢀ1 3356,
3068, 2924, 1613, 1326; LRMS (FAB+) m/z (rel intensity) 436 [59,
(M+H)], 253 (26), 184 (100); HRMS (FAB+) calcd for C20H30
N3O2S2Si (M+H) 436.1549, found 436.1545.
4.1.22. N-{2-Fluoro-4-[3-(4-trimethylsilanylbenzyl)thioureido-
methyl]phenyl}methanesulfonamide (15)
By the same procedure described above, the product was ob-
tained from 12 and 9a as solid in 72% yield. Mp 70–72 °C; 1H
NMR (400 MHz, CDCl3) d 7.45 (d, 2H, J = 8.0 Hz), 7.32 (d, 2H,
J = 8.0 Hz), 7.22 (d, 2H, J = 8.0 Hz), 6.97 (br s, 1H), 6.94 (m, 2H),
4.61 (s, 2H), 4.55 (s, 2H), 2.91 (s, 3H), 0.21 (s, 9H); 13C NMR

116
M. Chang et al. / Bioorg. Med. Chem. 18 (2010) 111–116
(100 MHz, CDCl3) d 182.3, 155.7, 153.2, 140.1, 137.3, 133.7, 126.7,
124.4, 123.7, 123.4, 114.8, 48.1, 47.2, 39.8, ꢀ1.2; IR (KBr) cmꢀ1
3360, 3260, 3025, 2955, 1331, 1157; LRMS (FAB+) m/z (rel inten-
sity) 440 [100, (M+H)], 360 (17), 202 (43), 163 (68); HRMS
(FAB+) calcd for C19H27FN3O2S2Si (M+H) 440.1298, found 440.1296.
References and notes
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4.2. Culture of DRG neurons
}
Jurva, U.; Wellner, E. ChemMedChem 2008, 3, 152; (d) Warneck, J. B.; Cheng, F.
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DRG neurons were prepared from neonatal Sprague–Dawley
rats. DRGs of all spinal levels were dissected aseptically and col-
lected. Ganglia were incubated sequentially for 30 min at 37 °C in
200 U/mL collagenase and 2.5 mg/mL trypsin. The digestion was
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3 days in DME/F12 medium containing 1.2 g/L sodium bicarbonate,
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4.2.1. 45Ca2+ Uptake assays
Terasaki plates containing DRG neurons grown for 3 days were
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calcium- and magnesium-free Hank’s balanced salt solution. The
solution in each well was removed from the individual wells. For
antagonistic studies, medium (10 lL) containing 10 l
Ci/mL 45Ca2+
and 0.5 M capsaicin together with the test concentration of the
compound was added to each well. The neurons were incubated
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magnesium-free Hank’s balanced salt solution and dried in an
oven. Sodium dodecyl sulfate (0.3%, 10 lL) was then added to dis-
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were transferred to scintillation vials and counted in 3 mL of aqua-
sol-2 scintillant. Antagonist activities of test compounds were gi-
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11. Frankel, M.; Broze, M.; Gertner, D.; Rotman, A.; Shenhar, A.; Zilkha, A. J. Med.
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reduce the response to 0.5 lM capsaicin by 50%). The IC50 values
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were estimated at least three replicates at each concentrated. Each
compound was tested at least in two independent experiments.
Acknowledgements
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This research was supported by the SRC program of KOSEF
(Research Center for Women’s Diseases) and by the grant from
AmorePacific Corporation.