4-(2-Pyridyl)piperazine-1-benzimidazoles as potent TRPV1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2004.11.021

A series of 4-(2-pyridyl)piperazine-1-benzimidazole analogues based on compound 1 was synthesized and evaluated for TRPV1 antagonist activity in capsaicin-induced (CAP) and pH 5.5-induced (pH) FLIPR assays in a human TRPV1-expressing HEK293 cell line. Potent TRPV1 antagonists were identified through SAR studies. From these studies, several antagonists were found, with IC₅₀ values ranging from 32 nM to ～5000 nM. Among these, 11 [IC₅₀ = 90 nM (CAP) and 104 nM (pH)] was further evaluated and found to be orally available in rats (F% = 19.7).

Full text of DOI:10.1016/j.bmcl.2004.11.021

Bioorganic & Medicinal Chemistry Letters 15 (2005) 719–723
4-(2-Pyridyl)piperazine-1-benzimidazoles as potent
TRPV1 antagonists
Bin Shao,* Jincheng Huang, Qun Sun, Kenneth J. Valenzano,
Lori Schmid and Scott Nolan
Purdue Pharma LP, 6 Cedar Brook Drive, Cranbury, NJ 08512, USA
Received 10 September 2004; revised 5 November 2004; accepted 5 November 2004
Available online 25 November 2004
Abstract—A series of 4-(2-pyridyl)piperazine-1-benzimidazole analogues based on compound 1 was synthesized and evaluated for
TRPV1 antagonist activity in capsaicin-induced (CAP) and pH5.5-induced (pH) FLIPR assays in a human TRPV1-expressing
HEK293 cell line. Potent TRPV1 antagonists were identified through SAR studies. From these studies, several antagonists were
found, with IC50 values ranging from 32nM to ꢀ5000nM. Among these, 11 [IC50 = 90nM (CAP) and 104nM (pH)] was further
evaluated and found to be orally available in rats (F % = 19.7).
ꢀ 2004 Elsevier Ltd. All rights reserved.
The ability of capsaicin (CAP) (Fig. 1), the pungent
ingredient of hot chili peppers, and related ÔvanilloidÕ
analogs of CAP such as resiniferatoxin (RTX), to acti-
vate mammalian nociceptors and cause pain has been
known for some time.1,2 The mechanism of action is
now known to be the result of the gating of a highly
Ca2+-permeable, nonselective cation channel, the tran-
sient receptor potential TRPV1 vanilloid receptor, origi-
nally known as the VR1 receptor.3 The results of knock-
out studies in rodents lacking the TRPV1 gene4,5 and
recent pre-clinical data using TRPV1 antagonists6
clearly point to the potential of developing therapeutics
based on the antagonism of the receptor for treatment of
both inflammatory and neuropathic pain.
antagonist (IC50 value: 35nM, F% = 15). To further ex-
pand on the SAR, we designed analogs with isostere
replacements of the urea moiety. One such transforma-
tion is depicted in Figure 2. By incorporation of the urea
with the benzene moiety, we designed novel benzimida-
zole analogs. The synthetic route for such compounds is
described in Scheme 1. The synthesis of compounds in
the benzimidazole series started with commercially
available phenenediamine 3. Treatment of 3 with DCI
in refluxing THF gave urea 4, which was then converted
to intermediate 2-chlorobenzimidazole 5. Dichloropyr-
idine 6 was treated with piperazine 7 at 80ꢁC to give
compound 8. The coupling between 5 and 8 was accom-
plished at high temperature. A mixture of 5 and 8 in
p-xylene was heated in a sealed tube at 145ꢁC for 3 days
to give the desired products 9–21.
In addition to capsazepine (CPZ) (Fig. 1), a competitive
TRPV1 antagonist that has been well characterized,7
several classes of potent synthetic antagonists have been
published recently.8–12 Some of the representative struc-
tures are shown in Figure 1.
All final compounds were purified to >97%. The purity
of the compounds was determined by RP-HPLC and
correct molecular weight was confirmed by mass spectro-
metry (LC/MS with an electrospray sample inlet sys-
1
In this paper, we report for the first time a series of 4-(2-
pyridyl)piperazine-1-benzimidazoles as potent TRPV1
antagonists. Our work was initiated with compound 1
(Fig. 1),12 a potent and orally bioavailable TRPV1
tem).13 Structures were further confirmed by H NMR
spectroscopy.14
The compounds were evaluated for TRPV1 antagonist
activity based on their ability to block CAP-induced
activation or low pH-induced activation of the human
TRPV1 channel in a HEK293 cell line. The tests were
carried out measuring CAP- or pH-mediated calcium
*
Corresponding author. Tel.: +1 609 409 5135; fax: +1 609 409 6936;
e-mail: bin.shao@pharma.com
0960-894X/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.11.021

720
B. Shao et al. / Bioorg. Med. Chem. Lett. 15 (2005) 719–723
OH
OH
OH
OCH3
N
Cl
O
O
N
N
H
O
NH
N
O
S
O
HO
O
HN
O
NH
O
O
I
OH
Cl
Capsaicin
Capsazepine
I-RTX
1
Cl
OH
NH
NH
O
HN
HN
O
S
HN
O
CF3
MeO2SHN
F
SC0030
SB366791
2
Figure 1. Structures of capsaicin, capsazepine, and other known TRPV1 antagonists.
presence of the asymmetric center in the middle piper-
azine ring plays an important role for the potency of
the compounds. If the methyl in the piperazine is in
the same configuration as in 7b, the potencies of the
resulting compounds were enhanced; that is, 11
(IC50 = 90 28nM) and 13 (IC50 = 113 42nM) were
more potent than 9 (IC50 = 136 29nM), and 10
(IC50 = 726 99nM), respectively. The effect of
enhancement on potency by the (R)-methyl is even
N
X
N
Cl
Cl
N
N
N
N
N
O
NH
more obvious in human pH assay, where 11 (IC50
104 41nM) is 16-fold more potent than
=
9
(IC50 = 1688 344nM). However, if the methyl in the
piperazine is in the configuration as in 7c, the potencies
of the resulting compounds were diminished; that is, 12
and 14 were much less potent than 9 and 10,
respectively.
benzimidazole : X = NH
benzoxazole : X = O
Figure 2. Design of benzimidazoles and benzoxazoles from 1.
We then investigated the effect of subsequent change of
the substitution on the benzene ring of the benzimidaz-
ole. When 9, the first member of the series was designed,
we intentionally retained the t-butyl group of 1 because
of its importance uncovered in the urea series.12 We sus-
pect that substitution on the benzene ring of the benzimi-
dazole series might also play a critical role in potency.
As anticipated, when t-butyl was replaced with chlorine,
the potency of 15 was decreased about threefold com-
pared to 11. When replaced with methoxy group, the
potency of 16 decreased further, about fivefold com-
pared to 11. We further probed additional substitution
patterns on the benzene ring with compounds 10, 13,
14. It was found that disubstitution on the benzene ring
influx with a fluorometric imaging plate reader (FLIPR),
in which either 100nM CAP or pH5.5 were used as
agonists for the respective assays.
The benzimidazole series attracted further attention
when the first member of this series, compound 9 proved
to be active in the human CAP assay but moderate in
human pH assay (Table 1). We investigated the effect
of introducing an asymmetric center into the piperazine
ring by utilizing the commercially available 2-(R)-methyl
piperazine (7b) and 2-(S)-methyl piperazine (7c), in the
synthesis of target molecules. As shown in Table 1, the

B. Shao et al. / Bioorg. Med. Chem. Lett. 15 (2005) 719–723
721
H
Y
Z
NH2
NH2
Y
Z
Y
Z
N
a
b
N
O
Cl
N
H
N
H
5a-e
3a-e
4a-e
Y
Z
a
H
tBu
Me
H
b
c
d
e
Me
Cl
Me
OMe
iPr
H
Y
Z
N
c
Cl
5b
N
5f
Ar
N
N
Q
Ar
N
H
N
d
e
X
Y
N
Z
+
Ar-Cl
N
H
Q
N
H
Q
8a-g
6a-e
9-21
7a-c
Scheme 1. Reagents and conditions: (a) CDI, THF, reflux, 4h. (b) POCl3, DBU, reflux. (c) NaH, DMF, MeI. (d) DIEA, acetonitrile, reflux. (e) 5, p-
xylene, 145ꢁC.
Table 1. Variation of substitution on the benzene ring and piperazine ring
Cl
Y
Z
X
N
N
Q
N
N
No.
X
Y
Z
Q
IC50 (nM) human CAP
IC50 (nM) human pH
9
NH
NH
NH
NH
NH
NH
NH
NH
N-Me
N-Me
O
t-Bu
Me
t-Bu
t-Bu
Me
Me
Cl
H
H
H
136 29
726 99
1688 344
>25,000
104 41
3608 988
10,000 2442
>25,000
—
10
11
12
13
14
15
16
17
18
25
26
Me
H
(R) Me
(S) Me
(R) Me
(S) Me
(R) Me
(R) Me
H
90.4 28.1
948 222
113 42
H
Me
Me
H
5773 2803
325 116
665 226
5447 2059
3128 1671
2143 952
305 92
OMe
Me
Me
H
H
—
>25,000
—
Me
Me
t-Bu
t-Bu
(R) Me
H
(R) Me
>10,000
1409 767
O
H
IC50 values are the mean SEM of at least three determinations.
was tolerated as demonstrated, but a decrease in po-
tency was observed. The potency for 10 is approximately
sixfold less than 9. Once again, we observed the signifi-
cant influence of an asymmetric center in the piperazine
ring on potency. In the human CAP assay, compound
13 (IC50 = 113 42nM), with (R)-methyl configuration
as 7b, is equipotent to 11 (IC50 = 90.4 28.1nM),
sixfold more potent than 10 (IC50 = 726 99nM),
and almost 50-fold more potent than its enantiomer
14 (IC50 = 5773 2803nM). In general, appropriate
substitution on the benzene ring of the benzimid-
azole seems required in this series to maintain
potency.15
We further investigated the importance of the NH of the
benzimidazole in determining the potency of the com-
pounds. It was found that in the CAP assay the potency
of 17 (IC50 = 5447 2059nM) was reduced almost
eightfold compared to 10 (IC50 = 726 99nM). Note
that the introduction of a (R)-methyl group on the
piperazine ring (18) that benefits other members of the
series does not compensate the detrimental effect of
the N-methylation; 18 (IC50 = 3128 1671nM) is about
27-fold less potent than 13 (IC50 = 113 42nM).
To further illustrate the importance of the NH in
benzimidazole, we replaced it with an oxygen atom to

722
B. Shao et al. / Bioorg. Med. Chem. Lett. 15 (2005) 719–723
Table 3. PK parameters of compound 11 following single 3mg/kg iv
and 30mg/kg oral dose
Ar
N
S
H2N
Y
OH
Z
Vd
CL
t1/2
F%
6.87L/kg
8.02L/h/kg
0.59h
HN
Y
O
S
b
a
N
Q
+
O
S
N
O
19.7
Z
22
24
23
Y
Z
electronic factors play a role in the increased potency for
20. Finally a chloro thiadiazole was introduced for 21,
and this significantly reduced potency, about sevenfold.
In contrast to that observed in the human CAP assay, all
replacements of the original chloropyridine resulted in a
decrease in potency in the human pH assay.
25: Y = tBu, Z = H, Q = H
26: Y = tBu, Z = H, Q = (R)-M
e
Scheme 2. Reagents and conditions: (a) ethanol, reflux. (b) 8, p-xylene,
145ꢁC.
Within this series, 11 was selected for in vivo pharmaco-
kinetic (PK) study in rat. The in vivo profile of 11 is
summarized in Table 3. The PK study was designed to
estimate systemic drug exposure following a single
3mg/kg iv and 30mg/kg oral administration to rats. Fol-
lowing iv administration, compound 11 showed a mod-
erate terminal half life (t1/2 = 0.6h), due to its relatively
rapid clearance (CL = 8.0L/h/kg). Following oral
administration of 30mg/kg, compound 11 was slowly
absorbed (Tmax = 3h, Cmax = 300ng/mL). More impor-
tantly, the oral dosing confirmed that 11 was orally bio-
available (F % = 19.7), similar to lead 1 (F % = 15).
generate benzoxazoles (Fig. 2). The synthesis of corre-
sponding benzoxazoles is shown in Scheme 2. It started
with commercially available aminophenols 22. Treat-
ment of 22 with O-ethyl-S-methyl dithiocarbonate 23
at reflux in ethanol gave 24, which was used without
purification in the following step. As in the benzimid-
azole series, the desired benzoxazoles 25 and 26 were ob-
tained when the mixture of 24 and 8 was heated at high
temperature. It was found that the potency of 25 was
significantly decreased, 15-fold compared to 9. With
the beneficial configuration of (R)-methyl group in
the piperazine, the potency of 26 (IC50 = 305 92nM)
in the CAP assay was recovered compared to 25
(IC50 = 2143 952nM), but was still much less active
than 11 (IC50 = 90 28nM).
In summary, we have prepared a series of TRPV1 antag-
onists based on the lead compound 1. The SAR studies
uncovered some important factors for the design of
potent TRPV1 antagonists in the benzimidazole series.
In addition, we have identified a compound from this
series, 11, that is orally available in rats.
It is known that changes in the hetero aromatic ring can
also influence the potency of compounds.12 With that in
mind, we also investigated a few different hetero aro-
matic moieties that are known to maintain or improve
potency in other series (Table 2). When the chloropyr-
idine in 11 (IC50 = 90.4 28.1nM) was replaced with a
methyl pyridine in 19 (IC50 = 70.4 19.1nM), the po-
tency in the CAP assay increased slightly. The potency
increased threefold when a trifluoromethylpyridine was
used for 20 (IC50 = 32.4 9.0nM). It would appear that
Acknowledgements
The authors thank Dr. Z. Chen, Dr. J. Whitehead, Dr.
S. Victory, and Dr. L. Tafesse for their contribution to
this project. The authors thank Dr. R. Goehring for
the thorough review of the manuscript.
Table 2. Variation of aromatic ring
References and notes
H
N
1. Szallasi, A.; Blumberg, P. M. Pharmacol. Rev. 1999, 51,
159.
2. Caterina, M. J.; Julius, D. Annu. Rev. Neurosci. 2001, 24,
487.
3. Montell, C.; Bringbaumer, L.; Flockerzi, V. Cell 2002,
108, 595.
N
N Ar
N
Me
No. Ar
IC50 (nM) human CAP IC50 (nM) human pH
11
90.4 28.1
70.4 19.1
32.4 9.0
776 255
104 41
597 150
1778 672
>10,000
N
4. Davis, J.; Gray, J.; Gunthorpe, M.; Hatcher, J.; Davey, P.;
Overend, P.; Harries, M.; Latchman, J.; Clapham, C.;
Atkinson, K.; Hughes, S.; Rance, K.; Grau, E.; Harper,
A.; Pugh, P.; Rogers, D.; Bingham, S.; Randall, A.;
Sheardown, S. Nature 2000, 405, 183.
5. Caterina, M. A.; Malmberg, A.; Martin, W.; Trafton, J.;
Petersen-Zeitz, K.; Koltzenburg, M.; Basbuam, A.; Julius,
D. Science 2000, 288, 306.
Cl
19
N
Me
20
N
F3C
6. Pomonis, J.; Harrison, J.; Mark, L.; Bristol, D.; Valenz-
ano, K.; Walker, K. J. Pharmacol. Exp. Ther. 2003, 306,
387.
N S
21
N
Cl
7. Walpole, C. S. J.; Bevan, S.; Bovermann, G.; Boelsterli, J.
J.; Breckenridge, R.; Davis, J. W.; Hughes, G. A.; James,
IC50 values are the mean SEM of at least three determinations.

B. Shao et al. / Bioorg. Med. Chem. Lett. 15 (2005) 719–723
723
I.; Oberer, L.; Wunter, J.; Wrigglesworth, R. J. Med.
Chem. 1994, 37, 1942.
J = 3.6, 13Hz), 3.16 (m, 1H), 2.38 (s, 6H), 1.59 (d, 3H,
J = 6.4Hz). MS: 356.1 (MH+). Compound 15: (CD3OD) d
8.21 (dd, 1H, J = 1.6, 4.8Hz), 7.78 (dd, 1H, J = 1.6,
7.6Hz), 7.24 (s, 1H), 7.20 (d, 1H,J = 8Hz), 7.02 (dd, 1H,
J = 4.8, 8Hz), 7.01 (d, 1H, J = 8Hz), 4.36 (m, 1H), 3.86
(m, 3H), 3.62 (dt, 1H, J = 3.2, 12Hz), 3.18 (dd, 1H,
J = 2.8, 13Hz), 3.07 (dt, 1H, J = 3.2, 13Hz), 1.46 (d, 3H,
J = 6.8Hz). MS: 362.1 (MH+). Compound 16: (CD3OD) d
8.24 (dd, 1H, J = 1.8, 4.8Hz), 7.80 (dd, 1H, J = 1.8,
7.9Hz), 4.31 (m, 1H), 3.91 (m, 2H), 3.80 (dt, 1H, J = 3.5,
12Hz), 3.25 (dd, 1H, J = 3.2, 12Hz), 3.15 (dt, 1H, J = 4.0,
12Hz), 1.56 (d, 3H, J = 6.6Hz). MS: 358.1 (MH+).
8. Gunthorpe, M.; Rami, H.; Jerman, J.; Smart, D.; Gill, C.;
Soffin, E.; Hannan, S.; Lappin, S.; Egerton, J.; Smith, G.;
Worby, A.; Howett, L.; Owen, D.; Nasir, S.; Davies, C.;
Thompson, M.; Wyman, P.; Randall, A.; Davis, J.
Neuropharmacology 2004, 46, 133.
9. Seabrook, G.; Sutton, K.; Jarolimek, W.; Hollingworth,
G.; Teague, S.; Webb, J.; Clark, N.; Boyce, S.; Kerby, J.;
Ali, Z.; Chou, M.; Middleton, R.; Kaczorowski, G.; Jones,
A. J. Pharmacol. Exp. Ther. 2002, 303, 1052.
10. Suh, Y.; Lee, Y.; Min, K.; Park, O.; Seung, H.; Kim, H.;
Park, H.; Choi, J.; Lee, J.; Kang, S.; Oh, U.; Koo, J.; Joo,
Y.; Kim, S.; Kim, J.; Park, Y. Bioorg. Med. Chem. Lett.
2003, 13, 4389.
11. McDonnell, M.; Zhang, S.; Nasser, N.; Dubin, A.; Dax, S.
Bioorg. Med. Chem. Lett. 2004, 14, 531.
12. Sun, Q.; Tafesse, L.; Islam, K.; Zhou, X.; Victory, S.;
Zhang, C.; Hachicha, M.; Schmid, L.; Patel, A.; Rotsh-
teyn, Y.; Valenzano, K.; Kyle, D. Bioorg. Med. Chem.
Lett. 2003, 13, 3611.
13. LC–MS was performed on an Agilent Series 1100 MSD
instrument with an electrospray sample inlet system.
HPLC profile generated on an Eclipse XDB-C18 rapid
resolution 4.6 · 50mm column with a gradient of 85:15 to
10:90 of 0.1% TFA/acetonitrile with 0.1% TFA and UV
detection at 260nm.
14. NMR and MS data for compounds in Table 1 and Table
2. Compound 9: 1H NMR (400MHz): (CD3OD) d 8.21
(dd, 1H, J = 1.6, 4.8Hz), 7.77 (dd, 1H, J = 1.6, 7.6Hz),
7.34 (d, 1H, J = 2Hz), 7.21 (dd, 1H, J = 0.4, 8.4Hz), 7.14
(dd, 1H, J = 2, 8.4Hz), 7.01 (dd, 1H, J = 4.8, 7.6Hz), 3.70
(m, 4H), 3.49 (m, 4H), 1.37 (s, 9H). MS: 370.2 (MH+).
Compound 10: (CD3OD) d 8.25 (dd, 1H, J = 1.6, 4.8Hz),
7.82 (dd, 1H, J = 1.6, 8Hz), 7.06 (dd, 1H, J = 4.8, 7.6Hz),
3.82 (m, 4H), 3.58 (m, 4H), 2.38 (s, 6H). MS: 342.1
(MH+). Compound 11: (CD3OD) d 8.22 (dd, 1H, J = 1.6,
4.8Hz), 7.78 (dd, 1H, J = 1.6, 7.6Hz), 7.33 (dd, 1H,
J = 0.8, 2Hz), 7.19 (dd, 1H, J = 0.8, 8.4Hz), 7.12 (dd, 1H,
J = 1.6, 8.4Hz), 7.02 (dd, 1H, J = 4, 8Hz), 4.37 (m, 1H),
3.84 (m, 3H), 3.58 (m, 1H), 3.20 (dd, 1H, J = 4, 12Hz),
3.08 (dt, 1H, J = 3.2, 12Hz), 1.45 (d, 3H, J = 6.4Hz), 1.37
(s, 9H). MS: 384 (M+). Compound 12: (CD3OD) d 8.22
(dd, 1H, J = 1.6, 4.8Hz), 7.78 (dd, 1H, J = 1.6, 7.6Hz),
7.34 (d, 1H, J = 1.6Hz), 7.20 (d, 1H, J = 8.4Hz), 7.13 (dd,
1H, J = 2, 8.4Hz), 7.02 (dd, 1H, J = 4.8, 8Hz), 4.36
(m, 1H), 3.85 (m, 3H), 3.60 (dt, 1H, J = 2.8, 12Hz), 3.20
(dd, 1H, J = 4, 12Hz), 3.08 (dt, 1H, J = 3.2, 13Hz), 1.45
(d, 3H, J = 6.4Hz), 1.37 (s, 9H). MS: 384 (M+). Com-
pound 13: (CD3OD) d 8.25 (dd, 1H, J = 1.6, 4.8Hz), 7.82
(dd, 1H, J = 2, 8Hz), 7.07 (dd, 1H, J = 4.4, 8Hz), 4.30 (m,
1H), 3.90 (m, 4H), 3.26 (dd, 1H, J = 1.6, 13Hz), 3.17 (m,
1H), 2.38 (s, 6H), 1.59 (d, 3H, J = 6.8Hz). MS: 356.1
(MH+). Compound 14: (CD3OD) d 8.25 (dd, 1H, J = 1.2,
4.4Hz), 7.81 (dd, 1H, J = 1.6, 7.6Hz), 7.07 (dd, 1H,
J = 4.8, 7.6Hz), 4.31 (m, 1H), 3.88 (m, 4H), 3.26 (dd, 1H,
Compound 17: (CD3OD)
d 8.23 (dd, 1H, J = 1.6,
4.8Hz), 7.78 (dd, 1h, J = 2, 8Hz), 7.27 (br s, 1H), 7.14
(br s, 1H), 7.02 (dd, 1H, J = 4.8, 7.6Hz), 3.69 (s, 3H), 3.56
(m, 4H), 3.45 (m, 4H), 2.39 (s, 3H), 2.35 (s, 3H). MS:
356.1 (MH+). Compound 18: (CDCl3) d 8.14 (dd, 1H,
J = 1.6, 4.8Hz), 7.54 (dd, 1H, J = 1.6, 8Hz), 7.36 (s, 1H),
6.96 (s, 1H), 6.80 (dd, 1H, J = 4.8, 8Hz), 3.70 (m, 1H),
3.55 (m, 2H), 3.33 (m, 3H), 3.15 (m, 1H), 2.31 (s, 3H), 2.29
(s, 3H), 1.18 (s, 3H), 1.09 (d, 3H, J = 6.4Hz). MS: 370
(MH+). Compound 19: (CDCl3)
d 8.17 (d, 1H,
J = 4.8Hz), 7.44 (d, 1H, J = 7.6Hz), 7.42 (s, 1H), 7.27
(d, 1H, J = 8.4Hz), 7.13 (d, 1H, J = 8.4Hz), 6.91 (dd, 1H,
J = 4.8, 7.2Hz), 4.42 (m, 1H), 3.97 (d, 1H, J = 12Hz), 3.62
(dt, 1H, J = 3.2, 12Hz), 3.47 (d, 1H, J = 12Hz), 3.33 (d,
1H, J = 13Hz), 3.18 (dd, 1H, J = 3.2, 12Hz), 3.06 (dt, 1H,
J = 2.8, 12Hz), 2.32 (s, 3H), 1.45 (d, 3H, J = 6.8Hz), 1.33
(s, 9H). MS: 364.2 (MH+). Compound 20: (CDCl3) d
8.49(d, 1H, J = 4.8Hz), 7.93 (dd, 1H, J = 1.6, 8.0Hz), 7.42
(s, 1H), 7.26 (d, 1H, J = 8.4Hz), 7.14 (dd, 1H, J = 1.6,
8.4Hz), 7.08 (dd, 1H, J = 4.8, 8.0Hz), 4.37 (m, 1H), 3.89
(d, 1H, J = 12Hz), 3.64 (dt, 1H, J = 3.2, 12Hz), 3.56 (d,
1H, J = 13Hz), 3.45 (d, 1H, J = 13Hz), 3.37 (dd, 1H,
J = 3.6, 12Hz), 3.17 (dt, 1H, J = 3.2, 12Hz), 1.39 (d, 3H,
J = 6.8Hz), 1.35 (s, 9H). MS: 418.2 (MH+). Compound
21: (CD3OD) d 7.34 (s, 1H), 7.20 (d, 1H, J = 8.4Hz), 7.13
(dd, 1H, J = 1.6, 8.4Hz),4.38 (m, 1H), 4.05 (br d, 2H, J =
12Hz), 3.90 (br d, 1H, J = 13Hz), 3.58 (dt, 1H,
J = 3.6, 12Hz), 3.27 (dd, 1H, J = 3.6, 12Hz), 3.20 (dt,
1H, J = 3.6, 12Hz), 1.43 (d, 3H, J = 6.4Hz), 1.37 (s, 9H).
MS: 391.1 (MH+). Compound 25: (CDCl3) d 8.23 (dd,
1H, J = 1.6, 4.8Hz), 7.65 (dd, 1H, J = 2, 7.6Hz), 7.46
(d, 1H, J = 1.6Hz), 7.20 (dd, 1H, J = 0.4, 8.4Hz), 7.10
(dd, 1H, J = 2, 8.4Hz), 6.91 (dd, 1H, J = 5.2, 7.6Hz), 3.88
(m, 4H), 3.50 (m, 4H), 1.37 (s, 9H). MS: 371.1 (MH+).
Compound 26: (CDCl3) d 8.23 (dd, 1H, J = 1.6, 4.8Hz),
7.65 (dd, 1H, J = 2, 7.6Hz), 7.47 (d, 1H, J = 2Hz), 7.20
(d, 1H, J = 8.4Hz), 7.10 (dd, 1H, J = 2, 8.4Hz), 6.91 (dd,
1H, J = 4.8, 8Hz), 4.60 (m, 1H), 4.60 (d, 1H, J = 13Hz),
3.84 (m, 2H), 3.67 (dt, 1H, J = 3.6, 13Hz), 3.17 (dd, 1H,
J = 4, 12Hz), 3.08 (dt, 1H, J = 3.2, 12Hz), 1.52 (d, 3H,
J = 6.8Hz), 1.37 (s, 9H). MS: 385.2 (MH+).
15. Unpublished results indicated that if there is no substitu-
tion on the benzene ring the resulting benzimidazoles are
inactive toward the TRPV1 receptor.