Synthesis and evaluation of thiazole carboxamides as vanilloid receptor 1 (TRPV1) antagonists

Article abstract of DOI:10.1016/j.bmcl.2005.08.100

A thiazole derivative, 2-(2,6-dichlorobenzyl)-N-(4-isopropylphenyl) thiazole-4-carboxamide (1), was identified as a TRPV1 antagonist. We synthesized various thiazole analogs and evaluated them for their ability to block capsaicin- or acid-induced calcium influx in TRPV1-expressing CHO cells. The IC₅₀ values of the most potent antagonists were ca. 0.050 μM in these assays.

Full text of DOI:10.1016/j.bmcl.2005.08.100

Bioorganic & Medicinal Chemistry Letters 15 (2005) 5211–5217
Synthesis and evaluation of thiazole carboxamides
as vanilloid receptor 1 (TRPV1) antagonists
Ning Xi,a,* Yunxin Bo,a Elizabeth M. Doherty,a Christopher Fotsch,a
Narender R. Gavva,b Nianhe Han,a Randall W. Hungate,a Lana Klionsky,b Qingyian Liu,a
Rami Tamir,b Shimin Xu,a James J. S. Treanorb and Mark H. Normana
aChemistry Research and Discovery, Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA 91320, USA
bDepartment of Neuroscience, Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA 91320, USA
Received 2 August 2005; accepted 18 August 2005
Available online 3 October 2005
Abstract—A thiazole derivative, 2-(2,6-dichlorobenzyl)-N-(4-isopropylphenyl) thiazole-4-carboxamide (1), was identified as a
TRPV1 antagonist. We synthesized various thiazole analogs and evaluated them for their ability to block capsaicin- or acid-induced
calcium influx in TRPV1-expressing CHO cells. The IC50 values of the most potent antagonists were ca. 0.050 lM in these assays.
Ó 2005 Elsevier Ltd. All rights reserved.
The vanilloid receptor 1 (VR1 or TRPV1), a non-selec-
tive cation channel within the transient receptor poten-
tial (TRP) family, is highly expressed in sensory
neurons located primarily in the dorsal root ganglia.1
TRPV1 is activated by a variety of stimuli such as heat
and acid, and exogenous chemical stimuli such as capsa-
icin (the pungent component found in chili peppers).
Activation of TRPV1 induces the initial excitation of
primary sensory neurons that often leads to a burning
sensation. Prolonged stimulation with TRPV1 agonists
can desensitize sensory nerves, making them less sensi-
tive to subsequent painful stimuli. However, TRPV1
agonists are neurotoxic and cause initial excitatory ef-
fects on sensory neurons, making their use as analgesics
limited.2 TRPV1 receptor antagonists, on the other
hand, inhibit the activation of the primary sensory
neurons, so they should be devoid of the neurotoxicity
associated with activation and desensitization of the
nerve cell. Therefore, TRPV1 antagonists may serve as
better analgesic agents than TRPV1 agonists.3
robenzyl)-N-(4-isopropylphenyl) thiazole-4-carboxam-
ide (1), was discovered by high-throughput screening
measuring Ca2+ influx in Chinese hamster ovary (CHO)
cells.5 For the purpose of our structure–activity relation-
ship (SAR) study, we measured the inhibition of capsaicin
(CAP) and acid (pH 5) induced influx of 45Ca2+ into CHO
cells that express rat–human chimera TRPV1.6 Our goal
was to improve the potency over compound 1 as well as
to gain a better understanding of the pharmacophores re-
quired for activity at the TRPV1 receptor. Toward this
end, we first optimized the left-side aryl amide portion fol-
lowed by the central core and then the right-side aryl por-
tion of compound 1 (Fig. 1).
We began our initial SAR studies by examining the
effect of varying the left phenyl ring and prepared a
O
Cl
S
N
NH
In our work toward the discovery of new analgesic agents,
we identified a series of thiazole carboxamides as TRPV1
antagonists.4 The initial lead compound, 2-(2,6-dichlo-
Cl
right
aryl
left aryl
amide
central
core
1
Keywords: Vanilloid receptor
carboxamides.
*
1 (TRPV1); Antagonists; Thiazole
Figure 1. 2-(2,6-Dichlorobenzyl)-N-(4-isopropylphenyl) thiazole-4-
carboxamide (1) identified as a TRPV1 antagonist through high-
throughput screening.
Corresponding author. Tel: +1 805 447 2285; fax: +1 805 480 3016;
e-mail: nxi@amgen.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.08.100

5212
N. Xi et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5211–5217
Cl
O
Y
X
Cl
O
S
a
Y
X
S
p
NH2
+
p
N
NH
HO
N
R
m
o
R
m
Cl
o
Cl
2a-n
3
4a-n
Scheme 1. Reagents and conditions: (a) HATU, DMF, 0–23 °C, 70–95% yield.
series of substituted aryl amides. As illustrated in
Scheme 1, compounds 4a–n were synthesized by the
condensation of substituted anilines 2a–n with commer-
cially available 2-(2,6-dichlorobenzyl) thiazole-4-car-
boxylic acid (3) in the presence of HATU.7 The assay
results for these aryl amides are reported in Table 1.
Accordingly, we prepared more electronegative aryl
amide analogs, 4g–j. The p-CN substituted phenyl amide
(4g) was comparable in potency to both compound 1 and
the p-Br analog (4f). The most potent analog was the p-
CF3 analog 4h with IC50 values of 0.14 and 0.09 lM in
the CAP- and acid-mediated assays, respectively. The
larger homolog (p-CF2CF3, 4i), however, was slightly less
potent in these assays (IC50 = 0.29 in the CAP assay and
0.35 lM in the acid assay). The trends in potencies ob-
served for the substituted 3-pyridyl analogs (4j,k) were
similar to their phenyl counterparts (4h,e). For example,
the p-CF3-pyridyl (4j) was as potent as the p-CF3-phenyl
analog (4h), whereas the p-OMe-pyridyl (4k) had IC50
values >4 lM in both assays, as was also observed for
the corresponding p-OMe-phenyl (4e). In contrast, shift-
ing the pyridyl nitrogen from the 3- to the 2-position
caused a reduction in potency (i.e., 4l vs f).
We found that the potency at TRPV1 was sensitive
to the substitution on the aryl amides. For example,
the larger tert-butyl homolog (4a) and the truncated
4-ethyl analog (4b) were 1.5- to 2-fold less potent
than 1 in the CAP-mediated assay. The decrease in
activity for the unsubstituted phenyl analog (4c)
was greater than 10-fold. Compounds possessing a
strongly electron-donating para-substituent, such as
p-NMe2 (4d) and p-OMe (4e), also showed signifi-
cantly lower potencies (IC50 values >4 lM in both
CAP- and acid-mediated assays). In contrast, elec-
tron-withdrawing para-substituents improved activity
at the TRPV1 receptor. For example, the p-Br analog
(4f) had an IC50 = 0.40 lM in the CAP-mediated as-
say, making it >10-fold more potent than the p-
OMe analog (4e) and 1.5-fold more potent than the
p-Et analog (4b). These results suggest that it is the
electronic effects of bromide that cause the activity
enhancement, since bromide has similar size to those
of OMe and Et groups, as measured by molecular
refractivity, MR.8
Finally, the position of the substituent was important
for TRPV1 activity. For example, moving the bromine
substituent from the para-position (4f) to the ortho- or
meta-positions (4m,n) resulted in a decrease in potency
to >4 lM.
In the next phase of our investigation, we kept the most
potent left aryl amide (p-CF3-phenyl, 4h) and modified
the central core (Table 2, compounds 25a–i). A thiazole
regioisomer and a substituted thiazole analog were
Table 1. Structures and assay results of thiazole analogs with variations at the left phenyl amide portion
Cl
O
S
Y
X
p
N
NH
R
m
Cl
o
Compound
R
X
Y
CAPa IC50 SEM (lM)
Acida IC50 SEM (lM)
1
p-Pri
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
0.37 0.19
0.57 0.24
0.81 0.13
>4
0.52 0.30
0.30 0.05
1.45 0.86
>4
4a
4b
4c
4d
4e
4f
p-But
p-Et
H
p-NMe2
p-OMe
p-Br
>4
>4
1.27 0.49
>4
0.40 0.09
0.45 0.06
0.14 0.03
0.29 0.03
0.11 0.04
>4
0.46 0.11
0.72 0.20
0.088 0.019
0.35 0.16
0.13 0.01
>4
4g
4h
4i
p-CN
p-CF3
p-CF2CF3
p-CF3
p-OMe
p-Br
4j
4k
4l
N
CH
CH
CH
>4
>4
>4
>4
4m
4n
o-Br
m-Br
CH
CH
>4
>4
a The activation assays were carried out in a rat–human chimera of the TRPV1 channel expressed in CHO cells. Results are the average of at least two
independent experiments with three replicates at each concentration.

N. Xi et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5211–5217
Table 2. Structures and assay results of TRPV1 antagonists with different central cores
5213
Cl
O
Ar
F3C
NH
Z
Cl
Compound
Ar
Z
CAPa IC50 SEM (lM)
Acida IC50 SEM (lM)
S
4h
CH2
0.14 0.03
0.088 0.019
N
N
25a
25b
25c
25d
25e
CH2
CH2
CH2
CH2
CH2
0.79 0.025
0.062 0.014
0.23 0.12
3.42 1.49
1.01 0.50
1.78 0.55
0.200 0.008
0.23 0.11
>4
S
N
N
O
NH
N
N
S
N
1.02 0.32
S
S
25f
Bond
>4
>4
>4
>4
N
N
25g
CH2CH2
S
S
25h
25i
O
0.87b
1.28 0.86
N
N
NH
0.051 0.023
0.048 0.009
a The activation assays were carried out in a rat–human chimera of the TRPV1 channel expressed in CHO cells. Results are the average of at least two
independent experiments with three replicates at each concentration.
b Single experimental determination.
prepared and tested. In addition, the central core was re-
placed with two other five-membered heterocycles: oxa-
zole and imidazole rings. As part of the central core
modifications, the linker between the thiazole group
and dichlorophenyl ring was also altered (e.g., CH2,
CH2CH2, O, and NH, or removed). The syntheses of
these core analogs are shown in Schemes 2–6.
followed by ester hydrolysis with 1 N NaOH provided
oxazole acid 15 in 15% overall yield. Similarly, 4,5-dihy-
dro-1H-imidazole-4-ester 14 was obtained in 63%
yield via the cyclization of 12 with 2,3-diamino propa-
noic ester 11. Oxidation of 14 with MnO2 in CH2Cl2
proceeded smoothly to yield the corresponding imidaz-
ole ester, which was hydrolyzed to give acid 16 in
excellent yield.
Schemes 2 and 3 illustrate the synthesis of the key inter-
mediates containing the different core structures (i.e.,
compounds 8, 9, 15, and 16). Thiazole 5-carboxylic acids
8 and 9 were obtained in good yields by the condensa-
tion of a-chloro-b-ketoesters 5 and 6 with 2-(2,6-dichlor-
ophenyl) ethanethioamide 7 in EtOH,9 followed by a
basic hydrolysis of the resulting esters. Oxazole acid
1510 and imidazole acid 1611 (Scheme 3) were prepared
through the oxidation of the corresponding dihydro
intermediates 13 and 14. Cyclization of serine methyl es-
ter 10 with acetimidate 12 afforded 4,5-dihydrooxazole
13. Oxidation of 13 with CuBr2 under basic conditions
Compounds with different linking groups between the
thiazole and the dichlorophenyl (Scheme 4, compounds
19a–c) were constructed through the condensation of
thioamides 18a,b and thiourea 18c with ethyl bromo-
pyruvate 17.12 Thioamide 18a and thiourea 18c were
purchased from commercial sources, while 3-(2,6-
dichlorophenyl) propanethioamide 18b was prepared
from 3-(2,6-dichlorophenyl) propanenitrile according
to the method of Klimesova, et al.13 Oxygen-linked thi-
azole analog 24 was synthesized using a copper-cata-
lyzed procedure, as shown in Scheme 5.14 Coupling of

5214
N. Xi et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5211–5217
O
HO
Cl
R
O
O
Cl
S
H2N
a, b
+
R
EtO
N
Cl
S
Cl
Cl
7
R = H
R = H
5
6
8
9
Me
Me
Scheme 2. Reagents and conditions: (a) EtOH, pyridine, reflux, R = H, 33% and R = Me, 80%; (b) 1 N NaOH, MeOH/THF, 75%.
XH
Cl
Cl
O
X
HN
MeO
a or b
+
MeO
NH3
N
MeO
O
Cl
Cl
Cl
10
11
12
13
14
X = O
X = O
NH
NH
Cl
O
X
c or d
N
HO
then e
Cl
15
16
X = O
NH
Scheme 3. Reagents and conditions: (a) i-Pr2NEt, CH2Cl2, rt, 51% for X = O; (b) Et3N, MeOH, rt, 63%, CuBr2, DBU, CH2Cl2, rt, 31% for X = NH;
(c) CuBr2, DBU, CH2Cl2, rt, 31% for X = O; (d) MnO2, CH2Cl2, rt, 46% for X = NH; (e) 1 N NaOH, MeOH/THF, 70–86%.
Cl
Cl
O
S
S
O
a, b
+
Br
N
H2N
Z
Z
HO
EtO2C
Cl
Cl
17
18a Z = bond
19a
19b
19c
Z = bond
CH2CH2
NH
18b
18c
CH2CH2
NH
Scheme 4. Reagents and conditions: (a) EtOH, pyridine, reflux, >80%; (b) 1 N NaOH, MeOH/THF, 90%.
Cl
Cl
HO
S
S
HO
a
+
Cl
HO
N
O
N
20
O
Cl
Cl
21
22
Cl
Cl
O
S
S
c
b
N
O
N
O
H
HO
Cl
Cl
23
24
Scheme 5. Reagents and conditions: (a) CuI, K2CO3, DMF, microwave, 240 °C, 10 min, 24%; (b) MnO2, CH2Cl2, rt, 86%; (c) SeO2, H2O2, THF,
room temperature, 82%.
2-chlorothiazole 20 with 2,6-dichlorophenol 21 with
microwave heating in the presence of CuI afforded alco-
hol 22. Oxidation of alcohol 22 with MnO2 gave alde-
hyde 23, which was then converted to acid 24 in
excellent yield by oxidation with SeO2/H2O2.
The final steps to prepare amides 25a–i required the
coupling of acids 8, 9, 15, 16, 19a–c, and 24 with
p-trifluoromethyl aniline, as illustrated in Scheme 6.
Compound 25e was obtained by N-methylation of
the imidazole ring of 25c with MeI under basic

N. Xi et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5211–5217
5215
Changes to the central core significantly influenced
potency, as demonstrated by the assay data summa-
rized in Table 2. For example, shifting the carboxamide
group from the 4-position (e.g., 4h) to the 5-position
(e.g., 25a) resulted in a 5-fold decrease in potency in
the CAP-mediated assay and 20-fold decrease in poten-
cy in the acid-mediated assay. The effects of replacing
the sulfur atom in thiazole 4h with either oxygen or
nitrogen are illustrated by oxazole 25b or imidazole
25c. Oxazole 25b showed an IC50 = 0.062 lM in the
CAP-mediated assay, which was about 2-fold more po-
tent than 4h. In the acid-mediated assay, however, 25b
was 2-fold less potent than 4h. Imidazole 25c displayed
IC50 values of 0.23 lM in both the CAP- and acid-
mediated assays. Introducing a methyl group to the
central core was poorly tolerated, as shown by 4-meth-
yl 5-carboxamide 25d (IC50 > 3 lM in both the CAP-
and acid-mediated assays). Similarly, the methylated
Cl
O
8
16
a
Ar
9
19a-c
24
Z
F3C
NH
15
Cl
25a-i
Me
Cl
O
N
b
25c
N
F3C
NH
Cl
25e
Scheme 6. Reagents and conditions: (a) p-trifluoromethyl aniline,
HATU, i-Pr2NEt, DMF, rt, 41–90%; (b) MeI, K2CO3, DMF, rt, 34%.
conditions, and the position of the methyl group was
unambiguously confirmed by NMR spectroscopic
methods.15
O
NH
28a-e
S
S
b, c, d
a
Ar
Ar
Ar-NH2
N
F3C
H2N
N
N
H
H
26a-e
27a-e
Scheme 7. Reagents and conditions: (a) benzoyl isothiocyanate, THF, then 1 N NaOH, 90%; (b) ethyl bromopyruvate, EtOH, pyridine, reflux,
>80%; (c) 1 N NaOH, MeOH/THF, 90%; (d) p-trifluoromethyl aniline, HATU, i-Pr2NEt, DMF, rt, 70–90%.
Table 3. Structures and assay results of thiazole analogs with variations at the right phenyl portion
O
NH
S
Ar
N
F3C
N
H
Compound
Ar
CAPa IC50 SEM (lM)
Acida IC50 SEM (lM)
Cl
25i
0.051 0.023
0.048 0.009
Cl
Cl
Cl
28a
28b
28c
28d
28e
>4
>4
CF3
1.75 0.71
1.78 0.37
0.36 0.03
0.090 0.006
1.41 0.02
1.74 0.07
0.88 0.03
0.082 0.014
O
S
NH2
O
Cl
Cl
Cl
N
Cl
Me
Me
a The activation assays were carried out in a rat–human chimera of the TRPV1 channel expressed in CHO cells. Results are the average of at least two
independent experiments with three replicates at each concentration.

5216
N. Xi et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5211–5217
imidazole 25e was >15-fold less potent than imidazole
25c.
Acknowledgment
We thank Duncan Smith for carrying out NMR spectro-
scopic studies to confirm the structure of compound 24e.
Altering the linker between the thiazole and the right
dichlorophenyl moiety afforded compounds 25f–i. Com-
pounds with either shorter (no spacer, 25f) or longer
linker (–CH2CH2–, 25g) were less potent in both the
CAP- and acid-mediated assays (IC50s > 4 lM). Chang-
ing the –CH2– linker to an oxygen atom did not improve
activity (e.g., 25h). In contrast, the NH-linked derivative
25i had significantly improved TRPV1 potency
(IC50 = 0.051 lM in the CAP assay and 0.048 lM in
the acid assay), which was about 2-fold more potent
than compound 4h.
References and notes
1. Nagy, I.; Santha, P.; Jancso, G.; Urban, L. Eur. J.
Pharmacol. 2004, 500, 351.
2. Szallasi, A.; Blumberg, P. M. Pharmacol. Rev. 1999, 51, 159.
3. (a) Szallasi, A.; Appendino, G. J. Med. Chem. 2004, 47,
2717; (b) Valenzano, K. J.; Sun, Q. Curr. Med. Chem.
2004, 11, 3185; (c) Rami, H. K.; Gunthorpe, M. J. Drug
Discov. Today: Ther. Strateg. 2004, 97, 1; (d) Lopez-
Rodriguez, M. L.; Viso, A.; Ortega-Gutierrez, S. Mini
Rev. Med. Chem. 2003, 733, 3.
4. Doherty, E. M.; Fotsch, C. H.; Han, N.; Hungate, R. W.;
Liu, Q.; Norman, M. H.; Xi, N.; Xu, S. U.S. Patent Appl.
Publ. US 2004/157845, 2004.. Chem. Abstr. 2004, 141,
190788.
5. Gavva, N. R.; Tamir, R.; Qu, Y.; Klionsky, L.; Zhang, T.
J.; Immke, D.; Wang, J.; Zhu, D.; Vanderah, T. W.;
Porreca, F.; Doherty, E. M.; Norman, M. H.; Wild, K.
W.; Bannon, A. W.; Louis, J. C.; Treanor, J. J. S. J.
Pharmacol. Exp. Ther. 2005, 313, 374.
6. For assay conditions, see: Doherty, E. M.; Fotsch, C.; Bo,
Y.; Chakrabarti, P. P.; Chen, N.; Gavva, N.; Han, N.;
Kelly, M. G.; Kincaid, J.; Klionsky, L.; Liu, Q.; Ognya-
nov, V. I.; Tamir, R.; Wang, X.; Zhu, J.; Norman, M. H.;
Treanor, J. S. J. Med. Chem. 2005, 48, 71, All compounds
were tested in a separate assay for agonist activity, and the
compounds reported herein behaved as antagonists.
7. HATU: o-(7-azabenzotriazol-1-yl)-n,n,n0,n0-tetra-methyl
uranium hexafluorophosphate. For a discussion on the
use of HATU in amide coupling reactions, see: Carpino,
L. A.; Imazumi, H.; El-Faham, A.; Ferrer, F. J.; Zhang,
C.; Lee, Y.; Foxman, B. M.; Henklein, P.; Hanay, C.;
Mugge, C.; Wenschuh, H.; Klose, J.; Beyermann, M.;
Bienert, M. Angew. Chem., Int. Ed. 2002, 41, 441.
8. Molecular refractivity (MR): Et, 10.30; OMe, 7.87; CN,
6.33; Br, 8.88; CF3, 5.02 and CF2CF3, 9.23. see: Kubinyi,
H.. In Wolff, M. E., Ed.; BurgerÕs Medicinal Chemistry
and Drug Discovery; John Wiley and Sons: New York,
1995; Vol. 1, pp 507–509.
Finally, we investigated the substituent effect of the
right-side aromatic ring based on modifications to com-
pound 25i. Scheme 7 shows the synthesis of compounds
28a–e (Table 3). The thioureas 27a–e were obtained by
one-pot reactions involving the condensation of anilines
26a–e with benzoyl isothiocyanate followed by a basic
hydrolysis to remove the benzoyl group.16 The resulting
thioureas were condensed with bromopyruvate followed
by the hydrolysis of ester and coupling with p-trifluo-
romethyl aniline to provide the target compounds
28a–e.
Small structural changes in this area had a signifi-
cant impact on potency. For example, changing
one of the chlorine atoms on the phenyl moiety to
a CF3 group (e.g., 28a) resulted in a reduction in
potency (IC50s > 4 lM in both the CAP- and acid-
mediated assays). Deletion of one chlorine atom also
caused a reduction in activity, as observed with
compound 28b (IC50s > 1 lM in both assays). Substi-
tution on the para-position was also unfavourable.
For example, para-sulfonamide analog 28c had IC50
values of ꢀ1.7 lM in both the CAP- and acid-med-
iated assays.
Pyridyl analog 28d was much less potent than the corre-
an
sponding
phenyl
counterpart
28i,
with
9. Abbotto, A.; Bradamante, S.; Facchetti, A.; Pagani, G. A.
J. Org. Chem. 2002, 67, 5753.
10. (a) Cossu, S.; Giacomelli, G.; Conti, S.; Falorni, M.
Tetrahedron 1994, 50, 5083; (b) Pihko, P. M.; Koskinen,
A. M. P. J. Org. Chem. 1998, 63, 92.
IC50 = 0.36 lM in the CAP assay, and 0.88 lM in the
acid assay. Changing both chloride atoms to –CH3
groups furnished a potent TRPV1 antagonist 28e with
IC50 values of ꢀ0.09 lM in both assays.
11. (a) Jones, R. C. F.; Ward, G. J. Tetrahedron Lett. 1988, 29,
3853; (b) You, S.-L.; Kelly, J. W. Org. Lett. 2004, 6, 1681.
12. (a) Chan, J. H.; Hong, J. S.; Kuyper, L. F.; Jones, M. L.;
Baccanari, D. P.; Tansik, R. L.; Boytos, C. M.; Rudolph, S.
K.; Brown, A. D. J. Heterocycl. Chem. 1997, 34, 145; (b)
Wiggall, K. J.; Richardson, S. K. J. Heterocycl. Chem. 1995,
32, 867.
In conclusion, through SAR studies based on com-
pound 1, we designed several novel thiazole analogs
that are potent TRPV1 receptor antagonists. In addi-
tion, we found that compounds with a strong elec-
tron-withdrawing para-substituent on the left phenyl
amide portion were more potent than the analogs
with electron-donating para-substituents (e.g., 4h,i vs
4d,e). Excellent antagonistic potencies were also ob-
served for the oxazole analog 25b. The NH-linked
analog 25i was the most potent TRPV1 receptor
antagonist in this series with IC50 values of
0.050 lM for both the CAP- and acid-mediated as-
says. Finally, we found that variations at the right
phenyl ring were less tolerated, and most changes
in this region led to a drop in potency at TRPV1
receptor.
13. Thioamide 15b was prepared using the following method:
Cl
Cl
a. BH3, THF
O
b. PPh3, imidazole, I2
87% for two steps
HO
I
Cl
Cl
Cl
c. NEt4CN, CH2Cl2, reflux, 52%
d. H2S, pyridine, 100%
H2N
S
Cl

N. Xi et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5211–5217
For similar thioamide synthesis, see: Klimesova, V.; Otcen-
5217
n.O.e.
asek, M.; Waisser, K. Eur. J. Med. Chem. 1996, 31, 389.
14. For similar copper-catalyzed coupling procedures, see:
(a) Hazeldine, S. T.; Polin, L.; Kushner, J.; White, K.;
Bouregeois, N. M.; Crantz, B.; Palomino, E.; Corbett,
T. H.; Horwitz, J. P. J. Med. Chem. 2002, 45, 3130;
(b) Fujiwara, H.; Kitagawa, K. Heterocycles 2000, 53,
409.
H
Me Cl
O
N
N
F3C
NH
Cl
24e
15. NMR spectroscopic methods including 2D NOESY,
1H/13C HSQC, and HMBC were used to confirm the
structure of compound 24e. A strong NOE was observed
between the N-methyl and the imidazole C–H:
16. (a) Herr, R. J.; Kuhler, J. L.; Meckler, H.; Opalka, C. J.
Synthesis 2000, 11, 1569; (b) Alhede, B.; Clausen, F. P.;
Juhl-Christensen, J.; McCluskey, K. K.; Preikschat, H. F.
J. Org. Chem. 1991, 56, 2139.