Synthesis and biological evaluation of 5-substituted and 4,5-disubstituted-2-arylamino oxazole TRPV1 antagonists

Article abstract of DOI:10.1016/j.bmc.2010.04.099

The synthesis and structure-activity relationships of a series of 5-monosubstituted and 4,5-disubstituted 2-arylaminooxazoles as novel antagonists of the transient receptor potential vanilloid 1 (TRPV1) receptor are described. The 7-hydroxy group of the t

Full text of DOI:10.1016/j.bmc.2010.04.099

Bioorganic & Medicinal Chemistry 18 (2010) 4821–4829
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and biological evaluation of 5-substituted and
4,5-disubstituted-2-arylamino oxazole TRPV1 antagonists
*
Richard J. Perner , John R. Koenig, Stanley DiDomenico, Arthur Gomtsyan, Robert G. Schmidt,
Chih-Hung Lee, Margaret C. Hsu , Heath A. McDonald, Donna M. Gauvin, Shailen Joshi,
Teresa M. Turner à, Regina M. Reilly, Philip R. Kym, Michael E. Kort
Neuroscience and Pain Research, Global Pharmaceutical Research and Development, Dept. R4DE AP9A/L-15, Abbott Laboratories, 100 Abbott Park Road,
Abbott Park, IL 60064-6115, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and structure–activity relationships of a series of 5-monosubstituted and 4,5-disubstituted
2-arylaminooxazoles as novel antagonists of the transient receptor potential vanilloid 1 (TRPV1) receptor
are described. The 7-hydroxy group of the tetrahydronaphthyl moiety on the 2-amino substituent of the
oxazole ring was important for obtaining excellent in vitro potency at the human TRPV1 receptor, while a
variety of alkyl and phenyl substituents at the 4- and 5-positions of the oxazole ring were well tolerated
and yielded potent TRPV1 antagonists. Despite excellent in vitro potency, the 5-monosubstituted com-
pounds suffered from poor pharmacokinetics. It was found that 4,5-disubstitution on the oxazole ring
was critical to the improvement of the overall pharmacokinetic profile of these analogues, which led
to the discovery of compound (R)-27, a novel TRPV1 antagonist with good oral activity in preclinical ani-
mal models of pain.
Received 26 February 2010
Revised 28 April 2010
Accepted 30 April 2010
Available online 10 May 2010
Keywords:
TRPV1
TRPV1 antagonist
Oxazole
Pain
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
profile of TRPV1 antagonists can be significantly broadened if the
receptor blockade occurs both in the peripheral as well as in the
The TRPV1 (transient receptor potential vanilloid 1) receptor is
a well-characterized member of the transient receptor potential
(TRP) superfamily of ion channels.1–3 The role of TRPV1 in the
transmission of pain signaling has been extensively discussed.4,5
The TRPV1 receptor is termed a polymodal receptor, since it can
be activated not only by endogenous lipid agonists, such as
anandamide and arachidonic acid metabolites, but also by heat
and acidic extracellular media, as well as the exogenous vanilloid
capsaicin.6 In addition, TRPV1 activation can be potentiated by
pro-nociceptive mediators such as bradykinin, ATP, NGF, and oth-
ers.7 Taken together, these observations demonstrate the signifi-
cant role this receptor plays as a principle integrator of multiple
pain-producing stimuli and, thus, the role of TRPV1 in pain signal-
ing pathways.
central nervous system.9 Therefore, development of selective
TRPV1 receptor antagonists with good CNS penetration presents
an important opportunity to treat a variety of pathological pain
states.
Within our TRPV1 antagonist discovery program we have
extensively investigated a series of 1-benzyl-3-(isoquinolin-5-
yl)ureas, exemplified by the early lead 1 (Fig. 1), as well as 1-ben-
zyl-3-(1H-indazol-4-yl)ureas such as 2.10–13 The structure–activity
relationship studies surrounding this class of compounds have
been very fruitful and have provided a number of selective TRPV1
antagonists for further study, including our first clinical candidates
R4
O
N
For this reason, the discovery of small molecule antagonists of
TRPV1 has been the subject of intense investigations among many
pain research groups. It is well documented that TRPV1 antagonists
can effectively reduce inflammatory hyperalgesia in animal mod-
els,8 and more recently, it was demonstrated that the analgesic
HN
Ar
N
R5
H
O
NH
Ar
CF3
3
hTRPV1
IC50 (nM)
Ar
4
9
3
1
1: isoquinolin-5-yl
2: 1H-indazol-4-yl
* Corresponding author. Tel.: +1 847 937 1023; fax: +1 847 937 9195.
E-mail address: richard.j.perner@abbott.com (R.J. Perner).
Development sciences.
à
Preclinical development.
Figure 1. General structures of urea TRPV1 antagonists.
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.04.099

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R. J. Perner et al. / Bioorg. Med. Chem. 18 (2010) 4821–4829
ABT-102 and ABT-116.14 As these promising candidates progressed
into clinical development, we sought to identify second-generation
TRPV1 antagonists from a different structural class compared to
ABT-102, with improved CNS penetration while maintaining the
favorable analgesic and pharmacokinetic properties. In implement-
ing this strategy we sought to replace the urea moiety with a suit-
able group that allowed for a favorable interaction with the TRPV1
receptor. The 2-aminobenzoxazole fragment has been reported to
be a bioisostere for the urea in a series of acyl CoA: cholesterol
acyltransferase (ACAT) inhibitors.15 While there are several differ-
ent ways to cyclize the urea in our molecules, herein we describe
the SAR studies on the chemotype resulting from the cyclization
of the oxygen atom with the benzylic carbon of the urea nitrogen
substituent to form the 2-arylaminooxazoles 3.
tetrahydronaphthalenes 4h and 4i, respectively, and the hydroxyl
groups could be selectively protected as the t-butyldimethylsilyl
ethers 4j and 4k. This result circumvented the Birch reduction
and allowed for a more streamlined approach to the preparation
of tetrahydronaphthalene analogues using method A by reducing
the overall number of steps from eight to five. Compound 4j was
converted to 5j and reacted with 7f according to Scheme 1 to
afford the silyl-protected oxazole, which was N-methylated and
then treated with tetrabutylammonium fluoride to yield 21. For
the synthesis of 22, reaction of the aniline function of 4h with ben-
zyl chloroformate gave 12, which was converted to the tetrahydro-
naphthalene 4e through a multi-step process of activation of the
hydroxyl group with methanesulfonyl chloride and displacement
of the resulting mesylate with sodium azide to give 13. The azide
was reduced under Staudinger conditions and the resulting alkyl
amine differentially protected with a t-butoxycarbonyl group to
yield 14. The aniline of 14 was then deprotected to afford 4e for
elaboration to the desired oxazole 22 according to Scheme 1.
Scheme 4 illustrates an alternate route (method B) for the
synthesis of 4- and 5-monosubstituted and 4,5-disubstituted 2-
arylaminooxazoles 3. This method was much better suited to
the synthesis of analogues wherein an electron-withdrawing
group was present on the aromatic ring in the 5-position of the
oxazole. Such analogues (e.g., R5 = p-CF3Ph) could only be pre-
pared in very low yield using method A, which inhibited the abil-
ity to scale up these compounds for in vivo evaluation. In this
route, the oxazole ring was constructed in the first step through
reaction of aldehyde 15 with a variety of p-toluenesulfonylmeth-
yl isocyanide (TosMIC) derivatives in methanol at reflux to give
oxazoles 16a, 16c, and 16d in very high yield.20 Chlorination of
16 by treatment with lithium bis(trimethylsilyl)amide in tetrahy-
drofuran at low temperature, followed by reaction with hexa-
chloroethane afforded chlorides 17a, 17c, and 17d in nearly
quantitative yield using the method of Atkins and Vedejs.21 The
desired analogues were then furnished in very good yield by
heating 17 with 4, most effectively in an alcohol solvent with
catalytic p-toluenesulfonic acid. In this manner, compounds 10f,
19, 20, 27, and 28 were synthesized.
2. Chemistry
The synthesis of 4- and 5-monosubstituted and 4,5-disubsti-
tuted 2-arylaminooxazoles 3 was accomplished using two general
synthetic routes. In the first route (method A) shown in Scheme 1,
the oxazole ring was constructed in the final step through reaction
of aryl isothiocyanates 5 with a-azidoketones 7 in the presence of
triphenylphosphine in 1,4-dioxane at 85 °C according to Dhar
et al.16 The requisite isothiocyanates 5 were prepared by standard
methods through treatment of anilines
ocarbonyldiimidazole or di-2-pyridyl thionocarbonate in methy-
lene chloride, while -azidoketones 7 were obtained by reacting
the corresponding -bromoketones 6 with sodium azide in acetone
4 with either thi-
a
a
following the procedure of Patonay et al.17 In this manner, 23 and
25 were synthesized from commercially available anilines 4a and
4f (after conversion to the silyl ether 4d), respectively, while 24
was synthesized from 4b18 (Table 1).
The synthesis of the tetrahydronaphthalene analogues 9–11 is
shown in Scheme 2. Ethyl enol ether 4c, prepared from the Birch
reduction of 7-ethoxynaphthalen-1-amine,19 was converted to iso-
cyanate 5c and reacted with azidoketones 7a–j in the presence of
triphenylphosphine to give the oxazoles 8 as described for method
A. The enol ethers 8a–j were hydrolyzed with hydrochloric acid to
yield the b-tetralones 9a–j, which were reduced with sodium boro-
hydride to afford the desired 7-hydroxytetralin analogues 10a–j
(Table 2). Ketone 9f was also reacted with methylmagnesium bro-
mide and titanium tetrachloride to afford the tertiary alcohol 11.
The tetrahydronaphthalene amine fragments 4j and 4e
necessary for the synthesis of analogues 21 and 22, respectively,
were synthesized as shown in Scheme 3. It was found the 7-hydro-
xy (4f) and 6-hydroxy (4g) 1-aminonaphthalenes could be selec-
tively hydrogenated in the presence of Raney nickel to yield the
Tetrahydronaphthalenes 4j–k or 4h–i shown in Scheme 3 could
be utilized directly for the synthesis of 19 and 27–32 according to
Scheme 4. It was found during the course of this investigation that
protection of the hydroxyl group was not necessary, thus further
optimizing this synthetic route. For the synthesis of 20, 4h was
converted to 4l via protection of the aniline group of 4h with ben-
zyl chloroformate to afford 12, which was O-methylated with
methyl iodide and silver oxide and then N-deprotected to yield
4l (Scheme 3).
Method A
X
S
N
C
N
a
c
O
CF3
Ar
Ar NH2
+
O
HN
Ar
CF3
4
5
6f: X = Br
7f: X = N3
21-25
b
TBSO
EtO
R
N
Ar =
N
N
H3C
O
a
b
c
d
e: R = NHBoc
j: R = 7-OTBS
Scheme 1. Reagents and conditions: (a) thiocarbonyldiimidazole or di-2-pyridyl thionocarbonate, CH2Cl2, rt; (b) NaN3, acetone, rt; (c) PPh3, 1,4-dioxane, 85 °C.

R. J. Perner et al. / Bioorg. Med. Chem. 18 (2010) 4821–4829
4823
Table 1
For 4-monosubstituted analogues such as 26 (R4 = Ph and
R5 = H), a different route was required for the synthesis of oxazole
16h (Scheme 5).24 Bromoketone 6a was first treated with sodium
formate to yield 2-oxo-2-phenylethyl formate, which was then
reacted with ammonium acetate in acetic acid at reflux to give
16h in moderate yield. Compound 16h was converted to 17h, then
reacted with 4j to afford 26 as described for method B.
In vitro biological activity of 2-amino-5-(p-trifluoromethyl)phenyloxazole analogues
in the human TRPV1 Ca2+ influx assaya
N
R
O
CF3
Hydroxytetrahydronaphthalene 27 was successfully resolved
into the constituent enantiomers by preparative chiral chromatog-
raphy. While this method provided for the separation of the enan-
tiomers, information about the absolute configuration of the early
and late eluting compounds could not be obtained. To aid in assign-
ing the absolute configuration to each enantiomer, bromo analogue
30 was synthesized as shown in Scheme 6. The requisite 2,4-dib-
romooxazole 18 was prepared from 16a by treatment with lithium
bis(trimethylsilyl)amide in tetrahydrofuran at low temperature,
followed by reaction with 2 equiv of a solution of bromine in tetra-
hydrofuran. 18 was subsequently reacted with 4j to afford 30 as de-
scribed for method B. Interestingly, the 4-bromo-2-chlorooxazole
17b (Scheme 4) was not reactive enough to yield any of the desired
product, necessitating the use of 18. Compound 30 was successfully
resolved by chiral chromatography, and the crystal structure of the
early eluting enantiomer was solved which provided the absolute
configuration (Fig. 2). This enantiomer, (R)-30, was converted to
the corresponding enantiomer of 27 via Negishi coupling reaction
using dimethylzinc and bis(diphenylphosphino)ferrocene palla-
dium(II) chloride.25 Through chiral HPLC experiments using this
material and the racemate, the configurations of the early and late
eluting enantiomers of 27 were determined.
Compound
R
IC50 (nM)
374 73
HN
O
9f
HN
HO
HO
10f
11
8.3 1.6
HN
HN
840 182
19
120 25
HO
HN
H3CO
20
21
22
23
150 28
277 48
327 32
229 27
H3C
N
HO
3. Results and discussion
Patterned after our early urea leads, the isoquinoline and inda-
zole analogues 23 and 24 (Table 1) were the prototype molecules
in this series. While these two heterocycles yielded many potent
analogues in the urea series, this was not the case in the oxazole
series. 23 and 24 were on the order of 50-fold and 10-fold less po-
tent, respectively, than the corresponding urea analogues at inhib-
iting capsaicin activation of the recombinant human TRPV1
receptor in a 1321 stable cell line in the calcium influx functional
assay. The breakthrough came when the naphthol moiety, present
in our original TRPV1 high-throughput screening hit,10 was
employed (compound 25). This analogue had very good in vitro
potency with an IC50 value of 10 nM, which demonstrated the
viability of this chemotype. However, there was concern going for-
ward with this fragment due to the fact it would likely impart poor
pharmacokinetic properties for this class of molecules through fast
metabolism of the phenol group. Thus, we investigated the par-
tially saturated tetrahydronaphthalene ring system, which had
been disclosed as part of a series of urea TRPV1 antagonists.19 In-
deed, the 7-hydroxytetrahydronaphthalene analogue 10f retained
the in vitro potency of the naphthol analogue with an IC50 of
8.3 nM, while at the same time hinting at improved aqueous solu-
bility properties of these molecules over the completely aromatic
system. The importance of the 7-hydroxy substituent was illus-
trated through various modifications. For example, ketone 9f was
45-fold less potent than 10f, while shifting the hydroxyl group to
the 6-position led to a 14-fold loss in potency (compound 19). Con-
version to the tertiary alcohol (compound 11) or methyl ether
(compound 20) also resulted in a reduction in TRPV1 antagonist
potency with IC50 values of 840 nM and 150 nM, respectively. Fi-
nally, methylation of the nitrogen atom linking the oxazole (com-
pound 21) or replacement of the hydroxyl group with an amino
group as in 22 resulted in a 33-fold and 39-fold loss of TRPV1 activ-
ity, respectively.
HN
H2N
HN
HN
N
N
24
25
101
10
5
1
N
H
HN
HO
a
All values were derived from a 1321 stable cell line expressing hTRPV1, and are
the mean SEM of at least three separate experiments run in triplicate.
For analogues wherein R4 was a substituent other than hydro-
gen, methyl, or ethyl, an alternate synthesis of 17 was employed
as shown in Scheme 4. TosMIC was reacted with 15 in methanol
at reflux to yield 16a (R4 = H), which was subsequently brominated
by treatment with lithium bis(trimethylsilyl)amide in a mixed sol-
vent of THF/DMPU at low temperature, followed by reaction with a
solution of bromine (1 equiv) in tetrahydrofuran to afford 16b in
good overall yield.22 Suzuki coupling reactions on 16b then gave
the desired 4-alkyl and 4-aryl oxazoles 16e–g.23 Chlorination as
discussed above for Scheme 4 furnished the chlorooxazoles 17e–
g in very high yield, which were coupled with 4j to afford 29, 31,
and 32, respectively.

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R. J. Perner et al. / Bioorg. Med. Chem. 18 (2010) 4821–4829
N
R5
O
NCS
HN
N3
R5
EtO
EtO
a
b
4c
+
O
7a-j
5c
8a-j
c
N
N
N
R5
R5
CF3
O
HN
O
O
HN
HN
e
d
HO
Me
O
HO
11
9a-j
10a-j
6-10 R5
6-10 R5
a
b
c
d
e
Ph
f
g
h
i
4-CF3-Ph
4-Cl-Ph
2-CH3-Ph
3-CH3-Ph
4-CH3-Ph
4-tBu-Ph
4-OCH3-Ph
4-pyrrolidinyl-Ph
benzyl
j
Scheme 2. Reagents and conditions: (a) di-2-pyridyl thionocarbonate, CH2Cl2, rt; (b) PPh3, 1,4-dioxane, 85 °C; (c) 2 M aq HCl, THF, 40 °C; (d) TiCl4, MeMgCl, THF–CH2Cl2,
À40 °C to 0 °C; (e) NaBH4, EtOH, 0 °C.
Table 2
tent analogues (e.g., 10f). One significant difference was that larger
para substituents such as pyrrolidinyl (compound 10i) led to less
In vitro biological activity of 8-(oxazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-ol
analogues in the human TRPV1 Ca2+ influx assaya
potent analogues, while in the urea series this type of amino sub-
stituent often yielded single-digit nanomolar compounds.12 Final-
R4
N
ly, alkyl and aralkyl substitution at the 5-position also led to a
drastic reduction in TRPV1 antagonist potency. For example, the
benzyl analogue 10j had an IC50 value of 1820 nM.
R5
O
HN
HO
Despite the excellent in vitro potency, compound 10f was pre-
cluded from in vivo evaluation due to a short half-life, high
clearance, and low (5%) oral bioavailability (Table 4). However,
from our investigation of the pharmacokinetic properties of a
related benzimidazole series (data not shown), we reasoned that
a 4,5-disubstituted oxazole would possess improved pharmacoki-
netics over the monosubstituted derivatives. Gratifyingly, this
proved to be the case and the results are shown in Table 4. Not only
did the 4-methyl analogue 27 have a better pharmacokinetic profile
than 10f, the excellent in vitro potency was retained with an IC50
value of 3.2 nM. Moreover, the compound had very good CNS
penetration, a characteristic we considered to be important for
maximal broad spectrum analgesic activity for TRPV1 antagonists,
with a brain tissue to plasma ratio of 3.9 Structure–activity relation-
ship studies around the 4-position revealed small, straight-chain
alkyl groups were well tolerated, however, branching such as the
isopropyl analogue 29 resulted in reduced potency (Table 3).
Surprisingly, phenyl substituents at the 4-position were also well
tolerated, often resulting in very potent single-digit nanomolar
analogues (compounds 31 and 32). The poor physicochemical
properties and low CNS penetration of 31 and 32 made these com-
pounds less interesting from a drug development perspective.
Selected compounds were screened for analgesic activity in
preclinical animal pain models and the most interesting analogues,
such as 27 and 28 with potent TRPV1 antagonist activity and high
brain levels, were resolved and the individual enantiomers were
evaluated. For example, in the case of 27, the R-enantiomer
Compound
R4
R5
IC50 (nM)
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
26
H
H
H
H
H
H
H
H
H
H
Ph
Ph
187 27
416 78
157 20
62 11
2-CH3-Ph
3-CH3-Ph
4-CH3-Ph
4-t-Bu-Ph
4-CF3-Ph
4-Cl-Ph
4-OCH3-Ph
4-Pyrrolidinyl-Ph
Benzyl
26
8.3 1.6
15
4
2
81 16
101 23
1820 171
864 212
H
a
All values were derived from a 1321 stable cell line expressing hTRPV1, and are
the mean SEM of at least three separate experiments run in triplicate.
Satisfied that the 7-hydroxytetrahydronaphthalene moiety was
the optimal group for the left-side of the molecule, we turned our
investigation to the 4- and 5-positions of the oxazole ring and the
results are summarized in Table 2. Monosubstitution between
these two positions seemed to favor the 5-position (e.g., cf. com-
pounds 10a and 26). In addition, much of the SAR observed for
the urea series was conserved in the oxazole series. For example,
para substitution on the aromatic ring in the 5-position was pre-
ferred (10d), and electronegative substituents yielded the most po-

R. J. Perner et al. / Bioorg. Med. Chem. 18 (2010) 4821–4829
4825
NH2
NH2
NH2
a
b
HO
HO
TBSO
4f: 7-OH
4g: 6-OH
4h: 7-OH
4i: 6-OH
4j: 7-OTBS
4k: 6-OTBS
c
CH3
O
NH2
NHCbz
Boc
HN
NHCbz
Boc
HN
NH2
NHCbz
N3
HO
d
f
g
e
4l
13
14
12
4e
Scheme 3. Reagents and conditions: (a) Raney Ni, aq NaOH, EtOH, H2, 1300 psi, 85 °C; (b) TBSCl, imidazole, CH2Cl2, rt; (c) (i) benzyl chloroformate, Hunig’s base, CH2Cl2, rt;
(ii) 1 M aq NaOH, rt; (d) (i) Ag2O, MeI, CH3CN, rt; (ii) 10% Pd/C, MeOH, H2, 1 atm, rt; (e) (i) MsCl, Hunig’s base, CH2Cl2, 0 °C; (ii) NaN3, DMF, 75 °C; (f) (i) PPh3, THF–H2O, rt;
(ii) Boc2O, Hunig’s base, CH2Cl2, rt; (g) 20% Pd(OH)2, MeOH, H2, 60 psi, rt.
Method B
H
N
CHO
c
a
X
O
10f, 19, 20
F3C
CF3
15
16a: X = H
b
17a: X = Cl
d
e
R4
Br
R4
N
4j, f
g
4j, h
N
N
27, 28
29, 31, 32
X
X
X
O
O
O
CF3
CF3
CF3
16c: X = H, R4 = Me
16d: X = H, R4 = Et
16b: X = H
17b: X = Cl
16e: X = H, R4 = i-Pr
b
16f: X = H, R4 = 4-CN-Ph
16g: X = H, R4 = 4-F-Ph
b
b
17c: X = Cl, R4 = Me
17d: X = Cl, R4 = Et
17e: X = Cl, R4 = i-Pr
17f: X = Cl, R4 = 4-CN-Ph
17g: X = Cl, R4 = 4-F-Ph
Scheme 4. Reagents and conditions: (a) TosMIC, K2CO3, MeOH, reflux; (b) n-BuLi or LiHMDS, hexachloroethane, THF, À78 °C; (c) 4j, CH3CN, microwave, 150 °C or 4k, i-PrOH,
80 °C or 4l, i-PrOH, microwave, 150 °C; (d) TosCH(R4)NC, K2CO3, MeOH, reflux; (e) LiHMDS, Br2 (1 equiv), THF–DMPU, À78 °C; (f) n-BuOH, reflux or, CH3CN, microwave,
150 °C; (g) (i) 2-propenylboronic acid pinacol ester, K2CO3, Pd[P(Ph)3]4, DME–H2O, reflux; (ii) 5% Pd/C, MeOH, H2, 30 psi, rt; or 4-cyanophenylboronic acid or 4-
fluorophenylboronic acid, aq Na2CO3, [P(Ph)3]2PdCl2, toluene–EtOH, reflux; (h) CH3CN, microwave, 150 °C or n-BuOH, reflux.
Ph
N
O
NH2
HN
a
c
TBSO
HO
N
+
Br
X
O
O
6a
16h: X = H
17h: X = Cl
4j
26
b
Scheme 5. Reagents and conditions: (a) (i) HCO2Na, DMF, rt; (ii) NH4OAc, HOAc, reflux; (b) LiHMDS, hexachloroethane, THF, À78 °C; (c) CH3CN, microwave, 150 °C.
(R)-27 was slightly less potent in vitro than the S-enantiomer (S)-
27 (15 nM vs 5 nM). However, (R)-27 had superior half-life, clear-
ance, and oral bioavailability values compared to (S)-27 (Table 4).
(R)-27 was orally active in animal models of pain, exhibiting a
statistically significant (p <0.01) 52% increase in the paw with-
drawal latency in the rat carrageenan hotbox model of thermal

4826
R. J. Perner et al. / Bioorg. Med. Chem. 18 (2010) 4821–4829
Br
N
H
Br
N
CF3
N
O
HN
a
b, c
Br
HO
O
O
CF3
CF3
30
18
16a:
Scheme 6. Reagents and conditions: (a) n-BuLi, Br2 (2 equiv), THF, À78 °C; (b) 4j, i-PrOH, reflux; (c) Et3NÁ3HF, THF, rt.
Table 4
Pharmacokinetic profilea of compounds 10f, 27, (R)-27, and (S)-27
Parameter
10f
27
(R)-27
(S)-27
hTRPV1 IC50 (nM)
Vb iv (L/kg)
CLp (L/h/kg)
t1/2 iv (h)
8.3 1.6
5.4
5.1
0.7
0.023
5
3.2 0.5
10
2.4
2.8
0.096
33
15
3
4.8 1.0
12
4.4
1.9
0.02
7
6.8
1.2
3.8
0.13
52
Cmax po (
l
g/mL)
F po: rat (%)
a
Pharmacokinetic analysis determined in rat (three animals per group each iv
and oral) following administration of 10 lmol/kg.
Table 5
TRP channel antagonist selectivity and in vivo analgesic activity of (R)-27
hTRPV1 (IC50
)
0.015 0.003
37
lM
rTRPV2 (IC50
hTRPV3 (IC50
hTRPV4 (IC50
hTRPA1 (IC50
)
lM
)
)
)
>100
>100
>100
>100
lM
lM
lM
lM
hTRPA1 (agonist) (EC50
)
hTRPM8 (IC50
)
44
52% increase in paw withdrawal latency @
10
mol/kg versus vehicleb
ED50 = 14
mol/kgc
lM
Carrageenan (thermal
hyperalgesia)
l
Osteoarthritisa
l
(inflammatory pain)
a
Values were determined from three-part dose response experiments, with 6–12
animals per dose group.
b
Figure 2. X-ray crystal structure of (R)-30.
p <0.01.
c
95% confidence interval: 11–20 lmol/kg.
Table 3
In vitro human TRPV1 Ca2+ influx assay biological activity a and brain to plasma ratios
of 8-(oxazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-ol analogues
(Table 5). In terms of off-target effects, (R)-27 was found to have a
benign cardiovascular safety profile, with no hemodynamic
changes observed up to 57Â the estimated clinical Cmax in the
anesthetized dog. (R)-27 had a clean hERG profile and was not
an inhibitor of five major human CYP enzymes. In addition, (R)-
27 was negative in Ames and micronucleus assays. In assays to as-
sess the in vitro selectivity, (R)-27 was found to be highly selective
for the TRPV1 receptor versus other TRP channels (Table 5), and
R4
N
CF3
O
HN
HO
exhibited only very weak binding (<40% @ 10 lM) in a screen of
a diverse array of receptors, ion channels, reuptake sites, and en-
zymes (CEREP, Poitiers, France).
Compound
R4
IC50 (nM)
Brain/plasma
10f
27
(R)-27
(S)-27
28
H
8.3 1.6
3.2 0.5
0
3
3
3
3.7
ndc
nd
0.13
0.21
Me
Me
Me
Et
i-Pr
Br
15
3
4. Conclusion
4.8 1.0
2.1 0.4
114 38
9
2.0 0.4
1.3 0.2
In conclusion, a novel series of oxazole TRPV1 antagonists were
synthesized and evaluated. These compounds satisfied our goal of
identifying potent non-urea TRPV1 antagonists with good CNS
penetration. Many of the analogues had excellent in vitro potency
at the human TRPV1 receptor. The key to the excellent potency was
the hydroxyl group at the 7-position of the tetrahydronaphthalene
ring on the amino group of the oxazole ring. para-Substitution on
the phenyl group at the 5-position of the oxazole was preferred,
and electronegative substituents led to the most potent analogues.
While these analogues had good vitro activity, their oral bioavail-
ability was very poor. The 4,5-disubstituted analogues were
29
30b
31
32
4-CN-Ph
4-F-Ph
a
All values were derived from a 1321 stable cell line expressing hTRPV1, and are
the mean SEM of at least three separate experiments run in triplicate.
b
Value is from one determination run in triplicate.
nd = not determined.
c
hyperalgesia at 10
lmol/kg po, and an ED50 of 14 lmol/kg (95% CI,
11–20
l
mol/kg po) in the rat osteoarthritis model of chronic pain26

R. J. Perner et al. / Bioorg. Med. Chem. 18 (2010) 4821–4829
4827
pursued in an effort to improve the pharmacokinetic properties. It
5.3. N-(7-Ethoxy-5,8-dihydronaphthalen-1-yl)-5-[4-(trifluoro-
was discovered a variety of 4-alkyl and 4-aryl substituents were
tolerated in the presence of the 5-phenyl substituent, and resulted
in compounds with excellent in vitro potency and good oral bio-
availability. One analogue, 27, was resolved and the enantiomer
with the better pharmacokinetic profile, (R)-27, was fully charac-
terized. (R)-27 showed many attributes desired in a drug develop-
ment candidate such as excellent in vitro potency, good activity in
preclinical animal pain models, cardiovascular safety, selectivity
for the target, as well as good ADME properties.
methyl)phenyl]oxazol-2-amine (8f)
A solution of 5c (398 mg, 1.72 mmol), 7f (473 mg, 2.07 mmol),
and triphenyl phosphine (542 mg, 2.07 mmol) in 1,4-dioxane
(9 mL) was heated at 85 °C for 30 min. The solution was cooled
to room temperature and evaporated in vacuo. The residue was
chromatographed on silica gel, eluting with 25% EtOAc/hexane to
afford 150 mg (22%) of the title compound as a yellow solid. 1H
NMR (300 MHz, DMSO-d6) d 9.38 (s, 1H), 7.81–7.70 (m, 4H), 7.65
(d, J = 8.5 Hz, 1H), 7.62 (s, 1H), 7.18 (t, J = 8.2 Hz, 1H), 6.97 (d,
J = 8.4 Hz, 1H), 4.88–4.81 (m, 1H), 3.79 (q, J = 6.7 Hz, 2H), 3.52–
3.43 (m, 2H), 3.70–3.30 (m, 2H), 1.26 (t, J = 6.8 Hz, 3H); MS (ESI+)
m/z 401 (M+H).
5. Experimental section
1H NMR spectra were obtained on Varian Mercury, Varian
Mercury plus, Varian UNITY plus (300 MHz), and Varian Inova
(500 MHz) spectrometers using tetramethylsilane as internal
standard. The mass spectra (electron spray ionization (ESI) and
dissolvable chemical ionization (DCI)) were recorded on Finni-
gin-4000 instruments. Elemental combustion analyses were ob-
tained from Robertson Microlit Laboratories or Quantitative
Technologies, Inc. and were within 0.4% of theoretical values.
Purification via column chromatography was carried out on EM
Science Silica Gel 60 (230–400 mesh) in glass flash columns or
using an Analogix Intelliflash 280 flash chromatograph outfitted
with Analogix Super Flash columns. Reactions were routinely con-
ducted under inert atmosphere (N2) using commercial high purity
solvents as received. Isoquinolin-5-amine (4a), 8-aminonaphtha-
len-2-ol (4f), and 5-aminonaphthalen-2-ol (4g) were obtained
from commercial sources. The syntheses of 1-(4-amino-1H-inda-
zol-1-yl)ethanone (4b),18 7-ethoxynaphthalen-1-amine (4c),19
and 4-phenyloxazole (16h)23 have been described. Bromoketones
6a–d and 6f–i were purchased from commercial sources, as were
1-(isocyanomethylsulfonyl)-4-methylbenzene, 1-(1-isocyanoeth-
ylsulfonyl)-4-methylbenzene, and 1-(1-isocyanopropylsulfonyl)-
4-methylbenzene.
5.4. 8-{5-[4-(Trifluoromethyl)phenyl]oxazol-2-ylamino}-3,4-
dihydronaphthalen-2(1H)-one (9f)
A solution of 8f (150 mg, 0.375 mmol) in THF (2.3 mL) was trea-
ted with 2 M aq HCl (0.76 mL, 1.5 mmol), and the mixture was
heated at 40 °C for 1 h. After cooling to room temperature, the
solution was brought to pH 8 with saturated NaHCO3 solution,
and extracted with EtOAc. The organic extracts were washed with
H2O, dried over Na2SO4, filtered and evaporated in vacuo to yield
140 mg (100%) of the title compound as a brown solid. 1H NMR
(300 MHz, DMSO-d6) d 9.56 (s, 1H), 7.80–7.70 (m, 4H), 7.67 (d,
J = 7.8 Hz, 1H), 7.62 (s, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.06 (d,
J = 7.4 Hz, 1H), 3.58 (s, 2H), 3.06 (t, J = 6.8 Hz, 2H), 2.51–2.45 (m,
2H). MS (ESI+) m/z 373 (M+H). Anal. Calcd for C20H15F3N2O2: C,
64.51; H, 4.06; N, 7.52. Found: C, 64.53; H, 3.73; N, 7.52.
5.5. 8-{5-[4-(Trifluoromethyl)phenyl]oxazol-2-ylamino}-1,2,3,
4-tetrahydronaphthalen-2-ol (10f)
A solution of 9f (60.0 mg, 0.161 mmol) in ethanol (6 mL) at
0 °C was treated with NaBH4 (7.0 mg, 0.18 mmol). The reaction
was stirred at 0 °C for 1 h, then poured into H2O and extracted
with EtOAc. The extracts were dried over Na2SO4, and concen-
trated in vacuo. The residue was chromatographed on silica
gel, eluting with 70% to 85% EtOAc/hexane to afford 34 mg
(56%) of the title compound as a tan solid. 1H NMR (300 MHz,
DMSO-d6) d 9.33 (s, 1H), 7.80–7.69 (m, 4H), 7.62 (s, 1H), 7.55
(d, J = 7.4 Hz, 1H), 7.14–7.06 (m, 1H), 6.88 (d, J = 7.2 Hz, 1H),
4.83 (d, J = 4.1 Hz, 1H), 3.99–3.85 (m, 1H), 2.98–2.69 (m, 4H),
1.94–1.80 (m, 1H), 1.69–1.53 (m, 1H). MS (ESI+) m/z 375
(M+H). Anal. Calcd for C20H17F3N2O2: C, 64.17; H, 4.58; N, 7.48.
Found: C, 64.44; H, 4.26; N, 7.33.
The following is a description of the synthesis of 10f using
method A, and is typical for the syntheses of 9f, 10a–j, 11, and
21–25.
5.1. 2-Ethoxy-8-isothiocyanato-1,4-dihydronaphthalene (5c)
A solution of 4c19 (200 mg, 1.06 mmol) in CH2Cl2 (2.5 mL) was
added to a solution of di-(2-pyridyl)thionocarbonate (246 mg,
1.06 mmol) in CH2Cl2 (5 mL) at room temperature. After stirring
at room temperature for 18 h, the mixture was concentrated, then
filtered through silica gel, eluting with 5% EtOAc/hexane. Evapora-
tion of the filtrate in vacuo afforded 225 mg (92%) of the title
compound as a pale pink solid. 1H NMR (300 MHz, DMSO-d6) d
7.30–7.17 (m, 3H), 4.89–4.83 (m, 1H), 3.81 (q, J = 7.0 Hz, 2H),
3.52–3.45 (m, 2H), 3.39–3.33 (m, 2H), 1.27 (t, J = 7.0 Hz, 3H); MS
(DCI+) m/z 232 (M+H).
The following is a description of the synthesis of 27 using meth-
od B, and is typical for the syntheses of 19, 20, and 26–32.
5.6. 8-Amino-1,2,3,4-tetrahydronaphthalen-2-ol (4h)
5.2. 2-Azido-1-[4-(trifluoromethyl)phenyl]ethanone (7f)
A hydrogenation reaction vessel was charged with 100 mL eth-
anol, 8-aminonaphthalen-2-ol (4f) (5.00 g, 31.4 mmol), 0.2 g of 50%
w/w NaOH solution, and 2 g of Raney Ni (wet 40 wt % load). The
vessel was vacuum purged with hydrogen several times before
heating to 85 °C and maintaining a hydrogen pressure of 1300
psi. The mixture was filtered after 6 h, and the filtrate was concen-
trated to yield 4.97 g (97%) of the title compound as a brown solid.
1H NMR (500 MHz, DMSO-d6) d 6.78 (t, J = 7.6 Hz, 1H), 6.44 (d,
J = 7.8 Hz, 1H), 6.30 (d, J = 7.5 Hz, 1H), 4.75 (d, J = 4.1 Hz, 1H),
4.63 (s, 2H), 3.99–3.85 (m, 1H), 2.85–2.56 (m, 3H), 2.20 (dd,
J = 16.5, 7.6 Hz, 1H), 1.94–1.79 (m, 1H), 1.68–1.44 (m, 1H). 13C
NMR (125 MHz, DMSO-d6) d 27.35, 31.41, 33.36, 65.81, 111.35,
116.48, 119.13, 125.53, 136.00, 146.12.
To a solution of 2-bromo-1-[4-(trifluoromethyl)phenyl]etha-
none (6f) (1.22 g, 4.57 mmol) in acetone (75 mL) was added so-
dium azide (0.59 g, 9.1 mmol) all in one portion. The reaction
mixture was stirred at ambient temperature for 18 h and then con-
centrated in vacuo. The residue was partitioned between CH2Cl2
and H2O. The separated aqueous phase was extracted with CH2Cl2.
The combined organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The result was 0.82 g
(78%) of the title compound as an orange oil, which solidified on
standing overnight. 1H NMR (300 MHz, DMSO-d6) d 8.13 (d,
J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 4.96 (s, 2H).

4828
R. J. Perner et al. / Bioorg. Med. Chem. 18 (2010) 4821–4829
5.7. 7-(tert-Butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphth-
C21H19F3N2O2: C, 64.94; H, 4.93; N, 7.21. Found: C, 64.54; H,
alen-1-amine (4j)
4.55; N, 6.96.
Crystallographic data (excluding structure factors) for the struc-
tures in this paper have been deposited with the Cambridge Crys-
tallographic Data Centre as supplementary publication number
CCDC766241. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK,
(fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
A mixture of 4h (2.33 g, 14.3 mmol), tert-butylchlorodimeth-
ylsilane (2.60 g, 17.2 mmol), and imidazole (2.90 g, 42.3 mmol)
was stirred in CH2Cl2 (40 mL) at room temperature overnight.
The mixture was washed several times with water and brine, dried
over Na2SO4, filtered, and concentrated in vacuo to afford 2.6 g
(65%) of the title compound as a dark purple oil. 1H NMR
(300 MHz, DMSO-d6) d 6.77 (dd, J = 7.8, 7.4 Hz, 1H), 6.42 (d,
J = 7.8 Hz, 1H), 6.28 (d, J = 7.4 Hz, 1H), 4.70 (br s, 2H), 4.18–4.08
(m, 1H), 2.78 (dt, J = 16.5, 5.4 Hz, 1H), 2.73–2.61 (m, 2H), 2.26
(dd, J = 16.6, 7.3 Hz, 1H), 1.90–1.81 (m, 1H), 1.71–1.60 (m, 1H),
0.88 (s, 9H), 0.09 (s, 6H); MS (ESI+) m/z 278 (M+H).
Acknowledgements
We thank Mr. R. Henry for X-ray analysis of (R)-30. We also
thank the High Pressure and Process Research labs for scale-up of
intermediates, and the Structural Chemistry group for excellent
NMR and MS support.
5.8. 4-Methyl-5-[4-(trifluoromethyl)phenyl]-1,3-oxazole (16c)
Supplementary data
A
mixture of 4-(trifluoromethyl)benzaldehyde (3.45 mL,
25.8 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (5.40 g,
25.8 mmol), and K2CO3 (4.28 g, 31.0 mmol) in methanol (125 mL)
was heated to reflux. After 2.5 h the volatiles were evaporated, and
the residue was partitioned between Et2O and H2O. The aqueous
phase was extracted with Et2O, and the combined organic extract
was washed with brine, dried (Na2SO4), and concentrated in vacuo.
The crude product was purified by chromatography on silica gel
(Analogix Intelliflash 280; 10–30% ethyl acetate/hexanes eluant;
SF65–400 g column), which yielded 4.01 g (68%) of the title com-
pound as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) d 8.44
(s, 1H), 7.90–7.81 (m, 4H), 2.42 (s, 3H). MS (DCI+) m/z 228 (M+H).
Supplementary data (experimental and characterization data
for all compounds, and the protocols for IC50 determination and
the carrageenan experiment) associated with this article can be
found, in the online version, at doi:10.1016/j.bmc.2010.04.099.
References and notes
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A solution of lithium bis(trimethylsilyl)amide (1.0 M in THF,
19 mL, 19 mmol) was added dropwise to a solution of 16c (4.0 g,
18 mmol) in THF (80 mL) at À78 °C. After stirring 30 min, solid
hexachloroethane (8.34 g, 35.2 mmol) was added in one portion,
and the reaction was allowed to gradually warm to ambient tem-
perature. After 16 h the reaction was quenched with half-saturated
NH4Cl solution. The product was extracted with Et2O, and the com-
bined organic layer was washed with brine, dried (MgSO4), filtered,
and concentrated in vacuo. The residue was purified by chromatog-
raphy on silica gel (Analogix Intelliflash 280; 0–25% EtOAc/hex-
anes; SF65-600 g column; loading with hexane/CH2Cl2) to yield
4.69 g (100%) of the title compound as a white solid. 1H NMR
(300 MHz, DMSO-d6) d 7.89–7.84 (m, 2H), 7.84–7.79 (m, 2H),
2.40 (s, 3H). MS (DCI+) m/z 262 (M+H).
5.10. 8-{5-[3-Methyl-4-(trifluoromethyl)phenyl]oxazol-2-ylamino}-
1,2,3,4-tetrahydronaphthalen-2-ol (27)
A solution of 4j (1.08 g, 3.89 mmol) and 17c (1.02 g, 3.89 mmol)
in 15 mL n-butanol was heated to reflux for 1.5 h. The reaction
mixture was cooled to ambient temperature and partitioned be-
tween ethyl acetate and saturated aqueous NaHCO3 solution. The
separated organic phase was washed with brine, dried (Na2SO4),
filtered, and concentrated at the rotary evaporator to give a dark
red oil. Hexane was added to the residue, and upon mixing a solid
formed which was collected by suction filtration, washed with
hexanes and dried under vacuum. The result was 0.89 g (59%) of
the title compound as a white solid. 1H NMR (300 MHz, DMSO-
d6) d 9.20 (s, 1H), 7.81–7.74 (m, 2H), 7.70–7.62 (m, 2H), 7.58–
7.51 (m, 1H), 7.15–7.06 (m, 1H), 6.90–6.82 (m, 1H), 4.81 (d,
J = 4.0 Hz, 1H), 3.98–3.85 (m, 1H), 3.00–2.81 (m, 2H), 2.80–2.66
(m, 1H), 2.56–2.42 (m, 1H), 2.33 (s, 3H), 1.93–1.80 (m, 1H), 1.69–
1.52 (m, 1H). MS (ESI+) m/z 389 (M+H). Anal. Calcd for
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