Novel vanilloid receptor-1 antagonists: 1. Conformationally restricted analogues of trans-cinnamides

Article abstract of DOI:10.1021/jm070189q

The vanilloid receptor-1 (VR1 or TRPV1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role as an integrator of multiple pain-producing stimuli. From a high-throughput screening assay, measuring calcium uptake in

Full text of DOI:10.1021/jm070189q

J. Med. Chem. 2007, 50, 3497-3514
3497
Novel Vanilloid Receptor-1 Antagonists: 1. Conformationally Restricted Analogues of
trans-Cinnamides†
Mark H. Norman,*,‡ Jiawang Zhu,‡ Christopher Fotsch,‡ Yunxin Bo,‡ Ning Chen,‡ Partha Chakrabarti,‡ Elizabeth M. Doherty,‡
Narender R. Gavva,§ Nobuko Nishimura,‡ Thomas Nixey,‡ Vassil I. Ognyanov,‡ Robert M. Rzasa,‡ Markian Stec,‡
Sekhar Surapaneni,| Rami Tamir,§ Vellarkad N. Viswanadhan,‡ and James J. S. Treanor§
Department of Chemistry Research and DiscoVery, Department of Neuroscience, and Department of Pharmacokinetics and Drug Metabolism,
Amgen Inc., One Amgen Center DriVe, Thousand Oaks, California 91320-1799
ReceiVed February 19, 2007
The vanilloid receptor-1 (VR1 or TRPV1) is a member of the transient receptor potential (TRP) family of
ion channels and plays a role as an integrator of multiple pain-producing stimuli. From a high-throughput
screening assay, measuring calcium uptake in TRPV1-expressing cells, we identified an N-aryl trans-
cinnamide (AMG9810, compound 9) that acts as a potent TRPV1 antagonist. We have demonstrated the
antihyperalgesic properties of 9 in vivo and have also reported the discovery of novel, orally bioavailable
cinnamides derived from this lead. Herein, we expand our investigations and describe the synthesis and
biological evaluation of a series of conformationally constrained analogues of the s-cis conformer of compound
9. These investigations resulted in the identification of 4-amino- and 4-oxopyrimidine cores as suitable
isosteric replacements for the trans-acrylamide moiety. The best examples from this series, pyrimidines 79
and 74, were orally bioavailable and exhibited potent antagonism of both rat (IC50 ) 4.5 and 0.6 nM,
respectively) and human TRPV1 (IC50 ) 7.4 and 3.7 nM, respectively). In addition, compound 74 was
shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo in the capsaicin-
induced hypothermia model in rats; however, it was ineffective at preventing thermal hyperalgesia induced
by complete Freund’s adjuvant in rats.
Introduction
associated with arthritis.8 The analgesic effects of capsaicin,
when delivered topically, come from its selective action on a
certain population of unmyelinated primary sensory neurons.
In small doses, capsaicin stimulates these neurons and induces
the release of neurotransmitters such as substance P. Upon
continued stimulation, the neurotransmitters are depleted causing
selective damage of the nerves and, thereby, desensitizing them
toward further stimulus. The nerve damage and analgesic actions
of capsaicin are preceded by an intense painful hyperalgesia
caused by activation of an ion channel known as the vanilloid
receptor 1 (VR1 or TRPV1), which is selectively expressed in
sensory neurons.9 TRPV1 was first cloned and characterized in
late 1997 by David Julius and co-workers.10
Over the last several years, an elegant series of experiments,
both genetic and pharmacological, have positioned TRPV1 as
a key target for developing novel pain therapeutics.11 The
approach followed by several groups, including the effort
conducted in our laboratories, has been directed toward identify-
ing selective antagonists of TRPV1.12,13 The concept is that these
molecules would be able to produce analgesia without the
associated nerve damage seen with capsaicin. Early support of
this approach came from the study of capsaicin derivatives. For
example, capsazepine (2), an analogue of capsaicin and the first
reported antagonist of TRPV1, reversed hyperalgesia associated
with inflammatory and neuropathic pain in the guinea pig.14
Other evidence for the role of TRPV1 in pain sensation has
come from studies with TRPV1 knock-out mice.15,16 These
TRPV1-deficient mice had a decreased sensitivity to painful
heat in inflammatory pain models.
Pain is a complex perceptual experience that can have a
profound impact on the quality of a person’s life. From the
beginning of human existence, man has endured pain in all its
many forms and for centuries has sought methods to relieve it.
For example, ancient civilizations recorded accounts of pain
on stone tablets and illustrated various treatments, such as
pressure, heat, water, and sun. Pharmaceutical intervention also
dates as far back as 5000 years ago when Sumerian texts report
the effect of the poppy plant (opium) for treating pain and
Egyptians used willow extracts (salicylic acid) to reduce the
redness and pain of inflamed joints.1-3 In the intervening years,
physicians and scientists have discovered and developed many
analgesic agents that have dramatically improved peoples lives.
However, despite the many years of effort to effectively manage
pain, individuals still suffer from its physical and emotional
consequences, and improved treatments are still needed today.4
Ironically, one of the most recent pain targets has also been
modulated unknowingly for centuries.5 This pain target is linked
to the natural product capsaicin (1, Figure 1), the pungent
component of chili peppers.6 For example, early European folk
medicine employed hot pepper extracts (hence capsaicin) to
relieve toothaches, and native Americans were also known to
have massaged chili pods onto their inflamed gums to ease
dental pain.7 Capsaicin is still in wide use today and is the active
pharmacological ingredient of several topical analgesic creams
used to relieve minor aches and pains of muscles and joints
† Dedicated to the memory of our friend and colleague, Vassil I.
Ognyanov.
During the past few years, several other classes of TRPV1
antagonists structurally unrelated to the exogenous agonist cap-
saicin have been described in the literature, and their chemistry
and pharmacology have been reviewed.11-13,17,18 Some of the
most frequently reported structural classes of TRPV1 antagonists
* To whom correspondence should be addressed. Tel.: 805-447-1552.
Fax: 805-380-3015. E-mail: markn@amgen.com.
‡ Department of Chemistry Research and Discovery.
§ Department of Neuroscience.
| Department of Pharmacokinetics and Drug Metabolism.
10.1021/jm070189q CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/22/2007

3498 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15
Norman et al.
Figure 1. The TRPV1 agonist, capsaicin (1), and representative examples of TRPV1 antagonists (2-8).
Figure 2. Conformationally restricted analogues of the proposed bioactive s-cis conformer of cinnamide 9.
have been ureas,19 thio-ureas,20 amides,19a,c,21-23 benzimida-
zoles,24 and piperazine carboxamides,21b,c,25 and are exemplified
by compounds 3-8 shown in Figure 1.
In addition to these structural classes, we have recently
described the discovery of a series of N-aryl-cinnamides as
potent TRPV1 antagonists.22,26,27 In these investigations, we
identified the N-aryl cinnamide AMG9810 (9, Figure 2) as a
potent, competitive antagonist that blocks the capsaicin-, heat-,
and pH-induced uptake of 45Ca2+ in TRPV1-expressing Chinese
hamster ovary (CHO) cells.22a Furthermore, we demonstrated
that cinnamide 9 was effective at preventing a capsaicin-induced
eye wiping response in a dose-dependent manner as well as
reversing thermal and mechanical hyperalgesia in a model of
inflammatory pain induced by intraplantar injection of complete
Freund’s adjuvant (CFA) in rats.26
To further advance our understanding of this series, we have
conducted a conformational analysis of several N-aryl-cinna-
mides to gain insights into the optimum orientation of the
pharmacophoric elements required for TRPV1 inhibitory activ-
ity.28 In these studies, we examined the conformational prefer-
ences of several N-aryl cinnamides using Monte Carlo searching
and ab initio quantum mechanical calculations at 6-31G* level.29

Head: TRPV1 Antagonists: Conformationally Restricted Cinnamides
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15 3499
Scheme 1a
a Reagents and conditions: (a) N,N′-dimethylethylenediamine, CuI, K3PO4, dioxane, 85 °C; (b) LDA, THF, 4-t-butylbenzaldehyde; (c) MsCl, CH2Cl2; (d)
DBU, THF; (e) neat, 190 °C, 5 min, microwave.
We found that the s-cis conformation of compound 9 (Figure
2) was preferred over the s-trans conformation by 2.6 kcal/mol
and that analogues that were better able to adopt the s-cis
conformation were more potent TRPV1 antagonists. Based on
this conformational analysis, we proposed that the bioactive
conformer of the N-aryl cinnamide of compound 9 was s-cis,
with a coplanar arrangement of the amide carbonyl, the
cinnamide double bond, and the â-substituted aryl group being
optimal.
ridine (31) with 4-(t-butyl)benzyl bromide (32) followed by a
copper-catalyzed aryl amidation of the resulting pyridone (33)
with 3,4-ethylenedioxyiodobenzene (28).35
The next series of compounds examined contained various
six-membered aromatic and heteroaromatic rings in place of
the acrylamide core of compound 9. The replacement cores
included phenyl (12), each of the four pyridyl (13-16), three
pyrimidinyl (17-19), and two pyridazinyl (20-21) regioiso-
mers, as well as the pyrazine (22) and triazine (23) ring systems.
The majority of these derivatives were prepared by one of two
general methods: (1) by the addition of the t-butylphenyl group
to the core system by a Suzuki coupling36 followed by
introduction of the aminobenzodioxane group (Scheme 2); or
(2) by reversing the sequence and coupling the heterocyclic core
with 7-aminobenzodioxane first, followed by a Suzuki coupling
to incorporate the t-butylphenyl group (Scheme 3). Both
methods proved to be useful in providing the appropriately
substituted derivatives, and the synthetic method chosen was
dictated mainly by the availability of starting materials.
The first general method is outlined in Scheme 2 and provided
target compounds 12, 13, 16-18, 21, and 22 in two to four
steps from readily available starting materials. For example,
Suzuki palladium-mediated coupling of 4-t-butylphenylboronic
acid (34) to 1-chloro-3-iodobenzene (35), 2,6-dibromopyridine
(36), 4,6-dichloropyrimidine (37), and 2,6-dichloropyrazine (38)
gave halo-intermediates 42-45, respectively. The corresponding
phenyl (12), pyridinyl (16), pyrimidinyl (17), and pyrazinyl (22)
target compounds were obtained by treatment of intermediates
42-45 with 1,4-benzodioxan-6-amine (52) under palladium-
mediated or thermal coupling conditions.37
The remaining three compounds illustrated in Scheme 2 (13,
18, and 21) required additional modifications of the initial
intermediates to produce leaving groups that would allow for
the final addition of the aminobenzodioxane moiety. For
example, Suzuki coupling of 4-t-butylphenylboronic acid (34)
with 4-bromopyridine (39), 4-chloro-2-(methylthio)pyrimidine
(40), and 3-chloro-5-methoxypyridazine (41)38 gave intermedi-
ates 46, 48, and 50, respectively. Following the Suzuki coupling,
the pyridine N-oxide of 46 was generated by treatment with
methylrhenium trioxide and hydrogen peroxide,39 and the
intermediate N-oxide was converted to 2-bromopyridine, 47,
by reaction with triphenylphosphonium bromide. Palladium-
mediated coupling of 47 with 1,4-benzodioxan-6-amine (52)
provided the desired pyridine analogue, 13. To prepare the 2,4-
pyrimidine derivative, 18, the initial sulfide intermediate 48 was
first oxidized to sulfoxide 49 with m-chloroperoxybenzoic acid,
and the sulfoxide group was then displaced with 1,4-benzo-
dioxan-6-amine (52). In the case of pyridazine derivative 21,
the initial methoxy intermediate 50 was demethylated by treat-
To test this hypothesis and to extend our study of the
structure-activity relationships (SAR) of this chemical class,
we have investigated a variety of replacements of the acrylamide
core (10-27; Figure 2).30 In the initial phase of the investigation,
we examined the effect of restricting the s-cis conformer of
cinnamide 9 in two general ways: (1) by connecting the amide
nitrogen to the R-position of the cinnamide to form lactam 10
and the corresponding dihydro-isomer, pyridone 11 [cyclization
A, Figure 2]; and (2) by incorporating the â-position of the
cinnamide and the amide carbonyl into various six-membered
aromatic rings to give compounds 12-23 [cyclization B, Figure
2]. Constraining cinnamide 9 in these two ways allowed for
the thorough evaluation of 14 different core replacements in
which the position of the ring heteroatoms were systematically
varied (W, X, Y, and Z; Figure 2), while the position of the
t-butylphenyl and the benzodioxane groups remained constant.
As a second phase of this study, we modified the nature of the
“linker” group (V, Figure 2) between the pyrimidine heterocyclic
core and the benzodioxane moiety to give compounds 24-27.
The synthesis and biological evaluation of lactam 10, pyridone
11, and substituted heterocycles 12-27 are described herein.
This study culminated in the identification of isosteric replace-
ments for the acrylamide moiety (e.g., 4-amino- and 4-oxo-
pyrimidine) and has provided us with a novel class of TRPV1
antagonists for further investigation.31
Chemistry
The syntheses of lactam 10 and pyridone 11 are illustrated
in Scheme 1. Commercially available 3,4-ethylenedioxyiodo-
benzene (28) was coupled with δ-valerolactam (29) under
copper-mediated amidation conditions32 to provide lactam 30
in moderate yield. The desired pyridone 10 was obtained from
the aldol condensation of lactam 30 with 4-t-butylbenzaldehyde
followed by dehydration of the resulting benzyl alcohol.33
Attempts to convert lactam 10 to give pyridone 11 directly
with dichlorodicyanobenzoquinone (DDQ) or by catalytic
dehydrogenation with Pd/C were unsuccessful and, therefore,
an alternative synthetic route was required. Ultimately, pyridone
11 was prepared in a two-step sequence by a regioselective,
solvent-free, thermal C-benzylation reaction34 of 2-hydroxypy-

3500 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15
Norman et al.
Scheme 2a
a Reagents and conditions: (a) PS-Pd(PPh3)4, Na2CO3; (b) Pd(PPh3)4, aq Na2CO3, DME, 90 °C; (c) Pd(PPh3)4, aq Na2CO3, CH3CN, 90 °C; (d) Pd(PPh3)4,
aq K2CO3, DME, 90 °C; (e) CH3ReO3, H2O2, CH2Cl2; (f) Ph3P, Br2, NEt3, CH2Cl2; (g) m-CPBA, CH2Cl2; (h) 47% HI, 150 °C; (i) POCl3; (j) 1,4-benzodioxan-
6-amine, Pd2(dba)3, dppf, NaOt-Bu, toluene, reflux; (k) 1,4-benzodioxan-6-amine, Pd(OAc)2, BINAP, NaOt-Bu, toluene, DMF, 90 °C; (l) 1,4-benzodioxan-
6-amine, 1,4-dioxane, reflux; (m) 1,4-benzodioxan-6-amine, EtOH, 180 °C, microwave; (n) 1,4-benzodioxan-6-amine, 1,4-dioxane, EtOH, reflux.
Scheme 3a
a Reagents and conditions: (a) Pd(OAc)2, 2-(di-t-butylphosphino)biphenyl, K3PO4, toluene, reflux; (b) Pd2(dba)3, dppf, NaOt-Bu, toluene, 150 °C, microwave;
(c) EtOH, rt; (d) t-BuOH, NaHCO3, rt; (e) 4-t-butylphenylboronic acid, Pd(PPh3)4, aq Na2CO3, CH3CN, 90 °C, 8 h; (f) 4-t-butylphenylboronic acid, PS-
resin-bound Pd(PPh3)4, aq Na2CO3, DME/EtOH, 120 °C, microwave; (g) 4-t-butylphenylboronic acid, Pd(PPh3)4, aq Na2CO3, CH3CN, 90 °C, 14 h; (h)
4-t-butylphenylboronic acid, 1,4-dioxane, Pd(PPh3)4, aq K2CO3, 130 °C, microwave.
ment with hydroiodic acid, and the resulting pyridazinol was
converted to chloropyridazine 51 by treatment with phosphorus
oxychloride. Direct addition of 1,4-benzodioxan-6-amine (52)
to chloropyridazine 51 provided the desired pyridazine 21.

Head: TRPV1 Antagonists: Conformationally Restricted Cinnamides
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15 3501
Scheme 4a
a Reagents and conditions: (a) glyoxilic acid, K2CO3, MeOH; (b) H2SO4, HCOOH; (c) NH2NH2, H2O, AcOH, reflux; (d) POCl3; (e) 1,4-benzodioxan-
6-amine (52), EtOH, 180 °C, microwave; (f) Rieke Zn, EtOH, 72 °C.
Scheme 5a
a Reagents and conditions: (a) 1,4-dioxane, reflux; (b) Cs2CO3, DMF, 65 °C; (c) CH3I, MP-carbonate, acetone; (d) NaH, 2,3-dihydrobenzo[b][1,4]dioxine-
6-carbaldehyde, 1,3-dimethylimidazolium iodide, dioxane; (e) NaBH4, MeOH, rt; (f) benzoyl chloride, pyridine, THF; (g) Pd/C, H2.
The second general synthetic method allowed for the prepara-
tion of compounds 14, 15, 19, and 23 and is illustrated in
Scheme 3. In this method, 1,4-benzodioxan-6-amine (52) was
coupled with 2-chloro-4-iodopyridine (53), 3-bromo-5-iodopy-
ridine (54), 2,4-dichloropyrimidine (55), or 2,4-dicholoro-1,3,5-
triazine (56) under palladium-mediated coupling conditions to
give intermediates 57-60, respectively. The desired target
compounds (15, 14, 19, and 23) were obtained from the Suzuki
coupling of 57-60 with 4-t-butylphenylboronic acid. The
regiochemical assignment of pyridine 15 was confirmed based
Pyrimidine derivatives with alternative linking groups (V)
were prepared as outlined in Scheme 5 (compounds 24-27).
The N-methyl analogue (24) was prepared by alkylation of
pyrimidine 17 with methyl iodide. Displacement of the chloro
group of intermediate 44 with 3,4-(ethylenedioxy)phenol (67)41
or 3,4-(ethylenedioxy)thiophenol (68) provided pyrimidines 25
and 26, respectively. The methylene-linked derivative (27) was
prepared in a four-step sequence starting from chloropyrimidine
44 according to an analogous procedure described by Miyashita
and co-workers.42 Treatment of 44 with 2,3-dihydrobenzo[b]-
[1,4]dioxine-6-carbaldehyde, 1,3-dimethylimidazolium iodide,
and sodium hydride provided ketone 69, which was reduced
with sodium borohydride to give benzylic alcohol 70 in good
yield. Finally, dehydration of 70 was accomplished by acylation
of the benzylic alcohol with benzoyl chloride followed by
hydrogenation of the resulting ester to give compound 27.
The synthesis of the final set of compounds is illustrated in
Scheme 6 (pyrimidines 73, 74, 78, and 79). These compounds
were prepared to examine the effect of incorporating the
pyrimidine core with two of the best flanking groups identified
from our earlier SAR investigations in the cinnamide series,
7-substituted quinoline and 4-trifluoromethylphenyl.22a The
trifluoromethyl derivative (73) was prepared by the Suzuki
coupling of 4-trifluoromethylphenylboronic acid (71) to 4,6-
dichloropyrimidine followed by the treatment of the resulting
chloropyrimidine intermediate 72 with 1,4-benzodioxan-6-
amine. Similarly, the O-linked quinoline analogue, pyrimidine
74, was prepared by the treatment of chloropyrimidine 72 with
the alkoxide of commercially available 7-hydroxyquinoline.
1
on comparison of the H NMR and NOESY correlations with
its isomeric pyridine analogue, 13.
A longer synthetic route was needed to prepare the last
isomeric pyridazine isomer required for this investigation
(compound 20, Scheme 4). Following the method described by
Dean and co-workers, 4-t-butylphenylacetonitrile (61) was
condensed with glyoxylic acid under basic conditions to provide
potassium (Z)-3-aryl-cyanopropenoate (62).40 Cyanopropenoate
62 was converted to the aryl maleic anhydride 63 under acidic
conditions, which was then reacted with hydrazine to provide
pyridazinedione 64. Compound 64 was converted to dichloro-
pyridazine 65 by treatment with phosphorus oxychloride. The
reaction of dichloropyridazine 65 with 1,4-benzodioxan-6-amine
(52) provided chloropyridazine 66 in moderate yield. A small
amount (3%) of the bis-addition product was isolated; however,
the regioisomeric product resulting from the displacement of
the 3-chloro group was not observed. Chloropyridazine 66 was
dehalogenated with Rieke Zn to provide the targeted pyridazine
20.

3502 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15
Norman et al.
Scheme 6a
a Reagents and conditions: (a) 4,6-dichloropyrimidine (37), Pd(PPh3)4, aq Na2CO3, CH3CN, 80 °C; (b) 1,4-benzodioxan-6-amine (52), EtOH, 180 °C,
microwave; (c) 7-hydroxyquinoline, DMF, NaH, rt; (d) DDQ, CH2Cl2, rt; (e) Pd/C, H2, MeOH; (f) Pd2(dba)3, dppf, NaOt-Bu, toluene, microwave, 200 °C;
(g) neat, 200 °C, microwave.
Oxidation of 7-nitrotetrahydroquinoline (75)43 with DDQ pro-
Table 1. In Vitro TRPV1 Activities for Cinnamide 9 and Compounds
10 and 11a
vided quinoline 76, and subsequent reduction of the nitro group
cleanly gave intermediate 77. Reaction of 7-aminoquinoline (77)
with chloropyrimidines 44 and 72 gave the final two target
pyrimidines 78 and 79, respectively.44
Results and Discussion
Based on our previous SAR investigations in the cinnamide
series, we postulated that the s-cis conformer of compound 9
was the conformational isomer responsible for optimum potency
at the TRPV1 channel.28 In an attempt to lock the flanking
t-butylphenyl and benzodioxane groups of compound 9 into this
preferred conformation, we replaced the olefin double bond and
the carbonyl of the acrylamide moiety with 18 different cyclic
cores (10-27). We envisaged that confining the groups in this
way would reduce rotational degrees of freedom and translate
into increased inhibitory activity at the receptor. In addition to
locking the orientation of the t-butylphenyl and benzodioxane
groups into preferred positions, the diverse heterocycles exam-
ined would help increase our understanding of the key structural
features required for activity in the core region of these TRPV1
antagonists and may also provide derivatives with improved
pharmacokinetic properties.
a Constrained derivatives resulting from cyclization route A, Figure 2.
b IC50 values based on inhibition of capsaicin- (500 nM) or acid- (pH 5)
induced influx of 45Ca2+ into rat TRPV1-expressing CHO cells. (Each IC50
value reported represents an average of at least two independent experiments
with three replicates at each concentration ((SEM).)
The derivatives prepared in this study were evaluated for their
ability to inhibit capsaicin (CAP)- and acid (pH 5)-induced
influx of 45Ca2+ into rat TRPV1-expressing CHO cells. IC50
values obtained for the conformationally constrained derivatives
10-27 are summarized in Tables 1-4, and the activity of
cinnamide 9 is included for comparison. It should be noted that
all compounds tested in this study were full antagonists and
had EC50 values >4 µM in a separate assay measuring agonist
activity.
The first two core replacements examined the effect of linking
the amide nitrogen of cinnamide 9 to the R-position to form
lactam 10 and pyridone 11 (Table 1). In lactam 10, the position
of both the carbonyl and the double bond are maintained,
whereas only the position of the carbonyl is conserved in
pyridone 11 (relative to compound 9). In both cases, however,
a dramatic loss in activity was observed, with lactam 10 and
pyridone 11 giving IC50 values of >4 µM in both the capsaicin-
and the acid-mediated assays. These results are consistent with
our earlier SAR studies in the cinnamide series, where we found
that alkylation of the amide nitrogen of compound 9 led to a
significant decrease in TRPV1 inhibitory activity.
The next series of derivatives investigated in this study
examined the effect of incorporating the â-position of cinnamide
9 and its amide carbonyl into various six-membered aromatic
rings (compounds 12-23; Table 2). Unlike the first two
constrained derivatives (lactam 10 and pyridone 11), this series
of compounds maintained the NH group found to be important
for the TRPV1 activity of cinnamide 9. In addition to the amide
NH, our earlier SAR studies indicated that the amide carbonyl
of cinnamide 9 was also critical for activity. For example, we
found that all TRPV1 activity was lost when the amide of
compound 9 was reduced to the corresponding secondary
amine.22a Therefore, it was not surprising that the phenyl
derivative (12), which eliminates the corresponding heteroatom

Head: TRPV1 Antagonists: Conformationally Restricted Cinnamides
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15 3503
Table 2. In Vitro TRPV1 Activities for Cinnamide 9 and Compounds
12-23a
acceptor of cinnamide 9. Incorporation of a nitrogen into the
W position of the ring led to a dramatic increase in potency as
compared to compound 12. Although pyridine 13 was 3-4-
fold less active than cinnamide 9 in both the capsaicin- and the
acid-mediated assays, this result demonstrated that an N-
substituted heterocyclic ring could serve as an isosteric replace-
ment to the acrylamide core. The remaining three isomeric
pyridine analogues, 14, 15, and 16, were prepared to determine
the optimal placement of the nitrogen atom within the hetero-
cyclic core. As the nitrogen atom was moved counterclockwise
around the ring, TRPV1 activity decreased. The inhibition of
45Ca2+ influx for the pyridine analogues ranked in the following
order: 13 > 14 . 15, 16. The results obtained for the pyridyl
isomers indicated that the position adjacent to the aminoben-
zodioxane moiety was the optimal position of the nitrogen (i.e.,
W ) N), and that the nitrogen in pyridine 13 could serve as an
adequate replacement for the cinnamide carbonyl oxygen of
compound 9.
The next set of derivatives contained two nitrogens within
the heterocyclic core and consisted of the three isomeric
pyrimidines (17-19), the two isomeric pyridazines (20-21),
and the 2,6-disubsituted pyrazine analogue (22). The inhibition
for these analogues ranked in the following order: 17 > 20, 21
> 18, 19, 22. The 4,6-disubstituted pyrimidine (17) was the
most potent pyrimidine isomer and had an IC50 ) 120 nM in
the capsaicin-mediated assay. The two pyridazine isomers (20
and 21) showed comparable potencies, while the pyrazine
derivative (22) was significantly less active than either of the
pyridazines. The general trends observed for these diaza-
heterocycles are consistent with results obtained in the pyridine
series (13-16). For example, the results suggest that (1) the
nitrogen in the position that mimics the cinnamide carbonyl is
preferred (i.e., W ) N in compounds 17 and 20), and (2) the
nitrogen between the t-butylphenyl and benzodioxane groups
is detrimental to activity (i.e., Z ) N in compounds 18, 19, and
22).
The final constrained derivative evaluated in this study was
the 1,3,5-triazine derivative, 23. This analogue had an IC50 of
760 nM in the capsaicin-mediated assay, but was less active at
blocking 45Ca2+ influx when the channel was activated by low
pH. The results obtained for compound 23 are consistent with
the SAR results observed for the pyridine and pyrimidine
derivatives, wherein the contribution of adding the third nitrogen
into the ring appears to be additive. For example, triazine 23
can be viewed as the result of adding the key nitrogen (at
position W) to the 2,6-disubstituted pyrimidine isomer 19.
Adding the nitrogen to this position leads to a compound with
significantly increased activity (i.e., 23 vs 19). Similarly, the
addition of a nitrogen at the “nonpreferred” position (at position
Z) to the potent 4,6-disubstituted pyrimidine derivative resulted
in a significant decrease in activity (i.e., 17 vs 23).
a NH-linked derivatives resulting from cyclization route B, Figure 2.
b IC50 values based on inhibition of capsaicin- (500 nM) or acid- (pH 5)
induced influx of 45Ca2+ into rat TRPV1-expressing CHO cells. (Each IC50
value reported represents an average of at least two independent experiments
with three replicates at each concentration ((SEM).)
Table 3. In Vitro TRPV1 Activities for Pyrimidines 24-27a
rTRPV1 (CAP)b
IC50 (nM)
rTRPV1 (acid)b
IC50 (nM)
cmpd
V
17
24
25
26
27
NH
NMe
O
S
CH2
120 ( 50
>4000
680 ( 120
2200 ( 260
670 ( 3
>4000
290 ( 100
>4000
The SAR results outlined above demonstrate that the 4-ami-
nopyrimidine core of compound 17 is a suitable isosteric
replacement for the acrylamide moiety of compound 9. To see
how the pharmacophores of these two compounds compared,
we calculated the low-energy conformations of cinnamide 9 and
pyrimidine 17 and superimposed the resulting structures (Figure
3). In both cases, a flat conformation is preferred wherein the
benzodioxane, the core (acrylamide or 4-aminopyrimidine), and
the t-butylphenyl groups are coplanar. The two low-energy
conformations superimpose well and the alignment of the
cinnamide carbonyl of 9 and the pyrimidine nitrogen of
compound 17 are clearly favorable (the structures are off-set
slightly for illustrative purposes).
914 ( 173
>4000
a Alternative linking groups (V) from cyclization route A, Figure 2. b IC50
values based on inhibition of capsaicin- (500 nM) or acid- (pH 5) induced
influx of 45Ca2+ into rat TRPV1-expressing CHO cells. (Each IC50 value
reported represents an average of at least two independent experiments with
three replicates at each concentration ((SEM).)
in this region of the molecule, exhibited poor inhibitory activity
in the TRPV1 assays.
To further test the hypothesis that a heteroatom is required
in this position of the molecule, we prepared the 2-aminopy-
ridine analogue (compound 13) to mimic the hydrogen-bond

3504 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15
Norman et al.
Table 4. In Vitro TRPV1 Activities for Pyrimidines 17, 73, 74, 78, and 79
a IC50 values based on inhibition of capsaicin- (500 nM) or acid- (pH 5) induced influx of 45Ca2+ into rat or human TRPV1-expressing CHO cells. (Each
IC50 value reported represents an average of at least two independent experiments with three replicates at each concentration ((SEM).)
Figure 3. Minimum-energy conformations of compounds 9 (green) and 17 (orange) and their aligned structures.
In the second phase of our investigation, we made changes
to the linking group between the pyrimidine heterocycle and
the benzodioxane moiety (Table 3). As we observed in the
cinnamide series, N-methylation resulted in a loss of activity
(24 vs 17).22a However, the O-linked derivative (4-oxopyrimi-
dine 25) maintained significant TRPV1 inhibitory activity, with
IC50 values of 290 and 670 nM in the capsaicin- and acid-
mediated assays, respectively. This result is in contrast to the
substantial decrease in activity that we observed for the
corresponding ester analogue of cinnamide 9 and demonstrates
that a hydrogen bond donating linker at this position is not an
absolute requirement for TRPV1 antagonism.22a Taken together,
these results also suggest that the loss in activity observed upon
N-methylation is likely due to an unfavorable conformational
change that results between the 4-aminopyrimidine core and
the benzodioxane group rather than due to the loss of the NH
hydrogen-bond donor in compound 17. The S- and CH2-linked
analogues (26 and 27) were significantly less active than the
O- or NH-linked pyrimidines, 25 and 17.
aminobenzodioxane group of cinnamide 9 with a 7-aminoquino-
line group led to enhanced TRPV1 inhibitory activity in our in
vitro assays.22a In addition, we found that we could reduce
metabolism within the cinnamide series by using a triflourom-
ethylphenyl in place of the t-butylphenyl group while at the
same time maintaining comparable potency. Therefore, we
prepared and evaluated the corresponding derivatives with the
new 4-aminopyrimidine core and found that the SAR was
consistent with the cinnamides series (compounds 73, 78, and
79; Table 4). For example, replacement of the t-butylphenyl
with the trifluoromethylphenyl group resulted in a slight decrease
in activity (compound 73 vs 17); however, potency was
increased 25-60-fold by the replacement of the benzodioxane
with the 7-aminoquinoline group (compound 78 vs 17). The
effect of combining both the aminoquinoline and the trifluo-
romethylphenyl substituents on the 4-aminopyrimidine core was
also examined. This combination gave an additional 3- to 20-
fold increase in potency over compound 78 at the human TRPV1
receptor. Finally, the effect of these two modifications were
evaluated within the O-linked series, as exemplified by 4-oxo-
pyrimidine 74. As was observed for the corresponding 4-amino-
pyrimidine analogue, 79, the 4-oxopyrimidine derivative, 74,
was a potent TRPV1 antagonist in both the capsaicin- and acid-
mediated assays.
With the pyrimidine ring identified as an acceptable alterna-
tive to the acrylamide core, we were interested in examining
the effect of incorporating some of the optimum pharmacophoric
elements identified from our cinnamide SAR investigations into
this new class of TRPV1 antagonists. The results of both the
rat and the human receptors are reported in Table 4. For
example, we knew from our previous studies that replacing the
Due to the excellent in vitro activities of pyrimidines 74, 78,
and 79, the pharmacokinetic profiles of these compounds were

Head: TRPV1 Antagonists: Conformationally Restricted Cinnamides
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15 3505
Table 5. Mean Pharmacokinetic Parameters of Compounds 9, 74, 78,
and 79 Following Intravenous Administration in Sprague-Dawley Rats
dosec
AUC0-∞
CL
Vss
t1/2
(mg/kg)
(ng‚h/mL)
(L/h/kg)
(L/kg)
(h)
9a
78a
79a
74b
3
2
2
2
680
340
320
4.4
2.9
3.1
1.2
2.1
3.1
3.0
3.0
1.1
1.6
1.7
2.8
1590
a n ) 2 animals per study. Interanimal variability was less than or equal
to 30%. b Data is the mean of four studies. Variability for CL, Vss and t1/2
values ranged from 29 to 40%, and variability for AUC0-∞ was 77%.
c Dosed as a solution in DMSO.
Figure 4. (a) Effect of compound 74 in the reversal of capsaicin-
induced hypothermia model in rats (40 mg/kg, p.o.). (b) Effect of
compound 74 in the CFA-induced thermal hyperalgesia model in rats
10, 20, and 40 mg/kg, p.o.
Table 6. Mean Pharmacokinetic Parameters of Compounds 9, 74, 78,
and 79 Following Oral Administrationa in Sprague-Dawley Rats
Cmax
tmax
AUC0-∞
bioavailability,
(ng/mL)
(h)
(ng‚h/mL)
F
oral (%)
surface of the hind paw of Sprague-Dawley rats, producing
an intense inflammatory response.26 After 21 h, compound 74
was administered orally at 10, 20, or 40 mg/kg. Three hours
after dosing, a thermal stimulation was applied to the inflamed
paw and withdrawal latencies were measured. Although a slight
increase in the paw withdrawal latencies were observed at the
1 h time point with the highest dose, the effect of compound
74 was not significant in this pain model.
9b
78b
79b
74c
25
34
26
0.5
0.5
5.0
1.2
24
79
94
3
5
6
300
2040
31
a Dosed at 5 mg/kg as a suspension in 5% Tween 80 in Oraplus. b n )
2 animals per study. Interanimal variability was less than or equal to 30%.
c Data is the mean of five studies. Variability for Cmax, tmax, and Foral values
ranged from 39 to 50% and variability for AUC0-∞ was 84%.
evaluated in Sprague-Dawley rats (Tables 5 and 6; the
pharmacokinetic data for compound 9 is also included for
comparison). Both of the 4-aminopyrimidine derivatives (78 and
79) showed similar pharmacokinetic profiles, exhibiting high
clearances that approached liver blood flow following an
Summary
We have described the synthesis and biological evaluation
of a series of conformationally constrained analogues of the
s-cis conformer of cinnamide 9 and have demonstrated that the
2-aminopyridine and 4-aminopyrimidine cores are suitable
isosteric replacements for the acrylamide moiety (compounds
13, 17, and 73, 78, and 79). These conformational constraints
allowed for a favorable planar alignment of the key pharma-
cophoric elements found in cinnamide 9 (e.g., the benzodioxane
and t-butylphenyl) and also established that the nitrogen in
pyridine 13 and the nitrogen adjacent to the aminobenzodioxane
group in pyrimidine 17 (i.e., W ) N) could serve as replace-
ments for the cinnamide carbonyl oxygen. Additionally, we
determined that the NH-linker is not required for activity in
this new series of TRPV1 antagonists and found that it can be
replaced with an oxygen and still maintain potency (compound
25). Finally, we demonstrated that potent, orally available
TRPV1 antagonists could be prepared by combining the
7-substituted quinoline and the trifluoromethylphenyl groups
with the 4-amino- and 4-oxopyrimidine cores (compounds 79
and 74). In fact, the new 4-oxopyrimidine derivative 74 was
not only 10-fold more potent than the original lead, cinnamide
9 (e.g., rTRPV1, IC50 ) 7.4 nM vs 79 nM, respectively), but
also had significantly improved pharmacokinetic properties (e.g.,
lower clearance, CLin vivo ) 1.2 vs 4.4 L/h/kg, and higher oral
bioavailability, Foral ) 31% vs 3%, respectively). Compound
74 was also shown to be efficacious in vivo at blocking
capsaicin-induced hypothermia in rats; however, it did not show
significant activity in the CFA-induced pain model. This
investigation has provided us with novel scaffolds for the further
study of related TRPV1 antagonists. Additional SAR analysis,
as well as in vivo efficacy of related compounds, will be reported
in parts 2 and 3 of this series.
intravenous dose. This resulted in low exposures (AUC0-∞
)
340 and 320 ng‚h/mL, respectively) and modest half-lives (t1/2
) 1.6-1.7 h). When administered orally compounds 78 and
79 showed low bioavailability possibly due to high first-pass
metabolism. On the other hand, changing the NH-linking group
to an oxygen significantly improved the i.v. pharmacokinetic
profile. The 4-oxopyrimidine derivative, 74, had a low to
moderate clearance (CLin vivo ) 1.2 L/h/kg) and a longer half-
life (t1/2 ) 2.8 h), which resulted in five times the exposure in
plasma as compared to its corresponding NH-linked derivative,
79. Similarly, the pharmacokinetic profile of compound 74 was
significantly better than either of the 4-aminopyrimidines, 78
or 79, or cinnamide 9 when administered orally. Upon oral
dosing, compound 74 showed approximately 10-fold improve-
ment in Cmax, a 5-fold improvement in AUC0-∞, and good
bioavailability (Foral ) 31%) as compared to that of pyrimidines
78 and 79.
On the basis of its potent in vitro activity at TRPV1 and its
good pharmacokinetic profile, 4-oxopyrimidine 74 was evaluated
in two in vivo models; one designed to access its “on-target”
activity (antagonism of TRPV1 in vivo) and the second one to
determine its potential analgesic activity (Figure 4). Initially,
compound 74 was evaluated for its ability to reverse capsaicin-
induced hypothermia in rats,15 an on-target biochemical chal-
lenge model. The results are illustrated in Figure 4a. In this
model, compound 74 or vehicle was administered orally to
Sprague-Dawley rats (treatment 1) and temperature was
monitored by radiotelemetry. After 90 min, 10 mg/kg of
capsaicin or vehicle was injected into the peritoneal cavity
(treatment 2). In the vehicle/capsaicin group, a significant drop
in core body temperature (∼1.5 °C) was observed. Pretreatment
of compound 74 completely blocked this capsaicin-induced
hypothermic response when dosed at 40 mg/kg, p.o. With this
encouraging result, 4-oxopyrimidine 74 was also evaluated for
its ability to block thermal hyperalgesia in the CFA model in
rats (Figure 4b). In this model, CFA was injected into the plantar
Experimental Section
Functional 45Ca2+ Uptake Assays. Chinese hamster ovary
(CHO) cells stably expressing human or rat TRPV1 channels were
generated by transfecting pcDNA3.1 expression vector containing
human or rat TRPV1 cDNAs. CHO cells were maintained in
Dulbecco’s modified Eagle’s medium supplemented with 10%

3506 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15
Norman et al.
dialyzed fetal bovine serum, penicillin, streptomycin, l-glutamine,
and nonessential amino acids. A calcium phosphate method was
used for stable transfection (5 µg of DNA per 2 × 106 cells in 60
mm dishes), and 800 µg/mL geneticin was used as a selection agent.
After 2 weeks of selection, single colonies were picked and screened
for expression of TRPV1 in the agonist-induced 45Ca2+ uptake
assay. Positive clones were expanded and used in studies described
here.
Gaussian98 software,46 utilizing the B3LYP hybrid density func-
tional and the 6-31G* basis set. The lowest-energy conformers from
these 10 calculations for both compound 9 and compound 17 were
used for the final assessment for the results that are as shown in
Figure 3.
Chemistry. Unless otherwise noted, all materials were obtained
from commercial suppliers and used without further purification.
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/MS obtained on an
Agilent 1100 or HP 1100 spectrometer. Purity was determined on
an Agilent 1100 spectrometer by method A, Phenomenex Luna C8
column (100 × 4.6 mm, 5µ) at 40 °C with a 1.0 mL/min flow rate
using a gradient of 5-100% 5 mM ammonium acetate in aceto-
nitrile in 5 mM ammonium acetate in water, pH 6.5, over 15 min,
or by method B, Phenomenex Luna C8 column (100 × 4.6 mm, 5
µ) at 40 °C with a 1.0 mL/min flow rate using a gradient of 50-
100% 0.1% formic acid in acetonitrile in 0.1% formic acid in water
over 10 min. Alternatively, purity was determined on an HP 1100
spectrometer by method C, YMC-AQ-C18 column (150 × 4.6 mm,
5 µ) at room temperature with a 1.0 mL/min flow rate using a
gradient of 10-100% 0.1% HCOOH in acetonitrile in 0.1%
HCOOH in water over 14 min; method D, Phenomenex Luna C8
column (100 × 4.6 mm, 5 µ) at 40 °C with a 1 mL/min flow rate
using a gradient of 5-100% 0.1% TFA in acetonitrile in 0.1% TFA
in water over 15 min; method E, YMC-ODS-AM C18 column
(100 × 2.1 mm, 5 µ) at 40 °C with a 0.5 mL/min flow rate using
a gradient of 10-100% 0.1% TFA in acetonitrile in 0.1% TFA in
water over 15 min; method F, DS-AM C18 column (100 × 2.1
mm, 5 µ) at 40 °C with a 0.5 mL/min flow rate using a gradient of
10-100% 0.1% HCOOH in acetonitrile in 0.1% HCOOH in water
over 15 min; or by method G, Synergi MAX-RP C12 column (50
× 2.0 mm, 4 µ) at 40 °C with a 0.8 mL/min flow rate using a
gradient of 10-100% 0.1% TFA in acetonitrile in 0.1% TFA in
water over 5 min. Silica gel chromatography was performed using
either glass columns packed with silica gel (200-400 mesh, Aldrich
Chemical) or prepacked silica gel cartridges (Biotage or Redisep).
Melting points were determined on a Buchi-545 melting point
apparatus and are uncorrected. NMR spectra were determined with
a Bruker 300 MHz or 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 electrospray (ES) ionization
modes (positive or negative). High-resolution mass spectral (HRMS)
data were determined on a 7T Bruker FTICR mass spectrometer
using ES ionization mode (positive). Combustion analyses were
performed by Atlantic Microlab, Inc., Norcross, GA, and were
within 0.4% of calculated values, unless otherwise noted.
(E)-3-(4-tert-Butylbenzylidene)-1-(2,3-dihydrobenzo[b][1,4]-
dioxin-6-yl)piperidin-2-one (10). To a solution of δ-valerolactam
(29; 0.79 g, 8.0 mmol) in 1,4-dioxane (7.0 mL) was added 3,4-
ethylenedioxyiodobenzene (28; 1.8 g, 6.7 mmol), potassium
phosphate tribasic (2.8 g, 13 mmol), and N,N′-dimethylethylene-
diamine (0.071 mL, 0.67 mmol). The reaction vessel was carefully
evacuated and refilled with N2 (3×). Copper(I) iodide (0.064 g,
0.33 mmol) was added, and the reaction vessel was carefully
evacuated and refilled again with N2 (3×). The reaction mixture
was stirred at 85 °C for 20 h and allowed to cool to room
temperature. The mixture was filtered and the filtrate was passed
through a plug of silica gel, and the filter cake was washed with
EtOAc. The combined filtrates were evaporated under reduced
pressure, and the residue was purified by silica gel column
chromatography (gradient: 60-100% EtOAc/hexanes) to give 0.87
g (56%) of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)piperidin-2-one
(30) as an off-white solid. MS (ESI, pos. ion) m/z: 378 (M + 1).
1H NMR (400 MHz, DMSO-d6): δ 1.75-1.85 (m, 4 H), 2.33 (t, J
) 6.3 Hz, 2 H), 3.51 (t, J ) 5.6 Hz, 2 H), 4.23 (s, 4 H), 6.69 (dd,
J ) 8.6, 2.3 Hz, 1 H), 6.75 (d, J ) 2.3 Hz, 1 H), 6.82 (d, J ) 8.6
Hz, 1 H).
Two days prior to the assay, cells were seeded in Cytostar 96-
well plates (Amersham) at a density of 20 000 cells/well. The
activation of TRPV1 is followed as a function of cellular uptake
of radioactive calcium (45Ca2+, ICN). All the 45Ca2+ uptake assays
had a final 45Ca2+ at 10 µCi/mL. These assays were conducted as
follows: (1) agonist assay, compounds were incubated with TRPV1-
expressing CHO cells in 1:1 ratio of F-12 and HBSS (Hanks’
buffered saline solution) supplemented with BSA 0.1 mg/mL and
1 mM HEPES (pH 7.4) at room temperature for 2 min in the
presence of 45Ca2+ prior to compound washout; (2) capsaicin
antagonist assay, compounds were preincubated with TRPV1
expressing CHO cells in HBSS (Hanks’ buffered saline solution)
supplemented with BSA 0.1 mg/mL and 1 mM HEPES (pH 7.4)
at room temperature for 2 min prior to addition of 45Ca2+ and
capsaicin (final concentration, 0.5 µM) in F-12 and then left for an
additional 2 min prior to compound washout; (3) proton antagonist
assay, compounds were preincubated with TRPV1 expressing CHO
cells at room temperature for 2 min prior to addition of 45Ca2+ in
30 mM Hepes/Mes buffer (final pH 5) and then left for an additional
2 min prior to compound washout; (4) compound washout and
analysis, assay plates were washed two times with PBS and 0.1
mg/mL BSA using an ELX405 plate washer (Bio-Tek Instruments,
Inc.) immediately after the functional assay. Radioactivity in the
96-well plates was measured using a MicroBeta Jet (Perkin-Elmer,
Inc.). IC50 values were calculated by generating antagonist inhibition
curves using Xlfit version 2.0.6 (ID Business Solutions, Ltd). The
reported results were the average of at least two independent
experiments with three replicates at each concentration ((SEM).
Radiotelemetry in Rats. Male Sprague-Dawley rats (CRL,
Wilmington, MA) weighing 175-250 g (6-8 weeks of age) were
single-housed and allowed to acclimate for 1 week in the animal
care facility prior to start of the experiment. The temperature in
the room used for radiotelemetry experiments was maintained at
20 ( 2 °C. To implant the radiotelemetry probe (model ER-4000
PDT; Mini Mitter, Brend, OR), rats were lightly anesthetized using
isoflourane (IsoFlo, Abbott Laboratories, Chicago, IL) at a con-
centration of 2% isoflourane at 2 L/min oxygen flow. In right lateral
recumbence, the left, lateral abdominal wall was clipped and cleaned
with Betadine solution (Purdue Frederick Company, Stamford, CT)
followed by 70% alcohol in water. A 3-4 mm incision was made
through the skin and abdominal wall into which a sterilized probe
was inserted. The surgical site was closed with absorbable suture
material (4-0 Vicryl, Ethicon Inc, Somerville, NJ) and black silk
suture material (4-0, Ethicon, Inc. Somerville, NJ), and the animals
were returned to home caging for recovery and allowed 3 days of
recovery prior to the drug experiment.
On the day of the experiment, single-housed animals were placed
on radiotelemetry receivers. A baseline of body core temperature
was recorded for 30 min prior to the drug administration. Rats (eight
per group) were either treated with vehicle or single to various doses
of TRPV1 antagonists in a dose volume of 5 mL/kg in an Ora-
Plus/5% Tween-80 (oral gavage), and the body core temperature
recordings were continued for two more hours.
Molecular Modeling. The molecular modeling studies were
carried out using molecular dynamics/mechanics45 and ab initio
quantum mechanics.46 The conformational search was carried out
with high-temperature molecular dynamics, and simulations were
conducted using the MacroModel.45 Energy calculations were
performed using the Merck molecular (MMFF94) force field47 in
aqueous medium using the GB/SA water model.48 The 10 lowest-
energy conformations of compounds 9 and 17 were chosen for
further optimization by quantum mechanics. Calculations were
performed using density functional theory, as implemented in

Head: TRPV1 Antagonists: Conformationally Restricted Cinnamides
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15 3507
To a flame-dried, N2-purged, 15 mL, round-bottomed flask was
added 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)piperidin-2-one (30;
0.30 g, 1.3 mmol) and THF (5.0 mL). The mixture was cooled to
-78 °C and then lithium diisopropylamide (1.8 M solution in
heptane/THF/ethylbenzene, 0.79 mL, 1.4 mmol) was added. The
reaction mixture was stirred for 10 min at -78 °C and then warmed
to 0 °C. After stirring for 30 min at 0 °C, the solution was again
cooled to -78 °C. 4-tert-Butylbenzaldehyde (0.26 mL, 1.5 mmol)
was added, and the mixture was stirred at -78 °C for 30 min. The
reaction mixture was allowed to warm to 0 °C, stirred at 0 °C for
15 min, and then poured into a saturated aqueous solution of NH4-
Cl. The solution was extracted with EtOAc, and the combined
organic extracts were successively washed with H2O and saturated
aqueous NaCl, dried over Na2SO4, and filtered. The filtrate was
evaporated under reduced pressure, and the residue was dissolved
in CH2Cl2 (10 mL) and treated with triethylamine (0.54 mL, 3.9
mmol). The mixture was cooled to 0 °C, treated with methane-
sulfonyl chloride (0.20 mL, 2.6 mmol), and stirred at 0 °C for 2 h
and at 25 °C for 1 h. The reaction mixture was poured into a
saturated aqueous solution of NH4Cl and extracted with EtOAc.
The combined organic extracts were washed successively with H2O
and saturated aqueous NaCl, dried over Na2SO4, and filtered. The
filtrate was evaporated under reduced pressure, and the residue was
dissolved in THF (10 mL) and treated with 1,8-diazabicyclo(5.4.0)-
undec-7-ene (0.58 mL, 3.9 mmol) at 25 °C. The reaction mixture
was stirred for 24 h at 25 °C and then poured into a mixture of 0.1
N HCl and EtOAc/hexanes (1:1). The organic phase was separated
and washed successively with H2O, saturated aqueous solution of
NaHCO3, H2O, and saturated aqueous NaCl, then dried over Na2-
SO4, and filtered. The filtrate was evaporated under reduced
pressure, and the residue was purified by silica gel column
chromatography (gradient: 10-45% EtOAc/hexanes) to give 0.15
g (31%) of the title compound as a white solid. MS (ESI, pos. ion)
g, 2.3 mmol), polystyrene triphenylphosphine palladium(0) (0.50
g, 0.11 mmol/g, 0.055 mmol), and 1:1 DME/EtOH (20 mL). The
solution was heated at 75 °C for 18 h. The reaction mixture was
allowed to cool to room temperature, filtered, and evaporated to
give 3-(4-tert-butylphenyl)chlorobenzene (42). MS (ESI, pos. ion)
m/z: 245 (M + 1). This material was used without further
purification.
The crude 3-(4-tert-butylphenyl)chlorobenzene (42) was dis-
solved in toluene (4 mL) and 1,4-benzodioxan-6-amine (52; 300
mg, 1.99 mmol), Pd2dba3 (25 mg, 0.027 mmol), 1,1′-bis(diphe-
nylphosphino)ferrocine (dppf; 25 mg, 0.045 mmol), and sodium
tert-butoxide (230 mg, 2.4 mmol) were added. The mixture was
heated at 150 °C for 10 min in a microwave and then evaporated
under reduced pressure. The residue was purified by silica gel
column chromatography (gradient: 5-20% EtOAc/hexanes). The
material was purified further by preparative HPLC (gradient: 10-
90% CH3CN/H2O, 0.1% TFA) to give 8 mg (1% overall yield based
on 1-chloro-3-iodobenzene (35)) of the title compound as a white
1
solid. H NMR (400 MHz, CDCl3): δ 1.35 (s, 9 H), 4.25 (m, 4
H), 6.71 (m, 2 H), 6.80 (m, 1 H), 6.92 (m, 1 H), 7.07 (m, 1 H),
7.16 (m, 1 H), 7.27 (m, 1 H), 7.44 (d, J ) 8.5 Hz, 2 H), 7.50 (d,
J ) 8.5 Hz, 2 H). HRMS calcd for (C24H25NO2)H+, 360.19581;
found, 360.19619. LC/MS retention time: [E] 10.96 min; [G] 3.06
min.
[4-(4-tert-Butyl-phenyl)-pyridin-2-yl]-(2,3-dihydro-benzo[1,4]-
dioxin-6-yl)-amine (13). To 4-bromopyridine hydrochloride (39;
8.9 g, 46 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.6
g, 1.4 mmol) in a round-bottomed flask was added 1,2-dimethoxy-
ethane (250 mL) with stirring under N2. After 20 min, a solution
of aqueous sodium carbonate (9.7 g in 70 mL of H2O) and 4-tert-
butylbenzeneboronic acid (34; 9.8 g, 55 mmol) were added
sequentially to the mixture, and the mixture was stirred at reflux
overnight. The reaction mixture was allowed to reach room
temperature and the 1,2-dimethoxyethane was evaporated under
reduced pressure. To the residue was added EtOAc, and the aqueous
phase was separated and extracted with EtOAc (2 × 100 mL). The
organic layers were combined, washed with saturated aqueous NaCl,
dried over Na2SO4, and filtered. The filtrate was evaporated under
reduced pressure, and the residue was purified by silica gel flash
chromatography (20% EtOAc/hexanes) to give 8.7 g (75%) of 4-(4-
tert-butyl-phenyl)pyridine (46) as a white solid. MS (ESI, pos. ion)
1
m/z: 378 (M + 1). H NMR (400 MHz, DMSO-d6): δ 1.30 (s, 9
H), 1.86-1.93 (m, 2 H), 2.81-2.87 (m, 2 H), 3.64-3.69 (m, 2 H),
4.25 (s, 4 H), 6.77 (dd, J ) 8.3, 2.2 Hz, 1 H), 6.84-6.87 (m, 2 H),
7.39 (d, J ) 8.6 Hz, 2 H), 7.45 (d, J ) 8.3 Hz, 2 H), 7.60 (s, 1 H).
Anal. (C24H27NO3): C, H, N.
3-(4-tert-Butylbenzyl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-
pyridin-2(1H)-one (11). A mixture of 2-hydroxypyridine (31; 2.5
g, 26 mmol) and 4-(tert-butyl)benzyl bromide (32; 1.6 mL, 8.8
mmol) was heated in a microwave at 190 °C for 5 min. The reaction
mixture was partitioned between a mixture of saturated aqueous
solution of NaHCO3 and EtOAc. The organic phase was separated,
washed successively with H2O and saturated aqueous NaCl, dried
over Na2SO4, and filtered. The filtrate was evaporated under reduced
pressure, and the residue was purified by silica gel column
chromatography (gradient: 50-100% EtOAc/hexanes, then 100%
EtOAc) to give 0.23 g (11%) of 3-(4-tert-butylbenzyl)pyridin-2(1H)-
one (33) as a yellow solid, which was used in the next step without
additional purification. Analytically pure material was obtained
through second purification by silica gel chromatography (gradi-
ent: 75-100% EtOAc/hexanes) to afford a white solid. MS (ESI,
1
m/z: 212 (M + 1). H NMR (400 MHz, DMSO-d6): δ 1.31 (s, 9
H), 7.54 (d, J ) 8.3 Hz, 2 H), 7.69 (d, J ) 4.7 Hz, 2 H), 7.73 (d,
J ) 8.3 Hz, 2 H), 8.62 (d, J ) 4.1 Hz, 2 H).
To a mixture of 4-(4-tert-butyl-phenyl)pyridine (46; 8.7 g, 41.3
mmol) and methyltrioxorhenium(VII) (170 mg, 0.7 mmol) in CH2-
Cl2 (18 mL) was added hydrogen peroxide (12 mL) dropwise with
stirring at room temperature under N2. The reaction mixture was
stirred at room temperature for 18 h then partitioned between CH2-
Cl2 and saturated aqueous NaCl. The aqueous layer was extracted
with CH2Cl2 (40 mL) and the combined organic layers were dried
over Na2SO4 and filtered. The filtrate was evaporated, and the
resulting residue was dried in vacuo to give 8.9 g (95%) of 4-(4-
tert-butyl-phenyl)-pyridine 1-oxide as an off-white solid. MS (ESI,
1
pos. ion) m/z: 242 (M + 1). H NMR (400 MHz, DMSO-d6): δ
1.25 (s, 9 H), 3.64 (s, 2 H), 6.10 (dd, J ) 6.5, 6.7 Hz, 1 H), 7.15
(d, J ) 8.2 Hz, 2 H), 7.18 (dd, J ) 6.7, 2.1 Hz, 1 H), 7.22 (dd, J
) 6.5, 2.0 Hz, 1 H), 7.28 (d, J ) 8.2 Hz, 2 H), 11.52 (s, 1 H).
Following the procedure described for compound 30, 3-(4-tert-
butylbenzyl)pyridin-2(1H)-one (33; 0.10 g, 0.41 mmol) was reacted
with 3,4-ethylenedioxyiodobenzene (28; 0.13 g, 0.50 mmol) to
provide 0.13 g (80%) of the title compound as a white solid. MS
1
pos. ion) m/z: 228 (M + 1). H NMR (400 MHz, DMSO-d6): δ
1.31 (s, 9 H), 7.51 (d, J ) 7.3 Hz, 2 H), 7.71 (d, J ) 8.2 Hz, 2 H),
7.75 (d, J ) 5.8 Hz, 2 H), 8.25 (d, J ) 5.6 Hz, 2 H). To a solution
of triphenylphosphine (2.4 g, 9.1 mmol) in CH2Cl2 (10 mL) was
added bromine (0.43 mL, 8.5 mmol) with stirring at 0 °C. The
mixture was stirred at 0 °C for 10 min, and 4-(4-tert-butyl-phenyl)-
pyridine 1-oxide (1.5 g, 6.5 mmol) was added, followed by Et3N
(1.2 mL). The reaction mixture was stirred at 0 °C for 1 h and at
room temperature for 18 h. The reaction mixture was then
partitioned between CH2Cl2 and saturated aqueous NaCl. The
aqueous layer was extracted with CH2Cl2, and the combined organic
layers were dried over Na2SO4 and filtered. The filtrate was
evaporated under reduced pressure, and the resulting residue was
purified by silica gel flash chromatography (10% EtOAc/hexanes)
to give 0.25 g (13%) of 2-bromo-4-(4-tert-butyl-phenyl)-pyridine
(47) as a light-yellow oil. MS (ESI, pos. ion) m/z: 293 (M + 1).
1
(ESI, pos. ion) m/z: 376 (M + 1). H NMR (400 MHz, DMSO-
d6): δ 1.25 (s, 9 H), 3.70 (s, 2 H), 4.28 (s, 4 H), 6.21 (dd, J ) 6.7,
6.8 Hz, 1 H), 6.81 (dd, J ) 8.5, 2.4 Hz, 1 H), 6.90 (d, J ) 2.3 Hz,
1 H), 6.94 (d, J ) 8.6 Hz, 1 H), 7.18 (d, J ) 8.2 Hz, 2 H), 7.22
(dd, J ) 6.7, 1.5 Hz, 1 H), 7.30 (d, J ) 8.2 Hz, 2 H), 7.46 (dd, J
) 6.8, 1.8 Hz, 1 H). Anal. (C24H25NO3): C, H, N.
3-(4-tert-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-
yl)phenyl-1-amine (12). An aqueous solution of K2CO3 (3.0 mL,
6 mmol, 2 M) was added to a slurry of 1-chloro-3-iodobenzene
(35; 0.50 g, 2.1 mmol), 4-tert-butylphenylboronic acid (34; 0.41

3508 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15
Norman et al.
1H NMR (400 MHz, CDCl3): δ 1.37 (s, 9 H), 7.42-7.58 (m, 6
H), 7.71 (s, 1 H), 8.39-8.42 (m, 1 H).
evaporated under reduced pressure, and the residue was purified
by silica gel column chromatography (33% EtOAc/hexanes) to
provide 0.56 g (52%) of the title product as a yellow oil. MS (ESI,
pos. ion) m/z: 361 (M + 1). 1H NMR (400 MHz, CDCl3): δ 1.34
(s, 9 H), 4.27 (s, 4 H), 5.94 (s, 1 H), 6.71 (m, 3 H), 6.86 (d, J )
8.5 Hz, 1 H), 7.10 (d, J ) 1.8 Hz, 1 H), 7.44 (d, J ) 8.3 Hz, 2 H),
7.81 (d, J ) 7.3 Hz, 2 H), 8.31 (d, J ) 5.6 Hz, 1 H). Anal.
(C23H24N2O2‚0.5H2O): C, H, N.
To an oven-dried, 50 mL, round-bottomed flask was added
2-bromo-4-(4-tert-butyl-phenyl)-pyridine (47; 183 mg, 0.63 mmol)
and 1,4-benzodioxan-6-amine (52; 191 mg, 1.3 mmol), followed
by anhydrous toluene (60 mL) and DMF (6 mL). Nitrogen was
bubbled through the solution via a needle for 1 h. Palladium acetate
(21 mg, 0.01 mmol) and BINAP (59 mg, 0.01 mmol) were then
added to the mixture, followed by sodium tert-butoxide (170 mg,
1.8 mmol). The reaction mixture was heated in a 90 °C oil bath
for 18 h. After cooling to room temperature, the reaction mixture
was dissolved in ether, washed with saturated aqueous NaCl, dried
over Na2SO4, and filtered. The filtrate was evaporated under reduced
pressure, and the residue was purified by silica gel flash chroma-
tography (25% EtOAc/hexanes) to give 0.13 g (53%) of the title
compound as a light-tan solid. Mp 162.1-163.1 °C. MS (ESI, pos.
6-(4-tert-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-
yl)pyridin-2-amine (16). The intermediate 2-bromo-6-(4-tert-
butylphenyl)pyridine (43) was prepared by the method described
for the preparation of compound 46 from 2,6-dibromopyridine (36;
2.4 g, 10 mmol), tetrakis(triphenylphosphine)palladium(0) (0.36 g,
0.3 mmol), aqueous sodium carbonate(1.1 g, 10 mmol in 15 mL
of H2O), and 4-tert-butylbenzeneboronic acid (34; 1.8 g, 10 mmol)
in 1,2-dimethoxyethane (50 mL). The solvent was evaporated, and
the residue was extracted with EtOAc (2×). The organic layers
were combined, dried over Na2SO4, filtered, and evaporated to give
2.98 g of 43 as a crude yellow solid. A portion of this crude material
(1.0 g, 3.4 mmol), and 1,4-benzodioxan-6-amine (52; 1.0 g, 6.8
mmol) were added to an oven-dried, 50 mL, round bottomed flask
followed by toluene (170 mL) and DMF (17 mL). The reaction
was stirred at room temperature for 1 h as N2 was bubbled though
the solution. Palladium acetate (76 mg, 0.34 mmol) and BINAP
(212 mg, 0.34 mmol) were then added to the mixture, followed by
sodium tert-butoxide (915 mg, 9.5 mmol). The reaction mixture
was heated in a 90 °C oil bath for 18 h. After cooling to room
temperature, the crude reaction mixture was dissolved in ether and
washed with saturated aqueous NaCl. The organic layer was
separated, dried over Na2SO4, filtered, and evaporated. The residue
was purified by column chromatography (1:8 to 1:4 EtOAc/hexanes)
to give 0.29 g (24%) of the title compound as a yellow foam. MS
1
ion) m/z: 361 (M + 1). H NMR (400 MHz, DMSO-d6): δ 1.32
(s, 9 H), 4.19 (d, J ) 5.1 Hz, 2 H), 4.22 (d, J ) 5.1 Hz, 2 H), 6.76
(d, J ) 8.7 Hz, 1 H), 6.97-7.02 (m, 3 H), 7.39 (s, 1 H), 7.53 (d,
J ) 8.4 Hz, 2 H), 7.61 (d, J ) 8.4 Hz, 1 H), 8.15 (d, J ) 5.9 Hz,
1 H), 8.90 (br s, 1 H). Anal. (C23H24N2O2): C, H, N.
5-(4-tert-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-
yl)pyridin-3-amine (14). A mixture of 3-bromo-5-iodopyridine (54;
340 mg, 1.19 mmol), 1,4-benzodioxane-6-amine (52; 300 mg, 2
mmol), Pd2dba3 (20 mg, 0.022 mmol), dppf (20 mg, 0.036 mmol),
sodium tert-butoxide (140 mg, 1.44 mmol), and toluene (4 mL)
was heated at 150 °C for 10 min in a microwave. The solvent was
removed under reduced pressure, and the residue was purified by
silica gel chromatography (gradient: 1-3% MeOH/CH2Cl2) to give
362 mg (99%) of 5-bromo-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-
yl)pyridin-3-amine (58) as a light-yellow solid. MS (ESI, pos. ion)
m/z: 307, 309 (M + 1). 1H NMR (400 MHz, CDCl3): δ 4.27 (m,
4 H), 5.54 (s, 1 H), 6.63 (d, J ) 8.0 Hz, 1 H), 6.68 (s, 1 H), 6.85
(d, J ) 8.0 Hz, 1 H), 7.36 (s, 1 H), 8.09 (s, 1 H), 8.14 (s, 1 H).
A mixture of 5-bromo-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-
pyridin-3-amine (58; 154 mg, 0.502 mmol), 4-tert-butylphenylbo-
ronic acid (34; 107 mg, 0.60 mmol), polystyrene triphenylphosphine
palladium(0) (45 mg, 0.11 mmol/g, 0.005 mmol), 2 M aqueous
solution of Na2CO3 (0.75 mL), and a 1:1 mixture of DME/EtOH
(4 mL) was heated at 120 °C for 5 min in a microwave. The
resulting slurry was filtered. The filtrate was evaporated under
reduced pressure, and the residue was purified by silica gel column
chromatography (gradient: 10-40% EtOAc/hexanes) to give 106
1
(ESI, pos. ion) m/z: 361 (M + 1). H NMR (400 MHz, DMSO-
d6): δ 1.32 (s, 9 H), 4.19-4.24 (m, 4 H), 6.69 (d, J ) 8.2 Hz, 1
H), 6.78 (d, J ) 8.7 Hz, 1 H), 7.08-7.10 (m, 1 H), 7.22 (d, J )
7.4 Hz, 1 H), 7.49 (d, J ) 8.4 Hz, 2 H), 7.52-7.60 (m, 2 H), 7.94
(d, J ) 8.4 Hz, 2 H), 8.89 (br s, 1 H). Anal. (C23H24N2O2‚0.25
H2O): C, H, N.
6-(4-tert-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-
yl)pyrimidin-4-amine (17). To a 500 mL, round-bottomed flask
containing 4,6-dichloropyrimidine (37; 5.20 g, 34.9 mmol) in 1,4-
dioxane (100 mL) was added 4-tert-butylphenylboronic acid (34;
4.31 g, 24.2 mmol) and Pd(PPh3)4 (1.01 g, 0.87 mmol). A solution
of 2 M K2CO3 (44 mL) was added, and the mixture was stirred
under N2 at 90 °C for 5 h. The reaction mixture was allowed to
cool to room temperature and concentrated in vacuo to reduce the
volume to ∼50 mL. The residue was partitioned between EtOAc
(100 mL) and H2O (200 mL). The aqueous phase was extracted
with EtOAc (2 × 100 mL). The combined organic phases were
washed with saturated aqueous NaCl, dried over Na2SO4, filtered,
and concentrated in vacuo to yield 9.67 g of thick magenta colored
oil. The crude material was purified by silica gel chromatography
(gradient: 0-30% EtOAc/hexanes), followed by a second silica
gel chromatography (gradient: 50-100% CHCl3/hexanes) to give
5.42 g (63%) of 6-[4-(tert-butyl)phenyl]-4-chloropyrimidine (44)
as a white solid. MS (ESI, pos. ion.) m/z: 247 (M + 1). 1H NMR
(300 MHz, CDCl3): δ 1.38 (s, 9 H), 7.55 (d, J ) 8.7 Hz, 2 H),
7.73 (s, 1 H), 8.02 (d, J ) 8.7 Hz, 2 H), 9.02 (s, 1 H).
A mixture of 6-[4-(tert-butyl)phenyl]-4-chloropyrimidine (44;
0.25 g, 1.0 mmol) and 1,4-benzodioxane-6-amine (52; 0.15 g, 1.0
mmol) in 1,4-dioxane (5 mL) was heated at reflux under N2 for 3
h. The reaction mixture was allowed to reach room temperature
and then was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (1:2 EtOAc/hexanes)
to provide the title product as an off-white solid, yield 0.185 g
(51%). Mp 199-202 °C. MS (ESI, pos. ion) m/z: 362 (M + 1).
1H NMR (400 MHz, CDCl3): δ 1.31 (s, 9 H), 4.28 (s, 4 H), 6.82
(m, 3 H), 6.97 (s, 1 H), 7.48 (d, J ) 8.5 Hz, 2 H), 7.88 (d, J ) 8.5
Hz, 2 H), 8.61 (s, 1 H). Anal. (C22H23N3O2‚0.25 H2O): C, H, N.
4-(4-tert-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-
yl)pyrimidin-2-amine (18). To a 100 mL, round-bottomed flask
1
mg (59%) of the title compound as an off-white solid. H NMR
(400 MHz, CDCl3): δ 1.36 (s, 9 H), 4.26 (m, 4 H), 5.63 (s, 1 H),
6.65 (d, J ) 8.5 Hz, 1 H), 6.71 (s, 1 H), 6.83 (d, J ) 8.5 Hz, 1 H),
7.43 (s, 1 H), 7.48 (m, 4 H), 8.22 (s, 1 H), 8.31 (s, 1 H). HRMS
calcd for (C23H24N2O2)H+, 361.19105; found, 361.19077. LC/MS
retention time: [E] 7.88 min; [F] 8.13 min.
2-(4-tert-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-
yl)pyridin-4-amine (15). To a 50 mL, round-bottomed flask was
added 2-chloro-4-iodopyridine (53; 0.29 g, 1.2 mmol), 1,4-
benzodioxane-6-amine (52; 0.18 g, 1.2 mmol), Pd(OAc)2 (13 mg,
0.06 mmol), 1,1,4,7,7-pentakis(1H-benzimidazol-2-ylmethyl)-1,4,7-
triazaheptane (DTPB; 18 mg, 0.060 mmol), K3PO3 (0.51 g, 2.4
mmol), and toluene (8 mL). The mixture was heated to reflux for
10 h. The reaction mixture was allowed to reach room temperature,
and the solvent was removed under reduced pressure. Purification
of the residue by silica gel column chromatography (1:1 EtOAc/
hexanes) afforded 0.17 g (54%) of 2-chloro-N-(2,3-dihydrobenzo-
[b][1,4]dioxin-6-yl)pyridin-4-amine (57). MS (ESI, pos. ion) m/z:
264 (M + 1).
To a 100 mL, round-bottomed flask containing 2-chloro-N-(2,3-
dihydrobenzo[b][1,4]dioxin-6-yl)pyridin-4-amine (57; 0.26 g, 1.0
mmol), was added 4-tert-butylphenylboronic acid (34; 0.55 g, 3.0
mmol), acetonitrile (6 mL), and 10% aqueous solution of Na2CO3
(6 mL). Pd(PPh3)4 (0.058 g, 0.050 mmol) was added, and the
mixture was heated at 90 °C for 8 h. The mixture was allowed to
reach room temperature, diluted with 5% aqueous solution of NaCl
(10 mL), and then extracted with EtOAc (35 mL). The organic
layer was dried over Na2SO4 and filtered. The filtrate was

Head: TRPV1 Antagonists: Conformationally Restricted Cinnamides
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15 3509
was added 4-chloro-2-(methylthio)pyrimidine (40; 0.32 g, 2.0 mmol,
Aldrich), 4-tert-butylphenylboronic acid (34; 0.35 g, 2.0 mmol),
CH3CN (15 mL), and 10% aqueous Na2CO3 (10 mL). Pd(PPh3)4
(0.45 g, 0.39 mmol) was added, and the mixture was heated at 90
°C for 6 h. The product was extracted with EtOAc (15 mL). The
combined organic extracts were washed with 5% aqueous NaCl,
dried over Na2SO4, filtered, and concentrated in vacuo. Purification
by silica gel chromatography (20% EtOAc/hexanes) afforded 0.45
g (89%) 4-(4-tert-butylphenyl)-2-(methylthio)pyrimidine (48) as a
clear oil. 1H NMR (400 MHz, CDCl3): δ 1.36 (s, 9 H), 2.65 (s, 3
H), 7.34 (d, J ) 4.0 Hz, 1 H), 7.52 (d, J ) 8.0 Hz, 2 H), 8.03 (d,
J ) 8.0 Hz, 2 H), 8.51 (d, J ) 4.0 Hz, 1 H). MS (ESI, pos. ion)
m/z: 259 (M + 1).
filter cake was washed with MeOH and CH2Cl2 and then dissolved
in H2O (500 mL). The aqueous solution was cooled with an ice-
water bath, and the crystalline precipitate was collected by filtration.
The mother liquor was concentrated, and the resulting residue was
redissolved into H2O (250 mL). Subsequent cooling afforded
additional product. The crops were combined and dried in the air
to afford 8.85 g (44%) of (Z)-3-(4-tert-butylphenyl)-3-cyanoacrylate
1
(62). MS (ESI, pos. ion) m/z: 230 (M + 1). H NMR (400 MHz,
DMSO-d6): δ 1.28 (s, 9 H), 7.03 (s, 1 H), 7.42-7.55 (m, 4 H).
A solution of (Z)-3-(4-tert-butylphenyl)-3-cyanoacrylate (62; 8.65
g, 32.35 mmol) in 88% formic acid (80 mL) containing concentrated
H2SO4 (6 mL) was stirred at reflux for 3 h. The reaction mixture
was allowed to cool to room temperature and then cooled further
in an ice bath. The resulting solid precipitate was filtered, washed
with H2O, and air-dried to afford 6.25 g (84%) of 3-(4-tert-
butylphenyl)furan-2,5-dione (63). MS (ESI, pos. ion) m/z: 231 (M
+ 1). 1H NMR (400 MHz, CDCl3): δ 1.36 (s, 9 H), 6.95 (s, 1 H),
7.54 (dt, J ) 8.8, 2.1 Hz, 2 H), 7.93 (dt, J ) 8.8, 2.1 Hz, 2 H).
To a 100 mL, round-bottomed flask was added 4-(4-tert-
butylphenyl)-2-(methylthio)pyrimidine (48; 0.11 g, 0.43 mmol),
m-CPBA (0.15 g, 0.85 mmol), and CH2Cl2 (10 mL). The reaction
mixture was stirred at room temperature for 1 h. The solution was
concentrated with a rotary evaporator, and the residue was purified
by silica gel chromatography with 1:2 EtOAc/hexanes to afford
0.10 g (86%) of 4-(4-tert-butylphenyl)-2-(methylsulfinyl)pyrimidine
To a solution of 3-(4-tert-butylphenyl)furan-2,5-dione (63; 6.05
g, 26.3 mmol) in acetic acid (50 mL) was added hydrazine hydrate
(1.4 mL) dropwise with stirring at room temperature. The reaction
mixture was stirred at room temperature for 1.5 h and heated at
reflux for 4.5 h. The reaction mixture was allowed to cool to room
temperature, and the resulting precipitate was collected via filtration
through a filter funnel to afford 3.57 g of 4-(4-tert-butylphenyl)-
1,2-dihydropyridazine-3,6-dione (64). The filtrate was evaporated
under reduced pressure, and the residue was purified by silica gel
column chromatography (10% MeOH/CH2Cl2) to give 0.367 g of
additional product. The combine yield was 3.94 g (61%). MS (ESI,
1
(49) as a white solid. H NMR (400 MHz, CDCl3): δ 1.37 (s, 9
H), 3.43 (s, 3 H), 7.57 (d, J ) 8.0 Hz, 2 H), 7.88 (d, J ) 8.00 Hz,
1 H), 8.10 (d, J ) 12.0 Hz, 2 H), 8.89 (d, J ) 4.0 Hz, 1 H). MS
(ESI, pos. ion) m/z: 275 (M + 1).
A mixture of 4-(4-tert-butylphenyl)-2-(methylsulfinyl)pyrimidine
(49; 0.47 g, 1.7 mmol) and 1,4-benzodioxane-6-amine (52; 0.26 g,
1.7 mmol) in 1,4-dioxane (8 mL) and EtOH (8 mL) was heated at
reflux under N2 for 22 h. The reaction mixture was allowed to reach
room temperature and evaporated under reduced pressure. The
residue was purified by silica gel chromatography (1:5 EtOAc/
hexanes) to provide 0.31 mg (51%) of the title product as a yellow
solid. Mp 199-202 °C. MS (ESI, pos. ion) m/z: 362 (M + 1). 1H
NMR (400 MHz, CDCl3): δ 1.37 (s, 9 H), 4.27 (m, 4 H), 6.85 (d,
J ) 8.7 Hz, 1 H), 7.06 (m, 3 H), 7.39 (d, J ) 2.5 Hz, 1 H), 7.52
(dd, J ) 6.7, 1.7 Hz, 2 H), 7.99 (dd, J ) 6.7, 1.7 Hz, 2 H), 8.41
(d, J ) 5.2 Hz, 1 H). Anal. (C22H23N3O2‚0.25 H2O): C, H, N.
(2-(4-tert-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-
yl)pyrimidin-4-amine (19). A mixture of 2,4-dichloropyrimidine
(55; 1.0 g, 6.7 mmol) and 1,4-benzodioxane-6-amine (52; 1.0 g,
6.7 mmol) in EtOH (30 mL) was stirred at room temperature for
12 h. The solvent was removed in vacuo, and the residue was taken
in CH2Cl2/MeOH (2:1 v/v, 8 mL). The insoluble material was
filtered through a fritted glass funnel, and the filtrate was evaporated
under reduced pressure. The residue was purified by silica gel
column chromatography (1:3 ethyl acetate/hexanes) to give 0.40 g
(23%) of 2-chloro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimi-
din-4-amine (59) as a yellow oil. MS (ESI, pos. ion) m/z: 264 (M
+ 1).
To a 100 mL, round-bottomed flask containing 2-chloro-N-(2,3-
dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-4-amine (59; 0.12 g,
0.46 mmol) was added 4-tert-butylphenylboronic acid (34; 0.16 g,
0.91 mmol), acetonitrile (10 mL), and 10% aqueous solution of
Na2CO3 (6 mL). Pd(PPh3)4 (0.036 g, 0.023 mmol) was added, and
the mixture was heated at 90 °C for 14 h. After cooling to 25 °C,
the mixture was diluted with 5% aqueous NaCl (10 mL) and the
product was extracted with EtOAc (35 mL), dried over Na2SO4,
filtered, and concentrated in vacuo. The product was purified by
silica gel chromatography (1:3 EtOAc/hexanes) to provide 0.10 g
(60%) of the title compound as an off-white solid. Mp 68-71 °C.
MS (ESI, pos. ion) m/z: 362 (M + 1). 1H NMR (400 MHz,
CDCl3): δ 1.36 (s, 9 H), 4.28 (s, 4 H), 6.50 (d, J ) 5.9 Hz, 1 H),
6.76 (s, 1 H), 6.85 (m, 2 H), 6.95 (d, J ) 2.4 Hz, 1 H), 7.48 (dd,
J ) 6.7, 1.8 Hz, 2 H), 8.29 (dd, J ) 6.7, 1.8 Hz, 2 H), 8.34 (d, J
) 5.9 Hz, 1 H). Anal. (C22H23N3O2‚0.1H2O): C, H, N.
1
pos. ion) m/z: 245 (M+1). H NMR (400 MHz, CDCl3): δ 1.36
(s, 9 H), 7.24 (s, 1 H), 7.51 (d, J ) 8.5 Hz, 2 H), 7.77 (d, J ) 8.5
Hz, 2 H).
A mixture of 4-(4-tert-butylphenyl)-1,2-dihydropyridazine-3,
6-dione (64) (3.38 g, 13.8 mmol) and POCl3 (20 mL) was stirred
at 72 °C for 5 h under N2. The reaction mixture was cooled to
room temperature and the excess of POCl3 was evaporated under
reduced pressure. The residue was quenched with crushed ice, and
the mixture was neutralized by the addition of a saturated aqueous
solution of NaHCO3. The solid precipitate was collected by
filtration, and the filter cake was washed with H2O and dried in
vacuo to afford 3.1 g (93%) of 4-(4-tert-butylphenyl)-3,6-dichlo-
ropyridazine (65) as a tan solid. MS (ESI, pos. ion) m/z: 245
(M+1). 1H NMR (400 MHz, CDCl3): δ 1.38 (s, 9 H), 7.44-7.51
(m, 3 H), 7.52-7.58 (m, 2 H).
A mixture of 4-(4-tert-butylphenyl)-3,6-dichloropyridazine (65)
(0.150 g, 0.53 mmol) and 1,4-benzodioxan-6-amine (52) (0.080 g,
0.53 mmol) in EtOH (3 mL) was stirred at 180 °C for 20 min in a
microwave. The reaction mixture was evaporated under reduced
pressure, and the residue was purified by silica gel flash column
chromatography (3:1 EtOAc/hexanes) to afford 0.14 g (65%) of
5-(4-tert-butylphenyl)-6-chloro-N-(2,3-dihydrobenzo[b][1,4]dioxin-
6-yl)pyridazin-3-amine (66). MS (ESI, pos. ion) m/z: 396 (M+1).
1H NMR (400 MHz, CDCl3): δ 1.36 (s, 9 H), 4.27 (s, 4 H), 6.71-
6.80 (m, 1 H), 6.81-6.90 (m, 2 H), 6.94 (s, 1 H), 7.06 (s, 1 H),
7.34-7.43 (m, 2 H), 7.45-7.56 (m, 2 H). MS (ESI, pos. ion) m/z:
396 (M+1).
A mixture of 5-(4-tert-butylphenyl)-6-chloro-N-(2,3-dihydrobenzo-
[b][1,4]dioxin-6-yl)pyridazin-3-amine (66) (0.053 g, 0.134 mmol),
EtOH (8 mL) and Zn (highly reactive Rieke metal, suspension in
THF, 2 mL, 0.1 g/mL) was heated at 72 °C for 48 h under N2. The
reaction mixture was allowed to cool to room temperature and was
filtered through a pad of Celite. The filtrate was evaporated under
reduced pressure and the residue was purified by reverse phase
HPLC (Phenomenex, Luna 10 µM C18(2), 100 Å, 150 × 30 mm;
1-99% CH3CN(0.1% TFA)/H2O (0.1%TFA)) followed by prepara-
tive TLC (Whatman Silica Gel 60 Å (20 × 20 cm, 1000 µm); 5%
MeOH/ CH2Cl2 + 1% NH4OH) to afford 0.015 g (30%) of the
5-(4-tert-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-
yl)pyridazin-3-amine (20). A mixture of 2-(4-tert-butylphenyl)-
acetonitrile (61; 13.01 g, 75.08 mmol), glyoxylic acid hydrate (10.43
g, 113.3 mmol), and potassium carbonate (26.34 g, 190.6 mmol)
was suspended in MeOH (250 mL) and heated at reflux for 1 h.
The reaction mixture was allowed to reach room temperature, and
the resulting thick solid precipitate was collected by filtration. The
1
title compound. MS (ESI, pos. ion) m/z: 362 (M+1). H NMR
(CDCl3) δ 1.36 (s, 9 H), 4.25-4.32 (m, 4 H,) 6.78-6.84 (m, 1 H),
6.86-6.92 (m, 2 H), 7.12 (d, J ) 1.9 Hz, 1 H), 7.22 (br s, 1 H),

3510 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15
Norman et al.
7.49-7.56 (m, 4 H), 8.88 (d, J ) 1.9 Hz, 1 H). Anal. (C22H23N3O2‚
0.75H2O): C, H, N.
through the solution for 5 min and then stirred at 120 °C for 20
min in a microwave. The reaction mixture was partitioned between
H2O (50 mL) and EtOAc (50 mL). The aqueous phase was extracted
with EtOAc (2 × 50 mL). The combined organic phases were
washed with saturated aqueous NaCl. The organic phase was dried
over Na2SO4, filtered, and concentrated in vacuo to afford 0.53 g
of a light brown solid. The solid was washed with CH2Cl2 and
purified by silica gel chromatography (gradient: 30-70% EtOAc/
hexanes) to afford 265 mg (57%) of the title compound as a light-
6-(4-tert-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-
yl)pyridazin-4-amine (21). A 2 N aqueous solution of K2CO3 (3.0
mL) and Pd(PPh3)4 (0.295 g, 0.26 mmol) were added to a solution
of 3-chloro-5-methoxypyridazine (41)38 (0.330 g, 2.28 mmol) and
4-tert-butylphenylboronic acid (34) (0.616 g, 3.46 mmol) in
diethylene glycol dimethyl ether (4.0 mL). The yellow suspension
was stirred at 90 °C for 18 h under N2. The reaction mixture was
allowed to cool to room temperature and was filtered through a
pad of Celite. The filtrate was evaporated under reduced pressure
and the residue was diluted with EtOAc. The organic phase was
separated, washed successively with H2O and saturated aqueous
NaCl, dried over Na2SO4, and filtered. The filtrate was evaporated
under reduced pressure, and the residue was purified by silica gel
chromatography (70% EtOAc/hexanes) to afford 0.52 g (88%) of
3-(4-tert-butylphenyl)-5-methoxypyridazine (50). MS (ESI, pos. ion)
1
yellow solid. MS (ESI, pos. ion.) m/z: 362 (M + 1). H NMR
(300 MHz, DMSO-d6): δ 1.33 (s, 9 H), 4.13-4.33 (m, 4 H), 6.83
(d, J ) 8.9 Hz, 1 H), 7.13 (dd, J ) 8.8, 2.5 Hz, 1 H), 7.46-7.62
(m, 3 H), 7.98 (d, J ) 8.5 Hz, 2 H), 8.09 (s, 1 H), 8.43 (s, 1 H),
9.39 (s, 1 H). Anal. (C22H23N3O2‚0.25H2O): C, H, N.
4-(4-tert-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-
yl)-1,3,5-triazin-2-amine (23). To a 5 mL reaction vial was added
2,4-dichloro-1,3,5-triazine (56; 0.407 g, 2.72 mmol), 1,4-benzo-
dioxane-6-amine (52; 0.412 g, 2.73 mmol), and t-BuOH (3 mL).
The gray mixture was stirred at room temperature for 20 min. The
reaction mixture was poured into 50 mL of saturated aqueous
NaHCO3. The aqueous phase was extracted with EtOAc (50 mL).
The organic phase was dried over Na2SO4, filtered, and concentrated
in vacuo. The crude material was purified by silica gel chroma-
tography (gradient: 0-100% EtOAc/hexanes) to provide 0.376 g
(52%) of 4-chloro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,5-
1
m/z: 243 (M+1). H NMR (400 MHz, CDCl3): δ 1.39 (s, 9 H),
4.00 (s, 3 H), 7.25 (d, J ) 2.8 Hz, 1 H), 7.51-7.60 (m, 2 H),
7.96-8.03 (m, 2 H), 8.88 (d, J ) 2.8 Hz, 1 H).
A mixture of 3-(4-tert-butylphenyl)-5-methoxypyridazine (50)
(0.24 g, 1.00 mmol) and 47% HI (3.0 mL) was stirred at 150 °C
for 90 min in a microwave. The reaction mixture was filtered, and
the filter cake was washed successively with H2O then CH2Cl2.
The material was allowed to air-dry to give 0.20 g (88%) of 6-(4-
tert-butylphenyl)pyridazin-4-ol as pale-yellow crystals. MS (ESI,
1
triazin-2-amine (60) as a tan solid. H NMR (300 MHz, CDCl3):
1
δ 4.25-4.33 (m, 4 H) 6.85-6.97 (m, 2 H) 7.18 (s, 1 H) 7.35 (s, 1
H), 8.44-8.56 (m, 1 H). MS (ESI, pos. ion) m/z: 265 (M + 1).
To a 5 mL microwave reaction vial was added 4-chloro-N-(2,3-
dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,5-triazin-2-amine (60; 0.190
g, 0.716 mmol), 4-tert-butylphenylboronic acid (34; 0.156 g, 0.878
mmol), tetrakis(triphenylphosphine) palladium(0) (0.049 g, 0.042
mmol) and 1,4-dioxane (3 mL). Ar was bubbled through the solution
for 5 min. A 2 M aqueous solution of K2CO3 (2.0 M, 0.900 mL,
1.80 mmol) was added to the solution as the Ar bubbling was
continued. The reaction mixture was stirred at 130 °C for 10 min
in microwave. The reaction mixture was partitioned between H2O
and EtOAc. The aqueous phase was extracted with EtOAc (2 ×
20 mL). The combined organic layers were washed with saturated
aqueous NaCl, dried over Na2SO4, filtered, and concentrated in
vacuo. The resulting brown residue was purified by silica gel
chromatography to afford 0.048 g (19%) of the title compound as
a white solid. 1H NMR (300 MHz, CDCl3): δ 1.38 (s, 9 H), 4.25-
4.35 (m, 4 H,) 6.89 (d, J ) 8.67 Hz, 1 H), 7.03 (br s, 1 H), 7.19
(br s, 1 H), 7.35 (br s, 1 H), 7.53 (d, J ) 8.7 Hz, 2 H), 8.36 (d, J
) 8.3 Hz, 2 H), 8.75 (br s, 1 H). MS (ESI, pos. ion) m/z: 363 (M
+ 1). Anal. (C21H22N4O2): C, H, N.
pos. ion) m/z: 229 (M+1). H NMR (CD3OD): δ 1.40 (s, 9 H),
7.70 (d, J ) 2.8 Hz, 1 H), 7.73-7.79 (m, 2 H), 7.83-7.90 (m, 2
H), 8.78 (d, J ) 2.8 Hz, 1 H). 6-(4-tert-Butylphenyl)pyridazin-4-
ol (0.248 g, 1.0 mmol) was reacted with POCl3 (3.0 mL) under the
conditions described for compound 65 to give 0.13 g (51%) of the
title compound as a crystalline solid. MS (ESI, pos. ion) m/z: 247
(M+1). 1H NMR (400 MHz, CDCl3): δ 1.39 (s, 9 H), 7.54-7.60
(m, 2 H), 7.87 (d, J ) 2.3 Hz, 1 H), 8.02 (d, J ) 8.7 Hz, 2 H),
9.13 (d, J ) 2.1 Hz, 1 H).
Reaction of 3-(4-tert-butylphenyl)-5-chloropyridazine (51) (0.063
g, 0.256 mmol) with 1,4-benzodioxan-6-amine (52) (0.050 g, 0.327
mmol), under the conditions described for compound 66, gave 0.074
g (80%) of the title compound as tan solid. MS (ESI, pos. ion)
1
m/z: 362 (M+1). H NMR (400 MHz, DMSO-d6): δ 1.32 (s, 9
H), 4.25 (s, 4 H), 6.72-6.95 (m, 3 H), 7.21 (d, J ) 2.6 Hz, 1 H),
7.52 (d, J ) 8.3 Hz, 2 H), 7.87 (d, J ) 8.3 Hz, 2 H), 8.70 (d, J )
2.6 Hz, 1 H), 8.97 (s, 1 H). Anal. (C22H23N3O2‚0.25H2O): C, H,
N.
6-(4-tert-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-
yl)pyrazin-2-amine (22). To a 20 mL microwave reaction tube
was added 2,6-dichloropyrazine (38; 0.516 g, 3.46 mmol), 4-tert-
butylbenzeneboronic acid (34; 0.558 g, 3.13 mmol), Pd(PPh3)4
(0.402 g, 0.348 mmol), and 1,4-dioxane (8 mL). The mixture was
deoxygenated by bubbling argon through the solution for 5 min.
Potassium carbonate (1.80 mL of a 2.0 M solution, 3.60 mmol)
was added. The solution was heated at 140 °C for 20 min in a
microwave. The reaction mixture was partitioned between H2O and
EtOAc. The aqueous phase was extracted with EtOAc (2 × 50
mL). The combined organic phases were washed successively with
H2O and saturated aqueous NaCl. The organic phase was dried over
Na2SO4, filtered, and concentrated in vacuo to afford 1.34 g of
pale yellow oil. The crude product was purified by silica gel
chromatography (EtOAc/hexanes 0-20%), followed by additional
silica gel chromatography (0-60% CH2Cl2/hexanes) to afford 412
mg (48%) of 2-(4-tert-butylphenyl)-6-chloropyrazine (45) as a clear
6-(4-tert-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-
yl)-N-methylpyrimidin-4-amine (24). To a glass vial was added
4-(4-tert-butylphenyl)-6-chloropyrimidine (44; 0.10 g, 0.4 mmol),
2,3-dihydrobenzo[b][1,4]dioxin-6-amine (52; 0.06 g, 0.4 mmol),
and EtOH (1.5 mL). The reaction mixture was stirred in a
microwave at 170 °C for 15 min. The solution was concentrated in
vacuo and the crude product was dissolved in acetone (5 mL).
Iodomethane (0.1 mL, 3.2 mmol) and MP-carbonate (0.25 g, 0.8
mmol) were added, and the reaction mixture was shaken at room
temperature for 16 h. The reaction mixture was concentrated in
vacuo, and the crude residue was purified by silica gel chroma-
tography (1:1 ethyl acetate/hexanes) to afford 3.53 g (71%) of the
1
title compound as a yellow oil. H NMR (400 MHz, CDCl3): δ
1.32 (s, 9 H), 3.54 (s, 3 H), 4.28 (s, 4 H), 6.42 (dd, J ) 2.4, 8.4
Hz, 1 H), 6.46 (d, J ) 2.4 Hz, 1 H), 6.71(s, 1 H), 6.83 (d, J ) 8.4
Hz, 1 H), 7.41 (d, J ) 8.4 Hz, 2 H), 7.70 (d, J ) 8.4 Hz, 2 H),
7.98 (s, 1 H). HRMS calcd for (C23H25N3O2)H+, 376.20250; found,
376.20240. LC/MS retention time: [A] 11.16 min; [C] 6.29 min.
4-(4-tert-Butylphenyl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-
yloxy)pyrimidine (25). To a 50 mL, round-bottomed flask was
added 3,4-(ethylenedioxy)phenol (67;41 46 mg, 302 µmol), 4-(4-
tert-butylphenyl)-6-chloropyrimidine (44; 75 mg, 302 µmol), cesium
carbonate (99 mg, 302 µmol), and DMF (2 mL). The reaction
mixture was stirred at 65 °C for 30 min and then allowed to cool
1
oil. MS (ESI, pos. ion.) m/z: 247 (M + 1). H NMR (300 MHz,
CDCl3): δ 1.38 (s, 9 H), 7.54 (d, J ) 8.5 Hz, 2 H), 7.97 (d, J )
8.5 Hz, 2 H), 8.49 (s, 1 H), 8.92 (s, 1 H).
To a 5 mL microwave reaction tube was added 2-(4-tert-
butylphenyl)-6-chloropyrazine (45; 0.315 g, 1.28 mmol), 2,3-
dihydrobenzo[b][1,4]dioxin-6-amine (52; 0.203 g, 1.34 mmol),
tris(dibenzylideneacetone)dipalladium(0) (0.0333 g, 0.0364 mmol),
2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.0320
g, 0.0813 mmol), and sodium tert-butoxide (0.1487 g, 1.55 mmol)
in toluene (3 mL). The mixture was deoxygenated by bubbling Ar

Head: TRPV1 Antagonists: Conformationally Restricted Cinnamides
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15 3511
to room temperature. The reaction mixture was diluted with water
(20 mL) and extracted with EtOAc (2 × 40 mL). The combined
organic extracts were washed successively with H2O, saturated
aqueous NaCl, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by silica gel chromatography,
eluting with 40% EtOAc/hexanes to give 48 mg (44%) of the title
compound as a white solid. Mp 137-138 °C. 1H NMR (400 MHz,-
CDCl3): δ ppm 1.36 (s, 9 H), 4.29 (s, 4 H), 6.67 (dd, J ) 8.80,
2.74 Hz, 1 H), 6.74 (d, J ) 2.74 Hz, 1 H), 6.92 (d, J ) 8.80 Hz,
1 H), 7.21 (s, 1 H), 7.52 (d, J ) 8.61 Hz, 2 H), 7.98 (d, J ) 8.61
Hz, 2 H), 8.84 (s, 3 H). (ESI, pos. ion) m/e: 363 (M+ + 1). Anal.
(C22H22N2O): C, H, N.
H), 4.07 (s, 2 H), 4.26 (s, 4 H), 6.82 (m, 3 H), 7.51 (m, 3 H), 7.98
(d, J ) 8.8 Hz, 2 H), 9.19 (s, 1 H). HRMS: Calcd for (C23H25N3O2)-
H+: 361.19160; Found: 361.19011. LC/MS retention time: [B]
8.66 min; [D] 9.70 min.
N-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-6-(4-(trifluorometh-
yl)phenyl) pyrimidin-4-amine (73). To a 500 mL, round-bottomed
flask was added 4,6-dichloropyrimidine (37) (14 g, 95 mmol),
4-(trifluoromethyl)phenylboronic acid (71) (6.0 g, 32 mmol),
acetonitrile (95 mL) and 1 M aqueous solution of sodium carbonate
(95 mL). The mixture was deoxygenated by sparging the solution
with N2 for 15 min. The catalyst, Pd(PPh3)4 (1.9 g, 1.6 mmol),
was added and the resulting yellow mixture was stirred at 80 °C
for 15 h. After cooling to 25 °C, the reaction mixture was
concentrated under reduced pressure to remove the acetonitrile. The
residue was diluted with an aqueous solution of NaHCO3 and
extracted with CH2Cl2 (3×). The combined extracts were dried over
Na2SO4 and filtered. The filtrate was evaporated under reduced
pressure and the residue was purified by silica gel column
chromatography (gradient: 1.5-10% EtOAc/hexanes) to afford 3.4
g (41%) of 4-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidine (72)
4-(4-tert-Butylphenyl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-
ylthio)pyrimidine (26). This material was prepared according to
the method describe for compound 25 from 4-(4-tert-butylphenyl)-
6-chloropyrimidine (44; 123 mg, 499 µmol), 3,4-(ethylenedioxy)-
thiophenol (68; 84 µL, 499 µmol), and cesium carbonate (325 mg,
997 µmol) in DMF (1 mL). The crude product was purified by
silica gel chromatography (40% EtOAc/hexanes) to afford 123 mg
(65%) of the title compound as a white solid. Mp: 132-133 °C.
1H NMR (400 MHz, CDCl3): δ ppm 1.34 (s, 9 H), 4.29 - 4.38
(m, 4 H), 6.99 (d, J ) 8.22 Hz, 1 H), 7.09 - 7.14 (m, 1 H), 7.17
(d, J ) 2.93 Hz, 2 H), 7.47 (d, J ) 8.61 Hz, 2 H), 7.82 (d, J )
1
as a white solid. MS (ESI, pos. ion) m/z: 259 (M + 1). H NMR
(300 MHz, CDCl3): δ 7.78-7.81 (m, 3 H), 8.20 (d, J ) 8.1 Hz,
2 H), 9.09 (s, 1 H).
8.80 Hz, 2 H), 8.94 (s, 1 H). MS (ESI, pos. ion) m/e: 379 (M+
1). Anal. (C22H22N2O2S): C, H, N.
+
To a 5-mL microwave vial was added 4-chloro-6-(4-(trifluo-
romethyl)phenyl)pyrimidine (72; 0.10 g, 0.39 mmol), 2,3-dihydro-
benzo[b][1,4]dioxin-6-amine (52; 0.089 g, 0.59 mmol), and EtOH
(4.0 mL). The reaction mixture was stirred at 180 °C for 30 min in
a microwave. After cooling to room temperature, the reaction
mixture was concentrated in vacuo, and the residue was dissolved
in CH2Cl2. The solution was washed successively with 10% aqueous
Na2CO3, H2O, and saturated aqueous NaCl. The organic layer was
dried over Na2SO4 and filtered. Silica gel was added to the filtrate,
and the solvent was removed with a rotary evaporator. The crude
material was purified by silica gel chromatography (gradient, 10-
40% EtOAc/hexanes) to afford 0.064 g (46%) of the title compound
4-(4-tert-Butylphenyl)-6-((2,3-dihydrobenzo[b][1,4]dioxin-6-
yl)methyl)pyrimidine (27). Sodium hydride (60% dispersion in
mineral oil, 10 mg, 0.3 mmol) was added to a stirred solution of
4-(4-tert-butylphenyl)-6-chloropyrimidine (44; 50 mg, 0.2 mmol),
2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (36 mg, 0.3 mmol),
and 1,3-dimethylimidazolium iodide (5 mg, 0.1 mmol) in dioxane
(20 mL). The mixture was stirred at reflux for 1 h. The reaction
mixture was concentrated under reduced pressure and the residue
was partitioned between EtOAc (100 mL) and H2O (70 mL). The
organic extract was dried over Na2SO4, filtered, and concentrated.
Purification by silica gel chromatography (2:3 ethyl acetate/hexanes)
afforded 44 mg (58%) of (6-(4-tert-butylphenyl)pyrimidin-4-yl)-
(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanone (69) as a tan oil.
1H NMR (400 MHz, CDCl3): δ 1.37 (s, 9 H), 4.28 (m, 4 H), 6.96
(d, J ) 8.4 Hz, 1 H), 7.55 (d, J ) 8.4 Hz, 1 H), 7.72 (m, 2 H),
8.11 (d, J ) 8.4 Hz, 2 H), 8.34 (s, 1 H), 9.35 (s, 1 H). MS (ESI,
pos. ion) m/z: 375 (M + 1).
Sodium borohydride (20 mg, 0.5 mmol) was added to a stirred
solution of (6-(4-tert-butylphenyl)pyrimidin-4-yl)(2,3-dihydrobenzo-
[b][1,4]dioxin-6-yl)methanone (69; 0.10 g, 1 mmol) in MeOH (5
mL), and the mixture was stirred at room temperature for 1 h. The
reaction mixture was concentrated under reduced pressure, and the
residue was partitioned between EtOAc (10 mL) and H2O (20 mL).
The organic extract was dried over Na2SO4, filtered, and concen-
trated. Purification by silica gel chromatography (1:1 ethyl acetate/
hexanes) afforded 74 mg (74%) of the title compound as a tan oil.
1H NMR (400 MHz, DMSO-d6): δ 1.33 (s, 9 H), 4.19 (s, 4 H),
5.59 (s, 1 H), 6.27 (s, 1 H), 6.78 (d, J ) 8.8 Hz, 1 H), 6.91 (m, 2
H), 7.59 (d, J ) 8.8 Hz, 2 H), 8.13 (d, J ) 8.8 Hz, 2 H), 9.07 (s,
1 H). MS (ESI, pos. ion) m/z: 377 (M + 1).
1
as a yellow solid. H NMR (400 MHz, DMSO-d6): δ 4.21-4.28
(m, 4 H), 6.85 (d, J ) 8.6 Hz, 1 H), 7.06 (dd, J ) 8.7, 2.4 Hz, 1
H), 7.22 (d, J ) 1.0 Hz, 1 H), 7.35 (d, J ) 1.8 Hz, 1 H), 7.91 (d,
J ) 8.2 Hz, 2 H), 8.22 (d, J ) 8.0 Hz, 2 H), 8.71 (d, J ) 0.6 Hz,
1 H), 9.61 (s, 1 H). MS (ESI, pos. ion) m/z: 374 (M + 1). Anal.
(C19H14F3N3O2): C, H, N.
7-(6-(4-(Trifluoromethyl)phenyl)pyrimidin-4-yloxy)quino-
line (74). To a 100 mL, round-bottomed flask containing 6-(4-
trifluoromethylphenyl)-4-chloropyrimidine (72; 2.5 g, 9.7 mmol)
and 7-hydroxyquinoline (2.0 g, 14 mmol) in DMF (30 mL), was
added sodium hydride (0.54 g, 60%, 14 mmol) in portions. The
mixture was stirred at room temperature for 4 h, and the reaction
was quenched carefully with ice-water. The mixture was diluted
with EtOAc (100 mL), and the organic layer was washed with H2O
(50 mL). The insoluble material was filtered and collected, and
the organic phase was dried with Na2SO4, filtered, and concentrated.
The insoluble material and the residue were combined and purified
by silica gel chromatography (50% EtOAc/hexanes) to provide 2.4
g (67%) of the title product as a white solid. Mp 178-180 °C. MS
1
(ESI, pos. ion) m/z: 368 (M + 1). H NMR (400 MHz, CDCl3):
δ 7.44 (m, 3 H), 7.78 (d, J ) 8.0 Hz, 2 H), 7.93 (d, J ) 8.0 Hz,
2 H), 8.22 (m, 3 H), 8.88 (s, 1 H), 8.96 (dd, J ) 4.4, 1.6 Hz, 1 H).
Anal. (C20H12F3N3O): C, H, N.
Benzoyl chloride (45 mg, 0.3 mmol) was added to a stirred
solution of (6-(4-tert-butylphenyl)pyrimidin-4-yl)(2,3-dihydrobenzo-
[b][1,4]dioxin-6-yl)methanol (70) (100 mg, 0.3 mmol) and pyridine
(1.0 mL, 12.3 mmol) in anhydrous THF (7 mL). The mixture was
stirred at room temperature for 16 h. The solution was concentrated
under reduced pressure and the residue was dissolved in EtOAc
(20 mL) and washed with H2O (2 × 20 mL). The organic extract
was dried over MgSO4 and passed through a silica gel plug to
afford 96 mg of crude (6-(4-tert-butylphenyl)pyrimidin-4-yl)(2,3-
dihydrobenzo[b][1,4]dioxin-6-yl)methyl benzoate. A solution of this
crude material (50 mg, 1 mmol) and 10% palladium-carbon (200
mg) in MeOH (5 mL) was stirred under H2 (balloon) for 20 h. The
reaction mixture was filtered through a layer of Celite and the filtrate
was concentrated in vacuo. Purification by silica gel chromatog-
raphy (1:4 ethyl acetate/hexanes) afforded 11 mg (10%) of the title
compound as a tan oil. 1H NMR (400 MHz, CDCl3): δ 1.37 (s, 9
N-(6-(4-tert-Butylphenyl)pyrimidin-4-yl)quinolin-7-amine (78).
A solution of 7-nitro-1,2,3,4-tetrahydro-quinoline (74;43 4.0 g, 22
mmol) in dichloromethane (500 mL) was stirred at 25 °C and treated
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (10 g, 44 mmol)
in portions. The reaction mixture was stirred at 25 °C for 1 h and
filtered, and the filter cake was washed with CH2Cl2. The combined
filtrate was evaporated under reduced pressure to give the crude
product as a brown solid (4.4 g). The solid was dissolved in hot
EtOAc (200 mL), and the solution was treated with decolorizing
carbon (1 g) and filtered though Celite. The filtrate was concentrated
under reduced pressure, and the residue was purified by silica gel
chromatography (25% EtOAc/hexanes) to give 3.2 g (81%) of
7-nitroquinoline (75) as an off-white solid. MS (ESI, pos. ion)

3512 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15
Norman et al.
m/z: 175 (M + 1). 1H NMR (400 MHz, DMSO-d6): δ 7.77-7.80
(m, 1 H), 8.29 (d, J ) 9.0 Hz, 1 H), 8.35 (dd, J ) 9.0, 2.3 Hz, 1
H), 8.60 (d, J ) 8.3 Hz, 1 H), 8.82 (d, J ) 2.0 Hz, 1 H), 9.13 (dd,
J ) 4.2, 1.6 Hz, 1 H).
Waligora for conducting the in vivo pharmacology studies, and
Annette Bak for her formulations support.
Supporting Information Available: Elemental analysis or
HRMS and HPLC data for final compounds 10-27, 73, 74, 78,
and 79. This material is available free of charge via the Internet at
http://pubs.acs.org.
The solution of 7-nitroquinoline (75; 3.2 g, 18 mmol) in MeOH
(200 mL) was purged with N2 and treated with 10% palladium on
carbon (1.0 g). The suspension was purged with H2 and stirred under
1 atm H2 for 16 h. The mixture was purged with N2 and filtered
through Celite. The filtrate was concentrated under reduced pressure,
and the residue was purified by silica gel column chromatography
(gradient: 5-10% MeOH/ CH2Cl2) to give 710 mg (27%) of
quinolin-7-amine (76) as a brown solid. MS (ESI, pos. ion) m/z:
145 (M + 1). 1H NMR (400 MHz, DMSO-d6): δ 5.75 (br s, 2 H),
6.93 (s, 1 H), 6.98 (d, J ) 8.6 Hz, 1 H), 7.07 (dd, J ) 7.8, 4.2 Hz,
1 H), 7.60 (d, J ) 8.6 Hz, 1 H), 8.00 (d, J ) 7.8 Hz, 1 H), 8.58 (d,
J ) 2.9 Hz, 1 H).
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lin-7-amine (76; 0.124 g, 0.861 mmol), tris(dibenzylideneacetone)-
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pos. ion.) m/z: 355 (M + 1). H NMR (300 MHz, DMSO-d6): δ
1.33 (s, 9 H), 7.31-7.45 (m, 2 H), 7.58 (d, J ) 8.6 Hz, 2 H),
7.77-7.87 (m, 1 H), 7.88-7.97 (m, 1 H), 8.01 (d, J ) 8.5 Hz, 2
H), 8.26 (d, J ) 7.2 Hz, 1 H), 8.66 (d, J ) 1.8 Hz, 1 H), 8.75-
8.93 (m, 2 H), 10.10 (s, 1 H). Anal. (C23H22N4‚0.3H2O): C, H, N.
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amine (79). A mixture of 4-chloro-6-(4-trifluoromethylphenyl)-
pyrimidine (72; 0.30 g, 1.2 mmol) and 7-quinolylamine (76; 0.17
g, 1.2 mmol) was stirred at 200 °C for 10 min in a microwave.
The resulting solid was partitioned between saturated aqueous
solution of NaHCO3 (100 mL) and EtOAc (200 mL). The organic
phase was washed with saturated aqueous NaCl, dried over Na2-
SO4, and filtered. The filtrate was concentrated under reduced
pressure, and the residue was purified by silica gel column
chromatography (60% EtOAc/hexanes) to give the crude reaction
product. The crude material was recrystallized from CH2Cl2/EtOAc/
hexanes and purified further by silica gel chromatography (50%
EtOAc/CH2Cl2) to give a solid that was triturated with 1:1 CH2-
Cl2/hexanes (50 mL). The solid was collected by suction filtration
and dried in vacuo at 60 °C overnight to afford 135 mg (32%) of
the title product as a pale-tan solid. Mp 259.6-260.3 °C. 1H NMR
(400 MHz, DMSO-d6): δ 7.41 (dd, J ) 8.2, 4.2 Hz, 1 H), 7.46 (s,
1 H), 7.83 (dd, J ) 8.9, 2.1 Hz, 1 H), 7.93-7.97 (m, 3 H), 8.27-
8.29 (m, 3 H), 8.68 (d, J ) 1.5, 1 H), 8.85 (dd, J ) 4.2, 1.6 Hz, 1
H), 8.91 (s, 1 H), 10.22 (s, 1 H). MS (ESI, pos. ion) m/z: 367 (M
+ 1). Anal. (C24H27NO3): C, H, N): C, H, N.
Acknowledgment. The authors thank Paul Reider, Randy
Hungate, Jean-Claude Louis, and Chris Fibiger for their support
in this research program. Special thanks also goes to Yax Sun
for helpful discussions regarding molecular modeling and to
Randy Jenkins for his technical assistance in conducting the
NOE experiments. We also acknowledge Alana Rattan for her
excellent project management assistance, Jocelyn McCormick,
Michelle Carmouche, James Davis, Dawn Zhu, and Dan

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