Synthesis and dual PPARα/δ agonist effects of 1,4-disubstituted 1,2,3-triazole analogues of GW 501516

Article abstract of DOI:10.1016/j.ejmech.2010.03.035

Ten 1,4-disubstituted 1,2,3-triazoles 2ae2j were prepared and tested for their ability to increase oleic acid oxidation in human myotubes using a high-throughput multiwell assay. Compounds 2e (2-{4-[(1- (3-fluoro-4- (trifluoromethyl)phenyl)-1H-1,2,3-triaz

Full text of DOI:10.1016/j.ejmech.2010.03.035

European Journal of Medicinal Chemistry 45 (2010) 3047e3055
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and dual PPARa/d agonist effects of 1,4-disubstituted 1,2,3-triazole
analogues of GW 501516
a
b
b
a
ꢀ
*
ꢁ b
Calin C. Ciocoiu , Natasa Nikolic , Huyen Hoa Nguyen , G. Hege Thoresen , Arne J. Aasen ,
Trond Vidar Hansen a
,
a School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO BOX 1068, Blindern, N-0316 Oslo, Norway
b School of Pharmacy, Department of Pharmaceutical Biosciences, University of Oslo, PO BOX 1068, Blindern, N-0316 Oslo, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
Ten 1,4-disubstituted 1,2,3-triazoles 2ae2j were prepared and tested for their ability to increase oleic
acid oxidation in human myotubes using a high-throughput multiwell assay. Compounds 2e (2-{4-[(1-
(3-fluoro-4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methylthio]-2-methylphenoxy}acetic acid)
and 2i (2-{4-[(1-(3-chloro-4-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methylthio]-2-methyl-
phenoxy}acetic acid) exhibited potent agonist activities. Compounds 2e and 2i also exhibited powerful
Received 2 November 2009
Received in revised form
23 March 2010
Accepted 23 March 2010
Available online 27 March 2010
agonist effects for both PPAR
a
and PPAR
d
in a luciferase-based assay. Consequently, these triazoles can
be categorized as dual PPAR agonists.
Keywords:
Triazoles
GW 501516
Agonists
Ó 2010 Elsevier Masson SAS. All rights reserved.
PPAR
PPAR
a
d
Multiwell assay
1. Introduction
Interestingly, when obese rhesus monkeys were treated with
GW 501516 (1) [5b], an increased level in the plasma HDL choles-
terol as well as a decrease in the plasma triglyceride level was
observed. Based on these observations, compound 1 is an inter-
esting lead compound for the development of remedies against
diabetes and the metabolic syndrome. Shen and coworkers repor-
The peroxisome proliferator-activated receptors (PPARa, PPARd
and PPARg) belong to the nuclear receptor family of proteins and
function as ligand-activated transcription factors [1]. These recep-
tors play a key role in various tissues by controlling the expression
of genes involved in lipid and carbohydrate metabolism. Agonists
acting on the PPARs have been shown to have beneficial effects on
lipid and glucose metabolism by decreasing triglyceride levels and
increasing high density cholesterol level (HDL). Furthermore, PPAR
agonists have the ability to improve glucose tolerance in type 2
diabetic patients [2]. Dyslipidemia and insulin resistance, two
major components of the metabolic syndrome, have usually been
treated with either the fibrate or the TZD classes of drugs that target
ted several PPARa/d dual agonists when the methyl-thiazole
heterocycle in 1 was replaced with a 1,2,4-thiadiazole moiety [6].
Recently, a regioselective copper(I) catalyzed cycloaddition reac-
tion between terminal alkynes and azides affording 1,4-disubsti-
tuted 1,2,3-triazoles in high yields [7] was reported independently
by the Sharpless and the Meldal groups. This reaction has found
many applications [8]. For example,1,4-disubstituted 1,2,3-triazoles
have recently been employed as mimics for amides [9] in combi-
natorial chemistry library syntheses [10], in modifications of
natural products [11] and in situ library screening [12]. Grimm’s
bioisosteric rule [13] suggests bioisosteric substitution with tri-
azoles should be five-membered heterocyclic rings such as the
thiazole heterocyclic ring in GW 501516 (1) [14]. Furthermore,
using our recently reported in vitro high-throughput multiwell
assay method [15], fast access to measuring agonist effects in
a whole cell-based system has become available to us. Since
development of new agonists that target the PPARs is still of great
interest within medicinal chemistry and drug discovery [16], we
PPAR
a
and PPAR
g
receptors, respectively [3,4]. In contrast, no drugs
and only a few selective
have been developed that target the PPAR
and potent ligands that target this receptor have been identified [5].
The thiazole based compound GW 501516 (1) (Fig. 1) has been
reported to be both highly potent and selective against the PPAR
receptor [5a].
d
d
* Corresponding author. Tel.: þ47 22857450; fax: þ47 22855947.
E-mail address: t.v.hansen@farmasi.uio.no (T.V. Hansen).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.03.035

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C.C. Ciocoiu et al. / European Journal of Medicinal Chemistry 45 (2010) 3047e3055
Fig. 1. Structures of GW 501516 (1) and triazoles 2ae2j.
decided to prepare triazole analogues of GW 501516 (1). Herein, our
synthetic efforts and the biological evaluation of in vitro agonist
effects of ten 1,4-disubstituted 1,2,3-triazole analogues of 1 are
reported.
14C-labeled oleic acid at different concentrations of triazoles 2ae2j
are compiled in Fig. 2. The EC50-values for the five triazoles 2d, 2e,
2i, 2j and 2h were obtained from Fig. 3 (Table 1). Compounds 2e
and 2i were also tested against the three peroxisome proliferator-
activated receptors (PPARa, PPARd and PPARg) in a luciferase-based
transient transfection assay (Fig. 4).
2. Chemistry
4. Results and discussion
1,2,3-Triazoles can be prepared from the thermally induced
Huisgen dipolar cycloaddition reaction between azides and alkynes
[17]. This cycloaddition reaction usually affords mixtures of 1,4- and
1,5-disubstituted 1,2,3-triazoles [18]. Recently, the groups of
Sharpless and Meldal independently reported that 1,4-disubsti-
tuted 1,2,3-triazoles are specifically prepared from azides and
terminal alkynes under copper(I) catalysis [7]. Our synthetic efforts
towards the target 1,4-disubstituted 1,2,3-triazoles 2ae2j started
with the synthesis of alkyne 7 and azides 4ae4j. The azides 4ae4j
were obtained from the anilines 5ae5j using standard diazotization
conditions (Scheme 1) [19]. Terminal alkyne 7 was obtained in 54%
isolated yield over a two step sequence from the known p-mer-
captophenol 5 via 6 [20]. Reaction of the alkyne 7 with the azides
4ae4j under copper(I) catalysis using Sharpless and coworkers’
conditions [7a] yielded triazole esters 8ae8j. Basic aqueous
hydrolysis of esters 8ae8j afforded the target compounds 2ae2j
(Scheme 2). The 1,2,3-triazoles 2ae2j were obtained in 20e48%
overall yields in a four step sequence from p-mercaptophenol 5. The
spectral data of all new products were in accord with their assigned
structures.
All ten triazoles showed the ability to induce oxidation of oleic
acid (Table 1, Fig. 2); however, all were less potent than GW 501516
(1). The most potent triazoles were 2d, 2e and 2j which exhibited
a 10-fold lower potency than the lead compound GW 501516 (1)
(Table 1, Figs. 2AeC, Fig. 3A). The EC50-values for these three tri-
azoles from these experiments were calculated to be 1.8 nM,
0.85 nM, and 1.4 nM, respectively. Triazoles 2h and 2i exhibited
a 100-fold lower potency compared to lead GW 501516 (1) (Table 1,
Figs. 2D,E, Fig. 3B).
We next investigated the effects of triazoles 2e and 2i exercised
on the three different peroxisome proliferator-activated receptors
(PPAR
fection system. Interestingly, 2e and 2i both activated PPAR
as PPAR at 10 M concentration. Triazole 2i was as efficient as the
known PPAR agonist ((2E,4E,8Z,11Z,14Z,17Z)-eicosa-2,4,8,11,14,17-
hexaenoic acid) at this concentration, while 2e was slightly less
efficient (Fig. 4A). Triazole 2e was as efficient at 10 M as GW
501516 (1) towards PPAR (Fig. 4B). No activity towards PPAR was
observed for compounds 2e and 2i.
a
, PPAR
d
and PPAR
g) in a luciferase-based transient trans-
a
as well
d
m
a
m
d
g
Dual activation of PPARs is currently of interest as remedies
against several diseases such as metabolic disorders, type II dia-
3. Biological evaluation
betes and cardiovascular diseases [21]. Activation of PPAR
been reported to reduce the levels of triglycerides in blood while
activation of PPAR has been reported to enhance both the fatty
acid metabolism and the HDL cholesterol level. So far very few
potent PPAR dual agonists have been reported in the literature
[6,22]. Our results reported herein augment the limited structural
a has
GW 501516 (1) as well as all ten 1,4-disubstituted 1,2,3-triazoles
2ae2j, at five different concentrations, was exposed for 96 h to fully
differentiated human skeletal muscle cells cultured in 96-well
plates. After this period of time, the level of oxidation of oleic acid
was measured by detection of the accumulation of 14C-labeled
oxidized oleic acid [15]. The results from the oxidation of
d
a/d
information available for activation of both PPAR
results merit further investigations.
a and PPARd. These
5. Conclusions
We have prepared ten new triazole analogues of the known
PPAR agonist GW 501516 (1). Five of these analogues proved to be
potent, activating the fatty acid oxidation in human myotubes in
concentrations below 10 M. Interestingly, dual PPAR agonist
d
m
a/d
effects were observed for both compounds 2e and 2i. Further
studies towards preparing more potent dual agonists are underway.
These efforts will be reported in due course.
Scheme 1. (a) Reagents and conditions: NaNO2, NaN3, H2O:HCl (1:1), 0 ꢀC, r.t.

C.C. Ciocoiu et al. / European Journal of Medicinal Chemistry 45 (2010) 3047e3055
3049
Scheme 2. Reagents and conditions: (a) propargyl bromide, Cs2CO3, CH3CN; (b) ethyl bromoacetate, Cs2CO3, CH3CN; (c) sodium ascorbate, CuSO4$5H2O, t-BuOH, H2O, azides 4ae4j;
(d) LiOH, THF, H2O.
6. Experimental
points are uncorrected. Flash column chromatography was per-
formed on silica gel 60 (40e63 m, Fluka). LC/MS analyses were
performed on an Agilent Technologies 1200 Series (Eclipse XDB-
C18, 5
The purities of the final products 2ae2j were >98% as judged from
the HPLC analyses. The purities of all intermediates were >95% as
judged by NMR and HPLC analyses.
m
6.1. General methods
m
m 4.6 ꢁ 150 mm), coupled with an Agilent 6310 ion Trap.
All dry solvents were commercially available. NMR spectra were
recorded on a Bruker DP ꢁ 300 spectrometer. Melting points were
measured using a Barnstead Electrothermal apparatus. Melting
Fig. 2. Oxidation of oleic acid in human myotubes in the presence of the triazoles 2ae2j at different concentrations. Myotubes were cultured and oleic acid oxidation assessed as
described in Section 6.34. GW 501516 (1) was used as positive control.

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C.C. Ciocoiu et al. / European Journal of Medicinal Chemistry 45 (2010) 3047e3055
Fig. 3. Non-linear fit curves of oleic acid oxidation in human myotubes in the presence of different concentrations of the triazoles 2d, 2e, 2j (A), 2i and 2h (B). Myotubes were
cultured and oleic acid oxidation assessed as described in Section 6.34. GW 501516 (1) was used as positive control.
6.2. Azidobenzene (4a)
(625 mg, 5 mmol) according to the general procedure. 1H NMR
(300 MHz, CDCl3):
d
¼ 2.25 (d, J ¼ 1.95 Hz, 3H), 6.76e6.75 (m, 2H),
General procedure: the amine (1 mmol) was suspended in HCl/
H2O (1:1) (10 mL) and cooled to 0 ꢀC. An aqueous solution of
sodium nitrite (82.8 mg, 1.2 mmol) was added dropwise, and the
reaction mixture was stirred at 0 ꢀC for 1 h. An aqueous solution of
sodium azide (1.2 mmol) was added dropwise. The reaction
mixture was stirred at room temperature for another 3 h, and
extracted with hexane (3 ꢁ 50 mL). The organic layers were washed
with brine (2 ꢁ 100 mL), dried over MgSO4 and concentrated. The
title compound was prepared in 36% yield (434 mg, 3.64 mmol) as
a brown oil from aniline (3a) (10 mmol) according to the general
7.15 (t, J ¼ 8.21 Hz, 1H). 13C NMR (75 MHz, CDCl3):
d
¼ 13.98 (d,
J ¼ 3.34 Hz), 106.27 (d, J ¼ 26.03 Hz), 114.31 (d, J ¼ 3.40 Hz), 121.40
(d, J ¼ 17.51 Hz), 132.12 (d, J ¼ 6.31 Hz), 139.02 (d, J ¼ 9.91 Hz),
161.61 (d, J ¼ 246.30 Hz).
6.5. 1-Azido-4-trifluoromethylbenzene (4d)
The title compound was prepared in 55% yield (1028 mg,
5.5 mmol) as a light yellow oil from 4-trifluoromethylaniline (3d)
(10 mmol) according to the general procedure. 1H NMR (300 MHz,
procedure. 1H NMR (300 MHz, CDCl3):
7.14e7.19 (m, 1H), 7.35e7.40 (m, 2H). 13C NMR (75 MHz, CDCl3):
¼ 118.97, 124.81, 129.69, 139.95.
d
¼ 7.04e7.07 (m, 2H),
CDCl3):
NMR (75 MHz, CDCl3):
(q, J ¼ 3.75 Hz), 127.04 (q, J ¼ 32.7 Hz), 143.6 (distorted q, J ¼ 1.2 Hz).
d
¼ 7.10 (d, J ¼ 8.27 Hz, 2H), 7.60 (d, J ¼ 8.35 Hz, 2H). 13C
d
¼ 119.39, 123.94 (q, J ¼ 269.8 Hz), 126.95
d
6.3. 1-Azido-4-methylbenzene (4b)
6.6. 4-Azido-2-fluoro-1-trifluoromethylbenzene (4e)
The title compound was prepared in 41% yield (274 mg,
2.06 mmol) as a yellow oil from p-toluidine (3b) (536 mg, 5 mmol)
according to the general procedure. 1H NMR (300 MHz, CDCl3):
The title compound was prepared in 46% yield (187 mg,
0.91 mmol) as a yellow oil from 3-fluoro-4-trifluoromethylaniline
(3e) (358 mg, 2 mmol) according to the general procedure. 1H NMR
¼ 2.34 (s, 3H), 6.93 (d, J ¼ 8.39 Hz, 2H), 7.16 (d, J ¼ 8.07 Hz, 2H). 13
C
(300 MHz, CDCl3):
d
¼ 6.82e6.91 (m, 2H), 7.57 (t, J ¼ 8.1 Hz, 1H). 13
C
d
NMR (75 MHz, CDCl3):
d
¼ 20.78, 118.80, 130.2, 134.56, 137.12.
NMR (75 MHz, CDCl3):
d
¼ 107.79 (d, J ¼ 24.14 Hz), 114.47 (d,
J ¼ 3.51 Hz), 114.81 (qd, J ¼ 33.60, 12.78 Hz), 122.40 (qd, J ¼ 271.61,
1.27 Hz), 128.46 (qd, J ¼ 4.61, 3.05 Hz), 146.05 (distorted dq,
J ¼ 10.07, 0.78 Hz), 160.60 (dq, J ¼ 257.70, 2.06 Hz).
6.4. 4-Azido-2-fluoro-1-methylbenzene (4c)
The title compound was prepared in 70% yield (533 mg,
3.53 mmol) as an orange oil from 3-fluoro-4-methylaniline (3c)
6.7. 1-Azido-4-methoxybenzene (4f)
The title compound was prepared in 11% yield (67 mg,
0.45 mmol) asa light yellowoilfrom4-methoxyaniline (3f) (492 mg,
4 mmol) according to the general procedure. 1H NMR (300 MHz,
Table 1
Substitution pattern (see Fig. 1) and EC50-values for the prepared triazoles.
a
CDCl3):
d
¼ 3.79 (s, 3H), 6.68e6.91 (m, 2H), 6.93e6.97 (m, 2H). 13
C
Compound
R1
R2
EC50 (nM)
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
H
F
H
F
H
F
H
Cl
F
H
n.d.b
n.d.
n.d.
1.8
NMR (75 MHz, CDCl3):
d
¼ 55.52, 115.08, 119.94, 132.30, 156.95.
CH3
CH3
CF3
6.8. 4-Azido-2-fluoro-1-methoxybenzene (4g)
CF3
0.85
n.d.
n.d.
10
12
1.4
OCH3
OCH3
OCF3
OCF3
OCF3
e
The title compound was prepared in 49% yield (330 mg,
1.97 mmol) as a brown solid from 3-fluoro-4-methoxyaniline (3g)
(564 mg, 4 mmol) according to the general procedure.
Mp ¼ 56e57 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼ 3.87 (s, 3H),
2j
1
6.71e6.83 (m, 2H), 6.93 (t, J ¼ 9.0 Hz,1H). 13C NMR (75 MHz, CDCl3):
e
0.07
a
d
¼ 55.57, 107.74 (d, J ¼ 21.81 Hz), 114.33e114.49 (m, 2 ꢁ C), 132.90
Results of three experiments.
n.d. ¼ not determined.
b
(d, J ¼ 8.57 Hz), 145.03 (d, J ¼ 10.82 Hz), 152.75 (d, J ¼ 248.11 Hz).

C.C. Ciocoiu et al. / European Journal of Medicinal Chemistry 45 (2010) 3047e3055
3051
Fig. 4. Activation of the ligand-binding domain of PPAR
a
(A), PPAR
d
(B), PPAR
g
(C) of triazoles 2e and 2i in comparison with known agonists in a luciferase-based transfection assay.
: GW 501516 (1); PPAR : BRL (rosiglitazone).
Positive controls: PPAR : EHA ((2E,4E,8Z,11Z,14Z,17Z)-eicosa-2,4,8,11,14,17-hexaenoic acid); PPAR
a
d
g
6.9. 1-Azido-4-trifluoromethoxybenzene (4h)
6.13. Ethyl 2-[2-methyl-4-(prop-2-ynylthio)phenoxy]acetate (7)
To solution of 2-methyl-4-(prop-2-ynylthio)phenol (6)
The title compound was prepared in 57% yield (215 mg,
1.06 mmol) as a light yellow oil from 4-trifluoromethoxyaniline
(3h) (1.86 mmol) according to the general procedure. 1H NMR
a
(178 mg, 1 mmol) in dry CH3CN (20 mL) was added Cs2CO3
(489 mg, 1.5 mmol). To the mixture was added dropwise a solution
of ethyl bromoacetate (1.4 mmol) in dry CH3CN (5 mL). The mixture
was stirred for 4 h under Ar at r.t., then diluted with water and
extracted with ethyl acetate (3 ꢁ100 mL). The combined organic
layers were dried over MgSO4 and concentrated. The residue was
purified by column chromatography on silica gel with hexane/ethyl
acetate (4:1) to obtain the title compound as a light yellow oil in
(300 MHz, CDCl3):
NMR (75 MHz, CDCl3):
(distorted q, J ¼ 0.66 Hz), 138.82, 146.02 (q, J ¼ 1.96 Hz).
d
¼ 7.01e7.06 (m, 2H), 7.19e7.22 (m, 2H). 13C
d
¼ 120.13, 120.45 (q, J ¼ 257.16 Hz), 122.61
6.10. 4-Azido-2-chloro-1-trifluoromethoxybenzene (4i)
74% yield (196 mg, 0.74 mmol). 1H NMR (300 MHz, CDCl3):
d
¼ 1.29
The title compound was prepared in 77% yield (460 mg,
1.93 mmol) as an orange oil from 3-chloro-4-trifluoro-
methoxyaniline (3i) (528 mg, 2,5 mmol) according to the general
(t, J ¼ 7.14 Hz, 3H), 2.22 (t, J ¼ 2.61, 1H), 2.27 (s, 3H), 3.49 (d,
J ¼ 2.60 Hz, 2H), 4.26 (q, J ¼ 7.14 Hz, 2H), 4.62 (s, 2H), 6.65 (d,
J ¼ 8.12 Hz, 1H), 7.27e7.33 (m, 2H). 13C NMR (75 MHz, CDCl3):
procedure. 1H NMR (300 MHz, CDCl3):
d
¼ 6.94 (dd, J ¼ 8.82,
2.70 Hz, 1H), 7.13 (d, J ¼ 2.68 Hz, 1H), 7.30 (dd, J ¼ 8.82, 1.26 Hz, 1H).
13C NMR (75 MHz, CDCl3):
d
¼ 14.09, 16.09, 24.23, 61.27, 65.59, 71.47, 80.17, 111.55, 125.81,
128.19, 130.99, 135.10, 156.10, 168.74.
d
¼ 118.27, 120.46 (q, J ¼ 259.23 Hz),
121.179, 123.88 (distorted q, J ¼ 1.08 Hz), 128.95, 139.84, 142.04 (q,
J ¼ 1.89 Hz).
6.14. Ethyl 2-{2-methyl-4-[(1-phenyl-1H-1,2,3-triazol-4-yl)
methylthio]phenoxy}acetate (8a)
6.11. 4-Azido-2-fluoro-1-trifluoromethoxybenzene (4j)
General procedure: the alkyne 7 (1 mmol) and the azide
(1 mmol) were solved in t-BuOH/H2O (1:1, 10 mL). Sodium ascor-
bate (40 mg, 20 mol %) and copper sulfate (10 mg, 5 mol %) were
added. The mixture was stirred at ambient temperature over night.
A precipitate was formed. Water/ice (50 mL) was added, the
precipitate was filtered off, washed with aqueous NH3 (3.5% ꢁ
100 mL) and cold water. The precipitate was purified by column
chromatography using hexane/ethyl acetate (4:1) as eluent. The
title compound was prepared in 80% yield (234 mg, 0.61 mmol) as
a white solid from 7 (200 mg, 0.76 mmol) and azidobenzene (4a)
(90 mg, 0.76 mmol) according to the general procedure.
The title compound was prepared in 49% yield (243 mg,
1.1 mmol) as an orange oil from 3-fluoro-4-trifluoromethoxyaniline
(3j) (2.25 mmol) according to the general procedure. 1H NMR
(200 MHz, CDCl3):
NMR (50 MHz, CDCl3):
J ¼ 3.73 Hz), 120.49 (qd, J ¼ 259.0, 0.46 Hz), 124.92, 133.26 (dq,
J ¼ 12.72, 2.15 Hz), 140.49 (d, J ¼ 8.73 Hz), 155.20 (d, J ¼ 254.50 Hz).
d
¼ 6.75e6.90 (m, 2H), 7.20e7.33 (m, 1H). 13C
d
¼ 108.32 (d, J ¼ 22.15 Hz), 114.86 (d,
6.12. 2-Methyl-4-(prop-2-ynylthio)phenol (6)
Mp ¼ 49e50 ꢀC. 1H NMR (300 MHz, CDCl3):
¼ 1.24 (t, J ¼ 7.14 Hz,
d
To a solution of p-mercapto-2-methylphenol (5) (140 mg,
1 mmol) in dry CH3CN (20 mL) was added Cs2CO3 (326 mg,
1 mmol). To this mixture was added dropwise a solution of prop-
argyl bromide (0.85 mmol) in dry CH3CN (5 mL). The mixture was
stirred for 2 h at r.t., then diluted with water and extracted with
ethyl acetate (3 ꢁ 100 mL). The organic layers were combined,
dried (MgSO4) and concentrated. The residue was purified by
column chromatography on silica gel with hexane/ethyl acetate
(4:1) affording 2-methyl-4-(prop-2-ynylthio)phenol in 67% yield
(119 mg, 0.67 mmol) as a yellow oil. 1H NMR (300 MHz, CDCl3):
3H), 2.21 (s, 3H), 4.17e4.24 (m, 4H), 4.58 (s, 2H), 6.58 (d, J ¼ 8.42 Hz,
1H), 7.14 (dd, J ¼ 2.15, 8.41 Hz, 1H), 7.19 (d, J ¼ 1.65 Hz, 1H),
7.35e7.49 (m, 3H), 7.60e7.64 (m, 3H). 13C NMR (75 MHz, CDCl3):
d
¼ 14.05, 16.05, 30.46, 61.23, 65.53, 111.63, 120.10, 120.35, 126.17,
128.28, 128.60, 129.63,130.38,134.59, 136.90, 145.74,155.75,168.71.
6.15. Ethyl 2-{2-methyl-4-[(1-p-tolyl-1H-1,2,3-triazol-4-yl)
methylthio]phenoxy}acetate (8b)
The title compound was prepared in 92% yield (99 mg,
0.24 mmol) as a white solid from 7 (70 mg, 0.26 mmol) and
1-azido-4-methylbenzene (4b) (35 mg, 0.26 mmol) according to
the general procedure. Mp ¼ 99e100 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼ 2.23e2.45 (m, 4H), 3.50 (d, J ¼ 2.6 Hz, 2H), 4.89 (s, 1H), 6.74 (d,
J ¼ 8.2 Hz, 1H), 7.26e7.33 (m, 2H). 13C NMR (75 MHz, CDCl3):
d
¼ 15.64, 24.60, 71.52, 80.28, 115.54, 124.71, 124.82, 131.94, 135.71,
154.03.
d
¼ 1.25 (t, J ¼ 7.14 Hz, 3H), 2.21 (s, 3H), 2.37 (s, 3H), 4.16 (s, 2H), 4.21

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C.C. Ciocoiu et al. / European Journal of Medicinal Chemistry 45 (2010) 3047e3055
(q, J ¼ 7.14 Hz, 2H), 4.58 (s, 2H), 6.59 (d, J ¼ 8.40 Hz, 1H), 7.14 (dd,
J ¼ 8.40, 2.17 Hz, 1H), 7.19 (d, J ¼ 1.64 Hz, 1H), 7.25 (d, J ¼ 8.22 Hz,
2H), 7.49e7.52 (m, 2H), 7.61 (s, 1H). 13C NMR (75 MHz, CDCl3):
55.59, 61.30, 65.62, 111.68, 114.71, 120.28, 122.08, 126.37, 128.33,
130.37, 130.49, 134.61, 145.61, 155.78, 159.73, 168.79.
d
¼ 14.08, 16.07, 21.01, 30.54, 61.25, 65.57, 111.65, 120.07, 120.29,
6.20. Ethyl 2-{4-[(1-(3-fluoro-4-methoxyphenyl)-1H-1,2,3-triazol-
4-yl)methylthio]-2-methylphenoxy}acetate (8g)
126.31, 128.27, 130.12, 130.34, 134.57, 134.68, 138.68, 145.63, 155.74,
168.74.
The title compound was prepared in 78% yield (255 mg,
0.59 mmol) as a white solid from 7 (200 mg, 0.76 mmol) and
4-azido-2-fluoro-1-methoxybenzene (4g) (127 mg, 0.76 mmol)
according to the general procedure. Mp ¼ 111e112 ꢀC. 1H NMR
6.16. Ethyl 2-{4-[(1-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-4-
yl)methylthio]-2-methylphenoxy}acetate (8c)
The title compound was prepared in 59% yield (192 mg,
0.46 mmol) as a white solid from 7 (207 mg, 0.78 mmol) and
4-azido-2-fluoro-1-methylbenzene (4c) (118 mg, 0.78 mmol)
according to the general procedure. Mp ¼ 101e102 ꢀC. 1H NMR
(300 MHz, CDCl3):
d
¼ 1.25 (t, J ¼ 7.14 Hz, 3H), 2.20 (s, 3H), 3.90 (s,
3H), 4.15 (s, 2H), 4.21 (q, J ¼ 7.14 Hz, 2H), 4.58 (s, 2H), 6.58 (d,
J ¼ 8.41 Hz, 1H), 7.02 (t, J ¼ 8.78 Hz, 1H), 7.11e7.18 (m, 2H), 7.33
(ddd, J ¼ 8.81, 2.53, 1.59 Hz, 1H), 7.42 (dd, J ¼ 11.34, 2.58 Hz, 1H),
7.55 (s,1H). 13C NMR (75 MHz, CDCl3):
d
¼ 14.08,16.08, 30.44, 56.46,
(300 MHz, CDCl3):
d
¼ 1.23 (t, J ¼ 7.12 Hz, 3H), 2.19e2.27 (m, 6H),
4.13e4.23 (m, 4H), 4.57 (s, 2H), 6.57 (d, J ¼ 8.38 Hz, 1H), 7.11e7.37
61.26, 65.53, 109.46 (d, J ¼ 22.79 Hz), 111.64, 113.66 (d, J ¼ 2.68 Hz),
116.19 (d, J ¼ 3.87 Hz), 120.14, 126.13, 128.31, 130.07 (d, J ¼ 8.79 Hz),
130.38, 134.60, 145.82, 147.95 (d, J ¼ 10.53 Hz), 152.18 (d,
J ¼ 248.98 Hz), 155.78, 168.72.
(m, 5H), 7.60 (s, 1H). 13C NMR (75 MHz, CDCl3):
d
¼ 14.03, 14.19 (d,
J ¼ 3.26 Hz), 16.01, 30.41, 61.20, 65.48, 107.66 (d, J ¼ 27.20 Hz),
111.60, 115.32 (d, J ¼ 3.66 Hz), 119.95, 125.42 (d, J ¼ 17.29 Hz),
126.09, 128.24, 130.34, 132.19 (d, J ¼ 6.04 Hz), 134.55, 135.74 (d,
J ¼ 10.05 Hz), 145.83, 155.73, 161.14 (d, J ¼ 247.07 Hz), 168.67.
6.21. Ethyl 2-{2-methyl-4-[(1-(4-trifluoromethoxyphenyl)-1H-
1,2,3-triazol-4-yl)methylthio]phenoxy}acetate (8h)
6.17. Ethyl 2-{2-methyl-4-[(1-(4-trifluoromethylphenyl)-1H-1,2,3-
triazol-4-yl)methylthio]phenoxy}acetate (8d)
The title compound was prepared in 61% yield (214 mg,
0.46 mmol) as a white solid from 7 (200 mg, 0.76 mmol) and
1-azido-4-(trifluoromethoxy)benzene (4h) (154 mg, 0.76 mmol)
according to the general procedure. Mp ¼ 103e104 ꢀC. 1H NMR
The title compound was prepared in 96% yield (112 mg,
0.25 mmol) as a white solid from 7 (70 mg, 0.26 mmol) and 1-azido-
4-(trifluoromethyl)benzene (4d) (48 mg, 0.26 mmol) according to
the general procedure. Mp ¼ 110e111 ꢀC. 1H NMR (300 MHz,
(300 MHz, CDCl3):
d
¼ 1.25 (t, J ¼ 7.14 Hz, 3H), 2.20 (s, 3H), 4.15 (s,
2H), 4.21 (q, J ¼ 7.14 Hz, 2H), 4.59 (s, 2H), 6.58 (d, J ¼ 8.42 Hz, 1H),
7.12 (dd, J ¼ 8.42, 2.03 Hz, 1H), 7.18 (d, J ¼ 1.47 Hz, 1H), 7.33 (d,
J ¼ 8.30 Hz, 2H), 7.59 (bs, 1H), 7.65e7.70 (m, 2H). 13C NMR (75 MHz,
CDCl3):
d
¼ 1.26 (t, J ¼ 7.14 Hz, 3H), 2.21 (s, 3H), 4.17 (s, 2H), 4.22
(q, J ¼ 7.14 Hz, 2H), 4.60 (s, 2H), 6.58 (d, J ¼ 8.44 Hz, 1H), 7.13 (dd,
J ¼ 8.42, 2.17 Hz, 1H), 7.19 (d, J ¼ 1.71 Hz, 1H), 7.63 (s, 1H), 7.75
(d, J ¼ 8.88 Hz, 2H), 7.80 (d, J ¼ 8.84 Hz, 2H). 13C NMR (75 MHz,
CDCl3):
d
¼ 14.06, 16.08, 30.46, 61.27, 65.47, 111.57, 120.06, 120.28 (q,
J ¼ 258.25 Hz), 121.77, 122.18 (distorted q, J ¼ 0.66 Hz), 125.99,
CDCl3):
d
¼ 14.10, 16.12, 30.52, 61.32, 65.48, 111.59, 119.88, 120.29,
128.34, 130.58, 134.74, 135.31, 148.79 (q, J ¼ 1.83 Hz), 155.83, 168.73.
123.52 (q, J ¼ 271.94 Hz), 125.94, 127.04 (q, J ¼ 3.77 Hz), 128.42,
130.55 (q, J ¼ 30.21 Hz),130.69,134.86,139.33 (distorted q, J ¼ 1 Hz),
146.39, 155.91, 168.76.
6.22. Ethyl 2-{4-[(1-(3-chloro-4-trifluoromethoxyphenyl)-1H-
1,2,3-triazol-4-yl)methylthio]-2-methylphenoxy}acetate (8i)
6.18. Ethyl 2-{4-[(1-(3-fluoro-4-trifluoromethylphenyl)-1H-1,2,3-
triazol-4-yl)methylthio]-2-methylphenoxy}acetate (8e)
The title compound was prepared in 95% yield (360 mg,
0.72 mmol) as a white solid from 7 (200 mg, 0.76 mmol) and
4-azido-2-chloro-1-(trifluoromethoxy)benzene
(4i)
(180 mg,
The title compound was prepared in 77% yield (94 mg, 0.2 mmol)
as a white solid from 7 (70 mg, 0.26 mmol) and 4-azido-2-fluoro-1-
(trifluoromethyl)benzene (4e) (54 mg, 0.26 mmol) according to the
general procedure. Mp ¼ 84e85 ꢀC. 1H NMR (300 MHz, CDCl3):
0.76 mmol) according to the general procedure. Mp ¼ 112e113 ꢀC.
1H NMR (300 MHz, CDCl3):
d
¼ 1.25 (t, J ¼ 7.14 Hz, 3H), 2.21 (s, 3H),
4.15 (s, 2H), 4.21 (q, J ¼ 7.14 Hz, 2H), 4.59 (s, 2H), 6.58 (d, J ¼ 8.44 Hz,
1H), 7.12 (dd, J ¼ 8.42, 2.08 Hz, 1H), 7.18 (d, J ¼ 1.67 Hz, 1H), 7.44 (dd,
J ¼ 8.90, 1.28 Hz, 1H), 7.56e7.60 (m, 2H), 7.85 (d, J ¼ 2.57 Hz, 1H). 13C
d
¼ 1.26 (t, J ¼ 7.14 Hz, 3H), 2.21 (s, 3H), 4.15 (s, 2H,), 4.21 (q,
J ¼ 7.14 Hz, 2H), 4.60 (s, 2H), 6.58 (d, J ¼ 8.43 Hz, 1H), 7.12 (dd,
J ¼ 8.42, 2.1 Hz, 1H), 7.18 (d, J ¼ 1.57 Hz, 1H), 7.53e7.75 (m, 4H). 13C
NMR (75 MHz, CDCl3):
d
¼ 14.08, 16.10, 30.44, 61.30, 65.47, 111.60,
119.45, 119.47, 120.33 (q, J ¼ 259.65 Hz), 121.69, 123.54 (distorted q,
J ¼ 1.22 Hz), 125.87, 128.40, 128.91, 130.60, 134.78, 135.73, 148.89 (q,
J ¼ 1.51 Hz), 146.46, 155.89, 168.72.
NMR (75 MHz, CDCl3):
d
¼ 14.07,16.09, 30.45, 61.31, 65.42,108.93 (d,
J ¼ 25.54 Hz), 111.58, 115.00 (d, J ¼ 3.90 Hz), 118.15 (qd, J ¼ 33.70,
12.65 Hz), 119.80, 122.01 (qd, J ¼ 272.45, 1.15 Hz), 125.76, 128.44,
128.75 (qd, J ¼ 4.58, 2.53 Hz),130.70,134.89,140.76 (d, J ¼ 10.30 Hz),
146.69, 155.93, 160.22 (dq, J ¼ 258.74, 1.94 Hz), 168.72.
6.23. Ethyl 2-{4-[(1-(3-fluoro-4-trifluoromethoxyphenyl)-1H-1,2,3-
triazol-4-yl)methylthio]-2-methylphenoxy}acetate (8j)
6.19. Ethyl 2-{4-[(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)
methylthio]-2-methylphenoxy}acetate (8f)
The title compound was prepared in 53% yield (82 mg,
0.17 mmol) as a yellow solid from 7 (85 mg, 0.32 mmol) and 4-azido-
2-fluoro-1-(trifluoromethoxy)benzene (4j) (71 mg, 0.32 mmol)
according to the general procedure. Mp ¼ 80e81 ꢀC. 1H NMR
The title compound was prepared in 72% yield (446 mg,
1.08 mmol) as a white solid from 7 (400 mg, 1.51 mmol) and 1-
azido-4-methoxybenzene (4f) (225 mg,1.51 mmol) according to the
general procedure. Mp ¼ 63e64 ꢀC. 1H NMR (300 MHz, CDCl3):
(300 MHz, CDCl3):
d
¼ 1.26 (t, J ¼ 7.14 Hz, 3H), 2.21 (s, 3H), 4.16 (s,
2H), 4.22 (q, J ¼ 7.14 Hz, 2H), 4.60 (s, 2H), 6.58 (d, J ¼ 8.44 Hz,1H), 7.12
(dd, J ¼ 8.40, 2.17 Hz, 1H), 7.19 (d, J ¼ 1.62 Hz, 1H), 7.37e7.50 (m, 2H),
7.57 (s, 1H), 7.59e7.67 (m, 1H). 13C NMR (75 MHz, DMSO-d6):
d
¼ 1.26 (t, J ¼ 7.14 Hz, 3H), 2.22 (s, 3H), 3.83 (s, 3H), 4.17 (s, 2H), 4.22
(q, J ¼ 7.14 Hz, 2H), 4.59 (s, 2H), 6.59 (d, J ¼ 8.41 Hz, 1H), 6.94e7.00
(m, 2H), 7.15 (dd, J ¼ 8.40, 2.10 Hz, 1H), 7.19 (d, J ¼ 1.64 Hz, 1H),
d
¼ 14.09, 16.12, 30.46, 61.32, 65.47, 109.96 (d, J ¼ 23.34 Hz), 111.60,
7.52e7.56 (m, 3H). 13C NMR (75 MHz, CDCl3):
d
¼ 14.12, 16.12, 30.58,
115.96 (d, J ¼ 4.05 Hz), 119.94, 120.33 (q, J ¼ 260.02 Hz), 124.82,

C.C. Ciocoiu et al. / European Journal of Medicinal Chemistry 45 (2010) 3047e3055
3053
125.86, 128.44, 130.66, 134.83, 135.60e136.80 (m, 2 ꢁ C), 146.51,
154.81 (d, J ¼ 255.53 Hz), 155.92, 168.76.
126.49, 127.08 (q, J ¼ 3.72 Hz), 128.43 (q, J ¼ 32.42 Hz), 129.77,
133.24, 139.18 (distorted q, J ¼ 1.12 Hz), 145.50, 156.57, 172.38. MS
(ESI) m/z 422.1, [M ꢂ H]ꢂ, HRMS calcd for C19H16F3N3O3S [M]þ:
423.0864; found 423.0875.
6.24. 2-{2-Methyl-4-[(1-phenyl-1H-1,2,3-triazol-4-yl)methylthio]
phenoxy}acetic acid (2a)
6.28. 2-{4-[(1-(3-Fluoro-4-trifluoromethyphenyl)-1H-1,2,3-triazol-
4-yl)methylthio]-2-methylphenoxy}acetic acid (2e)
General procedure: to a stirred solution of ester (1 mmol) in THF
(10 mL) and H2O (5 mL) at 0 ꢀC was added slowly 625
mL of 2.0 M
LiOH. The reaction mixture was stirred until TLC indicated
completion of the reaction and then diluted with 50 mL H2O. The
reaction mixture was washed with hexane (3 ꢁ 50 mL). The organic
layers were then washed with H2O (3 ꢁ 50 mL). The combined
water phases were acidified with 0.1 M HCl and extracted with
diethyl ether, dried over MgSO4, concentrated and recrystallized
from CH2Cl2. The title compound was prepared in 37% yield (77 mg,
0.22 mmol) as a white solid from 8a (231 mg, 0.60 mmol) according
to the general procedure. Mp ¼ 138e139 ꢀC. 1H NMR (300 MHz,
The title compound was prepared in 42% yield (102 mg,
0.23 mmol) as a white solid from 8e (258 mg, 0.55 mmol) according
to the general procedure. Mp ¼ 134e135 ꢀC. 1H NMR (300 MHz,
DMSO-d6):
d
¼ 2.14 (s, 3H), 4.24 (s, 2H), 4.67 (s, 2H), 6.77 (d,
J ¼ 8.46 Hz, 1H), 7.17e7.23 (m, 2H), 7.96 (d, J ¼ 3.69 Hz, 2H), 8.12
(d, J ¼ 12.10 Hz, 1H), 8.77 (s, 1H). 13C NMR (75 MHz, DMSO-d6):
d
¼ 15.82, 29.16, 64.80, 108.62 (d, J ¼ 25.83 Hz), 111.93, 115.61
(d, J ¼ 3.50 Hz), 115.89 (qd, J ¼ 32.97, 12.30 Hz), 121.66, 122.23
(q, J ¼ 272.45 Hz), 125.36, 126.99, 129.00e129.06 (m), 129.50,
133.17, 140.90 (d, J ¼ 10.76 Hz), 145.74, 155.35, 159.35 (dq,
J ¼ 254.53, 2.07 Hz), 170.14. MS (ESI) m/z 440.0, [M ꢂ H]ꢂ, HRMS
calcd for C19H15F4N3O3S [M]þ: 441.0770; found 441.0776.
DMSO-d6):
d
¼ 2.15 (s, 3H), 4.23 (s, 2H), 4.67 (s, 2H), 6.79 (d,
J ¼ 8.46 Hz,1H), 7.18e7.24 (m, 2H), 7.45e7.50 (m, 1H), 7.56e7.61 (m,
2H), 7.83e7.86 (m, 2H), 8.57 (s, 1H), 12.97 (s, 1H). 13C NMR (75 MHz,
DMSO-d6):
d
¼ 15.81, 29.15, 64.47, 111.91, 119.85, 121.21, 125.47,
126.89, 128.49, 129.37, 129.79, 130.06, 136.47, 144.92, 155.19, 170.03.
MS (ESI) m/z 354.1 [M ꢂ H]ꢂ, HRMS calcd for C18H17N3O3S [M]þ:
355.0991; found 355.0989.
6.29. 2-{4-[(1-(4-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)
methylthio]-2-methylphenoxy}acetic acid (2f)
The title compound was prepared in 40% yield (33 mg,
0.08 mmol) as a white solid from 8f (80 mg, 0.2 mmol) according to
the general procedure. Mp ¼ 84e85 ꢀC. 1H NMR (300 MHz, DMSO-
6.25. 2-{2-Methyl-4-[(1-p-tolyl-1H-1,2,3-triazol-4-yl)methylthio]
phenoxy}acetic acid (2b)
d6):
d
¼ 2.15 (s, 3H), 3.82 (s, 3H), 4.21 (s, 2H), 4.66 (s, 2H), 6.78
The title compound was prepared in 58% yield (76 mg,
0.21 mmol) as a white solid from 8b (142 mg, 0.36 mmol) according
to the general procedure. Mp ¼ 127e128 ꢀC. 1H NMR (300 MHz,
(d, J ¼ 8.44 Hz, 1H), 7.09e7.13 (m, 2H), 7.18e7.23 (m, 2H), 7.74
(d, J ¼ 9.04 Hz, 2H), 8.45 (s, 1H). 13C NMR (75 MHz, DMSO-d6):
d
¼ 15.82, 29.20, 55.45, 64.84, 111.90, 114.76, 121.18, 121.51, 125.43,
DMSO-d6):
d
¼ 2.15 (s, 3H), 2.37 (s, 3H), 4.22 (s, 2H), 4.67 (s, 2H),
126.85, 129.35, 129.91, 133.03, 144.61, 155.25, 159.09, 170.11. MS
(ESI) m/z 384.1, [M ꢂ H]ꢂ, HRMS calcd for C19H19N3O4S [M]þ:
385.1096; found 385.1098.
6.78 (d, J ¼ 8.44 Hz, 1H), 7.18e7.23 (m, 2H), 7.36 (d, J ¼ 8.17 Hz, 2H),
7.72 (d, J ¼ 8.48 Hz, 2H), 8.51 (s, 1H),12.88 (s, 1H). 13C NMR (75 MHz,
DMSO-d6):
d
¼ 15.83, 20.47, 29.20, 64.79, 111.92, 119.74, 121.10,
125.48, 126.90, 129.38, 130.12, 133.07, 134.25, 138.11, 144.78, 155.24,
170.11. MS (ESI) m/z 368.1 [M ꢂ H]ꢂ, HRMS calcd for C19H19N3O3S
[M]þ: 369.1147; found 369.1141.
6.30. 2-{4-[(1-(3-Fluoro-4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)
methylthio]-2-methylphenoxy}acetic acid (2g)
The title compound was prepared in 44% yield (103 mg,
0.26 mmol) as a white solid from 8g (255 mg, 0.59 mmol) according
to the general procedure. Mp ¼ 128e129 ꢀC. 1H NMR (300 MHz,
6.26. 2-{4-[(1-(3-Fluoro-4-methylphenyl)-1H-1,2,3-triazol-4-yl)
methylthio]-2-methylphenoxy}acetic acid (2c)
DMSO-d6):
d
¼ 2.15 (s, 3H), 3.91 (s, 3H), 4.22 (s, 2H), 4.68 (s, 2H),
The title compound was prepared in 48% yield (84 mg,
0.22 mmol) as a white solid from 8c (190 mg, 0.46 mmol) according
to the general procedure. Mp ¼ 133e134 ꢀC. 1H NMR (200 MHz,
6.78 (d, J ¼ 8.46 Hz, 1H), 7.18e7.24 (m, 2H), 7.33e7.39 (m, 1H),
7.64e7.68 (m, 1H), 7.81 (dd, J ¼ 12.09, 2.59 Hz, 1H), 8.55 (s, 1H),
12.98 (s, 1H). 13C NMR (75 MHz, DMSO-d6):
d
¼ 15.82, 29.18, 56.26,
DMSO-d6):
d
¼ 2.15 (s, 3H), 2.29 (s, 3H), 4.22 (s, 2H), 4.67 (s, 2H),
64.70, 108.62 (d, J ¼ 22.92 Hz), 111.92, 114.36 (d, J ¼ 2.50 Hz), 116.18
(d, J ¼ 3.63 Hz), 121.30, 125.52, 126.93, 129.34, 129.50 (d,
J ¼ 9.07 Hz), 133.04, 144.90, 147.10 (d, J ¼ 10.38 Hz), 151.19 (d,
J ¼ 245.72 Hz), 155.21, 170.07. MS (ESI) m/z 402.1, [M ꢂ H]ꢂ, HRMS
calcd for C19H18FN3O4S [M]þ: 403.1002; found 403.0999.
6.78 (d, J ¼ 8.26 Hz, 1H), 7.21 (d, J ¼ 10.02 Hz, 2H), 7.49 (t,
J ¼ 8.14 Hz, 1H), 7.62e7.76 (m, 2H), 8.61 (s, 1H), 12.98 (s, 1H). 13C
NMR (75 MHz, DMSO-d6):
d
¼ 13.74 (d, J ¼ 2.95 Hz), 15.80, 29.13,
64.68, 106.97 (d, J ¼ 27.42 Hz), 111.91, 115.36 (d, J ¼ 3.47 Hz), 121.27,
124.58 (d, J ¼ 17.16 Hz), 125.44, 126.90, 129.35, 132.59 (d,
J ¼ 6.04 Hz), 133.04, 135.49 (d, J ¼ 10.39 Hz), 145.03, 155.20, 160.51
(d, J ¼ 244.34 Hz), 170.04. MS (ESI) m/z 386.1, [M ꢂ H]ꢂ, HRMS calcd
for C19H18FN3O3S [M]þ: 387.1053; found 387.1062.
6.31. 2-{2-Methyl-4-[(1-(4-trifluoromethoxyphenyl)-1H-1,2,3-
triazol-4-yl)methylthio]phenoxy}acetic acid (2h)
6.27. 2-{2-Methyl-4-[(1-(4-trifluoromethylphenyl)-1H-1,2,3-
triazol-4-yl)methylthio]phenoxy}acetic acid (2d)
The title compound was prepared in 53% yield (80 mg,
0.18 mmol) as a white solid from 8h (160 mg, 0.34 mmol) according
to the general procedure. Mp ¼ 149e150 ꢀC. 1H NMR (300 MHz,
The title compound was prepared in 66% yield (91 mg,
0.21 mmol) as a white solid from 8d (144 mg, 0.32 mmol) according
to the general procedure. Mp ¼ 235e236 ꢀC. 1H NMR (300 MHz,
DMSO-d6):
d
¼ 2.15 (s, 3H), 4.24 (s, 2H), 4.68 (s, 2H), 6.78 (d,
J ¼ 8.37 Hz, 1H), 7.17e7.24 (m, 2H), 7.59 (d, J ¼ 8.61 Hz, 2H),
7.97e8.02 (m, 2H), 8.64 (s, 1H), 12.96 (s, 1H). 13C NMR (75 MHz,
DMSO-d6):
d
¼ 2.11 (s, 3H), 4.18e4.20 (m, 4H), 6.67 (d, J ¼ 8.43 Hz,
DMSO-d6):
d
¼ 15.80, 29.14, 64.69, 111.89, 119.92 (q, J ¼ 256.98 Hz),
1H), 7.12e7.17 (m, 2H), 7.97 (d, J ¼ 8.59 Hz, 2H), 8.12 (d, J ¼ 8.58 Hz,
2H), 8.67 (s, 1H). 13C NMR (300 MHz, DMSO-d6):
¼ 16.00, 29.56,
67.42, 112.04, 120.25, 121.41, 123.71 (q, J ¼ 272.05 Hz), 123.59,
121.50, 121.83, 122.47, 125.39, 126.92, 129.45, 133.12, 135.33, 145.19,
147.69 (q, J ¼ 1.72 Hz), 155.24, 170.06. MS (ESI) m/z 438.1, [M ꢂ H]ꢂ,
HRMS calcd for C19H16F3N3O4S [M]þ: 439.0814; found 439.0823.
d

3054
C.C. Ciocoiu et al. / European Journal of Medicinal Chemistry 45 (2010) 3047e3055
6.32. 2-{4-[(1-(3-Chloro-4-trifluoromethoxyphenyl)-1H-1,2,3-
triazol-4-yl)methylthio]-2-methylphenoxy}acetic acid (2i)
GAL4-hPPARd and pSG5-GAL4-hPPARg. 10 mM of the compounds
and controls and DMSO (negative control) was added to the media
5 h after transfection. Transfected cells were maintained for 24 h
before lysis by reporter lysis buffer. Binding of the ligands to the
LBD of PPARs activates GAL4 binding to UAS, which in turn stim-
ulates the tk promoter to drive luciferase expression. Luciferase
activity was measured using a luminometer (TD-20/20 lumin-
ometer Turner Designs, Sunnyvale, CA) and normalized against
protein content. The following compounds were used as positive
The title compound was prepared in 47% yield (160 mg,
0.34 mmol) as a white solid from 8i (360 mg, 0.72 mmol) according
to the general procedure. Mp ¼ 157e158 ꢀC. 1H NMR (300 MHz,
DMSO-d6):
d
¼ 2.15 (s, 3H), 4.24 (s, 2H), 4.68 (s, 2H), 6.78 (d,
J ¼ 8.50 Hz, 1H), 7.18e7.25 (m, 2H), 7.81 (dd, J ¼ 8.98, 1.28 Hz, 1H),
8.02 (dd, J ¼ 8.97, 2.64 Hz, 1H), 8.29 (d, J ¼ 2.60 Hz, 1H), 8.74 (s, 1H),
12.98 (s, 1H). 13C NMR (75 MHz, DMSO-d6):
d
¼ 15.80, 29.11, 64.68,
controls:
acid (EHA), GW 501516 (1) and rosiglitazone (BRL) for PPAR
PPAR , and PPAR , respectively.
(2E,4E,8Z,11Z,14Z,17Z)-eicosa-2,4,8,11,14,17-hexaenoic
111.91, 119.91 (q, J ¼ 259.06 Hz), 120.19, 121.69, 122.15, 124.34 (dis-
torted q, J ¼ 1.06 Hz), 125.34, 126.91, 127.34, 129.41, 133.08, 135.95,
143.38 (q, J ¼ 1.76 Hz), 145.43, 155.23, 170.03. MS (ESI) m/z 472.3
[M ꢂ H]ꢂ, HRMS calcd for C19H15ClF3N3O4S [M]þ: 473.0424; found
473.0429.
a,
d
g
Acknowledgment
Fruitful discussions with professor Arild Chr. Rustan are grate-
fully acknowledged.
6.33. 2-{4-[(1-(3-Fluoro-4-trifluoromethoxyphenyl)-1H-1,2,3-
triazol-4-yl)methylthio]-2-methylphenoxy}acetic acid (2j)
References and notes
The title compound was prepared in 63% yield (76 mg,
0.17 mmol) as awhite solid from 8j (130 mg, 0.27 mmol) according to
the general procedure. Mp ¼ 140e141 ꢀC.1H NMR (300 MHz, DMSO-
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d6):
d
¼ 2.15 (s, 3H), 4.24 (s, 2H), 4.67 (s, 2H), 6.78 (d, J ¼ 8.42 Hz, 1H),
7.17e7.24 (m, 2H), 7.71e7.95 (m, 2H), 8.06e8.24 (m,1H), 8.71 (s,1H).
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d
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L-glutamine (2 MM), penicillin (50 U/mL), strep-
tomycin (50 G/mL), fungizone (2.5
m
m
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