Synthesis of 3-phenylnaphthalenic derivatives as new selective MT2 melatoninergic ligands

Article abstract of DOI:10.1016/j.bmc.2008.08.052

A series of naphthalenic analogues of melatonin were prepared and evaluated as melatonin receptor MT₂ selective ligands. Activity and MT₂ selectivity can be modulated with suitable variations of the C-3 phenyl and the acyl group on t

Full text of DOI:10.1016/j.bmc.2008.08.052

Bioorganic & Medicinal Chemistry 16 (2008) 8339–8348
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis of 3-phenylnaphthalenic derivatives as new selective MT2
melatoninergic ligands
Sophie Poissonnier-Durieux a, Mohamed Ettaoussi a, Basile Pérès a, Jean A. Boutin b, Valérie Audinot b,
Caroline Bennejean c, Philippe Delagrange c, Daniel Henri Caignard c, Pierre Renard c, Pascal Berthelot a,
Daniel Lesieur a, Saïd Yous a,
*
a Faculté de Pharmacie, Laboratoire de Chimie Thérapeutique (EA 1043), 3 rue du Professeur Laguesse, BP 83, 59006 Lille Cedex, France
b Division de Pharmacologie Moléculaire et Cellulaire, Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France
c Institut de Recherches Internationales Servier, 6 Place des Pléiades, 92415 Courbevoie Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of naphthalenic analogues of melatonin were prepared and evaluated as melatonin receptor MT2
selective ligands. Activity and MT2 selectivity can be modulated with suitable variations of the C-3 phenyl
and the acyl group on the C-1 side chain. Surprisingly, in contrast with what had been previously
described in other series (2-benzylindoles, 2-benzylbenzofurans and 3-phenyltetralins), the presence
of a C-3 phenyl with a functional group on the meta position seems to be primordial for MT2 affinity
and selectivity. Indeed, N-[2-(3-(3-hydroxymethylphenyl)-7-methoxynaphth-1-yl)ethyl]acetamide (21)
is one of the best MT2 selective ligands described until now and behaves as an antagonist.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 17 June 2008
Revised 18 August 2008
Accepted 22 August 2008
Available online 27 August 2008
Keywords:
Melatonin
MT2 receptors
3-Phenylnaphthalene
Selective antagonists
1. Introduction
Many series of MLT receptor agonists have been reported. Some
of these MLT receptor agonist ligands are currently under clinical
Melatonin (N-acetyl-5-methoxytryptamine, MLT) is synthe-
sized and released by the pineal gland in a circadian fashion, with
high levels occurring during the night. Indeed its synthesis is reg-
ulated by the day–night alternance and by the way MLT transmits
to the organism information about the photoperiod.1 This pineal
neurohormone regulates and modulates a myriad of physiological
functions including, in mammals, the control of seasonal reproduc-
tion,2 circadian adjustments,3 immunoresponsiveness4 and vascu-
lar regulation,5 among others. The diversity of MLT’s response
within the body may be attributed to the fact that its receptors
are expressed in a wide variety of tissues.6–13 To date, two mam-
malian MLT receptors have been cloned (MT1 and MT2).2,3,7,8 Both
are G-protein coupled receptors.14 Recently another MLT binding
site (MT3)15 has been described in hamster as homologue of the
cytoplasmic quinone reductase 216 (see Charts 1 and 2).
evaluation or have been approved for their sleep inducing proper-
ties or for circadian phase shift action. Agomelatine17 characterized
as an MT1/MT2 agonist and 5-HT2C antagonist18 is in registration
for depression. Ramelteon is at present the only melatonin recep-
tor agonist marketed for the treatment of insomnia,19 and other li-
gands such as LY 15673520 have been tested in clinical trials for
their hypnotic properties.
Recently receptor subtype selectivity has registered some
important advances leading to the identification of a small num-
ber of selective compounds.21a,b While only few examples of MT1
selective antagonists are reported,22 several series of MT2
or
23–34
MT3 ligands have been described and are competitive agonists or
antagonists with varying degrees of selectivity.35–37 MT2 receptor
selective ligands belong to various structural classes displaying
different degrees of binding affinity and selectivity; they comprise
benzofuran28 and tetrahydronaphtalenic derivatives,29 6,7-dihy-
The physiological significance of MT1, MT2 and MT3 subtypes
can be ascertained with the continual development of specific
and selective affinity ligands. As more knowledge is gained about
these receptors, their importance as therapeutic targets in patho-
physiological states will increase.
dro-5H-benzo[c]azepino[2,1-a]indoles,25
2-N-acylaminoalkylin-
doles,24 and tetrahydroisoquinoline derivatives.38 Luzindole, the
first competitive MLT receptor antagonist discovered, shows high-
er affinity for the MT2 than for the MT1 subtype.39 This compound
was first used to demonstrate the presence of MT2 receptors
mediating inhibition of dopamine release in rabbit retina and
phase shift of circadian rhythms in the rodent biological clock
[the suprachiasmatic nucleus (SCN)].3 Like luzindole, other MT2
* Corresponding author. Tel./fax: +33 (0)320964375.
E-mail address: said.yous@univ-lille2.fr (S. Yous).
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.08.052

8340
S. Poissonnier-Durieux et al. / Bioorg. Med. Chem. 16 (2008) 8339–8348
NHCOR
NHCOCH3
NHCOc-C4H7
CH3
O
N
H
R = CH3 ; 4-PADOT
R = C2H5 ; 4-PPDOT
S 28407
Luzindole
CH3
NHCOnPr
NHCOCH3
O
CH3
CH3
O
N
CH3
O
O
CH3
CH2
O
N
O
CH3
O
S 24014
K 185
Chart 1. Chemical structures of MT2-selective antagonists and partial agonists.
NHCOCH3
NHCOR1
NHCOCH3
CH3
O
CH3
O
CH3
O
N
H
R2
Melatonin (MLT)
Agomelatine (1)
9-34
Chart 2. Chemical structures of MLT, agomelatine (1) and general structure of compounds 9–34.
selective antagonists including 4-phenyl-2-acylaminotetralins39
are structurally characterized by the presence of a phenyl or a
benzyl group on the nucleus bearing the 3-alkylamido side
chain.40 Therefore, along this line of thought and expanding on
what had been already reported, we first developed a new series
of N-[2-(2-arylalkylbenzofuran-3-yl)ethylamide.28 The presence
of a lipophilic substituent out of the plane of the aromatic nu-
cleus is a common and consistent structural motif found in most
of these MLT ligands, and with others, we have hypothesized that
this arrangement was the key feature for MT2 selectivity.23,25,28,30
In this paper we present a novel series of 3-phenylnaphthalen-
ic derivatives as MT2 selective ligands. In a previous work, we
introduced a phenyl substituent in the C-3 position (9)41 of the
naphthalenic bioisoster of MLT (agomelatine, 1).17 To investigate
in detail the influence of structural variations on both affinity
and selectivity (C-3 phenyl group substitution, length of the side
chain, nature of the acyl group, etc.), the synthesis of additional
compounds (10, 13 and 19–34) has been performed. For all these
compounds, the synthesis, the binding data (human MT1 and
MT2), and some activity results for the human MT2 receptors
are reported.
yl)ethylamine hydrochloride,17 N-acylated derivatives 1–4 were
first prepared as previously reported by some of us42 according
to a variant of the Schotten–Baumann reaction43 by treatment
in a biphasic medium with the appropriate acid chlorides in
the presence of potassium carbonate as base. Subsequently, bro-
mination of compounds 1–4 using bromine in acetic acid44 led
to the 3-bromo derivatives 5–8 which were reacted under Suzu-
ki conditions in the presence of the appropriate aryl boronic
acids and palladium acetate (method A) or triphenylphosphine
palladium (method B)45 to afford compounds 9–18. Saponifica-
tion of the methyl ester 10 with aqueous sodium hydroxide gave
access to the corresponding carboxylic acid 19 (Scheme 2). Alco-
hols 20–25 were obtained either from the corresponding esters
by treatment with lithium aluminum hydride in THF and diethyl
ether (method A) or from aldehydes 12–13 by treatment with
sodium borohydride in methanol (method B). Treatment of 21
with 45% HBr in acetic acid46 led to 26, which was reacted either
with sodium iodide47 to give 27 or with sodium methoxide48 to
afford 28 (Scheme 3). Catalytic hydrogenation of the cyano
group of 14 and of the nitro group of 15 to the corresponding
amines 29 and 30 was performed over Raney nickel and 10% pal-
ladium on charcoal, respectively. Acetamide 34 was generated
from amine 30 by action of acetyl chloride and potassium car-
bonate in a biphasic medium. Attempts to achieve N-methyla-
tion of 30 with formaldehyde and sodium cyanoborohydride
were unsuccessful due to the formation of the N,N-dimethyl-
amine 33 as the major reaction product. Treatment of 30 with
ethyl chloroformate and DIPEA provided carbamate 31. Unfortu-
nately, attempts to reduce 31 with lithium aluminum hydride
did not give access to N-methylamine 32. The final strategy em-
2. Results and discussion
2.1. Chemistry
The syntheses of 3-aryl naphthalene derivatives have been
accomplished as described in Schemes 1–3. Introduction of aryl
substituents on the 3-position of the heterocycle was carried out
by three steps (Scheme 1). Starting from 2-(7-methoxynaphth-1-

S. Poissonnier-Durieux et al. / Bioorg. Med. Chem. 16 (2008) 8339–8348
8341
NH2,HCl
NHCOR1
CH3
O
CH3
O
b
a
1; R1 = CH3
2; R1 = C2H5
3; R1 = C3H7
4; R1 = c-C4H7
NHCOR1
NHCOR1
CH3
CH3
O
O
c or d
Br
R2
5; R1 = CH3
9; R1 = CH3 andR2 = H
10; R1 = CH3 andR2 =
11; R1 = CH R =
6; R1 = C2H5
7; R1 = C3H7
8; R1 = c-C4H7
m
-COOCH3
p
o
-COOCH3
-CHO
3 and
2
12; R1 = CH3 and R2 =
13; R1 = CH3 andR2 =
14; R1 = CH3 and R2 =
m
m
m
-CHO
-CN
-NO2
-COOCH3
-COOCH3
15; R1 = CH
R =
3 and
16; R1 = C2H5 and R2 =
and R2
2
m
17; R1 = C3H7
=
m
18; R1 = c-C4H7 and R2 =
m
-COOCH3
Scheme 1. Synthesis of Compounds 1–18. Reagents: (a) R1COCl, K2CO3, methylene chloride, water; (b) Br2, acetic acid; (c) R2C6H4B(OH)2, Pd(OCOCH3)2, NaHCO3,
Br+NÀ(C4H9)4, dioxane, water (method A); (d) R2C6H4B(OH)2, Pd(PPh3)4, Na2CO3, toluene, water, ethanol (method B).
NHCOR1
NHCOCH3
CH3
O
CH3
O
a
COOH
COOCH3
19
10-11, 16-18
b
NHCOCH3
NHCOR1
CH3
O
CH3
O
c
CHO
CH2OH
12-13
20-25
Scheme 2. Synthesis of Compounds 19–25. Reagents: (a) NaOH, methanol, water; (b) LiAlH4, ether, tetrahydrofuran (method A); (c) NaBH4, methanol (method B).
ployed a two-step reaction sequence involving treatment with
ethyl orthoformate followed by reduction with sodium borohy-
dride and provided the desired N-methylamine 32 as the only
product.
2.2. Pharmacology
The chemical structures, binding affinities and MT1/MT2 selec-
tivity ratios of the new compounds are reported in Table 1. These

8342
S. Poissonnier-Durieux et al. / Bioorg. Med. Chem. 16 (2008) 8339–8348
NHCOCH3
CH3
O
R2
a
b
27
21
26
R2 = CH2I
R2 = CH2OH
R2 = CH2Br
c
28
R2 = CH2OCH3
d
14
29
R2 = CN
R2 = CH2NH2
f
31
R2 = NHCOOC2H5
g,h
32
e
R2 = NHCH3
15
30
R2 = NO2
R2 = NH2
33
R2 = N(CH3)2
i
j
34
R2 = NHCOCH3
Scheme 3. Synthesis of Compounds 26–34. Reagents: (a) 45% HBr–AcOH; (b) NaI, acetone; (c) CH3ONa, methanol; (d) H2, Raney nickel, ethanol; (e) H2, Pd/C, methanol; (f)
ClCOOC2H5, DIPEA, THF; (g) TFA, HC(OC2H5)3; (h) NaBH4, ethanol; (i) 37% HCHO, NaBH3CN, acetonitrile; (j) CH3COCl, K2CO3, methylene chloride, water.
compounds were evaluated for their binding affinity for human
MT1 and MT2 receptors stably transfected in Human Embryonic
Kidney (HEK 293) cells or Chinese Hamster Ovarian (CHO) cells,
using 2-[125I]iodomelatonin as radioligand.41 At each receptor,
binding affinities were verified for more than fifty selective and
non-selective molecules, either using the transfected HEK 293 or
the CHO cell lines. The correlations between affinities in HEK 293
and CHO cells are highly significant (r = 0.98), for both MT1 and
MT2 receptors. This high correlation allows the comparison of the
affinities on the receptors expressed in two different cell types
and to draw structure–activity relationships.
We can therefore assume either that the additional pocket is wider
than previously described or that, in this case, the naphthalene ring
is accommodated within the receptor in a different way than that
of the other aromatic nuclei. On the other hand, compound 9 acts
as a partial MT2 agonist. We therefore selected this compound as a
lead to investigate structure–affinity (selectivity) and structure–
activity relationships for MT1 and MT2 subtypes.
(i) We first introduce a hydroxymethyl group on the various
positions of the C-3 phenyl ring, the choice of this substituent
being justified by its hydrophilic character and its H-bond donor
and acceptor capability. The results obtained show that MT2 affin-
ity and selectivity strongly depend on the position of this group on
the phenyl ring, the meta regioisomer (21) being the most favour-
able: compound 21 (MT1/MT2 ratio 763) is about sixfold more
selective than the lead 9 and, respectively, 250- and 50-fold more
selective than its ortho and para isomers. Moreover, this com-
pound presents an affinity for MT2 similar to that of MLT and acts
as an MT2 antagonist.
(ii) In the tetrahydronaphthalenic series, variations of the acyl
group on the C-1 side chain had shown that acetyl was not the
optimum group for selectivity, the best results being obtained with
the bulkier cyclobutyl.29 We then replace the methyl group of the
acetamido side chain of 21 by homologous alkyl and cycloalkyls.
Surprisingly the results are opposite to those obtained in the tetral-
inic series: the cyclobutyl derivative 25 shows the worst MT2 affin-
ity (48 nM) and MT1/MT2 selectivity ratio (31), whereas the two
alkyl homologous 23–24 retain good MT2 affinities (0.52 and
0.28 nM, respectively) and a threefold lower selectivity than the
acetyl one (21) which remains the best compound.
The intrinsic activity of the most interesting compounds (selec-
tivity ratio higher than 50 and Ki lower than 10 nM) has been eval-
uated only on the MT2 receptor subtype, due to the weak affinity
for the MT1 subtype. The results are shown in Table 2. The
[
35S]GTP
cS binding assay used to determine the functional activity
of the compounds was performed using Chinese Hamster Ovarian
(CHO) cell lines stably expressing the human MT2 receptors.
Introduction of a phenyl substituent in the C-3 position of the
naphthalene ring of agomelatine causes a 140-fold decrease in
the MT1 but maintains the MT2 binding affinity, leading to a vari-
ation of the MT1/MT2 selectivity ratio from 0.2 to 132 (9).41 These
results are in agreement with what is reported in previous stud-
ies24: a hypothesis on selective binding to the MT2 receptor is
based on the presence of an additional pocket at the MT2 receptor,
positioned out of the plane of the aromatic nucleus that character-
ises MLT receptor ligands. Contrary to 2-benzylindoles, 2-ben-
zylbenzofurans and 3-phenyltetralins, the 3-phenyl ring of
compound 9 is not out of the plane of the naphthalene nucleus.

S. Poissonnier-Durieux et al. / Bioorg. Med. Chem. 16 (2008) 8339–8348
8343
Table 1
MT1 and MT2 receptor binding affinities of 3-phenylnaphthalene compounds
NHCOR1
NHCOCH3
CH3
O
CH3
O
R2
Agomelatine (1)
Compound
R1
R2
Ki SEM (nM) MT1
Ki SEM (nM) MT2
MT1/MT2
MLT
Agomelatine
—
—
—
—
0.14 0.03
0.06 0.01
0.41 0.04
0.27 0.04
0.3
0.2
9
CH3
H
53.0 12
0.37 0.05
132
20
21
CH3
CH3
o-CH2OH
m-CH2OH
5.90 0.12
275 79.5
1.86 0.03
0.36 0.02
3
763
22
CH3
p-CH2OH
297 21.5
23.0 5.70
14
23
24
25
C2H5
C3H7
c-C4H7
m-CH2OH
m-CH2OH
m-CH2OH
125 10.3
60.3 7.10
1510 277
0.52 0.06
0.28 0.03
48.3 1.91
240
215
31
28
13
10
19
26
27
29
30
32
33
31
34
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
m-CH2OCH3
m-CHO
m-COOCH3
m-COOH
m-CH2Br
m-CH2I
m-CH2NH2
m-NH2
m-NHCH3
m-N(CH3)2
m-NHCOOC2H5
m-NHCOCH3
204 2.03
137 0.17
24.7 10.9
3830 1130
50.7 1.33
126 28.4
1390 100
82 23
82.5 0.50
49.8 2.10
124 7.52
38.4 4.39
0.95 0.09
0.42 0.003
0.64 0.18
43.3 12.5
0.56 0.16
0.71 0.11
3.40 0.32
0.27 0.04
0.51 0.01
0.94 0.29
8.30 0.50
7.54 2.67
214
326
39
89
91
178
409
304
162
53
15
5
Concentration–response curves were analyzed by non-linear regression comparing a one-site and a two sites analysis. All the curves were found to be monophasic with a Hill
number close to unity (not shown). Binding affinities (nM) are expressed as mean Ki SEM of at least three independent experiments. The selectivity ratio between MT1 and
MT2 receptors is calculated for each compound.
Table 2
Intrinsic activity values
(a) Methylether: Substitution of the alcoholic function for the
corresponding methylether (28) leads to a threefold lower
MT2 affinity with a slightly higher MT1 affinity. The selectivity
ratio (MT1/MT2 = 214), being near that of the unsubstituted
compound (9).
Compound
MT2
EC50 SEM (nM) Emax SEM (%) Kb SEM (nM) Imax SEM (%)
MLT
0.49 0.05
100
91
56
nd
nd
nd
0.8 0.5
nd
nd
nd
(b) Carbonyl derivatives: Replacing the hydroxymethyl group
by a carboxaldehyde (13) results in preservation of MT2 and a
twofold increase of MT1 affinity. This explains the good and
slightly reduced selectivity ratio (MT1/MT2 = 326). Compound
13 is one of the best in this series contrary to the other carbonyl
derivatives: the methylester 10 shows a twofold lower affinity
on the MT2 subtype but a 10-fold higher on the MT1, whereas
the corresponding carboxylic acid (19) has a strongly reduced
affinity on both MT1 (3830 nM) and MT2 (43.3 nM) subtypes.
The selectivity ratios of these compounds are low (39 and 89,
respectively).
Agomelatine (1) 0.1 0.04
9
7
6
1
2.4 0.8
0.76 0.4
1.3 0.02
0.7 0.2
0.6 0.03
21
13
23
24
26
27
28
29
30
32
33
23
95.5 0.5
61.5 13.6
54.3 10.6
51.5 8.5
72.5 7.5
89
77
87
37
72
45 2.6
45.7 1.4
51 4.7
32.3 5.8
<10
32.5
<10
41
1
0.3
0.7 0.3
2.2 1.9
0.8 0.1
4.1 1.8
1.7 0.8
8.7 1.9
0.8 0.3
0.9 0.4
1.3 0.3
1
0.2
nc
9
8
5
0
1
13.3
nc
8
7
1.3 0.2
0.5 0.2
1.5 0.5
4
5
47.2
30
3
87 17
(c) Halomethyl derivatives: The bromomethyl (26) and iodo-
methyl (27) derivatives possess a similar binding profile with
the same degree of MT2 affinity as 21 and a two- to fivefold
higher affinity for the MT1 subtype, the respective selectivity
ratios being 91–178.
(d) Nitrogen derivatives: The bioisosteric replacement of the
hydroxyl group of 21 by a primary amine leads to noticeable
but quite similar loss of MT1 and MT2 binding affinities. Never-
theless, the resulting compound 29 retains a good MT2 affinity
(3.4 nM) and one of the best MT1/MT2 selectivity ratio (409).
The corresponding aromatic primary amine (30)41 that comes
from deletion of the methylene bridge has the same MT2 affin-
ity as 21 and only a threefold higher MT1 affinity leading to a
Concentration–response curves were analyzed by non-linear regression. Agonist
potency was expressed as EC50 SEM (nM) while the maximal efficacy, Emax SEM
was expressed as a percentage of that observed with melatonin 1 lM (=100%).
Antagonist potency to inhibit the effect of melatonin (30 or 3 nM, respectively, for
MT1 and MT2 receptors) was expressed as KB SEM Imax (maximal inhibitory effect)
was expressed as a percentage of that observed with melatonin at 3 nM for MT2
receptor. Data are mean of at least three independent experiments.
nd: not determined; nc: not calculated.
(iii) Starting from 21, it was therefore interesting to substitute
the hydroxymethyl with other functional groups aiming at varying
lipophilic, electronic and/or steric parameters.

8344
S. Poissonnier-Durieux et al. / Bioorg. Med. Chem. 16 (2008) 8339–8348
Table 3
Elemental analyses
4.2. General procedure for the synthesis of 3-bromo
compounds (5–8)
Compound
% C
% H
% N
The method adopted for the synthesis of N-[2-(3-bromo-7-
methoxynaphth-1-yl)ethyl] acetamide (5) is described. To a solu-
tion of 1 (2 g, 8.22 mmol) in glacial acetic acid (40 mL) heated to
Calcd
Found
Calcd
Found
Calcd
Found
9
86.92
73.19
73.19
76.06
76.72
73.64
74.05
74.80
72.71
75.62
75.62
75.62
76.01
76.36
77.09
64.09
57.53
76.01
68.65
82.44
70.92
68.65
76.21
73.38
86.87
72.88
73.22
75.76
76.65
73.70
73.93
74.55
72.46
75.76
75.33
75.44
75.81
76.21
76.98
63.92
57.53
75.97
68.56
82.28
70.58
68.29
75.97
73.29
7.29
6.14
6.14
6.09
5.85
6.44
6.71
6.52
5.82
6.63
6.63
6.63
6.93
7.21
6.99
5.38
4.83
6.93
6.55
7.26
6.45
6.55
7.23
6.43
7.32
6.17
6.08
6.10
5.99
6.44
6.77
6.48
5.76
6.40
6.61
6.71
6.98
7.15
7.05
5.37
4.83
6.92
6.46
7.32
6.44
6.25
7.34
6.41
5.79
3.71
3.71
4.03
8.13
3.58
3.45
3.35
3.85
4.01
4.01
4.01
3.85
3.71
3.60
3.40
3.05
3.85
7.28
4.81
6.89
7.28
7.73
7.44
5.83
3.69
3.63
4.01
7.76
3.58
3.64
3.32
3.86
4.01
4.22
3.86
3.80
3.72
3.53
3.42
3.06
3.82
6.94
4.74
6.68
7.19
7.80
7.39
10
11
13
14
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
70 °C was added dropwise
a solution of bromine (1.6 mL,
9.92 mmol) in 6 mL of glacial acetic acid. The mixture was stirred
for 6 h at this temperature, poured after cooling into ice–water
and extracted with ethyl acetate. The organic phase was dried
over MgSO4, filtered, and concentrated under reduced pressure.
The residue was recrystallized from toluene to give 1.9 g (73%)
of pure 5: mp 104–106 °C; IR (neat, cmÀ1) 3293, 1633; 1H NMR
(300 MHz, DMSO-d6) d 1.83 (s, 3H), 3.12 (t, J = 8.3 Hz, 2H), 3.33
(m, 2H), 3.94 (s, 3H), 7.22 (dd, J = 9.0 and 2.4 Hz, 1H), 7.46 (d,
J = 2.0 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H),
8.00 (d, J = 2.0 Hz, 1H), 8.14 (br s, 1H).
4.2.1. N-[2-(3-Bromo-7-methoxynaphth-1-yl)ethyl]
propionamide (6)
Recrystallized from ethanol; yield 89%; mp 146–148 °C; IR
(neat, cmÀ1) 3421, 1642; 1H NMR (300 MHz, DMSO-d6) d 1.00
(t, J = 7.6 Hz, 3H), 2.07 (qu, J = 7.6 Hz, 2H), 3.13 (m, 2H), 3.33
(m, 2H), 3.94 (s, 3H), 7.23 (dd, J = 8.8 and 2.0 Hz, 1H), 7.44 (s,
1H), 7.59 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.97–8.06
(m, 2H).
4.2.2. N-[2-(3-Bromo-7-methoxynaphth-1-yl)ethyl]butyramide
(7)
very good selectivity ratio (304). Conversion of this primary
amine to secondary (32) and then to tertiary (33) induces a
gradual and slight loss of MT2 affinity (0.51 and 0.94, respec-
tively) and selectivity (MT1/MT2 ratio: 162 and 53, respec-
tively). By contrast, replacement of the amine group (32) by
carbamate (31) or acetamide (34) gives derivatives of low and
comparable MT1/MT2 selectivity ratios (15 and 5, respectively)
resulting from a 10-fold loss of MT2 binding affinity with a par-
allel increase of MT1, particularly in the case of the acetamido
compound.
Recrystallized from ethanol; yield 48%; mp 86–88 °C; IR (neat,
cmÀ1) 3234, 1637; 1H NMR (300 MHz, DMSO-d6) d 0.84 (t,
J = 7.4 Hz, 3H), 1.51 (m, 2H), 2.04 (t, J = 7.4 Hz, 2H), 3.13 (m, 2H),
3.35 (m, 2H), 3.95 (s, 3H), 7.23 (dd, J = 9.0 and 2.5 Hz, 1H), 7.44
(d, J = 2.1 Hz, 1H), 7.60 (d, J = 2.5 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H),
8.00 (d, J = 2.1 Hz, 1H), 8.04 (br s, 1H).
4.2.3. N-[2-(3-Bromo-7-methoxynaphth-1-yl)ethyl]cyclobutyl
carboxamide (8)
Recrystallized from ethanol; yield 62%; mp 154–155 °C; IR
(neat, cmÀ1) 3253, 1616; 1H NMR (300 MHz, DMSO-d6) d 1.68–
2.17 (m, 6H), 2.96 (m, 1H), 3.12 (m, 2H), 3.34 (m, 2H), 3.94 (s,
3H), 7.23 (dd, J = 8.9 and 2.1 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.57
(d, J = 2.1 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.87 (br s, 1H), 7.99 (d,
J = 1.6 Hz, 1H).
3. Conclusion
The data highlight the role of the phenyl group located in
the C-3 position of the naphthalene nucleus and confirm the
presence of a hydrophobic pocket at the MT2 receptor subtype.
On the other hand, the MT2 binding affinity as well as the
MT1/MT2 selectivity ratio strongly depend on the presence,
the location and the nature of functional groups on the C-3
phenyl group. Indeed the MT2 affinities varies from 0.30 nM
for 30 to over 43 nM for 19 and the selectivity ratios (MT1/
MT2) from 5 for 34 to over 763 for 21. This suggests the deci-
sive intervention of some other parameters related to these
functionalities.
4.3. General procedure for the synthesis of the 3-phenyl
derivatives (9–18)
4.3.1. Method A
The method adopted for the synthesis of N-[2-(3-phenyl-7-
methoxynaphth-1-yl)ethyl] acetamide (9) is described. Under N2,
a
solution of 5 (1.2 g, 3.7 mmol), phenylboronic acid (0.5 g,
4.0 mmol), palladium acetate (30 mg) potassium carbonate (1.0 g,
7.3 mmol) and tetrabutylammonium bromide (20 mg) in 20 mL
of dioxane and 10 mL of water was stirred at 80 °C for 4 h. After
cooling and filtration, the filtrate was dissolved in ethyl acetate
and washed with brine. The organic phase was dried over
MgSO4, filtered and concentrated under reduced pressure. The res-
idue was recrystallized from toluene to give 0.85 g (71%) of pure 9:
mp 127–129 °C; IR (neat, cmÀ1) 3250, 1632; 1H NMR (300 MHz,
DMSO-d6) d 1.84 (s, 3H), 3.21 (t, J = 7.5 Hz, 2H), 3.38 (m, 2H),
3.97 (s, 3H), 7.21 (dd, J = 9.0 and 2.0 Hz, 1H), 7.38 (t, J = 7.3 Hz,
1H), 7.50 (t, J = 7.3 Hz, 2H), 7.61 (d, J = 7.3 Hz, 2H), 7.78 (d,
J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.93 (d, J = 9.0 Hz, 1H), 8.03 (s, 1H),
8.17 (br s, 1H). Anal. (C21H21NO2) C, H, N.
4. Experimental
4.1. Chemistry
Melting points were determined on a Buchi SMP-20 capillary
apparatus and are uncorrected. IR spectra were recorded on a Per-
kin-Elmer 297 or a Vector 22 Bruker spectrometer. 1H NMR spectra
were recorded on an AC 300 Bruker spectrometer. Chemical shifts
are reported in d units (parts per million) relative to (CH3)4Si.
Elemental analyses for new compounds were performed by CNRS
Laboratories (Vernaison, France) (see Table 3). Obtained results
were within 0.4% of the theoretical values.

S. Poissonnier-Durieux et al. / Bioorg. Med. Chem. 16 (2008) 8339–8348
8345
4.3.2. Method B
4.3.8. 3-[4-(2-Propionylaminoethyl)-6-methoxynaphth-2-yl]
benzoic acid methyl ester (16)
The method adopted for the synthesis of N-[2-(3-(2-formylphe-
nyl)-7-methoxynaphth-1-yl)ethyl] acetamide (12) is described.
Tetrakis(triphenylphosphine)palladium (0) (0.2 g) was added under
N2 to a stirred solution of 5 (2 g, 6.2 mmol) in 30 mL of toluene. After
10 min, a solution of sodium carbonate (2.9 g, 27 mmol) in 10 mL of
water, then a solution of 3-formylphenylboronic acid (1.02 g,
6.8 mmol) in 6 mL of ethanol were added and the mixture was re-
fluxed overnight. After cooling, the mixture was filtered and the fil-
trate was diluted with 50 mL of ethyl acetate and 50 mL of water.
The organic layer was dried over MgSO4, filtered and concentrated
under reduced pressure. The oily residue was purified by column
chromatography (SiO2, acetone/cyclohexane (2:8)) to give 2.15 g
(61%) of pure 12: oil; IR (neat, cmÀ1) 3420, 1686, 1653; 1H NMR
(300 MHz, DMSO-d6) d 1.83 (s, 3H), 3.21 (m, 2H), 3.39 (m, 2H),
3.98 (s, 3H), 7.26 (dd, J = 9.1 and 1.2 Hz, 1H), 7.44 (d, J = 1.2 Hz,
1H), 7.58–7.66 (m, 2H), 7.69 (s, 2H), 7.79 (d, J = 7.6 Hz, 1H), 7.82
(s, 1H), 7.94–7.99 (m, 2H), 8.13 (br s, 1H), 9.95 (s, 1H).
Method A: recrystallized from ethanol; yield 73%; mp 113–
115 °C; IR (neat, cmÀ1) 3364, 1722, 1665; 1H NMR (300 MHz,
DMSO-d6) d 1.00 (t, J = 7.6 Hz, 3H), 2.10 (qu, J = 7.6 Hz, 2H), 3.23
(m, 2H), 3.41 (m, 2H), 3.92 (s, 3H), 3.98 (s, 3H), 7.23 (dd, J = 8.7
and 2.2 Hz, 1H), 7.62–7.71 (m, 3H), 7.94–8.00 (m, 2H), 8.02–8.12
(m, 3H), 8.32 (s, 1H). Anal. (C24H25NO4) C, H, N.
4.3.9. 3-[4-(2-Butyrylaminoethyl)-6-methoxynaphth-2-yl]
benzoic acid methyl ester (17)
Method A: recrystallized from ethanol; yield 52%; mp 86–88 °C;
IR (neat, cmÀ1) 3371, 1722, 1663; 1H NMR (300 MHz, DMSO-d6) d
0.81 (t, J = 7.4 Hz, 3H), 1.50 (m, 2H), 2.06 (t, J = 7.4 Hz, 2H), 3.23 (m,
2H), 3.42 (m, 2H), 3.92 (s, 3H), 3.98 (s, 3H), 7.23 (dd, J = 9.0 and
2.3 Hz, 1H), 7.62–7.71 (m, 3H), 7.95–7.99 (m, 2H), 8.03–8.11 (m,
3H), 8.32 (s, 1H). Anal. (C25H27NO4) C, H, N.
4.3.10. 3-[4-(2-Cyclobutylcarbonylaminoethyl)-6-methoxyna-
phth-2-yl]benzoic acid methyl ester (18)
4.3.3. 3-[4-(2-Acetylaminoethyl)-6-methoxynaphth-2-yl]
benzoic acid methyl ester (10)
Method A: recrystallized from ethanol; yield 43%; mp 128–
130 °C; IR (neat, cmÀ1) 3299, 1720, 1635; 1H NMR (300 MHz,
DMSO-d6) d 1.66–2.17 (m, 6H), 2.99 (m, 1H), 3.23 (m, 2H), 3.42
(m, 2H), 3.92 (s, 3H), 3.98 (s, 3H), 7.24 (dd, J = 8.6 and 2.0 Hz,
1H), 7.61 (d, J = 2.1 Hz, 1H), 7.63–7.69 (m, 2H), 7.91 (br s, 1H),
7.95–7.99 (m, 2H), 8.08 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 1.5 Hz, 1H),
8.32 (s, 1H). Anal. (C26H27NO4) C, H, N.
Method A: recrystallized from ethanol; yield 65%; mp 148–
150 °C; IR (neat, cmÀ1) 3369, 1724, 1661; 1H NMR (300 MHz,
DMSO-d6) d 1.86 (s, 3H), 3.23 (m, 2H), 3.40 (m, 2H), 3.92 (s, 3H),
3.98 (s, 3H), 7.22 (dd, J = 9.0 and 2.5 Hz, 1H), 7.62–7.71 (m, 3H),
7.94–7.99 (m, 2H), 8.05–8.10 (m, 2H), 8.17 (br s, 1H), 8.32 (s,
1H). Anal. (C23H23NO4) C, H, N.
4.3.4. 4-[4-(2-Acetylaminoethyl)-6-methoxynaphth-2-yl]
benzoic acid methyl ester (11)
4.3.11. 3-(4-(2-Acetylaminoethyl)-6-methoxynaphth-2-yl)
benzoic acid (19)
Method A: purified by column chromatography (SiO2, acetone/
cyclohexane (3:7)) and recrystallized from ethanol; yield 52%;
mp 147–149 °C; IR (neat, cmÀ1) 3429, 1712, 1672; 1H NMR
(300 MHz, DMSO-d6) d 1.84 (s, 3H), 3.22 (m, 2H), 3.35 (m, 2H),
3.91 (s, 3H), 3.98 (s, 3H), 7.23 (d, J = 9.0 Hz, 1H), 7.67 (s, 1H), 7.75
(s, 1H), 7.92–8.23 (m, 7H). Anal. (C23H23NO4) C, H, N.
To a solution of 10 (1.5 g, 3.97 mmol) in 50 mL of methanol was
added 10 mL of an aqueous solution of NaOH (0.5 g, 11.91 mmol).
The mixture was refluxed for 2 h, poured into 100 mL of water and
then extracted twice with ether. The aqueous layer was acidified with
10 mL of concentrated HCl and the resulting precipitate was filtered,
washed with water, then recrystallized from ethanol to give 1.24 g
(86%) of pure 19: mp 221–223 °C; IR (neat, cmÀ1) 3500–3400,
3275, 1677, 1638; 1H NMR (300 MHz, DMSO-d6) d 1.86 (s, 3H), 3.22
(m, 2H), 3.41 (m, 2H), 3.99 (s, 3H), 7.23 (dd, J = 9.0 and 2.6 Hz, 1H),
7.64 (t, J = 7.9 Hz, 1H), 7.66 (s, 1H), 7.71 (s, 1H), 7.93–8.00 (m, 2H),
8.06 (dd, J = 7.9 and 1.6 Hz, 1H), 8.10 (s, 1H), 8.17 (br s, 1H), 8.33 (d,
J = 1.6 Hz, 1H), 13.14 (br s, 1H). Anal. (C22H21NO4) C, H, N.
4.3.5. N-[2-(3-(3-Formylphenyl)-7-methoxynaphth-1-yl)ethyl]
acetamide (13)
Method B: purified by column chromatography (SiO2, acetone/
cyclohexane (3:7)) and recrystallized from ethanol; yield 68%;
mp 123–125 °C; IR (neat, cmÀ1) 3390, 1694, 1666; 1H NMR
(300 MHz, DMSO-d6) d 1.86 (s, 3H), 3.23 (m, 2H), 3.40 (m, 2H),
3.98 (s, 3H), 7.24 (dd, J = 9.1 and 2.4 Hz, 1H), 7.68 (d, J = 2.4 Hz,
1H), 7.74 (t, J = 7.5 Hz, 1H), 7.77 (s, 1H), 7.92 (d, J = 7.5 Hz, 1H),
7.97 (d, J = 9.1 Hz, 1H), 8.15–8.20 (m, 3H), 8.34 (s, 1H), 9.95 (s,
1H). Anal. (C22H21NO3) C, H, N.
4.4. General procedure for the synthesis of the 3-(hydroxyme-
thyl)phenyl compounds (20–25)
4.4.1. Method 1
The method adopted for the synthesis of N-[2-(3-(3-hydroxym-
ethylphenyl)-7-methoxynaphth-1-yl)ethyl] acetamide (21) is de-
scribed. A solution of 10 (2.1 g, 5.5 mmol) in 30 mL of ether and
10 mL of THF was cooled to À5 °C and then lithium aluminum hy-
dride (0.6 g, 16.5 mmol) was added portionwise. The mixture was
stirred at room temperature for 6 h, then excess of lithium alumi-
num hydride was hydrolyzed with an aqueous solution of NaOH
20%. The resulting precipitate was filtered, washed with THF and
the filtrate was concentrated under reduced pressure. The residue
was purified by column chromatography (SiO2, acetone/cyclohex-
ane (3:7)) and recrystallized from ethanol to give 1.92 g (72%) of
pure 21.
4.3.6. N-[2-(3-(3-Cyanophenyl)-7-methoxynaphth-1-yl)
ethyl]acetamide (14)
Method A: recrystallized from ethanol; yield 58%; mp 141–
143 °C; IR (neat, cmÀ1) 3300, 2260, 1640; 1H NMR (300 MHz,
DMSO-d6) d 1.86 (s, 3H), 3.23 (m, 2H), 3.38 (m, 2H), 3.99 (s, 3H),
7.24 (d, J = 8.7 Hz, 1H), 7.68 (s, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.77
(s, 1H), 7.83 (d, J = 7.1 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1H), 8.12–8.23
(m, 3H), 8.30 (s, 1H). Anal. (C22H20N2O2) C, H, N.
4.3.7. N-[2-(3-(3-Nitrophenyl)-7-methoxynaphth-1-yl)
ethyl]acetamide (15)
Method A: recrystallized from ethanol; yield 87%; mp 142–
144 °C; IR (neat, cmÀ1) 3306, 1633; 1H NMR (300 MHz, DMSO-d6)
d 1.85 (s, 3H), 3.23 (m, 2H), 3.40 (m, 2H), 3.98 (s, 3H), 7.24 (dd,
J = 8.7 and 2.6 Hz, 1H), 7.68 (d, J = 2.6 Hz, 1H), 7.77–7.83 (m, 2H),
7.98 (d, J = 8.7 Hz, 1H), 8.18 (br s, 1H), 8.21–8.25 (m, 2H), 8.29 (d,
J = 7.7 Hz, 1H), 8.58 (s, 1H). Anal. (C21H20N2O4) C, H, N.
4.4.2. Method 2
The method adopted for the synthesis of compound 21 is de-
scribed. To a solution of 13 (1 g, 2.9 mmol) in 40 mL of methanol
was added portionwise sodium borohydride (0.08 g, 5.8 mmol).
The mixture was stirred at room temperature for 10 min and con-

8346
S. Poissonnier-Durieux et al. / Bioorg. Med. Chem. 16 (2008) 8339–8348
centrated under reduced pressure. The residue was taken off with
ethyl acetate and the organic layer was washed with an aqueous
solution of 1 N HCl, dried over MgSO4, filtered and concentrated
under reduced pressure to afford a crude residue, which was
recrystallized from ethanol to give 2.03 g (76%) of pure 21: mp
153–155 °C; IR (neat, cmÀ1) 3500–3400, 3294, 1625; 1H NMR
(300 MHz, DMSO-d6) d 1.86 (s, 3H), 3.23 (m, 2H), 3.41 (m, 2H),
3.98 (s, 3H), 4.62 (d, J = 5.6 Hz, 2H), 5.30 (t, J = 5.6 Hz, 1H), 7.21
(dd, J = 8.8 and 2.0 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.46 (t,
J = 7.6 Hz, 1H), 7.62–7.70 (m, 3H), 7.75 (s, 1H), 7.93 (d, J = 8.8 Hz,
1H), 8.03 (s, 1H), 8.17 (br s, 1H). Anal. (C22H23NO3) C, H, N.
17 mmol). After stirring for 1 day at room temperature, the mix-
ture was poured into water, the resulting precipitate was filtered,
washed with water and recrystallized from ethanol; yield 55%;
mp 118–120 °C; IR (neat, cmÀ1) 3261, 1626; 1H NMR (300 MHz,
DMSO-d6) d 1.86 (s, 3H), 3.21 (m, 2H), 3.37 (m, 2H), 3.98 (s, 3H),
4.83 (s, 2H), 7.22 (dd, J = 8.9 and 2.4 Hz, 1H), 7.44–7.52 (m, 2 H),
7.66 (d, J = 2.4 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.75 (d, J = 7.6 Hz,
1H), 7.89 (s, 1H), 7.94 (d, J = 8.9 Hz, 1H), 8.06 (s, 1H), 8.17 (br s,
1H). Anal. (C22H22BrNO2) C, H, N.
4.4.9. N-[2-(3-(3-Iodomethylphenyl)-7-methoxynaphth-1-yl)
ethyl]acetamide (27)
4.4.3. N-[2-(3-(2-Hydroxymethylphenyl)-7-methoxynaphth-1-
yl)ethyl]acetamide (20)
To a solution of 26 (0.35 g, 0.85 mmol) in 20 mL of acetone was
added sodium iodide (0.14 g, 0.94 mmol). The mixture was re-
fluxed for 2 h. After cooling and filtration, the filtrate was concen-
trated under reduced pressure to afford a crude residue, which was
recrystallized from toluene; yield 60%; mp 155–157 °C; IR (neat,
cmÀ1) 3263, 1635; 1H NMR (300 MHz, DMSO-d6) d 1.85 (s, 3H),
3.21 (m, 2H), 3.37 (m, 2H), 3.98 (s, 3H), 4.73 (s, 2H), 7.22 (dd,
J = 8.9 and 2.4 Hz, 1H), 7.44–7.46 (m, 2H), 7.63–7.71 (m, 3H),
7.88 (s, 1H), 7.94 (d, J = 8.9 Hz, 1H), 8.04 (s, 1H), 8.16 (br s, 1H).
Anal. (C22H22INO2) C, H, N.
Method B: recrystallized from cyclohexane; yield 92%; mp 57–
59 °C; IR (neat, cmÀ1) 3500–3250, 1636; 1H NMR (300 MHz,
DMSO-d6) d 1.86 (s, 3H), 3.17 (m, 2H), 3.39 (m, 2H), 3.99 (s, 3H),
4.47 (s, 2H), 5.15 (br s, 1H), 7.21 (dd, J = 8.8 and 2.6 Hz, 1H),
7.29–7.46 (m, 3H), 7.58–7.67 (m, 2H), 7.72 (s, 1H), 7.87 (d,
J = 8.8 Hz, 1H), 8.16 (br s, 1H). Anal. (C22H23NO3) C, H, N.
4.4.4. N-[2-(3-(4-Hydroxymethylphenyl)-7-methoxynaphth-1-
yl)ethyl]acetamide (22)
Method A: recrystallized from ethanol; yield 52%; mp 164–
166 °C; IR (neat, cmÀ1) 3400–3200, 1645; 1H NMR (300 MHz,
DMSO-d6) d 1.86 (s, 3H), 3.20 (m, 2H), 3.38 (m, 2H), 3.97 (s, 3H),
4.56 (d, J = 5.7 Hz, 2H), 5.26 (t, J = 5.7 Hz, 1H), 7.20 (dd, J = 8.9 and
2.3 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 2.3 Hz, 1H), 7.68 (d,
J = 1.8 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.91 (d, J = 8.9 Hz, 1H), 8.03
(d, J = 1.8 Hz, 1H), 8.17 (br s, 1H). Anal. (C22H23NO3) C, H, N.
4.4.10. N-[2-(3-(3-Methoxymethylphenyl)-7-methoxynaphth-1-
yl)ethyl]acetamide (28)
To a solution of 26 (0.1 g, 0.24 mmol) in 2 mL of methanol was
added dropwise sodium methoxide (0.026 g, 0.48 mmol) in 10 mL
of methanol. The mixture was refluxed for 4 h and progressively al-
lowed to cool to room temperature, then concentrated under re-
duced pressure. The residue was taken off with ether and
washed with water. The organic layer was dried over MgSO4 and
concentrated under reduced pressure to afford a crude residue,
which was recrystallized from ethanol; yield 75%; mp 86–87 °C;
IR (neat, cmÀ1) 3267, 1635; 1H NMR (300 MHz, DMSO-d6) d 1.86
(s, 3H), 3.21 (m, 2H), 3.30 (s, 3H), 3.37 (m, 2H), 3.97 (s, 3H), 4.52
(s, 2H), 7.21 (dd, J = 8.9 and 2.4 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H),
7.48 (t, J = 7.5 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.68 (d, J = 1.8 Hz,
1H), 7.70–7.74 (m, 2H), 7.94 (d, J = 8.9 Hz, 1H), 8.04 (d, J = 1.6 Hz,
1H), 8.16 (br s, 1H). Anal. (C23H25NO3) C, H, N.
4.4.5. N-[2-(3-(3-Hydroxymethylphenyl)-7-methoxynaphth-1-
yl)ethyl]propionamide (23)
Method A: recrystallized from ethanol; yield 72%; mp 135–
137 °C; IR (neat, cmÀ1) 3300–3200, 1627; 1H NMR (300 MHz,
DMSO-d6) d 1.00 (t, J = 7.6 Hz, 3H), 2.10 (qu, J = 7.6 Hz, 2H), 3.21
(m, 2H), 3.41 (m, 2H), 3.98 (s, 3H), 4.60 (d, J = 5.6 Hz, 2H), 5.29 (t,
J = 5.6 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H),
7.45 (t, J = 7.6 Hz, 1H), 7.59–7.68 (m, 3H), 7.74 (s, 1H), 7.93 (d,
J = 8.7 Hz, 1H), 8.00–8.10 (m, 2H). Anal. (C23H25NO3) C, H, N.
4.4.11. N-[2-(3-(3-Aminomethylphenyl)-7-methoxynaphth-1-
yl)ethyl]acetamide hydrochloride (29)
4.4.6. N-[2-(3-(3-Hydroxymethylphenyl)-7-methoxynaphth-1-
yl)ethyl]butyramide (24)
An NH3-oversaturated solution of 14 (1.2 g, 3.5 mmol) in
100 mL of methanol was hydrogenated over Raney nickel under
pressure (50 bar) at 60 °C for 12 h. After filtration and evaporation,
the oily residue was dissolved in dry ether and treated with gas-
eous HCl. The precipitate was filtered and recrystallized from iso-
propanol to give 0.43 g (32%) of pure 29: mp 239–241 °C; IR
(neat, cmÀ1) 3425–3200, 3258, 1624; 1H NMR (300 MHz, DMSO-
d6) d 1.86 (s, 3H), 3.21 (m, 2H), 3.39 (m, 2H), 3.99 (s, 3H), 4.13
(m, 2H), 7.23 (dd, J = 8.8 and 2.1 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H),
7.54 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.75 (d, J = 1.7 Hz,
1H), 7.82 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 8.02 (d,
J = 1.7 Hz, 1H), 8.09 (s, 1H), 8.29 (br s, 1H), 8.56 (br s, 3H). Anal.
(C22H25 ClN2O2) C, H, N.
Method A: recrystallized from ethanol; yield 25%; mp 113–
115 °C; IR (neat, cmÀ1) 3300–3200, 1626; 1H NMR (300 MHz,
DMSO-d6)
d 0.83 (t, J = 7.5 Hz, 3H), 1.51 (m, 2H), 2.06 (t,
J = 7.5 Hz, 2H), 3.21 (m, 2H), 3.41 (m, 2H), 3.98 (s, 3H), 4.60 (s,
2H), 5.28 (br s, 1H), 7.21 (dd, J = 8.9 and 2.2 Hz, 1H), 7.32 (d,
J = 7.7 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.59–7.68 (m, 3H), 7.73 (s,
1H), 7.93 (d, J = 8.9 Hz, 1H), 8.03 (s, 1H), 8.07 (t, J = 5.5 Hz, 1H).
Anal. (C24H27NO3) C, H, N.
4.4.7. N-[2-(3-(3-Hydroxymethylphenyl)-7-methoxynaphth-1-
yl)ethyl]cyclobutyl carboxamide (25)
Method A: recrystallized from ethanol; yield 40%; mp 131–
133 °C; IR (neat, cmÀ1) 3300–3200, 1627; 1H NMR (300 MHz,
DMSO-d6) d 1.67–2.18 (m, 6H), 2.99 (m, 1H), 3.19 (m, 2H), 3.40
(m, 2H), 3.98 (s, 3H), 4.61 (s, 2H), 5.27 (br s, 1H), 7.22 (dd, J = 9.0
and 2.1 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H),
7.60 (d, J = 2.1 Hz, 1H), 7.63–7.68 (m, 2H), 7.73 (s, 1H), 7.89–7.96
(m, 2H), 8.03 (br s, 1H). Anal. (C25H27NO3) C, H, N.
4.4.12. N-[2-(3-(3-Aminophenyl)-7-methoxynaphth-1-yl)
ethyl]acetamide hydrochloride (30)
A solution of 15 (3 g, 8.2 mmol) in 100 mL of methanol was
hydrogenated over 10% Pd/C (0.1 g) at atmospheric pressure for
6 h. After filtration and evaporation, the oily residue was dissolved
in dry ether and treated with HCl gas. The precipitate was filtered
and recrystallized from 1-propanol; yield 79%; mp 259–261 °C; IR
(neat, cmÀ1) 3253, 3100–2700, 1612; 1H NMR (300 MHz, DMSO-
d6) d 1.84 (s, 3H), 3.21 (m, 2H), 3.38 (m, 2H), 3.97 (s, 3H), 7.24
(dd, J = 9.0 and 2.3 Hz, 1H), 7.34 (dd, J = 7.8 and 1.3 Hz, 1H), 7.58
4.4.8. N-[2-(3-(3-Bromomethylphenyl)-7-methoxynaphth-1-yl)
ethyl]acetamide (26)
To a solution of 21 (0.6 g, 1.7 mmol) in 10 mL of glacial acetic
acid was added a solution of 45% HBr in acetic acid (3.1 mL,

S. Poissonnier-Durieux et al. / Bioorg. Med. Chem. 16 (2008) 8339–8348
8347
(t, J = 7.8 Hz, 1H), 7.60–7.66 (m, 3H), 7.71 (br s, 3H), 7.78 (dd, J = 7.8
and 1.3 Hz, 1H), 7.94 (d, J = 9.0 Hz, 1H), 8.01 (d, J = 1.9 Hz, 1H), 8.21
(br s, 1H). Anal. (C21H23ClN2O2) C, H, N.
3.39 (m, 2H), 3.97 (s, 3H), 6.75 (dd, J = 8.3 and 1.9 Hz, 1H), 7.02–
7.07 (m, 2H), 7.20 (dd, J = 8.9 and 2.6 Hz, 1H), 7.29 (t, J = 8.3 Hz,
1H), 7.64 (m, 2H), 7.92 (d, J = 8.9 Hz, 1H), 8.00 (s, 1H), 8.16 (br s,
1H). Anal. (C23H26N2O2) C, H, N.
4.4.13. N-[2-(3-(3-Ethoxycarbonylaminophenyl)-7-methoxy-
naphth-1-yl)ethyl]acetamide (31)
4.4.16. N-[2-(3-(3-Acetylaminophenyl)-7-methoxynaphth-1-yl)
ethyl]acetamide (34)
To a solution of 30 (3 g, 8.1 mmol) in 30 mL of THF was added
diisopropylethylamine (4.3 mL, 24 mmol). After cooling to 0 °C,
ethyl chloroformate (1.2 mL, 12 mmol) was added dropwise, then
the mixture was stirred at room temperature for 1 h and concen-
trated under reduced pressure. The residue was taken off with
ethyl acetate and the organic layer was washed with water, 1 N
HCl aqueous solution and then with water, dried over MgSO4, fil-
tered and concentrated under reduced pressure to afford a crude
residue, which was recrystallized from ethanol to give 2.3 g (70%)
of pure 31: mp 155–157 °C; IR (neat, cmÀ1) 3381, 3322, 1721,
1671; 1H NMR (300 MHz, DMSO-d6) d 1.27 (t, J = 7.0 Hz, 3 H),
1.86 (s, 3H), 3.20 (m, 2H), 3.41 (m, 2H), 3.98 (s, 3H), 4.16 (qu,
J = 7.0 Hz, 2H), 7.21 (dd, J = 9.1 and 2.1 Hz, 1H), 7.37–7.41 (m,
2H), 7.44 (m, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 2.1 Hz, 1H),
7.90–7.95 (m, 3H), 8.17 (br s, 1H), 9.74 (br s, 1H). Anal.
(C24H26N2O4) C, H, N.
Potassium carbonate (0.36 g, 2.6 mmol) was added to a solution
of 30 (0.5 g, 1.3 mmol) in 10 mL of water and 30 mL of methylene
chloride. The mixture was stirred for 20 min at 0 °C and acetyl
chloride (0.2 g, 2.6 mmol) was added dropwise at the same tem-
perature. After stirring at room temperature for 2 h, the organic
layer was separated, washed with water, 1 N HCl aqueous solution,
and water until pH 7 was reached, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was recrystal-
lized from ethanol/water (1:1) to give 0.34 g (67%) of pure 34:
mp 218–220 °C; IR (neat, cmÀ1) 3341, 3276, 1683, 1650; 1H NMR
(300 MHz, DMSO-d6) d 1.86 (s, 3H), 2.12 (s, 3H), 3.21 (m, 2H),
3.39 (m, 2H), 3.99 (s, 3H), 7.21 (dd, J = 9.1 and 2.0 Hz, 1H), 7.38–
7.47 (m, 2H), 7.61 (d, J = 1.6 Hz, 1H), 7.63 (m, 1H), 7.66 (d,
J = 2.0 Hz, 1H), 7.93 (d, J = 9.1 Hz, 1H), 7.96 (s, 1H), 8.20 (s, 1H),
8.17 (br s, 1H), 10.09 (br s, 1H). Anal. (C23H24N2O3) C, H, N.
4.4.14. N-[2-(3-(3-Methylaminophenyl)-7-methoxynaphth-1-
yl)ethyl]acetamide hydrochloride (32)
4.5. Pharmacology
To a solution of N-[2-(3-(3-aminophenyl)-7-methoxynaphth-1-
yl)ethyl]acetamide (1 g, 3 mmol) in ethyl orthoformate (26 mL,
156 mmol) were added four drops of trifluoroacetic acid. The mix-
ture was refluxed for 3 h and concentrated under reduced pressure.
The residue was taken off with ether and the organic layer was
washed with water, dried over MgSO4, filtered and concentrated
under reduced pressure to afford a residue which was taken off
with 20 mL of ethanol. Sodium borohydride (0.17 g, 4.5 mmol)
was added portionwise and the mixture was stirred at room tem-
perature for 12 h, then refluxed for 2 h. After cooling, the mixture
was concentrated under reduced and the residue was dissolved
in 50 mL of methylene chloride. The organic layer was washed
with water, dried over MgSO4, filtered and concentrated under re-
duced pressure to afford a residue which was purified by column
chromatography (SiO2, acetone/cyclohexane (3:7)). Fractions that
contained 32 were combined and concentrated under reduced
pressure. The residue was dissolved in ether and treated with
HCl gas. The precipitate was filtered and recrystallized from aceto-
nitrile to give 0.53 g (46%) of pure 32: mp 186–189 °C; IR (neat,
cmÀ1) 3500–3250, 1673; 1H NMR (300 MHz, DMSO-d6) d 1.85 (s,
3H), 3.03 (s, 3H), 3.22 (m, 2H), 3.40 (m, 2H), 3.98 (s, 3H), 5.50–
6.20 (br s, 2H), 7.24 (dd, J = 9.0 and 2.4 Hz, 1 H), 7.56 (d, J = 7.6
Hz, 1 H), 7.65 (t, J = 7.6 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.70 (s,
1H), 7.87 (d, J = 7.6 Hz, 1H), 7.92–7.96 (m, 2H), 8.08 (s, 1H), 8.28
(br s, 1H). Anal. (C22H25ClN2O2) C, H, N.
4.5.1. Reagents and chemicals
2-[125I]Iodomelatonin (2200 Ci/mmol) was purchased from
NEN (Boston, MA). Other drugs and chemicals were purchased
from Sigma–Aldrich (Saint Quentin, France).
4.5.2. Cell culture
HEK (provided by A.D. Strosberg, Paris, France) and CHO cell
lines stably expressing the human melatonin MT1 or MT2 receptors
were grown in DMEM medium supplemented with 10% foetal calf
serum, 2 mM glutamine, 100 IU/mL penicillin and 100 lg/mL
streptomycin. Grown at confluence at 37 °C (95% O2/5% CO2), they
were harvested in PBS containing EDTA 2 mM and centrifuged at
1000g for 5 min (4 °C). The resulting pellet was suspended in Tris
5 mM (pH 7.5), containing EDTA 2 mM and homogenized using a
Kinematica polytron. The homogenate was then centrifuged
(95,000g, 30 min, 4 °C) and the resulting pellet suspended in
75 mM Tris (pH 7.5), 12.5 mM MgCl2 and 2 mM EDTA. Aliquots
of membrane preparations were stored at À80 °C until use.
4.5.3. Binding assays
2-[125I]Iodomelatonin binding assay conditions were essentially
as previously described.41 Briefly, binding was initiated by addition
of membrane preparations from stable transfected HEK or CHO
cells diluted in binding buffer (50 mM Tris–HCl buffer, pH 7.4, con-
taining 5 mM MgCl2) to 2-[125I]iodomelatonin (25 or 200 pM for
MT1 and MT2 receptors, respectively, expressed in HEK cells or
20 pM for MT1 and MT2 receptors expressed in CHO cells) and
the tested drug. Non-specific binding was defined in the presence
4.4.15. N-[2-(3-(3-Dimethylaminophenyl)-7-methoxynaphth-1-
yl)ethyl]acetamide (33)
To a solution of N-[2-(3-(3-aminophenyl)-7-methoxynaphth-1-
yl)ethyl]acetamide (0.4 g, 1.2 mmol) in 20 mL of acetonitrile were
added 37% aqueous formaldehyde (0.4 mL) and sodium cyanoboro-
hydride (0.23 g, 3.6 mmol). The mixture was stirred at room tem-
perature for 2 h and 2 N HCl aqueous solution was added
dropwise until formation of a white precipitate. Acetonitrile was
removed under reduced pressure and the residue was taken off
with 40 mL of ethyl acetate. The organic layer was washed with
10% aqueous potassium carbonate, dried over MgSO4, filtered and
concentrated under reduced pressure to afford a residue, which
was recrystallized from isopropylic ether to give 0.16 g (37%) of
pure 33: mp 127–130 °C; IR (neat, cmÀ1) 3264, 1635; 1H NMR
(300 MHz, DMSO-d6) d 1.86 (s, 3H), 2.99 (s, 6H), 3.21 (m, 2H),
of 1 lM melatonin. After a 120 min incubation at 37 °C, reaction
was stopped by rapid filtration through GF/B filters presoaked in
0.5% (v/v) polyethylenimine. Filters were washed three times with
1 mL of ice-cold 50 mM Tris–HCl buffer, pH 7.4.
Data from the dose–response curves (seven concentrations in
duplicate) were analysed using the program PRISM (Graph Pad
Software Inc., San Diego, CA) to yield IC50 (inhibitory concentration
50). Results are expressed as Ki = IC50/1 + ([L]/KD), where [L] is the
concentration of radioligand used in the assay and KD, the dissoci-
ation constant of the radioligand characterising the membrane
preparation.
[
35S]GTP
lished methodology.41 Briefly, membranes from transfected CHO
cS binding assay was performed according to pub-

8348
S. Poissonnier-Durieux et al. / Bioorg. Med. Chem. 16 (2008) 8339–8348
19. Pandi-Perumal, S. R.; Srinivasan, V.; Poeggeler, B.; Hardeland, R.; Cardinali, D. P.
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Nicolas, J. P.; Bennejean, C.; Delagrange, P.; Langlois, M. J. Med. Chem. 2000, 43,
4051.
27. Mor, M.; Spadoni, G.; Di Giacomo, B.; Diamantini, G.; Bedini, A.; Tarzia, G.;
Plazzi, P. V.; Rivara, S.; Nonno, R.; Lucini, V.; Pannacci, M.; Fraschini, F.;
Stankov, B. M. Bioorg. Med. Chem. 2001, 9, 1045.
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Nicolas, J. P.; Bennejean, C.; Delagrange, P.; Renard, P.; Lesieur, D. J. Med. Chem.
2002, 45, 2788.
29. Yous, S.; Durieux-Poissonnier, S.; Lipka-Belloli, E.; Guelzim, H.; Bochu, C.;
Audinot, V.; Boutin, J. A.; Delagrange, P.; Bennejean, C.; Renard, P.; Lesieur, D.
Bioorg. Med. Chem. 2003, 11, 753.
30. Rivara, S.; Mor, M.; Silva, C.; Zuliani, V.; Vacondio, F.; Spadoni, G.; Bedini, A.;
Tarzia, G.; Lucini, V.; Pannacci, M.; Fraschini, F.; Plazzi, P. V. J. Med. Chem. 2003,
46, 1429.
31. Rivara, S.; Mor, M.; Lorenzi, S.; Lodola, A.; Plazzi, P. V.; Spadoni, G.; Bedini, A.;
Tarzia, G. Arkivoc 2006, VIII, 8.
cells expressing MT2 receptor subtype and compounds were di-
luted in binding buffer (20 mM HEPES, pH 7.4, 100 mM NaCl,
3
l
M GDP, 3 mM MgCl2, and 20
started by the addition of 0.2 nM [35S]GTP
(20 g/mL) and drugs, and further followed for 1 h at room tem-
l
g/mL saponin). Incubation was
cS to membranes
l
perature. For experiments with antagonists, membranes were pre-
incubated with both the melatonin (3 nM) and the antagonist for
30 min prior the addition of [35S]GTP
cS. Non-specific binding
was defined using cold GTPcS (10 lM). Reaction was stopped by
rapid filtration through GF/B filters followed by three successive
washes with ice-cold buffer.
Usual levels of [35S]GTP
c
S binding (expressed in dpm) were for
CHO-MT2 membranes: 2000 for basal activity, 8000 in the presence
of melatonin 1 M and 180 in the presence of GTP S 10 M which
l
c
l
defined the non-specific binding. Data from the dose–response
curves (seven concentrations in duplicate) were analysed by using
the program PRISM (Graph Pad Software Inc., San Diego, CA) to
yield EC50 (effective concentration 50%) and Emax (maximal effect)
for agonists. Antagonist potencies are expressed as KB = IC50
1 + ([Ago]/EC50 ago), where IC50 is the inhibitory concentration of
antagonist that gives 50% inhibition of [35S]GTP
S binding in the
/
c
presence of a fixed concentration of melatonin ([Ago]) and EC50
ago is the EC50 of the molecule when tested alone. Imax (maximal
inhibitory effect) was expressed as a percentage of that observed
with melatonin at 3 nM for MT2 receptor.
32. Rivara, S.; Lodola, A.; Mor, M.; Bedini, A.; Spadoni, G.; Lucini, V.; Pannacci, M.;
Fraschini, F.; Scaglione, F.; Sanchez, R. O.; Gobbi, G.; Tarzia, G. J. Med. Chem.
2007, 50, 6618.
Acknowledgments
33. Bedini, A.; Spadoni, G.; Gatti, G.; Lucarini, S.; Tarzia, G.; Rivara, S.; Lorenzi, S.;
Lodola, A.; Mor, M.; Lucini, V.; Pannacci, M.; Scaglione, F. J. Med. Chem. 2006, 49,
7393.
34. Tsotinis, A.; Vlachou, M.; Papahatjis, D. P.; Calogeropoulou, T.; Nikas, S. P.;
Garratt, P. J.; Piccio, V.; Vonhoff, S.; Davidson, K.; Teh, M. T.; Sugden, D. J. Med.
Chem. 2006, 49, 3509.
The authors gratefully acknowledge the technical assistance of
Mrs. Anne Bonnaud.
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