Synthesis and SAR investigations for novel melanin-concentrating hormone 1 receptor (MCH1) antagonists part 1. The discovery of arylacetamides as viable replacements for the dihydropyrimidinone moiety of an HTS hit

Article abstract of DOI:10.1021/jm060381c

Melanin-concentrating hormone (MCH) is involved in the regulation of feeding, water balance, energy metabolism, general arousal and attention state, memory, cognitive functions, and psychiatric disorders. Herein, two new chemical series exemplified by N-[5-(1-{3-[2,2-bis-(4-fluoro-phenyl)-acetylamino]- propyl}-piperidin-4-yl)-2,4-difluoro-phenyl]-isobutyramide (SNAP 102739, 5m) and N-[3-(1-{3-[(S)-2-(4-fluorophenyl)-propionylamino]-propyl}-piperidin-4-yl)-4- methylphenyl]-isobutyramide ((S)-6b) are reported. These compounds were designed to improve the pharmacokinetic properties of the high-throughput screening lead compound 1 (SNAP 7941). The MCH₁ receptor antagonists 5m and (S)-6b show reasonable pharmacokinetic profiles (rat bioavailability = 48 and 81%, respectively). Compounds 5m and (S)-6b demonstrated the inhibition of a centrally administered MCH-evoked drinking effect, and compound 5m exhibited oral in vivo efficacy in the rat social interaction model of anxiety, with a minimum effective dose = 0.3 mg/kg.

Full text of DOI:10.1021/jm060381c

3870
J. Med. Chem. 2007, 50, 3870-3882
Synthesis and SAR Investigations for Novel Melanin-Concentrating Hormone 1 Receptor
(MCH1) Antagonists Part 1. The Discovery of Arylacetamides as Viable Replacements for the
Dihydropyrimidinone Moiety of an HTS Hit
Yu Jiang, Chien-An Chen, Kai Lu, Irena Daniewska, John De Leon, Ron Kong, Carlos Forray, Boshan Li,
Laxminarayan G. Hegde, Toni D. Wolinsky, Douglas A. Craig, John M. Wetzel, Kim Andersen, and Mohammad R. Marzabadi*
Departments of Chemistry, Cellular Science, and Target DiscoVery and Assessment, Lundbeck Research USA, Inc., 215 College Road,
Paramus, New Jersey 07652-1413
ReceiVed March 31, 2006
Melanin-concentrating hormone (MCH) is involved in the regulation of feeding, water balance, energy
metabolism, general arousal and attention state, memory, cognitive functions, and psychiatric disorders.
Herein, two new chemical series exemplified by N-[5-(1-{3-[2,2-bis-(4-fluoro-phenyl)-acetylamino]-propyl}-
piperidin-4-yl)-2,4-difluoro-phenyl]-isobutyramide (SNAP 102739, 5m) and N-[3-(1-{3-[(S)-2-(4-fluoro-
phenyl)-propionylamino]-propyl}-piperidin-4-yl)-4-methylphenyl]-isobutyramide ((S)-6b) are reported. These
compounds were designed to improve the pharmacokinetic properties of the high-throughput screening lead
compound 1 (SNAP 7941). The MCH1 receptor antagonists 5m and (S)-6b show reasonable pharmacokinetic
profiles (rat bioavailability ) 48 and 81%, respectively). Compounds 5m and (S)-6b demonstrated the
inhibition of a centrally administered MCH-evoked drinking effect, and compound 5m exhibited oral in
vivo efficacy in the rat social interaction model of anxiety, with a minimum effective dose ) 0.3 mg/kg.
Introduction
90% given 30 mg/kg, po.10a Compound 1 also reduced the
weight gain in young growing rats and in mature rats that were
fed a high-fat diet (Diet-Induced Obese rats).10b Additionally,
compound 4 (GW-803430) showed a 13% dose-dependent
weight loss after 12 days when administered to mice at 3 mg/
kg.10c Furthermore, compound 1 produced effects similar to the
clinically used antidepressants and anxiolytics in three different
animal models for depression and anxiety: the rat forced-swim
test, the rat social interaction assay, and the guinea pig maternal-
separation vocalization test.10b As well, Taisho and Arena have
recently reported a potent orally active MCH1 receptor antago-
nist 3 (ATC-0175), with anxiolytic and antidepressant activities
in rodents.10d Additional MCH1 receptor publications have
recently appeared in the literature describing the pharmacologi-
cal properties and the control of food intake by the resultant
diverse MCH1 receptor antagonists.10-12
The high-throughput screening of Lundbeck GPCR-directed
compound collection identified compound 1 as a high affinity
and selective MCH1 receptor antagonist. The in vitro and in
vivo properties of compound 1 were described recently.10b
However, experience with compound 1 as a highly metabolized
and hydrolyzed analog resulting in low bioavailability, as well
as experience with previously described dihydropyrimidinone-
substituted compounds,13 prompted a search for alternative
templates to circumvent hydrolysis and metabolism issues.
Studies in the discovery of alternative templates in place of the
dihydropyrimidinone moiety of compound 1 as well as the
optimization of the resultant MCH1 receptor antagonists and
the in vitro and in vivo properties of the optimal MCH1 receptor
antagonists 5 and 6, depicted in Figure 2, are described herein.
Melanin-concentrating hormone (MCH) is a cyclic peptide
originally isolated from salmonid pituitaries, where it was named
for its ability to cause aggregation of melanin within skin
melanophores, resulting in skin lightening.1 In mammals, MCH
is a cyclic 19-amino acid neuropeptide that is produced
predominantly by neurons in the lateral hypothalamus and zona
incerta, which project broadly throughout the brain.2 Mammalian
MCH is highly conserved between rat, mouse, and human
species, exhibiting 100% amino acid identity.2 The biological
function of MCH is mediated by two receptors, MCH1 receptor
and MCH2 receptor, which have been identified in several
species, including human, rhesus monkey, ferret, and dog;3
however, functional MCH2 receptor has not been found in rat,
mouse, hamster, guinea pig, or rabbit.4 Recent reports have
suggested that the MCH peptide plays a major role in regulation
of food intake and stress in rodents.5 For example, the central
administration of MCH stimulates food intake, while fasting
results in an increase in MCH expression.6 Furthermore, mice
lacking the gene encoding MCH are lean, hypophagic and
maintain elevated metabolic rates.7 In contrast, mice overex-
pressing the MCH gene are susceptible to obesity and insulin
resistance.8 In addition, MCH seems to be an activator of the
HPA stress axis.9 These findings suggest that small-molecule
antagonists of the MCH1 receptor can potentially be used in
the treatment of obesity and mood disorders.5
The promising in vitro and in vivo pharmacology of published
MCH1 receptor antagonists has made the MCH1 receptor an
attractive target for the development of a small molecule
antagonist.10a-k The progress of MCH1 receptor research for
antagonists acting at the receptor has been summarized by
several authors.11,12 Examples include the first described non-
peptide MCH1 receptor antagonist 2 (T-226296, Figure 1), which
suppressed MCH-stimulated food intake in rats at greater than
Synthetic Chemistry
The synthesis of final compounds 5 and 6 required the
synthesis of intermediate 7 shown in Scheme 1. The synthesis
of compound 7 was accomplished according to the procedures
depicted in Scheme 1. Bromobenzenes 8a/8b were treated with
nitric acid in the presence of sulfuric acid at <7 °C to afford
* To whom correspondence should be addressed. Phone: +1 (201) 350-
0196. Fax: +1 (201) 261-0623. E-mail: moma@lundbeck.com.
10.1021/jm060381c CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/02/2007

Melanin-Concentrating Hormone 1 Receptor Antagonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 16 3871
Figure 1. Representative nonpeptide MCH1 receptor antagonists.
Scheme 1a
11e in the presence of tetrabutylammonium iodide and palladium
acetate in water at 150 °C afforded compounds 13a-13e in
90-95% yields.15 Hydrogenation of compounds 13a-13e under
200 psi reduced the double bond to yield compounds 14a-14e
in a yield of 83-88%. Deprotection of compounds 14a-14e
in the presence of trifluoroacetic acid (TFA) in dichloromethane
(DCM) or hydrogen chloride in dioxane afforded 4-phenyl
piperidines 15a-15e in quantitative yields. The aminoalkyl
tether chains of compounds 7a-7e were introduced by sequen-
tial reactions of compounds 15a-15e with N-(n-bromoalkyl)-
phthalimides (n ) 0-4) in the presence of potassium carbonate
in N,N-dimethylformamide at 80 °C to afford compounds 16a-
16i in yields of 79-93%. Deprotection of compounds 16a-
16i with hydrazine in refluxing ethanol proceeded to give
compounds 7a-7i in 91-97% yields. In the case of the 3-carbon
tether analogs 7a-7c, 7e, and 7i, n ) 1, an alternative route of
the reaction of compounds 16a-16i with (3-bromo-propyl)-
carbamic acid tert-butyl ester followed by acidic removal of
the BOC group gave the desired compounds 7a-7c, 7e, and 7i
in 70-80% yields.
The intermediate diarylacetic acids 17b and 17c, shown in
Scheme 2, were synthesized from substituted benzenes and
glyoxylic acid monohydrate in acetic acid at 80 °C according
to literature procedures.16 The synthesis of the chiral advanced
carboxylic acids 18a/18b, shown in Scheme 3, needed for the
synthesis of compounds 6a/6b, followed Evans’ protocol to
afford a separable mixture of diastereoisomers in a ratio of
>98.5:1.5 in 60-80% yields.17 The chiral purity of the final
products 6a/6b were determined via chiral SFC to be >95%
ee. A Daicel AD column with diethylamine and methanol
modifiers was used in the determinations of the ratios.
As shown in Scheme 2, the amidation of acid chloride 17a
with compounds 7a-7e in the presence of triethylamine in
dichloromethane or the coupling of carboxylic acids 17b-17g
with compounds 7a-7e in the presence of EDC and DMAP in
DCM/DMF at room temperature afforded products 5a-5p in
50-85% yields.
a Reagents and conditions: (a) H2SO4, HNO3, below 7 °C, 45 min; (b)
Fe, NH4Cl, EtOH, reflux, 2 h; (c) acid chloride, base, THF, 0 °C then rt
2-3 h; (d) 12, Pd(OAc)2, TBAI, Na2CO3, H2O, 150 °C; (e) 10% Pd/C, H2,
EtOH, rt, 24-48 h; (f) 4 M HCl in 1,4-dioxane, rt, 1 h, or TFA, CH2Cl2,
rt, 1-2 h; (g) N-(n-bromoalkyl)-phthalimide, K2CO3, DMF, 80 °C, 4 h;
(h) H2NNH2, EtOH, reflux, 5 h. Compounds 10c/10d/10e are commercially
available from Sigma-Aldrich.
Similarly, the amidation of carboxylic acids 18a-18d with
compounds 7a-7e in the presence of EDC and DMAP in DCM/
DMF, shown in Scheme 3, at room temperature afforded
products 6a-6d in 50-85% yields.
nitrobenzenes 9a/9b in a yield of 99%.14 Reduction of the nitro
group in 9a/9b with iron in the presence of ammonium chloride
in ethanol at refluxing temperature afforded anilines 10a/10b
in 59% yields. Compounds 11a-11e were synthesized via
amidations of compounds 10a-10e using 2-methylpropionyl
chloride in the presence of triethylamine (TEA) in yields of
about 95%. Suzuki coupling of 4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid
tert-butyl ester (12) with iodobenzenes or bromobenzenes 11a-
Results and Discussion
An early exploratory library approach to identifying suitable
replacements for the dihydropyrimidinone moiety of compound
1 rendered 2,2-diarylacetamides and 2-aryl and 2-alkyl-aceta-
mides as viable surrogates, as depicted for compounds 5 and 6

3872 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 16
Jiang et al.
Figure 2. Two novel chemical series 5 and 6 of MCH1 receptor antagonists.
Scheme 2a
Table 1. Effect of the Tether Length on the MCH1 Receptor Affinities
of Compounds 5a-5ea
rMCH1b Ki ( SEM
cmpd
na
(nM)
1
NA
0
1
2
3
0.25 ( 0.01
1.9 ( 0.7
1.9 ( 0.2
50 ( 10
5a
5b
5c
5d
5e
47 ( 19
4
29 ( 1
a NA ) not applicable. b Mean values ( standard error of the mean
(SEM) determined in binding assays (n ) 3) to the recombinant rat MCH1.
Binding assays were performed by incubating membranes isolated from
transfected cells with varying concentrations of [3H]-1 in binding buffer
(50 mM Tris, 10 mM MgCl2, 0.16 mM PMSF, 1 mM 1,10-phenanthroline,
and 0.2% BSA, pH 7.4) at 25 °C for 90 min, as described previously.10b
See the Experimental Section for details on functional antagonism data of
the compounds assessed using FLIPR calcium mobility assay in cells stably
expressing rat MCH1.
a Reagents and conditions: (a) 7, DMAP, EDC, DCM/DMF, rt, 5 h; (b)
7, TEA, THF, rt, 5 h. Compounds 17a and 17d-17g are available from
Sigma-Aldrich.
Scheme 3a
observed for substitutions at the R2 position (5h, 5i, 5j, and
5p), depending on the substituents (H, alkyl, OH). A comparison
of compounds 5b-5p in Table 2 also showed that, while
fluorines at 2-, 4-, and 6-R3 (5m and 5n) and 6-CH3 positions
(5k and 5l) gave high affinity MCH1 receptor compounds, a
4-CH3 group weakened the MCH1 receptor affinity of the
desired product (cf. 5b and 5l vs 5o).
As part of the SAR studies, the effect of 2-aryl-2-alkylac-
etamide substitution, in place of the 2,2-diarylacetamide group,
on the MCH1 receptor affinity of compound 6 was explored.
The effect of the chirality of the acetamide group of compounds
6a and 6b on the MCH1 receptor affinities was initially
examined (Table 3). Within the enantiomeric pairs 6a and 6b,
(S)-6b was found to have higher affinity of 10 nM.
The effect of 2,2-dialkyl substitution on compounds 6b-6d
is shown in Table 4. While the monomethylated analog (S)-6b
exhibited an MCH1 receptor affinity of 10 nM, the cycloalkyl
groups, (CH2)5 and (CH2)4, slightly improved the affinity profiles
of analogs 6c and 6d.
Concurrent with the dihydropyrimidinone replacement studies,
blockage of the putative sites of metabolism of compound 1
were also studied, with an anticipated enhancement in the
pharmacokinetic (PK) properties of the resultant analogs. The
anilide moiety of compound 1 is potentially susceptible to
enzymatic hydroxylations and hydrolysis. Hence, the effect of
blocking the putative sites of metabolism of the anilides of
compounds 5 were investigated by measuring the plasma levels
of rats, dosed at 10 mg/kg po, at 1, 2, and 4 h. The brain levels
were measured at the conclusion of the plasma monitoring
period at 4 h.
a Reagents and conditions: (a) DMAP, EDC, DCM/DMF, rt, 5 h.
Compounds 18c/18d are available from Acros Organic U.S.A.
in Schemes 2 and 3. The subsequent medicinal chemistry efforts
in the optimization of analogs 5 and 6 are summarized herein.
The SAR of the 2,2-diarylacetamide replacements on the MCH1
receptor affinities of compounds 5a-5p is presented in Tables
1 and 2. Table 1 illustrates the effect of increasing tether length
on the MCH1 receptor affinities of compounds 5a-5e. The
optimal tether length for compounds 5a-5e was determined to
be two and three carbons, n ) 0 or 1, both displaying 1.9 nM
MCH1 receptor affinities. Within compounds 5a-5e, as the
linker length increased, n ) 2-4, a drop in affinity was seen at
n ) 2 and 3 (compounds 5c,d), followed by a slight improve-
ment at n ) 4 (compound 5e). Due to its favorable MCH1
receptor affinity profile and synthetic accessibility, compound
5b (n ) 1) was selected for further SAR studies. The formation
of the two-carbon tether (n ) 0, step g) outlined in Scheme 1
was accompanied by variable degrees of decomposition.
The substituent effects at the R1-R3 positions on the MCH1
receptor affinities of compounds 5b-5p are summarized in
Table 2. The relatively small H, F, and Cl substituents at R1
(5b, 5f, 5g) afforded low nanomolar affinity compounds. Minor
effects on the MCH1 receptor affinities of 0.6-14 nM were
The effect of para-R3 substitution (H vs 6-CH3) on the plasma
and the brain levels of compounds 5b and 5l is summarized in
Table 5. The two analogs 5b and 5l were administered po at 10

Melanin-Concentrating Hormone 1 Receptor Antagonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 16 3873
Table 2. Effect of R1-R3 Substitutions on the MCH1 Receptor
Affinities of Compounds 5b-5pa
Table 4. Effect of Monosubstitution vs Cyclic Analogs at Benzylic
Positions on the MCH1 Receptor Affinities of Compounds 6b-6da
rMCH1a Ki ( SEM
cmpd
R2/R2
(nM)
rMCH1a Ki ( SEM
(nM)
(S)-6b
6c
6d
Me/H
(CH2)5
(CH2)4
10 ( 1
cmpd
R1
R2
R3
1.9 ( 0.5
3.8 ( 0.7
5b
5f
5g
5h
5i
5j
5k
5l
H
F
H
H
H
H
H
H
H
H
H
1.9 ( 0.2
1.4 ( 0.2
2.4 ( 0.1
7.5 ( 1.3
14 ( 1
8.5 ( 0.5
0.62 ( 0.01
3.0 ( 0.4
1.8 ( 0.6
a Mean values ( standard error of the mean (SEM) determined in binding
assays (n ) 3) to the recombinant rat MCH1. Binding assays were performed
by incubating membranes isolated from transfected cells with varying
concentrations of [3H]-1 in binding buffer (50 mM Tris, 10 mM MgCl2,
0.16 mM PMSF, 1 mM 1,10-phenanthroline, and 0.2% BSA, pH 7.4) at
25 °C for 90 min, as described previously.10b See the Experimental Section
for details on functional antagonism data of the compounds assessed using
FLIPR calcium mobility assay in cells stably expressing rat MCH1.
Cl
H
H
H
F
Me
Et
n-pent
H
6-Me
6-Me
4,6-diF
H
F
H
H
5m
(SNAP 102739)
5n
5o
5p
F
H
H
H
H
2,4,6-triF
4-Me
6-Me
2.9 ( 1.4
500 ( 50
0.6 ( 0.2
Table 5. Plasma and Brain Levels of Compounds 5b and 5la
rat plasma
at 1 h
rat plasma
at 2 h
rat plasma
at 4 h
rat brain
at 4 h
OH
a Mean values ( standard error of the mean (SEM) determined in binding
assays (n ) 3) to the recombinant rat MCH1. Binding assays were performed
by incubating membranes isolated from transfected cells with varying
concentrations of [3H]-1 in binding buffer (50 mM Tris, 10 mM MgCl2,
0.16 mM PMSF, 1 mM 1,10-phenanthroline, and 0.2% BSA, pH 7.4) at
25 °C for 90 min, as described previously.10b See the Experimental Section
for details on functional antagonism data of the compounds assessed using
FLIPR calcium mobility assay in cells stably expressing rat MCH1.
cmpd
(ng/mL)
(ng/mL)
(ng/mL)
(ng/g)
5b (R3 ) H)
5l (R3 ) 6-CH3)
15 ( 2
69 ( 2
12 ( 2
59 ( 2
15 ( 2
75 ( 2
0 ( 2
13 ( 2
a The data were generated from pooled samples of three rats for each
time point, dosed at 10 mg/kg, po. The analytical limit of quantitation for
compounds 5b and 5l were determined to be (2 ng/mL for plasma and (2
ng/g for brain measurements. See the Experimental Section under “Rat
Pharmacokinetic Screening” for details.
Table 3. Effect of Chirality and R1 on the MCH1 Receptor Affinities of
Compounds 6a-6ba
chemical series of formula 5, partially described in Table 5,
the blockage of the para-anilide position appeared to give
compounds with more favorable plasma and brain levels.
Compounds 5m and (S)-6b were selected for further studies.
The PK data for compounds 5m and (S)-6b are summarized in
Table 6. Both compound 5m and compound (S)-6b showed
improved rat bioavailability (48-81%) profiles compared with
compound 1, which exhibited a bioavailability of 6% in rats.
Compounds 5m and (S)-6b were screened in an in-house
panel of 18 receptors as well a broad cross-reactivity panel and
were shown to be devoid of any activities that may contribute
to the in vivo efficacy studies outlined below.
MCH was recently reported to stimulate water intake
independent of food intake.18 Compounds 5m and (S)-6b
produced significant inhibition of MCH-evoked drinking when
tested at a screening concentration of 10 mg/kg po at 1 h, shown
in Figure 3. These data confirmed the specific blockage of a
centrally induced MCH-evoked drinking by compounds 5m and
(S)-6b.
The rat social interaction animal model is used as a predictive
tool for anxiolytic activity.19 The design and procedure for the
social interaction test was modified from that previously
described by Kennett et al.20 Animals were treated with either
vehicle (20% cyclodextrin), chlordiazepoxide (CDP; 5 mg/kg
p.o.), or compound 5m. When tested in the social interaction
test of anxiety, compound 5m, administered orally 1 h previ-
ously, produced a significant increase in social interaction time
relative to vehicle-treated rats, with a minimally effective dose
) 0.3 mg/kg (basal: 38.3 ( 5.7 s; chlordiazepoxide: 85.1 (
5.6 s; 5m: 69.3 ( 9.7 s, p < 0.05; Newman-Keuls post-hoc
test).
rMCH1a Ki ( SEM
cmpd
R1
(nM)
(S)-6a
(R)-6a
(S)-6b
(R)-6b
H
H
F
34 ( 7
37 ( 8
10 ( 1
28 ( 6
F
a Mean values ( standard error of the mean (SEM) determined in binding
assays (n ) 3) to the recombinant rat MCH1. Binding assays were performed
by incubating membranes isolated from transfected cells with varying
concentrations of [3H]-1 in binding buffer (50 mM Tris, 10 mM MgCl2,
0.16 mM PMSF, 1 mM 1,10-phenanthroline, and 0.2% BSA, pH 7.4) at
25 °C for 90 min, as described previously.10b See the Experimental Section
for details on functional antagonism data of the compounds assessed using
FLIPR calcium mobility assay in cells stably expressing rat MCH1.
mg/kg to rats, and the plasma levels were monitored at t ) 1,
2, and 4 h. At the conclusion of the plasma monitoring period
at 4 h, the rat brain levels were examined as well. Compound
5b (R3 ) H) shows low but stable plasma levels at t ) 1-4 h.
Compound 5b was not detected in the brain at t ) 4 h of the
monitoring period. On the other hand, compared to compound
5b, 5l, which is substituted at the para-anilide position with R3
) 6-CH3, showed improved initial plasma levels at t ) 1, 2,
and 4 h. The plasma levels of both analogs 5b and 5l were
maintained at a steady level throughout the four-hour plasma
monitoring period. Additionally, compared to compound 5l, 5b
also showed improved brain exposure levels at 4 h. Within the
See the Experimental Section under “MCH-induced water
intake” for more details.

3874 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 16
Jiang et al.
Table 6. PKa Data for Compounds 1, 5m, and (S)-6b in Ratsb
d
e
f
g
h
i
CLb
CLp
Cmax
Tmax
T1/2
Vss
cmpd
F%c
(L/hr/kg)
(L/hr/kg)
(ng/mL)
(hr)
(hr)
(L/kg)
1j
6
48
81
NDl
3.6
3.3
9.2
2.4
1.5
2.02 ( 0.03m
80 ( 2m
4.0
0.6
2.2
1.7
2.1
4.2
24
3.6
3.4
5mk
(S)-6bk
305 ( 2m
a PK ) pharmacokinetic. b See the Experimental Section under “Rat Pharmacokinetic Assay” for details. c F% ) rat bioavailability. d CLb ) blood clearance.
f
g
h
i
e CLp ) plasma clearance. Cmax ) maximal plasma concentration. Tmax ) time of maximal concentration. T1/2 ) half-life. Vss ) volume of distribution
at steady state. j The rats were dosed at 1 mg/kg po (n ) 2) and 1 mg/kg iv (n ) 2). k The rats were dosed at 2 mg/kg po (n ) 2) and 1 mg/kg iv (n ) 2).
l ND ) not determined. m The analytical limit of quantitation for compound 1 was determined to be (0.03 ng/mL for plasma measurements (Via a solid-
phase extraction step). The analytical limit of quantitation for compounds 5 m and (S)-6b were determined to be (2 ng/mL for plasma measurements.
mm, Analtech). Flash column chromatography was performed on
Merck silica gel 60 (230-400 mesh). Melting points (mp) were
determined in open capillary tubes on a Mel-Temp apparatus and
are uncorrected. Reverse phase high-pressure liquid chromatography
purification was performed using a Genesis HPLC column (ref
16R10985, 100 mm × 22.5 mm) containing C18-7 µm, 120 Å
silica. Microwave experiments were carried out using a Biotage
Emyrs Optimizer or Smithcreator. High-resolution MS data was
obtained using a Waters Q-TOF and Agilant 1100 system.
N-{3-[1-(2-Diphenylacetylamino-ethyl)-piperidin-4-yl]-phen-
yl}-isobutyramide (5a). Compound 5a was prepared from diphe-
Figure 3. Inhibition of MCH-evoked drinking in rats. MCH peptide
nylacetic acid chloride and N-{3-[1-(2-aminoethyl)-4-piperidinyl]-
was administered icv (10 µg in 5 µL saline). Antagonists (5 m or (S)-
phenyl}-2-methylpropanamide according to the general procedure
6b, 10 mg/kg, p.o.) were given orally before the MCH challenge. Water
B of 5b: 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1 H), 7.42-7.14
intake was monitored for 2 h. Results represent the means ( SEM of
(m, 13 H), 6.96-6.89 (m, 1 H), 6.67 (br s, 1 H), 4.97 (s, 1 H),
N determinations (N in parentheses). *p < 0.05; ***p < 0.001 vs MCH
3.50-3.37 (m, 2 H), 2.61-2.37 (m, 4 H), 2.11 (t, J ) 11.5 Hz, 2
alone.
H), 1.81-1.53 (m, 4 H), 1.25 (d, J ) 6.86 Hz, 6 H); ESMS m/e
484.2 (M + H)+; HRMS (FAB) calcd for C31H38N3O2 (M + H)+,
484.2958; found, 484.2933.
Conclusion
N-{3-[1-(3-Diphenylacetylamino-propyl)-piperidin-4-yl]-phen-
yl}-isobutyramide (5b). (a) General Procedure A for the
Synthesis of 5b. A mixture of 2,2-diphenylpropionic acid (0.200
mmol), N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methyl-
propanamide (0.200 mmol), 1-[3-(dimethylamino)propyl]3-ethyl-
carbodiimide (EDC, 0.400 mmol, 62.0 mg). and 4-dimethylami-
nopyridine (5.00 mg) was dissolved in CH2Cl2/DMF (1.00/0.100
mL), and the mixture was shaken on an orbital J-KEM shaker at
room temperature for 5 h. The reaction mixture was concentrated
in vacuo and purified by preparative TLC [silica, CH2Cl2/ammonia
(2.0 M in methanol) 100:5] to afford the desired product (78%
yield): 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1 H), 7.33-7.21
(m, 13 H), 6.94 (m, 2 H), 4.88 (s, 1 H), 3.39 (t, J ) 5.6 Hz, 2 H),
2.93 (d, J ) 11.3 Hz, 2 H), 2.52-2.36 (m, 4 H), 1.97 (t, J ) 11.3
Hz, 2 H), 1.83-1.58 (m, 6 H), 1.24 (d, J ) 7.6 Hz, 6 H); ESMS
m/e 498.4 (M + H)+; HRMS (FAB) calcd for C32H39N3O2 (M +
H)+, 498.3115; found, 498.3088.
(b) General Procedure B for the synthesis of 5a and 5c-5p.
A mixture of 2,2-diphenylacetyl chloride (0.300 mmol), N-{3-[1-
(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (0.250
mmol), and triethylamine (0.500 mmol) was dissolved in THF (2.00
mL), and the mixture was shaken on an Orbital J-KEM shaker at
room temperature for 5 h. The reaction mixture was concentrated
in vacuo, and the residue was purified by preparative TLC [silica,
CH2Cl2/ammonia (2.0 M in methanol) 100:5] to afford the desired
product.
N-{3-[1-(5-Diphenylacetylamino-pentyl)-piperidin-4-yl]-phen-
yl}-isobutyramide (5c). Compound 5c was prepared from diphe-
nylacetic acid chloride and N-{3-[1-(4-aminobutyl)-4-piperidinyl]-
phenyl}-2-methylpropanamide according to the general procedure
B for the synthesis of compound 5b: 1H NMR (400 MHz, CDCl3)
δ 7.47-7.13 (m, 14 H), 6.91-6.85 (m, 1 H), 5.91-5.82 (m, 1 H),
4.93 (s, 1 H), 3.33-3.15 (m, 4 H), 2.62-2.41 (m, 4 H), 2.28 (t, J
) 11.5 Hz, 2 H), 2.07-1.76 (m, 4 H), 1.65-1.52 (m, 2 H), 1.50-
1.36 (m, 2 H), 1.23 (d, J ) 6.86 Hz, 6 H); ESMS m/e 512.4 (M +
H)+; HRMS (FAB) calcd for C34H42N3O2 (M + H)+, 512.3271;
found, 512.3242.
In summary, two highly potent replacements for the dihy-
dropyrimidinone moiety of compound 1, (2,2-diaryl)acetamide,
and (2-aryl-2-alkyl)acetamide, represented by compounds 5m
and (S)-6b, were identified via an initial diversity-based library
approach, followed by medicinal chemistry efforts. Compounds
5m and (S)-6b exhibited reasonable PK properties. In vivo
efficacy experiments demonstrated that N-[5-(1-{3-[2,2-bis-(4-
fluoro-phenyl)-acetylamino]-propyl}-piperidin-4-yl)-2,4-difluoro-
phenyl]-isobutyramide (5m) and N-[3-(1-{3-[(S)-2-(4-fluoro-
phenyl)-propionylamino]-propyl}-piperidin-4-yl)-4-methylphenyl]-
isobutyramide ((S)-6b) inhibited a centrally induced MCH-
evoked drinking effect. In addition, compound 5m exhibited
an anxiolytic effect in the rat social interaction model of anxiety.
An alternative parallel approach that removed the amide moiety
in the linker of the compounds 5 and 6 is described in the
accompanying paper.
Experimental Section
General Methods. All reactions were performed under a nitrogen
atmosphere, and the reagents, neat or in appropriate solvents, were
transferred to the reaction vessel via syringe and cannula techniques.
Anhydrous solvents were purchased from Aldrich Chemical Co.
and used as received. The NMR spectra were recorded at Bruker
Avance (400 MHz) or GE QEPlus300 in CDCl3, MeOH-d4, or
DMSO-d6 as solvent, with tetramethylsilane as the internal standard,
unless otherwise noted. Chemical shifts (δ) are expressed in ppm,
coupling constants (J) are expressed in Hz, and splitting patterns
are described as follows: s ) singlet; d ) doublet; t ) triplet; q )
quartet; quintet; sextet; septet; br ) broad; m ) multiplet; dd )
doublet of doublets; dt ) doublet of triplets; td ) triplet of doublets;
dm ) doublet of multiplets; ddd ) doublet of doublet of doublets.
Elemental analyses were performed by Robertson Microlit Labo-
ratories, Inc. Unless otherwise noted, mass spectra were obtained
using electrospray ionization (ESMS, Micromass Platform II or
Quattro Micro) and (M + H)+ is reported. Thin-layer chromatog-
raphy (TLC) was carried out on glass plates precoated with silica
gel 60 F254 (0.25 mm, EM Separations Tech.). Preparative TLC
was carried out on glass sheets precoated with silica gel GF (2
N-{3-[1-(5-Diphenylacetylamino-pentyl)-piperidin-4-yl]-phen-
yl}-isobutyramide (5d). Compound 5d was prepared from diphe-
nylacetic acid chloride and N-{3-[1-(5-aminopentyl)-4-piperidinyl]-

Melanin-Concentrating Hormone 1 Receptor Antagonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 16 3875
phenyl}-2-methylpropanamide according to the general procedure
B for the synthesis of compound 5b: 1H NMR (400 MHz, CDCl3)
δ 7.41-7.13 (m, 14 H), 6.92-6.88 (m, 1 H), 5.91-5.82 (m, 1 H),
4.92 (s, 1 H), 3.32-3.25 (m, 4 H), 2.62-2.45 (m, 4 H), 2.28 (t, J
) 11.5 Hz, 2 H), 2.07-1.87 (m, 4 H), 1.65-1.54 (m, 2 H), 1.49-
1.39 (m, 2 H), 1.28-1.25 (m, 2 H), 1.23 (d, J ) 6.86 Hz, 6 H);
ESMS m/e 526.4 (M + H)+; HRMS (FAB) calcd for C34H44N3O2
(M + H)+, 526.3428; found, 526.3401.
piperidinyl]phenyl}-2-methylpropanamide according to the general
procedure A for the synthesis of compound 5b: 1H NMR (400
MHz, CDCl3) δ 7.65 (s, 1 H), 7.45 (s, 1 H), 7.40 (m, 1 H), 7.37-
7.19 (m, 11 H), 6.88 (d, J ) 7.3 Hz, 1 H), 6.34 (t, J ) 4.5
Hz, 1 H), 3.34-3.27 (m, 3 H), 2.94-2.87 (m, 2 H), 2.52 (septet,
J ) 6.9 Hz, 1 H), 2.46-2.34 (m, 4 H), 2.27 (t, J ) 6.9 Hz,
2 H), 2.00-1.91 (m, 2 H), 1.77-1.69 (m, 2 H), 1.69-1.52,
(m, 5 H), 1.30-1.20 (m, 12 H); ESMS m/e 568.4 (M + H)+;
HRMS (FAB) calcd for C37H50N3O2 (M + H)+, 568.3897; found,
568.3880.
N-{3-[1-(3-{[Bis(4-fluorophenyl)acetyl]amino}propyl)-4-pip-
eridinyl]-4-methylphenyl}-2-methylpropanamide (5k). Com-
pound 5k was prepared from bis(4-fluorophenyl)acetic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-meth-
ylpropanamide according to the general procedure A for the
synthesis of compound 5b: 1H NMR (400 MHz, CDCl3) δ 8.09
(s, 1 H), 7.98 (s, 1 H), 7.59 (d, J ) 1.8 Hz, 1 H), 7.54-7.51 (m,
1 H), 7.32 (m, 3 H), 7.21-7.18 (m, 1 H), 6.99-6.94 (m, 5 H),
4.87 (s, 1 H), 3.36 (q, J ) 5.8 Hz, 2 H), 2.92-2.97 (m, 2 H),
2.68-2.58 (m, 1 H), 2.5 (quintet, J ) 7.2 Hz, 1 H), 2.37 (t, J )
5.7 Hz, 2 H), 2.25 (s, 3 H), 2.01-1.92 (m, 2 H), 1.71-1.52 (m, 6
H), 1.16 (d, J ) 7.2 Hz, 6 H); ESMS m/e 548.4 (M + H)+; HRMS
(FAB) calcd for C33H40F2N3O2 (M + H)+, 548.3083; found,
548.3056.
N-[3-(1-{3-[(Diphenylacetyl)amino]propyl}-4-piperidinyl)-4-
methylphenyl]-2-methylpropanamide (5l). Compound 5l was
prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopro-
pyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide accord-
ing to the general procedure B for the synthesis of compound 5b:
1H NMR (400 MHz, CDCl3) δ 7.39-7.23 (m, 12 H), 7.14 (br, 1
H), 7.08 (d, J ) 8.4 Hz, 1 H), 6.90 (br, 1 H), 4.91 (s, 1 H), 3.41
(dd, J ) 6.4, 12.4 Hz, 2 H), 2.95 (d, J ) 12.4 Hz, 2 H), 2.66 (m,
1 H), 2.47 (m, 1 H), 2.40 (t, J ) 6.4 Hz, 2 H), 2.28 (s, 3 H), 2.03-
1.97 (m, 2 H), 1.74-1.62 (m, 6 H), 1.22 (d, J ) 7.2 Hz, 6 H);
ESMS m/e 512.3 (M + H)+; HRMS (FAB) calcd for C33H42N3O2
(M + H)+, 512.3271; found, 512.3247.
N-{5-[1-(3-{[Bis(4-fluorophenyl)acetyl]amino}propyl)-4-pip-
eridinyl]-2,4-difluorophenyl}-2-methylpropanamide (5m). Com-
pound 5m was prepared from bis(4-fluorophenyl)acetic acid and
N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2,4-difluorophenyl}-2-me-
thylpropanamide according to the general procedure A for the
synthesis of compound 5b: UV 254 nm, 100%; ELSD, 100%; 1H
NMR (400 MHz, CDCl3) δ 8.25 (t, J ) 8.4 Hz, 1 H), 7.67-7.57
(m, 1 H), 7.51 (s, 1 H), 7.36-7.25 (m, 4 H), 7.03-6.91 (m, 4 H),
6.81 (t, J ) 9.6 Hz, 1 H), 4.81 (s, 1 H), 3.45-3.31 (m, 2 H), 2.92
(m, 2 H), 2.83-2.67 (m, 1 H), 2.63-2.47 (m, 1 H), 2.47-2.33
(m, 2 H), 2.05-1.90 (m, 2 H), 1.82-1.72 (m, 2 H), 1.72-1.56
(m, 4 H), 1.22 (d, J ) 6.8 Hz, 6 H); ESMS m/e 570.2 (M + H)+;
HRMS (FAB) calcd for C32H36F4N3O2 (M + H)+, 570.2738; found,
570.2713.
N-{3-[1-(3-{[Bis(4-fluorophenyl)acetyl]amino}propyl)-4-pip-
eridinyl]-2,4,6-trifluorophenyl}-2-methylpropanamide (5n). Com-
pound 5n was prepared from bis(4-fluorophenyl)acetic acid and
N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2,4,6-trifluorophenyl}-2-
methylpropanamide according to the general procedure A for the
synthesis of compound 5b: 1H NMR (400 MHz, CDCl3) δ 7.89
(br s, 1 H), 7.36-7.28 (m, 4 H), 7.02-6.97 (m, 4 H), 6.78-6.70
(m, 2 H), 4.76 (s, 1 H), 3.41-3.39 (m, 2 H), 3.02-2.96 (m, 3 H),
2.65-2.55 (m, 2 H), 2.10-2.09 (m, 4 H), 1.73-1.65 (m, 4 H),
1.23 (d, J ) 6.92 Hz, 6 H); ESMS m/e 588.3 (M + H)+; HRMS
(FAB) calcd for C32H35F5N3O2 (M + H)+, 588.2649; found,
588.2652.
N-{3-[1-(3-Diphenylacetylamino-propyl)-piperidin-4-yl]-2-
methyl-phenyl}-isobutyramide (5o). Compound 5o was prepared
from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-pip-
eridinyl]-2-methylphenyl}-2-methylpropanamide according to the
general procedure B for the synthesis of compound 5b: 1H NMR
(400 MHz, CDCl3) δ 7.49 (d, J ) 8.0 Hz, 1 H), 7.35-7.19 (m, 11
H), 7.09-7.02 (m, 3 H), 4.90 (s, 1 H), 3.41 (dd, J ) 5.6, 11.6 Hz,
2 H), 2.99 (d, J ) 12.8 Hz, 2 H), 2.72 (m, 1 H), 2.59 (m, 1 H),
2.43 (t, J ) 6.4 Hz, 2 H), 2.19 (s, 3 H), 2.06-2.00 (m, 2 H), 1.75-
N-{3-[1-(6-Diphenylacetylamino-hexyl)-piperidin-4-yl]-phen-
yl}-isobutyramide (5e). Compound 5e was prepared from diphe-
nylacetic acid chloride and N-{3-[1-(6-aminohexyl)-4-piperidinyl]-
phenyl}-2-methylpropanamide according to the general procedure
B for the synthesis of compound 5b: 1H NMR (400 MHz, CDCl3)
δ 7.47-7.13 (m, 14 H), 6.91-6.85 (m, 1 H), 5.91-5.82 (m, 1 H),
4.93 (s, 1 H), 3.33-3.15 (m, 4 H), 2.62-2.41 (m, 4 H), 2.28 (t, J
) 11.5 Hz, 2 H), 2.07-1.76 (m, 4 H), 1.65-1.52 (m, 2 H), 1.50-
1.36 (m, 2 H), 1.28-1.25 (m, 2 H), 1.23 (d, J ) 6.86 Hz, 6 H),
1.05-1.01 (m, 2 H); ESMS m/e 540.8 (M + H)+; HRMS (FAB)
calcd for C35H45N3O2 (M + H)+, 540.3584; found, 540.3557.
N-{3-[1-(3-{[Bis(4-fluorophenyl)acetyl]amino}propyl)-4-pip-
eridinyl]phenyl}-2-methylpropanamide (5f). Compound 5f was
prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-
aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide accord-
ing to the general procedure A for the synthesis of compound 5b:
1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1 H), 7.39-7.31 (m, 3 H),
7.29-7.21 (m, 5 H), 7.02-6.96 (m, 4 H), 4.80 (s, 1 H), 3.40 (q, J
) 4.5 Hz, 2 H), 2.94 (d, J ) 10.2 Hz, 2 H), 2.51-2.38 (m, 4 H),
1.97 (dt, J ) 1.8, 10.4 Hz, 2 H), 1.81 (m, 2 H), 1.68 (quintet, J )
6.8 Hz, 2 H), 1.59 (m, 3 H), 1.23 (d, J ) 6.9 Hz, 6 H); ESMS m/e
534.3 (M + H)+; HRMS (FAB) calcd for C32H38F2N3O2 (M +
H)+, 534.2926; found, 534.2899.
N-{3-[1-(3-{[Bis(4-chlorophenyl)acetyl]amino}propyl)-4-pip-
eridinyl]phenyl}-2-methylpropanamide (5g). Compound 5g was
prepared from bis(4-chlorophenyl)acetic acid and N-{3-[1-(3-
aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide accord-
ing to the general procedure A for the synthesis of compound 5b:
1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1 H), 7.34-7.13 (m, 12
H), 4.75 (s, 1 H), 3.41 (q, J ) 4.5 Hz, 2 H), 2.94 (d, J ) 10.2 Hz,
2 H), 2.51-2.40 (m, 4 H), 1.97 (m, 2 H), 1.82 (m, 2 H), 1.68
(quintet, J ) 6.8 Hz, 2 H), 1.59 (m, 3 H), 1.25 (d, J ) 6.8 Hz, 6
H); ESMS m/e 566.2 (M + H)+; HRMS (FAB) calcd for C32H38-
Cl2N3O2 (M + H)+, 566.2335; found, 566.2311.
N-(3-{4-[3-(Isobutyrylamino)phenyl]-1-piperidinyl}propyl)-
2,2-diphenylpropanamide (5h). Compound 5h was prepared from
2,2-diphenylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-pip-
eridinyl]phenyl}-2-methylpropanamide according to the general
procedure A for the synthesis of compound 5b: 1H NMR (400
MHz, CDCl3) δ 7.46 (s, 1 H), 7.42 (s, 1 H), 7.39-7.18 (m, 12 H),
6.89 (d, J ) 7.7 Hz, 1 H), 6.23 (m, 1 H), 3.35 (q, J ) 6.4 Hz, 2
H), 2.85 (d, J ) 10.8 Hz, 2 H), 2.5 (quintet, J ) 7.4 Hz, 1 H),
2.45-2.36 (m, 1 H), 2.28 (t, J ) 6.4 Hz, 2 H), 1.99 (s, 3 H), 1.91-
1.82 (m, 2 H), 1.75-1.68 (m, 2 H), 1.65 (t, J ) 6.4 Hz, 2 H),
1.60-1.47 (m, 2 H), 1.23 (d, J ) 7.0 Hz, 6 H); ESMS m/e 512.4
(M + H)+; HRMS (FAB) calcd for C33H42N3O2 (M + H)+,
512.3271; found, 512.3248.
N-{3-[4-(3-Isobutyrylamino-phenyl)-piperidin-1-yl]-propyl}-
2,2-diphenyl-butyramide (5i). Compound 5i was prepared from
2,2-diphenylbutyric acid and N-{3-[1-(3-aminopropyl)-4-piperidi-
nyl]phenyl}-2-methylpropanamide according to the general proce-
dure A for the synthesis of compound 5b: 1H NMR (400 MHz,
CDCl3 δ 7.46 (s, 1 H), 7.41 (s, 1 H), 7.40-7.18 (m, 12 H), 6.88
(d, J ) 7.6 Hz, 1 H), 6.23 (m, 1 H), 3.35 (q, J ) 6.4 Hz, 2 H),
2.85 (d, J ) 10.8 Hz, 2 H), 2.5 (quintet, J ) 7.4 Hz, 1 H), 2.45-
2.36 (m, 1 H), 2.28 (t, J ) 6.4 Hz, 2 H), 1.97 (m, 2 H), 1.91-1.82
(m, 2 H), 1.75-1.68 (m, 2 H), 1.65 (t, J ) 6.4 Hz, 2 H), 1.60-
1.47 (m, 2 H), 1.25-1.23 (m, 3 H), 1.23 (d, J ) 7.0 Hz, 6 H);
ESMS m/e 526.7 (M + H)+; HRMS (FAB) calcd for C34H44N3O2
(M + H)+, 526.3428; found, 526.3419.
N-(3-{4-[3-(Isobutylrylamino)phenyl]-1-piperidinyl}propyl)-
2,2-diphenylheptanamide (5j). Compound 5j was prepared
from 2,2-diphenylheptanoic acid and N-{3-[1-(3-aminopropyl)-4-

3876 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 16
Jiang et al.
1.60 (m, 6 H), 1.30 (d, J ) 6.8 Hz, 6 H); ESMS m/e 512.5 (M +
H)+; HRMS (FAB) calcd for C33H42F5N3O2 (M + H)+, 512.3271;
found, 512.3248.
(2R)-2-(4-Fluorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-me-
thylphenyl]-1-piperidinyl}propyl)propanamide ((R)-6b). Com-
pound (R)-6b was prepared from (2R)-2-(4-fluorophenyl)propanoic
acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-
2-methylpropanamide according to the general procedure A for the
N-{3-[1-(3-{[Hydroxy(diphenyl)acetyl]amino}propyl)-4-pip-
eridinyl]-4-methylphenyl}-2-methylpropanamide (5p). A mixture
of hydroxy(diphenyl)acetic acid (100 mg, 0.44 mmol) and 1,1′-
carbonyldiimidazole (78 mg, 0.48 mmol) in CH2Cl2 (5 mL) was
stirred at room temperature for 3 h, then a solution of N-{3-[1-(3-
aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methyl propana-
mide (140 mg, 0.44 mmol) in CH2Cl2 (5 mL) was added. The
resulting mixture was stirred at room temperature for overnight,
evaporated in vacuo, and dissolved in a mixture of EtOAc and 1 N
NaOH. The organic layer was separated, washed twice with water,
dried over MgSO4, and concentrated. The residue was purified over
preparative TLC (10% 2 M NH3/MeOH in 50% EtOAc/ hexanes)
to give 111 mg (0.21 mmol, 48%) of (N-{3-[1-(3-{[hydroxy-
(diphenyl)acetyl]amino}propyl)-4-piperidinyl]-4-methylphenyl}-2-
methylpropanamide: 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1 H),
8.14 (s, 1 H), 7.80 (s, 1 H), 7.64-7.48 (m, 4 H), 7.32-7.16 (m, 6
H), 6.95 (d, J ) 8.0 Hz, 1 H), 6.64 (d, J ) 8.0 Hz, 1 H), 5.83-
5.62 (br, 1 H), 3.54-3.38 (m, 2 H), 3.11-2.94 (m, 2 H), 2.79-
2.59 (m, 1 H), 2.57-2.41 (m, 2 H), 2.26 (s, 3 H), 2.29-2.16 (m,
1 H), 2.16-1.91 (m, 4 H), 1.74-1.53 (m, 4 H), 0.86 (d, J ) 6.8
Hz, 6 H); ESMS m/e 528.4 (M + H)+; HRMS (FAB) calcd for
C33H42N3O3 (M + H)+, 528.3220; found, 528.3196.
2-Methyl-N-{4-methyl-3-[1-(3-{[(2R)-2-phenylpropanoyl]-
amino}propyl)-4-piperidinyl]phenyl}propanamide ((S)-6a). Com-
pound (S)-6a was prepared from (2S)-2-phenylpropanoic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-meth-
ylpropanamide according to the general procedure A for the
synthesis of compound 5b: 1H NMR (400 MHz, CDCl3) δ 7.63
(s, 1 H), 7.44 (d, J ) 2.0 Hz, 1 H), 7.38-7.26 (m, 5 H), 7.26-
7.18 (m, 1 H), 7.06 (d, J ) 8.0 Hz, 1 H), 6.74-6.63 (m, 1 H),
3.63-3.49 (m, 1 H), 3.38-3.23 (m, 2 H), 2.91 (ABq, 2 H), 2.71-
2.58 (m, 1 H), 2.58-2.45 (m, 1 H), 2.32 (t, J ) 6.4 Hz, 2 H), 2.26
(s, 3 H), 2.05-1.87 (m, 2 H), 1.77-1.55 (m, 6 H), 1.53 (d, J )
7.2 Hz, 3 H), 1.22 (d, J ) 6.8 Hz, 6 H); ESMS m/e 450.4 (M +
H)+; HCl salt of 2-methyl-N-{4-methyl-3-[1-(3-{[(2S)-2-
phenylpropanoyl]amino}propyl)-4-piperidinyl]phenyl}-
propanamide [R]D ) -34.3° (c 1, MeOH); HRMS calcd for
C28H40N3O2 (M + H)+, 450.3120; found, 450.3116.
2-Methyl-N-{4-methyl-3-[1-(3-{[(2S)-2-phenylpropanoyl]-
amino}propyl)-4-piperidinyl]phenyl}propanamide ((R)-6a). Com-
pound (R)-6a was prepared from (2R)-2-phenylpropanoic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-meth-
ylpropanamide according to the general procedure A for the
synthesis of compound 5b: 1H NMR (400 MHz, CDCl3) δ 7.61
(s, 1 H), 7.47-7.38 (m, 1 H), 7.37-7.26 (m, 5 H), 7.26-7.18 (m,
1 H), 7.06 (d, J ) 8.0 Hz, 1 H), 6.74-6.64 (m, 1 H), 3.64-3.50
(m, 1 H), 3.38-3.23 (m, 2 H), 2.92 (ABq, 2 H), 2.70-2.58 (m, 1
H), 2.58-2.42 (m, 1 H), 2.33 (t, J ) 6.4 Hz, 2 H), 2.26 (s, 3 H),
2.02-1.88 (m, 2 H), 1.76-1.55 (m, 6 H), 1.53 (d, J ) 7.2 Hz, 3
H), 1.22 (d, J ) 6.8 Hz, 6 H); ESMS m/e 450.2 (M + H)+; HCl
salt of 2-methyl-N-{4-methyl-3-[1-(3-{[(2R)-2-phenyl propanoyl]-
amino}propyl)-4-piperidinyl]phenyl}propanamide [R]D ) + 22.3°
(c 1, MeOH); HRMS calcd for C28H40N3O2 (M + H)+, 450.3115;
found, 450.3095.
1
synthesis of compound 5b: [R]D ) -9.1° (c 1.65, MeOH); H
NMR (400 MHz, CDCl3) δ 7.51 (d, J ) 2.0 Hz, 1 H), 7.37-7.28
(m, 2 H), 7.23-7.14 (m, 2 H), 7.08 (d, J ) 8.0 Hz, 1 H), 7.05-
6.96 (m, 2 H), 6.90-6.82 (m, 1 H), 3.54 (q, J ) 7.2 Hz, 1 H),
3.43-3.23 (m, 2 H), 2.95 (ABq, 2 H), 2.73-2.59 (m, 1 H), 2.57-
2.42 (m, 1 H), 2.42-2.32 (m, 2 H), 2.28 (s, 3 H), 2.07-1.91 (m,
2 H), 1.83-1.57 (m, 6 H), 1.51 (d, J ) 7.2 Hz, 3 H), 1.23 (d, J )
6.8 Hz, 6 H); ESMS m/e 468.3 (M + H)+; HRMS calcd for C28H39-
FN3O2 (M + H)+, 468.3026; found, 468.3026.
1-(4-Fluorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-methylphe-
nyl]-1-piperidinyl}propyl)cyclopentanecarboxamide (6c). Com-
pound 6c was prepared from 1-(4-fluorophenyl)cyclopentanecar-
boxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-
methylphenyl}-2-methylpropanamide according to the general
procedure A for the synthesis of compound 5b: 1H NMR (400
MHz, CDCl3) δ 7.43-7.37 (m, 3 H), 7.29-7.27 (m, 2 H), 7.09 (d,
J ) 8.4 Hz, 1 H), 7.04-7.00 (m, 2 H), 6.47 (br s, 1 H), 3.29 (dd,
J ) 5.6, 12.0 Hz, 2 H), 2.94 (d, J ) 12.0 Hz, 2 H), 2.66 (m, 1 H),
2.54-2.48 (m, 3 H), 2.33-2.30 (m, 2 H), 2.29 (s, 3 H), 2.03-
1.95 (m, 4 H), 1.84-1.60 (m, 10 H), 1.26 (d, J ) 6.8 Hz, 6 H);
ESMS m/e 522.3 (M + H)+; HRMS calcd for C31H43FN3O2 (M +
H)+, 522.3490; found, 522.3463.
1-(4-Fluorophenyl)-N-(3-{4-[5-(isobutylamino)-2-methylphe-
nyl]-1-piperidinyl}propyl)cyclohexanecarboxamide (6d). Com-
pound 6d was prepared from 1-(4-fluorophenyl)cyclohexanecar-
boxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-
methylphenyl}-2-methylpropanamide according to the general
procedure A for the synthesis of compound 5b: 1H NMR (400
MHz, CDCl3) δ 7.46-7.43 (m, 3 H), 7.26-7.22 (m, 2 H), 7.10 (d,
J ) 8.4 Hz, 1 H), 7.06-7.01 (m, 2 H), 6.74 (br s, 1 H), 3.31 (dd,
J ) 6.0, 12.0 Hz, 2 H), 2.96 (d, J ) 11.6 Hz, 2 H), 2.68 (m, 1 H),
2.52 (m, 1 H), 2.36-2.32 (m, 4 H), 2.29 (s, 3 H), 2.03-1.90 (m,
4 H), 1.74-1.61 (m, 12 H), 1.27 (d, J ) 6.8 Hz, 6 H); ESMS m/e
508.3 (M + H)+; HRMS calcd for C31H43FN3O2 (M + H)+,
508.3333; found, 508.3309.
1-Bromo-2,4-difluoro-5-nitrobenzene (9a). To a 0 °C mixture
of 1-bromo-2,4-difluorobenzene (20.0 g; 11.7 mL; 0.100 mol) and
H2SO4 (76.8 mL) was added HNO3 (68.0 mL) over 45 min at such
a rate that the internal temperature was <7 oC. The resulting mixture
was stirred for 1 h at 0 °C, poured into ice water (400 mL), stirred
vigorously for 2-3 min, and extracted with CH2Cl2 (400 mL). The
organic layers were washed with brine (1 × 500 mL), dried over
Na2SO4, filtered, and evaporated to give the product as a yellow
1
oil (23.5 g, 95%). H NMR (CDCl3) δ 8.39 (t, J ) 7.2 Hz, 1 H),
7.14 (ddd, J ) 0.3, 7.8, 9.9 Hz, 1 H).
1-Bromo-3-nitro-2,4,6-trifluorobenzene (9b). To a cooled
(1.3 °C) mixture of 1-bromo-2,4,6-trifluorobenzene (30.0 g; 142
mmol) and H2SO4 (115 mL) was added HNO3 (68%; 102 mL) over
1.5 h at such a rate that the internal temperature was <8 oC. After
stirring at 0 °C for 2 h, the resulting mixture was poured into ice
water (1850 mL), stirred vigorously for 30 min, and extracted with
CH2Cl2 (3 × 600 mL). The combined organic layers were washed
with water (2 × 600 mL), dried over MgSO4, filtered, and
concentrated to give the desired product as a clear yellow oil (35.0
(2S)-2-(4-Fluorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-me-
thylphenyl]-1-piperidinyl}propyl)propanamide ((S)-6b). Com-
pound (S)-6b was prepared from (2S)-2-(4-fluorophenyl)propanoic
acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-
2-methylpropanamide according to the general procedure A for the
1
g, 99%). H NMR (CDCl3) δ 7.01 (ddd, J ) 2.4, 7.8, 9.3 Hz, 1
H); 19F NMR (CDCl3) δ -116.20 to -116.10, -107.73 to -107.71,
-93.80 to -93.70.
1
synthesis of compound 5b: [R]D ) +13.5° (c 1.02, MeOH); H
5-Bromo-2,4-difluoroaniline (10a). To a solution of 1-bromo-
2,4-difluoro-5-nitrobenzene (5.04 g, 21.3 mmol) in EtOH (100 mL),
THF (50 mL), NH4Cl(satd) (25 mL), and H2O (25 mL) was added
iron powder (5.00 g, 89.5 mmol). The mixture was refluxed for 2
h and filtered through celite. The filter pad was washed with EtOAc
(3 × 50 mL). The filtrate was concentrated and the residue was
partitioned between EtOAc and brine. The organic layer was dried
over MgSO4 and concentrated. Purification by flash chromatography
(5-10% EtOAc/ Hexane) provided 2.60 g (59%) of 5-bromo-2,4-
NMR (400 MHz, CDCl3) δ 7.58-7.49 (m, 2 H), 7.37-7.29 (m, 2
H), 7.26-7.19 (m, 1 H), 7.06 (d, J ) 8.0 Hz, 1 H), 7.04-6.92 (m,
3 H), 3.56 (t, J ) 6.8 Hz, 1 H), 3.43-3.23 (m, 2 H), 2.95 (ABq,
2 H), 2.63-2.59 (m, 1 H), 2.59-2.45 (m, 1 H), 2.37 (t, J ) 6.0
Hz, 2 H), 2.27 (s, 3 H), 2.07-1.90 (m, 2 H), 1.82-1.57 (m, 6 H),
1.50 (d, J ) 7.2 Hz, 3 H), 1.22 (d, J ) 7.2 Hz, 6 H); ESMS m/e
468.3 (M + H)+; HRMS calcd for C28H39FN3O2 (M + H)+,
468.3020; found, 468.3000.

Melanin-Concentrating Hormone 1 Receptor Antagonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 16 3877
1
difluoroaniline. H NMR (400 MHz, CDCl3) δ 6.84-6.77 (m, 2
methyl-phenyl)-isobutyramide 11c according to the procedure for
the synthesis of compound 13a. ESMS m/e 303.0 (M - 56 + H)+.
4-(3-Isobutyrylamino-phenyl)-3,6-dihydro-2H-pyridine-1-car-
boxylic Acid tert-Butyl Ester (13d). Compound 13d was prepared
from tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-
dihydro-1(2H)-pyridinecarboxylate 12 and N-(3-iodo-phenyl)-isobu-
tyramide 11d according to the procedure for the synthesis of
compound 13a. ESMS m/e 343.5 (M - H)-.
H), 3.81-3.57 (br, 2 H); ESMS m/e 208.2 (M + H)+.
3-Bromo-2,4,6-trifluoroaniline (10b). Compound 10b was
prepared from 1-bromo-3-nitro-2,4,6-trifluorobenzene 9b according
to the procedure for the synthesis of compound 10a: 1H NMR (400
MHz, CDCl3) δ 6.85-6.76 (m, 1 H), 3.78-3.51 (br, 2 H).
N-(5-Bromo-2,4-difluorophenyl)-2-methylpropanamide (11a).
Into a solution of 2.6 g (12.6 mmol) of 5-bromo-2,4-difluoroaniline
10a and 2.1 mL (15.1 mmol) of triethylamine in 50 mL THF at
0 °C was slowly added 1.6 mL (15.1 mmol) of isobutyryl chloride.
The reaction mixture was stirred at room temperature for 2 h and
concentrated in vacuo. The residue was dissolved in EtOAc and
washed with H2O, saturated aqueous Na2CO3, and brine. The
organic layer was dried over MgSO4 and concentrated in vacuo to
give 3.30 g (11.8 mmol, 94%) of N-(5-bromo-2,4-difluorophenyl)-
2-methylpropanamide: ESMS m/e 278.1 (M + H)+; 1H NMR (400
MHz, CDCl3) δ 8.64 (m, 1 H), 7.27 (m, 1 H), 6.95 (m, 1 H), 2.56
(sept, J ) 6.35 Hz, 1 H), 1.29-1.22 (m, 6 H).
4-(3-Isobutyrylamino-2-methyl-phenyl)-3,6-dihydro-2H-pyri-
dine-1-carboxylic Acid tert-Butyl Ester (13e). Compound 13e was
prepared from tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate 12 and N-(3-iodo-2-
methyl-phenyl)-isobutyramide 11e according to the procedure for
the synthesis of compound 13a. ESMS m/e 357.4 (M - H)-.
tert-Butyl 4-[2,4-Difluoro-5-(isobutyrylamino)phenyl]-1-pip-
eridinecarboxylate (14a). A solution of tert-butyl 4-[2,4-difluoro-
5-(isobutyrylamino)phenyl]-3,6-dihydro-1(2H)-pyridinecarboxy-
late 13a (2.40 g, 6.31 mmol) and 10% Pd/C (500 mg) in EtOAc
(40.0 mL) and MeOH (10.0 mL) was hydrogenated (200 psi) at
room temperature overnight. The reaction mixture was filtered
through celite and washed with ethanol (3 × 10 mL). The combined
extracts were concentrated in vacuo to afford 2.04 g (5.34 mmol,
85%) of tert-butyl 4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-1-
piperidinecarboxylate: ESMS m/e 383.2 (M + H)+; 1H NMR (400
MHz, CDCl3) δ 8.22 (t, J ) 7.75 Hz, 1 H), 7.35-7.30 (br, 1 H),
6.82 (t, J ) 10.0 Hz, 1 H), 4.15-4.08 (m, 2 H), 2.94 (m, 1 H),
2.84-2.73 (m, 2 H), 2.58 (sept, J ) 6.89 Hz, 1 H), 1.81-1.72
(m, 2 H), 1.72-1.59 (m, 2 H), 1.48 (s, 9 H), 1.26 (d, J ) 6.89 Hz,
6 H).
4-(2,4,6-Trifluoro-3-isobutyrylamino-phenyl)-piperidine-1-
carboxylic acid tert-butyl ester (14b). Compound 14b was
prepared from tert-butyl 4-[2,4,6-trifluoro-3-(isobutyrylamino)-
phenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate 13b according to the
procedure for the synthesis of compound 14a. ESMS m/e 401.4
(M + H)+.
4-(5-Isobutyrylamino-2-methyl-phenyl)-piperidine-1-carboxy-
lic Acid tert-Butyl Ester (14c). Compound 14c was prepared from
4-(5-isobutyrylamino-2-methyl-phenyl)-3,6-dihydro-2H-pyridine-1-
carboxylic acid tert-butyl ester 13c according to the procedure for
the synthesis of compound 14a. ESMS m/e 361.2 (M + H)+.
4-(3-Isobutyrylamino-phenyl)-piperidine-1-carboxylic Acid
tert-Butyl Ester (14d). Compound 14d was prepared from 4-(3-
isobutyrylamino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid
tert-butyl ester 13d according to the procedure for the synthesis of
compound 14a. ESMS m/e 347.2 (M + H)+.
4-(3-Isobutyrylamino-2-methyl-phenyl)-piperidine-1-carboxy-
lic Acid tert-Butyl Ester (14e). Compound 14e was prepared from
4-(3-isobutyrylamino-2-methyl-phenyl)-3,6-dihydro-2H-pyridine-1-
carboxylic acid tert-butyl ester 13e according to the procedure for
the synthesis of compound 14a. ESMS m/e 361.2 (M + H)+.
N-[2,4-Difluoro-5-(4-piperidinyl)phenyl]-2-methylpropana-
mide (15a). Into a solution of tert-butyl 4-[2,4-difluoro-5-(isobu-
tyrylamino)phenyl]-1-piperidinecarboxylate 14a (6.54 g, 17.1 mmol)
in 1,4-dioxane (40.0 mL) was added 4 M HCl in 1,4-dioxane (160
mL) at room temperature. The reaction mixture was stirred for 1 h
and concentrated in vacuo. The residue was dissolved in 100 mL
of H2O and was basified with 10% KOH solution (50 mL). The
aqueous layer was extracted with CHCl3/i-PrOH (3:1, 3 × 150 mL).
The combined organic extracts were washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo to give 4.72 g (16.7
mmol, 98%) of N-[2,4-difluoro-5-(4-piperidinyl)phenyl]-2-meth-
ylpropanamide: ESMS m/e 283.3 (M + H)+; 1H NMR (400 MHz,
CD3OD) δ 7.59 (t, J ) 8.24 Hz, 1 H), 6.88 (t, J ) 10.9 Hz, 1 H),
3.23-3.13 (m, 2 H), 2.93 (m, 1 H), 2.84-2.73 (m, 2 H), 2.61 (sept,
J ) 6.76 Hz, 1 H), 1.81-1.74 (m, 2 H), 1.72-1.61 (m, 2 H), 1.10
(d, J ) 6.76 Hz, 6 H).
N-(3-Bromo-2,4,6-trifluorophenyl)-2-methylpropanamide (11b).
Compound 11b was prepared from 3-bromo-2,4,6-trifluoroaniline
10b according to the procedure for the synthesis of compound 11a.
ESMS m/e 296.3 (M + H)+; 1H NMR (400 MHz, CDCl3) δ 6.89-
6.82 (m, 1 H), 6.82-6.75 (m, 1 H), 2.63 (sept, J ) 6.75 Hz, 1 H),
1.27 (d, J ) 6.75 Hz, 6 H).
N-(3-Iodo-4-methyl-phenyl)-isobutyramide (11c). Compound
11c was prepared from 3-iodo-4-methyl-phenylamine 10c according
to the procedure for the synthesis of compound 11a. ESMS m/e
304.2 (M + H)+.
N-(3-Iodo-phenyl)-isobutyramide (11d). Compound 11d was
prepared from 3-iodo-phenylamine 10d according to the procedure
of 11a. ESMS m/e 290.2 (M + H)+; 1H NMR (400 MHz, CDCl3)
δ 7.94 (s, 1 H), 7.47 (d, J ) 8.22 Hz, 1 H), 7.41 (d, J ) 8.22 Hz,
1 H), 7.27-7.13 (br, 1 H), 7.00 (t, J ) 8.22 Hz, 1 H), 2.48 (sept,
J ) 7.39 Hz, 1 H), 1.23 (d, J ) 7.39 Hz, 6 H).
N-(3-Iodo-2-methyl-phenyl)-isobutyramide (11e). Compound
11e was prepared from 3-iodo-2-methyl-phenylamine 10e according
to the procedure for the synthesis of compound 11a. ESMS m/e
290.2 (M + H)+.
tert-Butyl 4-[2,4-Difluoro-5-(isobutyrylamino)phenyl]-3,6-di-
hydro-1(2H)-pyridine carboxylate (13a). To a 250-mL RB flask
containing tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-3,6-dihydro-1(2H)-pyridinecarboxylate 12 (3.31 g, 10.7 mmol),
K2CO3 (4.44 g, 32.1 mmol), and PdCl2dppf (870 mg, 1.07 mmol)
was added a solution of N-(5-bromo-2,4-difluorophenyl)-2-meth-
ylpropanamide 11a (3.28 g, 11.8 mmol) in DMF (100 mL) at room
temperature under argon. The mixture was heated to 80 °C under
argon overnight, cooled to room temperature, and filtered through
celite, and the celite was washed with EtOAc (3 × 20 mL). The
filtrates were washed with H2O (20 mL) and brine (20 mL), dried
over MgSO4, filtered, and concentrated in vacuo. The crude material
was purified by flash chromatography (10-20% EtOAc/hexane)
to give 2.40 g (6.31 mmol, 59%) of tert-butyl 4-[2,4-difluoro-5-
(isobutyrylamino)phenyl]-3,6-dihydro-1(2H)-pyridine carboxy-
late: ESMS m/e 379.3 (M - H)-; 1H NMR (400 MHz, CDCl3) δ
8.28 (t, J ) 8.78 Hz, 1 H), 7.24 (s, 1 H), 6.83 (t, J ) 9.97 Hz, 1
H), 6.00-5.83 (br, 1 H), 4.04 (m, 2 H), 3.58 (m, 2 H), 2.56 (sept,
J ) 6.78 Hz, 1 H), 2.47 (m, 2 H), 1.49 (s, 9 H), 1.27 (d, J ) 6.78
Hz, 6 H).
tert-Butyl 4-[2,4,6-Trifluoro-3-(isobutyrylamino)phenyl]-3,6-
dihydro-1(2H)-pyridinecarboxylate (13b). Compound 13b was
prepared from tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate 12 and N-(3-bromo-
2,4,6-trifluorophenyl)-2-methylpropanamide 11b according to the
procedure for the synthesis of compound 13a. ESMS m/e 397.6
(M - H)-; H NMR (400 MHz, CDCl3) δ 6.73 (m, 1 H), 5.84-
1
5.75 (br, 1 H), 4.05 (m, 2 H), 3.61 (m, 2 H), 2.62 (sept, J ) 6.50
Hz, 1 H), 2.37 (m, 2 H), 1.49 (s, 9 H), 1.28 (d, J ) 6.50 Hz, 6 H).
4-(5-Isobutyrylamino-2-methyl-phenyl)-3,6-dihydro-2H-pyri-
dine-1-carboxylic Acid tert-Butyl Ester (13c). Compound 13c was
prepared from tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate 12 and N-(3-iodo-4-
2-Methyl-N-[2,4,6-trifluoro-3-(4-piperidinyl)phenyl] propana-
mide (15b). Compound 15b was prepared from 4-(2,4,6-trifluoro-
3-isobutyrylamino-phenyl)-piperidine-1-carboxylic acid tert-butyl
ester 14b according to the procedure for the synthesis of compound
15a. ESMS m/e 301.2 (M + H)+; 1H NMR (400 MHz, CD3OD) δ

3878 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 16
Jiang et al.
6.80 (m, 1 H), 3.86-3.76 (m, 1 H), 3.08-2.97 (m, 3 H), 2.67-
2.54 (m, 3 H), 2.01-1.87 (m, 2 H), 1.65-1.56 (m, 2 H), 1.10 (d,
J ) 6.76 Hz, 6 H).
tert-Butyl 4-[5-(Isobutyrylamino)-2-methylphenyl]-1-piperidi-
necarboxylate (15c). Compound 15c was prepared from 4-(5-
isobutyrylamino-2-methyl-phenyl)-piperidine-1-carboxylic acid tert-
butyl ester 14c according to the procedure for the synthesis of
compound 15a. ESMS m/e 261.0 (M + H)+.
N-(3-Piperidin-4-yl-phenyl)-isobutyramide (15d). Compound
15d was prepared from 4-(3-isobutyrylamino-phenyl)-piperidine-
1-carboxylic acid tert-butyl ester 14d according to the procedure
for the synthesis of compound 15a. ESMS m/e 247.4 (M + H)+.
N-(2-Methyl-3-piperidin-4-yl-phenyl)-isobutyramide (15e).
Compound 15e was prepared from 4-(3-isobutyrylamino-2-methyl-
phenyl)-piperidine-1-carboxylic acid tert-butyl ester 14e according
to the procedure for the synthesis of compound 15a. ESMS m/e
261.0 (M + H)+.
ing to the general procedure for the synthesis of compound 16.
ESMS m/e 448.0 (M + H)+.
N-(3-{1-[5-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-pentyl]-pip-
eridin-4-yl}-phenyl)-isobutyramide (16g). Compound 16g was
prepared from N-(3-piperidin-4-yl-phenyl)-isobutyramide 15d ac-
cording to the general procedure for the synthesis of compound
16. ESMS m/e 462.2 (M + H)+.
N-(3-{1-[6-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-hexyl]-piperi-
din-4-yl}-phenyl)-isobutyramide (16h). Compound 16h was
prepared from N-(3-piperidin-4-yl-phenyl)-isobutyramide 15d ac-
cording to the general procedure for the synthesis of compound
16. ESMS m/e 476.3 (M + H)+.
N-(3-{1-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-pip-
eridin-4-yl}-2-methyl-phenyl)-isobutyramide (16i). Compound
16i was prepared from N-(2-methyl-3-piperidin-4-yl-phenyl)-isobu-
tyramide 15e according to the general procedure for the synthesis
of compound 16. ESMS m/e 448.3 (M + H)+.
General Procedure to Synthesize 16: A mixture of piperidine
15 (1.00 equiv, 0.023 mmol), N-(n-bromoalkyl)phthalimide (1.50
equiv, 0.034 mmol), Bu4NI (200 mg), and diisopropylethylamine
(5.00 equiv, 0.113 mmol) in dioxane (200 mL) was heated at
99 °C for 24 h. The reaction was monitored by TLC analysis (95:5
CH2Cl2/methanol). If necessary, an additional 0.0113 mmol of the
appropriate bromoalkylphthalimide was added to the reaction
mixture and heating was continued for an additional 48 h. The
reaction mixture was cooled to room temperature, the ammonium
salts were filtered out, and the solvent was removed under reduced
pressure. The crude product was chromatographed (silica) to give
the desired N-(n-phthalimidoalkyl)piperidine 16.
N-(5-{1-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-pip-
eridin-4-yl}-2,4-difluoro-phenyl)-isobutyramide (16a). Com-
pound 16a was prepared from N-[2,4-difluoro-5-(4-piperidinyl)-
phenyl]-2-methylpropanamide 15a according to the general procedure
to synthesize 16. ESMS m/e 470.2 (M + H)+; 1H NMR (400 MHz,
CDCl3) δ 8.06 (t, J ) 8.97 Hz, 1 H), 7.88-7.82 (m, 2 H), 7.72-
7.67 (m, 2 H), 7.29-7.23 (m, 1 H), 6.76 (t, J ) 8.97 Hz, 1 H),
3.78 (t, J ) 6.96 Hz, 2 H), 2.99-2.92 (m, 2 H), 2.74-2.64 (m, 1
H), 2.56 (sept, J ) 6.86 Hz, 1 H), 2.42 (t, J ) 6.62 Hz, 2 H),
1.98-1.90 (m, 2 H), 1.90-1.84 (m, 1 H), 1.72-1.65 (m, 2 H),
1.61-1.49 (m, 2 H), 1.27 (d, J ) 6.79 Hz, 6 H).
General Procedure to Synthesize 7: A solution of phthalimide-
protected amine 16a-16i with excess hydrazine hydrate (10 equiv)
in ethanol (0.5-1.0 M) was heated at 90 °C for 4 h. The reaction
mixture was monitored by TLC to completion. Upon completion
of the reaction, the mixture was cooled to room temperature, the
insoluble byproducts were removed by filtration through celite, and
the filtrate was concentrated in vacuo. The crude product was
chromatographed (dichloromethane-methanol-isopropylamine) to
give the desired products 7a-7i.
N-{5-[1-(3-Amino-propyl)-piperidin-4-yl]-2,4-difluoro-phen-
yl}-isobutyramide (7a). Compound 7a was prepared from N-(5-
{1-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-piperidin-4-yl}-
2,4-difluoro-phenyl)-isobutyramide 16a according to the general
procedure for the synthesis of compound 7. ESMS m/e 340.1 (M
1
+ H)+; H NMR (400 MHz, CD3OD) δ 7.66 (t, J ) 8.17 Hz, 1
H), 6.97 (t, J ) 8.17 Hz, 1 H), 3.14-3.08 (m, 2 H), 2.92-2.81
(m, 1 H), 2.73-2.66 (m, 3 H), 2.49-2.45 (m, 2 H), 2.18-2.10
(m, 2 H), 1.87-1.77 (m, 5 H), 1.76-1.68 (m, 1 H), 1.22 (d, J )
6.92 Hz, 6 H).
N-{3-[1-(3-Amino-propyl)-piperidin-4-yl]-2,4,6-trifluoro-phen-
yl}-isobutyramide (7b). Compound 7b was prepared from N-(3-
{1-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-piperidin-4-yl}-
2,4,6-trifluoro-phenyl)-isobutyramide 16b according to the general
procedure for the synthesis of compound 7. ESMS m/e 358.2 (M
N-(3-{1-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-pip-
eridin-4-yl}-2,4,6-trifluoro-phenyl)-isobutyramide (16b). Com-
pound 16b was prepared from 2-methyl-N-[2,4,6-trifluoro-3-(4-
piperidinyl)phenyl] propanamide 15b according to the general
procedure to synthesize compound 16. ESMS m/e 488.4 (M + H)+.
N-(3-{1-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-pip-
eridin-4-yl}-4-methyl-phenyl)-isobutyramide (16c). Compound
16c was prepared from tert-butyl 4-[5-(isobutyrylamino)-2-meth-
ylphenyl]-1-piperidinecarboxylate 15c according to the general
procedure to synthesize compound 16. ESMS m/e 448.2 (M + H)+.
N-(3-{1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-piperi-
din-4-yl}-phenyl)-isobutyramide (16d). Compound 16d was
prepared from N-(3-piperidin-4-yl-phenyl)-isobutyramide 15d ac-
cording to the general procedure to synthesize compound 16. ESMS
1
+ H)+; H NMR (400 MHz, CD3OD) δ 7.66 (t, J ) 8.17 Hz, 1
H), 6.97 (t, J ) 8.17 Hz, 1 H), 3.14-3.08 (m, 2 H), 2.92-2.81
(m, 1 H), 2.73-2.66 (m, 3 H), 2.49-2.45 (m, 2 H), 2.18-2.10
(m, 2 H), 1.87-1.77 (m, 5 H), 1.76-1.68 (m, 1 H), 1.22 (d, J )
6.92 Hz, 6 H).
N-{3-[1-(3-Amino-propyl)-piperidin-4-yl]-4-methyl-phenyl}-
isobutyramide (7c). Compound 7c was prepared from N-(3-{1-
[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-piperidin-4-yl}-4-
methyl-phenyl)-isobutyramide 16c according to the general procedure
for the synthesis of compound 7. ESMS m/e 318.2 (M + H)+.
N-{3-[1-(2-Amino-ethyl)-piperidin-4-yl]-phenyl}-isobutyra-
mide (7d). Compound 7d was prepared from N-(3-{1-[2-(1,3-dioxo-
1,3-dihydro-isoindol-2-yl)-ethyl]-piperidin-4-yl}-phenyl)-isobutyra-
mide 16d according to the general procedure for the synthesis of
compound 7. ESMS m/e 318.2 (M + H)+.
N-{3-[1-(3-Amino-propyl)-piperidin-4-yl]-phenyl}-isobutyra-
mide (7e). Compound 7e was prepared from N-(3-{1-[3-(1,3-dioxo-
1,3-dihydro-isoindol-2-yl)-propyl]-piperidin-4-yl}-phenyl)-isobu-
tyramide 16e according to the general procedure for the synthesis
of compound 7. ESMS m/e 304.3 (M + H)+.
N-{3-[1-(4-Amino-butyl)-piperidin-4-yl]-phenyl}-isobutyra-
mide (7f). Compound 7f was prepared from N-(3-{1-[4-(1,3-dioxo-
1,3-dihydro-isoindol-2-yl)-butyl]-piperidin-4-yl}-phenyl)-isobutyra-
mide 16f according to the general procedure for the synthesis of
compound 7. ESMS m/e 318.2 (M + H)+.
N-{3-[1-(5-Amino-pentyl)-piperidin-4-yl]-phenyl}-isobutyra-
mide (7g). Compound 7g was prepared from N-(3-{1-[5-(1,3-dioxo-
1,3-dihydro-isoindol-2-yl)-pentyl]-piperidin-4-yl}-phenyl)-isobu-
tyramide 16g according to the general procedure for the synthesis
of compound 7. ESMS m/e 332.2 (M + H)+.
1
m/e 420.2 (M + H)+; H NMR (400 MHz, CD3OD) δ 7.84-7.70
(m, 4 H), 7.59 (s, 1 H), 7.25-7.17 (m, 2 H), 6.95-6.89 (m, 1 H),
3.74-3.52 (m, 4 H), 3.19-2.97 (m, 4 H), 2.82-2.79 (m, 1 H),
2.56 (sept, J ) 6.76 Hz, 1 H), 2.11-1.84 (m, 4 H), 1.72-1.65 (m,
4 H), 1.13 (d, J ) 6.76 Hz, 6 H).
N-(3-{1-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-pip-
eridin-4-yl}-phenyl)-isobutyramide (16e). Compound 16e was
prepared from N-(3-piperidin-4-yl-phenyl)-isobutyramide 15d ac-
cording to the general procedure for the synthesis of compound
1
16. ESMS m/e 434.2 (M + H)+; H NMR (400 MHz, CD3OD) δ
7.84-7.70 (m, 4 H), 7.59 (s, 1 H), 7.25-7.17 (m, 2 H), 6.95-
6.89 (m, 1 H), 3.74-3.52 (m, 4 H), 3.19-2.97 (m, 4 H), 2.82-
2.79 (m, 1 H), 2.56 (sept, J ) 6.76 Hz, 1 H), 2.11-1.84 (m, 4 H),
1.72-1.65 (m, 4 H), 1.13 (d, J ) 6.76 Hz, 6 H).
N-(3-{1-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-piperi-
din-4-yl}-phenyl)-isobutyramide (16f). Compound 16f was pre-
pared from N-(3-piperidin-4-yl-phenyl)-isobutyramide 15d accord-

Melanin-Concentrating Hormone 1 Receptor Antagonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 16 3879
N-{3-[1-(6-Amino-hexyl)-piperidin-4-yl]-phenyl}-isobutyra-
mide (7h). Compound 7h was prepared from N-(3-{1-[6-(1,3-dioxo-
1,3-dihydro-isoindol-2-yl)-hexyl]-piperidin-4-yl}-phenyl)-isobu-
tyramide 16h according to the general procedure for the synthesis
of compound 7. ESMS m/e 346.2 (M + H)+.
0 °C for 2 h, and the excess peroxide was quenched at 0 °C with
1.5 N aqueous Na2SO3 (51 mL). After buffering to pH 9-10 with
aqueous NaHCO3 and evaporation of the THF, the oxazolidone
chiral auxiliary was recovered by EtOAc extraction (50 mL × 3).
The aqueous layer was acidified with 3 N HCl and extracted with
EtOAc. The organic layer was washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo to give 0.92 g (5.47
N-{3-[1-(3-Amino-propyl)-piperidin-4-yl]-2-methyl-phenyl}-
isobutyramide (7i). Compound 7i was prepared from N-(3-{1-[3-
(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-piperidin-4-yl}-2-
methyl-phenyl)-isobutyramide 16i according to the general procedure
for the synthesis of compound 7. ESMS m/e 318.2 (M + H)+.
Bis-(4-fluoro-phenyl)-acetic Acid (17b). Fluorobenzene (13.6
g, 0.142 mol) and glyoxylic acid monohydrate (2.35 g, 0.026 mol)
were dissolved in warm acetic acid (30.0 mL). The mixture was
cooled in an ice/water bath and concentrated sulfuric acid (20.0
mL) was added dropwise over 0.5 h. The resulting thick red
suspension was stirred at 80 °C for 12 h and then cooled to room
temperature. Water (300 mL) was added and the pH was adjusted
to 3 with potassium hydroxide pellets and 10% KOH solution. The
aqueous solution was extracted with ethyl acetate (3 × 100 mL),
and the combined organic extracts were washed with brine (100
mL), dried over sodium sulfate, filtered, and concentrated in vacuo
to give the desired product (5.18 g, 82%) as a red solid, which was
used in the subsequent step without further purification: 1H NMR
(400 MHz, CD3OD) δ 9.45 (br s, 1 H), 7.31-7.25 (m, 4 H), 7.06-
7.0 (m, 4 H), 5.01 (s, 1 H).
mmol, 64%) of (2S)-2-(4-fluorophenyl)propanoic acid: [R]D
)
+70° (c 1, MeOH); 1H NMR (400 MHz, CDCl3) δ 12.2-11.4 (br,
1 H), 7.31-7.24 (m, 2 H), 7.04-6.97 (m, 2 H), 3.72 (q, J ) 7.3
Hz, 1 H), 1.49 (d, J ) 7.3 Hz, 3 H); ESMS m/e 167.2 (M - H)+.
(2R)-2-(4-Fluorophenyl)propanoic Acid ((R)-18b). Compound
(R)-18b was prepared accordingly: [R]D ) -61.5° (c 1.04, MeOH);
1H NMR (400 MHz, CDCl3) δ 12.2-11.4 (br, 1 H), 7.31-7.24
(m, 2 H), 7.04-6.97 (m, 2 H), 3.72 (q, J ) 7.3 Hz, 1 H), 1.49 (d,
J ) 7.3 Hz, 3 H); ESMS m/e 167.2 (M - H)+.
Biological Evaluations. In Vitro Binding Assays. Rat MCH1
receptor binding assays were performed by incubating membranes
from modified HEK 293 cells (PEAKRAPID cells, Edge Biosystems,
Gaithersburg, MD) transiently transfected with the rat MCH-1
receptor with varying concentrations of [3H]-1 ([3H]SNAP- 7941)
in binding buffer (50 mM Tris, 10 mM MgCl2, 0.16 mM PMSF, 1
mM 1,10-phenanthroline, and 0.2% BSA, pH 7.4) at 25 °C for 90
min, as described previously. Similarly, R1A and D2 binding assays
were performed in membranes of cells expressing the human
recombinant R1A and D2 receptors using [125I]HEAT and [3H]-
spiperone, respectively. Membranes for the D2 assays were obtained
from Packard Bioscience.10b
In Vitro Functional Assays. Functional antagonism of the
compounds was assessed using FLIPR calcium mobility assay. HEK
293 cells stably expressing rat MCH1 were seeded on a 386-well
poly-D-lysine-coated black plates (Becton Dickinson Labware,
Bedford, MA). After 16 h incubation, cells were loaded with 1.5
µM Fluo4 fluorescent dye (Molecular Probs) in Hank’s balanced
salt solution (HBSS, Wisent Inc) for 60 min. Cells were then washed
and varying concentrations of testing compounds were added. After
20 min incubation, MCH peptide was added at 30 nM. Fluorescent
intensity in response to changes in intracellular calcium concentra-
tion was measured on a FLIPR-384 fluorescent reader. Data analysis
was performed using Activity Base software. IC50 values were
calculated using nonlinear curve fitting.
In Vivo Assays: Social Interaction Test (SIT). Rats were
allowed to acclimate to the animal care facility for 5 days and were
housed singly for 5 days prior to testing. Animals were handled
for 5 min per day. The design and procedure for the SIT was carried
out as previously described by Kennett et al. (1997). On the test
day, weight matched pairs of rats ((5%), unfamiliar to each other,
were given identical treatments and returned to their home cages.
Animals were randomly divided into five treatment groups, with
five pairs per group, and were given one of the following i.p.
treatments: test compound (10, 30, or 100 mg/kg), vehicle (1 mL/
kg), or chlordiazepoxide (5 mg/kg). Dosing is 1 h prior to testing.
Rats were subsequently placed in a white perspex test box or arena
(54 × 37 × 26 cm), whose floor was divided up into 24 equal
squares, for 15 min. An air conditioner was used to generate
background noise and to keep the room at approximately 74 °F.
All sessions were videotaped using a JVC camcorder (model GR-
SZ1, Elmwood Park, NJ) with either TDK (HG ultimate brand) or
Sony 30 min videocassettes. All sessions were conducted between
1300-1630 h. Active social interaction, defined as grooming,
sniffing, biting, boxing, and wrestling, following and crawling over
or under, was scored using a stopwatch (Sportsline model no. 226,
1/100 s discriminability). The number of episodes of rearing (animal
completely raises up its body on its hind limbs), grooming (licking,
biting, scratching of body), face washing (i.e., hands are moved
repeatedly over face), and number of squares crossed were scored.
Passive social interaction (animals are lying beside or on top of
each other) was not scored. All behaviors were assessed later by
an observer who was blind as to the treatment of each pair. At the
end of each test, the box was thoroughly wiped with moistened
paper towels.
Bis-(4-chloro-phenyl)-acetic Acid (17c). Compound 17c was
prepared from chlorobenzene and glyoxylic acid monohydrate
according to the procedure for the synthesis of compound 17b.
ESMS m/e 279.1 (M - H)-.
(2S)-2-(4-Fluorophenyl)propanoic Acid ((S)-18b). (4S)-3-[(4-
Fluorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one: To a so-
lution of (4S)-4-isopropyl-1,3-oxazolidin-2-one (2.0 g, 15.5 mmol)
in dry THF (20 mL) at -78 °C under argon was added dropwise
a 2.5 M solution of n-BuLi in hexanes (6.2 mL, 15.5 mmol). After
stirring at -78 °C for 15 min, (4-fluorophenyl)acetyl chloride (2.55
mL, 18.6 mmol) was added. The resulting reaction mixture was
stirred at -78 °C for 30 min and 0 °C for 15 min, quenched with
saturated NH4Cl (5 mL), and concentrated in vacuo. The residue
was dissolved in EtOAc (100 mL) and washed with saturated Na2-
CO3 followed by brine, dried over MgSO4, filtered, and concentrated
in vacuo. The crude material was purified by flash chromatography
(10-15% EtOAc/hexane) to give 2.83 g (10.7 mmol, 69%) of (4S)-
3-[(4-fluorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one: 1H
NMR (400 MHz, CDCl3) δ 7.30-7.25 (m, 2 H), 7.10 (t, J ) 8.5
Hz, 2 H), 4.46-4.41 (m, 1 H), 4.36-4.15 (m, 4 H), 2.40-2.28
(m, 1 H), 0.88 (d, J ) 7.6 Hz, 3 H), 0.79 (d, J ) 7.6 Hz, 3 H);
ESMS m/e 266.2 (M + H)+.
(4S)-3-[(2S)-2-(4-Fluorophenyl)propanoyl]-4-isopropyl-1,3-ox-
azolidin-2-one. To a solution of (4S)-3-[(4-fluorophenyl)acetyl]-
4-isopropyl-1,3-oxazolidin-2-one (2.81 g, 10.6 mmol) in dry THF
(40 mL) at -78 °C under argon was added dropwise a 1.0 M
solution of NaHMDS in THF (11.7 mL, 11.7 mmol) over a period
of 10 min. After stirring at -78 °C for 1 h, MeI (3.30 mL, 53.0
mmol) was added. The resulting reaction mixture was stirred at
-78 °C for 1 h and -40 °C for 2 h, quenched with HOAc (32
mmol) in ether (20 mL), and filtered over celite. The filtrate was
concentrated in vacuo, and the residue was dissolved in CH2Cl2
(100 mL) and washed with H2O followed by brine, dried over
MgSO4, filtered, and concentrated in vacuo. The crude material
was purified by flash chromatography (5-10% EtOAc in hexane)
to give 2.40 g (8.60 mmol, 81%) of (4S)-3-[(2S)-2-(4-fluorophenyl)-
propanoyl]-4-isopropyl-1,3-oxazolidin-2-one: 1H NMR (400 MHz,
CDCl3) δ 7.34-7.31 (m, 2 H), 7.02-6.96 (m, 2 H), 5.13 (q, J )
7.7 Hz, 1 H), 4.38-4.33 (m, 1 H), 4.18-4.13 (m, 2 H), 2.48-2.37
(m, 1 H), 1.49 (d, J ) 7.3 Hz, 3 H), 0.91 (apparent t, J ) 6.9 Hz,
6 H); ESMS m/e 280.2 (M + H)+.
(2S)-2-(4-Fluorophenyl)propanoic Acid ((S)-18b). To a solution
of (4S)-3-[(2S)-2-(4-fluorophenyl) propanoyl]-4-isopropyl-1,3-ox-
azolidin-2-one (2.40 g, 8.60 mmol) in 160 mL of THF/H2O (3:1)
at 0 °C, was added 30% H2O2 (7.8 mL, 68.8 mmol) followed by
LiOH (722 mg, 17.2 mmol). The resulting mixture was stirred at

3880 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 16
Jiang et al.
MCH-Induced Water Intake. MCH-induced water intake in
rats was studied according to the method described by Clegg et al.
(2003) with modifications.16 Briefly, male Sprague-Dawley rats
(250-400 g) implanted with a permanent intracerebroventricular
(icv) cannula, were procured from Charles River Laboratories and
housed individually with free access to rat chow and water under
standard husbandry conditions. After a week of acclimatization,
the rats were brought to the laboratory in their home cage and were
denied access to water for 2 h. Individual rats received either vehicle
(20% cyclodextrin) or the test compound at least 1 h prior to
administration of either saline or MCH (10 ug in 5 µL saline) icv.
The animals were given access to water immediately after the icv
administration, and the water consumption was measured at the
end of 2 h. To confirm that position as well as specificity of
blockade of MCH-induced water intake, rats were administered with
100 ng of angiotensin-II (icv in 5 µL saline) and water consumption
was measured for an additional 30 min. Animals that failed to
consume at least 3 mL of water following angiotensin-II challenge
were excluded from the analysis.
Supporting Information Available: IC50 values, LCMS purity
checks, and high-resolution mass spectrum data from compounds
of interest. This material is available free of charge via the Internet
at http://pubs.acs.org.
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