Discovery of orally efficacious melanin-concentrating hormone receptor-1 antagonists as antiobesity agents. Synthesis, SAR, and biological evaluation of bicyclo[3.1.0]hexyl ureas

Article abstract of DOI:10.1021/jm050886n

Melanin-concentrating hormone (MCH) is a cyclic, nonadecapeptide expressed in the CNS of all vertebrates that regulates feeding behavior and energy homeostasis via interaction with the central melanocortin system. Regulation of this interaction results in

Full text of DOI:10.1021/jm050886n

2294
J. Med. Chem. 2006, 49, 2294-2310
Discovery of Orally Efficacious Melanin-Concentrating Hormone Receptor-1 Antagonists as
Antiobesity Agents. Synthesis, SAR, and Biological Evaluation of Bicyclo[3.1.0]hexyl Ureas
Mark D. McBriar,*,† Henry Guzik,† Sherry Shapiro,† Jaroslava Paruchova,† Ruo Xu,† Anandan Palani,† John W. Clader,†
Kathleen Cox,‡ William J. Greenlee,† Brian E. Hawes,‡ Timothy J. Kowalski,‡ Kim O’Neill,‡ Brian D. Spar,‡ Blair Weig,‡
Daniel J. Weston,‡ Constance Farley,‡ and John Cook‡
Department of Chemical Research and Department of CardioVascular and Metabolic Diseases, Schering-Plough Research Institute,
2015 Galloping Hill Road, Kenilworth, New Jersey 07033-0539
ReceiVed September 7, 2005
Melanin-concentrating hormone (MCH) is a cyclic, nonadecapeptide expressed in the CNS of all vertebrates
that regulates feeding behavior and energy homeostasis via interaction with the central melanocortin system.
Regulation of this interaction results in modulation of food intake and body weight gain, demonstrating
significant therapeutic potential for the treatment of obesity. The MCH-1 receptor (MCH-R1) has been
identified as a key target in MCH regulation, as small molecule antagonists of MCH-R1 have demonstrated
activity in vivo. Herein, we document our research in a bicyclo[3.1.0]hexyl urea series with particular emphasis
on structure-activity relationships and optimization of receptor occupancy, measured both in vitro and via
an ex vivo binding assay following an oral dosing regimen. Several compounds have been tested in vivo
and exhibit oral efficacy in relevant acute rodent feeding models. In particular, 24u has proven efficacious
in chronic rodent models of obesity, showing a statistically significant reduction in food intake and body
weight over a 28 day study.
Introduction
vertebrates.7 Interaction of MCH with the central melanocortin
system plays a role in feeding behavior and energy homeostasis.
Initial studies showed that central administration of MCH to
rats induced hyperphagia and were followed by subchronic (7-
14 day) murine studies in which central infusion of MCH also
induced hyperinsulinemia, hyperleptinemia, and increased adi-
posity.8 In contrast, MCH null mice present a lean phenotype
characterized by hypophagia and increased energy expenditure.9
To date, two endogenous receptors for MCH have been
identified as G-protein coupled receptors, designated as MCH-
R1 and MCH-R2. MCH-R1 is expressed in hypothalamus of
rodents and higher mammalian species, while MCH-R2 is
expressed only in higher mammals such as ferrets, dogs, rhesus
monkeys, and humans.10 Due to this species-specific expression
pattern, the pharmacological role of MCH-R2 in metabolic
homeostasis is largely undefined. Conversely, the role of MCH-
R1 in food intake and energy expenditure has been extensively
studied. Specifically, MCH-R1 null mice are lean, have
decreased leptin and insulin levels, and are resistant to diet-
induced obesity.11
Antagonism of the MCH-R1 receptor has been the topic of
several publications demonstrating the promise of this target in
obesity therapy.12 Orally active MCH-R1 antagonists demon-
strating acute efficacy have been disclosed by several groups.13
Subchronic efficacy in mice has been observed upon oral dosing
with GW-856464 (1, Figure 1),14 indazoles such as 2 and 3,15
and aminopiperidines exemplified by compounds 4-6.16 Recent
publications from our laboratories have documented that biaryl
urea 7 (hMCH-R1 Ki ) 9 nM, Kb ) 2 nM) was orally
efficacious in a 28 day rodent obesity model, showing decreasing
food intake and weight gain in addition to a selective decrease
in fat mass relative to lean mass.17 Though orally active in vivo,
further studies with 7 were discontinued due to potential toxicity
issues. The biaryl aniline substructure embedded in 7 provided
a strongly positive result in an Ames assay, indicating the high
mutagenic potential of the biaryl aniline. Though pharmacoki-
netic studies provided no evidence of metabolism of 7 in vivo
The obesity epidemic has been recognized as a significant
human health threat affecting cultures throughout the world.
Identified by the World Health Organization (WHO) as one of
the top 10 global health problems, current estimates hold that
over 30% (∼60 million) of United States adults suffer from
obesity, which is defined as a body mass index (BMI) greater
than 30.1 Additionally, 30% of U.S. adults are classified as
overweight (BMI > 25) and are trending toward obesity. Similar
disturbing trends have been observed in other industrialized
countries, particularly those which have adopted a Western diet
and sedentary lifestyle. Often mischaracterized as an aesthetic
issue, obesity poses significant health risks including comor-
bidities such as type II diabetes, hypertension, coronary artery
disease, stroke, osteoarthritis, and several forms of cancer.2
Financial estimates of the direct and indirect costs of obesity
exceed $117 billion in the U.S. and are increasing rapidly.3
Though obesity-related cost estimates vary dramatically, the
direct links between obesity and these comorbidities remain
clear. Remediation of obesity via weight reduction has been
suggested as a primary goal; however, long-term weight
regulation remains difficult. Currently marketed weight reduc-
tion medications such as orlistat (Xenical) and sibutramine
(Meridia) suffer from limited efficacy or undesirable side effects
which limit patient compliance.4 The pending FDA approval
of rimonabant (Acomplia) may offer an alternative weight loss
treatment.5 Recent pharmacological approaches to induce weight
loss have included modulation of several metabolic processes
of which melanin-concentrating hormone (MCH) has been
increasingly prominent.6
Melanin-concentrating hormone is a cyclic, nonadecapeptide
which is expressed in the central nervous system of all
* To whom correspondence should be addressed. Tel: 908-740-2618.
Fax: 908-740-7152. E-mail: mark.mcbriar@spcorp.com.
† Department of Chemical Research.
‡ Department of Cardiovascular and Metabolic Diseases.
10.1021/jm050886n CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/07/2006

Bicyclo[3.1.0]hexyl Ureas as MCH-R1 Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7 2295
Figure 1. MCH-R1 antagonists exhibiting chronic oral efficacy.
Scheme 1. Preparation of Cyclopentenyl and Cyclopentyl
Ureasa
Figure 2. Diagnostic NOE observances for cyclopentanes 11, 16, and
bicylohexane 23a.
to produce the biaryl aniline, it was decided that any risk of
biaryl aniline exposure to the target population, regardless of
extent, was unacceptable in the context of antiobesity therapy.
Herein, efforts aimed at reducing the liabilities of the biaryl
urea 7 via modification of the central aryl ring to a bicyclic
structure are chronicled. Central to this effort was the incorpora-
tion of an ex vivo binding assay to guide compound selection
for further in vivo rodent studies. Oral efficacy of a resultant
bicyclic urea in a chronic (28d) rodent model is demonstrated.18
Chemistry
The synthesis of the cyclopentenyl derivative and cyclopentyl
derivatives proceeded according to Scheme 1. Aryl cyclopen-
tenone 818a underwent reductive amination with 1-(2-amino-
ethyl)pyrrolidine, followed by treatment with 3,5-dichlorophenyl
isocyanate to provide the racemic cyclopentenyl urea 9. Hy-
droxyl-directed reduction of olefin 1018a and careful chromato-
graphic separation provided the pure cis- and trans-cyclopen-
tanol isomers (11 and 12, respectively, in a 10:1 ratio).
Conformational analysis via 2D-NOESY NMR confirmed the
major product as the cis-isomer (Figure 2). Specifically, NOE
observances between protons on the cyclopentyl ring of 11 were
a (a) 1-(2-Aminoethyl)pyrrolidine, NaB(OAc)3H; (b) aryl isocyanate,
i-Pr2NEt, CH2Cl2; (c) H2, Pd/C, MeOH; (d) MsCl, Et3N, CH2Cl2, 0 °C to
room temperature; (e) 1-(3-aminopropyl)-4-methylpiperazine, K2CO3,
CH3CH2CN, 100 °C; (f) Ph3P, CBr4, THF.

2296 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7
McBriar et al.
Scheme 2. Preparation of Bicyclo[3.1.0]hexyl Ureas: Stork Routea
a (a) Butyllithium, THF, -78 °C, then 18, -78 °C to -20 °C; (b) 1 N HCl; (c) NaBH4, CeCl3, MeOH, 0 °C to room temperature; (d) Et2Zn, CH2I2,
CH2Cl2, 0 °C to room temperature; (e) Dess-Martin periodinane, pyridine, CH2Cl2, 0 °C to room temperature; (f) H2NCH2CH2R2, Ti(O-i-Pr)4, 18 h, then
NaBH4, MeOH; (g) aryl isocyanate, i-Pr2NEt, CH2Cl2; (h) TFA, CH2Cl2; (i) HCHO or i-BuCHO, NaB(OAc)3H, CH2Cl2; (j) tert-butyl carbamate, N,N′-
dimethylethylenediamine, CuI, K2CO3, toluene, 110 °C; (k) AcCl or MsCl, i-Pr2NEt, CH2Cl2; (l) 4-aminobutanol, Ti(O-i-Pr)4, 18 h, then NaBH4, MeOH;
(m) BOC2O, Et3N, CH2Cl2; (n) Ph3P, CBr4, THF, 0 °C to room temperature; (o) R2NH, K2CO3, CH3CN, 70 °C.
indicative. Formation of the mesylate of the cis-isomer and
displacement using 1-(3-aminopropyl)-4-methylpiperazine pro-
vided the secondary amine 13, which was treated with 3-chloro-
4-fluorophenyl isocyanate to afford the trans-cyclopentyl urea
14. Similarly, the cis-cyclopentanol 11 was brominated and
alkylated in a sequence proceeding with double configurational
inversion to give the cis-amine 15, which underwent isocyanate
treatment to provide the cis-cyclopentyl urea 16. Configuration
of the cis-cyclopentyl urea 16 was also confirmed via 2D-
NOESY NMR studies (Figure 2).
The initial synthesis of the bicyclohexyl series is outlined in
Scheme 2.18a Metal-halogen exhange of aryl bromides 17
followed by addition to 3-methoxy-2-cyclopenten-1-one and
subsequent acidic workup provided the 3-aryl enones 19. Direct
cyclopropanation of these derivatives was highly desirable in
the context of developing a streamlined synthesis. Several
methods were employed in this effort such as Corey’s sulfoxo-
nium ylide,19 diazomethane decomposition, and phase-transfer
conditions with dichlorocarbene. Of these, the sulfoxonium ylide
was most productive, though far from optimal (5-15% yield).
Consequently, recourse was made to Luche reduction20 and
cyclopropanation of the resultant allylic alcohols, followed by
Dess-Martin oxidation21 to provide the desired bicyclic ketones
21. The acid-sensitive nature of allylic alcohols derived from
the reduction of 19 necessitated chromatographic purification
via silica prewashed with triethylamine. Though circuitous, this
method was reproducible and proceeded well on scale. Reduc-
tive amination of 21 using titanium tetraisopropoxide as a
promotor followed by treatment with sodium borohydride
provided exclusively the trans-isomers 22 with respect to the
bicyclic core, as confirmed via 2D-NOESY NMR analysis of
the fully elaborated target ureas (Figure 2). Treatment with the
appropriate aryl isocyanate completed the synthesis of the
bicyclohexyl ureas 23. In cases where R2 ) BOC-piperazinyl,
acid treatment to remove the carbamate was followed by
derivatization to provide 23g and 23h.
Conversion of the bromo-derivative 21b to protected amine
21c was achieved via Buchwald amination.22 Following side
chain installation and urea formation, 24a was treated with acid
to generate the free aniline, which was subsequently derivatized
to provide 24b and 24c.
To facilitate SAR studies of side chain extension, reductive
amination of the bicyclic ketone was achieved using 4-ami-
nobutanol to obtain amino-alcohol 25. Protection of the amine
(BOC2O) was followed by bromination of the alcohol and
subsequent displacement by various amines. Carbamate removal
and isocyanate treatment proceeded uneventfully to afford 27.
Though suitable for SAR studies of the pendant side chain and
aryl urea, the synthetic route was limited in applicability toward
SAR of the aryl terminus. In this initial approach, commitment
to the terminal aryl substituent was made in the first step of the
synthesis via the metalated aryl species, with limited exception
such as in conversion of 21b to 21c, which precluded the use
of aryl groups containing substituents incompatible with metal-

Bicyclo[3.1.0]hexyl Ureas as MCH-R1 Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7 2297
Table 1. Representative Profile of Bicyclo[4.1.0]heptyl Urea MCH-R1 Antagonists
MCH-R1 Ki (nM)a
15.1 ( 3.7
11
16.4
1.1
73
11.4 ( 2.2
MCH-R1 Kb (nM)b
7
rat AUC(0-24h) (µM‚h)c
B/P (6 h)c
14
0.7
58
inactive
MCH-R1 ex vivo binding (6 h)d
DIO mouse food intake (24 h)e
active*
a Mean values (n ) 3) ( SEM. Inhibition of [125I]-MCH binding to h-MCH-R1 expressed in Chinese Hamster Ovary (CHO) cells. b Mean values (n )
3) of inhibition of MCH-mediated Ca2+ influx into cells expressing hMCH-R1 via FLIPR assay. c Mean values (n ) 3); dosed at 10 mg/kg, po. d Expressed
as % inhibition of MCH-ADO binding relative to vehicle control (n ) 3); dosed at 30 mg/kg, po. e Dosed at 30 mg/kg, po. Asterisk (*) indicates value is
significantly different from that of vehicle.
Scheme 3. Preparation of Bicyclo[3.1.0]hexyl Ureas: Suzuki Routea
a (a) NaBH4, CeCl3, MeOH, 0 °C to room temperature; (b) ArB(OH)2, K3PO4, Pd(dppf)Cl2, DME/H2O (4:1), 80 °C; (c) Et2Zn, CH2I2, CH2Cl2, 0 °C to
room temperature; (d) Dess-Martin periodinane, pyridine, CH2Cl2, 0 °C to room temperature; or TPAP, NMO, CH2Cl2; (e) 1-(3-aminopropyl)-4-
methylpiperazine, Ti(O-i-Pr)4, 18 h, then NaBH4, MeOH; (f) aryl isocyanate, i-Pr2NEt, CH2Cl2; (g) TBSCl, imid., DMF; (h) Et2Zn, ClCH2I, DCE, -20 to
0 °C; (i) TBAF, THF.
Scheme 4. Preparation of 32a
halogen exchange conditions. As a solution, an alternative
synthetic route was sought which would enable installation of
various aryl boronic acids via a cross-coupling protocol.
In a revised approach, the brominated product of the enol
tautomer of cyclopentane-1,3-dione (28)23 underwent Luche
reduction20 to provide the key intermediate 29 (Scheme 3).
Elaboration with various aryl groups was performed via Suzuki
coupling, and the remainder of the synthesis was carried out
similar to the previous route. With electron-rich aryl groups,
the allylic alcohols 30 were particularly acid-sensitive (vide
supra), and silylation of 29 prior to aryl installation was required.
a (a) 21u, Ti(O-i-Pr)4, 18 h, then NaBH4, MeOH; (b) 4-fluoro-3-
(trifluoromethyl)phenyl isocyanate, i-Pr2NEt, CH2Cl2; (c) H2, Pd/C, MeOH.
Cyclopropanation of the silyloxy-allyl derivatives 31 either
resulted in the identification of an alternative bicyclo[4.1.0]-
under standard conditions (Et2Zn, CH2I2) or with added ligands
heptane core.18,27 Evidence that this core served as a viable
such as TFA24 was unsuccessful. However, use of chloro-
alternative to the biaryl was coupled with inspection of various
iodomethane under Denmark25 conditions proceeded smoothly.
biological and structural models, indicating that further opti-
Deprotection of the hydroxyl and subsequent oxidation generated
mization would be useful. For example, similar in vitro and
the bicyclic ketones 21. Elaboration to the bicyclohexyl ureas
pharmacokinetic properties of structurally analogous bicyclo-
proceeded according to the initial route (Scheme 2).
[4.1.0]heptyl derivatives (+)-34 and (+)-35 (Table 1) did not
The monoalkylated piperazine derivative 32 was synthesized
lead to similar in vivo efficacy in a diet-induced obese (DIO)
via reductive alkylation with amine 3326 and subsequent urea
mouse model.27 This model was an acute feeding model in
which oral dosing was followed by measurement of body weight
formation followed by carbamate removal (Scheme 4).
gain and food intake relative to controls over 24 h. Given these
results, it was sought to incorporate a high throughput assay
Results and Discussion
Previously, a series of central aryl ring modifications to reduce
the mutagenic potential of biaryl urea 7 was described which
which could guide SAR development, and to which one could
relate in vivo efficacy. To this end, incorporation of an ex vivo

2298 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7
McBriar et al.
Figure 3. Cyclopentyl urea MCH-R1 antagonists.
Table 2. Initial Side Chain SAR of Bicyclohexanes
a Mean values (n ) 8) ( SEM. Inhibition of [125I]-MCH binding to h-MCH-R1 expressed in Chinese Hamster Ovary (CHO) cells. b Data from pooled
samples as described in ref 29, dosed at 10 mg/kg, po. c Expressed as a percent inhibition of MCH-ADO binding relative to vehicle control ( SEM (n )
3; dosed at 30 mg/kg, po). d Single diastereomer, absolute stereochemical configuration of the bicyclic core is enantiomeric to that shown. e Single diastereomer,
absolute stereochemical configuration of the bicyclic core is as shown.

Bicyclo[3.1.0]hexyl Ureas as MCH-R1 Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7 2299
Table 3. Representative Side Chain Basicity Requirements of
Bicyclohexanes
binding assay served as an expedient surrogate measure of
receptor occupancy.18,27 In this assay, compounds (+)-34 and
(+)-35 provided significantly different degrees of receptor
occupancy upon oral dosing, which was found to correlate with
the in vivo profile of each in the acute DIO mouse feeding
model. In the present study, the ex vivo binding assay served
as an indispensable tool for determining receptor occupancy of
several small molecule antagonists while negating the require-
ment for radiolabeling each of the individual molecules,
permitting rapid identification of compounds providing optimal
receptor coverage at several time points postdose.
Though significant overlap of side chain trajectories between
the biaryl (7) and bicyclo[4.1.0]heptyl [(+)-34 and (+)-35] ureas
was observed with models, the possibility of further constraining
the central bicycloalkyl ring to improve binding was considered.
The cyclopentyl core would have the additional benefit of
modestly reduced molecular weight, a property which has been
shown to favorably impact bioavailability.28 Cyclopentyl deriva-
tives were synthesized and tested for binding affinity to the
MCH-1 receptor (Figure 3). Cyclopentenyl derivative 9 provided
moderate binding affinity (Ki ) 605 nM), in contrast to previous
observations with cyclohexenyl derivatives, which were more
potent by at least 2 orders of magnitude.18a,27 Saturation of the
cyclopentyl substructure provided the trans-14 and cis-16
derivatives, of which the trans-isomer was considerably more
potent (Ki ) 161 and 2190 nM respectively for 14 and 16).
Again, this general trend was similar to that observed in the
cyclohexyl series, which was also amenable to incorporation
of a bicyclo[4.1.0]heptyl core.27
a Mean values (n ) 8) ( SEM. Inhibition of [125I]-MCH binding to
h-MCH-R1 expressed in Chinese Hamster Ovary (CHO) cells.
As an extension, it was reasoned that conversion of 14 to a
bicyclo[3.1.0]hexyl core might be tolerated. This hypothesis
proved correct upon testing of 23a (Ki ) 15 nM, Figure 3),
and it was decided to further develop this new series in order
to probe the SAR differences, if any, between it and the bicyclo-
[4.1.0]heptyl series. Many of the SAR trends generated in the
previous biaryl series served as useful guidelines.17 In particular,
3,4- or 3,5-disubstitution with electron-withdrawing substituents
was required on the aryl urea. Halogens or trifluoromethyl
groups on the aryl urea improved pharmacokinetic properties
in the series. The incorporation of cyclic amines on the side
chain terminus was important in order to provide selectivity
for MCH-R1 over the serotonin reuptake transporter and
muscarinic receptors such as M2.
properties related to absolute configuration of the bicyclic core,30
diastereomers (+)-23c and (-)-23d were separated and tested
individually (Table 2). Compound (+)-23c showed greater
binding affinity than diastereomer (-)-23d at h-MCH-R1;
however, pharmacokinetic properties such as rat AUC and
degree of ex vivo binding were considerably improved with
diastereomer (-)-23d. Subsequent biological studies were
generally performed on racemic material in order to optimize
throughput.
Focusing further on side chain structure, it was observed that
basicity of the nitrogen atom was critical for activity at MCH-
R1 (Table 3). Aliphatic amines proved optimal, while aryl
amines such as 23i resulted in diminution of affinity. Likewise,
amides such as 23j and nonbasic side chains as in 23k31 were
significantly less active. These results reinforced previous
observations regarding side chain SAR made in the biaryl
series.17
Regarding the terminal aryl ring of the bicyclic core, it was
discovered that simple, unsubstituted phenyl derivatives such
as 24e were suitable for potency (Table 4). This stood in stark
contrast to SAR developed in the biaryl urea17 and the bicyclo-
[4.1.0]heptyl urea27 series, wherein the position and nature of
substitution were of paramount significance with regard to
activity at MCH-R1. In these preceding studies, any divergence
from meta-substitution of the terminal aryl ring resulted in
significantly decreased activity, while the nitrile substituent
offered significant pharmacokinetic advantages such as increased
AUC and T1/2. Upon the observation that aryl SAR in the
bicyclohexyl series may be unique, a series of substituents was
then incorporated in order to further probe the structural
requirements at this position. It was discovered that simple alkyl
substituents (24n) or electron-rich groups (24j) were tolerated
well in terms of binding affinity. Further, emerging trends
indicated that para-substituents provided receptor occupancy
Initial exploration of the side chain terminus in the bicyclo-
[3.1.0]hexyl series was achieved by fixing the 3-cyanoaryl
substituent on the bicyclic core, which had been previously
shown to be optimal in the biaryl and bicyclo[4.1.0]heptyl
series.17,27 Representative variations of side chains are shown
in Table 2. While excellent potency was observed with most
substituents, extension of the side chain provided optimal
potency (compare 23g with 27b). Pharmacokinetic parameters
were screened according to an in-house rapid rat protocol,29
which indicated that many of the compounds provided accept-
able exposure in rodents. Further studies showed that the
bicyclohexanes had improved ex vivo binding at the 6 h
timepoint relative to the bicycloheptanes. In some cases (23e
and 27b), greater than 80% receptor occupancy was obtained.
Ex vivo binding studies were performed for several compounds,
establishing the general trend that >70% receptor occupancy
@ 6 h correlated with in vivo efficacy.18,27
Initial SAR studies were performed on racemic bicycloalkyl
cores in order to maintain simplicity. As a result, where chiral
side chains were used, compounds were initially tested as a
diastereomeric mixture and are reported as such. To define

2300 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7
Table 4. Aryl SAR of Bicyclohexanes
McBriar et al.
ex vivo bindingc
b
no.
R6
R4
h-MCH-R1 Ki (nM)a
rat AUC(0-6h) (ng h mL-1
251
)
6 h
24 h
24b
24c
24d
24e
24f
24g
24h
24i
m-NHAcPh
m-NHSO2MePh
p-SO2Me Ph
Ph
m-OCF3Ph
p-OCF3Ph
m-ClPh
m-SO2MePh
m-NH2Ph
m-FPh
3-Cl, 4-F
3-Cl, 4-F
3-Cl, 4-F
3-Cl, 4-F
3-Cl, 4-F
3-Cl, 4-F
3-Cl, 4-F
3-Cl, 4-F
3-Cl, 4-F
3-Cl, 4-F
3-CF3, 4-F
3-CF3, 4-F
3-Cl, 4-F
3-Cl, 4-F
3-Cl, 4-F
3-CF3, 4-F
3-CF3, 4-F
3-Cl, 4-F
3-Cl, 4-F
3-CF3, 4-F
3-CF3, 4-F
3-CF3, 4-F
2.5 ( 0.2
394 ( 3
9.3 ( 0.2
8.9 ( 0.5
29 ( 2
13 ( 1.5
15 ( 0.5
727 ( 70
10 ( 3
3.3 ( 0.2
2.3 ( 0.3
1.8 ( 0.1
33 ( 1
13 ( 1
2 ( 0.7
18 ( 4
0 ( 2
2336
1129
504
578
436
8 ( 4
79 ( 2
39 ( 3
96 ( 3
0 ( 2
12 ( 3
15 ( 1
24j
24k
24l
37 ( 2
73 ( 1
85 ( 2
100 ( 4
0 ( 3
25 ( 2
25 ( 1
73 ( 1
100 ( 2
65 ( 2
97 ( 1
99 ( 4
81 ( 2
100 ( 2
17 ( 2
0 ( 3
10 ( 2
29 ( 4
4 ( 2
722
888
2169
m-FPh
p-FPh
24m
24n
24o
24p
24q
24r
24s
24t
m-MePh
3-thiophenyl
3-pyridyl
m-OMePh
p-OMePh
3,5-diFPh
3,4-diFPh
p-CNPh
12 ( 1
11 ( 2
0 ( 2
1001
571
438
2735
1608
642
3081
1659
2.9 ( 0.2
2.8 ( 0.3
7 ( 0.5
7 ( 2
0 ( 4
4.4 ( 0.3
2.7 ( 0.2
4 ( 0.1
0 ( 3
24u
24v
24w
58 ( 7
36 ( 5
6 ( 4
3-CN, 4-F Ph
3-F, 4-CN Ph
3.5 ( 0.1
a Mean values (n ) 8) ( SEM. Inhibition of [125I]-MCH binding to h-MCH-R1 expressed in Chinese Hamster Ovary (CHO) cells. b Data from pooled
samples as described in ref 29, dosed at 10 mg/kg, po. c Expressed as a percent inhibition of MCH-ADO binding relative to vehicle control ( SEM (n )
3; dosed at 30 mg/kg, po).
Table 5. Functional Antagonism Data of Selected Compoundsa
Table 6. In Vivo Efficacy in DIO Micea
food intake at time indicated (% of vehicle)
no.
h-MCH-R1 Kb (nM)
24m
24q
24r
24u
32
15.0 ( 5.0
8.0 ( 3.0
9.0 ( 4.0
1.9 ( 1.1
9.0 ( 2.0
no.
2 h
6 h
24 h
23eb
24g
24u
27a
27b
27c
65.7 ( 11.8*
86.2 ( 6.3
77.3 ( 6.9
88.0 ( 4.3
81.1 ( 4.5*
92.0 ( 5.7
68.2 ( 7.4*
80.5 ( 5.3*
76.0 ( 5.4*
83.4 ( 6.4*
81.6 ( 5.7*
101.1 ( 4.5
80.8 ( 5.3*
85.9 ( 5.3*
78.1 ( 5.1*
94.1 ( 5.1
89.1 ( 5.8
102.0 ( 3.1
a Inhibition of MCH-mediated Ca2+ influx into cells expressing hMCH-
R1 via FLIPR assay. Mean values (n ) 3) ( SEM.
a Values expressed as a percent of vehicle ( SEM (dosed at 30 mg/kg,
po). Asterisk (*) indicates value is significantly different from that of vehicle.
b Denotes a mixture of diastereomers.
of >90% at 6 h postdose (Table 4). To exploit this trend,
receptor occupancy was measured at 24 h postdose for several
compounds. Notably, it was discovered that 24u provided >50%
receptor coverage after 24 h, which would be suitable for qd
dosing.
Functional antagonism at MCH-R1 was previously confirmed
in the structurally related biaryl and bicyclo[4.1.0]heptyl
series;17,18,27 thus, exhaustive functional data was not obtained
for the current series. Rather, a set of compounds was tested
for inhibition of MCH-mediated Ca2+ influx into cells express-
ing h-MCH-R1 via FLIPR assay (Table 5). As anticipated, all
compounds tested displayed functional antagonism at MCH-
R1 with low nanomolar activities.
Having established a means to achieve extended receptor
coverage, the more promising compounds were dosed orally in
the 24 h DIO mouse in order to determine efficacy (Table 6).
Results of a representative set of compounds indicated that
several provided a statistically significant reduction of food
intake relative to vehicle controls. Consistent with the previous
studies, receptor occupancy of >70% at 6 h translated into acute
efficacy in the DIO mouse model. Importantly, compounds with
low ex vivo binding lacked efficacy and served as controls for
two reasons. Primarily, the lack of efficacy observed with these
compounds validated our use of the ex vivo binding protocol
as a preliminary screen. Second, these results indicated that
changes in food intake were unlikely a function of inherent
compound toxicity. Compounds 23e, 24g, and 24u showed
efficacy at the endpoint of the study, and 24u was chosen for
detailed evaluation on the basis of a superior overall profile
relative to that of the others.
As a precursor to further studies, pharmacokinetic properties
of 24u were determined in rats (Table 7). Despite high receptor
occupancy over 24 h and demonstrative activity in vivo, 24u
exhibited modest AUC and T1/2 in rodents. Further studies using
3H-24u indicated a major metabolite in the brain, which was
subsequently identified as the product resulting from demeth-
ylation of the terminal piperazine nitrogen atom (32, Scheme
4). Importantly, it was discovered that following dosing with

Bicyclo[3.1.0]hexyl Ureas as MCH-R1 Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7 2301
Conclusions
Table 7. Rat Pharmacokinetic Profile of Compound 24ua
oral AUC(0-24h) (µM h)
3.9
4.0
21.8
5.6
A structurally unique bicyclo[3.1.0]hexyl urea series has been
discovered as MCH-R1 antagonists for potential treatment of
obesity. Through a number of SAR studies on this and
structurally related series, selectivity has been obtained over
non-MCH mechanisms, and the bicyclic moiety has been
established as an effective replacement for the previously
identified mutagenic biaryl aniline. Structure-activity studies
also enabled exploitation of terminal aryl ring variations in order
to optimize receptor occupancy. Incorporation of ex vivo binding
studies as a measure of receptor occupancy provided a means
to delineate the unique advantages of the bicyco[3.1.0]hexyl
ureas relative to prior series. Further, ex vivo binding was used
as a means to predict efficacy in vivo, which in turn was
extended to chronic (28 day) rodent models. Compound 24u
was shown to exhibit efficacy in these models, having positive
effects on food intake and weight gain throughout the duration
of the studies while exhibiting no toxicity or adverse behavorial
effects. Further studies regarding adiposity, energy expenditure,
and other metabolic parameters will be reported in due course.33
IV half-life (h)
IV clearance (mL min-1 kg-1
)
Vd(ss) (L kg-1
)
bioavailability, F (%)
27
a n ) 3; dosed at 10 mg/kg, iv/po.
Table 8. Effect of 24u in 5 day DIO Mice Feeding Studiesa
cumulative
food intake (g)
body weight
change (%)
vehicle
10 mg/kg 24u
30 mg/kg 24u
17.0 ( 0.4
14.9 ( 0.7*
11.7 ( 0.7*
0.79 ( 0.62
-2.26 ( 0.74*
-6.04 ( 0.88*
a Values expressed ( SEM measured at endpoint (n ) 11/group, dosed
po, qd). Asterisk (*) indicates value is significantly different from that of
vehicle.
Table 9. Effect of 24u in 28 Day DIO Mice Feeding Studiesa
cumulative
food intake (g)
body weight
change (%)
vehicle
10 mg/kg 24u
30 mg/kg 24u
96.6 ( 1.5
87.0 ( 2.0*
79.4 ( 1.6*
7.71 ( 1.24
-1.48 ( 2.04*
-9.83 ( 0.91*
Experimental Section
General. All reagents and solvents were obtained from com-
mercial suppliers and used without further purification. All reactions
were carried out under an inert atmosphere of nitrogen unless
otherwise noted. Silica gel chromatography was performed using
prepacked silica gel cartridges (Biotage). 1H and 13C NMR spectra
were obtained on a Varian Gemini-300 (300 MHz, 1H; 75.5 MHz,
a Values expressed ( SEM measured at endpoint (n ) 11/group, dosed
po, qd). Asterisk (*) indicates value is significantly different from that of
vehicle.
24u, the brain concentration of 32 (340 ng/g) was 17-fold greater
than that of the parent 24u (20 ng/g) after 24 h. Independent
analysis of 32 showed that despite similar binding affinity (Ki
1
13C) or XL-400 (400 MHz, H; 100 MHz, 13C) spectrometer and
are reported as ppm downfield from Me4Si. Purity was checked
via LCMS analysis, performed on an Applied Biosystems API-
100 mass spectrometer and Shimadzu SCL-10A LC column:
Alltech platinum C18, 3 µm, 33 mm × 7 mm ID; gradient flow:
0 min- 10% CH3CN, 5 min- 95% CH3CN, 7 min- 95% CH3CN,
7.5 min- 10% CH3CN, 9 min- stop. Elemental analyses were
performed by Quantitative Technologies, Inc., Whitehouse, NJ, and
were within 0.4% of calculated values unless otherwise noted.
In vitro and in vivo data given throughout the text and in Tables
1-6, with exception of 23j, 23k, 24n, 24o, 24q, and 24r were
collected for the amorphous hydrochloride salts. The hydrochloride
salts were prepared by mixing the final compound with an excess
of 1.0 M hydrogen chloride solution in diethyl ether followed by
evaporation of the solvent.
N-[3-(3-Cyanophenyl)-2-cyclopenten-1-yl]-N′-(3,5-dichloro-
phenyl)-N-[2-(1-pyrrolidinyl)ethyl]urea (9). A solution of ketone
818a (120 mg, 0.66 mmol) in CH2Cl2 (7 mL) was treated with 1-(2-
aminoethyl)pyrrolidine (110 µL, 0.86 mmol) followed by NaB-
(OAc)3H (212 mg, 1.0 mmol). After 18 h, the reaction mixture
was diluted with a solution of saturated aqueous NaHCO3 and
extracted with EtOAc (2×). The combined organic phases were
dried and concentrated in vacuo. The crude product was dissolved
in DCE (5 mL) and treated with diisopropylethylamine (350 µL,
2.0 mmol) followed by 3,5-dichlorophenyl isocyanate (250 mg, 1.32
mmol). After 36 h, the reaction mixture was diluted with saturated
aqueous NaHCO3 and extracted with CH2Cl2 (3×). The combined
organic phases were dried and concentrated in vacuo. Preparative
thin-layer chromatography (75% EtOAc/Hex), followed by filtra-
tion, an EtOH rinse, and concentration in vacuo, furnished 9 (11.5
mg, 4% over 2 steps) as a white solid: 1H NMR (300 MHz, CDCl3)
δ 11.51 (s, 1 H), 7.71 (s, 1 H), 7.68 (d, J ) 7.7 Hz, 1H), 7.57 (d,
J ) 7.7 Hz, 1H), 7.46 (dd, J ) 7.7, 7.7 Hz, 1H), 7.32 (d, J ) 1.6
Hz, 2 H), 6.94 (m, 1 H), 6.12 (m, 1 H), 5.67 (m, 1 H), 3.32-3.22
(m, 2H), 2.90-2.54 (m, 8 H), 2.09-1.54 (m, 6 H); LCMS: 469.4,
rt ) 5.61 min (M + H+), 91.5% purity; HRMS (FAB) m/z 469.1568
[(M + H)+; calcd for C25H27N4OCl2: 469.1562].
) 8 nM, Kb ) 9.0 nM) and good exposure (rat AUC0-6h
)
3472 ng‚h/mL), receptor occupancy was poor (ex vivo binding
27% @ 6 h, 0% @ 24 h) when dosed as parent. Though the ex
vivo assay does not distinguish between parent and metabolite,
it serves as a suitable measure of receptor occupancy. Feeding
studies were not undertaken with 32 based on our experience
with poor ex vivo binding translating to lack of efficacy in the
feeding model. Additionally, the fact that compounds incapable
of terminal N-demethylation have demonstrated efficacy (23e)
supports the hypothesis that efficacy with 24u is not driven
mainly by the formation of metabolite 32.
Counter-screening of 24u against a panel of 103 receptors
and enzymes was performed at CEREP,32 which revealed no
appreciable affinity to other targets related to weight loss such
as CB1, H3, or the serotonin reuptake transporter.
Having demonstrated acute efficacy, 24u was evaluated in a
subchronic (5 day) DIO mouse study (Table 8). At oral dosages
of 10 and 30 mg/kg (qd), 24u significantly decreased cumulative
food intake and body weight relative to vehicle controls. At
the endpoint, brains were harvested from a subset of mice (n )
3/group) for ex vivo binding studies at 24 h post-last dose.
Receptor occupancy >99% was observed at 30 mg/kg and
>65% at 10 mg/kg, which is consistent with the in vivo activity
observed at these doses. These results indicate that prolonged
dosing significantly increased receptor occupancy relative to
that seen during the acute studies (vide supra).
Similar effects were also seen upon chronic (28 day) oral
dosing with 24u to DIO mice (Table 9). Efficacy was observed
at 10 and 30 mg/kg, as evidenced by statistically significant
reductions in cumulative food intake and weight gain at the
endpoint of the study. As in the previous studies, no evidence
of adverse behavioral effects or compound toxicity was observed
with any of the treated animals.
cis-3-(3-Hydroxy-cyclopentyl)-benzonitrile (11) and (()-trans-
3-(3-Hydroxy-cyclopentyl)-benzonitrile (12). A solution of 1018a
(1.45 g, 7.83 mmol) in MeOH (70 mL) was treated with Pd/C (1.5

2302 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7
McBriar et al.
g, 0.7 mmol; 50% in H2O) and stirred under 1 atm H2 via balloon.
After 1 h, the reaction mixture was filtered through Celite, rinsed
with MeOH, and concentrated in vacuo. Flash chromatography
(25% EtOAc/Hex) provided 11 (Rf ) 0.35, 1.0 g, 68%) as a clear
oil: 1H NMR (300 MHz, CDCl3) δ 7.58-7.52 (m, 3 H), 7.45 (dd,
J ) 7.7, 7.7 Hz, 1H), 4.47 (m, 1 H), 3.07 (m, 1 H), 2.46 (ddd, J )
13.7, 8.8, 6.0 Hz, 1H), 2.09 (m, 1 H), 1.94-1.80 (m, 4 H), 1.63
(ddd, J ) 13.2, 8.8, 4.4 Hz, 1 H); followed by 12 (Rf ) 0.30, 120
mg, 8%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.49-7.45
(m, 3 H), 7.37 (m, 1H), 4.55 (m, 1 H), 3.41 (m, 1 H), 2.31-2.06
(m, 2 H), 1.90 (s, 1 H), 1.71-1.62 (m, 3 H), 1.54 (m, 1 H).
trans-3-{3-[3-(4-Methyl-piperazin-1-yl)-propylamino]-cyclo-
pentyl}-benzonitrile (13). A solution of alcohol 11 (220 mg, 1.18
mmol) in CH2Cl2 (10 mL) at 0 °C was treated with Et3N (350 µL,
2.5 mmol) followed by MsCl (140 µL, 1.80 mmol). After 3 h, the
reaction mixture was diluted with saturated aqueous NaHCO3 and
extracted with CH2Cl2 (3×). The combined organic phases were
dried and concentrated in vacuo. The residue was dissolved in
propionitrile (10 mL), treated with K2CO3 (830 mg, 6.0 mmol)
followed by 1-(3-aminopropyl)-4-methylpiperazine (1.02 mL, 6.0
mmol), and heated to 100 °C. After 18 h, the reaction mixture was
cooled to ambient temperature, diluted with H2O, and extracted
with CH2Cl2 (3×). The combined organic extracts were dried and
concentrated in vacuo. Flash chromatography (10% NH4OH/MeOH
(1:9), 90% CH2Cl2) provided 13 (200 mg, 52% over 2 steps) as a
clear oil: 1H NMR (300 MHz, CDCl3) δ 7.49-7.42 (m, 3 H), 7.35
(dd, J ) 7.7, 7.7 Hz, 1H), 3.27 (m, 1 H), 2.62 (t, J ) 7.1 Hz, 2 H),
2.37 (t, J ) 7.1 Hz, 2 H), 2.40-2.26 (m, 11 H), 2.26 (s, 3 H), 2.16
(m, 1 H), 1.93 (ddd, J ) 7.7, 4.5, 4.4 Hz, 1 H), 1.80-1.48 (m, 4
H).
N′-(3-Chloro-4-fluorophenyl)-N-[trans-3-(3-cyanophenyl)cy-
clopentyl]-N-[3-(4-methyl-1-piperazinyl)propyl]urea (14). A so-
lution of amine 13 (80 mg, 0.245 mmol) in CH2Cl2 (2 mL) was
treated with diisopropylethylamine (87 µL, 0.5 mmol) followed by
3-chloro-4-fluorophenyl isocyanate (40 µL, 0.319 mmol). After 18
h, the reaction mixture was diluted with saturated aqueous NaHCO3
and extracted with CH2Cl2 (3×). The combined organic phases were
dried and concentrated in vacuo. Preparative thin-layer chroma-
tography (5% MeOH/CH2Cl2), followed by filtration, an EtOH
rinse, and concentration in vacuo gave 14 (74 mg, 61%) as a clear
oil: 1H NMR (300 MHz, CDCl3) δ 9.17 (s, 1 H), 7.49-7.44 (m,
4 H), 7.39 (d, J ) 7.7 Hz, 1H), 7.31 (m, 1 H), 7.05 (dd, J ) 8.8,
8.8 Hz, 1 H), 4.23 (dddd, J ) 8.8, 8.8, 8.5, 8.5 Hz, 1 H), 3.50
(dddd, J ) 8.8, 8.8, 8.5, 8.5 Hz, 1 H), 3.37 (t, J ) 4.9 Hz, 2 H),
2.32-2.22 (m, 9 H), 2.25 (s, 3 H), 2.11-1.54 (m, 7 H); LCMS:
498.1, rt ) 4.09 min (M + H+), >99% purity; HRMS (FAB) m/z
498.2440 [(M + H)+; calcd for C27H34ClFN5O: 498.2436].
cis-3-{3-[3-(4-Methyl-piperazin-1-yl)-propylamino]-cyclopen-
tyl}-benzonitrile (15). A solution of alcohol 11 (300 mg, 1.60
mmol) in THF (10 mL) at 0 °C was treated with Ph3P (840 mg,
3.20 mmol) followed by CBr4 (1.06 g, 3.2 mmol). After 1 h, the
reaction mixture was diluted with Et2O, filtered through Celite, and
concentrated in vacuo. Flash chromatography (2f10% Et2O/Hex)
provided the bromide (340 mg, 85%) as a clear oil: 1H NMR (300
MHz, CDCl3) δ 7.51-7.40 (m, 4 H), 4.66 (m, 1 H), 3.63 (dddd, J
) 8.2, 8.2, 8.2, 8.2 Hz, 1 H), 2.56-2.28 (m, 4 H), 2.14 (dddd, J )
8.2, 5.5, 5.2, 4.9 Hz, 1 H), 1.70 (m, 1 H).
tion of amine 15 (80 mg, 0.245 mmol) in CH2Cl2 (2 mL) was treated
with diisopropylethylamine (87 µL, 0.5 mmol) followed by
3-chloro-4-fluorophenyl isocyanate (40 µL, 0.319 mmol). After 18
h, the reaction mixture was diluted with saturated aqueous NaHCO3
and extracted with CH2Cl2 (3×). The combined organic phases were
dried and concentrated in vacuo. Preparative thin-layer chroma-
tography (5% MeOH/ CH2Cl2), followed by filtration, an EtOH
rinse, and concentration in vacuo, gave 16 (96 mg, 79%) as a clear
oil: 1H NMR (300 MHz, CDCl3) δ 9.18 (s, 1 H), 7.54-7.47 (m,
4 H), 7.38 (d, J ) 7.7 Hz, 1H), 7.36 (m, 1 H), 7.06 (dd, J ) 8.8,
8.8 Hz, 1 H), 4.34 (m, 1 H), 3.37 (t, J ) 5.5 Hz, 2 H), 3.07 (m, 1
H), 2.59-2.40 (m, 9 H), 2.26 (s, 3 H), 2.26-1.79 (m, 7 H);
LCMS: 498.1, rt ) 4.03 min (M + H+), >99% purity; HRMS
(FAB) m/z 498.2431 [(M + H)+; calcd for C27H34ClFN5O:
498.2436].
General Synthesis of 21: Method A. (a) (3-Oxo-cyclopent-
1-enyl)-benzonitrile (8). A solution of 3-bromobenzonitrile (26.8
g, 147.1 mmol) in THF (1000 mL) at -78 °C was treated with a
solution of n-butyllithium (2.5 M in hexanes; 61.0 mL, 155 mmol)
such that the reaction temperature remained less than or equal to
-78 °C. After 15 min, a solution of 3-methoxy-2-cyclopenten-1-
one (15 g, 134 mmol) in THF (80 mL) was added such that the
reaction temperature remained less than or equal to -78 °C. The
reaction mixture was warmed to -20 °C over 1.5 h, quenched with
a solution of 1 N HCl, and concentrated in vacuo to remove THF.
A solution of 1 N HCl (100 mL) was added, and then the solution
was stirred for 45 min and extracted with EtOAc (3×). The
combined organic extracts were washed with saturated aqueous
NaHCO3 and brine, dried over MgSO4, filtered, and concentrated
in vacuo. The residue was crystallized at 0 °C from a solution of
1 N HCl, filtered, and rinsed with cold 1 N HCl, H2O, and ether to
provide 8 (14.4 g, 59%) as a pale yellow solid: 1H NMR (300
MHz, CDCl3) δ 7.90 (d, J ) 1.6 Hz, 1 H), 7.90 (d, J ) 7.7 Hz, 1
H), 7.74 (d, J ) 7.7 Hz, 1 H), 7.59 (d, J ) 7.7 Hz, 1 H), 6.63 (d,
J ) 1.6 Hz, 1 H), 3.07-3.03 (m, 2 H), 2.65-2.62 (m, 2 H).
(b) 3-(3-Hydroxy-cyclopent-1-enyl)-benzonitrile (10). A solu-
tion of 8 (7.88 g, 43.0 mmol) in methanol (100 mL) at 0 °C was
treated with CeCl3‚7H2O (20.5 g, 55.0 mmol) followed portionwise
by NaBH4 (2.10 g, 55.0 mmol). The reaction was warmed to
ambient temperature over 12 h, quenched with saturated aqueous
NH4Cl, and concentrated to remove MeOH. The concentrate was
diluted with H2O and extracted with EtOAc (3×). The combined
organic extracts were washed with saturated aqueous NaHCO3 and
brine, dried, and concentrated in vacuo. Trituration (10% EtOAc/
Hex) at 0 °C and filtration afforded the alcohol 10 (6.39 g, 80%)
as a white powder: 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J )
1.6 Hz, 1H), 7.70 (d, J ) 7.7 Hz, 1H), 7.55 (dd, J ) 7.7, 1.6 Hz,
1H), 7.45 (t, J ) 7.7 Hz, 1H), 6.30 (dd, J ) 3.8, 1.6 Hz, 1H), 5.05
(m, 1H), 2.90 (m, 1H), 2.65 (m, 1H), 2.56 (m, 1H), 1.92 (m, 1H),
1.62 (br s, 1H).
(c) 3-(4-Hydroxy-bicyclo[3.1.0]hex-1-yl)-benzonitrile (20a: R1
) m-CN). A solution of allylic alcohol 10 (0.50 g, 2.7 mmol) in
CH2Cl2 (75 mL) was treated with Et2Zn (1.0 M in hexanes; 14
mL, 14 mmol). After 10 min, the reaction mixture was cooled to
0 °C, treated with a solution of CH2I2 (1.13 mL, 14 mmol) in
CH2Cl2 (10 mL) dropwise over 10 min, and allowed to warm to
ambient temperature. After 48 h, the reaction mixture was quenched
slowly with saturated aqueous NH4Cl and stirred for 10 min. The
reaction mixture was extracted with CH2Cl2 (2×), and the combined
organic phases were washed with saturated aqueous NaHCO3, dried,
and concentrated in vacuo. Flash chromatography (40% EtOAc/
Hex) gave 20a (500 mg, 93%) as a clear oil: 1H NMR (300 MHz,
CDCl3) δ 7.46-7.32 (m, 4 H), 4.69 (ddd, J ) 12.1, 7.7, 4.4 Hz,
1H), 2.20-1.85 (m, 4H), 1.80 (br s, 1H), 1.38-1.25 (m, 2H), 0.85
(dd, J ) 8.2, 5.5 Hz, 1H).
The bromide from the previous step (340 mg, 1.36 mmol) was
dissolved in propionitrile (10 mL) and treated with K2CO3 (940
mg, 6.8 mmol) followed by 1-(3-aminopropyl)-4-methylpiperazine
(1.15 mL, 6.8 mmol) and heated to 100 °C. After 18 h, the reaction
mixture was cooled to ambient temperature, diluted with H2O, and
extracted with CH2Cl2 (3×). The combined organic extracts were
dried and concentrated in vacuo. Flash chromatography (10% NH4-
OH/MeOH (1:9), 90% CH2Cl2) provided 15 (376 mg, 85%) as a
clear oil: 1H NMR (300 MHz, CDCl3) δ 7.54-7.46 (m, 3 H), 7.40
(dd, J ) 7.7, 7.7 Hz, 1H), 4.67 (m, 1 H), 3.64 (m, 1 H), 3.25 (m,
1 H), 3.06 (m, 1 H), 2.68 (t, J ) 7.1 Hz, 2 H), 2.55-2.40 (m, 9
H), 2.28 (s, 3 H), 2.19-1.98 (m, 3 H), 1.75-1.67 (m, 4 H).
N′-(3-Chloro-4-fluorophenyl)-N-[cis-3-(3-cyanophenyl)cyclo-
pentyl]-N-[3-(4 -methyl-1-piperazinyl)propyl]urea (16). A solu-
(d) 3-(4-Oxo-bicyclo[3.1.0]hex-1-yl)-benzonitrile (21a). A solu-
tion of alcohol 20a (0.50 g, 2.51 mmol) in CH2Cl2 (25 mL) at 0
°C was treated with pyridine (445 µL, 5.50 mmol) followed by
Dess-Martin periodinane (2.12 g, 5.0 mmol) and warmed to
ambient temperature. After 2 h, 3 drops of H2O were added. After
30 min further, the reaction was quenched with saturated aqueous

Bicyclo[3.1.0]hexyl Ureas as MCH-R1 Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7 2303
NaHCO3 and saturated aqueous Na2SO3 and extracted with CH2Cl2
(3×). The combined organic phases were dried and concentrated
in vacuo. Flash chromatography (25% EtOAc/Hex) gave 21a (440
mg, 89%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.55-
7.52 (m, 2 H), 7.47-7.43 (m, 2H), 2.45 (m, 1H), 2.40-2.25 (m,
3H), 2.17 (dd, J ) 9.3, 5.5 Hz, 1H), 1.61-1.52 (m, 2H).
(e) 5-(3-Bromo-phenyl)-bicyclo[3.1.0]hexan-2-one (21b). Fol-
lowing procedures similar to that described for the synthesis of
21a and using m-dibromobenzene (51%, 4 steps): 1H NMR (300
MHz, CDCl3) δ 7.40-7.37 (m, 2 H), 7.23-7.14 (m, 2 H), 2.47-
2.24 (m, 5 H), 2.15 (dd, J ) 9.3, 3.3 Hz, 1 H), 1.58 (dd, J ) 8.8,
3.8 Hz, 1 H), 1.48 (dd, J ) 4.9, 3.8 Hz, 1 H).
(f) [3-(4-Oxo-bicyclo[3.1.0]hex-1-yl)-phenyl]-carbamic Acid
tert-Butyl Ester (21c). A tube purged with argon was charged with
21b (875 mg, 3.48 mmol), tert-butyl carbamate (490 mg, 4.18
mmol), K2CO3 (962 mg, 6.96 mmol), and CuI (34 mg, 0.18 mmol),
evacuated, and purged with argon. N,N′-dimethylethylenediamine
(37 µL, 0.35 mmol) and toluene (3 mL) were added, and the tube
was sealed and heated to 110 °C. After 18 h, the reaction mixture
was cooled to ambient temperature, filtered through Celite, rinsed
with EtOAc, and concentrated in vacuo. Flash chromatography
(20% EtOAc/Hex) gave 21c (450 mg, 45%) as a clear oil: 1H NMR
(300 MHz, CDCl3) δ 7.40 (s, 1 H), 7.23 (dd, J ) 7.7, 7.7 Hz, 1
H), 7.15 (d, J ) 8.7 Hz, 1 H), 6.91 (d, J ) 7.6 Hz, 1 H), 6.56 (s,
1 H), 2.43-2.22 (m, 4 H), 2.11 (dd, J ) 9.3, 3.3 Hz, 1 H), 1.46
(dd, J ) 9.3, 4.9 Hz, 1 H), 1.51 (s, 9 H), 1.40 (m, 1 H).
80 °C. After 1.5 h, the reaction was cooled to ambient temperature,
diluted with CH2Cl2, washed with aqueous NaHCO3, dried, and
concentrated in vacuo. Flash chromatography (2% Et2O/Hex)
afforded alcohol 31n (745 mg, 60%) as a clear oil: 1H NMR (300
MHz, CDCl3) δ 7.30-7.24 (m, 2 H), 7.24 (dd, J ) 8.2, 7.1 Hz, 1
H), 7.10 (d, J ) 7.1 Hz, 1 H), 6.12 (dd, J ) 3.8, 2.2 Hz, 1 H), 5.08
(m, 1 H), 2.88 (m, 1 H), 2.60 (m, 1H), 2.40 (m, 1 H), 2.37 (s, 3
H), 1.87 (m, 1 H), 0.96 (s, 9 H), 0.15 (s, 6 H).
(b) 5-m-Tolyl-bicyclo[3.1.0]hexan-2-one (21n). A solution of
Et2Zn (1.0 M in hexanes; 1.6 mL, 1.6 mmol) in DCE (3.5 mL) at
0 °C was treated with ClCH2I (231 µL, 3.17 mmol) dropwise over
5 min. After an additional 10 min, a solution of 31n (228 mg, 0.792
mmol) in DCE (0.5 mL) was added dropwise over 10 min and
allowed to warm to ambient temperature. After 2 h, the reaction
mixture was quenched slowly with saturated aqueous NH4Cl and
stirred for 10 min. The reaction mixture was extracted with CH2Cl2
(2×), and the combined organic phases were washed with saturated
aqueous NaHCO3, dried, and concentrated in vacuo. A second
iteration was performed using 517 mg, 1.80 mmol of 31n, 3.6 mL
of Et2Zn, and 523 µL of ClCH2I. Flash chromatography (2% Et2O/
Hex, pretreating the column with 2% Et3N/Hex) of the combined
crude products gave the cyclopropane (646 mg, 83%) as a clear
oil: 1H NMR (300 MHz, CDCl3) δ 7.22 (m, 1 H), 7.17-6.99 (m,
3 H), 4.68 (m, 1 H), 2.36 (s, 3 H), 2.17-1.90 (m, 3 H), 1.79 (ddd,
J ) 8.2, 4.4, 3.8 Hz, 1 H), 1.38-1.30 (m, 2 H), 0.96 (s, 9 H), 0.84
(dd, J ) 7.7, 5.4 Hz, 1 H), 0.15 (s, 3 H), 0.13 (s, 3 H).
General Synthesis of 21: Method B. (a) 3-Bromo-cyclopent-
2-enol (29). A solution of 3-bromo-cyclopentenone23 (21 g, 100
mmol) in methanol (200 mL) at 0 °C was treated with CeCl3‚7H2O
(56.6 g, 152 mmol) followed portionwise by NaBH4 (5.75 g, 152
mmol). The reaction was warmed to ambient temperature over 12
h, quenched with saturated aqueous NH4Cl, and concentrated to
remove MeOH. The concentrate was diluted with saturated aqueous
NaHCO3 and extracted with CH2Cl2 (3×). The combined organic
extracts were dried and concentrated in vacuo. Flash chromatog-
raphy (15% EtOAc/Hex) afforded alcohol 29 (11.8 g, 70%) as a
clear oil: 1H NMR (300 MHz, CDCl3) δ 5.98 (m, 1 H), 4.79 (m,
1 H), 2.80 (m, 1 H), 2.60-2.35 (m, 2 H), 1.82 (m, 1 H), 1.65 (m,
1 H).
(b) 3-(4-Methanesulfonyl-phenyl)-cyclopent-2-enol (30d: Ar
) p-MeO2SPh). A solution of bromide 29 (1.04 g, 6.3 mmol) in
3:1:1 tol:EtOH:H2O (300 mL) was treated with (4-methanesulfo-
nyl)phenyl boronic acid (1.6 g, 8.19 mmol), Na2CO3 (2.0 g, 19.0
mmol), LiCl (0.40 g, 9.4 mmol), and Pd(Ph3P)4 (0.74 g, 0.64 mmol)
and heated to 80 °C. After 1.5 h, the reaction was cooled to ambient
temperature, diluted with CH2Cl2 and 0.5 mL of Et3N, washed with
aqueous NaHCO3, dried, and concentrated in vacuo. Flash chro-
matography (35% EtOAc/Hex) afforded alcohol 30d (0.61 g, 40%)
as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.92 (d, J ) 8.2 Hz,
2 H), 7.66-7.45 (m, 3 H), 6.40 (dd, J ) 3.8, 1.6 Hz, 1H), 5.05 (m,
1H), 3.09 (d, J ) 7.1 Hz, 1 H), 3.05 (s, 3 H), 2.90 (m, 1 H), 2.64
(m, 1H), 2.53 (m, 1 H), 1.96 (m, 1H), 1.71 (br s, 1 H).
The cyclopropane from the previous step (646 mg, 2.14 mmol)
was dissolved in THF (5 mL) and treated with TBAF (1.0 M in
THF; 4.2 mL, 4.2 mmol). After 18 h, the reaction mixture was
concentrated in vacuo. Flash chromatography (25% Et2OAc/Hex)
afforded the alcohol (394 mg, 98%) as a clear oil: 1H NMR (300
MHz, CDCl3) δ 7.20 (dd, J ) 8.8, 7.1 Hz, 1 H), 7.02-6.97 (m, 3
H), 4.71 (m, 1 H), 2.35 (s, 3 H), 2.19-2.03 (m, 3 H), 1.90 (ddd,
J ) 8.2, 4.4, 3.8 Hz, 1 H), 1.31-1.25 (m, 2 H), 0.85 (dd, J ) 8.2,
5.5 Hz, 1 H).
A solution of alcohol from the previous step (394 mg, 2.09 mmol)
in CH2Cl2 (2 mL) at 0 °C was treated with pyridine (375 µL, 4.59
mmol) followed by Dess-Martin periodinane (1.77 g, 4.18 mmol)
and warmed to ambient temperature. After 2 h, 3 drops of H2O
were added. After 6 h further, the reaction was quenched with
saturated aqueous NaHCO3, saturated aqueous Na2SO3, and ex-
tracted with CH2Cl2 (3×). The combined organic phases were dried
and concentrated in vacuo. Flash chromatography (10% EtOAc/
Hex) gave 21n (185 mg, 47%) as a clear oil: 1H NMR (300 MHz,
CDCl3) δ 7.23 (dd, J ) 7.7, 7.7 Hz, 1 H), 7.08-7.04 (m, 3 H),
2.44-2.22 (m, 4 H), 2.36 (s, 3 H), 2.11 (dd, J ) 9.3, 6.0 Hz, 1 H),
1.60 (dd, J ) 9.3, 4.4 Hz, 1 H), 1.47 (dd, J ) 4.4, 3.3 Hz, 1 H).
Representative Procedure for the Synthesis of Compounds
23a-k. (a) N-[5-(3-Cyanophenyl)bicyclo[3.1.0]hex-2-yl]-N′-(3,
5-dichlorophenyl)-N-[2-(1-pyrrolidinyl)ethyl]urea (23a). A solu-
tion of ketone 21a (100 mg, 0.51 mmol) in CH2Cl2 (1 mL) was
treated with 1-(2-aminoethyl)pyrrolidine (98 µL, 0.77 mmol)
followed by titanium tetraisopropoxide (200 µL, 0.67 mmol). After
18 h, the reaction mixture was diluted with MeOH (1 mL) and
sodium borohydride (38 mg, 1.0 mmol) was added. After 2 h
further, the reaction mixture was diluted with a solution of saturated
aqueous NaHCO3 and extracted with CH2Cl2 (4×). The combined
organic phases were dried and concentrated in vacuo to provide
the crude amine (140 mg). A portion of the crude product (66 mg)
was dissolved in CH2Cl2 (2 mL) and treated with diisopropyleth-
ylamine (78 µL, 0.45 mmol) followed by 3,5-dichlorophenyl
isocyanate (63 mg, 0.335 mmol). After 18 h, the reaction mixture
was diluted with saturated aqueous NaHCO3 and extracted with
CH2Cl2 (3×). The combined organic phases were dried and
concentrated in vacuo. Preparative thin-layer chromatography (75%
EtOAc/Hex), followed by filtration, an EtOH rinse, and concentra-
tion in vacuo, furnished 23a (59 mg, 50% over 2 steps) as a clear
oil: 1H NMR (300 MHz, CDCl3) δ 11.24 (s, 1 H), 7.48-7.37 (m,
4 H), 7.29 (s, 2 H), 6.92 (s, 1 H), 5.06 (dddd, J ) 8.8, 8.8, 5.2, 5.2
Hz, 1 H), 2.96-2.66 (m, 5 H), 2.18-1.89 (m, 8 H), 1.73 (ddd, J
) 12.1, 8.2, 4.4 Hz, 1 H), 1.31-1.21 (m, 2 H), 0.95 (dd, J ) 6.6,
(c) 5-(4-Methanesulfonyl-phenyl)-bicyclo[3.1.0]hexan-2-one
(21d: Ar ) p-MeO2SPh). Following the procedure described for
the synthesis of 21a using 30d (70%, 2 steps): 1H NMR (300 MHz,
CDCl3) δ 7.92 (d, J ) 8.2 Hz, 2 H), 7.40 (d, J ) 8.2 Hz, 2 H),
3.05 (s, 3 H), 2.56-2.11 (m, 4 H), 1.64-1.58 (m, 3 H).
General Synthesis of 21: Method C. (a) tert-Butyl-dimethyl-
(3-m-tolyl-cyclopent-2-enyloxy)-silane (31n: Ar ) m-MePh). A
solution of 29 (1.55 g, 9.51 mmol) in DMF (5 mL) was treated
with imidazole (647 mg, 9.51 mmol) and TBSCl (1.43 g, 9.51
mmol). After 5 h, the reaction mixture was diluted with saturated
aqueous NH4Cl and extracted with Et2O (3×). The combined
organic extracts were dried and concentrated in vacuo to provide
the silyl ether (3.0 g, >99%) as a clear oil: 1H NMR (300 MHz,
CDCl3) δ 5.76 (m, 1 H), 4.73 (m, 1 H), 2.63 (m, 1 H), 2.46 (m, 1
H), 2.23 (m, 1 H), 1.69 (m, 1 H), 0.78 (s, 9 H), -0.03 (s, 6 H).
The silyl ether from the previous step (1.2 g, 4.35 mmol) in 3:1:1
tol:EtOH:H2O (70 mL) was treated with (3-methyl)phenyl boronic
acid (887 mg, 6.52 mmol), Na2CO3 (1.38 g, 13.0 mmol), LiCl (0.28
g, 6.52 mmol), and Pd(Ph3P)4 (0.50 g, 0.44 mmol) and heated to

2304 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7
McBriar et al.
6.6 Hz, 1H); LCMS: 483.3, rt ) 5.50 min (M + H+), 95.5% purity;
HRMS (FAB) m/z 483.1722 [(M + H)+; calcd for C26H29Cl2N4O:
483.1718]. Anal. (C26H28Cl2N4O‚HCl‚0.5H2O): C, H, N.
Following procedures similar to those described for compound
23a, we prepared the following compounds.
1.94 (m, 3 H), 1.74-1.52 (m, 7 H), 1.29-1.23 (m, 2 H), 0.94 (dd,
J ) 6.6, 6.6 Hz, 1H); LCMS: 481.1, rt ) 4.88 min (M + H+),
97.7% purity; HRMS (FAB) m/z 481.2173 [(M + H)+; calcd for
C27H29ClFN4O: 481.2170]. Anal. (C27H30ClFN4O‚HCl‚0.5H2O): C,
H, N.
(f) N-[trans-5-(3-Cyanophenyl)bicyclo[3.1.0]hex-2-yl]-N′-[4-
fluoro-3-(trifluoromethyl)phenyl]-N-[2-(4-methyl-1-piperazinyl)-
ethyl]urea (23g). Using 1-(2-aminoethyl)-4-Boc-piperazine and
4-fluoro-3-(trifluoromethyl)phenyl isocyanate, the Boc-protected
urea was obtained (29%, 2 steps): 1H NMR (300 MHz, CDCl3) δ
10.16 (s, 1 H), 7.66-7.38 (m, 6 H), 7.11 (dd, J ) 9.9, 9.3 Hz, 1
H), 5.08 (dddd, J ) 8.8, 8.8, 5.2, 5.2 Hz, 1 H), 3.59-3.43 (m, 6
H), 2.76-2.62 (m, 5 H), 2.17-1.97 (m, 4 H), 1.72 (ddd, J ) 7.6,
4.4, 4.4 Hz, 1 H), 1.47 (s, 9 H), 1.27-0.97 (m, 2 H), 0.96 (dd, J
) 7.1, 5.4 Hz, 1H).
A solution of the Boc-protected urea (0.45 g, 0.731 mmol) in
CH2Cl2 (7 mL) at 0 °C was treated with TFA (1.5 mL) and warmed
to ambient temperature. After 18 h, the reaction was quenched with
saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×). The
combined organic phases were dried and concentrated in vacuo to
give the free piperazine (370 mg, 98%) as a clear oil: 1H NMR
(300 MHz, CDCl3) δ 10.29 (s, 1 H), 7.71-7.37 (m, 6 H), 7.11
(dd, J ) 9.8, 9.3 Hz, 1 H), 5.07 (dddd, J ) 8.4, 8.4, 4.9, 4.9 Hz,
1 H), 3.56 (dd, J ) 15.9, 6.0 Hz, 1 H), 3.40 (dd, J ) 16.2, 6.0 Hz,
1 H), 2.99 (t, J ) 4.9 Hz, 2 H), 2.78-2.61 (m, 6 H), 2.18-1.93
(m, 4 H), 1.72 (ddd, J ) 7.7, 4.5, 4.4 Hz, 1 H), 1.36-1.23 (m, 2
H), 0.97 (dd, J ) 7.7, 5.5 Hz, 1H).
(b) N′-(3-Chloro-4-fluorophenyl)-N-[trans-5-(3-cyanophenyl)-
bicyclo[3.1.0]hex-2-yl]-N-[2-(1-pyrrolidinyl)ethyl]urea (23b). Us-
ing 3-chloro-4-fluorophenyl isocyanate (54%): 1H NMR (300 MHz,
CDCl3) δ 10.96 (s, 1 H), 7.46-7.36 (m, 5 H), 7.14 (m, 1 H), 7.00
(dd, J ) 8.8, 8.8 Hz, 1 H), 5.07 (dddd, J ) 8.8, 8.8, 5.2, 5.2 Hz,
1 H), 3.49 (dd, J ) 15.4, 7.1 Hz, 1 H), 3.39 (dd, J ) 15.4, 5.5 Hz,
1 H), 2.94 (dd, J ) 12.6, 7.1 Hz, 1 H), 2.94-2.73 (m, 4 H), 2.17-
1.85 (m, 8 H), 1.71 (ddd, J ) 12.1, 8.2, 4.4 Hz, 1 H), 1.28-1.20
(m, 2 H), 0.94 (dd, J ) 6.6, 6.6 Hz, 1H); LCMS: 467.3, rt ) 5.23
min (M + H+), 93.5% purity; HRMS (FAB) m/z 467.2020 [(M +
H)+; calcd for C26H29ClFN4O: 467.2014]. Anal. (C26H28ClFN4O‚
HCl‚H2O): C, H, N.
(c) (+)-N′-(3-Chloro-4-fluorophenyl)-N-[trans-5-(3-cyano-
phenyl)bicyclo[3.1.0]h ex-2-yl]-N-[2-[3(R)-hydroxy-1-pyrrolidin-
yl]ethyl]urea (23c) and (-)-N′-(3-Chloro-4-fluorophenyl)-N-
[trans-5-(3-cyanophenyl)bicyclo[3.1.0]hex-2-yl]-N-[2-[3(R)-hydroxy-
1-pyrrolidinyl]ethyl]urea (23d). Using (R)-3-hydroxy-1-(2-amino-
ethyl)pyrrolidine34 and 3-chloro-4-fluorophenyl isocyanate. Dia-
stereomers were separated via preparative HPLC using a chiral AD
column (25% i-PrOH/Hex, isocratic), flow rate 40 mL/min, to
provide (+)-23c (16%, 2 steps): [R]25 +65.5° (c 1.0, CHCl3); rt
D
1
) 76 min, 100% purity; H NMR (300 MHz, CDCl3) δ 10.49 (s,
1 H), 7.63 (dd, J ) 6.6, 2.2 Hz, 1 H), 7.46-7.43 (m, 2 H), 7.40-
7.36 (m, 2 H), 7.34 (m, 1 H), 6.98 (dd, J ) 8.8, 8.8 Hz, 1 H), 5.02
(dddd, J ) 8.8, 8.8, 5.2, 5.2 Hz, 1 H), 4.52 (m, 1 H), 3.48 (dd, J
) 15.4, 7.1 Hz, 1 H), 3.39 (dd, J ) 15.4, 5.5 Hz, 1 H), 3.10 (ddd,
J ) 8.2, 7.4, 6.6 Hz, 1 H), 2.93-2.73 (m, 4 H), 2.58 (m, 1 H),
2.29-1.81 (m, 6 H), 1.72 (ddd, J ) 12.1, 8.2, 4.4 Hz, 1 H), 1.31-
1.21 (m, 2 H), 0.94 (dd, J ) 6.6, 6.6 Hz, 1H); LCMS: 483.1, rt )
4.85 min (M + H+), >99% purity; HRMS (FAB) m/z 483.1960
[(M + H)+; calcd for C26H29ClFN4O2: 483.1963]; and (-)-23d
(20%, 2 steps): [R]25D -46.4° (c 1.0, CHCl3); rt ) 159 min, 100%
A solution of the piperazine from the previous step (80 mg, 0.155
mmol) in CH2Cl2 (2 mL) was treated with a solution of formal-
dehyde (50 µL, 0.6 mmol; 37% in H2O) followed by NaB(OAc)3H
(160 mg, 0.75 mmol) and Na2SO4 (350 mg, 2.5 mmol). After 18
h, the reaction was quenched with saturated aqueous NaHCO3 and
extracted with CH2Cl2 (3×). The combined organic phases were
dried and concentrated in vacuo. Preparative thin-layer chroma-
tography (5% MeOH/CH2Cl2) provided 23g (47 mg, 57%) as a
yellow solid: 1H NMR (300 MHz, CDCl3) δ 10.33 (s, 1 H), 7.76
(m, 1 H), 7.62 (m, 1 H), 7.48-7.44 (m, 2 H), 7.39-7.37 (m, 2 H),
7.11 (dd, J ) 8.8, 8.8 Hz, 1 H), 5.07 (dddd, J ) 8.8, 8.8, 5.2, 5.2
Hz, 1 H), 3.53 (dd, J ) 15.4, 7.1 Hz, 1 H), 3.41 (dd, J ) 15.4, 5.5
Hz, 1 H), 2.79-2.55 (m, 10 H), 2.33 (s, 3 H), 2.19-1.93 (m, 3 H),
1.71 (ddd, J ) 12.1, 8.2, 4.4 Hz, 1 H), 1.29-1.20 (m, 2 H), 0.96
(dd, J ) 6.6, 6.6 Hz, 1H); LCMS: 530.1, rt ) 4.85 min (M +
H+), 91.9% purity; HRMS (FAB) m/z 530.2538 [(M + H)+; calcd
for C28H32F4N5O: 530.2543]. Anal. (C28H31F4N5O‚HCl‚H2O): C,
H, N.
(g) N-[trans-5-(3-Cyanophenyl)bicyclo[3.1.0]hex-2-yl]-N′-[4-
fluoro-3-(trifluoromethyl)phenyl]-N-[2-[4-(2-methylpropyl)-1-
piperazinyl]ethyl]urea (23h). Following the procedure described
for 23g and using the piperazine intermediate from the synthesis
of 23g and isobutyraldehyde (65%, 2 steps): 1H NMR (300 MHz,
CDCl3) δ 10.48 (s, 1 H), 7.75 (m, 1 H), 7.65 (m, 1 H), 7.48-7.45
(m, 2 H), 7.39-7.37 (m, 2 H), 7.11 (dd, J ) 8.7, 8.7 Hz, 1 H),
5.08 (dddd, J ) 8.7, 8.7, 5.1, 5.1 Hz, 1 H), 3.53 (dd, J ) 15.3, 7.1
Hz, 1 H), 3.42 (dd, J ) 15.3, 5.5 Hz, 1 H), 2.71-2.52 (m, 10 H),
2.19-1.93 (m, 5 H), 1.78-1.69 (m, 2 H), 1.30-1.24 (m, 3 H),
0.99 (dd, J ) 6.6, 6.6 Hz, 6 H); LCMS: 572.1, rt ) 5.12 min (M
+ H+), 99% purity; HRMS (FAB) m/z 572.3020 [(M + H)+; calcd
for C31H38F4N5O: 572.3012]. Anal. (C31H37F4N5O‚2HCl): C, H,
N.
1
purity; H NMR (300 MHz, CDCl3) δ 10.50 (s, 1 H), 7.63 (dd, J
) 6.6, 2.2 Hz, 1 H), 7.47-7.44 (m, 2 H), 7.41-7.37 (m, 2 H),
7.30 (m, 1 H), 6.99 (dd, J ) 8.8, 8.8 Hz, 1 H), 5.05 (dddd, J )
8.8, 8.8, 5.2, 5.2 Hz, 1 H), 4.53 (m, 1 H), 3.50 (dd, J ) 15.4, 7.1
Hz, 1 H), 3.39 (dd, J ) 15.4, 5.5 Hz, 1 H), 3.17 (ddd, J ) 8.2, 7.4,
6.6 Hz, 1 H), 2.99-2.74 (m, 4 H), 2.54 (m, 1 H), 2.27-1.84 (m,
6 H), 1.72 (ddd, J ) 12.1, 8.2, 4.4 Hz, 1 H), 1.30-1.23 (m, 2 H),
0.95 (dd, J ) 6.6, 6.6 Hz, 1H); LCMS: 483.1, rt ) 4.84 min (M
+ H+), >99% purity; HRMS (FAB) m/z 483.1960 [(M + H)+;
calcd for C26H29ClFN4O2: 483.1963]. Anal. (C26H28ClFN4O2‚
HCl): C, H, N.
(d) N-[trans-5-(3-Cyanophenyl)bicyclo[3.1.0]hex-2-yl]-N′-[4-
fluoro-3-(trifluoromethyl)phenyl]-N-[2-(3(R)-hydroxy-1-pyrro-
lidinyl]ethyl]urea (23e). Using (R)-3-hydroxy-1-(2-aminoethyl)-
pyrrolidine and 4-fluoro-3-(trifluoromethyl)phenyl isocyanate (51%,
2 steps): 1H NMR (300 MHz, CDCl3) δ 10.68 (d, J ) 14.3 Hz, 1
H), 7.71-7.68 (m, 2 H), 7.46-7.36 (m, 4 H), 7.04 (dd, J ) 9.9,
9.9 Hz, 1 H), 5.06 (ddd, J ) 9.9, 7.1, 3.3 Hz, 1 H), 4.50 (m, 1 H),
3.50 (dd, J ) 15.4, 7.1 Hz, 1 H), 3.41 (dd, J ) 15.4, 7.1 Hz, 1 H),
3.13 (ddd, J ) 15.9, 15.4, 8.2 Hz, 1 H), 2.98-2.71 (m, 4 H), 2.55
(ddd, J ) 15.9, 15.9, 8.8 Hz, 1 H), 2.42 (br s, 1 H), 2.28-1.80 (m,
5 H), 1.72 (ddd, J ) 7.7, 7.1, 3.3 Hz, 1 H), 1.34-1.19 (m, 2 H),
0.94 (dd, J ) 7.1, 6.0 Hz, 1 H); LCMS: 517.1, rt ) 4.50 min (M
+ H+), 98.3% purity; HRMS (FAB) m/z 517.2250 [(M + H)+;
calcd for C27H29N4O2F4: 517.2227]. Anal. (C27H28N4O2F4‚HCl‚
0.5H2O): C, H, N.
(h) N′-(3-Chloro-4-fluorophenyl)-N-[trans-5-[4(methylsulfonyl)-
phenyl]bicyclo[3.1.0]hex-2-yl]-N-[2-(2-pyridinyl)ethyl]urea (23i).
Following procedures described for 23a and using 21d (synthesized
according to method B), 2-(2-aminoethyl)pyridine and 3-chloro-
4-fluorophenyl isocyanate: 1H NMR (300 MHz, CDCl3) δ 9.76
(s, 1 H), 8.65 (d, J ) 4.4 Hz, 1 H), 7.85 (d, J ) 8.2 Hz, 2 H),
7.75-7.67 (m, 2 H), 7.42 (m, 1 H), 7.38 (d, J ) 8.2 Hz, 2 H),
7.25-7.22 (m, 2 H), 7.06 (dd, J ) 8.8, 8.8 Hz, 1 H), 5.20 (dddd,
J ) 8.7, 8.7, 5.0, 5.0 Hz, 1 H), 3.93 (m, 1 H), 3.76 (m, 1 H), 3.23
(t, J ) 6.6 Hz, 2 H), 3.05 (s, 3 H), 2.27-1.99 (m, 3 H), 1.86 (ddd,
J ) 12.2, 8.2, 4.5 Hz, 1 H), 1.48 (t, J ) 4.9 Hz, 1 H), 1.37 (m, 1
H), 1.11 (dd, J ) 7.7, 5.4 Hz, 1 H); LCMS: 528.1, rt ) 4.39 min
(e) N′-(3-Chloro-4-fluorophenyl)-N-[trans-5-(3-cyanophenyl)-
bicyclo[3.1.0]hex-2-yl]-N-[2-(1-piperidinyl)ethyl]urea (23f). Us-
ing 1-(2-aminoethyl)piperidine and 3-chloro-4-fluorophenyl isocy-
1
anate (70%, 2 steps): H NMR (300 MHz, CDCl3) δ 10.55 (s, 1
H), 7.60 (dd, J ) 6.6, 2.2 Hz, 1 H), 7.47-7.44 (m, 2 H), 7.38-
7.37 (m, 2 H), 7.23 (m, 1 H), 7.03 (dd, J ) 8.8, 8.8 Hz, 1 H), 5.07
(dddd, J ) 8.8, 8.8, 5.2, 5.2 Hz, 1 H), 3.49 (dd, J ) 15.4, 7.1 Hz,
1 H), 3.37 (dd, J ) 15.4, 5.5 Hz, 1 H), 2.71-2.58 (m, 6 H), 2.18-

Bicyclo[3.1.0]hexyl Ureas as MCH-R1 Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7 2305
(M + H+), 92% purity; HRMS (FAB) m/z 528.1510 [(M + H)+;
calcd for C27H28ClFN3O3S: 528.1524].
) 7.7 Hz, 1 H), 5.03 (dddd, J ) 8.4, 8.4, 4.9, 4.9 Hz, 1 H), 3.51-
3.29 (m, 2 H), 2.67-2.27 (m, 7 H), 2.26 (s, 3 H), 2.16 (s, 3 H),
2.15-1.72 (m, 8 H), 1.65 (ddd, J ) 7.7, 4.5, 4.5 Hz, 1 H), 1.31-
1.21 (m, 2 H), 0.93 (dd, J ) 7.7, 5.5 Hz, 1 H); LCMS: 542.1, rt
) 4.50 min (M + H+), 99% purity; HRMS (FAB) m/z 542.2690
[(M + H)+; calcd for C29H38ClFN5O2: 542.2698].
N-[3-[trans-4-[[[(3-Chloro-4-fluorophenyl)amino]carbonyl][3-
(4-methyl-1-piperazinyl)propyl]amino]bicyclo[3.1.0]hex-1-yl]-
phenyl]methanesulfonamide (24c). Following the procedure used
for the synthesis of 24b and using 24j and methanesulfonyl chloride
(17%): 1H NMR (300 MHz, CDCl3) δ 9.35 (s, 1 H), 7.53 (dd, J
) 6.8, 3.0 Hz, 1 H), 7.37 (m, 1 H), 7.22 (dd, J ) 7.7, 7.1 Hz, 1
H), 7.09-6.98 (m, 4 H), 5.05 (dddd, J ) 8.4, 8.4, 4.9, 4.9 Hz, 1
H), 3.54-3.31 (m, 2 H), 2.99 (s, 3 H), 2.69-2.29 (m, 11 H), 2.26
(s, 3 H), 2.15-1.87 (m, 4 H), 1.68 (ddd, J ) 7.6, 4.4, 4.4 Hz, 1
H), 1.33-1.24 (m, 2 H), 0.93 (dd, J ) 7.1, 5.4 Hz, 1 H); LCMS:
578.1, rt ) 4.79 min (M + H+), >99% purity; HRMS (FAB) m/z
578.2368 [(M + H)+; calcd for C28H38ClFN5O3S: 578.2368].
N′-(3-Chloro-4-fluorophenyl)-N-[3-(4-methyl-1-piperazinyl)-
propyl]-N-[trans-5-[4-(methylsulfonyl)phenyl]bicyclo[3.1.0]hex-
2-yl]urea (24d). Following the procedure used for the synthesis of
23a and using 21d (synthesized via method B), 1-(3-aminopropyl)-
4-methylpiperazine, and 3-chloro-4-fluorophenyl isocyanate (24%,
2 steps): 1H NMR (300 MHz, CDCl3) δ: 9.40 (s, 1 H), 7.85 (d, J
) 8.2 Hz, 2 H), 7.59 (m, 1 H), 7.39 (m, 1 H), 7.30 (d, J ) 8.2 Hz,
2 H), 7.07 (dd, J ) 8.8, 8.8 Hz, 1 H), 5.06 (dddd, J ) 8.7, 8.7, 5.0,
5.0 Hz, 1 H), 3.53-3.29 (m, 2 H), 3.03 (s, 3 H), 2.78-2.30 (m, 12
H), 2.26 (s, 3 H), 2.15-1.82 (m, 3 H), 1.65-1.20 (m, 3 H), 0.92
(dd, J ) 7.7, 5.5 Hz, 1 H); LCMS: 563.1, rt ) 3.86 min (M +
H+), 90% purity; HRMS (FAB) m/z 563.2289 [(M + H)+; calcd
for C28H37ClFN4O3S: 563.2259].
(i) N′-(3-Chloro-4-fluorophenyl)-N-[trans-5-[4(methylsulfonyl)-
phenyl]bicyclo[3.1.0]hex-2-yl]-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-
urea (23j). Following procedures described for 23a and using 21d
(synthesized according to method B), N-(3-aminopropyl)-2-pyrro-
lidinone and 3-chloro-4-fluorophenyl isocyanate: 1H NMR (300
MHz, CDCl3) δ 8.55 (s, 1 H), 7.83 (d, J ) 8.2 Hz, 2 H), 7.60 (m,
1 H), 7.47 (m, 1 H), 7.29 (d, J ) 8.2 Hz, 2 H), 7.03 (m, 1 H), 6.35
(s, 1 H), 4.81 (dddd, J ) 8.8, 8.8, 4.9, 4.9 Hz, 1 H), 3.69-3.53
(m, 2 H), 3.04-3.00 (m, 6 H), 2.26-1.97 (m, 3 H), 1.73 (ddd, J )
12.2, 8.2, 4.5 Hz, 1 H), 1.44-1.31 (m, 1 H), 1.11 (dd, J ) 7.7, 5.3
Hz, 1 H); LCMS: 548.1, rt ) 4.51 min (M + H+), 90% purity;
HRMS (FAB) m/z 548.1772 [(M + H)+; calcd for C27H32-
ClFN3O4S: 548.1786]. Anal. (C27H31ClFN3O4S‚3H2O): C, H, N.
(j) 4-[[[[(3-Chloro-4-fluorophenyl)amino]carbonyl][(trans-5-
[4-(methylsulfonyl)phenyl]bicyclo[3.1.0]hex-2-yl]amino]methyl]-
1-(methylsulfonyl)piperidine (23k). Following procedures de-
scribed for 23a and using 21d (synthesized according to method
B), N-methanesulfonyl-4-(1-aminomethyl)piperidine,31 and 3-chloro-
4-fluorophenyl isocyanate: 1H NMR (300 MHz, CDCl3) δ 7.84-
7.80 (m, 2 H), 7.54 (dd, J ) 8.2, 2.2 Hz, 1 H), 7.33-7.30 (m, 2
H), 7.21 (m, 1 H), 7.04 (m, 1 H), 6.71 (m, 1 H), 4.75 (dddd, J )
8.8, 8.8, 4.9, 4.9 Hz, 1 H), 3.81 (d, J ) 10.4 Hz, 2 H), 3.35 (dd, J
) 14.8, 6.6 Hz, 1 H), 3.27 (m, 1 H), 3.03 (s, 3 H), 2.76 (s, 3 H),
2.64 (t, J ) 9.9 Hz, 2 H), 2.24-1.81 (m, 7 H), 1.41-1.33 (m, 4
H), 1.11 (dd, J ) 7.7, 5.3 Hz, 1 H); LCMS: 598.1, rt ) 4.55 min
(M + H+), 96% purity; HRMS (FAB) m/z 598.1584 [(M + H)+;
calcd for C27H34ClFN3O5S2: 598.1612]. Anal. (C27H33ClFN3O5S2‚
0.5H2O): C, H, N.
[3-(4-{3-(3-Chloro-4-fluoro-phenyl)-1-[3-(4-methyl-piperazin-
1-yl)-propyl]-ureido}-bicyclo[3.1.0]hex-1-yl)-phenyl]-carbam-
ic Acid tert-Butyl Ester (24a). Following procedures similar to
those described for the synthesis of compound 23a and using 21c,
1-(3-aminopropyl)-4-methylpiperazine, and 3-chloro-4-fluorophenyl
isocyanate (68%, 2 steps): 1H NMR (300 MHz, CDCl3) δ 9.25 (s,
1 H), 7.54 (m, 1 H), 7.38 (m, 1 H), 7.18-7.05 (m, 4 H), 6.86 (d,
J ) 7.7 Hz, 1 H), 6.52 (s, 1 H), 5.03 (dddd, J ) 8.2, 8.2, 4.9, 4.9
Hz, 1 H), 3.45-3.32 (m, 2 H), 2.30-2.11 (m, 9 H), 2.25 (s, 3 H),
2.11-1.85 (m, 3 H), 1.65 (ddd, J ) 7.6, 4.4, 4.4 Hz, 1 H), 1.51 (s,
9 H), 1.25-1.20 (m, 2 H), 0.93 (dd, J ) 7.1, 5.4 Hz, 1 H).
N-[trans-5-(3-Aminophenyl)bicyclo[3.1.0]hex-2-yl]-N′-(3-chloro-
4-fluorophenyl)-N-[3-(4-methyl-1-piperazinyl)propyl]urea (24j).
A solution of 24a (640 mg, 1.07 mmol) in 20% TFA/CH2Cl2 (10
mL) was stirred at ambient temperature. After 12 h, the reaction
mixture was concentrated in vacuo, diluted with CH2Cl2, poured
into saturated aqueous NaHCO3, and extracted with CH2Cl2 (2×).
The combined organic phases were dried and concentrated in vacuo
to provide 24j (470 mg, 88%) as a yellow oil: 1H NMR (300 MHz,
CDCl3) δ 9.27 (s, 1 H), 7.53 (dd, J ) 6.6, 2.7 Hz, 1 H), 7.39 (m,
1 H), 7.07 (dd, J ) 7.7, 2.2 Hz, 1 H), 7.06 (dd, J ) 9.3, 4.9 Hz,
1 H), 6.60-6.51 (m, 4 H), 5.03 (dddd, J ) 8.2, 8.2, 4.9, 4.9 Hz, 1
H), 3.62 (s, 2 H), 3.50-3.32 (m, 2 H), 2.70-2.33 (m, 10 H), 2.27
(s, 3 H), 2.11-1.82 (m, 5 H), 1.63 (ddd, J ) 7.6, 4.4, 4.4 Hz, 1
H), 1.29-1.20 (m, 2 H), 0.91 (dd, J ) 7.1, 5.4 Hz, 1 H); LCMS:
501.1, rt ) 4.02 min (M + H+), 94% purity; HRMS (FAB) m/z
500.2597 [(M + H)+; calcd for C27H36ClFN5O: 500.2592].
N-[3-[trans-4-[[[(3-Chloro-4-fluorophenyl)amino]carbonyl][3-
(4-methyl-1-piperazinyl)propyl]amino]bicyclo[3.1.0]hex-1-yl]-
phenyl]acetamide (24b). A solution of 24j (75 mg, 0.15 mmol)
was dissolved in CH2Cl2 (3 mL) and treated with diisopropyleth-
ylamine (52 µL, 0.30 mmol) followed by acetyl chloride (17 µL,
0.23 mmol). After 12 h, diisopropylethylamine (52 µL, 0.30 mmol),
acetyl chloride (17 µL, 0.23 mmol), and DMAP (5 mg) were added.
After 18 h further, the reaction mixture was diluted with saturated
aqueous NaHCO3 and extracted with CH2Cl2 (2×). The combined
organic phases were dried and concentrated in vacuo. Preparative
thin-layer chromatography (10% MeOH/CH2Cl2) furnished 24b (30
mg, 37%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 9.28 (s, 1
H), 7.54 (dd, J ) 6.6, 2.2 Hz, 1 H), 7.41-7.26 (m, 3 H), 7.21 (dd,
J ) 8.2, 7.7 Hz, 1 H), 7.05 (dd, J ) 8.8, 8.8 Hz, 1 H), 6.94 (d, J
N′-(3-Chloro-4-fluorophenyl)-N-[3-(4-methyl-1-piperazinyl)-
propyl]-N-[trans-5-phenylbicyclo[3.1.0]hex-2-yl]urea (24e). Fol-
lowing the procedure used for the synthesis of 23a and using 21e
(Ar ) phenyl, synthesized via method B), 1-(3-aminopropyl)-4-
methylpiperazine, and 3-chloro-4-fluorophenyl isocyanate (44%, 2
steps): 1H NMR (300 MHz, CDCl3) δ 9.27 (s, 1 H), 7.54 (dd, J )
6.6, 2.7 Hz, 1 H), 7.39 (m, 1 H), 7.31-7.26 (m, 2 H), 7.20-7.18
(m, 3 H), 7.06 (dd, J ) 8.8, 8.8 Hz, 1 H), 5.07 (dddd, J ) 8.8, 8.8,
4.9, 4.9 Hz, 1 H), 3.52-3.31 (m, 2 H), 2.70-1.85 (m, 15 H), 2.27
(s, 3 H), 1.66 (ddd, J ) 12.1, 8.2, 4.4 Hz, 1 H), 1.32-1.23 (m, 2
H), 0.94 (dd, J ) 8.2, 5.5 Hz, 1 H); LCMS: 485.1, rt ) 4.94 min
(M + H+), 97% purity; HRMS (FAB) m/z 485.2478 [(M + H)+;
calcd for C27H35ClFN4O: 485.2483].
N′-(3-Chloro-4-fluorophenyl)-N-[3-(4-methyl-1-piperazinyl)-
propyl]-N-[trans-5-[3-(trifluoromethoxy)phenyl]bicyclo[3.1.0]-
hex-2-yl]urea (24f). Following the procedure used for the synthesis
of 23a and using 21f (Ar ) m-OCF3Ph, synthesized via method
B), 1-(3-aminopropyl)-4-methylpiperazine, and 3-chloro-4-fluo-
rophenyl isocyanate (31%, 2 steps): 1H NMR (300 MHz, CDCl3)
δ 9.24 (s, 1 H), 7.45 (m, 1 H), 7.41 (dd, J ) 7.1, 2.2 Hz, 1 H),
7.18 (d, J ) 7.7 Hz, 1 H), 7.11-7.00 (m, 5 H), 5.06 (dddd, J )
8.8, 8.8, 4.9, 4.9 Hz, 1 H), 3.51-3.29 (m, 2 H), 2.68-2.29 (m, 10
H), 2.24 (s, 3 H), 2.19-1.82 (m, 5 H), 1.69 (ddd, J ) 7.7, 4.4, 4.4
Hz, 1 H), 1.32-1.22 (m, 2 H), 0.94 (dd, J ) 7.7, 5.5 Hz, 1 H);
LCMS: 569.1, rt ) 5.05 min (M + H+), 93% purity; HRMS (FAB)
m/z 569.2319 [(M + H)+; calcd for C28H34ClF4N4O2: 569.2306].
Anal. (C28H33ClF4N4O2‚2HCl): C, H, N.
N′-(3-Chloro-4-fluorophenyl)-N-[3-(4-methyl-1-piperazinyl)-
propyl]-N-[trans-5-[4-(trifluoromethoxy)phenyl]bicyclo[3.1.0]-
hex-2-yl]urea (24g). Following the procedure used for the synthesis
of 23a and using 21g (Ar ) p-OCF3Ph, synthesized via method
B), 1-(3-aminopropyl)-4-methylpiperazine, and 3-chloro-4-fluo-
rophenyl isocyanate (76%, 2 steps): 1H NMR (300 MHz, CDCl3)
δ 9.26 (s, 1 H), 7.52 (dd, J ) 6.6, 2.2 Hz, 1 H), 7.36 (m, 1 H),
7.20-7.02 (m, 5 H), 5.06 (dddd, J ) 8.8, 8.8, 4.9, 4.9 Hz, 1 H),
3.52-3.29 (m, 2 H), 2.68-2.30 (m, 11 H), 2.26 (s, 3 H), 2.15-
1.84 (m, 4 H), 1.65 (ddd, J ) 7.7, 4.4, 4.4 Hz, 1 H), 1.31-1.20
(m, 2 H), 0.92 (dd, J ) 7.7, 5.5 Hz, 1 H); LCMS: 569.1, rt ) 4.92
min (M + H+), 90% purity; HRMS (FAB) m/z 569.2298 [(M +

2306 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7
McBriar et al.
H)+; calcd for C28H34ClF4N4O2: 569.2306]. Anal. (C28H33ClF4N4O2‚
2HCl‚0.5H2O): C, H, N.
N′-(3-Chloro-4-fluorophenyl)-N-[trans-5-(3-methylphenyl)-
bicyclo[3.1.0]hex-2-yl]-N-[3-(4-methyl-1-piperazinyl)propyl]-
urea (24n). Following the procedure used for the synthesis of 23a
and using 21n (Ar ) m-CH3Ph, synthesized via method C), 1-(3-
aminopropyl)-4-methylpiperazine, and 3-chloro-4-fluorophenyl iso-
cyanate (31%, 2 steps): 1H NMR (300 MHz, CDCl3) δ 9.21 (s, 1
H), 7.52 (dd, J ) 6.6, 2.7 Hz, 1 H), 7.36 (m, 1 H), 7.17 (dd, J )
7.7, 7.1 Hz, 1 H), 7.05 (dd, J ) 9.3, 8.8 Hz, 1 H), 7.00-6.98 (m,
3 H), 5.04 (dddd, J ) 8.2, 8.2, 4.9, 4.9 Hz, 1 H), 3.51-3.30 (m, 2
H), 2.68-2.30 (m, 7 H), 2.32 (s, 3 H), 2.27-1.89 (m, 8 H), 1.64
(ddd, J ) 7.7, 4.5, 4.5 Hz, 1 H), 1.33-1.23 (m, 2 H), 0.91 (dd, J
) 7.7, 5.5 Hz, 1 H); LCMS: 499.1, rt ) 5.35 min (M + H+), 96%
purity; HRMS (FAB) m/z 499.2635 [(M + H)+; calcd for C28H37-
ClFN4O: 499.2640].
N′-(3-Chloro-4-fluorophenyl)-N-[3-(4-methyl-1-piperazinyl)-
propyl]-N-[trans-5-(3-thienyl)bicyclo[3.1.0]hex-2-yl]urea (24o).
Following the procedure used for the synthesis of 23a and using
21o (Ar ) 3-thienyl, synthesized via method B), 1-(3-aminopropyl)-
4-methylpiperazine, and 3-chloro-4-fluorophenyl isocyanate (47%,
2 steps): 1H NMR (300 MHz, CDCl3) δ 9.19 (s, 1 H), 7.53 (dd, J
) 6.6, 2.7 Hz, 1 H), 7.35 (m, 1 H), 7.23 (dd, J ) 4.9, 2.7 Hz, 1
H), 7.04 (dd, J ) 8.8, 8.8 Hz, 1 H), 6.92 (m, 1 H), 6.82 (dd, J )
4.9, 1.1 Hz, 1 H), 4.99 (dddd, J ) 8.2, 8.2, 4.9, 4.9 Hz, 1 H),
3.45-3.33 (m, 2 H), 2.68-2.35 (m, 7 H), 2.27 (s, 3 H), 2.13-
1.85 (m, 8 H), 1.57 (ddd, J ) 7.1, 4.3, 4.3 Hz, 1 H), 1.33-1.17
(m, 2 H), 0.96 (dd, J ) 7.1, 4.9 Hz, 1 H); LCMS: 491.1, rt ) 4.35
min (M + H+), >99% purity; HRMS (FAB) m/z 491.2057[(M +
H)+; calcd for C25H33ClFN4OS: 491.2048].
N′-(3-Chloro-4-fluorophenyl)-N-[trans-5-(3-chlorophenyl)-
bicyclo[3.1.0]hex-2-yl]-N-[3-(4-methyl-1-piperazinyl)pro-
pyl]urea (24h). Following the procedure used for the synthesis of
23a and using 21h (Ar ) m-ClPh, synthesized via method B), 1-(3-
aminopropyl)-4-methylpiperazine, and 3-chloro-4-fluorophenyl iso-
cyanate (70%, 2 steps): 1H NMR (300 MHz, CDCl3) δ 9.31 (s, 1
H), 7.53 (dd, J ) 6.6, 2.2 Hz, 1 H), 7.37 (m, 1 H), 7.23-7.13 (m,
3 H), 7.08-7.02 (m, 2 H), 5.04 (dddd, J ) 8.7, 8.7, 4.9, 4.9 Hz, 1
H), 3.51-3.29 (m, 2 H), 2.68-2.30 (m, 11 H), 2.26 (s, 3 H), 2.19-
1.85 (m, 4 H), 1.68 (ddd, J ) 7.7, 4.5, 4.5 Hz, 1 H), 1.32-1.26
(m, 2 H), 0.92 (dd, J ) 7.7, 5.5 Hz, 1 H); LCMS: 519.3, rt ) 4.50
min (M + H+), 97% purity; HRMS (FAB) m/z 519.2086 [(M +
H)+; calcd for C27H34Cl2FN4O: 519.2094].
N′-(3-Chloro-4-fluorophenyl)-N-[3-(4-methyl-1-piperazinyl)-
propyl]-N-[trans-5-[3-(methylsulfonyl)phenyl]bicyclo[3.1.0]hex-
2-yl]urea (24i). Following the procedure used for the synthesis of
23a and using 21i (Ar ) m-SO2MePh, synthesized via method B),
1-(3-aminopropyl)-4-methylpiperazine, and 3-chloro-4-fluorophenyl
isocyanate (35%, 2 steps): 1H NMR (300 MHz, CDCl3) δ 9.36 (s,
1 H), 7.79-7.73 (m, 2 H), 7.53 (dd, J ) 6.6, 2.2 Hz, 1 H), 7.49-
7.47 (m, 2 H), 7.38 (m, 1 H), 7.06 (dd, J ) 8.8, 8.8 Hz, 1 H), 5.07
(dddd, J ) 8.7, 8.7, 4.9, 4.9 Hz, 1 H), 3.52-3.30 (m, 2 H), 3.05
(s, 3 H), 2.68-2.27 (m, 10 H), 2.26 (s, 3 H), 2.21-1.86 (m, 4 H),
1.78 (ddd, J ) 7.7, 4.5, 4.5 Hz, 1 H), 1.40-1.30 (m, 2 H), 0.99
(dd, J ) 7.1, 5.5 Hz, 1 H); LCMS: 563.1, rt ) 4.43 min (M +
H+), 95% purity; HRMS (FAB) m/z 563.2282 [(M + H)+; calcd
for C28H37ClFN4O3S: 563.2259].
N′-(3-Chloro-4-fluorophenyl)-N-[3-(4-methyl-1-piperazinyl)-
propyl]-N-[trans-5-(3-pyridinyl)bicyclo[3.1.0]hex-2-yl]urea (24p).
Following the procedure used for the synthesis of 23a and using
21p (Ar ) 3-pyridyl, synthesized via method B), 1-(3-aminopropyl)-
4-methylpiperazine, and 3-chloro-4-fluorophenyl isocyanate 17%,
2 steps): 1H NMR (300 MHz, CDCl3) δ 9.33 (s, 1 H), 8.47-8.42
(m, 2 H), 7.53 (dd, J ) 7.1, 2.7 Hz, 1 H), 7.49 (m, 1 H), 7.39 (m,
1 H), 7.22 (m, 1 H), 7.06 (dd, J ) 8.8, 8.8 Hz, 1 H), 5.09 (dddd,
J ) 8.2, 8.2, 4.9, 4.9 Hz, 1 H), 3.53-3.32 (m, 2 H), 2.70-2.32
(m, 11 H), 2.27 (s, 3 H), 2.16-1.85 (m, 4 H), 1.72 (ddd, J ) 7.1,
4.5, 4.5 Hz, 1 H), 1.34-1.27 (m, 2 H), 0.96 (dd, J ) 7.1, 5.5 Hz,
1 H); LCMS: 486.1, rt ) 3.26 min (M + H+), 91% purity; HRMS
(FAB) m/z 486.2424 [(M + H)+; calcd for C26H34ClFN5O:
486.2436].
N′-[4-fluoro-3-(trifluoromethyl)phenyl)-N-[trans-5-(3-
methoxyphenyl)bicyclo[3.1.0]hex-2-yl]-N-[3-(4-methyl-1-piper-
azinyl)propyl]urea (24q). Following the procedure used for the
synthesis of 23a and using 21q (Ar ) m-OCH3Ph, synthesized via
method B), 1-(3-aminopropyl)-4-methylpiperazine, and 4-fluoro-
3-(trifluoromethyl)phenyl isocyanate (31%, 2 steps): 1H NMR (300
MHz, CDCl3) δ 9.42 (s, 1 H), 7.77 (m, 1 H), 7.62 (dd, J ) 6.6, 2.7
Hz, 1 H), 7.20 (dd, J ) 8.7, 7.7 Hz, 1 H), 7.12 (dd, J ) 9.3, 9.3
Hz, 1 H), 6.79-6.71 (m, 2 H), 5.06 (dddd, J ) 8.2, 8.2, 4.9, 4.9
Hz, 1 H), 3.79 (s, 3 H), 3.54-3.32 (m, 2 H), 2.72-2.32 (m, 11 H),
2.25 (s, 3 H), 2.12-1.86 (m, 4 H), 1.66 (ddd, J ) 7.1, 4.5, 4.5 Hz,
1 H), 1.34-1.20 (m, 2 H), 0.94 (dd, J ) 7.1, 5.5 Hz, 1 H); LCMS:
549.1, rt ) 4.55 min (M + H+), 94% purity; HRMS (FAB) m/z
549.2862 [(M + H)+; calcd for C29H37F4N4O2: 549.2853].
N′-[4-fluoro-3-(trifluoromethyl)phenyl)-N-[trans-5-(4-
methoxyphenyl)bicyclo[3.1.0]hex-2-yl]-N-[3-(4-methyl-1-piper-
azinyl)propyl]urea (24r). Following the procedure used for the
synthesis of 23a and using 21r (Ar ) p-OCH3Ph, synthesized via
method C), 1-(3-aminopropyl)-4-methylpiperazine, and 4-fluoro-
3-(trifluoromethyl)phenyl isocyanate (47%, 2 steps): 1H NMR (300
MHz, CDCl3) δ 9.38 (s, 1 H), 7.77 (m, 1 H), 7.62 (dd, J ) 6.6, 2.7
Hz, 1 H), 7.15 (m, 1 H), 7.09 (d, J ) 8.8 Hz, 2 H), 6.84 (d, J )
8.8 Hz, 2 H), 5.06 (dddd, J ) 8.2, 8.2, 4.9, 4.9 Hz, 1 H), 3.78 (s,
3 H), 3.51-3.33 (m, 2 H), 2.72-2.34 (m, 11 H), 2.25 (s, 3 H),
2.10-1.84 (m, 4 H), 1.57 (ddd, J ) 7.1, 4.5, 4.5 Hz, 1 H), 1.28-
1.18 (m, 2 H), 0.90 (dd, J ) 7.1, 5.5 Hz, 1 H); LCMS: 549.1, rt
) 4.51 min (M + H+), 93% purity; HRMS (FAB) m/z 549.2861
[(M + H)+; calcd for C29H37F4N4O2: 549.2853].
N′-(3-Chloro-4-fluorophenyl)-N-[trans-5-(3-fluorophenyl)-
bicyclo[3.1.0]hex-2-yl]-N-[3-(4-methyl-1-piperazinyl)propyl]-
urea (24k). Following the procedure used for the synthesis of 23a
and using 21k (Ar ) m-FPh, synthesized via method B), 1-(3-
aminopropyl)-4-methylpiperazine, and 3-chloro-4-fluorophenyl iso-
cyanate (24%, 2 steps): 1H NMR (300 MHz, CDCl3) δ 9.31 (s, 1
H), 7.54 (dd, J ) 6.6, 2.2 Hz, 1 H), 7.41-7.20 (m, 2 H), 7.07 (dd,
J ) 8.2, 8.2 Hz, 1 H), 6.97 (d, J ) 8.2 Hz, 1 H), 6.94-6.82 (m,
2 H), 5.03 (dddd, J ) 8.2, 8.2, 4.9, 4.9 Hz, 1 H), 3.56-3.30 (m, 2
H), 2.67-2.27 (m, 7 H), 2.26 (s, 3 H), 2.15-1.84 (m, 8 H), 1.69
(ddd, J ) 7.7, 4.5, 4.5 Hz, 1 H), 1.38-1.23 (m, 2 H), 0.97 (dd, J
) 7.7, 5.5 Hz, 1 H); LCMS: 503.1, rt ) 4.82 min (M + H+), 96%
purity; HRMS (FAB) m/z 503.2395 [(M + H)+; calcd for C27H34-
ClF2N4O: 503.2389]. Anal. (C27H33ClF2N4O‚2HCl‚H2O): C, H,
N.
N-[trans-5-(3-fluorophenyl)bicyclo[3.1.0]hex-2-yl]-N′-[4-fluoro-
3-(trifluoromethyl)phenyl)-N-[3-(4-methyl-1-piperazinyl)propyl]-
urea (24l). Following the procedure used for the synthesis of 23a
and using 21l (Ar ) m-FPh, synthesized via method B), 1-(3-
aminopropyl)-4-methylpiperazine, and 4-fluoro-3-(trifluoromethyl)-
phenyl isocyanate (33%, 2 steps): 1H NMR (300 MHz, CDCl3) δ
9.48 (s, 1 H), 7.77 (m, 1 H), 7.60 (m, 1 H), 7.21 (m, 1 H), 7.14
(dd, J ) 8.8, 8.8 Hz, 1 H), 6.97 (d, J ) 8.8 Hz, 1 H), 6.95-6.85
(m, 2 H), 5.05 (dddd, J ) 8.2, 8.2, 4.9, 4.9 Hz, 1 H), 3.56-3.30
(m, 2 H), 2.67-2.27 (m, 7 H), 2.24 (s, 3 H), 2.15-1.77 (m, 8 H),
1.64 (ddd, J ) 7.7, 4.5, 4.5 Hz, 1 H), 1.38-1.23 (m, 2 H), 0.96
(dd, J ) 7.7, 5.5 Hz, 1 H); LCMS: 537.1, rt ) 4.83 min (M +
H+), >99% purity; HRMS (FAB) m/z 537.2656 [(M + H)+; calcd
for C28H34F5N4O: 537.2653].
N-[trans-5-(4-fluorophenyl)bicyclo[3.1.0]hex-2-yl]-N′-[4-fluoro-
3-(trifluoromethyl)phenyl)-N-[3-(4-methyl-1-piperazinyl)propyl]-
urea (24m). Following the procedure used for the synthesis of 23a
and using 21m (Ar ) p-FPh, synthesized via method B), 1-(3-
aminopropyl)-4-methylpiperazine, and 3-chloro-4-fluorophenyl iso-
cyanate (8%, 2 steps): 1H NMR (300 MHz, CD3OD) δ 7.82 (m, 1
H), 7.65 (m, 1 H), 7.28 (m, 1 H), 7.27 (dd, J ) 8.2, 8.2 Hz, 2 H),
7.01 (dd, J ) 8.2, 8.2 Hz, 2 H), 4.81 (dddd, J ) 8.1, 8.1, 4.5, 4.5
Hz, 1 H), 3.90-3.61 (m, 8 H), 3.59-3.32 (m, 8 H), 3.00 (s, 3 H),
2.20-1.96 (m, 5 H), 1.86 (ddd, J ) 7.1, 4.3, 4.3 Hz, 1 H), 1.51-
1.43 (m, 2 H), 1.07 (dd, J ) 7.7, 5.5 Hz, 1 H); LCMS: 537.1, rt
) 4.64 min (M + H+), >99% purity; HRMS (FAB) m/z 537.2663-
[(M + H)+; calcd for C28H34F5N4O: 537.2653].

Bicyclo[3.1.0]hexyl Ureas as MCH-R1 Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7 2307
N′-(3-Chloro-4-fluorophenyl)-N-[trans-5-(3, 5-difluorophenyl)-
bicyclo[3.1.0]hex-2-yl]-N-[3-(4-methyl-1-piperazinyl)propyl]-
urea (24s). Following the procedure used for the synthesis of 23a
and using 21s (Ar ) 3,5-diFPh, synthesized via method B), 1-(3-
aminopropyl)-4-methylpiperazine, and 3-chloro-4-fluorophenyl iso-
cyanate (30%, 2 steps): 1H NMR (300 MHz, CDCl3) δ 9.31 (s, 1
H), 7.53 (dd, J ) 6.6, 3.8 Hz, 1 H), 7.37 (m, 2 H), 7.06 (dd, J )
8.8, 8.8 Hz, 1 H), 6.67-6.58 (m, 3 H), 5.03 (dddd, J ) 8.2, 8.2,
4.9, 4.9 Hz, 1 H), 3.52-3.29 (m, 2 H), 2.70-2.36 (m, 7 H), 2.28
(s, 3 H), 2.12-1.86 (m, 8 H), 1.70 (ddd, J ) 7.7, 4.5, 4.5 Hz, 1
H), 1.35-1.26 (m, 2 H), 0.93 (dd, J ) 7.7, 5.5 Hz, 1 H); LCMS:
521.1, rt ) 4.44 min (M + H+), >99% purity; HRMS (FAB) m/z
521.2310 [(M + H)+; calcd for C27H33ClF3N4O: 521.2295]. Anal.
(C27H32ClF3N4O‚2HCl ‚3H2O): C, H, N.
N′-(3-Chloro-4-fluorophenyl)-N-[trans-5-(3, 4-difluorophenyl)-
bicyclo[3.1.0]hex-2-yl]-N-[3-(4-methyl-1-piperazinyl)propyl]-
urea (24t). Following the procedure used for the synthesis of 23a
and using 21t (Ar ) 3, 4-diFPh, synthesized via method B), 1-(3-
aminopropyl)-4-methylpiperazine, and 3-chloro-4-fluorophenyl iso-
cyanate (43%, 2 steps): 1H NMR (300 MHz, CDCl3) δ 9.33 (s, 1
H), 7.52 (dd, J ) 6.6, 2.7 Hz, 1 H), 7.37 (m, 1 H), 7.06 (dd, J )
8.8, 8.2 Hz, 1 H), 7.00 (dd, J ) 8.2, 8.2 Hz, 1 H), 6.88 (m, 1 H),
5.06 (dddd, J ) 8.2, 8.2, 4.9, 4.9 Hz, 1 H), 3.51-3.26 (m, 2 H),
2.68-2.29 (m, 7 H), 2.26 (s, 3 H), 2.10-1.85 (m, 8 H), 1.63 (ddd,
J ) 7.7, 4.5, 4.5 Hz, 1 H), 1.31-1.24 (m, 2 H), 0.89 (dd, J ) 7.7,
5.5 Hz, 1 H); LCMS: 521.3, rt ) 4.54 min (M + H+), 99% purity;
HRMS (FAB) m/z 521.2307 [(M + H)+; calcd for C27H33-
ClF3N4O: 521.2295]. Anal. (C27H32ClF3N4O‚2HCl‚H2O) C, H, N.
N-[trans-5-(4-Cyanophenyl)bicyclo[3.1.0]hex-2-yl]-N′-[4-fluoro-
3-(trifluoromethyl)phenyl)-N-[3-(4-methyl-1-piperazinyl)propyl]-
urea (24u). Following the procedure used for the synthesis of 23a
and using 21u (Ar ) p-CNPh, synthesized via method B), 1-(3-
aminopropyl)-4-methylpiperazine, and 4-fluoro-3-(trifluoromethyl)-
phenyl isocyanate (47%, 2 steps): 1H NMR (300 MHz, CDCl3) δ
11.93 (s, 1 H), 8.80 (s, 1 H), 7.99 (d, J ) 4.4 Hz, 1 H), 7.87 (dd,
J ) 8.2, 4.4 Hz, 1 H), 7.71 (d, J ) 8.2 Hz, 2 H), 7.36 (d, J ) 8.2
Hz, 2 H), 5.06 (dddd, J ) 8.2, 8.2, 4.9, 4.9 Hz, 1 H), 3.78-3.17
(m, 8 H), 2.81 (m, 4 H), 2.48 (dd, J ) 2.2, 1.6 Hz, 1 H), 2.15-
1.98 (m, 6 H), 1.82 (ddd, J ) 13.2, 11.5, 7.7 Hz, 1 H), 1.64 (dd,
J ) 4.9, 4.4 Hz, 1 H), 1.43 (m, 1 H), 1.08 (m, 1 H). LCMS: 544.1,
rt ) 4.45 min (M + H+), > 99% purity; HRMS (FAB) m/z
544.2699 [(M + H)+; calcd for C29H34F4N5O: 544.2699]. Anal.
(C29H33F4N5O‚2HCl‚H2O) C, H, N.
N-[trans-5-(3-Cyano-4-fluorophenyl)bicyclo[3.1.0]hex-2-yl]-
N′-[4-fluoro-3-(trifluoromethyl)phenyl)-N-[3-(4-methyl-1-piper-
azinyl)propyl]urea (24v). Following the procedure used for the
synthesis of 23a and using 21v (Ar ) 3-CN, 4-FPh, synthesized
via method B), 1-(3-aminopropyl)-4-methylpiperazine, and 4-fluoro-
3-(trifluoromethyl)phenyl isocyanate (52%, 2 steps): 1H NMR (300
MHz, CDCl3) δ 9.36 (s, 1 H), 7.75 (m, 1 H), 7.62 (dd, J ) 6.0, 2.2
Hz, 1 H), 7.42-7.38 (m, 2 H), 7.16-7.10 (m, 1 H), 5.06 (dddd, J
) 8.2, 8.2, 4.9, 4.9 Hz, 1 H), 3.56-3.31 (m, 2 H), 2.71-2.36 (m,
7 H), 2.26 (s, 3 H), 2.16-1.89 (m, 8 H), 1.69 (ddd, J ) 7.7, 4.5,
4.4 Hz, 1 H), 1.34-1.26 (m, 1 H), 0.91 (dd, J ) 7.7, 5.4 Hz, 1 H);
LCMS: 562.3, rt ) 4.18 min (M + H+), 98% purity; HRMS (FAB)
m/z 562.2609 [(M + H)+; calcd for C29H33F5N5O: 562.2605].
trans-3-[4-(4-Hydroxy-butylamino)-bicyclo[3.1.0]hex-1-yl]-
benzonitrile (25a). A solution of ketone 21a (synthesized as in
method A) (440 mg, 2.23 mmol) in CH2Cl2 (2 mL) was treated
with 4-amino-1-butanol (247 µL, 2.68 mmol) followed by titanium
tetraisopropoxide (800 µL, 2.68 mmol). After 18 h, the reaction
mixture was diluted with MeOH (2 mL) and sodium borohydride
(130 mg, 3.40 mmol) was added. After 1.5 h further, the reaction
mixture was diluted with a solution of saturated aqueous sodium/
potassium tartrate and CH2Cl2 and stirred vigorously. After 12 h,
the solution was extracted with CH2Cl2 (4×). The combined organic
phases were dried and concentrated in vacuo to provide 25a (560
mg, 88%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.49-
7.41 (m, 2 H), 7.39-7.29 (m, 2 H), 3.59 (t, J ) 4.9 Hz, 2 H),
3.59-3.51 (m, 7 H), 2.81 (m, 1 H), 2.67 (m, 1 H), 2.15-2.00 (m,
3 H), 1.90 (ddd, J ) 7.7, 4.5, 4.4 Hz, 1 H), 1.75-1.62 (m, 7 H),
1.20-1.12 (m, 2 H), 0.80 (dd, J ) 8.2, 5.5 Hz, 1 H.
trans-(4-Bromo-butyl)-[5-(3-cyano-phenyl)-bicyclo[3.1.0]hex-
2-yl]-carbamic Acid tert-Butyl Ester (26a). A solution of amine
25a (560 mg, 1.96 mmol) was dissolved in CH2Cl2 (4 mL) and
treated with triethylamine (280 µL, 2.0 mmol) followed by di-tert-
butyl carbonate (437 mg, 2.0 mmol). After 12 h, the reaction
mixture was diluted with EtOAc, washed with saturated aqueous
NH4Cl, NaHCO3, and brine, dried, and concentrated in vacuo. Flash
chromatography (50% EtOAc/Hex) gave the alcohol (700 mg, 92%)
as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.49-7.41 (m, 2 H),
7.39-7.29 (m, 2 H), 4.78 (dddd, J ) 8.3, 8.3, 5.2, 5.2 Hz, 1 H),
3.68 (t, J ) 6.6 Hz, 2 H), 3.32 (m, 1 H), 3.14 (m, 1 H), 2.11 (dd,
J ) 12.0, 8.2 Hz, 1 H), 2.01-1.88 (m, 3 H), 1.74-1.54 (m, 5 H),
1.46 (s, 9 H), 1.31-1.24 (m, 2 H), 0.93 (dd, J ) 7.7, 6.0 Hz, 1 H).
A solution of alcohol from the previous step (700 mg, 1.81 mmol)
in THF (9 mL) at 0 °C was treated with carbon tetrabromide (1.2
g, 3.6 mmol) followed by triphenylphosphine (1.05 g, 4.0 mmol)
and warmed to ambient temperature. After 45 min, the reaction
mixture was diluted with diethyl ether, filtered through Celite,
rinsed, and concentrated in vacuo. Flash chromatography (10%
EtOAc/Hex) gave 26a (770 mg, 95%) as a clear oil: 1H NMR
(300 MHz, CDCl3) δ 7.48-7.45 (m, 2 H), 7.39-7.37 (m, 2 H),
4.81 (dddd, J ) 8.3, 8.3, 5.2, 5.2 Hz, 1 H), 3.45 (t, J ) 6.6 Hz, 2
H), 3.42 (m, 1 H), 3.13 (m, 1 H), 2.15 (dd, J ) 12.0, 8.2 Hz, 1 H),
2.02-1.70 (m, 7 H), 1.48 (s, 9 H), 1.33-1.26 (m, 2 H), 0.95 (dd,
J ) 7.7, 6.0 Hz, 1 H).
N-[trans-5-(3-Cyanophenyl)bicyclo[3.1.0]hex-2-yl]-N′-[4-fluoro-
3-(trifluoromethyl)phenyl)-N-[4-(4-morpholinyl)butyl]urea (27a).
A solution of 26a (150 mg, 0.333 mmol) in CH3CN was treated
with K2CO3 (70 mg, 0.50 mmol) and morpholine (32 µL, 0.367
mmol) and heated to 70 °C. After 12 h, the reaction mixture was
cooled to ambient temperature, diluted with saturated aqueous
NH4Cl, and extracted with EtOAc (3×). The combined organic
extracts were washed with NaHCO3 and brine, dried, and concen-
trated in vacuo to provide the morpholine as a clear oil.
A solution of crude morpholine derivative (e0.333 mmol) in
20% TFA/CH2Cl2 (3.6 mL) was stirred at ambient temperature.
After 12 h, the reaction mixture was poured into saturated aqueous
NaHCO3 and extracted with CH2Cl2 (2×). The combined organic
phases were dried and concentrated in vacuo to provide the free
amine as a yellow oil. The residue was dissolved in CH2Cl2 (3
mL) and treated with diisopropylethylamine (87 µL, 0.50 mmol)
followed by 3-(trifluoromethyl)-4-fluorophenyl isocyanate (57 µL,
0.40 mmol). After 12 h, the reaction mixture was diluted with
saturated aqueous NaHCO3 and extracted with CH2Cl2 (2×). The
combined organic phases were dried and concentrated in vacuo.
Preparative thin-layer chromatography (5% MeOH/CH2Cl2) fur-
nished 27a (136 mg, 75% over 3 steps) as a clear oil: 1H NMR
(300 MHz, CDCl3) δ 7.59 (m, 1 H), 7.57 (m, 1 H), 7.48-7.44 (m,
2 H), 7.39-7.37 (m, 2 H), 7.12 (dd, J ) 8.8, 8.8 Hz, 1 H), 6.95 (s,
1 H), 5.00 (dddd, J ) 8.8, 8.8, 5.1, 5.1 Hz, 1 H), 3.71-3.65 (m, 5
H), 3.47-3.25 (m, 2 H), 2.49-2.46 (m, 6 H), 2.20-1.94 (m, 2 H),
1.85-1.58 (m, 4 H), 1.36-1.31 (m, 2 H), 0.99 (dd, J ) 7.1, 6.0
Hz, 1 H); LCMS: 546.1, rt ) 5.37 min (M + H+), 99% purity;
HRMS (FAB) m/z 545.2543 [(M)+; calcd for C29H32F4N4O2:
545.2540]. Anal. (C29H32F4N4O2‚HCl‚0.5H2O): C, H, N.
N-[trans-5-(4-Cyano-3-fluorophenyl)bicyclo[3.1.0]hex-2-yl]-
N′-[4-fluoro-3-(trifluoromethyl)phenyl)-N-[3-(4-methyl-1-piper-
azinyl)propyl]urea (24w). Following the procedure used for the
synthesis of 23a and using 21w (Ar ) 3-F, 4-CNPh, synthesized
via method B), 1-(3-aminopropyl)-4-methylpiperazine, and 4-fluoro-
3-(trifluoromethyl)phenyl isocyanate (54%, 2 steps): 1H NMR (300
MHz, CDCl3) δ 9.40 (s, 1 H), 7.74 (m, 1 H), 7.60 (m, 1 H), 7.50
(dd, J ) 7.7, 7.1 Hz, 1 H), 7.12 (dd, J ) 9.3, 9.3 Hz, 1 H), 7.00-
6.95 (m, 2 H), 5.02 (dddd, J ) 8.2, 8.2, 4.9, 4.9 Hz, 1 H), 3.55-
3.31 (m, 2 H), 2.69-2.35 (m, 7 H), 2.26 (s, 3 H), 2.14-1.90 (m,
8 H), 1.82 (ddd, J ) 7.7, 4.5, 4.4 Hz, 1 H), 1.44-1.31 (m, 1 H),
1.01 (dd, J ) 7.7, 5.4 Hz, 1 H); LCMS: 562.3, rt ) 4.18 min (M
+ H+), 98% purity; HRMS (FAB) m/z 562.2609 [(M + H)+; calcd
for C29H33F5N5O: 562.2605].

2308 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7
McBriar et al.
N-[trans-5-(3-Cyanophenyl)bicyclo[3.1.0]hex-2-yl]-N′-[4-fluoro-
3-(trifluoromethyl)phenyl)-N-[4-(4-methyl-1-piperazinyl)butyl]-
urea (27b). Following the procedure described for 27a and using
piperazine (36%, 3 steps): 1H NMR (300 MHz, CDCl3) δ 7.59
(m, 1 H), 7.57 (m, 1 H), 7.48-7.45 (m, 2 H), 7.39-7.37 (m, 2 H),
7.12 (dd, J ) 8.8, 8.8 Hz, 1 H), 7.03 (s, 1 H), 5.03 (dddd, J ) 8.7,
8.7, 5.0, 5.0 Hz, 1 H), 3.46-3.24 (m, 2 H), 2.64-2.40 (m, 8 H),
2.22 (s, 3 H), 2.20-1.95 (m, 6 H), 1.85-1.58 (m, 4 H), 1.39-
1.30 (m, 2 H), 0.99 (dd, J ) 7.7, 5.5 Hz, 1 H); LCMS: 558.1, rt
) 4.85 min (M + H+), 90% purity; HRMS (FAB) m/z 558.2851
[(M + H)+; calcd for C30H36F4N5O: 558.2856]. Anal. (C30H35F4N5O‚
2HCl): C, H, N.
N-[trans-5-(3-Cyanophenyl)bicyclo[3.1.0]hex-2-yl]-N′-[4-fluoro-
3-(trifluoromethyl)phenyl)-N-[4-(1-piperidinyl)butyl]urea (27c).
Following the procedure described for 27a and using piperidine
(65%, 3 steps): 1H NMR (300 MHz, CDCl3) δ 7.60 (m, 1 H),
7.58 (m, 1 H), 7.47-7.44 (m, 2 H), 7.39-7.37 (m, 2 H), 7.25 (s,
1 H), 7.12 (dd, J ) 8.8, 8.8 Hz, 1 H), 5.05 (dddd, J ) 8.7, 8.7, 5.0,
5.0 Hz, 1 H), 3.47-3.23 (m, 2 H), 2.47-2.43 (m, 6 H), 2.19-1.94
(m, 3 H), 1.85-1.30 (m, 13 H), 0.98 (dd, J ) 7.7, 5.5 Hz, 1 H);
LCMS: 544.1, rt ) 5.56 min (M + H+), 97% purity; HRMS (FAB)
m/z 543.2757 [(M)+; calcd for C30H34F4N4O: 543.2747]. Anal.
(C30H34F4N4O‚HCl‚0.5H2O): C, H, N.
(Amersham Life Science, Arlington Heights, IL), 125 pM [125I]-
MCH (New England Nuclear, Boston, MA), and 0.1-3000 nM
compound in 200 µL of MCH-R1 binding buffer (25 mM Hepes,
pH 7.4, 10 mM MgCl2, 10 mM NaCl, 5 mM MnCl2, 0.1% BSA)
for 2 h at room temperature in 96-well plates. Nonspecific binding
was determined by including 1 µM unlabeled MCH in the binding
reaction. Following the binding incubation, plates were analyzed
in a TOPCOUNT microplate scintillation counter (Packard) to
measure radioactivity bound to MCH-R1. Ki values were determined
using Prism (GraphPad software).
Functional Assays Measuring MCH-R1 Activity. The ability
of compounds to functionally antagonize MCH-R1 was determined
by measuring inhibition of MCH-stimulated increases in intracel-
lular Ca2+ using a FLIPR instrument. CHO-MCH-R1 cells were
grown in 384 well black/clear plates. Cells were washed with 50
µL of FLIPR buffer (Hank’s BSS, 0.1% BSA, 20 mM HEPES, 2.5
mM probenecid) and loaded with FLIPR buffer containing 0.04%
pluronic acid and 4 µM Fluo 3AM dye. Cells were then incubated
for 1 h at 37 °C. Subsequently, cells were washed twice with FLIPR
buffer and treated with 20 µL of vehicle (FLIPR buffer containing
2% DMSO) or compound. Cells were then stimulated with 30 nM
MCH and the change in intracellular Ca2+ level was determined
with a FLIPR instrument (Molecular Devices). Kb values were
determined using the Cheng-Prusoff formula.
N-[trans-5-(4-Cyanophenyl)bicyclo[3.1.0]hex-2-yl]-N′-[4-fluoro-
3-(trifluoromethyl)phenyl)-N-[3-(1-piperazinyl)propyl]urea (32).
A solution of 3326 (418 mg, 1.5 mmol) in CH2Cl2 (3 mL) was
treated with 21u (250 mg, 1.27 mmol) followed by titanium
tetraisopropoxide (440 µL, 1.5 mmol). After 18 h, the reaction
mixture was diluted with EtOH (1 mL) and sodium borohydride
(80 mg, 1.9 mmol) was added. After 2.5 h further, the reaction
mixture was diluted with H2O (2 mL). After 0.5 h further, the
reaction mixture was filtered through Celite and washed with EtOH.
The filtrate was concentrated in vacuo, diluted with a solution of
saturated aqueous NaHCO3, and extracted with CH2Cl2 (2×). The
combined organic phases were dried and concentrated in vacuo.
The product from the previous step (400 mg, 0.87 mmol) was
dissolved in CH2Cl2 (4 mL) and treated with diisopropylethylamine
(300 µL, 1.73 mmol) followed by 4-fluoro-(3-trifluoromethyl)-
phenyl isocyanate (200 µL, 1.30 mmol). After 18 h, the reaction
mixture was diluted with saturated aqueous NaHCO3 and extracted
with CH2Cl2 (3×). The combined organic phases were dried and
concentrated in vacuo. Flash chromatography (35f100% EtOAc/
Hex) furnished the urea (425 mg, 73%) as a clear oil: 1H NMR
(300 MHz, CDCl3) δ 9.10 (s, 1 H), 7.69 (dd, J ) 6.0, 2.7 Hz, 1
H), 7.55 (d, J ) 8.2 Hz, 2 H), 7.37-7.31 (m, 6 H), 7.25 (d, J )
8.2 Hz, 2 H), 7.12 (dd, J ) 9.8, 8.7 Hz, 1 H), 5.08 (s, 2 H), 5.06
(dddd, J ) 8.2, 8.2, 4.9, 4.9 Hz, 1 H), 3.52-3.38 (m, 7 H), 2.60-
2.35 (m, 5 H), 2.18-1.90 (m, 5 H), 1.78 (ddd, J ) 7.7, 4.5, 4.5
Hz, 1 H), 1.40-1.36 (m, 2 H), 0.99 (dd, J ) 7.1, 5.5 Hz, 1 H).
The urea from the previous step (375 mg, 0.67mol) in MeOH
(20 mL) was treated with 10% Pd/C (150 mg) and stirred under 1
atm H2 via ballon. After 40 min, the reaction mixture was filtered
through Celite, rinsed with MeOH, and concentrated in vacuo. Flash
chromatography (5f10% MeOH/CH2Cl2) provided 32 (210 mg,
59%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 9.54 (s, 1 H),
7.69-7.62 (m, 2 H), 7.56 (d, J ) 8.2 Hz, 2 H), 7.23 (d, J ) 8.2
Hz, 2 H), 7.22 (dd, J ) 8.2, 8.2 Hz, 1 H), 5.08 (dddd, J ) 8.2, 8.2,
4.9, 4.9 Hz, 1 H), 3.78-3.17 (m, 2 H), 2.81 (m, 4 H), 2.70-2.26
(m, 6 H), 2.21-1.60 (m, 6 H), 1.38-1.26 (m, 2 H), 1.02 (dd, J )
7.1, 5.5 Hz, 1 H); LCMS: 530.1, rt ) 4.10 min (M + H+), 96%
purity; HRMS (FAB) m/z 530.2525 [(M + H)+; calcd for
C28H32F4N5O: 530.2543].
Ex Vivo Binding Assay. Receptor occupation in brain following
oral dosing was determined using an ex vivo radioligand binding
assay. Mice were orally administered vehicle (HPâCD) or 30 mg/
kg of test compound and subsequently killed by CO2 asphyxiation
6 or 24 h after dosing. The brains were removed and immediately
frozen on dry ice. Sections (16 µm) of the caudate putamen were
cut and thaw-mounted onto microscope slides. The tissue was
exposed to MCH-R1 binding buffer containing 700 pM [125I]-
S36057 (NEN) for 30 min at room temperature. Nonspecific binding
was determined by including 1 µM MCH in the binding buffer.
The tissue was then washed with binding buffer and dried.
Radiolabeled S36057 bound to the tissue was visualized using a
Storm PhosphorImager (Molecular Dynamics) and quantified using
ImageQuant Software.
Animal Care and Maintenance. Male C57Bl/6NCrl:BR (Charles
River Inc., Wilmington, DE) mice were used for all experiments.
Mice arrived at 4-6 weeks of age and were individually housed
in polycarbonate cages with food (10% kcal as fat; D12450B;
Research Diets Inc, New Brunswick, NJ) and water available ad
libitum unless otherwise stated. They were maintained under a 12
h/12 h light/dark cycle at a temperature of 22 °C. Diet-induced
obese (DIO) mice were generated by feeding C57Bl/6NCrl:BR mice
a high fat diet (45% of calories from fat; D12451, Research Diets
Inc.) for 8-12 weeks beginning at 4 weeks of age. All studies were
conducted in an American Association for Laboratory Animal Care
accredited facility following protocols approved by the Schering-
Plough Research Institute Animal Care and Use Committee. The
procedures were performed in accordance with the principles and
guidelines established by the National Institutes of Health for the
care and use of laboratory animals.
(a) Dosing. In all studies performed, mice were orally dosed
with vehicle (5 or 10 mL/kg 20% hydroxypropyl-â-cyclodextrin
(HPâCD, Cetestar, Indianapolis, IN)) for 2-3 days prior to study
to acclimate them to handling and dosing. Compound was orally
administered in a 20% HPâCD solution, while Sibutramine was
orally administered as a suspension in 20% HPâCD.
(b) Feeding Studies. Two preweighed fresh 3-3.5 g food pellets
were presented to mice on the floor of the home cage every day.
Body weight (weighed to the nearest 0.1 g) and food intake
(weighed to the nearest 0.01 g) were measured daily.
MCH Receptor Binding Assay. CHO cells expressing MCH-
R1 (CHO-MCH-R1) were generated as described previously.35
Membranes from these cells were prepared by lysing cells with 5
mM HEPES for 15 min at 4 °C followed by centrifugation of the
cell lysates (12000 × g, 15 min). The pellet was resuspended in 5
mM HEPES by trituration with a 21 gauge needle. Binding of
compound to MCH-R1 was determined using an SPA-based
radioligand binding assay. CHO-MCH-R1 cell membranes (10 µg)
were incubated with 100 µg of wheat germ aggluttinin SPA beads
Acknowledgment. We thank Duane Burnett, Michael Gra-
ziano, and Margaret Van Heek for insightful suggestions and
comments; Jesse Wong, Jianshe Kong, Mark Liang, and Tao
Meng for scale-up of intermediates; Rebecca Osterman and
Andy Evans for analytical support via NMR studies; David Hesk

Bicyclo[3.1.0]hexyl Ureas as MCH-R1 Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7 2309
of melanin-concentrating hormone antagonists: novel antiobesity
agents. Expert Opin. Ther. Pat. 2004, 14, 313-325. (e) Kowalski,
T. J.; McBriar, M. D. Therapeutic potential of melanin-concentrating
hormone-1 receptor antagonists for the treatment of obesity. Expert
Opin. InVest. Drugs 2004, 13, 1113-1122.
for radiolabeled synthesis of 24u; and Michael Wong and
Christopher Boyce for critical reading of this manuscript.
Supporting Information Available: Results from elemental
analysis. This material is available free of charge via the Internet
at http://pubs.acs.org.
(13) See ref 12. Also, AMG-076 (Amgen) is currently undergoing phase
I clinical trials and is claimed to be orally active. No structure has
been reported. Investigational Drugs Database. http://www.iddb3.com/.
Updated May 11, 2005. Iddb ref 519061.
References
(14) (a) Handlon, A. L.; Al-Barazanji, K. A.; Barvian, K. K.; Bighan, E.
C.; Carlton, D. L.; Carpenter, A. J.; Cooper, J. P.; Daniels, A. J.;
Garrison, D. T.; Goetz, A. S.; Green, G. M.; Grizzle, M. K.; Guo,
Y. C.; Hertzog, D. L.; Hyman, C. E.; Ignar, D. M.; Peckham, G. E.;
Speake, J. D.; Britt, C.; Swain, W. R Discovery of potent and selective
MCH receptor-1 antagonists for the treatment of obesity. Presented
at the 228th National Meeting of the American Chemical Society,
Philadephia, PA, August, 2004; Abstract MEDI-193. (b) Investiga-
tional Drugs Database. http://www.iddb3.com/. Updated May 6, 2005.
Iddb ref 572384.
(15) (a) Souers, A. J.; Gao, J.; Brune, M.; Bush, E.; Wodka, D.;
Vasudevan, A.; Judd, A. S.; Mulhern, M.; Brodjian, S.; Dayton, B.;
Shapiro, R.; Hernandez, L. E.; Marsh, K. C.; Sham, H. L.; Collins,
C. A.; Kym, P. R. Identification of 2-(4-Benzyloxyphenyl)-N-[1-(2-
pyrrolidin-1-yl-ethyl)-1H-indazol-6-yl]acetamide, an orally efficacious
melanin-concentrating hormone receptor 1 antagonist for the treatment
of obesity. J. Med. Chem. 2005, 48, 1318-1321. (b) Souers, A. J.;
Gao, J.; Wodka, D.; Judd, A. S.; Mulhern, M.; Napier, J. J.; Brune,
M. E.; Bush, E. N.; Brodjian, S. J.; Dayton, B. D.; Shapiro, R.;
Hernandez, L. E.; Marsh, K. C.; Sham, H. L.; Collins, C. A.; Kym,
P. R. Synthesis and evaluation of urea-based indazoles as melanin-
concentrating hormone receptor 1 antagonists for the treatment of
obesity. Bioorg. Med. Chem. Lett. 2005, 15, 2752-2757. (c)
Vasudevan, A.; Souers, A. J.; Freeman, J.; Verzal, M. K.; Gao, J.;
Mulhern, M. M.; Wodka, D.; Lynch, J. K.; Engstrom, K. M.; Wagaw,
S. H.; Brodjian, S.; Dayton, B. D.; Falls, D.; Bush, E.; Brune, M.;
Shapiro, R. D.; Marsh, K. C.; Hernandez, L. E.; Collins, C. A.; Kym,
P. R. Aminopiperidine indazoles as orally efficacious melanin
concentrating hormone receptor-1 antagonists. Bioorg. Med. Chem.
Lett. 2005, 15, 5293-5297.
(16) (a) Vasudevan, A.; LaMarche, M. J.; Blackburn, C.; Che, J. L.;
Luchaco-Cullis, C. A.; Lai, S.; Marsilje, T. H.; Patane, M. A.; Souers,
A. J.; Wodka, D.; Geddes, B.; Chen, S.; Brodjian, S.; Falls, D. H.;
Dayton, B. D.; Bush, E.; Brune, M.; Shapiro, R. D.; Marsh, K. C.;
Hernandez, L. E.; Sham, H. L.; Collins, C. A.; Kym, P. R.
Identification of ortho-amino benzamides and nicotinamides as
MCHr1 antagonists. Bioorg. Med. Chem. Lett. 2005, 15, 4174-4179.
(b) Kym, P. R.; Iyengar, R.; Souers, A. J.; Lynch, J. K.; Judd, A. S.;
Gao, J.; Freeman, J.; Mulhern, M.; Zhao, G.; Vasudevan, A.; Wodka,
D.; Blackburn, C.; Brown, J.; Che, J. L.; Cullis, C.; Lai, S. J.;
LaMarche, M.; Marsilje, T.; Roses, J.; Sells, T.; Geddes, B.; Govek,
E.; Patane, M.; Fry, D.; Dayton, B. D.; Brodjian, S.; Falls, D.; Brune,
M.; Bush, E.; Shapiro, R.; Knourek-Segel, V.; Fey, T.; McDowell,
C.; Reinhart, G. A.; Preusser, L. C.; Marsh, K.; Hernandez, L.; Sham,
H. L.; Collins, C. A. Discovery and characterization of aminopip-
eridinecoumarin melanin concentrating hormone receptor 1 antago-
nists. J. Med. Chem. 2005, 48, 5888-5891. (c) Vasudevan, A.;
Verzal, M. K.; Wodka, D.; Souers, A. J.; Blackburn, C.; Che, J. L.;
Lai, S.; Brodjian, S.; Falls, D. H.; Dayton, B. D.; Govek, E.; Daniels,
T.; Geddes, B.; Marsh, K. C.; Hernandez, L. E.; Collins, C. A.; Kym,
P. R. Identification of aminopiperadine benzamides as MCHr1
antagonists. Bioorg. Med. Chem. Lett. 2005, 15, 3412-3416.
(17) Palani, A.; Shapiro, S.; McBriar, M. D.; Clader, J. W.; Greenlee, W.
J.; Spar, B.; Kowalski, T. J.; Farley, C.; Cook, J.; van Heek, M.;
Weig, B.; O’Neill, K.; Graziano, M.; Hawes, B. E. Biaryl ureas as
potent and orally efficacious melanin concentrating hormone receptor
1 antagonists for the treatment of obesity. J. Med. Chem. 2005, 48,
4746-4749.
(18) (a) Preliminary communication: McBriar, M. D.; Guzik, H.; Xu,
R.; Paruchova, J.; Li, S.; Palani, A.; Clader, J. W.; Greenlee, W. J.;
Hawes, B. E.; Kowalski, T. J.; O’Neill, K.; Spar, B.; Weig, B.
Discovery of bicycloalkyl urea melanin concentrating hormone
receptor antagonists: orally efficacious antiobesity therapeutics. J.
Med. Chem. 2005, 48, 2274-2277. (b) Presented in part: McBriar,
M. D.; Guzik, H.; Xu, R.; Paruchova, J.; Li, S.; Palani, A.; Shapiro,
S.; Clader, J. W.; Greenlee, W. J.; Hawes, B. E.; Kowalski, T. J.;
O’Neill, K.; Spar, B.; Weig, B. Design and synthesis of orally
efficacious melanin concentrating hormone (MCH) receptor antago-
nists as antiobesity therapeutics. Presented at the 229th National
Meeting of the American Chemical Society, San Diego, CA, March,
2005; Abstract MEDI-009.
(1) Hill, J. O.; Wyatt, H. R.; Reed, G. W.; Peters, J. C. Obesity and the
Environment: Where Do We Go from Here? Science 2003, 299,
853-855.
(2) Mokdad, A. H.; Ford, E. S.; Bowman, B. A.; Deitz, W. H.; Vinicor,
F.; Bales, V. S.; Marks, J. S. Prevalence of Obesity, Diabetes, and
Obesity-Related Health Risk Factors, 2001. JAMA 2003, 289, 76-
79.
(3) U.S. Department of Health and Human Services. The Surgeon
General’s Call to Action to PreVent and Decrease OVerweight and
Obesity 2001, Public Health SerVice; Office of the Surgeon General,
Rockville, MD, 2001; www.surgeongeneral.gov/topics/obesity.
(4) Gura, T. Obesity Drug Pipeline Not so Fat. Science 2003, 299, 849-
852.
(5) Sorbera, L. A.; Castaner, J.; Silvestre, J. S. Rimonabant hydrochlo-
ride: Antiobesity drug, aid to smoking cessation, treatment of alcohol
dependency, cannabinoid CB1 antagonist. Drugs Future 2005, 30,
128-137.
(6) Duhl, D. M.; Boyce, R. S. Obesity Therapeutics: Prospects and
Perspectives. Ann. Rep. Med. Chem. 2003, 38, 239-248.
(7) Baker, B. I. Melanin-concentrating hormone: a general vertebrate
neuropeptide. Int. ReV. Cytol. 1991, 126, 1-47.
(8) (a) Hanada, R.; Nakazato, M.; Matsukura, S.; Murakami, N.;
Yoshimatsu, H.; Sakata, T. Differential regulation of melanin-
concentrating hormone and orexin genes in the agouti-related protein/
melanocortin-4 receptor system. Biochem. Biophys. Res. Commun.
2000, 268, 88-91. (b) Stricker-Krongrad, A.; Dimitrov, T.; Beck,
B. Central and peripheral dysregulation of melanin-concentrating
hormone in obese Zucker rats. Brain Res. Mol. Brain Res. 2001, 92,
43-48. (c) Gomori, A.; Ishihara, A.; Ito, M.; Mashiko, S.; Matsushita,
H.; Yumoto, M.; Tanaka, T.; Tokita, S.; Moriya, M.; Iwaasa, H.;
Kanatani, A. Chronic intracerebroventricular infusion of MCH causes
obesity in mice. Am. J. Physiol.: Endocrinol. Metab. 2003, 284,
E583-E588. (d) Ito, M.; Gomori, A.; Ishihara, A.; Oda, Z.; Mashiko,
S.; Matsushita, H.; Yumoto, M.; Sano, H.; Tokita, S.; Moriya, M.;
Iwaasa, H.; Kanatani, A. Characterization of MCH-mediated obesity
in mice. Am. J. Physiol.: Endocrinol. Metab. 2003, 284, E940-
E945.
(9) Shimada, M.; Tritos, N. A.; Lowell, B. B.; Flier, J. S.; Maratos-
Flier, E. Mice lacking melanin-concentrating hormone are hypophagic
and lean. Nature 1998, 396, 670-674.
(10) (a) Tan, C. P.; Sano, H.; Iwaasa, H.; Pan, J.; Sailer, A. W.; Hreniuk,
D. L.; Feighner, S. D.; Palyha, O. C.; Pong, S. S.; Figueroa, D. J.;
Austin, C. P.; Jiang, M. M.; Yu, H.; Ito, J.; Ito, M.; Guan, X. M.;
MacNeil, D. J.; Kanatani, A.; Van der Ploeg, L. H.; Howard, A. D.
Melanin-concentrating hormone receptor subtypes 1 and 2: species-
specific gene expression. Genomics 2002, 79, 785-792. (b) Fried,
S.; O’Neill, K.; Hawes, B. E. Cloning and characterization of rhesus
monkey MCH-R1 and MCH-R2. Peptides 2002, 23, 1401-1408.
(11) (a) Shearman, L. P.; Camacho, R. E.; Stribling, D. S.; Zhou, D.;
Bednarek, M. A.; Hreniuk, D. L.; Feighner, S. D.; Tan, C. P.; Howard,
A. D.; Van der Ploeg, L. H.; MacIntyre, D. E.; Hickey, G. J.; Strack,
A. M. Chronic MCH-1 receptor modulation alters appetite, body
weight and adiposity in rats. Eur. J. Pharmacol. 2003, 475, 37-47.
(b) Chen, Y.; Hu, C.; Hsu, C. K.; Zhang, Q.; Bi, C.; Asnicar, M.;
Hsiung, H. M.; Fox, N.; Slieker, L. J.; Yang, D. D.; Heiman, M. L.;
Shi, Y. Targeted disruption of the melanin-concentrating hormone
receptor-1 results in hyperphagia and resistance to diet-induced
obesity. Endocrinology 2002, 143, 2469-2477. (c) Marsh, D. J.;
Weingarth, D. T.; Novi, D. E.; Chen, H. Y.; Trumbauer, M. E.; Chen,
A. S.; Guan, X. M.; Jiang, M. M.; Feng, Y.; Camacho, R. E.; Shen,
Z.; Frazier, E. G.; Yu, H.; Metzger, J. M.; Kuca, S. J.; Shearman, L.
P.; Gopal-Truter, S.; MacNeil, D. J.; Strack, A. M.; MacIntyre, D.
E.; Van der Ploeg, L. H.; Qian, S. Melanin-concentrating hormone
1 receptor-deficient mice are lean, hyperactive, and hyperphagic and
have altered metabolism. Proc. Natl. Acad. Sci. U.S.A. 2002, 99,
3240-3245.
(12) (a) McBriar, M. D.; Kowalski, T. J. Melanin-concentrating hormone
as a therapeutic target. Ann. Rep. Med. Chem. 2005, 40, 119-133.
(b) Dyke, H.; Ray, N. C. Recent developments in the discovery of
MCH-1R antagonists for the treatment of obesity - an update. Expert
Opin. Ther. Pat. 2005, 15, 1303-1313. (c) Shi, Y. Beyond skin
color: emerging roles of melanin-concentrating hormone in energy
homeostasis and other physiological functions. Peptides 2004, 25,
1605-1611. (d) Browning, A. Recent developments in the discovery

2310 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7
McBriar et al.
(19) Corey, E. J.; Chaykovsky, M. Dimethyloxosulfonium Methylide
((CH3)2SOCH2) and Dimethylsulfonium Methylide ((CH3)2SCH2).
Formation and application to organic synthesis. J. Am. Chem. Soc.
1965, 87, 1353-1364.
(29) Korfmacher, W. A.; Cox, K. A.; Ng, K. J.; Veals, J.; Hsien, Y.;
Wainhaus, S.; Broske, L.; Prelusky, D.; Nomeir, A.; White, R. E.
Cassette-accelerated rapid rat screen: a systematic procedure for the
doing and liquid chromatography/atomspheric pressure ionization
tandem mass spectrometric analysis of new chemical entities as part
of new drug discovery. Rapid Commun. Mass Spectrom. 2001, 15,
335-340.
(30) Simonyi, M.; Maksay, G. The Practice of Medicinal Chemistry;
Wermuth, C. G., Ed.; Academic Press: London, 1999; pp 420-421.
(31) Baudoin, B.; Jimonet, P.; Maignan, S.; Achard, D.; Mailliet, P.; Laoui,
A.; Nemecek, C. Preparation of 4-[(imidazolylmethyl)amino]chro-
man-8-carboxamides as protein farnesyltransferase inhibitors. WO
2001/009125.
(32) http://www.cerep.fr/cerep/users/index.asp. Accessed Sep 2, 2005.
(33) Kowalski, T. J.; Spar, B. D.; Weig, B.; Farley, C.; Cook, J.; Gao, J.;
Henry, M.; Ghibaudi, L.; Fried, S.; O’Neill, K.; Del Vecchio, R.;
McBriar, M. D.; Guzik, H.; Clader, J.; Hawes, B.; Hwa, J. Effects
of a selective melanin-concentrating hormone 1-receptor antagonist
on food intake and energy homeostasis in diet-induced obese mice.
Eur. J. Pharmacol. In press.
(34) Guzi, T. J.; Paruch, K.; Dwyer, M. P.; Doll, R. J.; Girijavallabhan,
V. M.; Mallams, A.; Alvarez, C. S.; Keertikar, K. M.; Rivera, J.;
Chan, T.-Y.; Madison, V.; Fischmann, T. O.; Dillard, L. W.; Tran,
V. D.; He, Z. M.; James, R. A.; Park, H.; Paradkar, V. M.; Hobbs,
D. W. Preparation of pyrazolopyrimidines as cyclin-dependent kinase
inhibitors. WO 2004/022561.
(20) Luche, J.-L. Lanthanides in organic chemistry, 1. Selective 1,2
reductions of conjugated ketones. J. Am. Chem. Soc. 1978, 100,
2226-2227.
(21) Dess, D. B.; Martin, J, C. Readily accessible 12-I-5 oxidant for the
conversion of primary and secondary alcohols to aldehydes and
ketones. J. Org. Chem. 1983, 48, 4155-4156.
(22) Klapars, A.; Huang, X.; Buchwald, S. L. A general and efficient
copper catalyst for the amidation of aryl halides. J. Am. Chem. Soc.
2002, 124, 7421-7428.
(23) Piers, E.; Grierson, J. R.; Lau, C. K.; Nagakura, I. Synthesis of
â-chloro, â-bromo, and â-iodo R,â-unsaturated ketones. Can. J.
Chem. 1982, 60, 210-223.
(24) Lorenz, J. C.; Long, J.; Yang, Z.; Xue, S.; Xie, Y.; Shi, Y. A novel
class of tunable zinc reagents (RXZnCH2Y) for efficient cyclopro-
panation of olefins. J. Org. Chem. 2004, 69, 327-334.
(25) Denmark, S. E.; Edwards, J. P. A comparison of (chloromethyl)-
and (iodomethyl)zinc cyclopropanation reagents. J. Org. Chem. 1991,
56, 6974-6981.
(26) Wolf, E.; Rossmanith, E.; Bartlett, R.; Schleyerbach, R. Preparation
of 3,5-di-tert-butyl-4-hydroxybenzamides as antiinflammatories. DE
1988/3702755 A1.
(27) Xu, R.; Li, S.; Paruchova, J.; McBriar, M. D.; Guzik, H.; Palani, A.;
Clader, J. W.; Cox, K.; Greenlee, W. J.; Hawes, B. E.; Kowalski, T.
J.; O’Neill, K.; Spar, B. D.; Weig, B.; Weston, D. J. Bicyclic [4.1.0]
heptanes as phenyl replacements for melanin concentrating hormone
(MCH) receptor antagonists. Bioorg. Med. Chem. In press.
(28) Vieth, M.; Siegel, M. G.; Higgs, R. E.; Watson, I. A.; Robertson, D.
H.; Savin, K. A.; Durst, G. L.; Hipskind, P. A. Characteristic physical
properties and structural fragments of marked oral drugs. J. Med.
Chem. 2004, 47, 224-232.
(35) Hawes, B. E.; Kil, E.; Green, B.; O’Neill, K.; Fried, S.; Graziano,
M. P. The melanin-concentrating hormone receptor couples to
multiple G proteins to activate diverse intracellular signaling
pathways. Endocrinology 2000, 141, 4524-4532.
JM050886N