Discovery, synthesis, and structure-activity relationship of 6-aminomethyl-7,8-dihydronaphthalenes as human melanin-concentrating hormone receptor 1 antagonists

Article abstract of DOI:10.1016/j.bmc.2011.07.038

Human melanin-concentrating hormone receptor 1 (hMCHR1) antagonists are promising targets for obesity treatment. We identified the tetrahydronaphthalene derivative 1a with modest binding affinity for hMCHR1 by screening an in-house G protein-coupled receptor (GPCR) ligand library. We synthesized a series of 6-aminomethyl-5,6,7,8-tetrahydronaphthalenes and evaluated their activity as hMCHR1 antagonists. Modification of the biphenylcarbonylamino group revealed that the biphenyl moiety played a crucial role in the interaction of the antagonist with the receptor. The stereoselective effect of the chiral center on binding affinity generated the novel 6-aminomethyl-7,8-dihydronaphthalene scaffold without a chiral center. Optimization of the amino group led to the identification of a potent antagonist 2s (4′-fluoro-N-[6-(1- pyrrolidinylmethyl)-7,8-dihydro-2-naphthalenyl][1,1′-biphenyl] -4-carboxamide), which significantly inhibited the nocturnal food intake in rats after oral administration. Pharmacokinetic analysis confirmed that 2s had good oral bioavailability and brain penetrance. This antagonist appears to be a viable lead compound that can be used to develop a promising therapy for obesity.

Full text of DOI:10.1016/j.bmc.2011.07.038

Bioorganic & Medicinal Chemistry 19 (2011) 5539–5552
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Discovery, synthesis, and structure–activity relationship
of 6-aminomethyl-7,8-dihydronaphthalenes as human melanin-concentrating
hormone receptor 1 antagonists
⇑
Makoto Kamata , Toshiro Yamashita, Toshihiro Imaeda, Toshio Tanaka, Jun Terauchi, Maki Miyamoto,
Taiichi Ora, Michiko Tawada, Satoshi Endo, Shiro Takekawa, Asano Asami, Nobuhiro Suzuki,
Yasutaka Nagisa, Yoshihide Nakano, Kaoru Watanabe, Hitomi Ogino, Koki Kato, Kaneyoshi Kato,
Yuji Ishihara
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85 Jusohonmachi, 2-Chome, Yodogawa-ku, Osaka 532-8686, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Human melanin-concentrating hormone receptor 1 (hMCHR1) antagonists are promising targets for obes-
ity treatment. We identified the tetrahydronaphthalene derivative 1a with modest binding affinity for
hMCHR1 by screening an in-house G protein-coupled receptor (GPCR) ligand library. We synthesized a
series of 6-aminomethyl-5,6,7,8-tetrahydronaphthalenes and evaluated their activity as hMCHR1 antag-
onists. Modification of the biphenylcarbonylamino group revealed that the biphenyl moiety played a cru-
cial role in the interaction of the antagonist with the receptor. The stereoselective effect of the chiral center
on binding affinity generated the novel 6-aminomethyl-7,8-dihydronaphthalene scaffold without a chiral
center. Optimization of the amino group led to the identification of a potent antagonist 2s (40-fluoro-N-
[6-(1-pyrrolidinylmethyl)-7,8-dihydro-2-naphthalenyl][1,10-biphenyl]-4-carboxamide), which signifi-
cantly inhibited the nocturnal food intake in rats after oral administration. Pharmacokinetic analysis
confirmed that 2s had good oral bioavailability and brain penetrance. This antagonist appears to be a via-
ble lead compound that can be used to develop a promising therapy for obesity.
Received 20 June 2011
Revised 19 July 2011
Accepted 20 July 2011
Available online 26 July 2011
Keywords:
MCH (melanin-concentrating hormone)
hMCHR1 (human MCH receptor 1)
Antagonist
Obesity
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Shimomura et al.10 and 4 other groups11–14 used ‘‘orphan recep-
tor strategy’’ and identified the orphan G protein-coupled receptor
Melanin-concentrating hormone (MCH) is a cyclic hypothalamic
neuropeptide which was originally isolated by Kawauchi et al. from
salmon pituitary as a hormone responsible for color changes in
response to environmental background.1 Human MCH is a cyclic
19-amino-acid peptide and is identical to rat MCH.2 MCH is present
in neurons of both central3 and peripheral nervous systems4,5 and is
predominantly expressed in lateral hypothalamus and zona incer-
ta.3 Both these regions have been implicated in various physiological
functions including feeding and energy balance.6 Among its poten-
tial functions, regulatory roles of MCH in feeding have been studied
in the past decade. Intracerebroventricular administration of MCH
promotes feeding behavior in rats. The mRNA levels of MCH in lat-
eral hypothalamus are upregulated during fasting and in obese
(ob/ob) mice.7 Mice lacking the MCH peptide gene are lean because
of hypophagia and show an increase in the metabolic rate.8 In con-
trast, transgenic mice overexpressing MCH in lateral hypothalamus
are obese and exhibit insulin resistance.9
(GPCR) SLC-1 as a human MCH receptor 1 (hMCHR1).15 MCH binds
the receptor expressed as 7-transmembrane (7TM) domain recep-
tor at nanomolar affinity and its mRNA was expressed in specific
brain regions implicated in feeding behavior, such as the hypothal-
amus and hippocampus.11 Further, MCH receptor expressed in the
central nervous system15 is up-regulated in ob/ob mice and by fast-
ing condition.16 Accordingly, hMCHR1 antagonists should be effec-
tive in inhibiting food intake, thereby providing a novel therapy for
treating obesity.
Through a screening of our in-house GPCR ligand library, we
identified the tetrahydronaphthalene derivative 1a (Fig. 1) with
Me
O
N
Me
N
H
1a
⇑
Corresponding author. Tel.: +81 6 6300 6619; fax: +81 6 6300 6306.
E-mail address: Kamata_Makoto@takeda.co.jp (M. Kamata).
Figure 1. Chemical structure of hit compound 1a.
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.07.038

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M. Kamata et al. / Bioorg. Med. Chem. 19 (2011) 5539–5552
modest binding affinity for hMCHR1 as one of the potential leads.
Our pharmacokinetic study showed that 1a exhibits good oral bio-
availability; hence, we started investigation of potential hMCHR1
antagonists as anti-obesity agents. We reported, for the first time,
the discovery of the small molecule hMCHR1 antagonist, T-226296
((ꢀ)-enantiomer of 1h), which has been identified in our medicinal
chemistry program.17 In the present report, we describe the details
of our initial medicinal chemistry efforts starting from 1a, focusing
especially on a distal phenyl ring, a core scaffold and an amino
group. Moreover, we discuss the validity of a unique docking mod-
el for hMCHR1 and antagonists on the basis of the results of a
structure–activity relationship (SAR) study.
10% Pd/C to afford 5,6,7,8-tetrahydro-2-naphthalenamine 7a as a
racemic mixture.
The intermediate 7a was converted to 1 and 9 by treatment
with an acid chloride (Method A) or carboxylic acid in the presence
of peptide coupling reagents (Method B). In another Method C, 1
and 9 were obtained by Suzuki coupling of boronic acid and bro-
mides 8a and 8b, which were prepared by the reaction of 7a and
bromobenzoyl chloride. Compounds 1n and 1o, containing a car-
boxylate or amino residue, were synthesized by hydrolysis of the
corresponding ester 9n or amide 9o, respectively. The sulfonamide
1r was also derived from 7a. Reduction of the oxo group in 1a with
borane afforded 1q. The enantiomers of 1g were separated by stan-
dard preparative chiral high-performance liquid chromatography
(HPLC).
2. Chemistry
The synthetic route to ester 1s is shown in Scheme 2. Stepwise
reductive deoxygenation of the Mannich base 1018 and demethyl-
ation of the resultant amine 11 gave phenol 12, which was acylated
using 4-biphenylcarboxylic acid to give 1s.
Compounds 2b–i with various amines were prepared as de-
picted in Scheme 3. Dihydronaphthalene derivative 2a was synthe-
sized by condensation of 6a with 40-chlorobiphenylcarboxylic acid
using peptide coupling reagents (EDC: 1-ethyl-3-(3-dimethylami-
nopropyl)carbodiimide). Acylation of the amino group of 6a by
the acid chloride method was unsuccessful owing to the very rapid
Tetrahydronaphthalene derivatives 1 were synthesized starting
from tetralone 3 as outlined in Scheme 1. Compound 3, prepared as
described in Section 6, was reacted with dimethylformamide
dimethylacetal to give enaminone 4a. The dimethylamino group
in 4a was replaced by heating the compound with methylamine
or pyrrolidine to afford 4b and 4c, respectively. Stepwise reduction
of 4a–c using NaBH(OAc)3 and subsequently with NaBH4 followed
by heating with concentrated hydrochloric acid gave 7,8-dihydro-
2-naphthalenamine 6a–c. Compound 6a was hydrogenated over
O
O
OH
R1
R1
R1
N
a
d
e
N
N
R2
R2
R2
H2N
AcHN
AcHN
AcHN
3
5a-c
6a-c
4a: NR1R2 = NMe2
4b: NR1R2 = NHMe
b
Me
c
N
1
2
HN
4c: NR R =
Me
Me
N
Me
O
Me
N
H
k
f
N
Me
N
6a
R
H
g (Method A) or
h (Method B)
H2N
1a-m, 1p and 9n, o
1q
7a
i (Method C)
l or m
j
g
Me
O
N
Me
N
Me
Me
N
Me
Me
O
S
O
O
N
H
N
H
N
Br
H
1n (R = CO2H)
1o (R = NH2)
8a, b
R
1r
Scheme 1. Reagents and conditions: (a) Me2NCH(OMe)2, 84%; (b) 40% MeNH2 in MeOH, 82%; (c) pyrrolidine, 88%; (d) NaBH(OAc)3, AcOH, THF then NaBH4, iPrOH; (e)
concentrated HCl, 64–79%; (f) H2/Pd–C, 1 M HCl, MeOH, 54%; (g) substituted benzoyl chloride, TEA, THF, 19–89%; (h) bromobenzoic acid, EDCꢁHCl, DMAP, HOBt, DMF, 36–86%;
(i) Pd(PPh3)4, substituted phenylboronic acid, 2 M Na2CO3, DME–THF, 7–92%; (j) biphenyl-4-sulfonyl chloride, TEA, MeCN, 59%; (k) 1 M BH3 in THF, 36%; (l) 1 M NaOH, EtOH,
95% for 1n; (m) 1 M NaOH, MeOH–THF, 100% for 1o.
O
HCl
Me
Me
N
Me
N
b
a
N
Me
Me
HO
Me
MeO
HCl
HCl
MeO
12
11
10
Me
O
N
Me
c
O
1s
Scheme 2. Reagents and conditions: (a) (i) NaBH4, MeOH, (ii) Pd/C, MeOH, 69%; (b) HBr, 72%; (c) 4-biphenylcarboxylic acid, EDCꢁHCl, pyridine, 53%.

M. Kamata et al. / Bioorg. Med. Chem. 19 (2011) 5539–5552
5541
Me
O
Cl
O
N
Me
b
a
N
Me
N
H
N
H
Me
H2N
6a
2a
13
Cl
Cl
R1
O
N
c
R2
N
H
Cl
2b-i
Scheme 3. Reagents and conditions: (a) 40-chlorobiphenylcarboxylic acid, EDCꢁHCl, HOBt, DMF, 54%; (b) ClCOOEt, THF, 82%; (c) R1R2NH, i-Pr2NEt, DMF, 8–63%.
Me
O
Me
Me
N
Me
Me
Me
b
a
N
H
N
N
H
O
O
Me
H2N
H2N
O
O
Me
Me
Br
6b
6d
14
Me
Me
Me
O
O
N
H
N
d
N
N
H
O
O
Me
Me
c
TFA
H
2j
2k
Cl
Cl
Me
O
N
R
e
N
H
2l-o
Cl
Scheme 4. Reagents and conditions: (a) Boc2O, TEA, MeCN, 87%; (b) 4-bromobenzoyl chloride, TEA, THF, 85%; (c) 4-chlorophenylboronic acid, Pd(PPh3)4, 2 M Na2CO3, THF,
69%; (d) TFA, 97%; (e) various acylating reagents, pyridine, 78–85%.
O
N
N
H
N
a
H2N
X
2p-s
6c
Scheme 5. Reagents and conditions: (a) substituted biphenylcarboxylic acid, EDCꢁHCl, HOBt, DMF, 56–67%.
C–N bond cleavage at the C-6 position; we used this feature of the
3. Homology modeling and automated docking
compound for converting the dimethylamino group in 2a. Reaction
of 2a with ethyl chlorocarbonate19 afforded chloride 13, which was
treated with various amines to afford a variety of dihydronaphtha-
lene derivatives 2b–i.
A homology model of hMCHR1 was constructed on the basis of
the crystal structure of bovine rhodopsin (PDB code 1F88) as a
structural template by using the Molecular Operating Environment
(MOE) 2005.0620 after truncating a part of the extracellular region
(residues 179–200). Primary sequence alignment between
hMCHR1 and bovine rhodopsin was performed using MOE. Several
different models were prepared by probing the possible rotamer
states of the residues Asp123, Tyr272, Tyr273, and Asn294 in the
TM ligand binding region. Antagonists of hMCHR1 were docked
into hMCHR1 models by using the automated docking program
GOLD.21 Reasonable binding modes were selected on the basis of
Gold Score and the SAR results. Further, to take into account the
flexibility of side chains, the resulting binding modes were refined
through energy minimization using MOE.
Secondary amine 2j and various acylated compounds 2l–o were
prepared as shown in Scheme 4. Selective protection of aliphatic
amine 6b with Boc group was successful under ice cooling condi-
tion to give 6d. Acylation of 6d with 4-bromobenzoyl chloride
and the subsequent Suzuki coupling reaction with 14 and 4-chloro-
phenylboronic acid afforded biphenyl derivative 2k. Removal of
Boc group in 2k using TFA afforded 2j as a salt, which was acylated
with various acid chlorides or isocyanate to give 2l–o.
Scheme 5 shows the preparation of 2p–s, which were synthe-
sized by condensation of 6c with the corresponding biphenylcarb-
oxylic acids.

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M. Kamata et al. / Bioorg. Med. Chem. 19 (2011) 5539–5552
the para-position are favorable for the potent activity. SARs of
4. Results and discussion
rMCHR1 indicated the same tendency as those of hMCHR1. The
docking views of 1g in hMCHR1 and details of the biphenyl binding
pocket are shown in Figure 2. This binding pocket is a hydrophobic
field formed by Phe213, Ala216, and Phe217 on TM5 and Tyr273
on TM6. As indicated by the tight SAR of the biphenyl moiety (Tables
1 and 2) and the docking model study, there is a linear biphenyl
pocket and a small hydrophobic binding site of the 40-substituent
in hMCHR1.
We examined the effect of replacement of the amide spacer (Z)
between the biphenyl group and the tetrahydronaphthalene core
(Table 3). Methylenamine derivative 1q and sulfonamide deriva-
tive 1r attenuated the activity. On the other hand, ester 1s showed
moderate binding affinity with IC50 value of the order of 10ꢀ7 M.
These findings are in agreement with the docking model shown
in Figure 2, which shows that the carbonyl group forms key inter-
action with the side chain of Gln127 on TM3 by hydrogen bonding
and the interaction with NH group on amide and hMCHR1 is
obscure.
We next investigated the contribution of the configuration at C-6
position of the tetrahydronaphthalene ring in receptor binding.
Interestingly, the IC50 values of (ꢀ)- and (+)-1g were the same (Table
4). Additionally, the previously reported T-22629617 ((ꢀ)-1h) also
exhibited equal binding affinity to (+)-1h. The details of the binding
pocketof theamino-terminalregion and oneof the 2 enantiomers 1g
and 2a are shown in Figure 3. This model suggested that the amino-
methyl group of (S)-1g forms equatorial bond at the C-6 position to
interact with carboxamide of Asn294 on TM7. The hydrogen bond
length between side-chain of Asn294 and the cationic amine may
signify the binding affinity. We then designed and synthesized dihy-
dronaphthalene derivative 2a without a chiral center. The activity of
compound 2a was found to be the same or more potent than that of
the corresponding 1g, as we had expected.
Replacement of the amino group in dihydronaphthalene deriv-
ative 2 having 40-chlorobiphenylamide moiety was then examined
(Table 5). Compound 2b containing an amine of low basicity (pKa
3.2),22 such as methoxylmethylamine, was poorly active. Since
the basicity of an aniline (2e: pKa 4.8)22 or a morpholine group
(2f: pKa 7.5)22 was weaker than that of dimethylamine moi-
ety (2a: pKa 9.3),22 the activity of both compounds decreased
We evaluated the binding affinities of the compounds prepared
in this study to hMCHR110,17 and rat MCHR1 (rMCHR1),10,17 and
expressed the compounds in Chinese hamster ovary (CHO) cells
using [125I]-MCH (4–19) as the ligand. Secondary in vitro func-
tional assay (GTPcS) was performed to establish that compounds
exhibit hMCHR1 antagonistic activity.17 At first, the importance
of [1,10-biphenyl]-4-carbonyl moiety of lead compound 1a was
indicated by the following results (Table 1). Removal of the termi-
nal phenyl ring diminished the activity (cf. 1a vs 1b). In addition,
the position of the terminal phenyl ring was found to be crucial
for binding affinity (cf. 1a vs. 1c and 1d).
Then, weexamined the effects of thesubstituent (X) onthe termi-
nal phenyl ring (Table 2). The para-position was the most effective in
hMCHR1 substitution (cf. 1g vs 1e and 1f). Among compounds with
various substituents X, the compounds 1g (X = 40-Cl), 1h (X = 40-F),
and 1i (X = 40-Me) showed potent binding affinities. Introduction
of any bulky or polar group like X decreased the activity of these
compounds (cf. 1i vs 1j–m; 1a vs 1n–p). These results suggest that
small lipophilic substituent groups such as halogen and methyl at
Table 1
In vitro binding affinity and antagonist activity (GTP
c
S) of tetrahydronaphthlene
derivatives 1a–d
Me
N
O
2
3
R
4
Me
N
H
Compd
R
hMCHR1
GTPcS
rMCHR1
Binding
Binding
a
a
a
IC50 (nM)
IC50 (nM)
IC50 (nM)
1a
1b
1c
1d
4-Ph
H
2-Ph
3-Ph
76
91
—
—
95
—
—
>10,000
>10,000
10,000
—
—
a
IC50 values are calculated with one experiment performed in duplicate.
Table 2
In vitro binding affinity and antagonist activity (GTPcS) of tetrahydronaphthalene derivatives 1e–p
Me
O
N
Me
N
H
X
Compd
X
hMCHR1
rMCHR1
a
a
a
Binding IC50 (nM)
GTP
c
S IC50 (nM)
Binding IC50 (nM)
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
20-Cl
17
65
340
11
43
18
43
220
—
23
220
8.0
24
12
21
210
—
30-Cl
140
5.3
14
8.4
19
84
1300
17
40-Cl
40-F
40-Me
40-Et
40-Pr
40-Ph
40-OMe
40-CO2H
40-NH2
40-CN
37
—
—
22
—
—
230
350
380
—
—
a
IC50 values are calculated with one experiment performed in duplicate.

M. Kamata et al. / Bioorg. Med. Chem. 19 (2011) 5539–5552
5543
Figure 2. Docking model of S-form of 1g with hMCHR1. (a) Overall structure (colored for helices) and (b) binding pocket of 1g (carbon atoms in yellow for ligand and in green
for receptor, nitrogen atoms in blue, oxygen atoms in red, and chlorine atom in light green).
of diethyl amine derivative 2c. The alkylene group in pyrrolidine
(2g) or piperidine (2h) moiety should be fitted in a wide space
leading to favorable lipophilic interaction with Leu103 and
Met104 on TM2 (Fig. 3). Methylphenethylamino analog 2d also re-
tained binding affinity with an IC50 value of 10ꢀ9 M order. Replace-
ment of the amino group revealed that amino basicity is a key
factor for tight interaction with the carboxamide of Asn 294 and
the size of the phenethylmethylamino group is presumably tolera-
ble for hMCHR1 binding pocket. Interestingly, intermediate 2k
with Boc group showed moderate binding affinity, indicating that
neutral compounds can be acceptable as hMCHR1 antagonists.
We introduced various acylated groups for methylamine of 2j. Acyl
derivatives 2l and 2m exhibited IC50 value of 10ꢀ9 M order and
showed equal affinity to 2j. On the other hand, formation of ure-
thane (2n) or urea (2o) resulted in approximately eightfold drop
in activity. The docking model of 2l and the receptor (Fig. 4) sug-
gests that the interaction between carbonyl moiety in acetyl group
and carboxamide of Asn294 should be by means of a hydrogen
bond. Moreover, alkyl group in acetyl or propionyl may result in
lipophilic interactions in the wide hydrophobic pocket composed
by Leu103, Met104, and Pro31, and a hydrophilic group such as a
urethane or a urea may be unfavorable for the binding affinity.
Table 3
In vitro binding affinity of tetrahydronaphthalene derivatives 1q–s
Me
N
Me
z
Compd
Z
hMCHR1
Binding IC50 (nM)
rMCHR1
Binding IC50 (nM)
a
a
1q
1r
1s
–CH2NH–
–SO2NH–
–CO2–
>1000
>1000
190
>1000
>1000
280
a
IC50 values are calculated with one experiment performed in duplicate.
accordingly. Replacement of dimethylamino (2a) with monometh-
ylamino (2j) or diethylamino (2c) group slightly decreased the
binding affinity. On the other hand, cyclization of distal amino
groups 2g–i increased the potent affinities as compared to those
Table 4
In vitro binding affinity and antagonist activity (GTPcS) of both enantiomers of 1g and dihydronaphthalene derivative 2a
Me
Me
O
N
O
N
Me
Me
N
H
N
H
1g
2a
Cl
Cl
Compd
hMCHR1
rMCHR1
a
a
a
Binding IC50 (nM)
GTPc
S IC50 (nM)
Binding IC50 (nM)
(ꢀ)-1g
(+)-1g
2a
3.5
3.4
1.8
9.4
9.1
6.6
5.3
6.2
2.7
a
IC50 values are calculated with one experiment performed in duplicate.

5544
M. Kamata et al. / Bioorg. Med. Chem. 19 (2011) 5539–5552
Figure 4. Detail of binding pocket of amino-terminal region with 2l. Acetyl group
forms a hydrogen bond with the side chain of Asn294 and binds in the hydrophobic
field composed of Leu103, Met104, and Pro31.
showed potent binding affinity and antagonist activity and was
thus selected for further modification.
Figure 3. Details of the binding pocket at the amino-terminal region with S-form of
1g (carbon atoms in yellow) and 2a (carbon atoms in white). The aminomethyl
group of each of the enantiomers takes an equatorial form at the C-6 position to
interact with the carbonyl group of Asn294 on TM7.
The optimization results of substituent (X) are summarized in
Table 6. The substituents (X) selected on the basis of the results ob-
tained for tetrahydronaphthalenes (Table 2) were introduced to
the para-position of the terminal phenyl ring of 2g. Incorporation
of methyl (2q), methoxy (2r), and fluoro (2s) groups exhibited po-
tent affinity for hMCHR1 as well as that of a chloro group.
Selected compounds with potent in vitro binding affinity were
further tested for their inhibitory effects on spontaneous food in-
take using KKAy mice. As shown in Table 7, all selected tetrahydro-
and dihydronaphthalene derivatives inhibited food intake after
oral administration (30 mg/kg). In particular, the compound 2s
exhibited statistically significant inhibitory effect on food intake
during 2 h. Moreover, 2s was effective until 25 h (31% inhibition
after 25 h at 30 mg/kg). Compound 2s was selected for further
evaluation.
Some researchers23 reported hMCHR1 antagonists with their dock-
ing models and described ionic interaction between carboxylate of
Asp123 with protonated amine moiety. We could not obtain rea-
sonable binding modes in our automatic docking study with dis-
tance constraints between any atom of ligands and an oxygen
atom of carboxylate of Asp123. In addition, carboxylate of a pro-
tein, in general, does not directly interact with carbonyl group of
a compound by hydrogen bonding. In fact, our proposed docking
model is in excellent agreement with hydrogen bond formation
with the side chain of Asn294 and other compounds, and no crucial
contradictory SAR is observed. Unfortunately, 2l and 2m showed
poor pharmacokinetic profiles in rat owing to insufficient rat hepa-
tic metabolic stability; however, this finding may open a new in-
sight into drug design. Compound 2g with the pyrrolidine moiety
In vitro GTP
antagonist of hMCHR1 (Tables 6) and rMCHR1 (rat GTP
IC50 = 11 nM). Compound 2s showed a significant suppressing ef-
cS assay has shown that compounds 2s act as an
cS
Table 5
In vitro binding affinity and antagonist activity (GTPcS) of dihydronaphthalene derivatives 2b–o
R1
O
N
R2
N
H
Cl
Compd
NR1R2
hMCHR1
rMCHR1
a
a
a
Binding IC50 (nM)
GTPc
S IC50 (nM)
Binding IC50 (nM)
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
NMe(OMe)
NEt2
NMe(CH2)2Ph
NMePh
4-Morpholinyl
1-Pyrrolidinyl
1-Piperidinyl
4-Me-1-piperazinyl
NHMe
NMeBoc
NMeCOMe
NMeCOEt
NMeCO2Et
NMeCONHEt
380
9.9
7.4
11
8.4
1.4
1.9
2.8
5.5
140
6.8
4.6
50
—
—
—
14
12
20
12
2.2
2.5
5.3
8.5
250
13
6.2
64
70
33
47
29
4.8
5.9
—
—
—
—
—
—
—
33
a
IC50 values are calculated with one experiment performed in duplicate.

M. Kamata et al. / Bioorg. Med. Chem. 19 (2011) 5539–5552
5545
Table 6
5. Conclusion
In vitro binding affinity and antagonist activity (GTP
c
S) of dihydronaphthalene
derivatives 2p–s
Lead optimization of the tetrahydronaphthalene derivative 1a
led to the discovery of a number of tetrahydro- and dihydronaph-
thalenes as potent hMCHR1 antagonists. The present investigation
revealed that the stereochemistry at C-6 position of the tetrahy-
dronaphthalene ring does not affect hMCHR1 binding affinity. Fur-
ther, the achiral dihydronaphthalene core was found to be an
excellent scaffold compared with the tetrahydronaphthalene nu-
cleus in terms of the binding affinity and difficulty in asymmetric
synthesis. A SAR study of the amino group at the C-6 position
showed that basicity was important for the potency within this
class of antagonists, and cyclic amino groups were found to be
more effective for the receptor. Among compounds with potent
in vitro affinity, 2s significantly suppressed nocturnal food intake
of SD rats at 1–10 mg/kg after oral administration. Pharmacoki-
netic study confirmed that 2s was orally bioavailable and could
penetrate the brain of SD rats. In addition to our previous finding,17
these results indicate that hMCHR1 antagonists could be useful for
treatment of feeding disorder and obesity in humans. Further eval-
uation of this series is ongoing, which includes evaluation of their
safety profiles. During the course of this study, we unexpectedly
found that compounds 2l and 2m, having acylamino group instead
of amino group, showed potent binding affinity. Docking study
suggested a possibility that their carbonyl group may interact with
side chain of Asn294 by hydrogen bonding. This finding may open
a new insight into the drug design of hMCHR1 antagonists.
O
N
N
H
X
Compd
X
hMCHR1
rMCHR1
Binding IC50a (nM) GTP
c
S IC50a (nM) Binding IC50a (nM)
2p
2q
2r
2s
H
Me
6.4
1.6
17
—
—
12
2.4
3.7
4.1
OMe 2.2
1.9
F
7.9
a
IC50 values are calculated with one experiment performed in duplicate.
Table 7
Effects of selected compounds on food intake
in KKAy mice
Compd
Mean food intake
inhibitiona (%)
30 mg/kg
1h
2g
2p
2s
63**
46**
52**
62**
6. Experimental section
**
P <0.01 Dunnett’s test.
Food intake during 2 h was measured.
a
Melting points (mp) were determined on a Yanagimoto micro
melting point apparatus or Buchi melting point apparatus and
are uncorrected. Proton nuclear magnetic resonance (1H NMR)
spectra were recorded on a Varian Gemini-200 (200 MHz) and JEOL
JNM-LA300 (300 MHz) NMR spectrometer. Chemical shifts were
reported in d value (ppm) with tetramethylsilane as an internal
standard. Splitting patterns are designated as follows: s, singlet;
d, doublet; t, triplet; dd, double doublet; br s, broad singlet; m,
multiplet. Coupling constants (J) are reported in hertz (Hz).
Elemental analyses (C, H, N) were carried out by Takeda Analytical
Research Laboratories, Ltd, and the results were within 0.4% of the-
oretical values. Thin-layer chromatography (TLC) analyses were
performed with silica gel 60 F254 plate (Merck Art. 5715), alumina
60 F254 plate (Type E) and NH TLC plates (Fuji Silysia Chemical Ltd).
Chromatographic separations were performed with Merck Alumin-
ium oxide 90 (basic, activity III) and NH silica gel (Fuji Silysia
Chemical Ltd). Yields are unoptimized. The purities of all com-
pounds tested in biological systems were assessed as being >95%
using elemental analysis.
Figure 5. Effect of 2s on nocturnal food intake in SD rats. The graph shows food
6.1. N-(5-Oxo-5,6,7,8-tetrahydro-2-naphthalenyl)acetamide (3)
#
intake measured for 12 h.
P <0.025 by Williams test. Each value represents
means SEM. n = 5.
To fuming nitric acid (1000 mL) was added portionwise 4-oxo-
4-phenylbutanoic acid (200 g, 1.12 mol) at ice-bath cooling and the
reaction mixture was stirred for 2 h. The solution was poured into
ice. The resulting precipitates were collected and washed with
water, ethanol and isopropyl ether. The solid was recrystallized
from hot EtOAc to afford 4-(3-nitrophenyl)-4-oxobutanoic acid
(157 g, 63%) as a white solid.
A mixture of 4-(3-nitrophenyl)-4-oxobutanoic acid (20.0 g,
87.3 mmol) and 10% Pd/C (4.0 g) in acetic acid (500 mL) was main-
tained under 0.4 Mpa of hydrogen for 3 h at room temperature.
Concentrated HCl (9.0 mL) was added to the solution and the
mixture was maintained under 0.4 Mpa of hydrogen for 4 h contin-
uously. The catalyst was filtered off and the filtrate was concen-
fect on spontaneous food intake in Sprague–Dawley (SD) rats at
night (Fig. 5). The minimum effective dose was 1 mg/kg or less at
oral administration. Pharmacokinetic study confirmed that 2s
had good oral bioavailability and excellent brain permeability in
SD rats [10 mg/kg, po: BA = 34.1%; Cmax = 0.15
AUC = 2.89 g h/mL (plasma); Cmax = 17.3 g/g, Tmax = 8 h, AUC =
218 g h/g (forebrain)], indicating that durable and high brain con-
lg/mL, Tmax = 8 h,
l
l
l
centration of 2s could achieve clear in vivo anorectic effect. Since
rMCHR1 antagonists suppressed food intake in rats by blocking
physiological function of MCH, hMCHR1 antagonists could be use-
ful for treatment of feeding disorders and obesity in humans.

5546
M. Kamata et al. / Bioorg. Med. Chem. 19 (2011) 5539–5552
trated in vacuo. The residue was washed with EtOAc to afford 4-(3-
aminophenyl)butanoic acid hydrochloride (18.4 g, 98%) as a white
solid.
2.90 mmol) and the reaction mixture was stirred for 30 min. The
mixture was concentrated in vacuo with water-bath cooling and
the residue was suspended with isopropanol (40 mL). To this sus-
pension was added NaBH4 (147 mg, 3.88 mmol) at ice-bath cooling
and the reaction mixture was stirred for 1 h. The mixture was con-
centrated in vacuo and the residue was quenched with water. Aque-
ous 1 M HCl was added to the residue and the solution was washed
with EtOAc. Potassium carbonate was added to the aqueous solution
and the basic solution was extracted with EtOAc. The extracts were
washed with brine and dried (Na2SO4). The solvent was evaporated
in vacuo to give 5a (350 mg, 69%) as an oil. A solution of 5a (5.40 g,
20.6 mmol) in concentrated HCl (150 mL) was heated at 100 °C for
6 h and the mixture was cooled to room temperature. The solution
was poured into 4 M NaOH and the solution was extracted with
EtOAc. The extracts were washed with brine and dried (Na2SO4).
The solvent was evaporated in vacuo and the residue was chromato-
graphed on Alumina (basic) eluting with EtOAc to give 6a (3.80 g,
93%) as a solid. 1H NMR (CDCl3) d: 2.22 (6H, s), 2.28 (2H, t,
J = 8.1 Hz), 2.74 (2H, t, J = 8.1 Hz), 2.94 (2H, s), 3.60 (2H, br s), 6.24
(1H, s), 6.45–6.47 (2H, m), 6.82 (1H, d, J = 8.4 Hz).
Acetic anhydride (12.3 mL, 131 mmol) was added dropwise to a
solution of 4-(3-aminophenyl)butanoic acid hydrochloride (23.5 g,
109 mmol) in pyridine (250 mL) and the reaction mixture was
stirred for 1 h at room temperature. The solution was concentrated
in vacuo and the residue was dissolved with EtOAc. The solution
was washed with 4 M HCl and brine. The extracts were dried
(Na2SO4) and the solvent was evaporated in vacuo. The residue
was recrystallized from EtOAc and hexane to give 4-[3-(acetyl-
amino)phenyl]butanoic acid (22.6 g, 94%) as a white solid.
To a suspension of 4-[3-(acetylamino)phenyl]butanoic acid
(1.00 g, 4.52 mmol) in nitromethane (20 mL) was added thionyl
chloride (361 lL, 4.97 mmol) at ice-bath cooling and the reaction
mixture was stirred for 1 h. Aluminum chloride (1.51 g, 11.3 mmol)
was added portionwise to this solution at room temperature. The
reaction mixture was stirred for 30 min, poured into ice, and ex-
tracted with EtOAc. The extracts were washed with brine, 4 M
NaOH and brine again. The extracts were dried (Na2SO4) and the
solvent was evaporated in vacuo. The residue was recrystallized
from EtOAc and hexane to give 3 (800 mg, 87%) as a white solid.
1H NMR (CDCl3) d: 2.07–2.16 (2H, m), 2.21 (3H, s), 2.62 (2H, t,
J = 6.0 Hz), 2.94 (2H, t, J = 6.0 Hz), 7.19–7.22 (1H, m), 7.57 (1H, br
s), 7.69 (1H, s), 7.97 (1H, d, J = 8.4 Hz).
The following compounds (6b and 6c) were prepared in the
same manner as described for 6a.
6.6. 6-[(Methylamino)methyl]-7,8-dihydro-2-naphthalenamine
(6b)
6.2. 6-Amino-2-[(dimethylamino)methylidene]-3,4-dihydro-
1(2H)-naphthalenone (4a)
Yield 90%. 1H NMR (CDCl3) d: 2.24 (2H, t, J = 7.8 Hz), 2.43 (3H, s),
2.74 (2H, t, J = 7.8 Hz), 3.28 (2H, s), 3.59 (2H, br s), 6.26 (1H, s),
6.44–6.47 (2H, m), 6.82 (1H, d, J = 8.7 Hz).
A mixture of dimethylformamide dimethylacetal (100 mL) and
3 (16.5 g, 81.3 mmol) was heated at 100 °C for 18 h under N2.
The mixture was cooled to room temperature and diluted with
EtOAc. The resulting precipitates were collected and washed with
EtOAc to afford 4a (17.9 g, 84%) as a yellow solid, mp 207–210 °C
(EtOAc). 1H NMR (CDCl3) d: 2.19 (3H, s), 2.79–2.83 (2H, m), 2.88–
2.92 (2H, m), 3.11 (6H, s), 7.14–7.17 (1H, m), 7.68 (1H, s), 7.69
(1H, s), 7.95 (1H, d, J = 8.1 Hz), 7.96 (1H, s).
6.7. 6-(1-Pyrrolidinylmethyl)-7,8-dihydro-2-naphthalenamine
(6c)
Yield 79%. 1H NMR (CDCl3) d: 1.76–1.80 (4H, m), 2.30 (2H, t,
J = 7.8 Hz), 2.47–2.49 (4H, m), 2.74 (2H, t, J = 7.8 Hz), 3.13 (2H, s),
3.59 (2H, br s), 6.26 (1H, s), 6.45–6.47 (2H, m), 6.82 (1H, d,
J = 8.7 Hz).
6.3. 6-Amino-2-[(methylamino)methylidene]-3,4-dihydro-
1(2H)-naphthalenone (4b)
6.8. 6-[(Dimethylamino)methyl]-5,6,7,8-tetrahydro-
2-naphthalenamine (7a)
A mixture of 40% methylamine in MeOH (178 mL) and 4a
(9.00 g, 34.8 mmol) was heated at 60 °C for 2 h under N2. The mix-
ture was cooled to room temperature, and the resulting precipi-
tates were collected and washed with EtOAc to afford 4b (7.00 g,
82%) as a yellow solid. 1H NMR (DMSO-d6) d: 2.05 (3H, s), 2.42–
2.47 (2H, m), 2.70–2.74 (2H, m), 2.97 (3H, m), 7.01 (1H, d,
J = 12.6 Hz), 7.39–7.44 (1H, m), 7.50–7.53 (1H, m), 7.69–7.74 (1H,
m), 7.91–9.77 (1H, m), 10.06 (1H, s).
A mixture of 6a (3.80 g, 18.8 mmol), concentrated HCl (1.60 mL)
and dry 10% Pd/C (380 mg) in MeOH (200 mL) was maintained un-
der an atmosphere of hydrogen (balloon) for 4 h. The mixture was
filtered through Celite and the filtrate was concentrated in vacuo.
Water was added to the residue and the solution was washed with
EtOAc. Potassium carbonate was added to the aqueous solution
and the basic solution was extracted with EtOAc. The extracts were
washed with brine and dried (Na2SO4). The solvent was evaporated
in vacuo to give 7a (2.06 g, 54%) as an oil. 1H NMR (CDCl3) d: 1.36
(1H, m), 1.93 (2H, m), 2.20–2.35 (3H, m), 2.22 (6H, s), 2.75 (3H, m),
3.49 (2H, m), 6.47 (2H, m), 6.88 (1H, d, J = 7.8 Hz).
6.4. 6-Amino-2-[1-pyrrolidinylmethylidene]-3,4-dihydro-1(2H)-
naphthalenone (4c)
A mixture of pyrrolidine(135 mL) and 4a (20.0 g, 77.4 mmol) was
heated at 110 °C for 2 h under N2. The mixture was cooled to room
temperatureand diluted with i-Pr2O. The resulting precipitateswere
collected and washed with i-Pr2O to afford 4c (19.3 g, 88%) as a
yellow solid. 1H NMR (CDCl3) d: 1.90 (4H, m), 2.18 (3H, s), 2.82
(2H, m), 2.91 (2H, m), 3.58 (4H, m), 7.15 (1H, d, J = 8.4 Hz), 7.66
(1H, s), 7.77 (1H, br s), 7.89 (1H, s), 7.98 (1H, d, J = 8.4 Hz).
6.9. Method A
6.9.1. N-[6-[(Dimethylamino)methyl]-5,6,7,8-tetrahydro-
2-naphthalenyl][1,10-biphenyl]-4-carboxamide hydrochloride
(1a)
To a solution of 7a (1.59 g, 7.77 mmol) and triethylamine
(1.08 mL, 7.77 mmol) in THF (25 mL) was added portionwise
[1,10-biphenyl]-4-carbonyl chloride (1.68 g, 7.77 mmol) at ice-bath
cooling, and the mixture was stirred at room temperature for 16 h.
The suspension was diluted with EtOAc and the solution was
washed with aqueous K2CO3 and brine. The extracts were dried
(Na2SO4) and the solvent was evaporated in vacuo. The residue
was chromatographed on Alumina (basic) eluting with hexane–
6.5. 6-[(Dimethylamino)methyl]-7,8-dihydro-2-
naphthalenamine (6a)
To an ice-cooled solution of 4a (500 mg, 1.94 mmol) in THF
(10 mL) and acetic acid (40 mL) was added NaBH(OAc)3 (615 mg,

M. Kamata et al. / Bioorg. Med. Chem. 19 (2011) 5539–5552
5547
EtOAc (1:1) to give a free base of 1a (2.10 g, 70%) as a white solid,
mp 164–166 °C (EtOAc–Hexane). 1H NMR (CDCl3, free base) d: 1.40
(1H, m), 1.94 (2H, m), 2.25–2.44 (3H, m), 2.83–2.93 (3H, m), 7.08
(1H, d, J = 8.4 Hz), 7.31 (1H, m), 7.39 (4H, m), 7.60–7.69 (4H, m),
7.84 (1H, br s), 7.93 (2H, d, J = 8.4 Hz).
Treatment of the free base with 1 equiv. of 4 M HCl–EtOAc gave
1a (97%) as a solid, mp >250 °C (MeOH–Et2O). Anal. Calcd for
the solution was washed with aqueous NaHCO3 and brine. The ex-
tracts were dried (Na2SO4) and the solvent was evaporated in vacuo.
Theresiduewas recrystallized fromTHF and EtOActo give 1g (1.30 g,
77%) as a white solid, mp 187–189 °C (THF–i-Pr2O). 1H NMR (CDCl3)
d: 1.33–1.50 (1H, m), 1.90–2.10 (2H, m), 2.16–2.47 (9H, m), 2.81–
2.99 (3H, m), 7.09 (1H, d, J = 8.0 Hz), 7.31 (1H, d, J = 7.6 Hz), 7.44
(3H, m), 7.56 (2H, d, J = 8.6 Hz), 7.66 (2H, d, J = 8.0 Hz), 7.78 (1H, s),
7.94 (2H, d, J = 8.0 Hz). Anal. Calcd for C26H27ClN2O: C, 74.54; H,
6.50; N, 6.69. Found: C, 74.46; H, 6.34; N, 6.75.
C
26H28N2OꢁHCl: C, 74.18; H, 6.94; N, 6.65. Found: C, 73.90; H,
6.86; N, 6.63.
The following compounds (1c, 1k and 1p and 8a, b) were pre-
pared in the same manner as described for 1a.
Enantiomeric pure compounds, (ꢀ)-1g and (+)-1g were ob-
tained by chromatographic separation by CHIRALCEL OD (50 mm
ID x 500 mm L) eluting with hexane/ethanol = 85:15.
6.9.2. N-[6-[(Dimethylamino)methyl]-5,6,7,8-tetrahydro-2-
naphthalenyl][1,10-biphenyl]-2-carboxamide hydrochloride
(1c)
(ꢀ)-1g: [
containing 13% of 2a).
(+)-1g: [ D = +48.4° (DMSO, c 0.499); >99.9% ee (94% purity
containing 6% of 2a).
The following compounds (1b, 1h–j and 1m) were prepared in
the same manner as described for 1g.
a
]
D = ꢀ47.3° (DMSO, c 0.493); >99.9% ee (87% purity
a
]
Yield 58%, mp 196–197 °C (MeOH–EtOAc). 1H NMR (DMSO-d6)
d: 1.39 (1H, m), 1.99 (1H, m), 2.17 (1H, m), 2.42 (1H, m), 2.78
(6H, s), 2.88 (1H, m), 3.06 (2H, t, J = 5.7 Hz), 3.38 (2H, s), 6.94–
7.62 (11H, m), 7.64 (1H, d, J = 1.7 Hz), 10.11 (1H, br s), 10.18 (1H,
s). Anal. Calcd for C26H28N2OꢁHClꢁ1.1H2O: C, 70.85; H, 7.13; N,
6.36. Found: C, 70.49; H, 6.77; N, 6.57.
6.10.2. N-[6-[(Dimethylamino)methyl]-5,6,7,8-tetrahydro-2-
naphthalenyl]benzamide (1b)
Yield 62%, mp 149–151 °C (EtOAc–i-Pr2O). 1H NMR (CDCl3) d:
1.28–1.60 (1H, m), 1.82–2.10 (2H, m), 2.12–2.50 (9H, m), 2.77–
3.00 (3H, m), 7.08 (1H, d, J = 8.1 Hz), 7.20–7.33 (1H, m), 7.40–
7.60 (4H, m), 7.70 (1H, s), 7.80–7.92 (2H, m). Anal. Calcd for
6.9.3. N-[6-[(Dimethylamino)methyl]-5,6,7,8-tetrahydro-2-
naphthalenyl]-40-propyl[1,10-biphenyl]-4-carboxamide (1k)
Yield 74%, mp 186–188 °C (EtOAc–i-Pr2O). 1H NMR (CDCl3) d:
0.98 (3H, t, J = 7.5 Hz), 1.40 (1H, m), 1.69 (2H, m), 1.94 (2H, m),
2.25 (6H, s), 2.25–2.45 (3H, m), 2.64 (2H, t, J = 7.5 Hz), 2.85 (3H,
m), 7.08 (1H, d, J = 7.8 Hz), 7.26 (3H, m), 7.46 (1H, s), 7.54 (2H, d,
J = 8.1 Hz), 7.67 (2H, d, J = 8.1 Hz), 7.81 (1H, s), 7.91 (2H, d,
J = 8.4 Hz). Anal. Calcd for C29H34N2O: C, 81.65; H, 8.03; N, 6.57.
Found: C, 81.30; H, 7.94; N, 6.40.
C
20H24N2Oꢁ0.7H2O: C, 74.83; H, 7.98; N, 8.73. Found: C, 74.83; H,
7.83; N, 8.76.
6.10.3. N-[6-[(Dimethylamino)methyl]-5,6,7,8-tetrahydro-2-
naphthalenyl]-40-fluoro[1,10-biphenyl]-4-carboxamide (1h)
Yield 70%, mp 179–180 °C (THF–i-Pr2O). 1H NMR (CDCl3) d:
1.36–1.52 (1H, m), 1.90–2.08 (2H, m), 2.19–2.48 (9H, m), 2.80–
3.05 (3H, m), 7.10 (1H, d, J = 9.4 Hz), 7.19 (2H, d, J = 8.6 Hz), 7.31
(1H, d, J = 8.2 Hz), 7.46 (1H, s), 7.59 (2H, dd, J = 5.2, 8.6 Hz), 7.65
(2H, d, J = 8.6 Hz), 7.67 (1H, s), 7.93 (2H, d, J = 8.6 Hz). Anal. Calcd
for C26H27FN2O: C, 77.58; H, 6.76; N, 6.96. Found: C, 77.42; H,
6.30; N, 7.02.
6.9.4. 40-Cyano-N-[6-[(dimethylamino)methyl]-5,6,7,8-
tetrahydro-2-naphthalenyl][1,10-biphenyl]-4-carboxamide (1p)
Yield 19%, mp 183–185 °C (EtOAc–i-Pr2O). 1H NMR (CDCl3) d:
1.42 (1H, m), 1.95 (2H, m), 2.26 (6H, s), 2.24–2.46 (3H, m), 2.84–
2.95 (3H, m), 7.10 (1H, d, J = 8.4 Hz), 7.30 (2H, m), 7.46 (1H, s),
7.74 (7H, m), 7.98 (2H, d, J = 8.4 Hz). Anal. Calcd for
C
27H27N3Oꢁ0.5H2O: C, 77.48; H, 6.74; N, 10.04. Found: C, 77.82;
6.10.4. N-[6-[(Dimethylamino)methyl]-5,6,7,8-tetrahydro-2-
naphthalenyl]-40-methyl[1,10-biphenyl]-4-carboxamide (1i)
Yield 36%, mp 181–182 °C (EtOAc–Hexane). 1H NMR (CDCl3) d:
1.30–1.51 (1H, m), 1.85–2.06 (2H, m), 2.23–2.47 (12H, m), 2.86–
3.00 (3H, m), 7.08 (1H, d, J = 8.4 Hz), 7.26–7.32 (3H, m), 7.46 (1H,
s), 7.53 (2H, d, J = 8.4 Hz), 7.68 (2H, d, J = 8.4 Hz), 7.78 (1H, s),
7.92 (2H, d, J = 8.4 Hz). Anal. Calcd for C27H30N2O: C, 81.37; H,
7.59; N, 7.03. Found: C, 81.26; H, 7.34; N, 7.13.
H, 6.69; N, 10.03.
6.9.5. 3-Bromo-N-[6-[(dimethylamino)methyl]-5,6,7,8-
tetrahydro-2-naphthalenyl]benzamide (8a)
Yield 43%. 1H NMR (DMSO-d6) d: 1.31 (1H, m), 1.89 (2H, m),
2.17 (6H, s), 2.17–2.35 (3H, m), 2.77 (3H, m), 7.04 (1H, d,
J = 8.4 Hz), 7.49 (3H, m), 7.79 (1H, d, J = 8.1 Hz), 7.94 (1H, d,
J = 7.8 Hz), 8.13 (1H, s), 10.20 (1H, s).
6.10.5. N-[6-[(Dimethylamino)methyl]-5,6,7,8-tetrahydro-2-
naphthalenyl]-40-ethyl[1,10-biphenyl]-4-carboxamide (1j)
Yield 76%, mp 137–138 °C (EtOAc–Hexane). 1H NMR (CDCl3) d:
1.29 (3H, t, J = 7.5 Hz), 1.41–1.51 (1H, m), 1.90–2.06 (2H, m), 2.23–
2.47 (6H, m), 2.26 (6H, s), 2.71 (2H, q, J = 7.5 Hz), 2.73–3.01 (3H, m),
7.09 (1H, d, J = 8.4 Hz), 7.31 (3H, m), 7.46 (1H, s), 7.56 (2H, d,
J = 8.4 Hz), 7.69 (2H, d, J = 8.4 Hz), 7.77 (1H, s), 7.92 (2H, d,
J = 8.4 Hz). Anal. Calcd for C28H32N2Oꢁ0.1H2O: C, 81.16; H, 7.83;
N, 6.76. Found: C, 80.98; H, 7.88; N, 6.80.
6.9.6. 4-Bromo-N-[6-[(dimethylamino)methyl]-5,6,7,8-
tetrahydro-2-naphthalenyl]benzamide (8b)
Yield 89%, mp 141–143 °C (EtOAc–i-Pr2O). 1H NMR (CDCl3) d:
1.40 (1H, m), 1.96 (2H, m), 2.26 (6H, s), 2.26–2.48 (3H, m), 2.82–
2.96 (3H, m), 7.08 (1H, d, J = 8.1 Hz), 7.28 (1H, m), 7.41 (1H, s),
7.61 (2H, d, J = 8.4 Hz), 7.73 (3H, m).
6.10. Method B
6.10.1. 40-Chloro-N-[6-[(dimethylamino)methyl]-5,6,7,8-
tetrahydro-2-naphthalenyl][1,10-biphenyl]-4-carboxamide (1g)
To a solution of 7a (831 mg, 4.07 mmol), 40-chloro[1,10-biphe-
nyl]-4-carboxylic acid (950 mg, 4.07 mmol), 1-hydroxybenzotria-
zole (690 mg, 4.47 mmol), 4-dimethylaminopyridine (500 mg,
4.13 mmol) and triethylamine (1.15 mL, 8.26 mmol) in dimethyl-
formamide (40 mL) was added EDCꢁHCl (1.17 g, 6.10 mmol) at ice-
bath cooling, and the mixture was stirred at room temperature for
20 h. The suspension was diluted with EtOAc and THF (1:1) and
6.10.6. N-[6-[(Dimethylamino)methyl]-5,6,7,8-tetrahydro-2-
naphthalenyl]-40-methoxy[1,10-biphenyl]-4-carboxamide (1m)
Yield 44%, mp 170–175 °C (EtOAc–Hexane). 1H NMR (CDCl3) d:
1.40 (1H, m), 1.90 (2H, m), 2.23–2.48 (9H, m), 2.90 (3H, m), 3.87
(3H, s), 7.00 (2H, d, J = 8.8 Hz), 7.09 (1H, d, J = 8.4 Hz), 7.30 (1H,
m), 7.47–7.75 (6H, m), 7.91 (2H, d, J = 8.4 Hz). Anal. Calcd for
C27H30N2O2ꢁ0.1H2O: C, 77.89; H, 7.31; N, 6.63. Found: C, 77.65;
H, 7.40; N, 6.72.

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M. Kamata et al. / Bioorg. Med. Chem. 19 (2011) 5539–5552
6.11. Method C
boxylate (100 mg, 0.219 mmol) in ethanol (3 mL) was added 1 M
NaOH (329 L) at room temperature. The mixture was stirred at
90 °C for 5 h, and then the solution was allowed to cool to room tem-
perature. Aqueous 1 M HCl (329 L, 0.329 mmol) was added to the
solution, and the resulting precipitates were collected and washed
with water to give 1n (88.9 mg, 95%) as a white solid, mp 143 °C
(decomp.) (EtOH–H2O). 1H NMR (DMSO-d6) d: 1.34 (1H, m), 1.91
(2H, m), 2.24 (6H, s), 2.24–2.30 (3H, m), 2.81 (3H, m), 7.05 (1H, d,
J = 8.4 Hz), 7.49 (1H, d, J = 8.4 Hz), 7.55 (1H, s), 7.89 (4H, m), 8.07
(4H, m), 10.18 (1H, s). Anal. Calcd for C27H28N2O3ꢁ2H2O: C, 69.81;
H, 6.94; N, 6.03. Found: C, 69.57; H, 7.01; N, 5.93.
l
6.11.1. N-[6-[(Dimethylamino)methyl]-5,6,7,8-tetrahydro-2-
naphthalenyl][1,10-biphenyl]-3-carboxamide hydrochloride
(1d)
l
Tetrakis(triphenylphosphine)palladium(0) (9.0 mg, 7.7 lmol)
was added to a solution of 8a (100 mg, 0.258 mmol), phenylborinic
acid (37.8 mg, 0.310 mmol) and 2 M Na2CO3 in dimethoxyethane
(3 mL) and THF (0.3 mL), and the mixture was heated for 5 h at
90 °C under N2. The suspension was diluted with EtOAc and the solu-
tion was washed with aqueous K2CO3 and brine. The extracts were
dried (Na2SO4) and the solvent was evaporated in vacuo. The residue
was chromatographed on Alumina (basic) eluting EtOAc to give a
free base of 1d. Treatment of the free base with 1 equiv. of 4 M
HCl–EtOAc gave 1d (100 mg, 92%) as a solid, mp 145–148 °C
(EtOAc–Et2O). 1H NMR (DMSO-d6) d: 1.43 (1H, m), 2.02 (1H, m),
2.21 (1H, m), 2.42 (1H, m), 2.81 (6H, s), 2.88 (3H, m), 3.09 (2H, m),
7.06 (1H, m), 7.42–7.65 (6H, m), 7.78–7.95 (4H, m), 8.22 (1H, s),
10.27 (1H, s). Anal. Calcd for C26H28N2OꢁHClꢁ1.7H2O: C, 69.16; H,
7.23; N, 6.24. Found: C, 68.93; H, 6.91; N, 6.29.
6.11.7. N-[6-[(Dimethylamino)methyl]-5,6,7,8-tetrahydro-2-
naphthalenyl]-40-[(trifluoroacetyl)amino] [1,10-biphenyl]-4-
carboxamide (9o)
Yield 80%, mp 235–237 °C (EtOAc–i-Pr2O). 1H NMR (CDCl3) d:
1.41 (1H, m), 2.05 (2H, m), 2.26 (6H, s), 2.26–2.42 (3H, m), 2.89
(3H, m), 7.09 (1H, d, J = 8.4 Hz), 7.29 (2H, m), 7.46 (1H, s), 7.69
(7H, m), 7.94 (2H, d, J = 8.1 Hz). Anal. Calcd for C28H28F3N3O2: C,
67.87; H, 5.70; N, 8.48. Found: C, 67.70; H, 5.53; N, 8.42.
The following compounds (1e, 1f, 1l, 9n and 9o) were prepared
in the same manner as described for 1d.
6.11.8. 40-Amino-N-[6-[(dimethylamino)methyl]-5,6,7,8-
tetrahydro-2-naphthalenyl]][1,10-biphenyl]-4-carboxamide
(1o)
6.11.2. 20-Chloro-N-[6-[(dimethylamino)methyl]-5,6,7,8-
tetrahydro-2-naphthalenyl][1,10-biphenyl]-4-carboxamide (1e)
Yield 74%, mp 176–177 °C (THF–Hexane). 1H NMR (CDCl3) d:
1.30–1.52 (1H, m), 1.90–2.10 (2H, m), 2.23–2.47 (9H, m), 2.80–
3.00 (3H, m), 7.09 (1H, d, J = 8.4 Hz), 7.28–7.38 (4H, m), 7.43–
7.52 (2H, m), 7.56 (2H, d, J = 8.4 Hz), 7.79 (1H, s), 7.93 (2H, d,
J = 8.4 Hz). Anal. Calcd for C26H27ClN2O: C, 74.54; H, 6.50; N, 6.69.
Found: C, 74.59; H, 6.61; N, 6.65.
To a solution of N-[6-[(dimethylamino)methyl]-5,6,7,8-tetrahy-
dro-2-naphthalenyl]-40-[(trifluoroacetyl)amino][1,10-biphenyl]-4-
carboxamide (850 mg, 1.72 mmol) in MeOH (8 mL) and THF (4 mL)
was added 1 M NaOH (1.72 mL) at 50 °C. The mixture was stirred
for 16 h, and then concentrated in vacuo. The residue was collected
and washed with water to give 1o (698 mg, 100%) as a solid, mp
148–150 °C (MeOH–H2O). 1H NMR (CDCl3) d: 1.31 (1H, m), 1.89
(2H, m), 2.15 (6H, s), 2.15–2.34 (3H, m), 2.83 (3H, m), 5.36 (2H,
s), 6.67 (2H, d, J = 8.4 Hz), 7.03 (1H, d, J = 8.1 Hz), 7.48 (4H, m),
7.68 (2H, d, J = 8.1 Hz), 7.96 (2H, d, J = 8.4 Hz), 10.02 (1H, s). Anal.
Calcd for C26H29N3Oꢁ1.1H2O: C, 74.47; H, 7.50; N, 10.02. Found:
C, 74.39; H, 7.41; N, 9.82.
6.11.3. 30-Chloro-N-[6-[(dimethylamino)methyl]-5,6,7,8-
tetrahydro-2-naphthalenyl][1,10-biphenyl]-4-carboxamide (1f)
Yield 78%, mp 138–139 °C (THF–i-Pr2O). 1H NMR (CDCl3) d:
1.38–1.52 (1H, m), 1.90–2.10 (2H, m), 2.23–2.47 (9H, m), 2.80–
3.00 (3H, m), 7.10 (2H, d, J = 8.0 Hz), 7.29–7.55 (4H, m), 7.61 (1H,
s), 7.68 (2H, d, J = 8.4 Hz), 7.75 (1H, s), 7.95 (2H, d, J = 8.4 Hz). Anal.
Calcd for C26H27ClN2O: C, 74.54; H, 6.50; N, 6.69. Found: C, 74.31;
H, 6.46; N, 6.66.
6.11.9. 6-[N-(4-Biphenylyl)methyl]amino-2-(N,N-
dimethylamino)methyltetralin (1q)
To a solution of 1a (0.172 g, free base) in THF (3 mL) was added
1 M borane in THF (2 mL) and the reaction mixture was heated un-
der reflux for 1 h. Water was added to the solution and then 6 M
hydrochloric acid was added thereto. After the mixture was stirred
at room temperature for 1 h, the reaction mixture was made basic
with an aqueous solution of 1 M NaOH and extracted with EtOAc.
The organic layer was washed with water, brine, dried and concen-
trated in vacuo. The residue was purified by alumina column
chromatography (EtOAc–Hexane, 1:4) and recrystallized from
EtOAc–Hexane to afford 1q (0.060 g). Mp 106–108 °C (EtOAc–
Hexane). 1H NMR (CDCl3) d: 1.35–1.41 (1H, m), 1.90–2.04 (2H, m),
2.19–2.37 (9H, m), 2.72–2.85 (3H, m), 4.34 (2H, s), 6.41–6.48 (2H,
m), 6.91 (1H, d, J = 8.4 Hz), 7.30–7.36 (1H, m), 7.40–7.45 (4H, m),
7.54–7.59 (4H, m). Anal. Calcd for C26H30N2ꢁ0.3H2O: C, 83.07; H,
8.20; N, 7.45. Found: C, 83.01; H, 8.18; N, 7.41.
6.11.4. N-[6-[(Dimethylamino)methyl]-5,6,7,8-tetrahydro-2-
naphthalenyl]-40-phenyl[1,10-biphenyl]-4-carboxamide
hydrochloride (1l)
Yield 7%, mp 220 °C (decomp.) (MeOH–Et2O). 1H NMR (DMSO-d6,
free base) d: 1.32 (1H, m), 1.93 (2H, m), 2.15 (6H, s), 2.15–2.36 (3H,
m), 2.74–2.94 (3H, m), 7.05 (1H, d, J = 8.4 Hz), 7.40–7.55 (5H, m),
7.73–7.91 (8H, m), 8.07 (2H, d, J = 8.4 Hz), 10.14 (1H, s). Anal. Calcd
for C32H32N2OꢁHClꢁ2H2O: C, 72.10; H, 7.00; N, 5.25. Found: C,
71.81; H, 6.57; N, 5.08.
6.11.5. Ethyl 40-[[[6-[(dimethylamino)methyl]-5,6,7,8-
tetrahydro-2-naphthalenyl]amino]-carbonyl] [1,10-biphenyl]-4-
carboxylate (9n)
Yield 68%, mp 156–158 °C (EtOAc–i-Pr2O). 1H NMR (CDCl3) d:
1.42 (4H, m), 1.95 (2H, m), 2.26 (6H, s), 2.26–2.42 (3H, m), 2.89
(3H, m), 4.41 (2H, q, J = 7.2 Hz), 7.09 (1H, d, J = 8.4 Hz), 7.31 (1H,
d, J = 8.4 Hz), 7.47 (1H, s), 7.70 (4H, m), 7.80 (1H, s), 7.96 (2H, d,
J = 8.4 Hz), 8.14 (2H, d, J = 8.4 Hz). Anal. Calcd for C29H32N2O3: C,
76.29; H, 7.06; N, 6.14. Found: C, 76.25; H, 7.07; N, 6.09.
6.11.10. N-{6-[(Dimethylamino)methyl]-5,6,7,8-
tetrahydronaphthalen-2-yl}biphenyl-4-sulfonamide
hydrochloride (1r)
4-Biphenylsulfonyl chloride (200 mg, 0.79 mmol) was added to
a
mixture of 7a (200 mg, 0.72 mmol) and TEA (0.401 mL,
2.88 mmol) in CH3CN (30 mL) at ice cooling bath and the mixture
was stirred for 3 h at same temperature. Water was added to the
reaction mixture and the solution was extracted with EtOAc. The
organic layer was washed with water, brine, dried, and then con-
centrated in vacuo. The residue was purified using alumina column
chromatography (hexane–EtOAc, 2:3). To the residue was added
6.11.6. 40-[[6-[(Dimethylamino)methyl]-5,6,7,8-tetrahydro-2-
naphthalenyl]amino]carbonyl][1,10-biphenyl]-4-carboxylic acid
(1n)
To a solution of ethyl 40-[[6-[(dimethylamino)methyl]-5,6,7,8-
tetrahydro-2-naphthalenyl]amino]carbonyl][1,10-biphenyl]-4-car-

M. Kamata et al. / Bioorg. Med. Chem. 19 (2011) 5539–5552
5549
4 M HCl–EtOAc and the salt was solidified by MeOH–i-Pr2O to give
1r (194 mg, 59%) as an amorphous solid. 1H NMR (DMSO-d6) d:
1.32–1.36 (1H, m), 1.91–1.96 (1H, m), 2.11 (1H, m), 2.30–2.39
(1H, m), 2.68–2.79 (4H, m), 2.74 (3H, s), 2.76 (3H, s), 2.90–3.10
(2H, m), 6.86–6.94 (3H, m), 7.40–7.52 (3H, m), 7.70 (1H, d,
J = 6.7 Hz), 7.85 (5H, s), 9.92 (1H, br s), 10.23 (1H, s). Anal. Calcd
for C25H28N2O2SꢁHClꢁ1.8H2O: C, 61.35; H, 6.51; N, 5.73. Found: C,
61.19; H, 6.82; N, 6.13.
(1.35 g, 10.0 mmol) and DMAP (1.22 g, 10.0 mmol) in DMF
(25 mL) was stirred at room temperature for 15 h. The mixture
was poured into H2O, and extracted with EtOAc. The extract was
washed with 2 M NaOH and dried (Na2SO4). After removal of the
solvent in vacuo, the residue was chromatographed on silica gel
(hexane–THF, 1:10) to give crude crystals, which were recrystal-
lized from EtOAc–Hexane to give 2a (1.12 g, 54%) as white crystals,
mp 204–207 °C. 1H NMR (CDCl3) d: 2.25 (6H, s), 2.34 (2H, t,
J = 7.8 Hz), 2.86 (2H, t, J = 7.8 Hz), 2.99 (2H, s), 6.34 (1H, s), 7.03
(1H, d, J = 8.7 Hz), 7.39 (1H, d, J = 8.1 Hz), 7.45 (2H, d, J = 8.7),
7.48 (1H, s), 7.56 (2H, d, J = 8.4 Hz), 7.67 (2H, d, J = 8.4 Hz), 7.78
(1H, s), 7.94 (2H, d, J = 8.4 Hz). Anal. Calcd for C26H25ClN2O: C,
74.90; H, 6.04; N, 6.72. Found: C, 74.64; H, 6.14; N, 6.56.
6.11.11. 2-(N,N-Dimethylamino)methyl-6-methoxytetralin
hydrochloride (11)
Aqueous solution of 1 M NaOH was added to 2-(N,N-dimethyl-
amino)methyl-6-methoxy-1-tetralone hydrochloride18 (3.08 g,
11.4 mmol) to convert a free form, which was extracted with
EtOAc. The extract was dried, and then concentrated. Sodium boro-
hydride (0.97 g, 25.6 mmol) was added to a MeOH solution (30 mL)
of the resulting residue under ice cooling bath, and the mixture
was then stirred at room temperature for 2 h. Water was added
to the reaction mixture. The solution was concentrated in vacuo
to remove MeOH, and then extracted with EtOAc. The organic layer
was washed with brine, dried and concentrated in vacuo. Concen-
trated hydrochloric acid (2.4 g) and 10% palladium–carbon (0.3 g)
were added to an ethanol solution (30 mL) of the resulting residue
and the mixture was stirred under atmospheric hydrogen pressure
at room temperature for 8 h. The catalyst was removed by filtra-
tion, and the filtrate was concentrated in vacuo. The residue was
recrystallized from MeOH–EtOAc to afford 11 (2.02 g, 69%): 1H
NMR (CDCl3) d: 1.22–1.49 (1H, m), 1.80–2.04 (2H, m), 2.12–2.44
(3H, m), 2.24 (6H, s), 2.79–2.98 (3H, m), 3.77 (3H, s), 6.60–6.72
(2H, m), 7.01 (1H, d, J = 8 Hz).
6.11.15. 40-Chloro-N-[6-(chloromethyl)-7,8-dihydro-2-
naphthalenyl][1,10-biphenyl]-4-carboxamide (13)
To a solution of 2a (0.75 g, 1.80 mmol) in THF (30 mL) was
added ethyl chloroformate (0.23 mL) at ꢀ78 °C. The mixture was
stirred for 30 min at room temperature, and concentrated in vacuo.
The residue was recrystallized from THF–hexane to give 13 (0.60 g,
82%) as yellow crystals, mp 179–181 °C. 1H NMR (DMSO-d6) d: 2.34
(2H, t, J = 8.1 Hz), 2.82 (2H, t, J = 8.1 Hz), 4.40 (2H, s), 6.61 (1H, s),
7.09 (1H, d, J = 8.1 Hz), 7.54–7.64 (4H, m), 7.79 (2H, d, J = 8.4 Hz),
7.84 (2H, d, J = 8.4 Hz), 8.04 (2H, d, J = 8.4 Hz), 10.28 (1H, s).
6.11.16. 40-Chloro-N-[6-[[N-methoxy(N-methyl)amino]methyl]-
7,8-dihydro-2-naphthalenyl][1,10-biphenyl]-4-carboxamide
(2b)
A mixture of 13 (65.0 mg, 0.150 mmol), N,O-dimethylhydroxyl-
amine hydrochloride (60.0 mg, 0.600 mmol) and N,N-diisopropyl-
ethylamine (0.26 mL, 1.5 mmol) in DMF (5 mL) was heated at
120 °C for 2 days. The reaction mixture was concentrated in vacuo,
the residue was poured into aqueous NaHCO3 and extracted with
EtOAc. The extract was washed with brine and dried (Na2SO4).
After removal of the solvent in vacuo, the residue was chromato-
graphed on silica gel (hexane–THF, 1:10) to give crude crystals,
which were recrystallized from EtOAc–Hexane to give 2b (41 mg,
63%) as yellow crystals, mp 190–192 °C. 1H NMR (CDCl3) d: 2.41
(2H, t, J = 8.1 Hz), 2.61 (3H, s), 2.86 (2H, t, J = 8.1 Hz), 3.37 (2H, s),
3.52 (3H, s), 6.39 (1H, s), 7.03 (1H, d J = 8.1 Hz), 7.36 (1H, d,
J = 8.1 Hz), 7.44 (2H, d, J = 8.4 Hz), 7.53 (1H, s), 7.55 (2H, d,
J = 8.4 Hz), 7.66 (2H, d, J = 8.4 Hz), 7.83 (1H, s), 7.93 (2H, d,
J = 8.4 Hz). Anal. Calcd for C26H25ClN2O2ꢁ0.3H2O: C, 71.24; H,
5.89; N, 6.39. Found: C, 71.02; H, 5.66; N, 6.39.
6.11.12. 2-(N,N-Dimethylamino)methyl-6-hydroxytetralin
hydrochloride (12)
The mixture of 11 (0.365 g) and 48% hydrobromic acid (10 mL)
was heated under reflux for 3 h. After cooling to room temperature,
the mixture was neutralized with an aqueous solution of 1 M
NaOH and made basic with a solution of 10% potassium carbonate.
The solution was extracted with EtOAc and the organic layer was
washed with brine, dried and concentrated in vacuo. The residue
was purified by alumina column chromatography (hexane–EtOAc,
2:1) and converted to a hydrochloride salt to afford 12 (0.211 g,
72%). 1H NMR (CDCl3) d: 1.21–1.50 (2H, m), 1.86–2.03 (2H, m),
2.25–2.44 (2H, m), 2.30 (6H, s), 2.68–2.91 (3H, m), 4.18 (1H, br
s), 6.52–6.62 (2H, m), 6.90 (1H, d, J = 8 Hz).
The compounds (2c–2i) were prepared by the similar procedure
for the preparation of 2b.
6.11.13. [(N,N-Dimethylamino)methyl]-6-tetralinyl 4-
biphenylylcarboxylate (1s)
4-Biphenylylcarboxylic acid (580 mg, 2.93 mmol) and EDCꢁHCl
(560 mg, 2.92 mmol) were added to pyridine solution (6 mL) of
12 (300 mg, 1.24 mmol) and the mixture was stirred at room tem-
perature for 3 days. Saturated sodium bicarbonate solution and
water were added to the reaction mixture and the solution was ex-
tracted with EtOAc. The organic layer was washed with water,
brine, dried, and then concentrated in vacuo. The residue was puri-
fied using alumina column chromatography (hexane–EtOAc, 10:1)
and recrystallized from hexane to give 1s (300 mg, 53%). Mp 85–
86 °C. 1H NMR (CDCl3) d: 1.39–1.49 (1H, m), 1.95–2.04 (2H, m),
2.20–2.48 (9H, m), 2.85–2.99 (3H, m), 6.93 (2H, m), 7.12–7.15
(1H, m), 7.38–7.50 (3H, m), 7.64–7.73 (4H, m), 8.25 (2H, d,
J = 8.7 Hz). Anal. Calcd for C26H27NO2: C, 81.01; H, 7.06; N, 3.63.
Found: C, 80.93; H, 7.10; N, 3.67.
6.11.17. 40-Chloro-N-[6-[-[(N,N-diethylamino)methyl]-7,8-
dihydro-2-naphthalenyl][1,10-biphenyl]-4-carboxamide (2c)
Yield 8%, yellow crystals, mp 142–144 °C (EtOAc–Hexane). 1H
NMR (CDCl3) d: 1.07 (6H, t, J = 7.2 Hz), 2.36 (2H, t, J = 5.1 Hz), 2.59
(4H, q, J = 7.2 Hz), 2.85 (2H, t, J = 5.1 Hz), 3.16 (2H, s), 6.38 (1H, s),
7.02 (1H, d, J = 8.4 Hz), 7.43–7.58 (6H, m), 7.67 (2H, d, J = 8.1 Hz),
7.79 (1H, s), 7.94 (2H, d, J = 8.1 Hz). Anal. Calcd for C28H29ClN2O:
C, 75.57; H, 6.57; N, 6.30. Found: C, 75.44; H, 6.66; N, 6.26.
6.11.18. 40-Chloro-N-(6-[[methyl(2-phenylethyl)amino]methyl]-
7,8-dihydro-2-naphthalenyl)[1,10-biphenyl]-4-carboxamide
(2d)
Yield 30%, yellow crystals, 173–175 °C (THF–hexane). 1H NMR
(CDCl3) d: 2.25–2.32 (2H, m), 2.32 (3H, s), 2.60–2.66 (2H, m),
2.77–2.83 (4H, m), 3.10 (2H, s), 6.32 (1H, s), 6.98 (1H, d,
J = 8.1 Hz), 7.18–7.29 (5H, m), 7.35–7.45 (4H, m), 7.54 (2H, d,
J = 8.7 Hz), 7.65 (2H, d, J = 8.4 Hz), 7.80 (1H, s), 7.92 (2H, d,
J = 8.4 Hz). Anal. Calcd for C33H31ClN2O: C, 78.17; H, 6.16; N, 5.52.
Found: C, 78.09; H, 6.20; N, 5.62.
6.11.14. 40-Chloro-N-[6-[-[(N,N-dimethylamino)methyl]-7,8-
dihydro-2-naphthalenyl] [1,10-bi- phenyl]-4-carboxamide (2a)
A mixture of 6a (1.00 g, 5.00 mmol), 4-chlorobiphenylcarboxy-
lic acid (2.31 g, 10.0 mmol), EDCꢁHCl (1.92 g, 10.0 mmol), HOBt

5550
M. Kamata et al. / Bioorg. Med. Chem. 19 (2011) 5539–5552
6.11.19. 40-Chloro-N-[6-[(methylanilino)methyl]-7,8-dihydro-2-
naphthalenyl][1,10-biphenyl]-4-carboxamide (2e)
diluted with EtOAc and the solution was washed with 10% K2CO3
and brine, dried over Na2SO4. The solution was passed through
NH silica gel (eluted with EtOAc) and concentrated in vacuo. The
oil was purified by silica gel column chromatography eluting 25%
- 50% EtOAc in hexane to give 14 (6.44 g, 85%) as a solid, which
was collected and washed with i-Pr2O. 1H NMR (CDCl3) d: 1.48
(9H, s), 2.20 (2H, t, J = 8.1 Hz), 2.80–2.85 (5H, m), 3.96 (2H, s),
6.24 (1H, s), 6.99 (1H, d, J = 7.8 Hz), 7.33 (1H, d, J = 9.0 Hz), 7.46
(1H, s), 7.61 (2H, d, J= 8.7 Hz), 7.72 (2H, d, J = 8.7 Hz), 7.80 (1H, s).
The following compound (2k) was prepared in the same man-
ner as described for 1d.
Yield 20%, yellow crystals, mp 177–179 °C (THF–hexane). 1H
NMR (CDCl 3)
(2H, m), 2.84–2.90 (2H, m), 3.00 (3H, s),
d: 2.23–2.28
4.00 (2H, s), 6.29 (1H, s), 6.68–6.76 (3H, m), 6.97 (1H, d,
J = 8.4 Hz), 7.20–7.25 (2H, m), 7.30–7.33 (1H, m), 7.43 (2H, m),
7.53–7.57 (3H, m), 7.66 (2H, d, J = 8.4 Hz), 7.76 (1H, s), 7.93 (2H,
d, J = 8.4 Hz). Anal. Calcd for C31H27ClN2O: C, 77.73; H, 5.68; N,
5.85. Found: C, 77.45; H, 5.57; N, 6.04.
6.11.20. 40-Chloro-N-[6-(4-morpholinylmethyl)-7,8-dihydro-2-
naphthalenyl][1,10-biphenyl]-4-carboxamide (2f)
Yield 30%, yellow crystals, mp 194–196 °C (THF–hexane). 1H
NMR (CDCl3) d: 2.34 (2H, t, J = 7.8 Hz), 2.45 (4H, m), 2.84 (2H, t,
J = 7.8 Hz), 3.06 (2H, s), 3.73 (4H, m), 6.36 (1H, s), 7.02 (1H, d,
J = 8.1 Hz), 7.36–7.57 (6H, m), 7.67 (2H, d, J = 8.4 Hz), 7.80 (1H, s),
7.94 (2H, d, J = 8.4 Hz). Anal. Calcd for C28H27ClN2O2: C, 73.27; H,
5.93; N, 6.10. Found: C, 73.30; H, 5.93; N, 5.98.
6.11.26. tert-Butyl (6-(40-chlorobiphenyl-4-ylcarboxamido)-3,4-
dihydronaphthalen-2-yl)methyl(methyl) carbamate (2k)
Yield 69%, white crystals, mp 191–193 °C (i-Pr2O). 1H NMR
(CDCl3) d: 1.48 (9H, s), 2.22 (2H, m), 2.82–2.88 (5H, m), 3.96 (2H,
m), 6.25 (1H, s), 7.01 (1H, d, J = 8.1 Hz), 7.38 (1H, d, J = 8.4 Hz),
7.42–7.46 (2H, m), 7.51–7.57 (3H, m), 7.66 (2H, d, J = 8.4 Hz),
7.80 (1H, s), 7.93 (2H, d, J = 8.7 Hz). Anal. Calcd for C30H31ClN2O3:
C, 71.63; H, 6.21; N, 5.57. Found: C, 71.65; H, 6.25; N, 5.52.
6.11.21. 40-Chloro-N-[6-(1-pyrrolidinylmethyl)-7,8-dihydro-2-
naphthalenyl][1,10-biphenyl]-4-carboxamide (2g)
Yield 40%, white crystals, mp 185–187 °C (THF–hexane). 1H
NMR (CDCl3) d: 1.83 (4H, m), 2.35 (2H, t, J = 8.1 Hz), 2.52 (4H, m),
2.84 (2H, t, J = 8.1 Hz), 3.18 (2H, s), 6.36 (1H, s), 7.02 (1H, d,
J = 8.4 Hz), 7.39–7.56 (6H, m), 7.66 (2H, d, J = 7.5 Hz), 7.82 (1H, s),
7.93 (2H, d, J = 7.5 Hz). Anal. Calcd for C28H27ClN2Oꢁ0.2H2O: C,
75.31; H, 6.18; N, 6.27. Found: C, 75.14; H, 5.99; N, 6.35.
6.11.27. 40-Chloro-N-[6-(methylamino)methyl]-7,8-dihydro-2-
naphthalenyl][1,10-biphenyl]-4-carboxamide 2,2,2-
trifluoroacetate (2j)
A solution of 2k (4.72 g, 9.38 mmol) in TFA (50 mL, 9.38 mmol)
was stirred for 30 min and concentrated in vacuo. The residue was
solidified with EtOAc and washed with same solvent to afford 2j
(4.70 g, 97%) as a light gray solid. Mp >210 °C (EtOAc, decomposi-
tion). 1H NMR (DMSO-d6) d: 2.29–2.34 (2H, t, J = 8.1 Hz), 2.59
(3H, s), 2.79–2.93 (2H, t, J = 8.1 Hz), 3.70 (2H, s), 6.58 (1H, s), 7.10
(1H, d, J = 8.4 Hz), 7.54–7.66 (4H, m), 7.78–7.85 (4H, m), 8.05
(2H, d, J = 8.4 Hz), 8.69 (2H, br s), 10.30 (1H, s). Anal. Calcd for
6.11.22. 40-Chloro-N-[6-(1-piperidinylmethyl)-7,8-dihydro-2-
naphthalenyl][1,10-biphenyl]-4-carboxamide (2h)
Yield 43%, white crystals, mp 209–211 °C (THF–hexane). 1H
NMR (CDCl3) d: 1.26–1.61 (6H, m), 2.30–2.36 (6H, m), 2.83 (2H, t,
J = 8.4 Hz), 3.02 (2H, s), 6.33 (1H, s), 7.01 (1H, d, J = 8.1 Hz), 7.36–
7.49 (4H, m), 7.55 (2H, d, J = 8.4 Hz), 7.66 (2H, d, J = 8.4 Hz), 7.81
(1H, s), 7.93 (2H, d, J = 8.1 Hz). Anal. Calcd for C29H29ClN2Oꢁ1.5H2O:
C, 71.96; H, 6.66; N, 5.79. Found: C, 71.42; H, 6.14; N, 5.64.
C27H24ClF3N2O3: C, 62.73; H, 4.68; N, 5.42; Cl, 6.86; F, 11.03. Found:
C, 62.51; H, 4.75; N, 5.27.
6.11.28. 40-Chloro-N-(6-((N-methylacetamido)methyl)-7,8-
dihydronaphthalen-2-yl)biphenyl-4-carboxamide (2l)
To a solution of 2j (200 mg, 0.39 mmol) in pyridine (2 mL) was
added acetic anhydride (0.073 mL, 0.77 mmol) at room tempera-
ture. The reaction mixture was stirred for 2 h and product was
crystallized. H2O was added to the mixture and the precipitates
were washed with CH3CN and i-Pr2O to afford 2l (135 mg, 78%)
as a white powder. Mp 233–235 °C (pyridine–H2O). 1H NMR
(DMSO-d6) d: 2.02–2.19 (5H, m), 2.73–2.93 (5H, m), 4.05 (2H, s),
6.20, 6.27 (1H, sx2), 7.02–7.07 (1H, m), 7.54–7.62 (4H, m), 7.78–
7.85 (4H, m), 8.05 (2H, d, J = 8.4 Hz), 10.22, 10.23 (1H, sx2). Anal.
Calcd for C27H25ClN2O2: C, 72.88; H, 5.66; N, 6.30; Cl, 7.97. Found:
C, 72.84; H, 5.71; N, 6.35.
6.11.23. 40-Chloro-N-[6-[(4-methyl-1-piperazinyl)methyl]-7,8-
dihydro-2-naphthalenyl][1,10-biphenyl]-4-carboxamide (2i)
Yield 21%, yellow crystals, mp 220–222 °C (THF–hexane). 1H
NMR (CDCl3) d: 2.30 (3H, s), 2.25–2.50 (10H, m), 2.83 (2H, t,
J = 8.1 Hz), 3.07 (2H, s), 6.35 (1H, s), 7.01 (1H, d, J = 8.1 Hz), 7.36
(1H, d, J = 7.8 Hz), 7.44 (2H, d, J = 8.4 Hz), 7.51 (1H, s), 7.55 (2H,
d, J = 8.4 Hz), 7.66 (2H, d, J = 8.4 Hz), 7.84 (1H, s), 7.93 (2H, d,
J = 8.4 Hz). Anal. Calcd for C29H30ClN3O: C, 73.79; H, 6.41; N, 8.90.
Found: C, 73.73; H, 6.45; N, 8.72.
6.11.24. tert-Butyl (6-amino-3,4-dihydronaphthalen-2-
yl)methyl(methyl)carbamate (6d)
The following compounds (2m–o) was prepared in the same
manner as described for 2l.
Di-tert-butyl dicarbonate (4.22 mL, 18.4 mmol) in CH3CN
(100 mL) was added dropwise to
a solution of 6b (3.46 g,
18.4 mmol) and triethylamine (2.56 mL, 18.4 mmol) in CH3CN
(50 mL) at 0 °C for 1 h. The reaction mixture was stirred for 3 h
at same temperature and concentrated in vacuo and the oil was
purified by silica gel column chromatography eluting 25% - 50%
EtOAc in hexane to give 6d (4.62 g, 87%) as a light yellow oil. 1H
NMR (CDCl3) d: 1.47 (9H, s), 2.15 (2H, t, J = 8.1 Hz), 2.73 (2H, t,
J = 8.1 Hz), 2.82 (3H, br s), 3.61 (2H, s), 4.08 (2H, br s), 6.17 (1H,
s), 6.46–6.48 (2H, m), 6.82 (1H, d, J = 8.7 Hz).
6.11.29. 40-Chloro-N-(6-((N-methylpropionamido)methyl)-7,8-
dihydronaphthalen-2-yl)biphenyl-4-carboxamide (2m)
Yield 80%, white crystals, mp 220–222 °C (EtOAc). 1H NMR
(DMSO-d6) d: 0.97–1.05 (3H, m), 2.07–2.18 (2H, m), 2.29–2.43
(2H, m), 2.73–2.82 (2H, m), 2.84, 2.92 (3H, sx2), 4.06 (2H, s),
6.18, 6.26 (1H, sx2), 7.01–7.06 (1H, m), 7.54–7.62 (4H, m), 7.78–
7.85 (4H, m), 8.05 (2H, d, J = 8.4 Hz), 10.22 (1H, s). Anal. Calcd for
C28H27ClN2O2ꢁ0.1H2O: C, 72.98; H, 5.95; N, 6.08; Cl, 7.72. Found:
C, 72.83; H, 5.96; N, 6.13.
6.11.25. tert-Butyl (6-(4-bromobenzamido)-3,4-
dihydronaphthalen-2-yl)methyl(methyl)carbamate (14)
4-Bromobenzoyl chloride (3.51 g, 16.0 mmol) was added drop-
wise to a solution of 6d (4.61 g, 16.0 mmol) and TEA (4.45 mL,
32.0 mmol) in THF (70 mL) at 0 °C for 1 h and the reaction mixture
was stirred for 2 h at same temperature. The reaction mixture was
6.11.30. Ethyl (6-(40-chlorobiphenyl-4-ylcarboxamido)-3,4-
dihydronaphthalen-2-yl)methyl(methyl) carbamate (2n)
Yield 79%, white crystals, mp 181–182 °C (EtOAc–i-Pr2O). 1H
NMR (DMSO-d6) d: 1.20 (3H, m), 2.11–2.16 (2H, m), 2.75–2.82
(5H, m), 3.98 (2H, s), 4.07 (2H, q, J = 6.9 Hz), 6.27 (1H, s), 7.04

M. Kamata et al. / Bioorg. Med. Chem. 19 (2011) 5539–5552
5551
(1H, d, J = 7.8 Hz), 7.54–7.61 (4H, m), 7.78–7.85 (4H, m), 8.05 (2H,
d, J = 8.4 Hz), 10.23 (1H, s). Anal. Calcd for C28H27ClN2O3: C, 70.80;
H, 5.73; N, 5.90. Found: C, 70.84; H, 5.79; N, 5.90.
the program GOLD. Resulting docking modes with receptor models
were subjected energy minimization with MOE. In the energy min-
imization process, the MMFF94s forcefield was used.
6.11.31. 40-Chloro-N-(6-((3-ethyl-1-methylureido)methyl)-7,8-
dihydronaphthalen-2-yl)biphenyl-4-carboxamide (2o)
Yield 85%, white crystals, mp 247–249 °C (pyridine–H2O, de-
comp.). 1H NMR (DMSO-d6) d: 1.01 (3H, t, J = 6.9 Hz), 2.07–2.12
(2H, m), 2.72–2.77 (5H, m), 3.02–3.10 (2H, m), 3.94 (2H, s), 6.20
(1H, s), 6.29 (1H, t, J = 5.4 Hz), 7.00 (1H, d, J = 8.1 Hz), 7.53–7.58
(4H, m), 7.77–7.84 (4H, m), 8.04 (2H, d, J = 8.1 Hz), 10.21 (1H, s).
Anal. Calcd for C28H28ClN3O2: C, 70.95; H, 5.95; N, 8.87; Cl, 7.48.
Found: C, 70.93; H, 6.00; N, 8.74.
6.13. Human MCHR1 and rat MCHR1 binding assays
CHO cell lines expressing human or rat MCHR1 were estab-
lished as described before (Shimomura, Y et al. B.B.R.C. 1999,
261, 622). Briefly, a cDNA encoding human or rat MCHR1 was
cloned from a cDNA library derived from embryonic brain (Gibco
BRL) and ligated to an expression vector plasmid, pAKKO-111H.
The constructed vector was introduced into the CHO dhfr- cell lines
and the transformed cells were selected in a selection medium
The compounds (2p–2s) were prepared from 6c by the similar
procedure for the preparation of 2a.
(ribonucleic acid and deoxyribonucleic acid free
10% dialysed FCS).
a-MEM containing
The cells were dispersed using phosphate-buffered saline (PBS),
pH 7.4 containing 0.2 mM EDTA and suspended in a 10 mM sodium
6.11.32. N-[6-(1-Pyrrolidinylmethyl)-7,8-dihydro-2-
naphthalenyl][1,10-biphenyl]-4-carboxamide (2p)
carbonate buffer containing 1 mM EDTA, 0.25 mM PMSF, 20
lg/mL
Yield 67%, white crystals, mp 176–177 °C (i-Pr2O). 1H NMR
(CDCl3) d: 1.75–1.90 (4H, m), 2.34 (2H, t, J = 8.1 Hz), 2.45–2.60
(4H, m), 2.85 (2H, t, J = 8.1 Hz), 3.18 (2H, s), 6.36 (1H, s), 7.02
(1H, d, J = 8.1 Hz), 7.27–7.55 (5H, m), 7.63 (2H, d, J = 7.3 Hz), 7.70
(2H, d, J = 8.4 Hz), 7.82 (1H, s), 7.94 (2H, d, J = 8.1 Hz). Anal. Calcd
for C28H28N2O: C, 82.32; H, 6.91; N, 6.86. Found: C, 81.99; H,
6.69; N, 6.91.
of leupeptin, 10 g/mL of phosphoramidon, and 1 g/mL pepstatin.
l
l
Then, the cells were homogenized with a polytron homogenizer
and centrifuged at 1000g for 10 min. The supernatants were ultra-
centrifuged twice at 100,000g for 60 min. The pellets were then
suspended in an assay buffer (25 mM Tris–HCl, pH 7.4 containing
0.1% BSA, 1 mM EDTA, 0.25 mM PMSF, 20
10 g/mL of phosphoramidon, and 1 g/mL pepstatin) and used
as membrane fractions.
Binding assays were performed in 96-well plates. The membrane
fraction (0.2 g protein was used for each assay) dissolved in the as-
say buffer containing 0.0625% CHAPS was incubated with 25 pM
125I]-MCH (4–19) and various concentrations of test compounds
at room temperature for 60 min. Nonspecific binding was defined
as [125I]-MCH (4–19) binding in the presence of 1
M MCH (Peptide
lg/mL of leupeptin,
l
l
6.11.33. 40-Methyl-N-[6-(1-pyrrolidinylmethyl)-7,8-dihydro-2-
naphthalenyl][1,10-biphenyl]-4-carboxamide compound (2q)
Yield 56%, yellow crystals, mp 176–177 °C (EtOAc–i-Pr2O). 1H
NMR (CDCl3) d: 1.81 (4H, m), 2.36 (2H, t, J = 8.1 Hz), 2.41 (3H, s),
2.52 (4H, m), 2.85 (2H, t, J = 8.1 Hz), 3.18 (2H, s), 6.36 (1H, s),
7.01 (2H, d, J = 8.1 Hz), 7.27–7.39 (3H, m), 7.49 (1H,s), 7.53 (2H,
d, J = 8.1 Hz), 7.69 (1H, d, J = 8.4 Hz), 7.81 (1H, s), 7.91 (2H, d,
J = 8.4 Hz). Anal. Calcd for C29H30N2Oꢁ0.2H2O: C, 81.73; H, 7.19;
N, 6.57. Found: C, 81.78; H, 7.09; N, 6.65.
l
[
l
Research Inc, Japan). The binding reaction was terminated by rapid
filtration through GF/C glass filter plates pre-soaked in 0.2% poly-
ethylenimine and 0.02% BSA, followed by washing three times with
300 lL of 50 mM Tris–HCl, pH 7.5. Then the plates were dried for 1 h
6.11.34. 40-Methoxy-N-[6-(1-pyrrolidinylmethyl)-7,8-dihydro-2-
naphthalenyl][1,10-biphenyl]-4-carboxamide (2r)
at 37 °C and Microscint-O scintillation fluid (Packard, USA) was
added. The radioactivity retained in the filters was determined with
Topcount scintillation counter (Packard, USA). The concentrations of
test compounds causing 50% inhibition of the specific binding (IC50
value) were derived by fitting the data into a pseudo-Hill equation:
log[%SB/(100 ꢀ %SB)] = n[log(C) ꢀ log(IC50)], where %SB is a specific
binding, n is a pseudo-Hill constant, and C is the concentration of the
test compound.
Yield 57%, pale yellow crystals, mp 187–188 °C (EtOAc–i-Pr2O).
1H NMR (CDCl3) d: 1.80 (4H, m), 2.36 (2H, t, J = 7.8 Hz), 2.52 (4H,
m), 2.86 (2H, t, J = 7.8 Hz), 3.18 (2H, s), 3.87 (3H, s), 6.36 (1H, s),
7.00–7.03 (3H, m), 7.26 (1H, m), 7.38 (1H, d, J = 8.3 Hz), 7.49 (1H,
s), 7.58 (2H, d, J = 8.6 Hz), 7.67 (1H, d, J = 8.2 Hz), 7.78 (1H, s),
7.90 (2H, d, J = 8.2 Hz). Anal. Calcd for C29H30N2O2: C, 79.42; H,
6.89; N, 6.39. Found: C, 79.21; H, 6.88; N, 6.35.
6.14. Human MCHR1 GTP
c
S binding assay
6.11.35. 40-Fluoro-N-[6-(1-pyrrolidinylmethyl)-7,8-dihydro-2-
naphthalenyl][1,10-biphenyl]-4-carboxamide (2s)
Membrane fraction (4
l
g protein was used for each assay) of
Yield 56%, white crystals, mp 189–192 °C (i-Pr2O). 1H NMR
(CDCl3) d: 1.75–1.90 (4H, m), 2.35 (2H, t, J = 8.2 Hz), 2.45–2.60
(4H, m), 2.84 (2H, t, J = 8.2 Hz), 3.18 (2H, s), 6.36 (1H, s), 7.01(1H,
d, J = 8.1 Hz), 7.16 (2H, t, J = 8.1 Hz), 7.38 (2H, d, J = 8.1 Hz), 7.48
(1H, br s), 7.56–7.61 (1H, m), 7.64 (2H, d, J = 8.4 Hz), 7.83 (1H, s),
7.93 (2H, d, J = 8.4 Hz). Anal. Calcd for C28H27FN2O: C, 78.85; H,
6.38; N, 6.57. Found: C, 78.75; H, 6.39; N, 6.45. MS (FAB) m/
z = 427 [M+H]+.
hMCHR1 was suspended in the GTP
HCl, pH 7.5 containing 0.1% BSA, 1 mM EDTA, 10 mM MgCl2,
100 mM NaCl, 1 M GDP, 0.25 mM PMSF, 20 g/mL of leupeptin,
10 g/mL of phosphoramidon, and 1 g/mL pepstatin) and incu-
bated with 0.33 nM [35S]GTP
S (NEN) and 0.3 nM MCH in the pres-
ence of the test compound at various concentrations. The mixture
was incubated for 60 min at room temperature and then filtered
onto GF/C plates. After washing three times with 300 lL of
cS assay buffer (50 mM Tris–
l
l
l
l
c
50 mM Tris–HCl buffer, pH 7.4, the plates were dried for 1 h at
37 °C. The radioactivity retained in the plates was determined
using with Topcount scintillation counter (Packard, USA). IC50 val-
ues were calculated as described above.
6.12. Homology modeling and ligand docking
The homology model of hMCHR1 was constructed using the crys-
tal structure of bovine rhodopsin (PDB code 1F88), which obtained
from the RCSB Protein Data Bank, as a structural template.24 The pri-
mary alignment of the amino acid sequences between hMCHR1 and
rhodopsin using MOE 2005.06. Construction of hMCHR1 homology
models and side chain rotamer search were performed with MOE.
Antagonists were docked into the obtained receptor models using
6.15. In vivo pharmacological study
All animal experiments were performed in compliance with the
Guidelines for the Care and Use of Laboratory Animals of Takeda
Pharmaceutical Company.

5552
M. Kamata et al. / Bioorg. Med. Chem. 19 (2011) 5539–5552
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istered orally to the control group, and 0.5% methylcellulose sus-
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Acknowledgments
The authors wish to thank Dr. M. Kawada, Dr. I. Aoki, and Mr. M.
Tanaka for separation of the enantiomers of 1g; Mr. E. Kotani for
preliminary SAR; and Mr. K. Ohnishi and Mr. M. Yamaguchi for
the pharmacokinetic study of 2s. We wish to express our sincere
gratitude to Dr. M. Fujino, Dr. O. Nishimura, Dr. A. Miyake, and
Dr. H. Onda for their encouragement and helpful discussion
throughout this research.
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