Design, chemical synthesis, and biological evaluation of novel triazolyl analogues of taranabant (MK-0364), a cannabinoid-1 receptor inverse agonist

Article abstract of DOI:10.1016/j.tet.2008.09.057

Being obese has various health problems that are related to type 2 diabetes mellitus, cardiovascular disease, hypertension, hyperlipidemia, and fibrinolytic abnormalities. Merck's taranabant (MK-0364), a CB1R inverse agonist, is currently in Phase 3 clini

Full text of DOI:10.1016/j.tet.2008.09.057

Tetrahedron 64 (2008) 10802–10809
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Design, chemical synthesis, and biological evaluation of novel triazolyl analogues
of taranabant (MK-0364), a cannabinoid-1 receptor inverse agonist
,
Min-ah Kim a, Hoseop Yun b, HyunJung Kwak b, Jeongmin Kim a, Jinhwa Lee a
*
a Central Research Laboratories, Green Cross Corporation, Yongin, Gyeonggi-do 446-770, Republic of Korea
b Department of Chemistry, Ajou University, Suwon, Gyeonggi-do 443-749, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2008
Received in revised form
18 September 2008
Accepted 18 September 2008
Available online 26 September 2008
Being obese has various health problems that are related to type 2 diabetes mellitus, cardiovascular
disease, hypertension, hyperlipidemia, and fibrinolytic abnormalities. Merck’s taranabant (MK-0364),
a CB1R inverse agonist, is currently in Phase 3 clinical trials, and is being actively pursued by Merck
toward obesity market. Merck intends to file for FDA approval of taranabant in 2008. In order to increase
solubility and potency of taranabant, or even possibly improve safety, novel triazole analogues of tar-
anabant have been designed and synthesized. We introduced a pivotal asymmetric center via the Evans
chiral auxiliary methodology and set up 1,2,4-triazole via substitution of a-bromoketone. Subsequently,
Keywords:
diastereoselective reduction was accomplished to install adjacent essential asymmetric center. This
method allowed us to prepare readily sub-gram scale of the target compounds in a convenient way. The
synthesized analogues were subjected to biological evaluation involving cannabinoid CB1 receptor
binding affinity. While the parent taranabant bears highly potent binding affinity to cannabinoid CB1
receptor, neither of the analog structures improved CB1 receptor binding affinities.
Ó 2008 Elsevier Ltd. All rights reserved.
Taranabant
Anti-obesity
Evans asymmetric reaction
Hydride reduction
1. Introduction
enormous opportunity to make a significant, positive impact on the
health and lives of obese people through the discovery and de-
Obesity is a multi-factorial, chronic disorder that has reached
epidemic proportions in most industrial countries and is now
threatening to become a global epidemic.1 The number of deaths
per year attributable to obesity is about 30,000 in the UK and nearly
400,000 in the USA, where obesity is set to overtake smoking as the
main preventable cause of illness and premature death.2–4 The total
direct and indirect costs of obesity were estimated to be approxi-
mately V32,800 million per year in the EU and $99.2 billion per year
in the USA.4,5 Obesity poses a major health risk for serious diet-
related chronic disease, including type 2 diabetes, cardiovascular
disease, hypertension and stroke, and some of cancers.2 For these
reasons, the World Health Organization declared obesity a global
epidemic6,7 and obesity is now considered as disease that needs
pharmacological treatments.8–10
velopment of additional pharmacotherapy options. At last it was
discovered that modulation of endocannabinoid system by specif-
ically blocking the cannabinoid receptor 1 (CB1) in both the brain
and periphery can provide a novel target for the treatment of
obesity.10
Recently, among arsenal to fight obesity, rimonabant
(SR141716), a selective cannabinoid-1 receptor (CB1R) inverse ag-
onist discovered by Sanofi Aventis, is currently on the market in the
European Union and in several other countries. On the other hand,
Merck’s taranabant (MK-0364), another CB1R inverse agonist, is
currently in Phase 3 clinical trials and Merck intends to file for FDA
approval of taranabant in 2008. Additional CB1 antagonist in the
late-stage pipeline includes CP-945,598 (otenabant) developed by
Pfizer (Fig. 1).
At the present time, only two drugs are approved by US FDA for
the long-term treatment of obesity: the dual serotonin–norepi-
nephrine reuptake inhibitor sibutramine and the pancreatic lipase
inhibitor orlistat. While these agents show clinical efficacy, both of
them have some tolerability or safety concerns.11 There is an
With our efforts to discover and develop a new medicine for the
treatment of obesity,12 we have recently reported a convenient total
synthesis of taranabant (MK-0364), a novel cannabinoid-1 receptor
inverse agonist as an anti-obesity agent.13 Recently, a pharmaco-
phore model for the binding of a low energy conformation of tar-
anabant in the CB1 receptor has been reported.14 Similar to
rimonabant, taranabant interacted with a group of aromatic resi-
dues (Phe200, Trp279, Trp356, and Tyr275) of CB1R through the
two phenyl rings and with Phe170 and Leu387 through the CF3-py
* Corresponding author. Tel.: þ82 31 260 9892; fax: þ82 31 260 9870.
E-mail address: jinhwalee@greencross.com (J. Lee).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.057

M.-a. Kim et al. / Tetrahedron 64 (2008) 10802–10809
10803
amine 3. The amine 3 would then be produced from the corre-
sponding alcohol 4 through mesylation and the subsequent dis-
placement by azide. In turn, we envisioned that the alcohol 4 would
be generated by diastereoselective reduction of ketone 5 and sub-
sequent introduction of cyano group via Pd-catalyzed cyanation.
O
S
NH
Cl
O
N
N
N
N
O
Me
N
N
The requisite 5 would be best installed by displacement of a-bro-
N
Cl
moketone 6 with 1,2,4-triazole. In order to provide the requisite
bromide 6, an appropriate carboxylic acid 7 would be required as
shown in Scheme 1.
Cl
Cl
Cl
rimonabant (SR141716)
SLV319
2.2. Total synthesis of triazolyl analogue of taranabant 1
O
NH2
NH
At the outset, the synthesis of carboxylic acid 7 was achieved as
described in Scheme 2. We have previously reported the prepara-
tion of acid 7 using Evans asymmetric chemistry protocol as shown
in method A, Scheme 2.13 During the course of our anti-obesity
program, non-trivial quantity of carboxylic acid 7 was required as
an intermediate. While several approaches were considered, one
attractive method was revealed by literature search (method B,
Scheme 2). This approach was appealing since the chiral auxiliary
appears to be relatively cheap, and many starting materials as well
as products are reported to be in crystalline forms. According to the
reports, the enolates of pseudoephedrine amides undergo highly
diastereoselective reactions with various alkyl halides.15
N
N
O
N
O
N
N
NC
Cl
N
H
N
Cl
CF3
Cl
otenabant (CP-945,598)
taranabant (MK-0364)
Figure 1. Structures of CB1R antagonists or inverse agonists/rimonabant (SR141716),
SLV319, taranabant (MK-0364), and otenabant (CP-945,598).
Thus, 3-bromophenyl acetic acid
8 was coupled with
ring. The strong hydrogen bond formed between the NH of tar-
anabant and the hydroxyl of ser383 was reported to be essential to
the superior CB1R binding affinity of taranabant. We envisioned
that placement of additional polar functional group or heterocycle
onto methyl group adjacent to the amide of taranabant might po-
tentially form hydrogen bond with the hydroxyl of tyr275 residue.
Among many heterocycles, we were particularly interested in
a triazole or tetrazole as a potential hydrogen acceptor, since these
small heterocycles might be able to increase solubility23 and po-
tency of taranabant, or even possibly improve safety.24 Herein we
wish to describe an asymmetric synthesis and biological evaluation
of novel triazole analogues of taranabant (MK-0364) featuring
Evans chiral auxiliary methodology to install a pivotal benzylic
stereogenic center (Fig. 2).
(þ)-pseudoephedrine under conditions of HOBt, EDCI, and NMM in
DMF to produce the corresponding tertiary amide 12 as a white
solid in 90% yield. Next, alkylation of pseudoephedrine amide 12
was accomplished by dianion formation with LiHMDS in THF in the
presence of 6 equiv of lithium chloride, followed by the addition of
1-(bromomethyl)-4-chlorobenzene at ꢀ10 ꢁC. As reported, the use
of lithium chloride accelerates alkylation reaction and is critical for
the complete conversion to 13. Next, the chiral auxiliary of 13 was
cleaved by standard conditions to produce the corresponding acid 7
in 70% yield.
With the requisite carboxylic acid 7 in hand, focus shifted to the
efficient preparation of the chiral alcohol 15 (Scheme 3). The first
approach toward 15 involves epoxide ring opening reaction using
1,2,4-triazole in the presence of a suitable base.16 Despite rather
extensive experimentation, we were unable to effect the requisite
coupling reaction in a satisfactory manner. We then examined the
feasibility of reacting 1-[(trimethylsilyl)methyl]-1,2,4-triazole (17)
with aldehyde 16 in the presence of tetrabutylammonium fluoride
(TBAF) to give triazolyl alcohol 15.17 The fluoride was anticipated to
attack the silyl group to generate triazolylmethyl anion that would
then react with aldehyde 16 to lead to alcohol 15. Under these
conditions, starting material 16 was invariably recovered from all
our experiments. This is probably due to a tendency to form enolate
anion by proton transfer to triazolylmethyl anion.17
2. Results and discussion
2.1. Synthetic plan
Our synthetic strategy for N-((2R,3S)-4-(4-chlorophenyl)-3-(3-
cyanophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-yl)-2-methyl-2-(5-
(trifluoromethyl)pyridin-2-yloxy)propanamide (1) is outlined in
Scheme 1. We reasoned that the target compound 1 can be
obtained by typical amide bond forming reaction of acid 2 and
At this stage, we were intrigued by the attractive possibility of
converting acid 7 into triazolyl ketone 5 via a-bromoketone 6 in
order to adopt diastereoselective reduction using bulky reducing
agent such as L-Selectride.13,18 Thus, acid 7 was converted into an
activated acyl chloride. The activated group was displaced with
diazomethane or commercially available trimethylsilyldiazo-
Tyr275
N
N
N
Trp279
O
methane (TMSCHN2). Subsequently,
formed into an -bromoketone
a
6
-diazoketone 18 was trans-
by exposure to aqueous
A
B
O
N
C
Phe170
Leu387
NC
Cl
N
H
a
hydrobromic acid uneventfully.19 Displacement reaction of bro-
mide 6 with a commercially available 1,2,4-triazole, sodium de-
rivative in DMF at ambient temperature proceeded smoothly to
yield the requisite intermediate 5. Systematic optimization of the
reaction sequence allowed us to avoid any tedious purification
steps of the corresponding intermediates, thereby providing 5 in
48% yield for four steps from acid 7 (Scheme 4).
CF3
Phe200
Leu360
Ser383
Trp356
1, triazole analog of taranabant (MK-0364)
The stage was set for the key diastereoselective reduction to
install adjacent essential asymmetric center for taranabant
Figure 2. Triazole analog of taranabant (MK-0364) and its potential receptor–ligand
interaction.

10804
M.-a. Kim et al. / Tetrahedron 64 (2008) 10802–10809
N
N
N
N
N
N
O
O
N
HO
NC
Cl
NH2
NC
Cl
OH
1
CF3
2
4
3
O
O
O
N
N
Br
N
Br
Br
Cl
OH
Br
Cl
Cl
6
7
5
Scheme 1. Retrosynthetic analysis of target compound, a taranabant (MK-0364) analog.
Method A13
O
O
O
b
a
Br
N
O
Br
OH
8
9
Ph
O
O
O
Br
OH
c
Br
Cl
N
O
Ph
Cl
7
10
Method B15
O
O
N
d
H
Br
N
OH
11
HCl
Br
OH
OH
8
12
O
O
f
Br
Cl
N
e
Br
Cl
OH
OH
13
7
Scheme 2. Preparation of acid 4. (a) (i) Pivaloyl chloride, Et3N, THF; (ii) n-BuLi, (S)-4-benzyloxazolidin-2-one, THF. (b) 1-(Bromomethyl)-4-chlorobenzene, NaHMDS, THF, ꢀ78 ꢁC. (c)
LiOOH, THF, H2O. (d) HOBt, EDCI, NMM, DMF. (e) 1-(Bromomethyl)-4-chlorobenzene, LiCl, LHMDS, THF, ꢀ78 ꢁC. (f) H2SO4, dioxane.
backbone. We previously demonstrated the effectiveness of this
process in the synthesis of taranabant.13 We were delighted to
discover that treatment of 5 with L-Selectride provided the desired
diastereomer in 99% yield (de >99:<1). Selectivity was measured
on GilsonÔ reverse-phase preparative HPLC. The GilsonÔ HPLC
chart of diastereoselective reduction of ketone 5 is shown in Fig. 3.
The specific optical rotation of triazolyl alcohol 15 thus obtained
was þ1.12.
Next, the cyano alcohol 4 was converted to cyano azide 20
through mesylation followed by displacement with azide. Trans-
formation of the azide 20 to amine 3 was conducted successfully
utilizing the Staudinger conditions (PPh3 in mildly heated toluene/
water).20 Purification was performed efficiently by GilsonÔ re-
verse-phase prep HPLC using CH3CN/water system containing 0.1%
TFA. Subsequently, the desired amine as a TFA salt form was treated
with saturated aqueous NaHCO3 solution to give rise to the free
amine form of structure 3. The specific optical rotation of 3 was
estimated to be þ0.41.
As described in Scheme 5, the cyano group was next introduced
to bromo alcohol 15 via a Pd-catalyzed cyanation. Initial experi-
ments to induce the cyanation of bromide 15 to nitrile 4 under the
conditions of using Zn(CN)2 and in situ generated Pd [P(o-tol)3]4 as
a catalyst in DMF were unsuccessful. After rather extensive exper-
imentation, we found out that the reaction conditions of using
Zn(CN)2 and Pd(PPh3)4 under microwave irradiation provided the
desired nitrile 4 in approximately 50% yield.
Finally, coupling of amine 3 with acid 2 under conditions of
NMM, EDC, and HOBt in DMF, followed by isolation by GilsonÔ
preparative HPLC produced triazolyl analog of taranabant 1 in 75%
yield. The specific optical rotation of 1 was measured to be þ0.21.17
The relative and absolute stereochemistries of the desired target
compound 1 were further secured through single-crystal X-ray

M.-a. Kim et al. / Tetrahedron 64 (2008) 10802–10809
10805
N
N
HN
N
N
O
N
Br
Cl
O
Br
Cl
OH
Br
Cl
OH
14
7
15
F-
O
O
N
Br
H
Br
Cl
OH
N
15
TMS
N
17
Cl
16
7
Scheme 3.
O
O
O
N2
Br
Br
a
Br
OH
b
Br
Cl
Cl
Cl
18
7
6
N
O
N
N
N
N
N
d
c
Br
Cl
Br
Cl
OH
5
15
Scheme 4. Preparation of triazolyl alcohol 15. (a) (i) Oxalyl chloride, cat. DMF, DCM, 0 ꢁC; (ii) TMSCHN2, DCM, 0 ꢁC. (b) HBr, ether, 0 ꢁC. (c) 1,2,4-Triazole, sodium derivative, DMF, rt.
(d) LiBH(sec-Bu)3, THF, ꢀ78 ꢁC.
analysis as illustrated in Figure 4. Crystallographic data for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
CCDC694621.
2.3. Another triazolyl analog of taranabant (MK-0364) 23
At the outset, we chose to evaluate the phenyl substituents on
triazolyl analogue of taranabant 1.
N
N
O
N
N
N
N
N
N
N
d
Br
Cl
+
Br
Cl
OH
Br
Cl
OH
5
15
15'
Figure 3. GilsonÔ reverse-phase preparative HPLC chart for diastereoselective reduction of 5.

10806
M.-a. Kim et al. / Tetrahedron 64 (2008) 10802–10809
N
N
N
N
N
N
N
N
N
a
b
c
Br
Cl
OH
NC
Cl
OH
NC
N3
Cl
N
15
4
20
N
N
N
N
N
O
O
d
O
N
O
N
+
HO
NC
Cl
NH2
NC
Cl
N
H
CF3
CF3
1
2
3
Scheme 5. Construction of taranabant analog 1 from triazolyl alcohol 4. (a) Zn(CN)2, Pd(PPh3)4, DMF. (b) (i) MsCl, TEA, ethyl acetate, 0 ꢁC; (ii) NaN3, DMF, 120 ꢁC, 2 h. (c) PPh3,
toluene/H2O. (d) EDCI, NMM, HOBt, DMF, rt.
Thus, construction of an analog 23 began with bromo alcohol 15.
The bromo alcohol 15 was converted to bromo azide 21 through
mesylation followed by displacement with azide in a similar way
previously described toward taranabant. The Staudinger reaction,
followed by purification by GilsonÔ reverse-phase preparative
HPLC using CH3CN/water containing 0.1% TFA was adopted suc-
cessfully for transformation of the azide 21 to amine 22 after
treatment with aqueous NaHCO3 solution. Finally, coupling of
amine 22 with acid 2 under conditions of NMM, EDCI, and HOBt in
DMF, followed by isolation by GilsonÔ preparative HPLC readily
produced analog 23 (Scheme 6).
affinity to cannabinoid CB1 receptor, neither of the analog struc-
tures results in better CB1 receptor binding affinities (CB1R
IC50¼123 nM for 1 vs CB1R IC50¼791 nM for 23 via in-house as-
say).21,22 Based on this in vitro binding affinity data, it is apparent
that the nitrogen atom in the triazolyl moiety is not contributing
positively to the affinity of triazolyl analogs of taranabant. It ap-
pears that 1,2,4-trizole group at the particular position is not likely
to act as an expected hydrogen bond acceptor, but appears to
provide only unfavorable steric bulkiness for the domain.
3. Summary
We have achieved a convenient total synthesis of triazolyl an-
alogue of taranabant (MK-0364) 1 by employing Evans asymmetry
reaction or Myers’ pseudoephedrine technology. We introduced
2.4. Biological evaluation
Triazolyl analog of taranabant (MK-0364) 1 and the structurally
similar analog 23 were screened via in vitro rat cannabinoid CB-1
binding assay. The synthesized analogues were subjected to bio-
logical evaluation involving cannabinoid CB1 receptor binding
affinity. While the parent taranabant bears highly potent binding
a triazolyl group via substitution of a-bromoketone 6 with 1,2,4-
triazole and accomplished subsequent diastereoselective reduction
to install adjacent essential asymmetric center for taranabant an-
alog 1. Using this synthetic route we efficiently prepared a struc-
turally similar analog 23 as well. The synthesized analogues were
subjected to biological evaluation involving cannabinoid CB1 re-
ceptor binding affinity. While the parent taranabant (MK-0364)
bears highly potent binding affinity to cannabinoid CB1 receptor, it
was discovered that either 1 or 23 did not improve rat CB1 receptor
binding affinities.
4. Experimental
4.1. General
All references to ether are to diethyl ether; brine refers to
a saturated aqueous solution of NaCl. Unless otherwise indicated,
all temperatures are expressed in degrees centigrade. All reactions
are conducted under an inert atmosphere at room temperature
unless otherwise noted, and all solvents are of the highest available
purity unless otherwise indicated. Microwave reaction was con-
ducted with a Biotage microwave reactor. 1H NMR spectra were
recorded on either a Jeol ECX-400 or a Bruker DPX-300 spectrom-
eter. Chemical shifts were expressed in parts per million (ppm,
d units). Coupling constants are in units of hertz (Hz). Splitting
patterns describe apparent multiplicities and are designated as s
(singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m
(multiplet), and br (broad). Mass spectra were obtained with either
Micromass, Quattro LC Triple Quadruple Tandem Mass Spec-
tometer, ESI, or Agilent, 1100LC/MSD, ESI. Fast atom bombardment
(FAB) method of Jeol JMS AX505WA spectrometer was adopted for
Figure 4. X-ray structure of compound 1.

M.-a. Kim et al. / Tetrahedron 64 (2008) 10802–10809
10807
N
N
N
N
N
N
a
b
Br
Cl
N3
Br
Cl
OH
15
21
N
N
N
N
N
O
N
O
c
O
N
O
N
HO
Br
Cl
NH2
Br
Cl
N
H
CF3
CF3
2
23
22
Scheme 6. Preparation of an analogue 23. (a) (i) MsCl, Et3N; (ii) NaN3, DMF, 120 ꢁC; (b) (i) PPh3, toluene/H2O; (ii) 0.1% TFA on Gilson prep HPLC; (iii) aq NaHCO3; (c) NMM, EDCI,
HOBt, DMF.
HRMS. Optical rotation data were obtained on a JASCO P-1030 au-
tomatic polarimeter. Melting point was measured on a BUCHI
Melting Point B-540. For preparative HPLC, ca. 100 mg of a product
was injected in 1 mL of DMSO onto a SunFireÔ Prep C18 OBD 5 mm
19_100 mm Column with a 10 min gradient from 10% CH3CN to 90%
CH3CN in H2O. Flash chromatography was carried out using Merck
silica gel 60 (230–400 mesh). Most of the reactions were monitored
by thin layer chromatography on 0.25 mm E. Merck silica gel plates
(60 F254), visualized with UV light using a 5% ethanolic phospho-
molybdic acid or p-anisaldehyde solution.
7.37–7.35 (m, 1H), 7.15 (d, 2H, J¼10.8 Hz), 6.84 (d, 2H, J¼8.4 Hz),
4.54–4.53 (m, 1H), 3.81–3.78 (m, 1H), 3.40–3.30 (m, 1H), 2.91–2.82
(m, 1H), 2.59 (s, 3H), 1.02 (d, 3H, J¼6.8 Hz); 13C NMR (100 MHz,
CDCl3)
d 173.9, 142.3, 141.2, 138.0, 132.4, 131.2, 130.9,130.8, 130.7,
129.1, 128.6, 128.5, 128.4, 127.9, 126.8, 126.7, 126.4, 123.0, 76.3, 58.0,
51.8, 40.5, 27.9, 14.2; LC–MS: m/e 486 (MþþH); HRMS (FAB) calcd
for C25H26O2NBrCl (Mþþ1) 486.0757, found 486.0835; mp 53.7 ꢁC.
4.1.3. (S)-2-(3-Bromophenyl)-3-(4-chlorophenyl)propanoic acid 7
Acetamide 13 (311 mg, 0.64 mmol) and sulfuric acid (18 N,
1.5 mL) in dioxane (3 mL) were heated at reflux for 2 h and then
cooled to 0 ꢁC. The pH of the mixturewas adjusted to pH ꢂ10 byslow
addition of 50% (w/w) aqueous sodium hydroxide solution, and the
resulting mixture was partitioned between water (10 mL) and
dichloromethane (20 mL). The aqueous layer was separated
andextractedwith dichloromethane(20 mL). Theaqueouslayerwas
acidified to pH ꢃ2 by the slow addition of 6 N aqueous sulfuric acid
solution and extracted with dichloromethane (3ꢄ20 mL). The
resulting organic layer was dried over sodium sulfate and concen-
4.1.1. 2-(3-Bromophenyl)-N-((1S,2S)-1-hydroxy-1-phenylpropan-
2-yl)-N-methylacetamide 12
To a solution of 3-bromopropionic acid 8 (2.06 g, 9.58 mmol) in
N,N-dimethylformamide (20 mL) were added (S,S)-(þ)-pseudoe-
phedrine 11 (2.3 g, 11.5 mmol), EDCI (2.75 g, 14.4 mmol), HOBt$H2O
(1.56 g, 11.5 mmol), and NMM (6.3 mL, 58.0 mmol). The mixture
was stirred at room temperature overnight. The product was di-
luted with ethyl acetate (20 mL) and washed with aqueous 1 N HCl
(10 mL), sodium bicarbonate (15 mL), and brine. The combined
organic extracts were dried over anhydrous magnesium sulfate,
filtered, and concentrated to dryness. The residue was purified on
GilsonÔ HPLC system to yield acetamide 12 (3.13 g, 8.64 mmol,
trated to afford acid 7 (70%).1H NMR (CDCl3, 500 MHz):
7.38 (d, 1H), 7.20–7.12 (m, 4H), 7.01 (m, 2H), 3.79–3.72 (m, 1H),
d 7.47 (s,1H),
26.3
3.36–3.29 (m, 1H), 2.99–2.92 (m, 1H); [
a]
þ74.7 (c 3.02, CHCl3).
90%). 1H NMR (400 MHz, CDCl3)
d
7.37–7.23 (m, 7H), 7.17–7.14 (m,
4.1.4. (S)-3-(3-Bromophenyl)-4-(4-chlorophenyl)-1-(1H-1,2,4-
2H), 4.55–4.51 (m, 2H), 4.18 (br, 1H), 3.79–3.70 (m, 1H), 3.61 (s, 2H),
triazol-1-yl)butan-2-one 5
3.00 (m, 1H), 2.80 (m, 3H), 1.07–1.06 (d, 3H, J¼6.4 Hz); 13C NMR
To a solution of acid 7 (3.46 g, 10.2 mmol) in dichloro-
(100 MHz, CDCl3)
d
172.5, 142.3, 137.2, 132.3, 132.2, 130.3, 130.0,
methane (30 mL) at 0 ꢁC were added N,N-dimethylformamide
(one drop) and oxalyl chloride (1.8 mL, 20.4 mmol) dropwise.
The reaction mixture was allowed to warm to room temperature
for 2 h and concentrated to dryness to give the crude acyl
chloride, which was used without further purification. To a so-
lution of diazomethane (2 M solution in diethyl ether, 10.2 mL,
20.4 mmol) in dichloromethane (20 mL) was added acyl chloride
in dichloromethane (4 mL) at 0 ꢁC. After stirring at room tem-
perature for 2 h, the reaction solution was concentrated in
129.0, 128.5, 127.8, 126.7, 122.8, 76.4, 58.3, 41.3, 27.5, 14.6; LC–MS:
m/e 362 (MþþH); HRMS (FAB) calcd for C18H21O2NBr (Mþþ1)
362.0677, found 362.0756.
4.1.2. (S)-2-(3-Bromophenyl)-3-(4-chlorophenyl)-N-((1S,2S)-1-
hydroxy-1-phenylpropan-2-yl)-N-methylpropanamide 13
Lithium chloride (541 mg, 12.8 mmol) is transferred to a flask
fitted with rubber septum containing a vacuum needle, and was
evacuated and immersed in an oil bath at 150 ꢁC. After heating for
15 h at 150 ꢁC, the flask is allowed to cool to 23 ꢁC and was flushed
with nitrogen. The reaction flask was charged with tetrahydrofuran
(2 mL) and cooled to ꢀ15 ꢁC. After 15 min, to the reaction flask was
slowly added LHMDS (7.4 mL, 7.44 mmol) and held at that tem-
perature for 1 h, then added 4-chlorobenzyl bromide. After 3 h, the
reaction solution was quenched by saturated aqueous ammonium
chloride solution. The combined organic extracts were dried over
anhydrous magnesium sulfate, filtered, and concentrated to dry-
ness. Purification by GilsonÔ HPLC system (elution with H2O and
acetonitrile) gave 869 mg of 13 (84%). 1H NMR (400 MHz, CDCl3)
vacuo. 1H NMR (400 MHz, DMSO-d6)
d 7.50 (m, 1H), 7.41–7.39
(m, 1H), 7.29–7.22 (m, 4H), 7.16–7.14 (m, 2H), 6.08 (br, 1H), 4.04–
3.99 (m, 1H), 3.29–3.24 (dd, 1H, J¼8.4, 14.0 Hz), 2.94–2.89 (dd,
1H, J¼7.4, 14.0 Hz).
The obtained diazoketone 18 (6.07 g,16.4 mmol) in diethyl ether
(70 mL) was treated with 48% aqueous HBr (2.23 mL) and was
stirred for 30 min at 0 ꢁC. The reaction mixture was diluted with
diethyl ether (30 mL) and then washed with saturated sodium bi-
carbonate and brine. The organic layer was dried over anhydrous
sodium sulfate, filtered, and concentrated under reduced pressure.
1H NMR (400 MHz, CDCl3)
7.18 (m, 3H), 7.12–7.10 (m, 1H), 6.99–6.97 (m, 2H), 4.24 (t, 1H,
d 7.44–7.42 (m, 1H), 7.36 (m, 1H), 7.23–
d
8.05 (s, 1H), 7.99 (s, 1H), 7.57–7.55 (m, 1H), 7.45–7.41 (m, 2H),

10808
M.-a. Kim et al. / Tetrahedron 64 (2008) 10802–10809
J¼7.6 Hz), 3.79 (d, 1H, J¼12.4 Hz), 3.70 (d, 1H, J¼12.8 Hz), 3.39–3.34
(dd, 1H, J¼7.6, 14.0 Hz), 2.94–2.89 (dd, 1H, J¼7.2, 14.0 Hz).
afford methanesulfonate, which was used without further purifi-
cation. To a solution of methanesulfonate in DMF (12 mL) was
added sodium azide (1.04 g, 16 mmol). After stirring at 120 ꢁC for
2 h, the reaction mixture was poured into water (10 mL) and the
product was extracted with ether (30 mL). The combined organic
extracts were washed with water, dried over anhydrous magne-
sium sulfate, filtered, and concentrated to dryness. The residue was
purified using GilsonÔ HPLC system to give the desired products 20
To the resulting yellow solution with N,N-dimethylformamide
(125 mL) was added 1,2,4-triazole sodium derivatives (2.23 g,
24.5 mmol) and stirred for 1 h at room temperature. The reaction
mixture was quenched with water, extracted with ethyl acetate,
and washed with brine. The organic layers were dried over mag-
nesium sulfate, filtrated, and evaporated to dryness to give a resi-
due that was purified by GilsonÔ HPLC system (48% in four steps).
as colorless oil. 1H NMR (400 MHz, CDCl3)
d 8.05 (s, 1H), 7.99 (s, 1H),
1H NMR (400 MHz, CDCl3):
d
7.96 (s, 1H), 7.86 (s, 1H), 7.47–7.45 (m,
7.57–7.55 (m, 1H), 7.45–7.41 (m, 2H), 7.37–7.35 (m, 1H), 7.15 (d, 2H,
J¼10.8 Hz), 6.84 (d, 2H, J¼8.4 Hz), 4.21 (td, 1H, J¼3.6, 8.8 Hz), 4.14
(dd, 1H, J¼3.2, 14.0 Hz), 3.96 (dd, 1H, J¼8.8, 14.0 Hz), 3.36 (dd, 1H,
J¼3.6, 13.2 Hz), 3.00 (m, 1H), 2.90 (m, 1H); 13C NMR (100 MHz,
1H), 7.30–7.29 (m, 1H), 7.24–7.20 (m, 3H), 7.02–7.00 (m, 1H), 6.96–
6.94 (m, 2H), 4.86 (d, 2H, J¼4.0 Hz), 3.91 (t, 1H, J¼7.6 Hz), 3.79 (dd,
1H, J¼7.4, 13.8 Hz), 3.70 (dd, 1H, J¼7.4, 13.8 Hz); 13C NMR (100 MHz,
CDCl3)
d
200.7, 152.4, 144.6, 138.5, 136.7, 132.8, 131.7, 131.3, 130.5,
CDCl3) d 152.9, 144.4, 140.9, 136.3, 132.7, 132.0, 130.4, 130.1, 128.9,
128.9, 127.1, 123.6, 57.8, 57.2, 38.0; LC–MS: m/e 404 (MþþH); HRMS
65.7, 52.0, 50.3, 38.2; LC–MS: m/e 378 (MþþH); HRMS (FAB) calcd
(FAB) calcd for C18H16ON3BrCl (Mþþ1) 404.0087, found 404.0165.
for C19H17N7Cl (Mþþ1) 378.1156, found 378.1234.
To the toluene (5 mL) solution of azide 20 from the previous step
was added water (1 mL) and the batch was heated to 75 ꢁC. A so-
lution of PPh3 (1.2 g, 4.68 mmol) in toluene (1 mL) was added to the
batch (slowly in order to control nitrogen evolution). The batch was
aged for an additional 17 h and then cooled to ambient tempera-
ture. Purification by GilsonÔ HPLC system (elution with 0.1% TFA of
H2O and acetonitrile) gave amine of the TFA salt form.
4.1.5. (2S,3S)-3-(3-Bromophenyl)-4-(4-chlorophenyl)-1-(1H-1,2,4-
triazol-1-yl)butan-2-ol 15
L-Selectride (1 M solution in THF, 15.4 mL) was added to a solu-
tion of ketone 5 (4.14 g, 10.2 mmol) in anhydrous THF (50 mL) un-
der N2 at ꢀ78 ꢁC. The mixture was stirred at ꢀ78 ꢁC for 1.5 h and
warmed to ꢀ40 ꢁC. The aqueous NaOH (3 N, 15.4 mL) and 30% H2O2
(7.7 mL) were added slowly and stirred vigorously for 2 h at 0 ꢁC.
The reaction mixture was diluted with ethyl acetate and the organic
phase was separated. The organic phase was washed with water,
saturated Na2S2O3, and brine, and dried over MgSO4. After evapo-
ration, the residue was purified using GilsonÔ HPLC system to give
the desired products 15 (4.10 g, 99%) as colorless oil. 1H NMR
The obtained amine of the TFA salt form was neutralized with
NaHCO3, dried over anhydrous magnesium sulfate, filtered, and
concentrated to dryness to yield free amine 3 (482 mg, 1.37 mmol,
44% for three steps). 1H NMR (DMSO-d6, 500 MHz):
d 8.39 (s, 1H),
7.93 (s, 1H), 7.67 (s, 1H), 7.61 (d, 1H), 7.65–7.39 (m, 2H), 7.18 (d, 2H),
7.01 (d, 2H), 4.08–4.02 (m, 1H), 3.88–3.82 (m, 1H), 3.38–3.24 (m,
(CDCl3, 500 MHz):
d
7.93 (s, 1H), 7.78 (s, 1H), 7.52 (m, 1H), 7.43–7.40
2H), 2.92 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 152.5, 144.2, 142.6,
(m, 1H), 7.24–7.18 (m, 4H), 7.07–7.04 (m, 2H), 4.15–4.10 (m, 2H),
3.81–3.77 (m, 1H), 3.71 (d, 1H, J¼4.0 Hz), 3.25 (dd, 1H, J¼8.0,
13.5 Hz), 2.97 (dd, 1H, J¼7.5, 13.5 Hz), 2.88–2.85 (m, 1H); 13C NMR
137.3, 133.1, 132.3, 132.0, 131.1, 130.4, 129.7, 128.7, 118.7, 113.0, 55.3,
54.6, 52.4, 37.9; LC–MS: m/e 352 (MþþH); HRMS (FAB) calcd for
C19H19N5Cl (Mþþ1) 352.1251, found 352.1329; [
a
]
þ0.41 (c 0.97,
26.9
(100 MHz, CDCl3)
d
151.7, 143.9, 142.4, 137.9, 132.4, 132.3, 132.2,
CHCl3).
130.7, 130.3, 128.8, 128.1, 122.9, 70.4, 55.2, 51.1, 38.7; LC–MS: m/e
406 (MþþH); HRMS (FAB) calcd for C18H18ON3BrCl (Mþþ1)
4.1.8. N-((2R,3S)-4-(4-Chlorophenyl)-3-(3-cyanophenyl)-1-(1H-
1,2,4-triazol-1-yl)butan-2-yl)-2-methyl-2-(5-
(trifluoromethyl)pyridin-2-yloxy)propanamide 1
27.2
406.0244, found 406.0322; mp 61.1 ꢁC; [
a]
þ1.12 (c 0.73, CHCl3).
4.1.6. 3-((2S,3S)-1-(4-Chlorophenyl)-3-hydroxy-4-(1H-1,2,4-
triazol-1-yl)butan-2-yl)benzonitrile 4
A dried heavy-walled Pyrex tube was charged with bromide
alcohol 15 (243.6 mg, 0.6 mmol), Zn(CN)2 (70.5 mg, 0.6 mmol), and
To a solution of 2-methyl-2-(5-(trifluoromethyl)pyridin-2-
yloxy)-propanoic acid (364 mg, 1.46 mmol) in acetonitrile (5 mL)
were added amine (428 mg, 1.22 mmol), cyanuric chloride (135 mg,
0.73 mmol), and then EDC (253 mg, 1.32 mmol). The mixture was
stirred at room temperature overnight. The product was extracted
with dichloromethane (10 mL). The combined organic extracts
were washed with water, dried over anhydrous magnesium sulfate,
filtered, and concentrated to dryness. The residue was purified on
GilsonÔ HPLC system to yield taranabant-triazole analogue 1
Pd(PPh3)4 (41.4 mg, 24 mmol) in DMF (3 mL). The reaction mixture
was exposed to microwave irradiation (180 ꢁC) for 5 min. The re-
action tube was allowed to reach room temperature before the
reaction mixture was diluted in acetonitrile and filtered with sy-
ringe filter. Purification by GilsonÔ HPLC system (elution with H2O
and acetonitrile) gave 65.7 mg of
4
(47%). 1H NMR (CDCl3,
(560 mg, 0.77 mmol, 63%). 1H NMR (CDCl3, 400 MHz):
d 8.24 (m,
500 MHz): 7.92 (s, 1H), 7.79 (s, 1H), 7.70 (s, 1H), 7.58–7.54 (m, 2H),
d
1H), 7.87 (s, 1H), 7.83 (dd, 1H, J¼8.8, 2.4 Hz), 7.54 (s, 1H), 7.51 (d, 1H,
J¼7.6 Hz), 7.42 (d, 1H, J¼9.2 Hz), 7.33 (t, 1H, J¼8.0 Hz), 7.24 (s, 1H),
7.05–7.02 (m, 3H), 6.96 (d, 1H, J¼8.8 Hz), 6.53 (d, 2H, J¼8.4 Hz),
4.80–4.73 (m, 1H), 3.97 (d, 2H, J¼3.6 Hz), 3.15 (d, 1H, J¼10.4 Hz),
2.71–2.61 (m, 2H), 1.76 (d, 6H, J¼9.6 Hz); 13C NMR (CDCl3,
7.42 (t, 1H, J¼8.0 Hz), 7.21–7.19 (m, 2H), 7.03 (d, 2H, J¼8.0 Hz), 4.18–
4.16 (m,1H), 4.12–4.09 (m,1H), 3.96 (br,1H), 3.73–3.69 (m,1H), 3.27
(dd, 1H, J¼7.0, 12.5 Hz), 3.01–2.92 (m, 2H); 13C NMR (100 MHz,
CDCl3)
d 151.7, 143.8, 141.6, 137.5, 134.1, 133.0, 132.5, 131.1, 130.6,
129.4, 128.8, 118.9, 112.8, 70.3, 55.2, 50.9, 38.8; LC–MS: m/e 353
500 MHz): d 174.54, 164.13, 152.67, 144.60, 144.46, 144.42, 141.85,
(MþþH); HRMS (FAB) calcd for C19H18ON4Cl (Mþþ1) 353.1091,
136.82, 136.44, 136.42, 133.03, 132.48, 131.60, 131.52, 130.14, 129.96,
128.69, 121.37, 121.11, 118.36, 113.47, 112.99, 81.96, 52.28, 50.30,
50.08, 39.09, 25.62, 25.22; LC–MS: m/e 583 (MþþH); HRMS (FAB)
26.6
found 353.1169; mp 70.4 ꢁC; [
a
]
þ8.63 (c 0.60, CHCl3).
4.1.7. 3-((2S,3R)-3-Amino-1-(4-chlorophenyl)-4-(1H-1,2,4-triazol-
1-yl)butan-2-yl)benzonitrile 3
calcd for C29H27O2N6F3Cl (Mþþ1) 583.1758, found 583.1836; mp
27.2
184.8 ꢁC; [
a
]
þ0.21 (c 3.115, CHCl3).
To a solution of alcohol (1.1 g, 3.1 mmol) in ethyl acetate (15 mL)
at 0 ꢁC were added triethylamine (0.52 mL, 3.74 mmol) and
methanesulfonyl chloride (0.36 mL, 4.68 mmol). After stirring at
0 ꢁC for 1.5 h, the reaction was quenched by addition of saturated
aqueous sodium bicarbonate (2 mL). After stirring at room tem-
perature for 1 h, the organic layer was separated, dried over
anhydrous sodium sulfate, filtered, and concentrated to dryness to
4.2. Pharmacological test: in vitro activity analysis
The compounds of the present invention were analyzed for their
binding characteristics for CB1 and CB2 and the pharmacological
activity thereof in accordance with the method disclosed in Ref. 21.
The analysis was performed using [3H]CP-55940, which is

M.-a. Kim et al. / Tetrahedron 64 (2008) 10802–10809
10809
a selectively radioactivity-labeled 5-(1,1-dimethyheptyl)-2[5-hy-
References and notes
droxy-2-(3-hydroxypropyl)-cyclohexyl]-phenol, purchased from
PerkinElmer Life Sciences, Inc. (Boston, Massachusetts, USA),
through a rat CB-1 receptor binding protocol as follows.
1. Klein, S.; Wadden, T.; Sugerman, H. J. Gastroenterology 2002, 123, 882–932.
2. Patel, P. N.; Pathak, R. Am. J. Health Syst. Pharm. 2007, 64, 481–489.
3. Bray, G. A. J. Med. Chem. 2006, 49, 4001–4007.
The tissue obtained from the brain of SD rats was homogenized
with a Dounce homogenate system in TME (50 mM Tris, 3 mM
MgCl2, and 1 mM EDTA, pH 7.4) at 4 ꢁC, and the homogenate was
centrifuged at 48,000 g for 30 min at 4 ꢁC. The pellet was resus-
pended in 5 mL of TME and the suspension was divided into ali-
quots and stored at ꢀ70 ꢁC until its use in the following assay.
4. Haslam, D. W.; James, W. P. T. Lancet 2005, 366, 1197–1209.
5. Fry, J.; Finley, W. Proc. Nutr. Soc. 2005, 64, 359–362.
6. Report of a WHO Consultation on Obesity: Obesity-Preventing and Managing
a Global Epidemic; World Health Organization: Geneva, 1997.
7. Antel, J.; Gregory, P. C.; Nordheim, U. J. Med. Chem. 2006, 49, 4008–4016.
8. Aronne, L. J.; Thornton-Jones, Z. D. Clin. Pharmacol. Ther. 2007, 81,
748–752.
9. Padwal, R. S.; Majumdar, S. R. Lancet 2007, 369, 71–77.
10. Bishop, M. J. J. Med. Chem. 2006, 49, 3999–4000.
The test compound (2 mL) was diluted in dimethylsulfoxide and
11. Li, Z.; Maglione, M.; Tu, W.; Mojica, W.; Aterburn, D.; Shugarman, L.; Hilton, L.;
Suttorp, M.; Solomon, V.; Shekelee, P. G.; Morton, S. C. Ann. Intern. Med. 2005,
142, 532–546.
12. Kang, S. Y.; Lee, S.-H.; Seo, H. J.; Jung, M. E.; Ahn, K.; Kim, J.; Lee, J. Bioorg. Med.
Chem. Lett. 2008, 18, 2385–2389.
13. Kim, M.-a.; Kim, J. Y.; Song, K.-S.; Kim, J.; Lee, J. Tetrahedron 2007, 63, 12845–
12852.
14. Lin, L. S.; Ha, S.; Ball, R. G.; Tsou, N. N.; Castonguay, L. A.; Doss, G. A.; Fong, T. M.;
Shen, C.-P.; Xiao, J. C.; Goulet, M. T.; Hagmann, W. K. J. Med. Chem. 2008, 51,
2108–2114.
was added to a deep well of a polypropylene plate, to which 50 mL of
[3H]CP-55940 diluted in a ligand buffer solution (0.1% bovine serum
albumin(BAS)þTME) was added. The tissue concentrations were
determined by Bradford protein analysis, and 148 mL of brain tissue
of the required concentration was added to the plate. The plate was
covered and placed in a 30 ꢁC incubator for 60 min, and then
transformed on GF/B filtermat pretreated in polyethylenimine (PEI)
using a cell harvester. Each filter was washed five times and dried at
60 ꢁC for 1 h. Then, the degree of radioactivity retained by the filter
was measured using Wallac MicrobetaÔ (PerkinElmer Life Sci-
ences, Inc., Massachusetts, USA) and the activity of the compound
for inhibiting CB1 receptor was determined therefrom.
15. (a) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc. 1994, 116,
9361–9362; (b) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496–6511.
16. Reider, P. J. Chimia 1997, 51, 306–308.
17. (a) Shimizu, S.; Ogata, M. J. Org. Chem. 1986, 51, 3897–3900; (b) Ogata, M.;
Matsumoto, H.; Takahashi, K.; Shimizu, S.; Kida, S.; Murabayashi, A.; Shiro, M.;
Tawara, K. J. Med. Chem. 1987, 30, 1054–1068.
18. Lin, L. S.; Lanza, T. J.; Jewell, J. P.; Liu, P.; Shah, S. K.; Qi, H.; Tong, X.; Wang, J.; Xu,
S. S.; Fong, T. M.; Shen, C.-P.; Lao, J.; Xiao, J. C.; Shearman, L. P.; Stribling, D. S.;
Rosko, K.; Strack, A.; Marsh, D. J.; Feng, Y.; Kumar, S.; Samuel, K.; Yin, W.; Van
der Ploeg, L. H. T.; Goulet, M. T.; Hagmann, W. K. J. Med. Chem. 2006, 49, 7584–
7587.
19. (a) Wong, A.; Welch, C. J.; Kuethe, J. T.; Vazquez, E.; Shaimi, M.; Henderson, D.;
Davies, I. W.; Hughes, D. L. Org. Biomol. Chem. 2004, 2, 168–174; (b) Coburn, C.;
Espeseth, A. S.; Stachel, S. J.; Olsen, D. B.; Hazuda, D.; Holloway, M. K. WO2005/
097767, 2005.
20. Yokokawa, F.; Asano, T.; Shioiri, T. Org. Lett. 2000, 2, 4169–4172.
21. Devane, W. A.; Dysarz, F. A., 3rd; Johnson, M. R.; Melvin, L. S.; Howlett, A. C. Mol.
Pharmacol. 1998, 34, 605–613.
22. For comparison, taranabant (MK-0364) demonstrated rat CB1 receptor binding
affinity IC50¼0.86 nM, while rimonabant (SR141716) displaying IC50¼4.50 nM
via in-house assay.
23. Triazole is small and constitutes three nitrogens in the ring. Thus, by
substituting H into a triazole, hydrophilicity of a molecule increases. Concur-
rent alteration of physicochemical properties including solubility was
observed.
24. Currently, Merck’s taranabant is in Phase 3 clinical trial for the treatment of
obesity in USA. Taranabant is not toxic per se, but people speculate that it
might have potential problem to cause depression or anxiety in human beings
when it is used in medium to high dose.
Acknowledgements
Financial support was provided by Green Cross Corporation
(GCC). We thank Professor Eun Lee (Seoul National University) for
allowing us to use JASCO P-1030 automatic polarimeter for optical
rotation data. We thank Ms. Mi Soon Kim and Mr. Sung-Han Lee
(GCC Central Research Laboratories) for the biological assays of
taranabant analogs 1 and 23. We also thank Mr. Jong Yup Kim (GCC)
for his assistance regarding analytical data. This work was partially
(Yun, H. and Kwak, H.) supported by the Korea Research Foundation
Grant funded by the Korean Government (MOEHRD) (KRF-2007-
412-J04001). Finally, we are grateful to Dr. Chong-Hwan Chang for
his initiative for small molecule programs at GCC.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.09.057.