Synthesis of novel bicyclo[4.1.0]heptane and bicyclo[3.1.0]hexane derivatives as melanin-concentrating hormone receptor R1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2007.06.048

To address the hERG liability of MCHR1 antagonists such as 1 and 2, new analogs such as 4 and 5 that incorporated a polar heteroaryl group were designed and synthesized. Biological evaluation confirmed that these new analogs retained MCH R1 activity with

Full text of DOI:10.1016/j.bmcl.2007.06.048

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4845–4850
Synthesis of novel bicyclo[4.1.0]heptane and bicyclo[3.1.0]hexane
derivatives as melanin-concentrating hormone
receptor R1 antagonists
Jing Su,a,* Haiqun Tang,a Brian A. McKittrick,a Huizhong Gu,b Tao Guo,b
Gang Qian,b Duane A. Burnett,a John W. Clader,a William J. Greenlee,a
Brian E. Hawes,c Kim O’Neill,c Brian Spar,c Blair Weig,c
Timothy Kowalskic and Steve Sorotad
aDepartment of Chemical Research, Schering-Plough Research Institute K15 2545,
2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
bPharmacopeia, Inc., PO Box 5350, Princeton, NJ 08543-5350, USA
cDepartment of Cardiovascular/Metabolic Diseases, Schering-Plough Research Institute K15 3600,
2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
dDepartment of Neurobiology, Schering-Plough Research Institute K15 2600,
2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Received 8 May 2007; revised 11 June 2007; accepted 13 June 2007
Available online 17 June 2007
Abstract—To address the hERG liability of MCHR1 antagonists such as 1 and 2, new analogs such as 4 and 5 that incorporated a
polar heteroaryl group were designed and synthesized. Biological evaluation confirmed that these new analogs retained MCH R1
activity with greatly attenuated hERG liabilities as indicated in the Rb efflux assay.
Ó 2007 Elsevier Ltd. All rights reserved.
Melanin-concentrating hormone (MCH) is a cyclic 19-
amino acid neuropeptide responsible for color changes
in fish skin.1 MCH is present in the brains of all verte-
brate species examined so far and it appears to be in-
volved in feeding behavior based on the following
observations: direct i.c.v. administration of MCH in rats
increases food intake in a dose-dependent manner2;
MCH mRNA is up-regulated in ob/ob mice and in
fasted mice3a; MCH overexpressing mice are hyper-
phagic, mildly obese, hyperglycemic, and insulin resis-
tant3b; MCH knockout mice are leaner than wild-type
mice.4 It is generally believed that MCH receptor R1
mediates the orexigenic effects of MCH5,6 and an exten-
sive number of reports on MCH receptor R1 antago-
nists for the potential treatment of obesity have
appeared in recent years.7,8
Recently Schering-Plough reported the discovery of
bicyclo[4.1.0]heptane 19 and bicyclo[3.1.0]hexane 28d as
potent MCH R1 receptor antagonists (Fig. 1). Concerns
about their strong inhibition of hERG K+ channel led
us to modify these lead structures and the results from
our investigation suggested that an increase in the
molecular polarity of the lead structures could result
in much reduced hERG activity.10 For example, com-
pound 3 had MCH R1 Ki 13 nM while its hERG activity
was significantly reduced compared with 1 in the Rb ef-
flux assay.11 The encouraging results prompted us to re-
place the 3-CN or 4-CN phenyl moiety in 1 and 2 with a
polar heteroaryl group. We describe herein our synthetic
efforts to such targets as 4 and 5 and other analogs as
well as their biological activities.
Our synthesis of bicyclo[4.1.0]heptane 4 is shown in
Scheme 1. Contrary to the established synthetic route
to 1,9 the cyclopropane ring in 4 was built before the
introduction of the thiazole ring.12 Thus, the cycloprop-
anation of allylic alcohol 613 was achieved in 90% yield
under Simmons–Smith condition. To build the thiazole
Keywords: Melanin-concentrating hormone receptor R1 antagonist;
Bicyclo[4.1.0]heptane; Bicyclo[3.1.0]hexane; hERG; Cyclopropanation.
*
Corresponding author. Tel.: +1 908 740 7489; fax: +1 908 740
7164; e-mail: jing.su@spcorp.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.06.048

4846
J. Su et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4845–4850
Cl
Cl
Cl
F
F
F
NH
NH
NH
OH
N
O
N
O
N
N
N
O
N
OH
S
N
CN
NH2
CN
2
1
3
MCH R1 Ki 22 nM
Rb efflux: 86% inh. at 5 μg/mL
MCH R1 Ki 9 nM
Rb efflux: 80% inh. at 5 μg/mL
MCH R1 Ki 13 nM
Rb efflux: 10% inh. at 5 μg/mL
Figure 1. Initial MCH R1 antagonists with various hERG profiles.
X
O
O
O
O
O
O
O
b-d
e
a
S
NH2
OH
OH
NH2
9
X = O
6
7
8
f
10 X = OCH2CH2O
CF3
F
O
O
N
O
O
N
g
k-m
h-j
N
N
H
N
S
S
CHO
N
N3
S
NH2
11
12
4
Scheme 1. Synthesis of bicyclo[4.1.0]heptane 4. Reagents and conditions: (a) ClCH2I (4 equiv), Et2Zn (8 equiv), DCE, rt, 72 h, 90%; (b) Dess–
Martin, DCM, rt, 3 h, 90%; (c) NaClO2, KH2PO4, CH3CH@C(CH3)2, rt, 15 h; (d) ClCO2Et, Et3N, DCM, then NH3 (20 equiv), 43%; (e) Lawesson’s
reagent (0.5 equiv), THF, rt, 1.5 h, 54% (1:1 9:10); (f) (CH2OH)2, TsOH, 73%; (g) NaHCO3 (4 equiv), 2.5 equiv 2-chloromalonaldehyde, THF, 50 °C,
14 h, 94%; (h) LiAlH4, 78%; (i) DPPA (3 equiv), DBU (2 equiv); (j) HCl, H2O, 89%; (k) 2-pyrrolidin-1-yl-ethylamine (1.04 equiv), NaBH4 (1.04
˚
equiv), MS3A, DCM, 67% (1:1 mixture of cis/trans product); (l) 4-fluoro-3-trifluoromethylphenyl isocyanate, 100%; (m) PPh3, 74%.
ring, the alcohol 7 was converted to the corresponding
amide 8 in 39% yield (three steps).14 The transformation
of 8 to thioamide 10 using Lawesson’s reagent afforded a
1:1 mixture of 9 and 10 (54% total yield). Without sep-
aration, 9 was converted back to ketal 10 in 73% yield
under standard conditions. Applying a literature proce-
dure15 to the thioamide 10 provided the thiazole 11 in
94% yield. Transformation of 11 to ketone 12 was
accomplished in three steps in 69% yield. The reductive
amination of 12 with 2-pyrrolidin-1-yl-ethylamine affor-
ded a mixture of cis and trans products (1:1, 67%). After
urea formation, the cis and trans ureas were separated
and the final reduction of the azide afforded the desired
product 4 in 25% yield from 12.
condition using Sm/CH2I2 gave the desired product 16
in 50–55% yield.16 After Dess–Martin oxidation, reduc-
tive amination, and urea formation, the intermediate 17
was obtained in 93% yield and was further converted to
the target 5 in 66% yield. Other derivatives of bicy-
clo[3.1.0]hexanes such as 23–28 with different side chains
were synthesized via this route (Scheme 3).17
The biological data for the above compounds are shown
in Table 1.18 Bicyclo[4.1.0]heptane 4 indeed had much
lower hERG activity in the Rb efflux assay (19% inhibi-
tion at 5 lg/mL vs 80% for 1), although it had weak
MCH R1 binding (Ki 431 nM). On the other hand, bicy-
clo[3.1.0]hexane 5 had a better MCH R1 binding (Ki
107 nM) and similar hERG activity (16% inhibition at
5 lg/mL). The addition of a polar group on the side
chain kept the binding unchanged (compound 23 Ki
99 nM). When the side chain with pyrrolidine was fur-
ther extended (compounds 24 and 25), 2- to 6-fold
improvement in MCH R1 binding was observed.
Replacing the pyrrolidine ring with 2,5-dimethylpipera-
zine essentially kept MCHR1 Ki unchanged (compound
26, Ki 19 nM) while the use of bridged piperazine
A different synthetic route to bicyclo[3.1.0]hexane 5 was
envisioned which would take advantage of the allylic
alcohol mediated cyclopropanation (Scheme 2). Com-
pound 14, prepared from the commercially available
aldehyde 13 in three steps, underwent Stille coupling
with 3-bromo-cyclopenten-2-ol8d to afford 15 in 50–
62% yield. Various cyclopropanation reaction condi-
tions were subsequently tried and eventually a modified

J. Su et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4845–4850
4847
OH
OH
Sn(CH3)3
a, b, c
d
e
S
N
S
S
N
S
N
N
CHO
OTBDPS
OTBDPS
OTBDPS
16
13
14
15
F
F
F3C
NH
F3C
NH
f-h
N
N
N
N
i-k
O
O
S
S
N
N
OTBDPS
NH2
5
17
Scheme 2. Synthesis of bicyclo[3.1.0]hexane 5. Reagents and conditions: (a) NaBH4, 58%; (b) TBDPSCl, imidazole, 100%; (c) n-BuLi, (CH3)3SnCl,
THF, À78 °C, 40 min, 73%; (d) 3-bromo-cyclopenten-2-ol, Pd(PPh3)4, LiCl, Na2CO3, THF, 70 °C, 15 h, 62%; (e) Sm (5 equiv), CH2I2 (5 equiv),
˚
THF, À25 °C, 1 h, 52%; (f) Dess–Martin, 95%; (g) 2-pyrrolidin-1-yl-ethylamine, MS3A, DCM, 98%; (h) 4-fluoro-3-trifluoromethylphenyl isocyanate,
100%; (i) TBAF; (j) DPPA, DBU; (k) LiAlH4, 66% in three steps.
O
Ar
R
N
N
O
O
n
H
c. side chain 20, or 21, or 22.
a, b
S
S
S
N
d, e, f or g
n = 1, 2
N
N
OTBDPS
N3
19
NH2
18
23-28
H2N
N
H2N
N
OTBS
N
H2N
NBoc
NBoc
n
20
21
22
˚
Scheme 3. Synthesis of bicyclo[3.1.0]hexanes 23–28. Reagents: (a) TBAF, 74%; (b) DPPA, DBU, 75%; (c) amine, MS3A, DCM, NABH4; (d)
ArNCO; (e) PPh3; (f) TBAF; (g) EtOAc/3 N HCl, 10–20% yield.
decreased the binding by 5-fold (compound 28, Ki
73 nM). An attempt to boost the binding by using 2,6-
dichloropyridyl as the urea moiety improved Ki only
modestly to 13 nM (compound 27). Importantly, all
these compounds showed much reduced hERG liability
in the Rb efflux assay and these results encouraged us to
pursue the optically pure compounds to further improve
the in vitro binding.
are 20- to 42-fold more active than the other set of
compounds (compounds 25a, 32a, 33a) derived from
enantiomer 19b. In addition, the data indicated that
the chirality of the side chain does not affect the
MCH R1 binding (compounds 32a versus 33a, 32b
vs 33b). As expected from the profiles of their race-
mic analogs, all these chiral compounds had much re-
duced hERG liability.
Scheme 4 outlines the synthesis of the optically pure
compounds 25, 32, and 33. After screening several
different intermediates under several chiral column
conditions, it was discovered that the enantiomers
of azidoketone 19 could be separated by a chiral
AD column.19 Each enantiomer then underwent
reductive amination with three amines 29–3117 and
a total of 6 final targets was synthesized. The data
(Table 2) clearly suggested that chirality of the core
structure in this series played an important role for
the MCH R1 activity. One set of compounds (com-
pounds 25b, 32b, 33b) derived from enantiomer 19a
Four of these chiral compounds were selected for the
mouse ex vivo assay to measure the receptor occu-
pancy.10 Compounds 32a, 32b, and 33a showed modest
inhibition of 16%, 20% and 26%, respectively, at 6 h
(30 mg/kg, po). To our disappointment, although com-
pound 33b was 40-fold more active than 33a in the
in vitro assay, 33b showed only modest improvement
in ex vivo binding (39% inhibition). Compared with
compound 310 (MCH Ki 13 nM, mouse ex vivo assay:
88% inhibition at 6 h, 30 mg/kg, po), this new type of
bicyclo[3.1.0]hexane derivatives showed lower ex vivo
efficacy in the mouse model.20

4848
J. Su et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4845–4850
Table 1. MCH R1 binding and hERG data for racemic compounds
CF3
O
F
O
Ar
R
N
N
n
N
H
N
N
H
S
N
N
S
NH2
NH2
5, 23-28
4
Compound
Ar
n
R
MCH R1 Ki (nM)
Rb % inh. at 5 lg/mL
4
5
4-F,3-CF3Ph
4-F,3-CF3Ph
431
107
3
3
19
16
1
N
N
S
23
24
25
4-F,3-CF3Ph
4-F,3-CF3Ph
4-F,3-CF3Ph
1
2
2
99
45
17
8
2
1
8
À4
À4
OH
OH
OH
N
N
S
R
N
26
4-F,3-CF3Ph
2
19
2
À8
NH
Cl
N
N
27
28
2
2
13.1 0.3
3
N
NH
NH
Cl
4-F,3-CF3Ph
73
7
14
˚
Scheme 4. Synthesis of optically pure bicyclo[3.1.0]hexanes 25, 32, and 33. Reagents: (a) chiral AD column, IPA/hexane; (b) amine, MS3A, DCM,
NABH4; (c) 4-fluoro-3-trifluoromethylphenyl isocyanate; (d) PPh3; (e) TBAF, 10% yield in four steps; (f) EtOAc/3 M HCl; (g) PPh3 (resin bound).
In summary, we have developed two different syn-
thetic routes to heteroaryl substituted bicy-
clo[4.1.0]heptane and bicyclo[3.1.0]hexane analogs,
respectively. Optically pure compounds were also ob-
tained and some of these compounds retained strong
binding with the MCH R1 receptor. All of these com-
pounds had significantly attenuated hERG liabilities
in the Rb efflux assay, thereby solving one of the
key hurdles in the development of the MCH R1
antagonists.

J. Su et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4845–4850
4849
Table 2. MCH R1 binding, hERG, and mouse ex vivo data for optically pure compounds
O
O
Ar
Ar
N
N
R
N
N
R
H
H
S
S
N
N
NH2
25b,32b,33b
NH2
25a,32a,33a
Compound
Ar
R
MCH R1
Ki (nM)
Rb % inh.
at 5 lg/mL
Mouse ex vivo % inh.
at 6 h (30 mg/kg, po)
N
R
25a
25b
4-F,3-CF3Ph
4-F,3-CF3Ph
167 10
6.6 0.2
6
8
OH
N
R
OH
Cl
S
N
32a
32b
33a
33b
117
8
À13
À12
17
20
16
26
39
2
2
3
2
N
R
NH
NH
NH
NH
Cl
Cl
S
N
N
N
6.1 0.5
171 61
4.0 0.2
N
R
Cl
Cl
R
S
N
Cl
Cl
R
S
N
22
Cl
Pan, J.; Pong, S.-S.; Feighner, S. D.; Tan, C. P.; Fukami, T.;
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Acknowledgments
We thank Dr. Andrew Evans for some of the NMR
work. Drs. Michael Czarniecki, Michael Graziano, Li
Qiang, Mark McBriar, T.K. Sasikumar, Wen-Lian
Wu, and Ruo Xu for their support, suggestions, and
encouragement.
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18. All compounds were tested with human MCH R1
receptor. Selected compounds were also tested with mouse
and rat MCH R1 receptors and very similar Ki values were
obtained.
19. Chiral AD column, 45% i-PrOH/hexane, 19a 17.6 min, 19b
32.9 min. Isomer 19b was then reduced to the corresponding
trans alcohol 35 which was converted to Mosher’s esters 36a
and 36b. Based on chemical shift difference of Ha in 36a and
36b (Dd = d36aÀd36b = 0.06 ppm) as well as that for other
protons, the absolute stereochemistry was then determined.
See also: Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973,
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O
OH
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S
S
N
N
N3
O
10. Su, J.; McKittrick, B. A.; Tang, H.; Burnett, D. A.;
Clader, J. W.; Greenlee, W. J.; McNemar, C.; Graziano,
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12. Direct cyclopropanation of a thiazole substituted cyclo-
hexene 34 using our initial route9 was tried under many
conditions without success.
N3
19b
35
O
CF3
Ph
S
R
O
O
Ha
Ha
Ph OMe
F3C OMe
+
S
S
N
N
N3
36a
N3
36b
Ha
O
Ha
OMe
CF3
Ph
OTBDPS
N
Ph
O
MeO
O
O
S
R
CF3
Het
Het
O
S
O
34
S-configuration
S-configuration
13. Genet, J. P.; Juge, S.; Achi, S.; Mallart, S.; Ruiz Montes,
J.; Levif, G. Tetrahedron 1988, 44, 5263.
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4748.
20. We assume the lower ex vivo binding of this new series is
related with its PK profiles, although no experimental
data are available.