Design of potent, orally available antagonists of the transient receptor potential vanilloid 1. Structure-activity relationships of 2-piperazin-1-yl-1H- benzimidazoles

Article abstract of DOI:10.1021/jm060065y

The vanilloid receptor-1 (VR1 or TRPV1) is a membrane-bound, nonselective cation channel that is predominantly expressed by peripheral neurons sensing painful stimuli. TRPV1 antagonists produce antihyperalgesic effects in animal models of inflammatory and neuropathic pain. Herein, we describe the synthesis and the structure-activity relationships of a series of 2-(4-pyridin-2- ylpiperazin-1-yl)-1H-benzo-[d]imidazoles as novel TRPV1 antagonists. Compound 46ad was among the most potent analogues in this series. This compound was orally bioavailable in rats and was efficacious in blocking capsaicin-induced flinch in rats in a dose-dependent manner. Compound 46ad also reversed thermal hyperalgesia in a model of inflammatory pain, which was induced by complete Freund's adjuvant (CFA).

Full text of DOI:10.1021/jm060065y

J. Med. Chem. 2006, 49, 3719-3742
3719
Design of Potent, Orally Available Antagonists of the Transient Receptor Potential Vanilloid 1.
Structure-Activity Relationships of 2-Piperazin-1-yl-1H-benzimidazoles
Vassil I. Ognyanov,*,† Chenera Balan,† Anthony W. Bannon,‡ Yunxin Bo,† Celia Dominguez,† Christopher Fotsch,†
Vijay K. Gore,† Lana Klionsky,‡ Vu V. Ma,† Yi-Xin Qian,† Rami Tamir,‡ Xianghong Wang,† Ning Xi,† Shimin Xu,†
Dawn Zhu,‡ Narender R. Gavva,‡ James J. S. Treanor,‡ and Mark H. Norman†
Department of Chemistry Research and DiscoVery and Department of Neuroscience, Amgen Inc., One Amgen Center DriVe, Thousand Oaks,
California 91320-1799
ReceiVed January 19, 2006
The vanilloid receptor-1 (VR1 or TRPV1) is a membrane-bound, nonselective cation channel that is
predominantly expressed by peripheral neurons sensing painful stimuli. TRPV1 antagonists produce
antihyperalgesic effects in animal models of inflammatory and neuropathic pain. Herein, we describe the
synthesis and the structure-activity relationships of a series of 2-(4-pyridin-2-ylpiperazin-1-yl)-1H-benzo-
[d]imidazoles as novel TRPV1 antagonists. Compound 46ad was among the most potent analogues in this
series. This compound was orally bioavailable in rats and was efficacious in blocking capsaicin-induced
flinch in rats in a dose-dependent manner. Compound 46ad also reversed thermal hyperalgesia in a model
of inflammatory pain, which was induced by complete Freund’s adjuvant (CFA).
Introduction
The vanilloid receptor-1 (VR1 or TRPV1)1 is a polymodal
nociceptor that belongs to the family of the transient receptor
potential (TRP) ion channels. The highly Ca2+ permeable
TRPV1 receptor is predominantly expressed in sensory neurons2-4
and is involved in the detection of painful stimuli. The
endogenous activators of TRPV1 are generated as a result of
tissue injury and inflammatory conditions in research animals5-7
and in humans8,9 and include heat (>42 °C), protons (pH 5),10
and ligands such as the endocannabinoid anandamide11 and
lipoxygenase metabolites.12 TRPV1 is also activated by exog-
enous ligands such as the vanilloid capsaicin (1)2 and its
ultrapotent analogue resiniferatoxin (RTX, 2) (Figure 1).13
TRPV1 hyperstimulation by capsaicin has an analgesic effect,
since it leads to long-term desensitization of the sensory neurons
to additional agonist challenges, including noxious stimuli such
as heat and acid. Capsaicin is the active component of various
topical muscle pain relievers, and both capsaicin and RTX have
been used to treat the pain associated with diabetic neuropathy
and arthritis.2,4 The clinical uses of TRPV1 agonists such as
Figure 1. The TRPV1 agonists capsaicin and resiniferatoxin and
selected examples of TRPV1 antagonists.
capsaicin, however, are limited due to side effects of a burning
sensation, irritation and neurotoxicity3 resulting from the
continuous influx of Ca2+ ions into the cells. On the other hand,
blockade of the pain-signaling pathway with a TRPV1 antago-
nist represents a promising strategy for the development of novel
analgesics14 with potentially fewer side effects. This rationale
is also supported by the observation that thermal hyperalgesia
is reduced in inflammatory pain models in knockout mice
lacking the TRPV1 gene.15,16
Capsazepine (3)17 (Figure 1), the first reported competitive
antagonist of TRPV1, emerged as a result of structure-activity
relationship (SAR) studies of capsaicin. It was demonstrated
that capsazepine blocks the capsaicin-induced uptake of Ca2+
in neonatal rat dorsal root ganglia and shows species-dependent
efficacies in various in vivo models of inflammatory hyper-
algesia and chronic pain.18-20 However, it was also found that
capsazepine blocks receptors other than TRPV1, such as voltage-
gated Ca2+ channels21 and nicotinic acetylcholine receptors,22
and does not act as an antagonist when the TRPV1 channel is
activated by heat or acid.
During the past few years, several classes of TRPV1
antagonists, either structurally related or not to the exogenous
agonists capsaicin and RTX, have been described, and their
chemistry and pharmacology have been reviewed.23-26 One
extensively studied class of TRPV1 antagonists is based on urea
templates.23,24,27-29 For example, the potent TRPV1 antagonist
N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)piperazine-1-car-
boxamide (BCTC) (4)30 (Figure 1) is a member of a well-studied
chemical series of urea-based TRPV1 antagonists that contains
a piperazine-1-carboxamide template. The BCTC template was
disclosed for the first time by Neurogen31 and more recently
by Johnson & Johnson,32 Bayer,33 GlaxoSmithKline,34 Abbott,35
and Purdue Pharma.36 While BCTC was found to be efficacious
* To whom correspondence should be addressed. Tel: 805-447-1509.
Fax: 805-480-1337. E-mail: vassilo@amgen.com.
† Department of Chemistry Research and Discovery.
‡ Department of Neuroscience.
10.1021/jm060065y CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/19/2006

3720 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12
OgnyanoV et al.
Scheme 1a,b
prepared from the hydroxymethyl derivative 6g. Ester 6k and
amides 6l and 6m were prepared from the carboxylic acid 6j
as illustrated in Scheme 2. The Boc protecting group of the
4-pyridin-2-ylpiperazines 8a, 8d, 8k, and 8m and was removed
with a saturated solution of HCl gas in ethyl acetate, while
trifluoroacetic acid was used for the deprotection of 8o and 8z.
Carbodiimide-assisted esterification of the 5-carboxylic acid 8g
with 2,3,4,5,6-pentafluorophenol gave the ester 8j, which upon
treatment with methylamine yielded the N-methylamide 8k.
Ketone 8m was prepared by treatment of the Weinreb amide 8i
with methylmagnesium bromide. The Boc protecting group of
8v was introduced by treating the piperazine derivative 8u with
Boc anhydride in the presence of 1 N NaOH. Treatment of the
4-pyridin-2-ylpiperazines 8v and 8ae with bromine in dichloro-
methane afforded the corresponding 5-bromo-substituted deriva-
tives 8w and 8af, respectively. Heck olefination of the Boc-
protected 5-bromo derivative 8w with methyl acrylate gave
alkene 8x. Dihydroxylation of the alkene 8x with catalytic
osmium tetroxide and stoichiometric N-methylmorpholine N-
oxide41 gave a glycol intermediate, which subsequently under-
went oxidative C-C cleavage with lead tetraacetate to produce
aldehyde 8y. Reduction of the aldehyde 8y with sodium
borohydride afforded the 5-hydroxymethyl derivative 8z.
a R1 ) H; X, Y, P, and Q ) C or N. bConditions: (a) N,N-
diisopropylethylamine, CH3CN, 180 °C, microwave; (b) N,N-diisopropyl-
ethylamine, DMSO, 80 °C; (c) Et3N, CuI, 3-methyl-1-butanol, 220 °C,
microwave; (d) N,N-diisopropylethylamine, dioxane, 190 °C, microwave;
(e) NaHCO3, 3-methyl-1-butanol, 150 °C, microwave; (f) N,N-diisopropyl-
ethylamine, 250 °C, microwave; (g) K2CO3, Cu powder, DMF, 120 °C.
in animal models of chronic pain, it has shown poor metabolic
stability, a short half-life, poor aqueous solubility, and moderate
oral bioavailability.36
As a continuation of our efforts to identify novel TRPV1
antagonists with improved bioavailability, we have investigated
conformationally constrained analogues of BCTC. We have
found that the rigidified analogue 5 (Figure 1), designed by the
isosteric replacement of the amide bond of BCTC (4) with an
imidazole ring,37 behaved as a relatively potent TRPV1 antago-
nist. Herein, we describe the synthesis and biological activity
of a series of 2-(4-pyridin-2-ylpiperazin-1-yl)-1H-benzo[d]-
imidazoles of type 5 as novel TRPV1 class of antagonists based
on constrained analogues of BCTC (Figure 1). Recently, we
were the first to disclose this novel 2-piperazin-1-yl-1H-
benzimidazole template in a patent application.38,39 In this paper,
we include an extensive SAR data set, which provides insights
into the binding mode of this novel class of TRPV1 antagonists.
For the purposes of our study, we employed rat TRPV1
channel recombinantly expressed in Chinese hamster ovary
(CHO) cells. The ability of compounds to inhibit both the
capsaicin- and pH-mediated influx of 45Ca2+ was examined. This
investigation provided an understanding of the SAR of this class
of compounds, resulting in the discovery of a potent new TRPV1
antagonist (e.g., compound 46ad) with good oral bioavailability
and in vivo activity in animal models of pain.
Additional piperazine building blocks of type I were prepared
as shown in Scheme 3. Under microwave irradiation, (R)-2-
methylpiperazine (7b) was coupled with the 2-chloropyridine
6b to give the corresponding mixture of products of N-arylation
9 and 8q (Scheme 3). Separation of the mixture by column
chromatography gave access to pure 9, which was formed by
arylation of the more hindered nitrogen atom of the piperazine
7b. The 4-chloro-substituted pyridines 10a and 10b were
coupled with N-Boc-protected piperazine (7d) in the presence
of base to give the 1-pyridin-4-ylpiperazines 11a and 11c,
respectively. The 6-chloropyrimidine 10c42 was reacted with 7d
in an analogous manner to produce 4-piperazin-1-ylpyrimidine
11e. The Boc protecting group of 4-pyridin-4-ylpiperazine 11a
was cleaved with trifluoroacetic acid, while in the case of 11c
and 11e the deprotection was achieved with a saturated solution
of HCl gas in ethyl acetate. Finally, condensing the aniline 12
with bis(2-chloroethyl)amine hydrochloride (13) under micro-
wave irradiation without any solvent43 gave rise to the 1-phenyl-
piperazine 14.
The piperazines used in the preparation of the N-aryl- and
N-heteroarylpiperazines of type I (Schemes 1-3) and 2-piper-
azinyl-1H-benzimidazoles of type V (Schemes 1 and 7) were
commercially available or were synthesized according to the
methods shown in Scheme 4. Coupling of the N-Fmoc protected
amino acids 15a and 15b with glycine methyl ester in the
presence of PS-carbodiimide furnished amides 16a and 16b,
which underwent intramolecular cyclization after treatment with
piperidine to give the corresponding diketopiperazines 17a
and 17b. Subsequent reduction of 17a and 17b with LiAlH4
gave the target 2-alkyl-substituted piperazines 7e and 7f,
respectively.
Chemistry
The majority of the compounds required for our SAR study,
represented by structure III, were prepared by two general routes
(methods A and B, Scheme 1). In method A, N-aryl- and
N-heteroarylpiperazines of type I were coupled with 2-chloro-
1H-benzimidazoles and related heterocycles of type II by
heating under conventional or microwave-assisted conditions
in the presence of a base. A similar type of N-arylation reaction
is utilized in method B, where chloro-heteroaromatic compounds
of type IV were coupled with 2-piperazinyl-1H-benzimidazoles
of type V.
Scheme 5 describes the preparation of 2-chloro-1H-benz-
imidazoles of type II required for the synthesis of the TRPV1
antagonists by general method A, Scheme 1. The 1,2-diamino-
arenes 18a-n were converted into the 2-chloro-1H-benz-
imidazoles 20a-o via the imidazolones 19a-o. 1,1′-Carbonyl-
diimidazole was used as carbonylating reagent for the prepara-
tion of imidazolones 19a-d, 19f-h, and 19j-o, while in the
case of 19e N,N-disuccinimidyl carbonate was employed. The
4-aryl-substituted imidazolone 19i was prepared by microwave-
assisted Suzuki arylation of the 4-bromobenzimidazolone 19f.
Schemes 2 and 3 detail the synthesis of the piperazine
building blocks of type I that were employed in general
method A. For example, the mono- and disubstituted 2-chloro-
pyridines 6a-n were coupled with unprotected and Boc-
protected piperazines 7a-f in the presence of a tertiary amine
and K2CO3 or NaHCO3 to give 1-pyridin-2-ylpiperazines 8a,
8c,d, 8f-i, 8o, 8q-u, 8ab-8ae, and 8ag, respectively. The
2-chloropyridines 6a-g and 6j were obtained from commercial
sources, and 6n was prepared according to the method of Koch
and Schnatterer,40 while the aldehyde 6h and the alcohol 6i were

Piperazinylbenzimidazoles as TRPV1 antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12 3721
Scheme 2a
a Conditions: (a) for 8a, 8g, 8h, 8i, 8o, 8s-u, and 8ag, Cu-powder, K2CO3, DMF, 120 °C; for 8c, 8d, 8f, 8q, 8r, 8ad, and 8ae, N,N-diisopropylethylamine,
NMP, 240 °C, microwave; for 8ab and 8ac, NaHCO3, 3-methylbutan-1-ol, 170 °C, microwave; (b) MnO2, 1:1 CH2Cl2/hexane, 20 °C; (c) 3 M MeMgBr in
Et2O, THF, 20 °C; (d) p-TsOH, MeOH, reflux; (e) (1) (COCl)2, DMF, 20 °C; (2) 28% NH4OH, 20 °C; (f) (1) (COCl)2, DMF, 20 °C; (2) CH3ONHCH3‚HCl,
10% K2CO3, CH2Cl2, 20 °C; (g) sat. solution of HCl in EtOAc, 20 °C; (h) 2,3,4,5,6-pentafluorophenol, 1,3-dicyclohexylcarbodiimide, EtOAc, 20 °C; (i) 2
M MeNH2 in THF, 20 °C; (j) TFA, CH2Cl2, 20 °C; (k) O(COO-t-Bu)2, 1 N NaOH, THF, 20 °C; (l) Br2, CH2Cl2, 20 °C; (m) CH2dCHCO2Me, Pd(OAc)2,
benzyltriethylammonium chloride, DMF, 40 °C; (n) (1) 4% OsO4 in H2O, N-methylmorpholine N-oxide, acetone, 20 °C; (2) Pb(OAc)4, CH2Cl2, 20 °C; (o)
NaBH4, MeOH, 0 °C;
Scheme 3a
a Conditions: (a) N,N-diisopropylethylamine, NMP, 240 °C, microwave; (b) Cu-powder, K2CO3, DMF, 120 °C; (c) TFA, CH2Cl2, 20 °C; (d) sat. solution
of HCl in EtOAc, 20 °C; (e) (1) 200 °C, microwave; (2) 1 N NaOH.
Finally, chlorination of the benzimidazolones 19a-o with
phosphorus oxychloride provided the necessary 2-chloro-1H-
benzimidazole intermediates 20a-o.
The 1,2-diaminoarenes 18b-e used in the preparation of the
2-chloro-1H-benzimidazoles 20b-e were synthesized according
to the reactions illustrated in Scheme 6. Acetylation of aniline

3722 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12
OgnyanoV et al.
Scheme 4a
a Conditions: (a) MeO2CCH2NH2‚HCl, 1-hydroxy-7-azabenzotriazole, N,N-diisopropylethylamine, PS-carbodiimide, CH2Cl2, 20 °C; (b) piperidine, CH2Cl2,
20 °C; (c) LiAlH4, THF, reflux.
Scheme 5a,b
a X and Y ) C or N. bConditions: (a) for 19a-d, 19f-h, 19j-o, 1,1′-carbonyldiimidazole, THF, 20 °C; for 19e, N,N-disuccinimidyl carbonate, MeCN,
75 °C; (b) 3,4,5-trifluorophenylboronic acid, PdCl2(PPh3)2, Na2CO3, MeO(CH2)2OMe, H2O, EtOH, 120 °C, microwave; (c) POCl3, 95 °C.
21 gave the N-acetylaniline 22, which was nitrated at the less
hindered ortho-position with a mixture of concentrated nitric
acid and concentrated sulfuric acid to give nitro derivative 23.
Subsequent hydrolysis of the N-acetyl group and reduction of
the nitro group of 23 with tin(II) chloride dihydrate afforded
the desired 1,2-diaminobenzene 18b. Partial palladium-catalyzed
hydrogenation of the symmetrical 2,6-dinitroaniline derivative
25 gave the nitro-substituted 1,2-diaminobenzene 18c. Nitration
of 2-aminopyridine 26 ortho to the amino group gave 27, which
was then reduced with tin(II) chloride dihydrate to form the
2,3-diaminopyridine 18d. The amino group at position 2 of the
regioisomeric 2,3-diaminopyridine 18e was introduced by
amination of the 2-chloropyridine 28 with 4-methoxybenzyl-
amine under microwave irradiation, followed by debenzylation
using trifluoroacetic acid.
Scheme 7 shows the preparation of 2-piperazinyl-1H-benz-
imidazoles building blocks of type V used in the synthesis of
TRPV1 antagonists via general method B (Scheme 1). Com-
pounds 30a and 30b were prepared by microwave-assisted
coupling of the piperazines 7a and 7c with the 2-chlorobenz-
imidazoles 20n and 20i, respectively.
Schemes 8-11 illustrate the synthesis of the TRPV1 antago-
nists that were prepared by modification of the substituents of
2-piperazin-1-yl-1H-benzimidazoles of type III. The starting
benzimidazoles used in Schemes 8-11 (31a,b, 33, 35, 37a,b,
39, 42, 43a, 44a,c, and 45) were synthesized by method A or
method B described in Scheme 1. Scheme 8 describes modifica-
tion of the substituents of 2-piperazin-1-yl-1H-benzimidazoles
by reactions involving nitro group transformations. The nitro
groups of 31a and 31b were reduced by palladium-catalyzed
hydrogenation to give the corresponding amines 32a and 32b,
while the nitro group of the bromo derivative 33 was reduced
with tin(II) chloride dihydrate to afford amine 34. Several
additional 2-piperazin-1-yl-1H-benzimidazoles were prepared
by reactions involving the amino group of 32a and 32b. For
example, reductive alkylation of 32a and 32b with aldehydes
was utilized to produce 32c, 32f, and 32g, while acylation of
32b with cyclohexanecarboxylic acid and di-tert-butyl dicar-
bonate afforded 32d and 32e, respectively.
Scheme 9 lists modifications based on reactions involving a
carbonyl group on the 5′-position of the pyridine ring. The
aldehyde 36 was obtained by oxidation of the hydroxymethyl
derivative 35 with activated manganese(IV) oxide. The car-
boxylic acid 38a was prepared by saponification of the ester
37a. Grignard addition of methylmagnesium bromide and
phenylmagnesium bromide to the carbonyl group of the alde-
hyde 36 gave the secondary alcohols 38c and 38d, respectively.
Alternatively, reduction of the ketone 37b with sodium boro-
hydride in methanol gave the corresponding secondary alcohol
38b.

Piperazinylbenzimidazoles as TRPV1 antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12 3723
Scheme 6a
a Conditions: (a) Ac2O, 20 °C; (b) concd HNO3, concd H2SO4, 0-20 °C; (c) 3 N NaOH, MeOH, 90 °C; (d) SnCl2‚H2O, EtOAc, EtOH, 70 °C; (e) H2,
10% Pd/C, EtOH, 20 °C; (f) 4-methoxybenzylamine, NaHCO3, 3-methyl-1-butanol, 220 °C, microwave; (g) TFA, CH2Cl2, 20 °C.
Scheme 7a
a Conditions: (a) for 30a, DMSO, 80 °C; for 30b, N,N-diisopropylethylamine, MeCN, 180 °C, microwave.
N-substituted benzimidazole derivatives were also prepared
(Scheme 10). For instance, treatment of the sodium salt of the
benzimidazole 39 with benzyl bromide gave the isomeric
mixture of 40 and 41, which was separated by column
chromatography. The regiochemical assignment for compounds
40 and 41 was confirmed on the basis of 2D-NOESY NMR
analysis.
Scheme 11 describes the preparation of 2-piperazin-1-yl-1H-
benzimidazoles by reactions involving bromo-functionalized
analogues. For example, Suzuki coupling of the aryl bromides
42, 34, and 43a with various arylboronic acids under conven-
tional heating or microwave irradiation gave the arylated
analogues 46a, 46e, and 46m, respectively. Analogously, Suzuki
coupling of 44a with various arylboronic acids gave the arylated
analogues 46b, 46q-v, and 46x-ab. Amine 46e was acylated
with acetoxyacetic acid in the presence of benzotriazol-1-
yloxytris(dimethylamino)phosphonium hexafluorophosphate and
N,N-diisopropylethylamine and subsequently hydrolyzed with
potassium carbonate in methanol to give the hydroxyacetylamino
derivative 46f. Arylation of the bromo-functionalized dia-
stereomeric mixture of secondary alcohols 44c with 3,4,5-
trifluorophenylboronic acid gave the mixture of the diastereo-
isomers 46k and 46l, which were next separated by preparative
HPLC. The configuration of each isomer at the chiral center of
the 1-hydroxyethyl substituent was assigned at random. To
prepare the 4-trifluoromethylcyclohexyl analogue 46p, the aryl
bromide 44a was treated with 4,4,5,5-tetramethyl-2-(4-tri-
fluoromethylcyclohex-1-enyl)[1,3,2]dioxaborolane to give 4-tri-
fluoromethylcyclohex-1-enyl intermediate, which was reduced
by palladium-catalyzed hydrogenation.
Several other derivatives were prepared by using organotin
and organozinc cross-coupling reactions. For example, Stille
coupling of the aryl bromides 44a and 45 with 2-tributyl-
stannylthiazole and tributylvinyltin in the presence of tetrakis-
(triphenylphosphine)palladium(0) as catalyst provided the thi-
azolyl analogue 46n and the vinyl analogue 46ac, respectively.
Further dihydroxylation of the vinyl analogue 46ac with catalytic
osmium tetraoxide and stoichiometric N-methylmorpholine
N-oxide41 gave glycol 46ad as a mixture of diastereoisomers.
Analogously, Stille coupling of 44a with 2-tributylstannyl-
pyrazine gave the pyrazine analogue 46w. Negishi coupling of
44a with 3,4-difluorobenzylzinc bromide furnished the 3,4-
difluorobenzyl analogue 46o. Selected bromo-substituted 2-pip-
erazin-1-yl-1H-benzimidazoles of type III were also employed
in Buchwald amination reactions. For example, N-alkylation of
43a with 2-(trimethylsilyl)ethoxymethyl chloride in the presence
of base provided the N-protected benzimidazole 43b. Subsequent
microwave irradiation of 43b with 4-(trifluoromethyl)benzyl-

3724 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12
OgnyanoV et al.
Scheme 8a
a Conditions: (a) H2, 10% Pd/C, EtOH, 20 °C; (b) 3,4,5-trifluorobenzaldehyde, NaBH(OAc)3, CHCl3, 20 °C; (c) O(COO-t-Bu)2, 1 N NaOH, THF, 20 °C;
(d) cyclohexanecarboxylic acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide‚HCl, CH2Cl2, 20 °C; (e) PhCH2CHO, NaBH(OAc)3, CHCl3, 20 °C; (f)
SnCl2‚H2O, DMF, 80 °C.
Scheme 9a
a
Conditions: (a) MnO2, CH2Cl2, 20 °C; (b) for 38a, (1) 1 N NaOH, THF, 50 °C; (2) 1 N HCl, 20 °C; for 38b, NaBH4, MeOH, 0 °C; for 38c, CH3MgBr,
THF, 0 °C; for 38d, C6H5MgBr, THF, 0 °C.
Scheme 10a
a Conditions: (a) (1) 50% NaH in mineral oil, DMF, 0-20 °C; (2) C6H5CH2Br, 0 to 20 °C; (3) separation by column chromatography.
amine in the presence of sodium tert-butoxide, tris(dibenzyl-
ideneacetone)dipalladium(0) as catalyst and 2-(di-tert-butylphos-
phino)biphenyl as phosphine ligand gave the benzylamine
derivative 46c. The target compound 46d was obtained after
cleavage of the 2-(trimethylsilyl)ethoxymethyl protective groups
of 46g with trifluoroacetic acid. The analogous Buchwald
amination reaction of the N-protected 44b with piperidine and
morpholine gave the corresponding piperidine derivative 46g
and the morpholine derivative 46i. Next, cleavage of the
protective group gave the target compounds 46h and 46j.

Piperazinylbenzimidazoles as TRPV1 antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12 3725
Scheme 11a
a Conditions: (a) for 46a, 42, 3,4-difluorophenylboronic acid, Pd(PPh3)4, 2 M Na2CO3, LiCl, MeO(CH2)2OMe, H2O, EtOH, 80 °C; for 46b, 43a,
4-trifluoromethylphenylboronic acid, Pd(PPh3)4, 2 M Na2CO3, dioxane, 170 °C, microwave; for 46c, 43b, 4-CF3C6H4CH2NH2, tris(dibenzylideneacetone)-
dipalladium(0), 2-(di-tert-butylphosphino)biphenyl, t-BuONa, toluene, 150 °C, microwave; for 46e, 34, 4-fluorophenylboronic acid, Pd(PPh3)2Cl2, Na2CO3,
dimethoxyethane, H2O, EtOH, 82 °C; for 46g, 44b, piperidine, tris(dibenzylideneacetone)dipalladium(0), 2-(di-tert-butylphosphino)biphenyl, t-BuONa, toluene,
150 °C, microwave; for 46i, 44b, morpholine, tris(dibenzylideneacetone)dipalladium(0), 2-(di-tert-butylphosphino)biphenyl, t-BuONa, toluene, 150 °C,
microwave; for 46k and 46l, 44c, (1) 3,4,5-trifluorophenylboronic acid, Pd(PPh3)4, 0.4 M Na2CO3, MeCN, 90 °C, (2) separation of diastereoisomers by prep.
HPLC; for 46m, 44a, 3,4,5-trifluorophenylboronic acid, Pd(PPh3)4, 2 M Na2CO3, dioxane, 170 °C, microwave; for 46n, 44a, 2-tributylstannylthiazole,
Pd(PPh3)4, dioxane, 140 °C, microwave; for 46o, 44a, 0.5 M 3,4-difluorobenzylzinc bromide, Pd(PPh3)4, THF, reflux; for 46p, 44a, (1) 4,4,5,5-tetramethyl-
2-(4-trifluoromethylcyclohex-1-enyl)[1,3,2]dioxaborolane, Pd(PPh3)4, Na2CO3, MeO(CH2)2OMe, 200 °C, microwave; (2) H2, 10% Pd/C, EtOH, 20 °C; for
46q, 44a, 4-trifluoromethylphenylboronic acid, Pd(PPh3)4, 2 M Na2CO3, LiCl, MeO(CH2)2OMe, H2O, EtOH, 80 °C; for 46r, 44a, phenylboronic acid,
Pd(PPh3)4, 2 M Na2CO3, LiCl, MeO(CH2)2OMe, H2O, EtOH, 80 °C; for 46s, 44a, 3-trifluoromethoxyphenylboronic acid, Pd(PPh3)2Cl2, Na2CO3,
dimethoxyethane, H2O, EtOH, 82 °C; for 46t, 44a, 4-tert-butylphenylboronic acid, Pd(PPh3)2Cl2, Na2CO3, dimethoxyethane, H2O, EtOH, 82 °C; for 46u,
44a, thiophen-2-ylboronic acid, Pd(PPh3)2Cl2, Na2CO3, dimethoxyethane, H2O, EtOH, 82 °C; for 46v, 44a, pyridin-4-ylboronic acid, Pd(PPh3)2Cl2, Na2CO3,
dimethoxyethane, H2O, EtOH, 82 °C; for 46w, 44a, 2-tributylstannylpyrazine, Pd(PPh3)4, dioxane, 140 °C, microwave; for 46x, 44a, 3-(6-methoxypyridyl)boronic
acid, Pd(PPh3)2Cl2, Na2CO3, dimethoxyethane, H2O, EtOH, 82 °C; for 46y, 44a, benzo[b]thiophen-2-ylboronic acid, Pd(PPh3)2Cl2, Na2CO3, dimethoxyethane,
H2O, EtOH, 82 °C; for 46z, 44a, 4-aminophenylboronic acid, Pd(PPh3)2Cl2, Na2CO3, dimethoxyethane, H2O, EtOH, 82 °C; for 46aa, 44a, 4-dimethylamino-
phenylboronic acid, Pd(PPh3)2Cl2, Na2CO3, dimethoxyethane, H2O, EtOH, 82 °C; for 46ab, 44a, trans-2-phenylvinylboronic acid, Pd(PPh3)2Cl2, Na2CO3,
dimethoxyethane, H2O, EtOH, 82 °C; for 46ac, 45, CH2dCHSnBu3, Pd(Ph3P)4, 3,5-di-tert-butylphenol, LiCl, dioxane, 95 °C; (b) 2-(trimethylsilyl)ethoxy-
methyl chloride, N,N-diisopropylethylamine, CH2Cl2, 20 °C; (c) TFA, CH2Cl2, 20 °C; (d) (1) CH3CO2CH2CO2H, benzotriazol-1-yloxytris(dimethyl-
amino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, CH2Cl2, 20 °C; (2) K2CO3, MeOH, 20 °C; (e) 4-methylmorpholine N-oxide, OsO4,
acetone, 20 °C.

3726 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12
OgnyanoV et al.
Table 1. Inhibition of 45Ca2+ Influx: BCTC (4) and Its Constrained
Analogue (5)
Table 2. Inhibition of 45Ca2+ Influx: Substituents on the Benzimidazole
Ring
IC50 (nM)
capsaicin
entry
R1
R2
R7
Cl
stimulus
pH stimulus
Results and Discussion
5
47a
39
47b
47e
47f
46a
47c
47d
42
H
H
H
H
H
H
H
H
H
H
t-Bu
t-Bu
CF3
CH3
CN
87 ( 18
310 ( 117
282 ( 53
301 ( 84
>4000
>4000
>4000
351 ( 34
>4000
The compounds were tested for their ability to block the
capsaicin- or acid-induced (pH 5) uptake of 45Ca2+ in CHO cells
expressing rat TRPV1. Functional activity is reported as IC50
(nM) in Tables 1-7. All compounds reported herein behaved
as antagonists.44 Results are the average of at least two
independent experiments with three replicates at each concentra-
tion.
Conformationaly constrained analogues of BCTC (4) could
be generated by incorporating the carboxanilide function into a
five-membered heterocyclic ring fused with the adjacent aro-
matic ring. For example, our initial results showed that isosteric
replacement of the carboxanilide function of BCTC (4) with a
benzimidazole ring system gave the constrained analogue 5 with
an IC50 value of 87 nM in the capsaicin-mediated assay and
310 nM in the pH-mediated assay (Table 1).
Since the constrained analogue 5 displayed reasonable
potency as TRPV1 antagonist, we decided to do a detailed
structure-activity relationship (SAR) investigation of 5 in order
to provide an understanding of the structural features that
influence the functional activity of this novel template. Our
initial strategy was to prepare analogues of 5 by stepwise
introduction of various substituents on the benzimidazole (Tables
2 and 3), the piperazine (Table 5), and the pyridine (Table 6)
rings of the 2-(4-pyridin-2-ylpiperazin-1-yl)-1H-benzo[d]imid-
azole template of 5. In addition, several analogues of 5 having
modified benzimidazole and pyridine rings were also prepared
(Tables 4 and 7, respectively). The results from this initial SAR
were used next in the design of a set of analogues by combining
the optimum substituents on all preferred sites of the template
of 5 (Table 8).
CF3 183 ( 24
CF3 110 ( 22
CF3 3350 ( 330
CF3 3300 ( 160
CF3 1230 ( 380
CO2CH3
3,4-difluoro-Ph CF3 1140 ( 260
F
Cl
Br
CF3 >4000
CF3 1130 ( 96
CF3 123 ( 13
CF3 577 ( 65
17250 ( 830
194 ( 58
157 ( 11
40
41
CH2Ph CF3
CH2Ph CF3
CF3 6480 ( 1180 151 ( 6
benzimidazole ring of 39 with the electron-donating methyl
group resulted in dramatic reduction of potency in both assays
(compound 47b). A similar decrease of antagonistic activity in
both assays was observed for the nitrile 47e, while ester 47f
was 11-fold less active in the caspsaicin-mediated assay but
remained inactive in the pH-mediated assay. In contrast, the
potency of the 3,4-difluorophenyl substituted 46a was similar
to that of 47f in the capsaicin assay but retained the activity of
39 in the pH assay. When the substituent R2 of the benz-
imidazole ring was halogen, the potency in the capsaicin-
mediated assay improved upon increasing of the size of the
halogen atom (i.e., F (47c) , Cl (47d) < Br (42)). The activity
of the bromo-substituted derivative 42 was comparable to that
of the trifluoromethyl derivative 39.
The effect of substituting the nitrogen atom of the benz-
imidazole ring was also investigated. N-Alkylation of the
analogue 39 with benzyl bromide gave the corresponding
isomeric products 40 and 41. The N-benzyl isomer 40 was 5-fold
less potent (IC50 ) 577 nM) in the capsaicin-mediated assay in
comparison with 39. In the case of the isomer 41, the decrease
of the potency in the capsaicin-mediated assay was more
pronounced (IC50 ) 6480 nM). In contrast, a 2-fold potency
increase was observed for both isomers in the pH-mediated
assay.
As exemplified by compound 47a in Table 2, replacement
of the chlorine substituent of the pyridine ring of 5 with a
trifluoromethyl group led to 2-fold potency decrease (IC50
)
183 nM) in the capsaicin-activated uptake assay and almost
unchanged potency (IC50 ) 282 nM) in the pH-mediated assay.
Due to the relatively similar potencies of the chloro analogue 5
and the trifluoromethyl analogue 47a, the remaining compounds
listed in Table 2 retained the trifluoromethyl substituent on the
pyridine ring (R7 ) CF3) and differed by the nature of the
substituents R1 and R2 on the benzimidazole ring. The potency
in the capsaicin-induced Ca2+ uptake assay was nearly restored
(IC50 ) 110 nM) when the tert-butyl substituent of the
benzimidazole ring of 47a was replaced with the strongly
electron-withdrawing trifluoromethyl group to provide the
analogue 39. Replacement of the trifluoromethyl group of the
In summary, the influence of the steric effects of the
substituents R2 on the potency of the TRPV1 antagonists in
Table 2 was more pronounced than the electronic effects, with
trifluoromethyl, bromo, and tert-butyl groups being the optimal
substituents. N-Alkylation of the benzimidazole ring was
detrimental to activity in the capsaicin-mediated assay, sug-
gesting certain steric limitations and/or specific requirement for
hydrogen-bond-donor interactions with binding site of the
receptor.
The compounds shown in Table 3 were prepared to inves-
tigate the influence of introducing additional substituents at the

Piperazinylbenzimidazoles as TRPV1 antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12 3727
Table 3. Inhibition of 45Ca2+ Influx: Substituents on the Phenyl Ring
Table 4. Inhibition of 45Ca2+ Influx: Variations to the Benzimidazole
of the Benzimidazole Ring
Ring
IC50 (nM)
IC50 (nM)
capsaicin
stimulus
pH
stimulus
capsaicin
stimulus
pH
entry
X
Y
entry
R3
stimulus
39
49a
49b
C
N
C
C
C
N
110 ( 22
301 ( 14
884 ( 560
1410 ( 58
39
H
5-Br
5-(4-CF3-Ph)
110 ( 22
166 ( 16
8240 ( 13
94 ( 9
301 ( 14
43 ( 2
201 ( 41
141 ( 26
74 ( 13
1,550 ( 65
1,090 ( 580
43a
46b
46d
44a
31a
32a
48
5-[NHCH2(4-CF3-Ph)]
4-Br
131 ( 12
(IC50 ) 26 nM), and the 4-tert-butylphenyl analogue 46t (IC50
) 13 nM). In the case of 46r, the lack of substitution of the
phenyl ring resulted in a decrease of potency (IC50 ) 141 nM)
in the capsaicin-mediated assay, in comparison with the
substituted phenyl analogues (46q, 46m, 46s, and 46t). Various
five-membered aromatic heterocycles (i.e., thiophene derivative
46u and thiazol derivative 46n) and six-membered aromatic
heterocycles (i.e., pyridine and pyrazine derivatives 46v-x) were
also tolerated at position 4 of the benzimidazole ring; however,
their potencies in the capsaicin-mediated assay were almost
equal or up to 5-fold lower than the potency of the corresponding
phenyl analogue 46r. The addition of a fused benzene ring to
the thiophene heterocycle of 46u (IC50 ) 373 nM) resulted in
the fused bicyclic analogue 46y (IC50 ) 26 nM) and a 14-fold
increase of potency in the capsaicin-mediated assay. We found
that saturated six-membered heterocycles such as the 1-piperidyl
group of analogue 46h and the morpholin-4-yl group of analogue
46j were well-tolerated. Saturation of the phenyl ring of the
4-(trifluoromethyl)phenyl analogue 46q (IC50 ) 51 nM) gave
the 4-(trifluoromethyl)cyclohex-1-yl derivative 46p, which was
the most potent 4-substituted compound shown in Table 3 with
IC50’s of 10 and 9 nM in the capsaicin-mediated and the pH-
mediated assays, respectively. Introduction of amino group at
para-position of the phenyl ring of 46r gave the 12-fold less
potent derivative 46z (IC50 ) 1900 nM) in the capsaicin-
mediated assay; however, the potency was almost restored in
the case of the bulkier dimethylaminophenyl derivative 46aa.
4-NO2
4-NH2
4-CF3
4-(4-CF3-Ph)
1660 ( 120 878 ( 35
3380 ( NA >4000
325 ( 21
51 ( 6
120 ( 11
37 ( 3
46q
46m 4-(3,4,5-trifluoro-Ph)
46s
46t
33 ( 8
26 ( 12
21 ( 20
4 ( 1
4-(3-CF3O-Ph)
4-(4-tert-butyl-Ph)
4-Ph
26 ( 14
13 ( 5
46r
46u
46n
46v
46w
46x
46y
46h
46j
141 ( 11
373 ( 92
688 ( 78
267 ( 23
129 ( 32
111 ( 15
26 ( 4
68 ( 27
221 ( 44
454 ( 63
188 ( 138
51 ( 20
99 ( 19
22 ( 0.6
21 ( 1
4-thiophen-2-yl
4-thiazol-2-yl
4-pyrid-4-yl
4-pyrazin-2-yl
4-[3-(6-methoxypyridyl)]
4-benzo[b]thiophen-2-yl
4-piperid-1-yl
29 ( 7
50 ( 2
4-morpholinyl
95 ( 11
9 ( 0.2
308 ( 14
69 ( 19
52 ( 10
140 ( 12
81 ( 8
46p
46z
4-[4-(trifluoromethyl)cyclohex-1-yl] 10 ( 3
4-(4-amino-Ph)
1900 ( 1
46aa 4-(4-(dimethylamino)-Ph)
46o 4-[CH2(3,4-difluoro-Ph)]
46ab 4-(CHdCH-Ph)
32c 4-[NHCH2(3,4,5-trifluoro-Ph)
108 ( 8
71 ( 11
185 ( 81
132 ( 9
4- and 5-positions of the benzimidazole ring of the trifluoro-
methyl analogue 39. We found that the introduction of additional
substituents at position 5 of the benzimidazole ring seemed to
provide limited benefits. For example, substitution of position
5 of 39 with a bromine atom gave the analogue 43a. This
substitution led to a 1.5-fold decrease of potency in the
capsaicin-mediated assay and a 7-fold increase in the pH-
mediated assay. Introduction of the bulkier (4-trifluoromethyl)-
phenyl group (i.e., 46b) resulted in additional loss of potency
in the capsaicin-mediated assay, relative to 43a; however, the
potency was restored to that of 39 when the (4-trifluoromethyl)-
phenyl group was attached to position 5 via a -NHCH2- linker
(i.e., 46d).
Several analogues having aryl substituents linked via a linker
group to position 4 of the benzimidazole ring were prepared.
For example, the analogue 46o having a -CH2- linker blocked
the uptake of 45Ca2+ with an IC50 of 71 nM in the capsaicin-
mediated assay and with IC50 of 52 nM in the pH-mediated
assay. In the case of the styryl analogue 46ab, the potency in
The introduction of substituents at position 4 of the trifluoro-
methyl analogue 39 initially did not look promising. For
example, the 4-bromo derivative 44a was nearly equipotent with
the 5-bromo derivative 43a. The 4-nitro derivative 31a was
approximately 13-fold less potent, and the 4-amino derivative
32a was 26-fold less potent than the corresponding bromo
derivative 44a in the capsaicin-mediated assay, while the
trifluoromethyl analogue 48 was approximately 2-fold less
potent. We observed dramatic increase in potency (161-fold,
IC50 ) 51 nM) in the capsaicin-mediated assay, and a 5-fold
increase (IC50 ) 37 nM) in the pH-mediated assay when the
(4-trifluoromethyl)phenyl group was transferred from position
5 (i.e., 46b) to position 4 (i.e., 46q) of the benzimidazole ring.
This promising result prompted us to prepare an additional
number of analogues substituted at position 4.
the capsaicin-mediated assay was almost unchanged (IC50
)
185 nM) in comparison with the potency of the phenyl analogue
46r (IC50 ) 141 nM). However, introduction of a -NHCH2-
linker between the 3,4,5-trifluorophenyl group and the benz-
imidazole ring of 46m (IC50 ) 33 nM) gave the analogue 32c,
which was found to be 4-fold less potent (IC50 ) 132 nM) in
the capsaicin-mediated assay.
In summary, the preliminary SAR observed for the com-
pounds listed in Table 3 revealed the existence of a relatively
large hydrophobic pocket in the TRPV1 receptor, since intro-
duction of bulky lipophilic groups at position 4 of the benz-
imidazole ring gave TRPV1 antagonists with improved or
retained potency, compared to compound 39. Attachment of
similar hydrophobic substituents at position 5 was less favorable
(i.e., compound 46b). However the potency could be improved
when the bulky hydrophobic group was attached via a -NHCH2-
linker (i.e., analogue 46d). Presumably, the addition of this linker
Further improvement of the potency in the capsaicin-mediated
assay was observed for the 3,4,5-trifluorophenyl analogue 46m
(IC50 ) 33 nM), the (3-trifluoromethoxy)phenyl analogue 46s

3728 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12
OgnyanoV et al.
Table 5. Inhibition of 45Ca2+ Influx: Substituents on the Piperazine Ring
IC50 (nM)
capsaicin
stimulus
pH
stimulus
entry
R3
R4
R5
R7
39
H
H
H
H
H
H
H
H
H
H
H
CF3
CF3
CF3
CF3
Br
Br
Br
Br
110 ( 22
48 ( 8
648 ( 39
3230 ( 130
6.7 ( 5
104 ( 11
4.3 ( 2
767 ( 693
301 ( 14
35 ( 9
50a
50b
50c
51a
51b
51c
51d
(R)-CH3
(R)-CH2CH3
(R)-CH2CH2CH3
(R)-CH3
(S)-CH3
H
>4000
>4000
2.6 ( 2
75 ( 5
1.8 ( 0.3
254 ( 17
4-(3,4,5-trifluoro-Ph)
4-(3,4,5-trifluoro-Ph)
4-(3,4,5-trifluoro-Ph)
4-(3,4,5-trifluoro-Ph)
(R)-CH3
(S)-CH3
H
Table 6. Inhibition of 45Ca2+ Influx: Substituents on the Pyridine Ring
allows the hydrophobic group of 46d to reach the space occupied
by the substituents at position 4.
Next we examined modifications to the benzimidazole ring.
As shown in Table 4, replacement of the phenyl ring of the
benzimidazole analogue 39 with a pyridine ring was detrimental
to activity. For example, the analogue 49a (X ) N; Y ) C)
was 14-fold less potent (IC50 ) 1550 nM), and its isomer 49b
(X ) C; Y ) N) was 10-fold less potent (IC50 ) 1090 nM)
than the parent compound 39 (IC50 ) 110 nM) in the capsaicin-
mediated assay. Similar reductions of potencies in the pH-
mediated assay were also noted.
Table 5 reports the results of substituted piperazine ring
analogues of type III, which carry trifluoromethyl, chloro, or
bromo substituents on the pyridine ring. Analogue 50a, which
was formed by introduction of (R)-methyl group at the carbon
atom of the piperazine ring adjacent to the nitrogen atom
attached to the benzimidazole ring, was 2-fold more potent (IC50
) 48 nM) than the unsubstituted analogue 39 (IC50 ) 110 nM)
in the capsaicin-induced 45Ca2+ uptake assay. The potency of
50a in the pH-mediated assay increased 9-fold (IC50 ) 35 nM)
in comparison to that of the parent compound 39. However,
stepwise elongation of the alkyl substituent of the piperazine
ring (e.g. compounds 50b and 50c) resulted in dramatic decrease
of the activity in the capsaicin-induced 45Ca2+ uptake assay and
loss of potency in the pH-mediated assay, suggesting that methyl
is optimal in terms of length and size. Replacement of the
trifluoromethyl group of the pyridine ring with bromine atom
(R7 ) Br) together with the simultaneous introduction of a (R)-
or (S)-methyl group onto the piperazine ring and the well-
tolerated (3,4,5-trifluoromethyl)phenyl group at position 4 of
the benzimidazole ring gave rise to the potent enantiomers 51a
IC50 (nM)
capsaicin
stimulus
pH
entry
R6
R7
3-CF3
H
4-CF3
H
H
3-Cl
3-I
3-CH3
3-CN
stimulus
39
52a
52b
52c 5-CF3
52d 6-CF3
52e
52f
52g
52h
52i
37b 5-C(dO)CH3
38b (R,S)-5-CH(OH)CH3 3-Cl
52j 5-CH2OH
52k 5-C(dO)NH2
52l 5-C(dO)NHCH3
H
H
H
110 ( 22
301 ( 14
5790 ( 4290 >40000
>5640 ( 58 11930 ( 14660
11290 ( 270 >40000
>40000
>40000
H
H
H
H
H
309 ( 25
221 ( 15
402 ( 117
6290 ( 500
705 ( 165
310 ( 50
1140 ( 580
7080 ( 280
3-CO2C2H5 23780 ( 6800 >40000
3-Cl
581 ( 13
461 ( 43
64 ( 10
430 ( 23
493 ( 58
832 ( 75
652 ( 92
98 ( 14
1000 ( 200
>40000
3-Cl
3-Cl
3-Cl
6). The 3′-trifluoromethyl substituted analogue 39 blocked the
uptake of 45Ca2+ with an IC50 of 110 nM in the capsaicin-
mediated assay and with an IC50 of 301 nM in the pH-mediated
assay, while the unsubstituted at the pyridine ring analogue 52a
was significantly less potent in both assays. The transfer of the
trifluoromethyl group from the 3′-position to the 4′-, 5′-, and
6′-positions of the pyridine ring also gave substantially less
active analogues (i.e., 52b, 52c, and 52d, respectively). These
results indicate that substitution of the pyridine ring is essential
for the potency, and that position 3′ is the optimum site.
Therefore, we focused our attention to 3-substituted analogues.
Unfortunately, modifications of the trifluoromethyl group of the
3′-substituted analogue 39 did not lead to an increase of potency,
as exemplified by the analogues 52e-i.46 The chloro analogue
52e was 3-fold less potent (IC50 ) 309 nM), and the bulkier
and 51b, respectively. The (R)-methyl enantiomer 51a (IC50
)
6.7 nM) was approximately 15-fold more potent than the (S)-
methyl enantiomer 51b (IC50 ) 104 nM) in the capsaicin-
mediated assay and 30-fold more potent in the pH-mediated
assay. This result indicates that R-configuration of the R4
substituent of the piperazine ring is preferred. This stereochem-
ical effect was more pronounced for the enantiomers 51c and
51d, having a methyl group attached to the carbon atom of the
piperazine ring adjacent to the nitrogen atom linked to the
pyridine ring. For example, the (R)-methyl enantiomer 51c (IC50
) 4.3 nM) was found to be 178-fold more potent than the
corresponding (S)-methyl enantiomer 51d (IC50 ) 767 nM) in
the capsaicin-mediated assay.
iodo-substituted analogue 52f was 2-fold less potent (IC50
)
221 nM) than 39 (IC50 ) 110 nM) in the capsaicin-mediated
assay. The methyl analogue 52g (IC50 ) 402 nM) was also
significantly less potent than 39, while a more dramatic
reduction of potency was observed for the cyano- and the
ethoxycarbonyl analogues 52h and 52i, respectively.
The second set of compounds shown in Table 6 was prepared
to study the influence of a second substituent on the pyridine
ring. The 3′-chloro-5′-acetyl derivative 37b was prepared as the
first compound of this series, since we had access to its synthetic
Several analogues were prepared to explore alternative
substitutions on the pyridine ring attached to the core piperazine
ring of the 2-piperazin-1-yl-1H-benzimidazole template (Table

Piperazinylbenzimidazoles as TRPV1 antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12 3729
Table 7. Inhibition of 45Ca2+ Influx: Variations to the Aromatic Ring
parent 2-(3-trifluoromethyl)pyridinyl analogue 39 (IC50 ) 110
nM) in the capsaicin-mediated assay but nearly equipotent in
the pH-mediated assay. Moving the nitrogen atom from the
ortho- to the para-position of the pyridine ring was detrimental
to activity (i.e., the 4-(3-trifluoromethyl)pyridinyl analogue 53b).
This result suggests that the presence of a hydrogen-bond-
accepting nitrogen atom at the ortho-position is important for
the binding with the TRPV1 receptor. This observation is in
agreement with the SAR of the pyridine fragment of the BCTC
series of TRPV1 antagonists reported previously.36 Replacement
of the trifluoromethyl group of 53b with a chlorine atom gave
the slightly less active analogue 53c. However, subsequent
addition of a second chlorine atom to 53c gave the analogue
53d, which showed about a 3-fold increase of potency (IC50
)
1370 nM) in the capsaicin-mediated assay. As exemplified by
the dichlorophenyl analogue 53e, removal of the nitrogen atom
of 53d led to a dramatic loss of potency in the capsaicin-
mediated assay, while the potency in the pH-mediated assay
was increased 2-fold. As might be expected, the pyrimidine
analogue 53f showed 2-fold potency improvement relative to
the pyridine analogue 53c in the capsaicin-mediated assay;
however, this trend did not extend to the pH-mediated assay,
in which 53f showed a dramatic loss of activity.
Finally, the analogues included in Table 8 were prepared to
study the influence of combining the best substituents (see
Tables 2-6) on the core and the flanking moieties of the novel
template of TRPV1 antagonists. The analogues were designed
by maintaining the optimum trifluoromethyl and (R)-methyl
groups for the substituent R2 of the benzimidazole ring and for
the substituent R4 of the piperazine ring, respectively, while
the substituents R3, R6, and R7 were varied. This effort led to
the identification of TRPV1 antagonists with substantially
improved potency. For example, the introduction of the 3,4,5-
trifluorophenyl group at the 4-position of the benzimidazole ring
and the hydroxymethyl group at the 5′-position of the pyridine
ring gave the potent analogue 35. This compound was 34-fold
more potent (IC50 ) 1.4 nM) then the parent 2-(3-trifluoro-
methyl)pyridinyl analogue 50 (IC50 ) 48 nM) in the capsaicin-
mediated assay and 50-fold more potent (IC50 ) 0.7 nM) in
the pH-mediated assay. Similar increases in potencies were also
observed for the analogues 32d-g that retained the hydroxy-
methyl group at R6 and have various bulky hydrophobic groups
as R3. It is worth noting that the bulkier N,N-dibenzylamino-
substituted analogue 32g (IC50 ) 1.9 nM) was approximately
precursor, the 1-(3-chloro-5-acetylpyridin-2-yl)piperazine (8n)
(Scheme 2). Compound 37b was found to be almost 2-fold less
potent (IC50 ) 581 nM) in the capsaicin-mediated assay and
nearly equipotent (IC50 ) 831 nM) to the 5′-unsubstituted
analogue 52e in the pH-mediated assay. This result suggested
that introduction of a second substituent at position 5′ of the
pyridine ring might be tolerated to some extent. Therefore, the
remaining compounds shown in Table 6 were prepared to probe
the influence of additional substituents at position 5′ of the
pyridine ring on the functional activity of the 3′-chloro-
substituted analogue 52e. For example, the potency of the
hydroxyethyl analogue 38b (IC50 ) 461 nM) was about the same
as that of 52e (IC50 ) 309 nM) in the capsaicin-mediated assay.
However, a substantial improvement of the activity of the 3′-
chloro analogue 52e was observed when a hydroxymethyl group
was introduced at position 5′ of the pyridine ring. Compound
52j was 5-fold more potent than 52e in the capsaicin-mediated
assay (IC50 ) 64 nM) and 7-fold more potent in the pH-mediated
assay (IC50 ) 98 nM). On the other hand, the potency of the
chloro analogue 52e was not improved in the case of the 5′-
amides 52k and 52l.
In summary, the SAR for the compounds included in Table
6 showed that position 3′ of the pyridine moiety is the optimum
site for substitution and that a trifluoromethyl group or chlorine
or iodine atoms are the most preferable substituents. Introduction
of a second substituent, preferably a hydroxymethyl group, at
position 5′ of the pyridine ring led to an increase in potency.
Table 7 displays the results of compounds 53a-f, which were
designed to explore the influence of an alternative type of
aromatic group attached to the piperazine ring on the functional
TRPV1 activity. The 2-trifluoromethyl-substituted phenyl ana-
logue 53a (IC50 ) 2060 nM) was 20-fold less potent than the
4-fold more potent than the benzylamino analogue 32f (IC50
)
7 nM), which provides an additional insight on the size of the
hydrophobic pocket of the TRPV1 receptor. Also well-tolerated
was the replacement of the hydroxymethyl group of 35 with
the bulkier (R,S)-[1-(1-hydroxyethyl)] and (R,S)-1-hydroxy-1-
phenylmethyl groups (i.e., 38c and 38d). The diastereoisomers
46k and 46l were prepared and separated to probe the influence
of the configuration of the chiral [1-(1-hydroxyethyl)] substituent
on the antagonistic activity. The isomer 46k was 4-fold more
potent (IC50 ) 0.6 nM) than the isomer 46l (IC50 ) 2.6 nM) in
the capsaicin-mediated assay and almost equipotent in the pH-
mediated assay. Addition of a second hydroxyl group to the
(R,S)-[1-(1-hydroxyethyl)] substituent of 38c gave the (R,S)-
1,2-dihydroxyethyl-substituted diastereomeric mixture 46ad,
which was approximately equipotent with 38c in both assays.
Replacement of the amino group of the analogue 46e (IC50
)
98 nM) with the bulkier hydroxyacetylamino group gave the
analogue 46f (IC50 ) 30 nM) and resulted in 3-fold increase of
the potency in the capsaicin-mediated assay.
These results indicate that relatively large, heteroatom-

3730 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12
OgnyanoV et al.
Table 8. Inhibition of 45Ca2+ Influx: Substituents on the Benzimidazole, Piperazine and Pyridine Rings
IC50 (nM)
capsaicin stimulus
entry
R3
R6
R7
pH stimulus
50
35
H
H
CF3
CF3
Cl
Cl
Cl
48 ( 8
35 ( 9
4-(3,4,5-trifluoro-Ph)
NHCO-cyclohexyl
4-NHCO2-t-Bu
NHCH2-Ph
N(CH2-Ph)2
4-(3,4,5-trifluoro-Ph)
4-(3,4,5-trifluoro-Ph)
4-(3,4,5-trifluoro-Ph)
4-(3,4,5-trifluoro-Ph)
4-(3,4,5-trifluoro-Ph)
4-(4-F-Ph)
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
(R,S)-CH(OH)CH3
(R,S)-CH(OH)Ph
(R)-CH(OH)CH3
(S)-CH(OH)CH3
(R,S)-CH(OH)CH2OH
NH2
NHCOCH2OH
CO2CH3
CO2H
1.4 ( 0.6
1.6 ( 0.3
2.1 ( 0.6
7.0 ( 0.4
1.9 ( 0.3
1.5 ( 0.5
2.8 ( 0.3
0.6 ( 0.4
2.6 ( 0.4
0.9 ( 0.7
98 ( 3.2
30 ( 2.1
0.3 ( 0.0
46 ( 19
0.7 ( 0.3
1.2 ( 0.2
1.1 ( 0.6
6.7 ( 1
32d
32e
32f
32g
38c
38d
46k
46l
46ad
46e
46f
37a
38a
45
Cl
0.9 ( 0.1
1.0 ( 0.2
3.7 ( 0.3
2.3 ( 0.2
3.0 ( 0.3
0.9 ( 0.7
33 ( 3.2
9.2 ( 1.2
0.3 ( 0.1
27 ( 2
CF3
CF3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
a
a
4-(4-F-Ph)
4-(3,4,5-trifluoro-Ph)
4-(3,4,5-trifluoro-Ph)
4-(3,4,5-trifluoro-Ph)
4-(3,4,5-trifluoro-Ph)
Br
CHdCH2
Cl
Cl
3.4 ( 1.1
1.3 ( 0.1
3.3 ( 0.2
1.7 ( 0.1
46ac
a The configuration was assigned at random.
containing substituents are well-tolerated at position 5′ of the
pyridine ring. We also found that the receptor-binding site is
even able to tolerate charged substituents at position 5′ of the
pyridine ring. For example, the substituted with a carboxylic
group analogue 38a maintained significant activity at the TRPV1
receptor. Nonpolar substituents, as exemplified with the bromide
45 and the vinyl-substituted analogue 46ac, were also well-
tolerated at position 5′ of the pyridine ring.
Pharmacokinetic Profile. Compound 46ad was selected for
in vivo pharmacokinetic (PK) study with intravenous (iv) and
oral (po) dosing in Sprague-Dawley rats, since it was one of
the most potent in vitro analogues in the capsaicin-mediated
Figure 2. Effect of compound 46ad on capsaicin-induced flinching
in rats.
assay (IC50 ) 0.9 nM) and in the pH-mediated assay (IC50
)
0.9 nM). Following iv administration of 1 mg/kg, 46ad
demonstrated a low rate of clearance (CL ) 270 mL/h/kg), a
relatively low volume of distribution (Vss ) 1893 mL/kg), and
an elimination half-life (t1/2) of 5.6 h. Compound 46ad was
relatively well-absorbed (tmax ) 4 h, Cmax ) 617 ng/mL)
following oral administration of 5 mg/kg and was found to be
orally bioavailable (F ) 17%).
In Vivo Profile. Compound 46ad was evaluated in two
animal models of nociception. The first model examined the
ability of 46ad to block the capsaicin-induced paw flinching in
rats, while the second investigated the effect of 46ad on com-
plete Freund’s adjuvant (CFA)-induced thermal hyperalgesia.
When dosed orally, the potent TRPV1 antagonist 46ad was
efficacious in vivo by blocking capsaicin-induced flinching in
rats (capsaicin 0.5 µg/0.25 mL per paw, eight animals per group)
with ED50 of 8.8 mg/kg (Figure 2).
Figure 3. Effect of compound 46ad on CFA-induced thermal
hyperalgesia in rats.
In the CFA-induced thermal hyperalgesia model, 46ad
significantly reversed thermal hyperlgesia produced by admin-
istration of CFA at a dose of 30 mg/kg, po (Figure 3).
the pyridine rings of the template and, second, by combining
the optimum substituents on all preferred sites of the template.
A summary of the SAR obtained in this study is illustrated in
Figure 4.
Conclusions
A novel class of TRPV1 antagonists was identified by
constraining analogues of BCTC (4) into a 2-(4-pyridin-2-
ylpiperazin-1-yl)-1H-benzo[d]imidazole template. A series of
compounds was prepared, first, by stepwise introduction of
various substituents on the benzimidazole, the piperazine, and
We found that N-benzylation of the benzimidazole ring was
detrimental to activity, suggesting certain steric limitations and/
or specific requirement for hydrogen-bond-donor interactions
with binding site at the receptor. On the other hand, substitution
at position 6 of the benzimidazole ring was well-tolerated, and

Piperazinylbenzimidazoles as TRPV1 antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12 3731
Figure 4. Summary of SAR.
MS obtained on Agilent 1100 and HP 1100 specrometers. Purity
of the compounds was determined on an Agilent 1100 spectrometer
by method A [Phenomenex Luna C8 column (100 × 4.6 mm) at a
1.0 mL/min flow rate using a gradient of 5-100% 5 mM
ammonium acetate (pH 5.5) in acetonitrile and 20 mM ammonium
acetate (pH 5.5) in water] and method B [Phenomenex Luna C8
column (100 × 4.6 mm) at a 1.0 mL/min flow rate using a gradient
of 10-100% 0.1% formic acid in acetonitrile and 0.1% formic acid
in water]. The purity of the compounds was determined on an HP
1100 spectrometer by method C [Gemini C18 column (150 × 4.6
mm) at a 1.25 mL/min flow rate using a gradient of 10-95% 5
mM ammonium acetate (pH 5.5) in acetonitrile and 20 mM
ammonium acetate (pH 5.5) in water] and method D [Synergi Max-
RP column (150 × 4.6 mm) at a 1.0 mL/min flow rate using a
gradient of 10-90% 0.1% formic acid in acetonitrile and 0.1%
formic acid in water]. Silica gel chromatography was performed
using either glass columns packed with silica gel (200-400 mesh,
Aldrich Chemical) or prepacked silica gel cartridges (Biotage).
Melting points were determined on a Buchi-545 melting point
trifluoromethyl, bromo, and tert-butyl groups were identified
as the optimal substituents. The introduction of an additional
substituent at position 5 of the benzimidazole ring seemed to
provide limited benefit, due to steric limitations. On the other
hand, the introduction of an additional substituent at position 4
of the benzimidazole ring led to significant enhancement of the
activity. For example, bulky hydrophobic groups were found
to be the preferred substituents at position 4, which revealed
the existence of a new, relatively large hydrophobic pocket in
the TRPV1 receptor.
We found that substitution of the piperazine ring with a
methyl group resulted in enhancement of potency and that the
preferred configuration of the substituents R4 and R5 was R. A
methyl group was found as the optimal R4 substituent, since
increase of the size and length of this substituent to ethyl and
n-propyl led to substantial decrease of activity.
Next we studied the structural features of the pyridine ring
that influence the functional activity of the novel template of
TRPV1 antagonists. The presence of substituents on the pyridine
ring and ortho-attachment of the pyridine ring to the piperazine
core were critical for potency. We found that position 3′ of the
pyridine ring was the most tolerated site for substitution, and a
trifluoromethyl group or chlorine or iodine atoms were the most
preferred substituents. Additional substitution of the pyridine
ring at position 5′ with various polar, charged, or hydrophobic
groups maintained or increased the potency.
Finally, the simultaneous introduction of bulky lipophilic
substituents at position 4 of the benzimidazole ring, a methyl
group as the substituent R4 of the piperazine core, and polar or
charged groups at position 5′ of the pyridine ring gave rise to
the most potent compounds in the series.
1
apparatus and are uncorrected. H NMR spectra were determined
with a Bruker DRX 400 MHz spectrometer. Chemical shifts are
reported in parts per million (ppm, δ units). Low-resolution mass
spectral (MS) data were determined on a Perkin-Elmer-SCIEX API
165 mass spectrometer using ES ionization modes (positive or
negative). Combustion analysis was performed by Atlantic Micro-
lab, Inc., Norcross, GA, and were within (0.4% of calculated values
unless otherwise noted. Combustion analysis and 1H NMR spectra
showed that fractional molar amounts of water or organic solvents
were tenaciously retained in some analytical samples, even after
prolonged drying under reduced pressure.
6-tert-Butyl-2-(4-(3-chloropyridin-4-yl)piperazin-1-yl)-1H-
benzo[d]imidazole (5). A mixture of the 2-chlorobenzoimidazole
20a (209 mg, 1 mmol), piperazine 8b (305 mg, 1.5 mmol), and
N,N-diisopropylethylamine (0.7 mL, 4 mmol) in DMSO (5 mL)
was stirred at 80 °C for 24 h. The mixture was then cooled to room
temperature, diluted with water (10 mL), and extracted with EtOAc
(2 × 20 mL). The combined organic phases were washed with water
(2 × 10 mL) and brine (5 mL), dried over Na2SO4, and filtered.
The filtrate was evaporated in vacuo and the residue was purified
by silica gel chromatography, eluting with 20% EtOAc/hexane to
give 0.17 g (46%) of the title compound as a yellow amorphous
As a result of this SAR investigation, we identified the potent
analogue 46ad, which showed good pharmacokinetic profile and
was found to be orally bioavailable. In vivo, compound 46ad
was found to be effective at preventing capsaicin-induced
flinching in rats in a dose-dependent manner, and it reversed
thermal hyperalgesia in a model of inflammatory pain, which
was induced by complete Freund’s adjuvant (CFA).
1
solid. MS (ESI, pos. ion) m/z: 370 (M + 1). H NMR (DMSO-
d6): δ 1.31 (s, 9 H), 3.36-3.42 (m, 4 H), 3.60-3.80 (m, 4 H),
7.00 (dd, J ) 8.2, 2.0 Hz, 1 H), 7.04 (dd, J ) 7.8, 4.7 Hz, 1 H),
7.14 (d, J ) 8.2 Hz, 1 H), 7.23 (d, J ) 1.6 Hz, 1 H), 7.84 (dd, J
) 7.8, 1.6 Hz, 1 H), 8.25 (dd, J ) 4.7, 2.0 Hz, 1 H). LC/MS
retention time: A, 9.60 min; B, 6.77 min.
4-Nitro-6-(trifluoromethyl)-2-(4-(3-(trifluoromethyl)pyridin-
2-yl)piperazin-1-yl)-1H-benzo[d]imidazole (31a). A mixture of
2-chlorobenzoimidazole 20c (1.5 g, 5.7 mmol), 1-(3-trifluoro-
methylpyridin-2-yl)piperazine (1.8 g, 7.8 mmol), and N,N-diiso-
propylethylamine (1 mL, 5.7 mmol) in 1,4-dioxane (1 mL) was
Experimental Section
Unless otherwise noted, all materials were obtained from
commercial suppliers and used without further purification. An-
hydrous solvents were obtained from Aldrich or EM Science and
used directly. All reactions involving air- or moisture-sensitive
reagents were performed under a nitrogen or argon atmosphere.
All microwave-assisted reactions were conducted with a Smith
synthesizer from Personal Chemistry, Uppsala, Sweden. All final
compounds were purified to >95% purity as determined by LC/

3732 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12
OgnyanoV et al.
heated in a microwave synthesizer at 200 °C for 40 min. The
mixture was evaporated in vacuo and the residue was purified by
silica gel column chromatography, eluting with 30% EtOAc/hexane
to give 2.1 g (80%) of the title compound as an orange solid. Mp:
(m, 2 H), 2.00-2.10 (m, 2 H), 2.59 (t, J ) 12.1 Hz, 1 H), 3.17 (dt,
J ) 12.1, 3.1 Hz, 1 H), 3.27 (dd, J ) 12.1, 2.9 Hz, 1H), 3.75 (dt,
J ) 12.1, 3.1 Hz, 1 H), 3.83 (t, J ) 12.5 Hz, 2 H), 3.95 (d, J )
11.3 Hz, 1 H), 4.49 (br s, 1 H), 4.65 (s, 2 H), 7.35 (br s, 1 H), 7.87
(d, J ) 2.9 Hz, 1 H), 8.27 (s, 1 H), 8.34 (br s, 1 H). LC/MS retention
time: A, 10.32 min; B, 8.42 min.
1
192.9-193 °C. MS (ESI, pos. ion) m/z: 461 (M + 1). H NMR
(CD3OD): δ 3.26-3.38 (m, 4 H), 3.76-3.88 (m, 4 H), 7.13 (dd, J
) 6.0, 5.6 Hz, 1 H), 7.68 (br s, 1 H), 7.97 (d, J ) 8.0 Hz, 1 H),
8.02 (s, 1 H), 8.42 (d, J ) 4.0 Hz, 1 H). Anal. (C18H14F6N6O2): C,
H, N.
(R)-tert-Butyl 2-(4-(3-Chloro-5-(hydroxymethyl)pyridin-2-
yl)-2-methylpiperazin-1-yl)-6-(trifluoromethyl)-1H-benzo[d]imid-
azol-4-ylcarbamate (32e). To a mixture of compound 32b (221
mg, 1.0 mmol) and 1 N NaOH (1 mL) in THF (5 mL) was added
di-tert-butyl dicarbonate (131 mg, 0.6 mmol) in one portion with
stirring at room temperature. The mixture was stirred at room
temperature for 30 min, diluted with water (20 mL), and extracted
with EtOAc (2 × 40 mL). The combined organic extracts were
washed with brine (20 mL), dried over Na2SO4, and filtered. The
filtrate was evaporated in vacuo and the residue was purified by
silica gel column chromatography, eluting with 60% EtOAc/hexane
to give 110 mg (41%) of the title compound as a light-yellow solid.
MS (ESI, pos. ion) m/e: 541 (M + 1). 1H NMR (CD3OD): δ 1.47
(d, J ) 6.6 Hz, 3 H), 1.55 (s, 9 H), 3.06 (dt, J ) 12.1, 3.1 Hz, 1
H), 3.17 (dd, J ) 12.3, 3.3 Hz, 1 H), 3.63 (dt, J ) 12.1, 3.5 Hz, 1
H), 3.82 (t, J ) 12.3 Hz, 2 H), 3.92 (d, J ) 12.7 Hz, 1 H), 4.37 (br
s, 1 H), 4.56 (s, 2 H), 7.20 (br s, 1 H), 7.77 (s, 1 H), 7.91 (br s, 1
H), 8.17 (s, 1 H). LC/MS retention time: A, 10.59 min; B, 8.51
min.
(R)-(5-Chloro-6-(3-methyl-4-(4-nitro-6-(trifluoromethyl)-1H-
benzo[d]imidazol-2-yl)piperazin-1-yl)pyridin-3-yl)methanol (31b).
A mixture of 2-chlorobenzoimidazole 20c (1.33 g, 5 mmol),
piperazine 8t (1.21 g, 5 mmol), and N,N-diisopropylethylamine
(1.75 mL, 10 mmol) in EtOH (4 mL) was heated in a microwave
synthesizer at 175 °C for 60 min. The mixture was evaporated in
vacuo and the residue was purified by silica gel column chroma-
tography, eluting with 60% EtOAc/hexane to give 1.81 g (77%) of
the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 471
1
(M + 1). H NMR (CD3OD): δ 1.51 (d, J ) 6.7 Hz, 3 H), 3.07
(dt, J ) 12.1, 2.7 Hz, 1 H), 3.17 (dd, J ) 12.5, 2.7 Hz, 1 H), 3.70
(dt, J ) 12.1, 2.7 Hz, 1 H), 3.83 (t, J ) 11.5 Hz, 2 H), 4.19 (d, J
) 12.9 Hz, 1 H), 4.56 (s, 2 H), 4.65 (br s, 1 H), 7.69-7.80 (m, 2
H), 8.10 (br s, 1 H), 8.17 (br s, 1 H).
6-(Trifluoromethyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)-
piperazin-1-yl)-1H-benzo[d]imidazol-4-amine (32a). Compound
31a (1.8 g, 3.9 mmol) was added to a suspension of 10% Pd/C
(0.16 g) in EtOH (50 mL) under a hydrogen atmosphere. The
reaction mixture was stirred at room temperature for 4 h and filtered
through a pad of Celite. The filtrate was evaporated under reduced
pressure and the residue was purified by silica gel column
chromatography, eluting with 45% EtOAc/hexane to give 1.1 g
(66%) of the title compound as a off-white amorphous solid. MS
(R)-(5-Chloro-6-(4-(4-(dibenzylamino)-6-(trifluoromethyl)-
1H-benzo[d]imidazol-2-yl)-3-methylpiperazin-1-yl)pyridin-3-yl)-
methanol (32g). To a solution of compound 32b (221 mg, 0.5
mmol) in MeCN (2 mL) was added benzaldehyde (0.085 mL, 0.55
mmol) dropwise with stirring at room temperature. After the
addition, the mixture was stirred at room temperature for 20 min
and then NaBH(OAc)3 (127 mg, 0.6 mmol) was added in one
portion. The mixture was stirred for 4 h at room temperature, 1 N
NaOH (5 mL) was added, and the mixture was extracted with
EtOAc (2 × 40 mL). The combined organic phases were washed
with brine (20 mL), dried over Na2SO4, and filtered. The filtrate
was evaporated in vacuo and the residue was purified by silica gel
chromatography, eluting with 60% EtOAc/hexane to give 112 mg
(42%) of the title compound as a light-yellow solid. MS (ESI, pos.
1
(ESI, pos. ion) m/z: 431 (M + 1). H NMR (CD3OD): δ 3.58-
3.66 (m, 4 H), 3.90-4.00 (m, 4 H), 6.90 (s, 1 H), 7.13 (s, 1 H),
7.45 (dd, J ) 7.6, 5.0 Hz, 1 H), 8.28 (dd, J ) 7.6, 1.4 Hz, 1 H),
8.74 (d, J ) 3.6 Hz, 1 H). Anal. (C18H16F6N6): C, H, N.
(R)-(6-(4-(4-Amino-6-(trifluoromethyl)-1H-benzo[d]imidazol-
2-yl)-3-methylpiperazin-1-yl)-5-chloropyridin-3-yl)methanol (32b).
Following the procedure described for compound 32a, compound
31b provided the title compound (96%) as a yellow gum. MS (ESI,
pos. ion) m/e: 441 (M + 1).
1
ion) m/z: 621 (M + 1). H NMR (CD3OD): δ 1.44 (d, J ) 6.3
Hz, 3 H), 3.06 (dt, 12.1, 3.1 Hz, 1 H), 3.16 (dd, J ) 12.5, 2.4 Hz,
1 H), 3.58 (dt, J ) 12.1, 2.4 Hz, 1 H), 3.79 (t, J ) 10.6, Hz, 2 H),
3.99 (d, J ) 12.9, Hz, 1 H), 4.44 (br s, 1 H), 4.55 (s, 2 H), 4.55-
4.70 (m, 2 H), 6.49 (br s, 2 H), 6.89 (br s, 1 H), 7.10-7.30 (m, 10
H), 7.76 (s, 1 H), 8.16 (s, 1 H). LC/MS retention time: A, 12.03
min; B, 9.81 min.
N-(3,4,5-Trifluorobenzyl)-6-(trifluoromethyl)-2-(4-(3-(tri-
fluoromethyl)pyridin-2-yl)piperazin-1-yl)-1H-benzo[d]imidazol-
4-amine (32c). NaBH(OAc)3 (211 mg, 1 mmol) was added to a
mixture of compound 32a (215 mg, 0.5 mmol) and 3,4,5-
trifluorobenzaldehyde (88 mg, 0.55 mmol) in chloroform (2 mL)
in one portion. The reaction mixture was stirred at room temperature
for 2 h and concentrated in vacuo. The residue was dissolved in
EtOAc (30 mL), washed successively with 1 N NaOH (15 mL)
and brine (15 mL), dried over MgSO4, and filtered. The filtrate
was evaporated in vacuo and the residue was purified by silica gel
chromatography, eluting with 25% EtOAc/hexane to give 175 mg
(61%) of the title compound as a white solid. MS (ESI, pos. ion)
(R)-(6-(4-(4-(Benzylamino)-6-(trifluoromethyl)-1H-benzo[d]-
imidazol-2-yl)-3-methylpiperazin-1-yl)-5-chloropyridin-3-yl)-
methanol (32f). Compound 32f was formed as a second product
of the reaction described for compound 32g and was isolated as a
light-yellow solid (yield 98 mg, 36%). MS (ESI, pos. ion) m/z:
531 (M + 1).1H NMR (CD3OD): δ 1.44 (d, J ) 6.3 Hz, 3 H),
3.06 (dt, 12.1, 3.1 Hz, 1 H), 3.16 (dd, J ) 12.5, 2.4 Hz, 1 H), 3.58
(dt, J ) 12.1, 2.4 Hz, 1 H), 3.73-3.93 (m, 3 H), 4.33 (br s, 1 H),
4.45 (s, 2 H), 4.55 (s, 2 H), 6.49 (s, 1 H), 6.89 (br s, 1 H), 7.25 (t,
J ) 7.1 Hz, 1 H), 7.33 (t, J ) 7.4 Hz, 2 H), 7.45 (d, J ) 7.4 Hz,
2 H), 7.76 (s, 1 H), 8.16 (s, 1 H). LC/MS retention time: A, 10.36
min; B, 7.86 min.
(R)-4-Bromo-2-(4-(3-chloro-5-nitropyridin-2-yl)-2-methyl-
piperazin-1-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (33).
A mixture of piperazine 8ad (970 mg, 3.79 mmol), 2-chloro-
benzoimidazole 20f (1.1 g, 3.79 mmol), N,N-diisopropylethylamine
(0.79 mL, 4.55 mmol), and copper(I) iodide (1 mg) in 3-methyl-
butan-1-ol (5 mL) was heated in a microwave synthesizer at 200
°C for 60 min. The solvent was evaporated under reduced pressure
and the residue was purified by silica gel column chromatography
(gradient 5-100% EtOAc/CH2Cl2) to give 1.1 g (58%) of the title
compound as a brown solid. MS (ESI, pos. ion) m/z: 519, 521 (M
+ 1).
1
m/z: 575 (M + 1). H NMR (CD3OD): δ 3.36-3.42 (m, 4 H),
3.60-4.72 (m, 4 H), 6.39 (s, 1 H), 6.92 (s, 1 H), 7.10-7.30 (m, 3
H), 8.06 (dd, J ) 7.8 Hz, 1.5 Hz, 1 H), 8.51 (d, J ) 3.7 Hz, 1 H).
Anal. (C25H19F9N6) C, H, N.
(R)-N-(2-(4-(3-Chloro-5-(hydroxymethyl)pyridin-2-yl)-2-
methylpiperazin-1-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-
4-yl)cyclohexanecarboxamide (32d). A mixture of compound 32b
(221 mg, 0.5 mmol), cyclohexanecarboxylic acid (71 mg, 0.55
mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hy-
drochloride (76 mg, 0.4 mmol) in dichloromethane (5 mL) was
stirred at room temperature for 36 h. Water (20 mL) was added
and the mixture was extracted with EtOAc (2 × 40 mL). The
combined organic phases were washed with brine (20 mL), dried
over Na2SO4, and filtered. The solvent was removed in vacuo and
the residue was purified by silica gel chromatography, eluting with
80% EtOAc/hexanes to give 94 mg (34%) of the title compound
1
as a white solid. MS (ESI, pos. ion) m/z: 551 (M + 1). H NMR
(R)-6-(4-(4-Bromo-6-(trifluoromethyl)-1H-benzo[d]imidazol-
2-yl)-3-methylpiperazin-1-yl)-5-chloropyridin-3-amine (34). A
(CD3OD): δ 1.26-1.75 (m, 8 H), 1.78-1.88 (m, 1 H), 1.90-2.00

Piperazinylbenzimidazoles as TRPV1 antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12 3733
mixture of compound 33 (1.1 g, 2.12 mmol) and tin(II) chloride
dihydrate (0.957 g, 4.24 mmol) in DMF (7 mL) was heated to 80
°C with stirring for 3 h. The reaction mixture was allowed to cool
to room temperature and was diluted with EtOAc (100 mL). To
the stirred mixture was added slowly a saturated aqueous solution
of NaHCO3 (200 mL) and Celite (10 g). The mixture was stirred
at room temperature for 18 h and was filtered. The organic layer
was separated from the filtrate and the aqueous layer was extracted
with EtOAc (2 × 100 mL). The combined organic extracts were
dried over MgSO4, filtered, and evaporated. The residue was
purified by flash silica gel column chromatography (gradient
0-20% MeOH/CH2Cl2) to give 0.444 g (44%) of the title
compound as a brown solid. MS (ESI, pos. ion) m/z: 489, 491 (M
+ 1).
(R)-(6-(3-Methyl-4-(6-(trifluoromethyl)-4-(3,4,5-trifluoro-
phenyl)-1H-benzo[d]imidazol-2-yl)piperazin-1-yl)-5-(trifluoro-
methyl)pyridin-3-yl)methanol (35). A mixture of piperazine 8aa
(825 mg, 3.0 mmol), 2-chlorobenzoimidazole 20i (1.05 g, 3.0
mmol), and N,N-diisopropylethylamine (1.05 mL, 6 mmol) in EtOH
(5 mL) was heated in a microwave synthesizer at 175 °C for 4 h.
The mixture was evaporated in vacuo and the residue was purified
by silica gel column chromatography, eluting with 60% EtOAc/
hexane to give 1.45 g (41%) of the title compound as a white solid.
MS (ESI, pos. ion) m/e: 590 (M + 1). 1H NMR (CD3OD): δ 1.43
(d, J ) 6.6 Hz, 3 H), 3.14 (dt, J ) 12.5, 3.1 Hz, 1 H), 3.32-3.42
(m, 3 H), 3.48 (d, J ) 11.7 Hz, 1 H), 3.62 (dt, J ) 12.1, 3.1 Hz,
1 H), 4.05 (dd, J ) 13.1, 2.1 Hz, 1 H), 4.46 (br s, 1 H), 4.65 (s, 2
H), 7.45 (s, 1 H), 7.49 (s, 1 H), 7.82-7.94 (m, 2 H), 8.06 (s, 1 H),
8.50 (s, 1 H). LC/MS retention time: A, 12.01 min; B, 11.86 min.
(R)-6-(3-Methyl-4-(6-(trifluoromethyl)-4-(3,4,5-trifluoro-
phenyl)-1H-benzo[d]imidazol-2-yl)piperazin-1-yl)-5-(trifluoro-
methyl)nicotinaldehyde (36). A suspension of compound 35 (1.18
g, 2 mmol) and MnO2 (3.48 g, 40 mmol) in CH2Cl2 (50 mL) was
stirred at room temperature for 4 h. The reaction mixture was
filtered though a pad of Celite and the filter cake was washed with
EtOAc. The filtrate was evaporated in vacuo to give 1.01 g (86%)
of the title compound as a white solid. MS (ESI, pos. ion) m/z:
588 (M + 1).
NaOH (0.11 mL) in THF (1 mL) was stirred at 50 °C for 16 h.
HCl (1 N, 0.11 mL) was added and the mixture was extracted with
EtOAc (2 × 20 mL). The combined organic phases were washed
with brine (5 mL), dried over Na2SO4, and filtered. The filtrate
was evaporated in vacuo and the residue was purified by silica gel
chromatography (10% MeOH/EtOAc) to give 38 mg (57%) of the
title compound as a white amorphous solid. MS (ESI, pos. ion)
1
m/z: 570 (M + 1). H NMR (CD3OD): δ 1.43 (d, J ) 6.7 Hz, 3
H), 3.16 (dt, J ) 12.1, 3.1 Hz, 1 H), 3.24-3.34 (m, 1 H), 3.65 (dt,
J ) 12.6, 3.1 Hz, 1 H), 4.02-4.22 (m, 3 H), 4.49 (br s, 1 H), 7.46
(br s, 2 H), 7.76-7.87 (m, 2 H), 8.18 (br s, 1 H), 8.73 (br s, 1 H).
LC/MS retention time: A, 9.89 min; B, 11.74 min.
1-(5-Chloro-6-(4-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-
yl)piperazin-1-yl)pyridin-3-yl)ethanol (38b). To a solution of
ketone 37b (0.3 g, 0.71 mmol) in MeOH (20 mL) was added
portionwise NaBH4 (0.037 g, 1.0 mmol) with stirring at 0 °C. The
reaction mixture was stirred at 0 °C for 30 min, quenched with 20
mL of saturated aqueous solution of NaHCO3, and diluted with
EtOAc (50 mL). The organic phase was separated, washed with
brine (20 mL), dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was crystallized from 1:1 EtOAc/hexane mixture
to give 0.27 g (90%) of the title compound. MS (ESI, pos. ion)
m/z: 426 (M + 1). 1H NMR (DMSO-d6): δ 1.26-1.37 (m, 3 H),
3.28-3.42 (m, 4 H), 3.62-3.74 (m, 4 H), 4.74 (dt, J ) 11.0, 6.3
Hz, 1 H), 5.34 (d, J ) 4.7 Hz, 1 H), 7.27 (d, J ) 7.8 Hz, 1 H),
7.31-7.39 (m, 1 H), 7.47 (s, 1 H), 7.79 (s, 1 H), 8.21 (s, 1 H),
11.89 (br s, 1 H). LC/MS retention time: A, 8.81 min; B, 4.47
min.
(R)-1-(6-((R)-3-Methyl-4-(6-(trifluoromethyl)-4-(3,4,5-trifluoro-
phenyl)-1H-benzo[d]imidazol-2-yl)piperazin-1-yl)-5-(trifluoro-
methyl)pyridin-3-yl)ethanol and (S)-1-(6-((R)-3-Methyl-4-(6-
(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzo[d]imidazol-
2-yl)piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)ethanol (38c).
To a solution of aldehyde 36 (88 mg, 0.15 mmol) in THF (2 mL)
was added CH3MgBr (0.063 mL, 0.19 mmol, 3.0 M in ether) at 0
°C, and the mixture was stirred at 0 °C for 10 min. After the addition
of a saturated aqueous solution of NH4Cl (5 mL), the mixture was
extracted with EtOAc (2 × 20 mL). The combined organic extracts
were washed with water (10 mL) and brine (10 mL), dried over
Na2SO4, and filtered. The filtrate was evaporated in vacuo and the
residue was purified by silica gel chromatography, eluting with 60%
EtOAc/hexane to give 78 mg (86%) of the title compound as a
mixture of diastereomers. MS (ESI, pos. ion) m/e: 604 (M + 1).
1H NMR (CD3OD): δ 1.45 (d, J ) 6.6 Hz, 3 H), 1.46 (d, J ) 6.6
Hz, 3 H), 3.13 (dt, J ) 12.2, 2.8 Hz, 1 H), 3.30-3.40 (m, 2 H),
3.48 (d, J ) 12.7 Hz, 1 H), 3.63 (dt, J ) 12.5, 3.1 Hz, 1 H), 4.04
(d, J ) 12.1 Hz, 1 H), 4.46 (br s, 1 H), 4.92 (q, J ) 6.6 Hz, 1 H),
7.45 (s, 1 H), 7.50 (s, 1 H), 7.82-7.96 (m, 2 H), 8.07 (s, 1 H),
8.52 (s, 1 H). LC/MS retention time: A, 12.28 min; B, 12.22 min.
(R)-(6-((R)-3-Methyl-4-(6-(trifluoromethyl)-4-(3,4,5-trifluoro-
phenyl)-1H-benzo[d]imidazol-2-yl)piperazin-1-yl)-5-(trifluoro-
methyl)pyridin-3-yl)phenylmethanol and (S)-(6-((R)-3-Methyl-4-(6-
(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzo[d]imid-
azol-2-yl)piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)phenyl-
methanol (38d). To a solution of the aldehyde 36 (88 mg, 0.15
mmol) in THF (2 mL) was added C6H5MgBr (0.19 mL, 0.19 mmol,
1.0 M solution in THF) at 0 °C. After the addition, the mixture
was stirred at 0 °C for 10 min. A saturated aqueous solution of
NH4Cl (5 mL) was added, and the mixture was extracted with
EtOAc (2 × 20 mL). The combined organic extracts were washed
with water (10 mL) and brine (10 mL), dried over Na2SO4, and
filtered. The fitrate was removed in vacuo and the residue was
purified by silica gel column chromatography (60% EtOAc/hexane)
to give 81 mg (89%) of the title compound as a mixture of
diastereoisomers. MS (ESI, pos. ion) m/z: 666 (M + 1). 1H NMR
(CD3OD): δ 1.33 (d, J ) 6.7 Hz, 3 H), 3.13 (dt, J ) 12.1, 3.5 Hz,
1 H), 3.20-3.30 (m, 2 H), 3.48 (d, J ) 11.3 Hz, 1 H), 3.52 (dt, J
) 12.1, 3.1 Hz, 1 H), 3.95 (d, J ) 12.5 Hz, 1 H), 4.36 (br s, 1 H),
5.78 (s, 1 H), 7.27 (t, J ) 6.7 Hz, 1 H), 7.20-7.45 (m, 4 H), 7.80
(br s, 2 H), 7.93 (s, 2 H), 8.40 (s, 2 H). LC/MS retention time: A,
12.81 min; B, 13.20 min.
(R)-Methyl 5-Chloro-6-(3-methyl-4-(6-(trifluoromethyl)-4-
(3,4,5-trifluorophenyl)-1H-benzo[d]imidazol-2-yl)piperazin-1-
yl)nicotinate (37a). A mixture of piperazine 8s (271 mg, 1.0 mmol),
2-chlorobenzoimidazole 20i (350 mg, 1.0 mmol), N,N-diisopropyl-
ethylamine (0.35 mL, 2 mmol) in EtOH (1 mL) was heated in a
microwave synthesizer at 175 °C for 1 h. The reaction mixture
was evaporated in vacuo and the residue was purified by silica gel
column chromatography (60% EtOAc/hexane) to give 163 mg
(28%) of the title compound as a white solid. MS ESI, pos. ion)
1
m/e: 584 (M + 1). H NMR (CD3OD): δ 1.42 (d, J ) 6.3 Hz, 3
H), 3.21 (dt, J ) 12.5, 3.1 Hz, 1 H), 3.31-3.38 (m, 1 H), 3.70 (dt,
J ) 12.5, 3.1 Hz, 1 H), 3.89 (s, 3 H), 4.08 (d, J ) 12.1 Hz, 1 H),
4.18 (t, J ) 14.0 Hz, 2 H), 4.50 (br s, 1 H), 7.47 (s, 2 H), 7.85 (br
s, 2 H), 8.19 (d, J ) 2.0 Hz, 1 H), 8.73 (d, J ) 2.0 Hz, 1 H).
LC/MS retention time: A, 12.85 min; B, 13.28 min.
1-(5-Chloro-6-(4-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-
yl)piperazin-1-yl)pyridin-3-yl)ethanone (37b). A mixture of piper-
azine 8n (0.6 g, 1.92 mmol), 2-chlorobenzoimidazole 20n (0.423
g, 1.92 mmol), and N,N-diisopropylethylamine (1 mL, 6 mmol) in
dioxane (1 mL) was heated in a microwave synthesizer at 190 °C
for 45 min. The reaction mixture was diluted with EtOAc (100
mL), washed with saturated aqueous solution of NaHCO3 (50 mL)
and brine (50 mL), dried over Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by silica gel column chroma-
tography (30% EtOAc in hexane) to give 0.67 g (82%) of the title
compound as a white amorphous solid. MS (ESI, pos. ion) m/z:
1
424 (M + 1). H NMR (DMSO-d6): δ 2.62 (s, 3 H), 3.70-3.81
(m, 8 H), 7.33-7.37 (m, 1 H), 7.41-7.45 (m, 1 H), 7.55 (s, 1 H),
8.25 (s, 1 H), 8.85 (s, 1 H). Anal. (C19H17ClF3N5O‚H2O): C, H,
N.
(R)-5-Chloro-6-(3-methyl-4-(6-(trifluoromethyl)-4-(3,4,5-tri-
fluorophenyl)-1H-benzo[d]imidazol-2-yl)piperazin-1-yl)nicotin-
ic Acid (38a). A mixture of ester 37a (58 mg, 0.1 mmol) and 1 N

3734 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12
OgnyanoV et al.
6-(Trifluoromethyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)pi-
perazin-1-yl)-1H-benzo[d]imidazole (39). A solution of 1-(3-
trifluoromethylpyridin-2-yl)piperazine (0.38 g, 1.6 mmol), 2-chloro-
benzoimidazole 20n (0.3 g, 1.36 mmol), and N,N-diisopropylethyl-
amine (0.28 mL, 1.6 mmol) in DMSO (10 mL) was heated to 80
°C for 16 h. The reaction mixture was left to reach room temperature
and was diluted with EtOAc (50 mL), washed with brine (2 × 20
mL), dried over Na2SO4, and filtered. The filtrate was evaporated
under reduced pressure and the residue was purified by silica gel
column chromatography (30% EtOAc/hexane) to afford 0.18 g
(30%) of the title compound as a solid. Mp: 221-224 °C. MS
(ESI, pos. ion) m/z: 416 (M + 1). 1H NMR (DMSO-d6): δ 3.26-
3.45 (m, 4 H), 3.67-3.74 (m, 4 H), 7.27 (d, J ) 7.0 Hz, 2 H),
7.34-7.38 (m, 1 H), 7.48 (s, 1 H), 8.12 (d, J ) 7.8 Hz, 1 H), 8.57
(d, J ) 4.3 Hz, 1 H), 11.94 (br s, 1 H). Anal. (C18H15F6N5): C, H,
N.
1-Benzyl-6-(trifluoromethyl)-2-(4-(3-(trifluoromethyl)pyridin-
2-yl)piperazin-1-yl)-1H-benzo[d]imidazole (40). To a solution of
compound 39 (415 mg, 1.0 mmol) in anhydrous DMF (5 mL) was
added sodium hydride (72 mg, 50% in mineral oil, 1.5 mmol) at 0
°C. The reaction mixture was stirred at room temperature for 0.5 h
and cooled to 0 °C. Benzyl bromide (171 mg, 1.0 mmol) was added,
and the mixture was stirred at room temperature for 16 h. The
reaction mixture was then quenched with saturated aqueous solution
of NaHCO3 (30 mL) and extracted with EtOAc (2 × 50 mL). The
combined organic extracts were dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by silica gel column
chromatography (25% EtOAc/hexane) to give 84 mg (17%) of the
title compound as a white solid. Mp: 154-157 °C. MS (ESI, pos.
ion) m/z: 506 (M + 1). 1H NMR (CDCl3): δ 3.30-3.40 (m, 4 H),
3.40-3.50 (m, 4 H), 5.30 (s, 2 H), 7.05 (dd, J ) 8.0, 4.8 Hz, 1 H),
7.18 (d, J ) 7.0 Hz, 2 H), 7.26-7.40 (m, 5 H), 7.47 (d, J ) 8.2
Hz, 1 H), 7.70 (d, J ) 8.2 Hz, 1 H), 7.89 (dd, J ) 7.6, 1.8 Hz, 1
H), 8.45 (dd, J ) 4.8, 1.2 Hz, 1 H), LC/MS retention time: A,
12.05 min; B, 11.93 min.
1-Benzyl-5-(trifluoromethyl)-2-(4-(3-(trifluoromethyl)pyridin-
2-yl)piperazin-1-yl)-1H-benzo[d]imidazole (41). The title com-
pound was obtained as a second product of the reaction described
for the preparation of compound 40 and isolated as a white solid
(yield 11 mg, 2%). MS (ESI, pos. ion) m/z: 506 (M + 1). 1H NMR
(CDCl3): δ 3.36-3.48 (m, 8 H), 5.29 (s, 2 H), 7.03 (dd, J ) 7.6,
4.5 Hz, 1 H), 7.08 (d, J ) 8.2 Hz, 1 H), 7.17 (d, J ) 7.0 Hz, 2 H),
7.27-7.44 (m, 4H), 7.87 (dd, J ) 7.8, 2.0 Hz, 1 H), 7.92 (s, 1 H),
8.45 (dd, J ) 4.8, 1.2 Hz, 1 H). Anal. (C25H21F6N5‚0.2EtOAc): C,
H, N.
6-Bromo-2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-
yl)-1H-benzo[d]imidazole (42). Following the procedure described
for compound 39, 1-(3-trifluoromethylpyridin-2-yl)piperazine and
2-chlorobenzoimidazole 20o provided the title compound (66%)
as a white amorphous solid. MS (ESI, pos. ion) m/z: 428 (M + 1).
1H NMR (DMSO-d6): δ 3.28-3.38 (m, 4 H), 3.60-3.70 (m, 4
H), 7.06 (s, 1 H), 7.14 (m, 1 H), 7.19-7.30 (m, 1 H), 7.36 (s, 1
H), 8.10 (d, J ) 7.4 Hz, 1 H), 8.56 (d, J ) 3.5 Hz, 1 H), 11.66 (s,
1 H). Anal. (C17H15BrF3N5): C, H, N.
chromatography (30% EtOAc/hexane) to afford 176 mg (69%) of
the title compound as an amorphous solid. MS (ESI, pos. ion) m/z:
624 (M + 1).
4-Bromo-6-(trifluoromethyl)-2-(4-(3-(trifluoromethyl)pyridin-
2-yl)piperazin-1-yl)-1H-benzo[d]imidazole (44a). Following the
procedure described for compound 39, 1-(3-trifluoromethylpyridin-
2-yl)piperazine and 2-chlorobenzoimidazole 20f provided the title
compound (90%) as a white solid. Mp: 196 °C. MS (ESI, pos.
ion) m/z: 494 (M + 1). 1H NMR (CDCl3): δ 3.40-3.50 (m, 4 H),
3.70-3.80 (m, 4 H), 7.09 (dd, J ) 8.0, 4.0 Hz, 1 H), 7.48 (s, 1 H),
7.53 (s, 1 H), 7.93 (d, J ) 8.0 Hz, 1 H), 8.48 (d, J ) 4.0 Hz, 1 H).
Anal. (C18H14BrF6N5): C, H, N.
4-Bromo-6-(trifluoromethyl)-2-(4-(3-(trifluoromethyl)pyridin-
2-yl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-ben-
zo[d]imidazole (44b). Following the procedure described for
compound 43b, compound 44a and 2-(trimethylsilyl)ethoxymethyl
chloride provided the title compound (34%) as a light-brown oil.
MS (ESI, pos. ion) m/z: 564 (M + 1). (R)-1-(6-((R)-4-(4-Bromo-
6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3-methylpiperazin-
1-yl)-5-chloropyridin-3-yl)ethanol and (S)-1-(6-((R)-4-(4-Bromo-
6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3-methylpiperazin-
1-yl)-5-chloropyridin-3-yl)ethanol (44c). A mixture of the
piperazines 8ag (766 mg, 3 mmol), 2-chlorobenzoimidazole 20f
(902 mg, 3 mmol), and N,N-diisopropylethylamine (1.05 mL, 6
mmol) in EtOH (2 mL) was heated in a microwave synthesizer at
175 °C for 1 h. The reaction mixture was evaporated in vacuo and
the residue was purified by silica gel chromatography (60% EtOAc/
hexane) to give 638 mg (41%) of the title compound as a mixture
1
of diastereoisomers. MS (ESI, pos. ion) m/z: 518 (M + 1). H
NMR (CD3OD): δ 1.44 (d, J ) 6.3 Hz, 3 H), 1.48 (d, J ) 6.7 Hz,
3 H), 3.05 (dt, J ) 12.5, 3.1 Hz, 1 H), 3.15 (dd, J ) 12.6, 3.8 Hz,
1 H), 3.64 (dt, J ) 12.5, 3.1 Hz, 1 H), 3.80 (t, J ) 12.5 Hz, 2 H),
4.49 (br s, 1 H), 4.78-4.85 (m, 1 H), 7.43 (br s, 1 H), 7.44 (br s,
1 H), 7.78 (d, J ) 2.0 Hz, 1 H), 8.18 (d, J ) 2.0 Hz, 1 H).
(R)-2-(4-(5-Bromo-3-chloropyridin-2-yl)-2-methylpiperazin-
1-yl)-6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzo[d]-
imidazole (45). A mixture of piperazine 8af (875 mg, 3 mmol),
2-chlorobenzoimidazole 20i (1.05 g, 3 mmol), and N,N-diisopro-
pylethylamine (1.05 mL, 6 mmol) in EtOH (5 mL) was heated in
a microwave synthesizer at 180 °C for 4 h. The reaction mixture
was evaporated in vacuo and the residue was purified by silica gel
chromatography (40% EtOAc/hexane) to give 3.09 g (34%) of the
title compound as a white solid. MS (ESI, pos. ion) m/z: 606 (M
1
+ 1). H NMR (CDCl3): δ 1.50 (d, J ) 6.6 Hz, 3 H), 3.10 (dt, J
) 12.1, 3.1 Hz, 1 H), 3.21 (dd, J ) 12.5, 3.5 Hz, 1 H), 3.68 (dt,
J ) 12.1, 3.1 Hz, 1 H), 3.80-4.00 (m, 2 H), 4.05 (br s, 1 H), 4.35
(br s, 1 H), 7.40-7.55 (m, 2 H), 7.70-7.90 (m, 1 H), 7.79 (d, J )
2.3 Hz, 1 H), 8.25 (d, J ) 2.0 Hz, 1 H), 8.25-8.40 (m, 1 H).
LC/MS retention time: A, 13.39 min; B, 14.06 min.
6-(3,4-Difluorophenyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)-
piperazin-1-yl)-1H-benzo[d]imidazole (46a). To a mixture of 3,4-
difluorophenylboronic acid (111 mg, 0.7 mmol) and 6-bromo-
benzoimidazole 42 (213 mg, 0.5 mmol) in ethylene glycol dimethyl
ether (2 mL) were added lithium chloride (63 mg, 1.5 mmol) and
2 M aqueous solution of sodium carbonate (0.75 mL, 1.5 mmol).
Nitrogen gas was bubbled through the mixture for 10 min and
tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) was
added. The reaction mixture was stirred at 80 °C under nitrogen
atmosphere for 16 h, cooled to room temperature, diluted with
EtOAc (50 mL), and filtered through Celite pad. The filtrate was
washed with water and brine, dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by silica gel column
chromatography (55% EtOAc/hexane) to give 96 mg (42%) of the
title compound as a white solid. MS (ESI, pos. ion) m/z: 460 (M
5-Bromo-6-(trifluoromethyl)-2-(4-(3-(trifluoromethyl)pyridin-
2-yl)piperazin-1-yl)-1H-benzo[d]imidazole (43a). Following the
procedure described for compound 39, 1-(3-trifluoromethylpyridin-
2-yl)piperazine and 2-chlorobenzoimidazole 20b provided the title
compound (83%) as a white solid. MS (ESI, pos. ion) m/z: 496
1
(M + 1). H NMR (DMSO-d6): δ 3.35-3.46 (m, 4 H), 3.67-
3.74 (m, 4 H), 7.27 (dd, J ) 7.8, 4.7 Hz, 1 H), 7.56 (s, 1 H), 7.59
(s, 1 H), 8.13 (dd, J ) 7.8, 2.0 Hz, 1 H), 8.57 (d, J ) 3.5 Hz, 1 H).
LC/MS retention time: A, 10.75 min; B, 9.05 min.
5-Bromo-6-(trifluoromethyl)-2-(4-(3-(trifluoromethyl)pyridin-
2-yl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-ben-
zo[d]imidazole (43b). To a solution of compound 43a (203 mg,
0.41 mmol) in dichloromethane (6 mL) were added N,N-diiso-
propylethylamine (148 mg, 1.15 mmol) and 2-(trimethylsilyl)-
ethoxymethyl chloride (94 mg, 0.57 mmol). The reaction mixture
was stirred at room temperature for 16 h. The solvent was removed
in vacuo and the residue was purified by silica gel column
1
+ 1). H NMR (DMSO-d6): δ 3.28-3.38 (m, 4 H), 3.60-3.70
(m, 4 H), 7.18-7.34 (m, 3 H), 7.40-7.51 (m, 3 H), 7.68-7.60
(m, 1 H), 8.09 (dd, J ) 7.8, 1.6 Hz, 1 H), 8.55 (dd, J ) 4.8, 1.2
Hz, 1 H). LC/MS retention time: A, 10.42 min; B, 7.54 min.
6-(Trifluoromethyl)-5-(4-(trifluoromethyl)phenyl)-2-(4-(3-(tri-
fluoromethyl)pyridin-2-yl)piperazin-1-yl)-1H-benzo[d]imid-
azole, Trifluoroacetic Acid Salt (46b). A mixture of 5-bromobenzo-

Piperazinylbenzimidazoles as TRPV1 antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12 3735
imidazole 43a (120 mg, 0.24 mmol), 4-(trifluoromethyl)phenyl-
boronic acid (60 mg, 0.32 mmol), tetrakis(triphenylphosphine)-
palladium(0) (28 mg, 0.02 mmol), and sodium carbonate (0.25 mL,
2 M solution in water) in dioxane (1.75 mL) was heated to 170 °C
in a microwave synthesizer for 20 min. The reaction mixture was
cooled to room temperature, diluted with EtOAc (10 mL), and
filtered through a Varian Chem-Elut (3 mL) diatomaceous earth
cartridge, and the filtrate was evaporated in vacuo. The residue
was purified by preparative HPLC (gradient 0.1% trifluoroacetic
acid in acetonitrile) to give 98 mg (72%) of the title compound as
2-(5-chloro-6-(4-(4-(4-fluorophenyl)-6-(trifluoromethyl)-1H-benzo-
[d]imidazol-2-yl)-3-methylpiperazin-1-yl)pyridin-3-ylamino)-2-
oxoethyl acetate as a brown solid. MS (ESI, pos. ion) m/z: 605
(M + 1).
A mixture of the acetate from the previous step (139 mg, 0.23
mmol) and potassium carbonate (63 mg, 0.46 mmol) in MeOH (1.5
mL) was stirred at room temperature for 30 min. The reaction
mixture was filtered and the filter cake was washed with MeOH
(2 mL). The combined filtrates were concentrated in vacuo, and
the residue was purified by silica gel column chromatography
(gradient 40-60% EtOAc/hexane) to give 45 mg (35%) of the title
compound as an orange solid. MS (ESI, pos. ion) m/z: 563 (M +
1). 1H NMR (CD3OD): δ 1.56 (d, J ) 6.4 Hz, 3 H), 3.05-3.3 (m,
2 H), 3.60-3.90 (m, 3 H), 4.05-4.30 (m, 3 H), 4.55 (br s, 1 H),
7.20-7.60 (m, 5 H), 8.0-8.17 (m, 2 H) 8.29 (d, J ) 2.4 Hz, 1 H),
8.53 (d, J ) 2.4 Hz, 1 H). LC/MS retention time: A, 10.54 min;
B, 5.81 min.
4-Piperidin-1-yl-6-(trifluoromethyl)-2-(4-(3-(trifluoromethyl)-
pyridin-2-yl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-
1H-benzo[d]imidazole (46g). Following the procedure described
for compound 46c, compound 44b and piperidine provided the title
compound (19%) as an oil. MS (ESI, pos. ion) m/z: 629 (M + 1).
4-Piperidin-1-yl-6-(trifluoromethyl)-2-(4-(3-(trifluoromethyl)-
pyridin-2-yl)piperazin-1-yl)-1H-benzo[d]imidazole, Trifluoro-
acetic Acid Salt (46h). Following the procedure described for
compound 46d, compound 46g and trifluoroacetic acid provided
the crude product, which was purified by preparative HPLC
(gradient 0.1% trifluoroacetic acid in acetonitrile) to give the title
compound (20%) as a colorless film. MS (ESI, pos. ion) m/z: 499
(M + 1). 1H NMR (CD3OD): δ 1.69 (s, 2 H), 1.89 (s, 4 H), 3.30-
3.50 (m, 8 H), 3.87 (s, 4 H), 7.16-7.30 (m, 2 H), 7.3 (s, 1H), 8.05
(s, 1 H), 8.50 (s, 1 H). LC/MS retention time: A, 12.22 min; B,
8.61 min.
4-Morpholino-6-(trifluoromethyl)-2-(4-(3-(trifluoromethyl)-
pyridin-2-yl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-
1H-benzo[d]imidazole (46i). Following the procedure described
for compound 46c, compound 44b and morpholine provided the
title compound (34%) as an amorphous solid.
4-Morpholino-6-(trifluoromethyl)-2-(4-(3-(trifluoromethyl)-
pyridin-2-yl)piperazin-1-yl)-1H-benzo[d]imidazole (46j). Fol-
lowing the procedure described for compound 46d, compound 46i
and trifluoroacetic acid provided the title compound (8%) as an
amorphous solid. MS (ESI, pos. ion) m/z: 501 (M + 1). 1H NMR
(CD3OD): δ 3.11-3.17 (m, 4 H), 3.43-3.50 (m, 4 H), 3.92 (dd,
J ) 11.7, 5.1 Hz, 8 H), 7.20 (s, 1 H), 7.28 (dd, J ) 7.4, 5.1 Hz, 1
H), 7.36 (s, 1 H), 8.04-8.12 (m, 1 H), 8.55 (d, J ) 3.9 Hz, 1 H).
LC/MS retention time: C, 16.61 min; D, 11.86 min.
1
an amorphous solid. MS (ESI, pos. ion) m/z: 560 (M + 1). H
NMR (CD3OD): δ 3.47-3.51 (m, 4 H), 3.85-3.89 (m, 4 H), 7.29
(dd, J ) 7.6, 4.5 Hz, 1 H), 7.34 (s, 1 H), 7.55 (d, J ) 7.8 Hz, 2 H),
7.73-7.81 (m, 3 H), 8.11 (d, J ) 7.8 Hz, 1 H), 8.56 (d, J ) 3.9
Hz, 1 H). Anal. (C25H18F9N5‚CF3CO2H): C, H, N.
N-(4-(Trifluoromethyl)benzyl)-6-(trifluoromethyl)-2-(4-(3-(tri-
fluoromethyl)pyridin-2-yl)piperazin-1-yl)-1-((2-(trimethylsilyl)-
ethoxy)methyl)-1H-benzo[d]imidazol-5-amine, Trifluoroacetic
Acid Salt (46c). A mixture of 5-bromobenzoimidazole 43b (88
mg, 0.14 mmol), 4-(trifluoromethyl)benzylamine (37 mg, 0.21
mmol), tris(dibenzylideneacetone)dipalladium(0) (8 mg, 0.01 mmol),
2-(di-tert-butylphosphino)biphenyl (8 mg, 0.03 mmol), and sodium-
tert-butoxide (31 mg, 0.33 mmol) in toluene (2 mL) was heated at
150 °C in a microwave synthesizer for 14 min. The reaction mixture
was cooled to room temperature, diluted with EtOAc (5 mL), and
filtered through a Celite pad. The filtrate was concentrated in vacuo,
and the residue was dissolved in MeOH (4 mL) and purified by
preparative HPLC (gradient 0.1% trifluoroacetic acid in acetonitrile)
to give the title compound as pale-yellow oil. MS (ESI, pos. ion)
m/z: 719 (M + 1).
N-(4-(Trifluoromethyl)benzyl)-6-(trifluoromethyl)-2-(4-(3-(tri-
fluoromethyl)pyridin-2-yl)piperazin-1-yl)-1H-benzo[d]imidazol-
5-amine, Trifluoroacetic Acid Salt (46d). Compound 46c was
treated with 1:1 mixture of CF3CO2H/CH2Cl2 (3 mL) and stirred
at room temperature for 12 h. The reaction mixture was concentrated
to yield a gummy residue, which was dissolved in MeOH (4 mL)
and purified by preparative HPLC (gradient 0.1% trifluoroacetic
acid in acetonitrile) to give 7 mg (8%) of the title compound as a
yellow amorphous solid. MS (ESI, pos. ion) m/z: 589 (M + 1).
1H NMR (CD3OD): δ 3.43-3.49 (m, 4 H), 3.75-3.82 (m, 4 H),
4.67 (s, 2 H), 6.49 (s, 1 H), 7.32 (dd, J ) 7.6, 4.9 Hz, 1 H), 7.53
(s, 1 H), 7.61 (d, J ) 8.0 Hz, 2 H), 7.67 (d, J ) 8.0 Hz, 2 H), 8.13
(d, J ) 8.0 Hz, 1 H), 8.58 (d, J ) 4.3 Hz, 1 H). LC/MS retention
time: A, 11.21 min; B, 8.27 min.
(R)-5-Chloro-6-(4-(4-(4-fluorophenyl)-6-(trifluoromethyl)-1H-
benzo[d]imidazol-2-yl)-3-methylpiperazin-1-yl)pyridin-3-
amine (46e). A mixture of compound 34 (444 mg, 0.909 mmol),
4-fluorophenylboronic acid (191 mg, 1.36 mmol), dichloro-bis-
(triphenylphosphine)palladium(II) (128 mg, 0.181 mmol), and
Na2CO3 (385 mg, 3.64 mmol) in a solution of 7:3:2 1,2-
dimethoxyethane/H2O/EtOH (4.5 mL) was heated to 82 °C for 3
h. The reaction mixture was cooled to room temperature and filtered.
The filter cake was washed with MeOH (20 mL), and the combined
filtrates were concentrated in vacuo. The residue was purified by
silica gel column chromatography (gradient 15-100% EtOAc/
hexane) to give 301 mg (66%) of the title compound as a brown
solid. MS (ESI, pos. ion) m/z: 505, 507 (M + 1). 1H NMR
(CD3OD): δ 1.39 (d, J ) 6.3 Hz, 3 H), 2.84-2.96 (m, 2 H), 3.30-
3.50 (m, 3 H), 3.80-4.00 (m, 1 H), 4.30-4.70 (m, 1 H), 7.08-
7.60 (m, 7 H), 7.9 (br s, 1 H). Anal. (C24H21ClF4N6‚0.5EtOAc‚
0.05H2O): C, H, N.
(R)-1-(5-Chloro-6-((R)-3-methyl-4-(6-(trifluoromethyl)-4-(3,4,5-
trifluorophenyl)-1H-benzo[d]imidazol-2-yl)piperazin-1-yl)pyri-
din-3-yl)ethanol (46k). The title compound was isolated by
preparative HPLC separation of the diastereoisomeric mixture of
products of the reaction for the preparation of compound 46l. The
R-configuration of the chiral secondary alcohol was assigned at
random. MS (ESI, neg ion) m/z: 570 (M - 1). 1H NMR
(CD3OD): δ 1.44 (d, J ) 6.7 Hz, 3 H), 1.49 (d, J ) 6.6 Hz, 3 H),
3.06 (dt, J ) 12.5, 3.2 Hz, 1 H), 3.15 (dd, J ) 12.1, 3.3 Hz, 1 H),
3.64 (dt, J ) 12.5, 3.1 Hz, 1 H), 3.80 (t, J ) 12.5 Hz, 2 H), 4.06
(d, J ) 12.9 Hz, 1 H), 4.40-4.52 (m, 1 H), 4.82 (q, J ) 6.4 Hz,
1 H), 7.46 (s, 2 H), 7.78 (d, J ) 1.9 Hz, 1 H), 7.86 (br s, 2 H),
8.18 (d, J ) 1.6 Hz, 1 H). LC/MS retention time: A, 12.04 min;
B, 11.58 min.
(R)-N-(5-Chloro-6-(4-(4-(4-fluorophenyl)-6-(trifluoromethyl)-
1H-benzo[d]imidazol-2-yl)-3-methylpiperazin-1-yl)pyridin-3-yl)-
2-hydroxyacetamide (46f). A mixture of compound 46e (117 mg,
0.232 mmol), acetoxyacetic acid (27 mg, 0.232 mmol), benzotriazol-
1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (154
mg, 0.348 mmol), and N,N-diisopropylethylamine (0.08 mL, 0.464
mmol) in CH2Cl2 (1.5 mL) was stirred at room temperature for 18
h. The reaction mixture was evaporated under reduced pressure
and the residue was purified by silica gel column chromatography
(gradient 0-100% EtOAc/hexane) to give 139 mg (99%) of (R)-
(S)-1-(5-Chloro-6-((R)-3-methyl-4-(6-(trifluoromethyl)-4-(3,4,5-
trifluorophenyl)-1H-benzo[d]imidazol-2-yl)piperazin-1-yl)pyri-
din-3-yl)ethanol (46l). To a solution of the diastereomeric mixture
44c (416 mg, 0.8 mmol) in MeCN (3 mL) was added 3,4,5-
trifluorophenylboronic acid (282 mg, 1.6 mmol), Pd(PPh3)4 (84 mg,
0.08 mmol), and Na2CO3 (4 mL, 0.4 M in water, 1.6 mmol). The
mixture was stirred at 90 °C under N2 atmosphere for 20 h, cooled
to room temperature, and diluted with water (20 mL). The reaction
mixture was extracted with EtOAc (2 × 40 mL). The combined
organic extracts were washed with brine (20 mL), dried over

3736 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12
OgnyanoV et al.
Na2SO4, and filtered. The filtrate was evaporated in vacuo and the
residue was purified by silica gel column chromatography (50%
EtOAc/hexane) to give 277 mg (61%) of the product of the reaction
as a mixture of diastereoisomers. Separation of the mixture by
preparative HPLC on a Chiralcel OD column (10% EtOH/hexane)
afforded the fast-running diastereoisomer 46l. The S-configuration
of the chiral secondary alcohol of the isomer 46l was assigned at
and the residue was purified by silica gel column chromatography
(10% ethyl acetate/hexane) to give 5.6 g (63%) of 4-(trifluoro-
methyl)cyclohex-1-enyl trifluoromethanesulfonate as an oil. MS
(ESI, pos. ion) m/z: 299 (M + 1).
To a solution of the triflate from the previous step (5.6 g, 18.8
mmol) in dioxane (100 mL) were added bisboronpinacolate (5.6
g, 22 mmol), potassium acetate (6 g, 61 mmol), PdCl2(dppf) (315
mg, 0.6 mml), and dppf (332 mg, 0.6 mmol), and the contents were
flushed with nitrogen. The reaction mixture was heated at 80 °C
overnight. The solvents were removed in vacuo, and the residue
was extracted with EtOAc and washed with water. The organic
layer was separated, dried over Na2SO4, and filtered. The filtrate
was evaporated and the residue was purified by silica gel column
chromatography (10% ethyl acetate/hexane) to give 4.23 g (81%)
of 4,4,5,5-tetramethyl-2-(4-trifluoromethyl-cyclohex-1-enyl)[1,3,2]-
dioxaborolane as white amorphous solid. MS (ESI, pos. ion) m/z:
277 (M + 1).
A mixture of 4-bromobenzoimidazole 44a (100 mg, 0.5 mmol),
4,4,5,5-tetramethyl-2-(4-trifluoromethyl-cyclohex-1-enyl)[1,3,2]-
dioxaborolane from the previous step (200 mg, 0.72 mmol),
Pd(PPh3)4 (58 mg, 0.05 mmol), and Na2CO3 (80 mg, 0.75 mmol)
in dimethoxyethane (1 mL) was subjected to microwave irradiation
at 200 °C with stirring for 40 min. The solvent was removed in
vacuo and the residue purified by silica gel chromatography (60%
EtOAc/hexane) to give 58 mg (52%) of 6-(trifluoromethyl)-4-(4-
(trifluoromethyl)cyclohex-1-enyl)-2-(4-(3-(trifluoromethyl)pyridin-
2-yl)piperazin-1-yl)-1H-benzo[d]imidazole, trifluoroacetic acid salt,
as a white solid. MS (ESI, pos. ion) m/z: 564 (M + 1). Mp: 214-
217 °C.
1
random. MS (ESI, neg ion) m/z: 570 (M-1). H NMR (CD3OD):
δ 1.44 (d, J ) 6.6 Hz, 3 H), 1.49 (d, J ) 6.6 Hz, 3 H), 3.06 (dt,
J ) 12.5, 3.1 Hz, 1 H), 3.15 (dd, J ) 12.1, 3.3 Hz, 1 H), 3.64 (dt,
J ) 12.5, 3.1 Hz, 1 H), 3.80 (t, J ) 12.5 Hz, 2 H), 4.06 (d, J )
12.9 Hz, 1 H), 4.40-4.52 (m, 1 H), 4.82 (q, J ) 6.4 Hz, 1 H),
7.46 (s, 2 H), 7.78 (d, J ) 1.9 Hz, 1 H), 7.86 (br s, 2 H), 8.18 (d,
J ) 1.6 Hz, 1 H). LC/MS retention time: A, 12.05 min; B, 11.57
min.
6-(Trifluoromethyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)-
piperazin-1-yl)-4-(3,4,5-trifluorophenyl)-1H-benzo[d]imidazole
(46m). A mixture of compound 44a (2.22 g, 4.5 mmol), 3,4,5-
trifluorophenylboronic acid (1.1 g, 6 mmol), PdCl2(PPh3)2 (35 mg,
0.05 mmol), Na2CO3 monohydrate (1 g, 8 mmol), dimethoxyethane
(7 mL), H2O (3 mL), and EtOH (2 mL) was subjected to microwave
irradiation at 120 °C with stirring for 10 min. The mixture was
diluted with water (10 mL) and extracted with EtOAc (2 × 20
mL). The combined organic phases were washed with brine (10
mL), dried over Na2SO4, and filtered. The filtrate was concentrated
in vacuo and the residue was purified by silica gel chromatography,
eluting with 35% EtOAc/hexane to give 1.7 g (69%) of the title
compound as a white amorphous solid. MS (ESI, pos. ion) m/z:
1
546 (M + 1). H NMR (CD3OD): δ 3.34-3.42 (m, 4 H), 3.74-
3.84 (m, 4 H), 7.22 (dd, J ) 7.4, 4.9 Hz, 1 H), 7.47 (br s, 2 H),
7.88 (br s, 2 H), 8.06 (dd, J ) 7.8, 1.5 Hz, 1 H), 8.51 (d, J ) 3.7
Hz, 1 H). Anal. (C24H16F9N5): C, H, N.
6-(Trifluoromethyl)-4-(4-(trifluoromethyl)cyclohex-1-enyl)-2-(4-
(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-1H-benzo[d]imid
azole, trifluoroacetic acid salt, from the previous step (10 mg) was
subjected to catalytic hydrogenation in EtOH (1 mL) using 10%
Pd/C (10 mg) as catalyst. The reaction was conducted at room
temperature under 1 atm of hydrogen for 2 days. The catalyst was
filtered through a Celite pad and the filter cake was washed with
methanol. The combined filtrates were evaporated in vacuo to give
10 mg (100%) of the title compound as a film. MS (ESI, pos. ion)
4-Thiazol-2-yl-6-(trifluoromethyl)-2-(4-(3-(trifluoromethyl)-
pyridin-2-yl)piperazin-1-yl)-1H-benzo[d]imidazole, Trifluoro-
acetic Acid Salt (46n). A mixture of compound 44a (148 mg, 0.3
mmol), 2-tributylstannylthiazole (187 mg, 0.5 mmol), Pd(PPh3)4
(46 mg, 0.04 mmol), and 1,4-dioxane (1 mL) was subjected to
microwave irradiation at 140 °C with stirring for 60 min. The
solvent was removed in vacuo and the residue was purified by
preparative HPLC (gradient 0.1% trifluoroacetic acid in acetonitrile)
to give 120 mg (80%) of the title compound as a white amorphous
solid. MS (ESI, pos. ion) m/z: 499 (M + 1). 1H NMR (CDCl3): δ
3.40-3.52 (m, 4 H), 3.84 (br s, 4 H), 7.10 (dd, J ) 8.0, 4.0 Hz, 1
H), 7.60-7.80 (m, 2 H), 7.81 (s, 1 H), 7.93 (dd, J ) 8.0, 4.0 Hz,
1 H), 8.49 (d, J ) 4.0 Hz, 1 H), 9.00 (d, J ) 4.0 Hz, 1 H), 10.55
(br s, 1 H). Anal. (C21H16F6N6S‚0.11TFA‚0.22H2O): C, H, N.
4-(3,4-Difluorobenzyl)-6-(trifluoromethyl)-2-(4-(3-(trifluoro-
methyl)pyridin-2-yl)piperazin-1-yl)-1H-benzo[d]imidazole, Tri-
fluoroacetic Acid Salt (46o). A mixture of 4-bromobenzoimidazole
44a (148 mg, 0.3 mmol), a 0.5 M solution of 3,4-difluorobenzylzinc
bromide in THF (2 mL, 1 mmol), and Pd(PPh3)4 (35 mg, 0.03
mmol) was heated at reflux for 12 h. The solvent was removed in
vacuo and the residue was purified by preparative HPLC (gradient
0.1% trifluoroacetic acid in acetonitrile) to give 25 mg (13%) of
the title compound as a white amorphous solid. MS (ESI, pos. ion)
1
m/z: 565 (M + 1). H NMR (CD3OD): δ 1.50-2.10 (m, 10 H),
3.31 (s, 4 H), 3.67 (s, 4 H), 7.00-7.20 (m, 2 H), 7.27 (s, 1 H),
7.97 (d, J ) 7.8 Hz, 1 H), 8.42 (s, 1 H). LC/MS retention time: A,
12.28 min; B, 3.21 min.
6-(Trifluoromethyl)-4-(4-(trifluoromethyl)phenyl)-2-(4-(3-
(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-1H-benzo[d]-
imidazole (46q). Following the procedure described for compound
46m, compound 44a and 4-trifluoromethylphenylboronic acid
provided the title compound (83%) as a white solid. MS (ESI, pos.
1
ion) m/z: 548 (M + 1). H NMR (CD3OD): δ 3.32-3.40 (m, 4
H), 3.76-3.82 (m, 4 H), 7.22 (dd, J ) 7.7, 2.8 Hz, 1 H), 7.47 (s,
1 H), 7.51 (s, 1 H), 7.77 (s, 1 H), 7.79 (s, 1 H), 8.08-8.04 (m, 3
H), 8.51 (d, J ) 3.9 Hz, 1 H). Anal. (C25H18F9N5): C, H, N.
4-Phenyl-6-(trifluoromethyl)-2-(4-(3-(trifluoromethyl)pyridin-
2-yl)piperazin-1-yl)-1H-benzo[d]imidazole (46r). Following the
procedure described for compound 46m, compound 44a and
phenylboronic acid provided the title compound (65%) as an
amorphous solid. MS (ESI, pos. ion) m/z: 492 (M + 1). 1H NMR
(CD3OD): δ 3.34-3.42 (m, 4 H), 3.72-3.80 (m, 4 H), 7.21 (dd,
J ) 7.5, 2.5 Hz, 1 H), 8.00-7.39 (m, 7 H), 8.04 (d, J ) 6.8 Hz,
1 H), 8.50 (d, J ) 4.5 Hz, 1 H). Anal. (C24H19F6N5): C, H, N.
4-(3-(Trifluoromethoxy)phenyl)-6-(trifluoromethyl)-2-(4-
(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-1H-benzo[d]-
imidazole, Trifluoroacetic Acid Salt (46s). Following the
procedure described for compound 46m, compound 44a and
3-(trifluoromethoxy)phenylboronic acid provided the crude product
which was purified by preparative HPLC (gradient 0.1% tri-
fluoroacetic acid in acetonitrile) to give the title compound (60%)
as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 576 (M
+ 1). 1H NMR (CDCl3): δ 3.40-3.50 (m, 4 H), 3.68-3.80 (m, 4
H), 7.08 (dd, J ) 8.0, 4.0 Hz, 1 H), 7.12-8.40 (m, 7 H), 8.50 (d,
J ) 4.0 Hz, 1 H). Anal. (C25H18F9N5O‚0.15TFA): C, H, N.
1
m/z: 542 (M + 1). H NMR (CDCl3): δ 3.20-3.30 (m, 4 H),
3.60-3.70 (m, 4 H), 4.15 (s, 2 H), 7.01-7.13 (m, 5 H), 7.26 (s, 1
H), 7.93 (d, J ) 8.0 Hz, 1 H), 8.45 (d, J ) 4.4 Hz, 1 H). LC/MS
retention time: A, 11.93 min; B, 6.42 min.
6-(Trifluoromethyl)-4-(4-(trifluoromethyl)cyclohexyl)-2-(4-
(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-1H-benzo[d]-
imidazole (46p). To 4-trifluoromethylcyclohexanone (4.98 g, 30
mmol) in THF (100 mL) was added lithium bistrimethylsilylamide
(30 mL, 1 M solution in THF) over a period of 30 min with stirring
at -78 °C. After stirring for 1 h at -78 °C, a solution of
N-phenyltrifluoromethanesulfonimide (10.71 g, 30 mmol) in THF
(100 mL) was added over a period of 30 min. The reaction mixture
was stirred at -78 °C for 2 h and slowly warmed to room
temperature over a period of 6 h. The reaction mixture was extracted
with EtOAc, and the combined organic extracts were washed with
water, dried over Na2SO4, and filtered. The filtrate was evaporated

Piperazinylbenzimidazoles as TRPV1 antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12 3737
4-(4-tert-Butylphenyl)-6-(trifluoromethyl)-2-(4-(3-(trifluoro-
methyl)pyridin-2-yl)piperazin-1-yl)-1H-benzo[d]imidazole (46t).
Following the procedure described for compound 46m, compound
44a and 4-tert-butylphenylboronic acid provided the title compound
(76%) as a white solid. Mp: 214 °C. MS (ESI, pos. ion) m/z: 548
(d, J ) 7.4 Hz, 1 H), 8.77 (d, J ) 5.5 Hz, 1 H). Anal. (C24H20F6N6‚
0.12TFA) C, H, N.
N,N-Dimethyl-4-(6-(trifluoromethyl)-2-(4-(3-(trifluoromethyl)-
pyridin-2-yl)piperazin-1-yl)-1H-benzo[d]imidazol-4-yl)benzenamine
(46aa). Following the procedure described for compound 46m,
compound 44a and 4-dimethylaminophenylboronic acid provided
the title compound (45%) as a tan amorphous solid. MS (ESI, pos.
ion) m/z: 535 (M + 1). 1H NMR (CDCl3): δ 3.07 (s, 6 H), 3.10-
3.20 (m, 4 H), 3.44-3.54 (m, 4 H), 6.98 (d, J ) 8.0 Hz, 2 H),
7.18-7.24 (m, 1 H), 7.28 (br s, 1 H), 7.41 (br s, 1 H), 7.50-7.60
(m, 2 H), 8.05 (d, J ) 8.0 Hz, 1 H), 8.50 (d, J ) 4.8 Hz, 1 H).
(E)-4-Styryl-6-(trifluoromethyl)-2-(4-(3-(trifluoromethyl)pyr-
idin-2-yl)piperazin-1-yl)-1H-benzo[d]imidazole (46ab). Following
the procedure described for compound 46m, compound 44a and
trans-2-phenylvinylboronic acid provided the title compound (53%)
as a solid. Mp: 117.9-118 °C. MS (ESI, pos. ion) m/z: 518 (M
+ 1). 1H NMR (CDCl3): δ 3.18 (s, 4 H), 3.63 (s, 4 H), 7.10-7.20
(m, 2H), 7.25-7.35 (m, 3 H), 7.50-7.60 (m, 5 H), 7.92 (s, 1 H),
8.43 (s, 1 H). Anal. (C26H21F6N5‚0.1H2O‚0.3EtOAc): C, H, N.
(R)-2-(4-(3-Chloro-5-vinylpyridin-2-yl)-2-methylpiperazin-
1-yl)-6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzo[d]-
imidazole (46ac). A mixture of compound 45 (2.73 g, 4.5 mmol),
tributylvinylstannane (1.5 mL, 5.0 mmol), Pd(Ph3P)4 (255 mg, 0.23
mmol), LiCl (570 mg, 13.5 mmol), and a few crystals of 2,6-di-
tert-butylphenol in dioxane (40 mL) was stirred at 95 °C for 5 h.
The reaction mixture was cooled to room temperature, diluted with
EtOAc (200 mL), washed with water (50 mL) and brine (50 mL),
dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo
and the residue was purified by silica gel chromatography (20%
EtOAc/hexane) to give 1.75 g (72%) of the title compound as a
gum. MS (ESI, pos. ion) m/z: 552 (M + 1). 1H NMR (CDCl3): δ
1.51 (d, J ) 6.6 Hz, 3 H), 3.11 (dt, J ) 12.5, 3.1 Hz, 1 H), 3.22
(dd, J ) 12.5, 4.0 Hz, 1 H), 3.69 (dt, J ) 12.5, 3.1 Hz, 1 H), 3.72
(s, 1 H), 3.60-4.08 (m, 3 H), 4.38 (br s, 1 H), 5.32 (d, J ) 11.0
Hz, 1 H), 5.71 (d, J ) 17.6 Hz, 1 H), 6.63 (dd, J ) 17.6, 11.0 Hz,
1 H), 7.44 (br s, 1 H), 7.50 (br s, 1 H), 7.74 (d, J ) 2.0 Hz, 1 H),
7.84 (br s, 1 H), 8.18 (d, J ) 1.6 Hz, 1 H), 8.37 (br s, 1 H).
(R)-1-(5-Chloro-6-((R)-3-methyl-4-(6-(trifluoromethyl)-4-(3,4,5-
trifluorophenyl)-1H-benzo[d]imidazol-2-yl)piperazin-1-yl)pyri-
din-3-yl)ethane-1,2-diol and (S)-1-(5-Chloro-6-((R)-3-methyl-4-
(6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzo[d]imidazol-
2-yl)piperazin-1-yl)pyridin-3-yl)ethane-1,2-diol (46ad). A mixture
of compound 46ac (1.65 g, 3 mmol), OsO4 (0.95 mL, 0.15 mmol,
4% in water), and N-methylmorpholine N-oxide (421 mg, 3.6 mmol)
in acetone (20 mL) was stirred at room temperature for 5 h. The
reaction mixture was treated with saturated NaHSO3 (20 mL) and
extracted with EtOAc (2 × 50 mL). The combined organic extracts
were washed with brine (30 mL), dried over Na2SO4, and filtered.
The filtrate was evaporated in vacuo and the residue was purified
by silica gel column chromatography (EtOAc) to give 1.09 g (62%)
of the desired product as a mixture of diastereoisomers. MS (ESI,
1
(M + 1). H NMR (CDCl3): δ 1.37 (s, 9 H), 3.43 (br s, 4 H),
3.70-3.82 (m, 4 H), 7.08 (br s, 1 H), 7.33 (s, 1 H), 7.50-7.60 (m,
3 H), 7.68 (s, 1 H), 7.92 (d, J ) 7.6 Hz, 1 H), 8.30 (s, 1 H), 8.47
(d, J ) 3.6 Hz, 1 H). Anal. (C28H27F6N5): C, H, N.
4-Thiophen-2-yl-6-(trifluoromethyl)-2-(4-(3-(trifluoromethyl)-
pyridin-2-yl)piperazin-1-yl)-1H-benzo[d]imidazole, Trifluoro-
acetic Acid Salt (46u). Following the procedure described for
compound 46m, compound 44a and (thiophen-2-yl)boronic acid
provided the crude product, which was purified by preparative
HPLC (gradient 0.1% trifluoroacetic acid in acetonitrile) to give
the title compound (57%) as a white amorphous solid. MS (ESI,
pos. ion) m/z: 498 (M + 1). 1H NMR (CD3OD): δ 3.40-3.50 (m,
4 H), 3.80-3.90 (m, 4 H), 7.20-7.25 (m, 2 H), 7.58 (d, J ) 10.5
Hz, 2 H), 7.61 (dd, J ) 5.2, 1.0 Hz, 1 H), 7.65 (dd, J ) 7.8, 1.5
Hz, 1 H), 8.54 (d, J ) 4.7 Hz, 1 H). Anal. (C22H16F6N6S‚1.5TFA):
C, H, N.
4-Pyridin-4-yl-6-(trifluoromethyl)-2-(4-(3-(trifluoromethyl)-
pyridin-2-yl)piperazin-1-yl)-1H-benzo[d]imidazole (46v). Fol-
lowing the procedure described for compound 46m, compound 44a
and pyridin-4-ylboronic acid provided the title compound (50%)
as a white solid. Mp: 293 °C. MS (ESI, pos. ion) m/z: 493 (M +
1
1). H NMR (CD3OD): δ 3.32-3.42 (m, 4 H), 3.74-3.86 (m, 4
H), 7.22 (dd, J ) 7.7, 4.9 Hz, 1 H), 7.51 (br s, 1 H), 7.65 (br s, 1
H), 8.06 (d, J ) 7.8 Hz, 1 H), 8.18 (br s, 2 H), 8.51 (d, J ) 4.2 Hz,
1 H), 8.61 (br s, 2 H). Anal. (C23H18F5N6): C, H, N.
4-Pyrazin-2-yl-6-(trifluoromethyl)-2-(4-(3-(trifluoromethyl)-
pyridin-2-yl)piperazin-1-yl)-1H-benzo[d]imidazole (46w). Fol-
lowing the procedure described for compound 46n, compound 44a
and 2-tributylstannylpyrazine provided the title compound (51%)
as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 494 (M +
1
1). H NMR (CDCl3): δ 3.40-3.52 (m, 4 H), 3.78-3.86 (m, 4
H), 7.08-7.14 (m, 1 H), 7.80 (s, 1 H), 7.90-7.96 (m, 2 H), 8.46-
8.52 (m, 1 H), 8.58 (s, 1 H), 8.68 (s, 1 H), 9.36 (br s, 1 H), 10.75
(br s, 1 H). Anal. (C22H17F6N7): C, H, N.
4-(6-Methoxypyridin-3-yl)-6-(trifluoromethyl)-2-(4-(3-(trifluo-
romethyl)pyridin-2-yl)piperazin-1-yl)-1H-benzo[d]imidazole, Tri-
fluoroacetic Acid Salt (46x). Following the procedure described
for compound 46m, compound 44a and 3-(6-methoxypyridyl)-
boronic acid provided the crude product, which was purified by
preparative HPLC (gradient 0.1% trifluoroacetic acid in acetonitrile)
to give the title compound (32%) as a white amorphous solid. MS
1
(ESI, pos. ion) m/z: 523 (M + 1). H NMR (CD3OD): δ 3.40-
3.50 (m, 4 H), 3.80-3.90 (m, 4 H), 3.99 (s, 3 H), 6.82 (d, J ) 8.6
Hz, 1 H), 7.26 (dd, J ) 8.1, 5.3 Hz, 1 H), 7.53 (s, 1 H), 7.62 (s, 1
H), 8.00 (dd, J ) 8.4, 2.2 Hz, 1 H), 8.08 (d, J ) 7.7 Hz, 1 H), 8.49
(d, J ) 1.9 Hz, 1 H), 8.53 (d, J ) 4.6 Hz, 1 H). Anal.
(C24H20F6N6O‚0.95TFA‚0.2H2O): C, H, N.
1
pos. ion) m/z: 586 (M + 1). H NMR (CD3OD): δ 1.49 (d, J )
6.3 Hz, 3 H), 3.06 (dt, J ) 12.5, 3.5 Hz, 1 H), 3.15 (dd, J ) 12.5,
3.3 Hz, 1 H), 3.56-3.70 (m, 3 H), 3.81 (t, J ) 11.7 Hz, 2 H), 4.07
(d, J ) 11.7 Hz, 1 H), 4.47 (br s, 1 H), 4.66 (t, J ) 5.5 Hz, 1 H),
7.40-7.52 (m, 2 H), 7.79 (s, 1 H), 7.88 (br s, 2 H), 8.19 (s, 1 H).
Anal. (C26H22ClN5F6O2‚0.8H2O): C, H, N.
4-Benzo[b]thiophen-2-yl-6-(trifluoromethyl)-2-(4-(3-(trifluo-
romethyl)pyridin-2-yl)piperazin-1-yl)-1H-benzo[d]imidazole (46y).
Following the procedure described for compound 46m, compound
44a and benzo[b]thiophen-2-ylboronic acid provided the title
compound (61%) as an off-white amorphous solid. MS (ESI, pos.
6-tert-Butyl-2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-
1-yl)-1H-benzo[d]imidazole (47a). A mixture of 2-chlorobenzo-
imidazole 20a (0.209 g, 1 mmol), 1-(3-trifluoromethylpyridin-2-
yl)piperazine (0.346 g, 1.65 mmol), and N,N-diisopropylethylamine
(0.28 mL, 1.6 mmol) in MeCN (1 mL) was heated in a microwave
synthesizer at 180 °C for 30 min. The reaction mixture was
evaporated under vacuo and the residue was purified by silica gel
column chromatography (30% EtOAc/hexane) to give 0.137 g
(34%) of the title compound as a white solid. Mp: 247-249 °C.
1
ion) m/z: 548 (M + 1). H NMR (CD3OD): δ 3.24-3.34 (m, 4
H), 3.70-3.80 (m, 4 H), 7.13 (dd, J ) 8.0, 1.2 Hz, 1 H), 7.20-
7.34 (m, 3 H), 7.56 (s, 1 H), 7.72-7.80 (m, 2 H), 7.98 (d, J ) 7.6
Hz, 1 H), 8.32 (s, 1 H), 8.42 (d, J ) 4.0 Hz, 1 H). Anal.
(C26H19F6N5S): C, H, N.
4-(6-(Trifluoromethyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)-
piperazin-1-yl)-1H-benzo[d]imidazol-4-yl)benzenamine (46z).
Following the procedure described for compound 46m, compound
44a and 4-aminophenylboronic acid provided the title compound
(48%) as amorphous solid. MS (ESI, pos. ion) m/z: 507 (M + 1).
1H NMR (CD3OD): δ 3.61-3.65 (m, 4 H), 4.01-4.03 (m, 4 H),
4.03 (s, 6 H), 7.11 (d, J ) 8.6 Hz, 2 H), 7.48 (dd, J ) 7.6, 4.5 Hz,
1 H), 7.54 (s, 1 H), 7.67 (s, 1 H), 7.81 (d, J ) 7.2 Hz, 2 H), 8.31
1
MS (ESI, pos. ion) m/z: 404 (M + 1). H NMR (DMSO-d6): δ
1.31 (s, 9 H), 3.25-3.35 (m, 4 H), 3.57-3.65 (m, 4 H), 7.01 (d, J
) 8.2 Hz, 1 H), 7.13 (d, J ) 8.2 Hz, 1 H), 7.22 (s, 1 H), 7.26 (dd,
J ) 7.8, 4.7 Hz, 1 H), 8.12 (d, J ) 7.8 Hz, 1 H), 8.57 (d, J ) 4.3
Hz, 1 H). LC/MS retention time: A, 9.91 min; B, 6.83 min.

3738 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12
OgnyanoV et al.
6-Methyl-2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-
yl)-1H-benzo[d]imidazole Hydrochloride (47b). Following the
procedure described for compound 47a, 2-chlorobenzoimidazole
20k and 1-(3-trifluoromethylpyridin-2-yl)piperazine provided the
crude reaction product. A solution of the product in EtOAc was
treated with a 1 M solution of hydrogen chloride in Et2O and the
mixture was evaporated under reduced pressure. The residue was
dried in vacuo to give the title compound (39%) as a white solid.
mmol), 1-(3-trifluoromethyl-pyridin-2-yl)piperazine (47 mg, 0.203
mmol), triethylamine (59 µL, 0.406 mmol), and copper(I) iodide
(1 mg, 0.005 mmol) in 3-methyl-butan-1-ol (0.5 mL) was heated
in a microwave synthesizer at 220 °C for 0.5 h. The reaction mixture
was cooled to room temperature and was filtered. The filtrate was
evaporated in vacuo and the residue was purified by preparative
HPLC (gradient 0.1% CF3CO2H/MeCN) to give 55 mg (65%) of
the title compound as a colorless solid. MS (ESI, positive ion)
1
1
MS (ESI, pos. ion) m/z: 362 (M + 1). H NMR (DMSO-d6): δ
m/z: 417 (M + 1). H NMR (CD3OD): δ 3.40-3.50 (m, 4 H),
2.33 (s, 3 H), 3.20-3.30 (m, 4 H), 3.50-3.64 (m, 4 H), 6.76 (d, J
) 7.4 Hz, 1 H), 7.02 (s, 1 H), 7.09 (d, J ) 7.4 Hz, 1 H), 7.20-
7.30 (m, 1 H), 8.12 (d, J ) 7.4 Hz, 1 H), 8.57 (d, J ) 3.5 Hz, 1
H), 11.33 (br s, 1 H). Anal. (C18H18F3N5‚HCl): C, H, N.
3.90-4.00 (m, 4 H), 7.26-7.31 (m, 1 H), 7.91 (s, 1 H), 8.11 (d, J
) 7.8 Hz, 1 H), 8.40-8.60 (m, 2 H). LC/MS retention time: A,
9.22 min; B, 5.93 min.
5-(Trifluoromethyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)-
piperazin-1-yl)-3H-imidazo[4,5-b]pyridine, Trifluoroacetic Acid
Salt (49b). Following the procedure described for compound 47c,
2-chlorobenzoimidazole 20e and 1-(3-trifluoromethylpyridin-2-yl)-
piperazine provided the title compound (2%) as an amorphous solid.
6-Fluoro-2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-
1H-benzo[d]imidazole, Trifluoroacetic Acid Salt (47c). A mixture
of the 2-chlorobenzimidazole 20g (170 mg, 1.0 mmol), 1-(3-
trifluoromethylpyridin-2-yl)piperazine (347 mg, 1.5 mmol), and
sodium bicarbonate (250 mg, 2.9 mmol) in isoamyl alcohol (2 mL)
was heated at 150 °C in a microwave synthesizer for 10 min. The
reaction mixture was cooled to room temperature, diluted with
MeOH (3 mL), and filtered. The filtrate was evaporated under
reduced pressure and the residue was purified by preparative HPLC
(gradient 0.1% trifluoroacetic acid in acetonitrile) to give 90 mg
(25%) of the title compound as an amorphous solid. MS (ESI, pos.
1
MS (ESI, pos. ion) m/z: 417 (M + 1). H NMR (DMSO-d6): δ
3.32-3.36 (m, 4 H), 3.76-3.79 (m, 4 H), 7.28 (dd, J ) 7.7, 4.8
Hz, 1 H), 7.47 (d, J ) 8.0 Hz, 1 H), 7.68 (d, J ) 7.8 Hz, 1 H),
8.13 (dd, J ) 7.8, 1.6 Hz, 1 H), 8.57 (d, J ) 4.0 Hz, 1 H). LC/MS
retention time: A, 9.39 min; B, 8.75 min.
(R)-2-(2-Methyl-4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-
1-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (50a). A mixture
of piperazine 8u (245 mg, 1 mmol), 2-chlorobenzoimidazole 20n
(176 mg, 0.8 mmol), N,N-diisopropylethylamine (0.34 mL, 2 mmol),
and copper iodide (19 mg, 0.1 mmol) in dioxane (2 mL) was heated
in a microwave synthesizer at 200 °C for 1.5 h. The reaction mixture
was evaporated in vacuo and the residue was purified by silica gel
column chromatography (EtOAc) to give 163 mg (38%) of the title
compound as a solid. Mp: 216.3-218.7 °C. MS (ESI, pos. ion)
1
ion) m/z: 366 (M + 1). H NMR (CD3OD): δ 3.43-3.49 (m, 4
H), 3.79-3.85 (m, 4 H), 7.07-7.14 (m, 1 H), 7.20 (dd, J ) 8.2,
2.3 Hz, 1 H), 7.28 (dd, J ) 7.8, 5.1 Hz, 1 H), 7.40 (dd, J ) 9.0,
4.3 Hz, 1 H), 8.10 (d, J ) 8.0 Hz, 1 H), 8.55 (d, J ) 4.0 Hz, 1 H).
Anal. (C17H15F4N5‚1.3CF3COOH): C, H, N.
6-Chloro-2-[4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl]-
1H-benzo[d]imidazole (47d). Following the procedure described
for compound 47a, 2-chlorobenzoimidazole 20j and 1-(3-tri-
fluoromethylpyridin-2-yl)piperazine provided the title compound
(47%) as a white solid. Mp: 228-231 °C. MS (ESI, pos. ion) m/z:
382 (M + 1).). 1H NMR (DMSO-d6): δ 3.18-3.28 (m, 4 H), 3.58-
3.68 (m, 4 H), 6.85-7.00 (m, 1 H), 7.10-7.30 (m, 3 H), 8.15 (d,
J ) 6.7 Hz, 1 H), 8.57 (d, J ) 3.9 Hz, 1 H), 11.65 (br s, 1 H).
Anal. (C17H15ClF3N5): C, H, N.
1
m/z: 430 (M + 1). H NMR (CDCl3): δ 1.44 (d, J ) 6.6 Hz, 3
H), 3.13-3.25 (dt, J ) 12.1, 3.5 Hz, 1 H), 3.35-3.52 (m, 2 H),
3.55-3.75 (m, 2 H), 3.83-3.97 (m, 1 H), 4.35 (br s, 1 H), 7.12
(dd, J ) 7.9, 4.9 Hz, 1 H), 7.20-7.30 (m, 2 H), 7.36-7.53 (m, 2
H), 7.71 (s, 1 H), 7.95 (dd, J ) 7.8, 2.0 Hz, 1 H), 8.25 (br s, 1 H)
8.51 (dd, J ) 4.9, 1.4 Hz, 1 H). LC/MS retention time: A, 10.39
min; B, 7.36 min.
2-(4-(3-(Trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-3H-ben-
zo[d]imidazole-5-carbonitrile, Trifluoroacetic Acid Salt (47e).
Following the procedure described for compound 47c, 2-chloro-
benzoimidazole 20h and 1-(3-trifluoromethylpyridin-2-yl)piperazine
provided the title compound (4%) as an amorphous solid. MS (ESI,
pos. ion) m/z: 373 (M + 1). 1H NMR (CD3OD): δ 3.46-3.54 (m,
4 H), 3.86-3.93 (m, 4 H), 7.31 (dd, J ) 7.8, 4.7 Hz, 1 H), 7.57 (d,
J ) 8.2 Hz, 1 H), 7.71 (dd, J ) 8.2, 1.6 Hz, 1 H), 7.78 (s, 1 H),
8.10-8.14 (m, 1 H), 8.58 (d, J ) 3.5 Hz, 1 H). Anal.
(C18H15F3N6‚1.4CF3CO2H): C, H, N.
(R)-2-(2-Ethyl-4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-
1-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (50b). A mixture
of 2-chlorobenzoimidazole 20n (0.082 g, 0.37 mmol) and piperazine
8ab (0.096 g, 0.37 mmol) in ethanol (2 mL) was heated at 170 °C
in a microwave sythesizer for 2 h. The reaction mixture was
evaporated in vacuo and the residue was purified by by preparative
HPLC (gradient 0.1% CF3CO2H/MeCN) to give 10 mg of a
colorless film. The film was dissolved in dichloromethane (2 mL)
and the solution was washed with a saturated aqueous solution of
NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by silica gel column chroma-
tography (gradient 0-15% MeOH/CH2Cl2) to give 5 mg (3%) of
the title compound as a white amorphous solid. MS (ESI, pos. ion)
Methyl 2-(4-(3-(Trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-
3H-benzo[d]imidazole-5-carboxylate, Trifluoroacetic Acid Salt
(47f). Following the procedure described for compound 47c,
2-chlorobenzoimidazole 20l and 1-(3-trifluoromethylpyridin-2-yl)-
piperazine provided the title compound (33%) as an amorphous
1
m/z: 444 (M + 1). H NMR (CD3OD): δ 0.93 (t, J ) 7.1 Hz, 3
H), 1.80-2.00 (m, 2 H), 3.17 (dt, J ) 12.1, 3.3 Hz, 1 H), 3.30-
3.40 (m, 1 H), 3.52 (t, J ) 12.3 Hz, 2 H), 3.64 (dt, J ) 12.5, 3.2
Hz, 1 H), 3.96 (d, J ) 12.8 Hz, 1 H), 4.10 (br s, 1 H), 7.24 (dd, J
) 7.7, 5.0 Hz, 1 H), 7.25-7.37 (m, 2 H), 7.46 (br s, 1 H), 8.06 (d,
J ) 7.8 Hz, 1 H), 8.52 (d, J ) 3.8 Hz, 1 H). LC/MS retention
time: A, 10.63 min; B, 7.37 min.
1
solid. MS (ESI, pos. ion) m/z: 406 (M + 1). H NMR (CD3OD):
δ 3.48-3.51 (m, 4 H), 3.86-3.90 (m, 4 H), 3.96 (s, 3 H), 7.30
(dd, J ) 7.4, 5.1 Hz, 1 H), 7.50 (d, J ) 8.2 Hz, 1 H), 8.01-8.06
(m, 2 H), 8.09-8.14 (m, 1 H), 8.57 (d, J ) 3.5 Hz, 1 H). LC/MS
retention time: C, 14.25 min, D, 8.14 min.
4,6-Bis(trifluoromethyl)-2-(4-(3-(trifluoromethyl)pyridin-2-
yl)piperazin-1-yl)-1H-benzo[d]imidazole (48). Following the pro-
cedure described for compound 47a, 2-chlorobenzoimidazole 20m
and 1-(3-trifluoromethylpyridin-2-yl)piperazine provided the title
compound (47%) as a white solid. Mp: 142 °C. MS (ESI, pos.
(R)-2-(2-Propyl-4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-
1-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (50c). Following
the procedure described for compound 50b, 2-chlorobenzoimidazole
20i and piperazine 8ac provided the title compound (2%) as a white
amorphous solid. MS (ESI, pos. ion) m/z: 458 (M + 1). 1H NMR
(CD3OD): δ 0.92 (t, J ) 7.3 Hz, 3 H), 1.20-1.40 (m, 2 H), 1.76-
2.00 (m, 2 H), 3.10-3.16 (m, 1 H), 3.28-3.32 (m, 1 H), 3.47 (br
s, 1 H), 3.52 (br s, 1 H), 3.62 (dt, J ) 12.3, 2.6 Hz, 1 H), 3.96 (d,
J ) 12.7 Hz, 1 H), 4.26 (br s, 1 H), 7.25 (dd, J ) 7.8, 4.8 Hz, 1
H), 7.26-7.36 (m, 2 H), 7.47 (br s, 1 H), 8.07 (d, J ) 7.9 Hz, 1
H), 8.52 (d, J ) 3.9 Hz, 1 H). LC/MS retention time: A, 11.31
min; B, 8.20 min.
1
ion) m/z: 484 (M + 1). H NMR (CD3OD): δ 3.34-3.44 (m, 4
H), 3.78-3.88 (m, 4 H), 7.22 (dd, J ) 7.8, 4.9 Hz, 1 H), 7.52 (s,
1 H), 7.65 (br s, 1 H), 8.06 (dd, J ) 7.9, 1.5 Hz, 1 H), 8.51 (d, J
) 3.7 Hz, 1 H). Anal. (C18H15F6N5): C, H, N.
6-(Trifluoromethyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)-
piperazin-1-yl)-1H-imidazo[4,5-b]pyridine, Trifluoroacetic Acid
Salt (49a). A mixture of 2-chloroimidazopyridine 20d (45 mg, 0.203

Piperazinylbenzimidazoles as TRPV1 antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12 3739
(R)-2-(4-(3-Bromopyridin-2-yl)-2-methylpiperazin-1-yl)-6-(tri-
fluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzo[d]imidazole
(51a). Following the procedure described for compound 47a,
2-chlorobenzoimidazole 20n and piperazine 8q provided the title
compound (73%) as a white amorphous solid. MS (ESI, pos. ion)
cedure described for compound 47a, piperazine 8f and 2-chloro-
benzimidazole 20n provided the title compound (68%) as a white
amorphous solid. MS (ESI, pos. ion) m/z: 416 (M + 1). 1H NMR
(CDCl3): δ 3.64-3.74 (m, 4 H), 3.78-3.88 (m, 4 H), 6.85 (d, J )
8.0 Hz, 1 H), 7.02 (d, J ) 8.0 Hz, 1 H), 7.37 (br s, 2 H), 7.58 (br
s, 1 H), 7.64 (t, J ) 8.0 Hz, 1 H). Anal. (C18H15F6N5): C, H, N.
2-(4-(3-Chloropyridin-2-yl)piperazin-1-yl)-6-(trifluorometh-
yl)-1H-benzo[d]imidazole (52e). Following the procedure described
for compound 47a, piperazine 8b and 2-chlorobenzimidazole 20n
provided the title compound (41%) as a white solid. Mp: 208-
210 °C. MS (ESI, pos. ion) m/z: 382 (M + 1). 1H NMR (DMSO-
d6): δ 3.37-3.43 (m, 4 H), 3.65-3.75 (m, 4 H), 7.06 (dd, J )
7.8, 4.7 Hz, 1 H), 7.28 (br s, 1 H), 7.32-7.42 (m, 1 H), 7.48 (br
s, 1 H), 7.86 (d, J ) 7.8 Hz, 1 H), 8.26 (d, J ) 4.7 Hz, 1 H), 11.89
(br s, 1 H). Anal. (C17H15ClF3N5‚0.25H2O): C, H, N.
2-(4-(3-Iodopyridin-2-yl)piperazin-1-yl)-6-(trifluoromethyl)-
1H-benzo[d]imidazole (52f). Following the procedure described
for compound 47a, piperazine 8c and 2-chlorobenzimidazole 20n
provided the title compound (58%) as a white amorphous solid.
MS (ESI, pos. ion) m/z: 474 (M + 1). 1H NMR (CDCl3): δ 3.00-
3.10 (m, 4 H), 3.18-3.28 (m, 4 H), 6.64 (d, J ) 7.6 Hz, 1 H), 6.66
(d, J ) 7.6 Hz, 1 H), 8.06 (d, J ) 7.6 Hz, 1 H), 8.07 (d, J ) 7.6
Hz, 1 H), 8.27 (d, J ) 4.4 Hz, 1 H), 8.28 (d, J ) 4.8 Hz, 1 H).
Anal. (C17H15F3IN5‚0.2H2O): C, H, N.
2-(4-(3-Methylpyridin-2-yl)piperazin-1-yl)-6-(trifluorometh-
yl)-1H-benzo[d]imidazole, Trifluoroacetic Acid Salt (52g). Fol-
lowing the procedure described for compound 47a, piperazine 30a
and 2-chloro-3-methylpyridine provided the crude product, which
was purified by preparative HPLC (gradient 0.1% trifluoroacetic
acid in acetonitrile) to give the title compound (73%) as a white
amorphous solid. MS (ESI, pos. ion) m/z: 362 (M + 1). 1H NMR
(CDCl3): δ 3.48-3.52 (m, 4 H), 3.94 (br s, 4 H), 7.19 (dd, J )
8.0 Hz, 4.0 Hz, 1 H), 7.40-7.48 (m, 2 H), 7.60 (s, 1 H), 7.84 (d,
J ) 8.0 Hz, 1 H), 8.11 (d, J ) 4.0 Hz, 1 H). Anal. (C18H18F3N5‚
2.3TFA‚1.4H2O): C, H, N.
2-(4-(6-(Trifluoromethyl)-1H-benzo[d]imidazol-2-yl)piperazin-
1-yl)nicotinonitrile (52h). Following the procedure described for
compound 47a, 2-piperazin-1-ylnicotinonitrile and 2-chlorobenz-
imidazole 20n provided the title compound (56%) as a white
amorphous solid. MS (ESI, pos. ion) m/z: 373 (M + 1). 1H NMR
(DMSO-d6): δ 3.75 (m, 8 H), 6.98 (dd, J ) 7.4, 4.7 Hz, 1 H),
7.20-7.60 (m, 3 H), 8.12 (d, J ) 7.8 Hz, 1 H), 8.45 (d, J ) 4.0
Hz, 1 H), 11.90 (s, 1 H). LC/MS retention time: A, 8.87 min; B,
5.71 min.
Ethyl 2-(4-(6-(Trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-
piperazin-1-yl)nicotinate Hydrochloride (52i). Following the
procedure described for compound 47a, piperazine 8e and 2-
chlorobenzimidazole 20n provided the crude reaction product. A
solution of the product in EtOAc was treated with a 1 M solution
of hydrogen chloride in Et2O and the mixture was evaporated under
reduced pressure. The residue was dried in vacuo to give the title
compound title compound (71%) as a white amorphous solid. MS
(ESI, pos. ion) m/z: 420 (M + 1). 1H NMR (CDCl3): δ 1.34 (t, J
) 7.2 Hz, 3 H), 3.45-3-55 (m, 4 H), 3.69-3.81 (m, 4 H), 4.32
(q, J ) 7.0 Hz, 2 H), 6.83 (dd, J ) 7.6, 4.9 Hz, 1 H), 7.26-7.36
(m, 2 H), 7.49 (br s, 1 H), 8.06 (dd, J ) 7.8, 2.0 Hz, 1 H), 8.28
(dd, J ) 4.7, 2.0 Hz, 1 H). Anal. (C20H20N5F3O2): C, H, N.
(5-Chloro-6-(4-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-
yl)piperazin-1-yl)pyridin-3-yl)methanol (52j). Following the pro-
cedure described for compound 31a, piperazine 8h and 2-chloro-
benzimidazole 20n provided the title compound (42%) as a solid.
Mp: 162-165 °C. MS (ESI, pos. ion) m/z: 412 (M + 1). 1H NMR
(DMSO-d6): δ 3.30-3.40 (m, 4 H), 3.65-3.75 (m, 4 H), 4.47 (d,
J ) 5.8 Hz, 2 H), 5.30 (t, J ) 5.5 Hz, 1 H), 7.20-7.50 (m, 3 H),
7.78 (d, J ) 2.0 Hz, 1 H), 8.19 (d, J ) 2.0 Hz, 1 H). Anal. (C18H17-
ClN5F3O): C, H, N.
1
m/z: 570 (M + 1). H NMR (CD3OD): δ 1.53 (d, J ) 6.8 Hz, 3
H), 3.09 (dt, J ) 12.4, 3.6 Hz, 1 H), 3.21 (dd, J ) 12.8, 3.4 Hz, 1
H), 3.60-3.98 (m, 3 H), 4.10 (d, J ) 11.2 Hz, 1 H), 4.51 (br s, 1
H), 6.97 (dd, J ) 8.0, 4.8 Hz, 1 H), 7.47 (br s, 2 H), 7.92 (br s, 2
H), 7.98 (dd, J ) 8.0, 1.2 Hz, 1 H) 8.28 (d, J ) 4.8 Hz, 1 H).
Anal. (C24H18BrF6N5): C, H, N.
(S)-2-(4-(3-Bromopyridin-2-yl)-2-methylpiperazin-1-yl)-6-(tri-
fluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzo[d]imidazole
(51b). Following the procedure described for compound 47a,
2-chlorobenzoimidazole 20i and piperazine 8r provided the title
compound (84%) as a white amorphous solid. MS (ESI, pos. ion)
1
m/z: 570 (M + 1). H NMR (CD3OD): δ 1.51 (d, J ) 6.4 Hz, 3
H), 3.00-3.05 (m, 1 H), 3.19 (dd, J ) 12.0, 3.2 Hz, 1 H), 3.60-
3.86 (m, 3 H), 4.07 (d, J ) 11.2 Hz, 1 H), 4.49 (br s, 1 H), 6.94
(dd, J ) 8.0, 4.8 Hz, 1 H), 7.36-7.60 (m, 2 H), 7.80-7.90 (m, 2
H), 7.96 (d, J ) 8.0 Hz, 1 H), 8.25 (dd, J ) 4.8, 1.6 Hz, 1 H). MS
m/z: 571 (M + 1). Anal. (C24H18BrF6N5): C, H, N.
(R)-2-(4-(3-Bromopyridin-2-yl)-3-methylpiperazin-1-yl)-6-(tri-
fluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzo[d]imidazole
(51c). Following the procedure described for compound 47a,
2-chlorobenzoimidazole 20i and piperazine 9 provided the title
compound (64%) as white amorphous solid. MS (ESI, pos. ion)
1
m/z: 570 (M + 1). H NMR (CD3OD): δ 1.12 (d, J ) 6.0 Hz, 3
H), 3.10-3.30 (m, 1 H), 3.50-3.65 (m, 2 H), 3.70-3.90 (m, 3 H),
4.05 (br s, 1H), 6.98 (dd, J ) 8.0, 4.8 Hz, 1 H), 7.47 (s, 2 H), 7.86
(br s, 2 H), 7.99 (dd, J ) 7.6, 1.6 Hz, 1 H), 8.29 (dd, J ) 4.4, 1.6
Hz, 1 H). LC/MS retention time: A, 12.89 min; B, 6.82 min.
(S)-2-(4-(3-Bromopyridin-2-yl)-3-methylpiperazin-1-yl)-6-(tri-
fluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzo[d]imidazole
(51d). Following the procedure described for compound 47a,
piperazine 30b and 2-chloropyridine 6b provided the title compound
(18%) as a white amorphous solid. MS (ESI, pos. ion) m/z: 570
(M + 1). 1H NMR (CD3OD): δ 1.12 (d, J ) 6.0 Hz, 3 H), 3.10-
3.30 (m, 1 H), 3.50-3.65 (m, 2 H), 3.70-3.90 (m, 3 H), 4.05 (br
s, 1H), 6.98 (dd, J ) 8.0, 4.8 Hz, 1 H), 7.47 (s, 2 H), 7.86 (br s,
2 H), 7.98 (dd, J ) 7.6, 1.6 Hz, 1 H), 8.28 (dd, J ) 4.4, 1.6 Hz,
1 H). LC/MS retention time: A, 12.81 min; B, 7.86 min.
2-(4-Pyridin-2-ylpiperazin-1-yl)-6-(trifluoromethyl)-1H-ben-
zo[d]imidazole (52a). Following the procedure described for
compound 5, 2-chlorobenzimidazole 20n and 1-(pyridin-2-yl)-
piperazine provided the title compound (19%) as amorphous solid.
MS (ESI, pos. ion) m/z: 570 (M + 1).1H NMR (DMSO-d6): δ
3.52-3.86 (m, 8 H), 6.62-6.72 (m, 1 H), 6.93 (d, J ) 8.6 Hz, 1
H), 7.28 (s, 1 H), 7.36 (d, J ) 8.2 Hz, 1 H), 7.47 (br s, 1 H), 7.58
(t, J ) 7.2 Hz, 1 H), 8.15 (d, J ) 3.5 Hz, 1 H), 11.89 (br s, 1 H).
Anal. (C17H16F3N5): C, H, N.
6-(Trifluoromethyl)-2-(4-(4-(trifluoromethyl)pyridin-2-yl)-
piperazin-1-yl)-1H-benzo[d]imidazole (52b). Following the pro-
cedure described for compound 31a, 2-chloro-4-(trifluoromethyl)-
pyridine and piperazine 30a provided the title compound (66%) as
a white amorphous solid. MS (ESI, pos. ion) m/z: 416 (M + 1).
1H NMR (CD3OD): δ 3.66-3.76 (m, 4 H), 3.78-3.88 (m, 4 H),
6.88 (d, J ) 5.2 Hz, 1 H), 7.10 (s, 1 H), 7.30 (d, J ) 8.2 Hz, 1 H),
7.36 (d, J ) 8.2 Hz, 1 H), 7.50 (s, 1 H), 8.32 (d, J ) 5.2 Hz, 1 H).
Anal. (C18H15F6N5): C, H, N.
6-(Trifluoromethyl)-2-(4-(5-(trifluoromethyl)pyridin-2-yl)-
piperazin-1-yl)-1 H-benzo[d]imidazole (52c). Following the pro-
cedure described for compound 47a, 1-(5-(trifluoromethyl)pyridin-
2-yl)piperazine and 2-chlorobenzimidazole 20n provided the title
compound (98%) as a white solid. Mp: 214 °C. MS (ESI, pos.
ion) m/z: 416 (M + 1). 1H NMR (CDCl3): δ 3.74 (d, J ) 7.2 Hz,
2 H), 3.76-3.86 (m, 4 H), 3.86-3.96 (m, 4 H), 6.74 (d, J ) 9.2
Hz, 2 H), 7.39 (br s, 1 H), 7.66 (br s, 1 H), 7.72 (dd, J ) 8.8, 2.0
Hz, 1 H), 8.45 (s, 1 H). Anal. (C18H15F6N5): C, H, N.
5-Chloro-6-(4-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-
piperazin-1-yl)nicotinamide (52k). Following the procedure de-
scribed for compound 31a, piperazine 8p and 2-chlorobenzimid-
azole 20n provided the title compound (81%) as a white amorphous
6-(Trifluoromethyl)-2-(4-(6-(trifluoromethyl)pyridin-2-yl)-
piperazin-1-yl)-1H-benzo[d]imidazole (52d). Following the pro-
1
solid. MS (ESI, pos. ion) m/z: 425 (M + 1). H NMR (DMSO-

3740 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12
OgnyanoV et al.
d6): δ 3.70-3.80 (m, 4 H), 3.80-4.00 (m, 4 H), 7.49-7.54 (m, 1
H), 7.58-7.62 (m, 1 H), 7.71 (s, 1 H), 7.76 (s, 1 H), 8.28 (br s, 1
H), 8.45 (s, 1 H), 8.93 (br s, 1 H). Anal. (C18H16ClN6F3O‚
0.4H2O): C, H, N.
5-Chloro-N-methyl-6-(4-(6-(trifluoromethyl)-1H-benzo[d]-
imidazol-2-yl)piperazin-1-yl)nicotinamide (52l). Following the
procedure described for compound 31a, piperazine 8l and 2-chloro-
benzimidazole 20n provided the title compound (62%) as a white
amorphous solid. MS (ESI, pos. ion) m/z: 439 (M + 1). 1H NMR
(DMSO-d6): δ 2.85 (d, J ) 3.9 Hz, 3 H), 3.60-3.70 (m, 4 H),
3.72-3.82 (m, 4 H), 7.34 (br s, 1 H), 7.38-7.59 (m, 2 H), 8.25 (s,
1 H), 8.59 (br s, 1 H), 8.72 (s, 1 H), 11.95 (br s, 1 H). Anal. (C19H18-
ClN6F3O‚0.1EtOAc): C, H, N.
compound at room temperature for 2 min prior to the addition of
45Ca2+ (ICN) and capsaicin (Sigma) in F12 medium, with a final
capsaicin concentration of 500 nM, and then left for an additional
2 min prior to compound washout. For the pH-mediated 45Ca2+
uptake assay, the cells were preincubated with compound at room
temperature for 2 min prior to the addition of 45Ca2+ in 30 mM
HEPES/MES buffer (final assay pH 5) and then left for an additional
2 min prior to compound washout. For the measurement of agonist
activity, the cells were incubated with compound in the presence
of 45Ca2+ in a 1:1 ratio of F12 medium to HBSS (Hanks buffered
saline solution) supplemented with BSA (0.1 mg/mL) and 1 mM
HEPES at pH 7.4 at room temperature for 2 min prior to compound
washout. For compound washout, the assay plates were washed
twice with phosphate-buffered saline containing BSA (0.1 mg/mL)
using an ELX405 plate washer (Bio-Tek Instruments Inc.). Radio-
activity remaining in the 96-well plates after washout was measured
using a MicroBeta Jet (Perkin-Elmer). IC50 data were calculated
using XLfit version 2.0.6 (ID Business Solutions Ltd).
Pharmacokinetic Studies. Male Sprague-Dawley rats (weight
range 225-280 g) with surgically implanted femoral vein and
jugular vein cannulae were obtained from Hilltop Lab Animals Inc.
(Scottsdale, PA). Animals were fasted overnight and the following
day compounds were administered either by oral gavage or by
intravenous bolus injection. Oral formulations were made 24-48
h prior to dosing, while intravenous formulations were made on
the day of dosing. Blood samples were collected over 8 h via jugular
cannula into a heparinized tube. Following centrifugation, plasma
samples were stored in a freezer to maintain -70 °C until analysis.
Lithium heparinized plasma samples (40 µL) were precipitated with
acetonitrile containing the internal standard (IS). The supernatant
was transferred into a 96-well plate, and an aliquot of 20 µL was
injected onto an LC-MS/MS system. The analytes were separated
by a reversed-phase on a C-18 analytical column. The analyte ions
were generated by an atmospheric pressure chemical ionization
(APCI) source and detected by a Sciex API3000 triple quadrupole
mass spectrometer operated in the multiple reaction monitoring
(MRM) mode. Study sample concentrations were determined from
a weighted (1/x2) linear regression of peak area ratios (analyte peak
area/IS peak area) versus the theoretical concentrations of the
calibration standards. Pharmacokinetic parameters were calculated
by noncompartmental methods using WinNonLin (Pharsight Corp.,
Mountainview, CA).
Method for Capsaicin-Induced Flinching Model. Male rats
(Sprague-Dawley; Charles River Laboratories, Wilmington, MA)
were allowed 5-7 days acclimation to the LAR prior to use in the
experiment. The day prior to the experiment, animals were
numbered sequentially by marking the tail with a permanent marker.
For the dose response study, the combined data from three separate
studies was used for analysis. The treatment groups are listed below.
The first treatment was either vehicle or 46ad administered via
oral gavage using a dose volume of 5 mL/kg in an Ora-Plus/5%
Tween 80 vehicle solution. Following the first treatment, rats were
placed into acclimation cages (12 cm × 26 cm × 12 cm front
height/15 cm rear height) that were identical to those to be used
for the behavioral scoring. Animals acclimated for 2 h prior to the
second treatment.
The second treatment for all groups was an intraplantar injection
of capsaicin, except in the vehicle/vehicle group, which received
an intraplantar injection of the vehicle [5% EtOH in phosphate-
buffered saline (PBS) without Ca2+, Mg2+] used for capsaicin. The
dose of capsaicin utilized was 0.5 µg administered in a volume of
25 µL. This dose of capsaicin was based on earlier characterization
work and found to be a minimally effective reproducible dose. The
intraplantar injection was made with a 3/10 cm3 insulin syringe
fitted with a 28.5-gauge needle. For the intraplantar injection, rats
were placed headfirst into a rat restrainer and the right foot was
marked (top and bottom) with a permanent marker to make a clear
identification of the injected foot. Next, with the foot extended,
the injection was made into the center of the bottom of the foot
(i.e., intraplantar). The rat was then immediately placed into an
6-(Trifluoromethyl)-2-(4-(2-(trifluoromethyl)phenyl)piperazin-
1-yl)-1H-benzo[d]imidazole (53a). Following the procedure de-
scribed for compound 31a, 1-(2-(trifluoromethyl)phenyl)piperazine
and 2-chlorobenzimidazole 20n provided the title compound (37%)
as a white solid. Mp: 268-269 °C. MS (ESI, pos. ion) m/z: 415
1
(M + 1). H NMR (DMSO-d6): δ 3.01 (br s, 4 H), 3.69 (br s, 4
H), 7.20-7.80 (m, 7 H), 11.86 (d, J ) 12.0 Hz, 1 H). Anal.
(C19H16N4F6): C, H, N.
6-(Trifluoromethyl)-2-(4-(3-(trifluoromethyl)pyridin-4-yl)-
piperazin-1-yl)-1H-benzo[d]imidazole (53b). Following the pro-
cedure described for compound 47a, piperazine 11d and 2-chloro-
benzimidazole 20n provided the title compound (20%) as a light-
yellow solid. Mp: 220-224 °C. MS (ESI, pos. ion) m/z: 416 (M
1
+ 1). H NMR (DMSO-d6): δ 2.46-2.56 (m, 4 H), 2.83-2.93
(m, 4 H), 6.30-6.50 (m, 3 H), 6.61 (br s, 1 H), 7.66 (d, J ) 5.9
Hz, 1 H), 7.78 (s, 1 H). Anal. (C18H15F6N5): C, H, N.
2-(4-(3-Chloropyridin-4-yl)piperazin-1-yl)-6-(trifluorometh-
yl)-1H-benzo[d]imidazole, Trifluoroacetic Acid Salt (53c). Fol-
lowing the procedure described for compound 47a, piperazine 11b
and 2-chlorobenzimidazole 20n provided the title compound (63%)
as trifluoroacetic acid salt after purification by preparative HPLC
(gradient 0.1% trifluoroacetic acid in acetonitrile). Mp: 159-161
1
°C. MS (ESI, pos. ion) m/z: 382 (M + 1). H NMR (DMSO-d6):
δ 3.60-3.80 (m, 4 H), 3.86-3.96 (m, 4 H), 7.33 (d, J ) 5.9 Hz,
1 H), 7.54-7.63 (m, 2 H), 7.70 (s, 1 H), 8.45 (d, J ) 5.9 Hz, 1 H),
8.63 (s, 1 H). LC/MS retention time: A, 8.70 min; B, 3.74 min.
2-(4-(3,5-Dichloropyridin-4-yl)piperazin-1-yl)-6-(trifluoro-
methyl)-1H-benzo[d]imidazole (53d). Following the procedure
described for compound 5, 1-(3,5-dichloropyridin-4-yl)piperazine
and 2-chlorobenzimidazole 20n provided the title compound (33%)
1
as amorphous solid. MS (ESI, pos. ion) m/z: 416 (M + 1). H
NMR (CD3OD): δ 3.60-3.64 (m, 4 H), 3.83-3.88 (m, 4 H), 7.52-
7.62 (m, 2 H), 7.65 (s, 1 H), 8.44 (s, 2 H). LC/MS retention time:
A, 9.76 min; B, 6.47 min.
2-(4-(2,6-Dichlorophenyl)piperazin-1-yl)-6-(trifluoromethyl)-
1H-benzo[d]imidazole (53e). Following the procedure described
for compound 5, piperazine 14 and 2-chlorobenzimidazole 20n
provided the title compound (63%) as a white solid. Mp: 263-
265 °C. MS (ESI, pos. ion) m/z: 415 (M + 1). 1H NMR (CDCl3):
δ 3.36-3.46 (m, 4 H), 3.72-3.82 (m, 4 H), 7.00-7.09 (m, 1 H),
7.20-7.56 (m, 3 H), 7.72 (s, 1 H), 8.28 (br s, 1 H). LC/MS retention
time: A, 10.98 min; B, 7.66 min.
2-(4-(5-Chloropyrimidin-4-yl)piperazin-1-yl)-6-(trifluoro-
methyl)-1H-benzo[d]imidazole (53f). Following the procedure
described for compound 5, piperazine 11f and 2-chlorobenzimid-
azole 20n provided the title compound (69%) as white solid. Mp:
1
66.6-66.7 °C. MS (ESI, pos. ion) m/z: 383 (M + 1). H NMR
(DMSO-d6): δ 3.01 (br s, 4 H), 3.17 (br s, 4 H), 6.59 (d, J ) 8.0
Hz, 1 H), 6.67 (d, J ) 8.0 Hz, 1 H), 6.78 (s, 1 H), 7.68 (s, 1 H),
7.86 (s, 1 H). Anal. (C16H14ClF3N6‚0.75H2O): C, H, N.
Functional 45Ca2+ Uptake Assays. Rat TRPV1-expressing CHO
cells were routinely maintained in DMEM medium with 10%
dialyzed fetal bovine serum, 1× nonessential amino acids, penicillin,
streptomycin, and L-glutamine. Two days before the assays were
run, the cells were seeded in Cytostar 96-well plates (Amersham)
at a density of 20 000 cells per well. All of the 45Ca2+ uptake assays
had a final 45Ca2+ concentration of 10 µCi/mL. For the capsaicin-
mediated 45Ca2+ uptake assay, the cells were preincubated with

Piperazinylbenzimidazoles as TRPV1 antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12 3741
observation chamber for flinch counting. At all times, animals were
treated gently as to minimize stress.
intermediates that were not included in the Experimental Section.
This material is available free of charge via the Internet at http://
pubs.acs.org.
The behavioral measure scored was number of flinches. Flinches
were recorded for 1 min by observers (2) who were blinded to the
treatment conditions. A flinch was defined as a “flick” of the paw
either when the animal lifts it from the floor or when the paw was
held-up. If the paw was just held up, the counting continued at a
constant pace until the paw was placed again on the chamber’s
surface. If the paw was held up and biting occurred, it was counted
as a response. Immediately following the 1-min test period, the
animals were transferred to another person who took blood for
determination of plasma levels of compound. Blood was taken via
a cardiac stick in animals anesthetized with CO2. Blood was
collected in heparinized tubes and kept on ice until centrifugation
at 14 000g for 5 min. Plasma (200 µL) was removed, kept at 4 °C
during experiment, and frozen at - 80 °C until submission for blood
level determinations. Percent maximal possible effect (%MPE) was
computed as ((Veh/Cap - Veh/Veh) - (Drug/Cap-Veh/Veh))/(Veh/
Cap - Veh/Veh).
Method for CFA-Induced Thermal Hyperalgesia. Prior to
being tested, male rats (Harlan Sprague-Dawley, Harlan Industries,
Indianapolis, IN) were allowed at least a 4-day acclimation period
to the testing environment, followed by a 2-day habituation to the
testing equipment and paradigm. The paw withdrawal latencies were
tested using a commercially available paw thermal stimulator
(Yaksh hot box, Anesthesiology Research Laboratory, Department
of Anesthesiology, University of California at San Diego). The
device consists of rat compartments (plexiglass cubicles) over a
glass surface maintained at a constant temperature of 30 °C;
underneath the glass lays a radiant heat source consisting of a high
intensity projector lamp bulb (EIKO CXL/CXR, 8V 50W). An
attached, angled mirror facilitates visualization of the footpad and
positioning of the radiant heat to the plantar surface of the paw.
Nociception was measured as the latency for the rat to remove its
paw when the radiant light is activated (current set at 4.75 A). A
daily calibration of the hot box’s settings was done in order to
produce a consistent paw withdrawal latency (PWL) of ap-
proximately 8-10 s as the baseline response. A 20-s cutoff was
imposed on the stimulus duration to prevent tissue damage. On
the day of testing, after 45 min of additional acclimation in the
plexiglass cubicles, thermal stimuli were delivered four times to
each hind paw in an alternating manner at a 5-min interstimulus
interval. The first PWL measurement was discarded (it tended to
be unusually high and variable), and the three subsequent measure-
ments were averaged to obtain baseline PWL.
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Acknowledgment. We thank our colleagues Sekhar Surapa-
neni, Annette Bak. and their co-workers in the PKDM and
pharmaceutics departments and Duncan Smith for providing the
2D-NOESY NMR analyses. We also acknowledge Randy
Hungate and Jean-Claude Louis for their support.
Note Added after ASAP Publication. This manuscript was
released ASAP on May 19, 2006, with an incorrect structure
for Table 5. The correct version was posted on May 24, 2006.
Supporting Information Available: Combustion analysis
results for all final compounds and synthetic procedures for

3742 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12
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JM060065Y