Synthesis and structure-affinity-activity relationships of novel benzofuran derivatives as MT2 melatonin receptor selective ligands

Article abstract of DOI:10.1021/jm0005252

A series of N-(2-phenylbenzofuran-3-yl) ethyl amide and N-(2-arylalkylbenzofuran-3-yl) ethyl amide derivatives were synthesized and evaluated as melatonin receptor ligands. The affinity of each compound for the two MT₁ and MT₂ melato

Full text of DOI:10.1021/jm0005252

2788
J . Med. Chem. 2002, 45, 2788-2800
Syn th esis a n d Str u ctu r e-Affin ity-Activity Rela tion sh ip s of Novel Ben zofu r a n
Der iva tives a s MT2 Mela ton in Recep tor Selective Liga n d s
Vale´rie Wallez,† Sophie Durieux-Poissonnier,† Philippe Chavatte,† J ean A. Boutin,‡ Vale´rie Audinot,‡
J ean-Paul Nicolas,‡ Caroline Bennejean,§ Philippe Delagrange,§ Pierre Renard,§ and Daniel Lesieur*,†
Institut de Chimie Pharmaceutique Albert Lespagnol, 3 rue du Professeur Laguesse, BP 83, 59006 Lille Cedex, France,
Division de Pharmacologie Mole´culaire et Cellulaire, Institut de Recherches Servier, 125 Chemin de Ronde,
78290 Croissy-sur-Seine, France, and Institut de Recherches Internationales Servier, 1 rue Carle He´bert,
92415 Courbevoie Cedex, France
Received December 11, 2000
A series of N-(2-phenylbenzofuran-3-yl) ethyl amide and N-(2-arylalkylbenzofuran-3-yl) ethyl
amide derivatives were synthesized and evaluated as melatonin receptor ligands. The affinity
of each compound for the two MT1 and MT2 melatonin receptor subtypes was determined by
binding studies using 2-[125I]iodomelatonin on human embryonic kidney cell line HEK293
membrane homogenates. The intrinsic activity of the most interesting compounds was evaluated
on the [35S]GTPγS binding assay. Introduction of a 2-phenyl substituent in the C-2 benzofuran
position leads to an agonist compound, 10q, which binds more strongly than melatonin itself
to both MT1 and MT2 subtypes. On the other hand, a 2-benzyl group in the same position
allows MT2 antagonist selective ligands to be obtained. The MT2 selectivity and antagonist
potency can be modulated with suitable modifications on the N-acyl and benzyl substituents,
and the most selective compounds 10c and 19 show affinity ratios of 123 and 192, respectively,
and bind to the MT2 subtype similarly to melatonin itself (0.1 nM). Nevertheless, 10c acts as
an MT1 and MT2 antagonist, whereas 19 is a partial agonist.
Ch a r t 1
In tr od u ction
Melatonin (5-methoxy-N-acetyltryptamine) (1a) (Chart
1) is a neurohormone synthesized in the pineal gland
during the dark period whatever the species considered
including humans.1 Synthesis of melatonin is regulated
by circadian and seasonal variations in day length.
Melatonin acts through the blood circulation as an
internal synchronizer of circadian rhythms. The central
and peripheral structures, which represent melatonin
receptors or binding sites, receive the information about
the photoperiod.
Two human melatonin receptors have been cloned2,3
and defined as MT1 and MT2 receptors.4 These two
receptors belong to the family of seven-transmembrane-
domain G-protein-coupled receptors. Both receptors
have similar binding for melatonin and display similar
rank orders for the binding of reference melatonin
ligands despite 60% homology between the two recep-
tors. Activation of these two receptor subtypes leads to
the inhibition of adenylyl cyclase probably through
activation of a Gi protein.2,3 The studies of their tissue
distribution2,3 in mammals show that these receptors
are localized in different areas of the brain (suprachi-
asmatic nucleus, pars tuberalis, hypothalamus, cerebel-
lum, cortex, hippocampus, cerebral vessels) and at the
peripheral level in the kidney, small intestine, and
caudal arteries.2-9 From these studies, it appears that
the two receptors are colocalized in the hippocampus
and suprachiasmatic nucleus. This diversity and the
differences in tissue distribution are in favor of different
functional roles for each receptor subtype. Pharmaco-
logical investigations with selective agonist or antago-
nist ligands are therefore necessary to determine the
physiological role of these melatonin receptor subtypes
and their implication in physiopathological processes.
This information will probably open new therapeutic
perspectives for selective ligands, different from the
chronobiotic properties of melatonin clearly demon-
strated in humans.10,11
* To whom correspondence should be addressed. Phone:
+33 3.20.96.40.20. Fax: +33 3.20.96.43.61. E-mail: dlesieur@
phare.univ-lille2.fr.
† Institut de Chimie Pharmaceutique Albert Lespagnol.
‡ Institut de Recherches Servier.
§ Institut de Recherches Internationales Servier.
10.1021/jm0005252 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/18/2002

Benzofuran Derivatives as Melatonin Receptor Ligands
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 13 2789
Ta ble 1. MT1 and MT2 Receptor Binding Affinities of Benzofuran Compounds
Ki ( SEM
(nM) (MT1)
Ki ( SEM
(nM) (MT2)
compd
n
R1
R2
R3
MT1/MT2
1a
1b
0.12 ( 0.02
0.15 ( 0.02
1.27 ( 0.02
14.3 ( 2.00
40.6 ( 1.70
24.0 ( 3.50
0.75 ( 0.10
80.0 ( 28.7
7.19 ( 1.92
84.5 ( 0.01
476 ( 53.0
66.4 ( 3.10
29.0 ( 2.00
31.5 ( 6.10
64.4 ( 15.7
288 ( 21.0
155 ( 14.0
229 ( 2.00
0.01 ( 0.01
8.67 ( 3.43
3.29 ( 0.43
698 ( 12.0
53.7 ( 12.0
55.0 ( 15.2
0.02 ( 0.01
12.9 ( 1.50
3.51 ( 2.30
21.6 ( 2.50
0.01 ( 0.01
1.01 ( 0.32
5.37 ( 0.16
0.04 ( 0.01
569 ( 90.0
42.7 ( 5.50
8.20 ( 2.31
0.31 ( 0.05
0.34 ( 0.02
0.05 ( 0.02
0.34 ( 0.03
0.32 ( 0.09
0.50 ( 0.20
0.23 ( 0.08
1.17 ( 0.34
0.22 ( 0.01
12.8 ( 1.90
340 ( 24.0
2.49 ( 1.05
3.53 ( 1.14
1.52 ( 0.56
8.25 ( 0.88
17.0 ( 6.70
10.6 ( 1.30
18.6 ( 3.00
0.02 ( 0.01
0.41 ( 0.04
0.20 ( 0.10
36.7 ( 1.80
0.69 ( 0.14
2.76 ( 0.57
0.01 ( 0.01
1.70 ( 0.10
0.06 ( 0.03
0.11 ( 0.02
0.02 ( 0.01
0.21 ( 0.02
0.35 ( 0.01
0.04 ( 0.01
79.9 ( 9.10
9.64 ( 1.16
3.21 ( 0.22
0.4
0.5
23
42
123
48
2.8
69
33
6.6
1.4
27
8.2
21
7.8
17
15
12
0.7
21
17
19
78
20
1.5
7.6
57
192
0.7
4.8
15
1.2
7.1
4.4
2.6
0
1
1
1
1
1
1
1
1
1
1
1
3
1
1
1
1
0
1
1
1
1
1
0
0
1
1
0
0
1
0
1
1
1
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-C2H5
-C2H5
-H
-H
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
11
12
13
14
15
16
17
18
19
-C6H5
-C6H4(OCH3) (o)
-C6H4(OCH3) (m)
-C6H4(OCH3) (p)
-C6H4(F) (m)
-C6H4(CF3) (m)
-C6H4(Cl) (m)
-C6H3(Cl)2 (o, o)
-C6H3(CF3)2 (m, m)
-C6H11
-C5H4N (m)
-C6H5
-C6H5
-C6H4(OCH3) (m)
-C6H5
-H
-C6H4(OCH3) (m)
-C6H5
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OH
-C6H5
-CH2I
-C6H5
-C3H7
-furyl
-CHdCH2
-CHdCH2
-CHdCH2
-furyl
-C6H5
-C6H5
-C6H4(OCH3) (m)
-C6H5
-C6H5
-C6H5
-CH2CHdCH2
-CH2CHdCH2
-CH2CHdCH2
-CHdCHCH3
-NHCH3
-NHCH3
-CH3
-C6H4(OCH3) (m)
-C6H5
20
21
22
23
24
25
26
-C6H5
-C6H5
-C6H5
-C6H5
-OC5H11
-OC6H13
-C6H5
-CH3
-CH3
-C6H5
The first MT2 selective antagonists 4-phenyl-2-pro-
pionamidotetraline and 4-phenyl-2-acetamidotetraline
(Chart 1) were reported in 1997 with MT1/MT2 affinity
ratios of about 300.12 These new pharmacological tools
have recently led to the identification of functional MT2
receptors in the suprachiasmatic nucleus, retina, and
rat caudal artery, respectively, involved in the resyn-
chronization of circadian rhythms,13 inhibition of dopa-
mine release,12 and vasodilatation.14 Selective MT2
agonists N-butanoyl-2-(2-methoxy-6H-isoindolo[2,1-a]-
indol-11-yl) ethylamine and (N-[2-(7-methoxy-1-naph-
thyl)ethyl] cyclobutylcarboxamide (Chart 1) have also
been reported15,16 with MT1/MT2 affinity ratios of about
80. To date there is no selective agonist or antagonist
for the MT1 receptor.
sterism with the indole heterocycle such as the naph-
thalene, benzothiophene, and benzofuran analogues.
Unfortunately most literature binding data have been
obtained from tissues expressing more than one receptor
subtype, and it is quite impossible to define structure-
affinity relationships for the different receptor subtypes
with the available binding data.
Here, we report the synthesis of new benzofuran
compounds and their binding characteristics on the
human MT1 and MT2 melatonin receptors. The benzo-
furan ring was selected for chemical modifications as it
has been reported that benzofuran analogues of mela-
tonin, such as N-acetyl-2-(5-methoxybenzo[b]furan-3-yl)
ethylamine (1b) (Chart 1 and Table 1), are good ligands
for the melatonin receptors,20 and are metabolically
more stable than melatonin.21 Different arylalkyl groups,
a cyclohexylmethyl and a phenyl, were introduced on
the 2 position of the benzofuran bioisostere (Table 1) to
modify the intrinsic activity, the affinity toward the two
receptor subtypes MT1 and MT2, and so the selectivity.
With this aim and to confirm the role of the N-acyl side
chain and the 5-methoxy group on the binding affinity
and the intrinsic activity, modifications were also made
to these two substituents (Table 1). For all these
compounds, the synthesis, the binding data, and some
activity results for the human MT1 and MT2 melatonin
receptors are reported.
The synthesis of selective melatonin receptor ligands
is still a challenge. During the past decade, the synthe-
sis and biological study of potent indole and non-indole
melatonin receptor ligands have improved our knowl-
edge of the structural requirements for the binding of
melatonin to its receptors: the key elements for high
binding affinity are the presence and the relative spatial
position of the methoxy group and the N-alkylamido side
chain linked to an appropriate spacer.17-19 The proton
donor NH indole is not essential, and several potent
ligands have been designed on the basis of their bioiso-

2790 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 13
Wallez et al.
Sch em e 1a
Sch em e 3a
a
Reagents: (a) H2, Raney nickel, ethanol; (b) BH3, THF; (c) HCl,
ether; (d) H2, Raney nickel, (CH3CO)2O; (e) CH3COCl, K2CO3, H2O,
methylene chloride.
bromo intermediate, which was not isolated, was sub-
stituted with sodium cyanide in DMSO.
The primary amines 9a -9q were prepared from the
nitriles 8a -8q by hydrogenation in the presence of
Raney nickel as catalyst in ethanol or by reduction with
a borane-tetrahydrofuran complex, and isolated in the
form of hydrochloride salts by treatment with HCl gas
in ether (Scheme 3). The N-acetyl derivatives 10a -10q
were then prepared through two methods of synthesis
(Scheme 3): by hydrogenation of the nitriles 8a -8d , 8i,
8j, 8l, 8m , 8o, and 8p in the presence of Raney nickel
as catalyst in acetic anhydride or from the amine
hydrochlorides 9e-9h , 9k , 9n , and 9q in a biphasic
medium (according to a variant of the Schotten-
Baumann procedure29) by treatment with the acetyl
chloride in the presence of K2CO3 as base.
a
Reagents: (a) R2(CHdCH)mCHO, Al2O3, methylene chloride;
(b) H2, Pd/C, methanol, dioxane; (c) NaH, (EtO)2POCH2CN, HMPT,
anhydrous THF.
Sch em e 2a
By using this last reaction with the appropriate acid
chlorides, the amine hydrochlorides 9a , 9c, and 9q led
to the N-acylated compounds 11-17 (Scheme 4). A
peptide coupling reaction type in the presence of 1-(3-
dimethylaminopropyl)-3-ethylcarbidiimide hydrochlo-
ride (EDCI) between the amine hydrochlorides 9a , 9c,
and 9q, liberated from the hydrochloride by washing
with a solution of K2CO3 and extracting with ether, and
vinylacetic acid gave the amides 18-20 (Scheme 4). This
reaction was made again between the amine hydrochlo-
ride 9q and the vinylacetic acid, but with addition of
triethylamine and 1-hydroxybenzotriazole hydrate
(HOBt) in the mixture (Scheme 4). An isomerization of
the unsaturated bond was then observed thanks to the
1H NMR studies, and the amide 21 was isolated. The
ureas 22 and 23 were finally obtained from the amine
hydrochlorides 9a and 9q by reaction of methylisocy-
anate in pyridine (Scheme 4).
a
Reagents: (a) NBS, AIBN, CCl4; (b) NaCN, DMSO.
Ch em istr y
Key intermediates in the synthesis of the target
compounds 10a -10q and 11-24 are the corresponding
acetonitriles 8a -8q (Schemes 1 and 2) and the primary
amines 9a -9q (Schemes 3 and 4).
The nitriles 8a -8p (Scheme 1) were prepared from
the previously described22,23 5-methoxy- or 5-ethyl-3-oxo-
2,3-dihydrobenzo[b]furans (2, 3) and the commercially
available 3-oxo-2,3-dihydrobenzo[b]furan (4). Com-
pounds 2-4 reacted with the appropriate aldehydes in
methylene chloride in the presence of aluminum oxide
as solid support24 to afford the corresponding R,â-
unsaturated ketones 5a -5p , which were hydrogenated
in methanol and dioxane with Pd/C as catalyst. A
Horner-Emmons reaction on the resulting ketones 6a -
6p with the carbanion formed in situ by sodium hydride
and the diethyl cyanomethylphosphonate as reactant25
in HMPT26 and tetrahydrofuran gave then the desired
nitriles 8a -8p .
Treatment of amide 10a with the BBr3/Me2S complex
gave the hydroxy compound30 24, which then reacted
with the appropriate alkyl iodide in the presence of K2-
CO3 as base to afford the corresponding ethers 25 and
26 (Scheme 5).
P h a r m a cology
To obtain the nitrile 8q (Scheme 2), the previously
described27,28 5-methoxy-3-methyl-2-phenylbenzo[b]fu-
ran (7) was first brominated with N-bromosuccinimide
in the presence of AIBN in CCl4, and the resulting
The compounds were evaluated for their binding
affinity for human MT1 and MT2 receptors stably
transfected in human embryonic kidney (HEK 293)
cells, using 2-[125I]iodomelatonin as radioligand.

Benzofuran Derivatives as Melatonin Receptor Ligands
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 13 2791
Sch em e 4a
a
Reagents: (a) R3COCl, K2CO3, H2O, methylene chloride; (b) K2CO3, water, ether; (c) CH2dCHCH2COOH, EDCI, methylene chloride;
(d) CH2dCHCH2COOH, EDCI, Et3N, HOBt, methylene chloride; (e) CH3NCO, pyridine.
Ta ble 2. Intrinsic Activity Values
MT1
MT2
EC50 ( SEM
Emax ( SEM
KB ( SEM
EC50 ( SEM
Emax ( SEM
KB ( SEM
compd
(nM)
(%)
(nM)
(nM)
(%)
(nM)
1a
1.92 ( 0.38
21 ( 4
100
48 ( 6
<10
ND
ND
0.47 ( 0.07
>10000
0.41 ( 0.18
0.72 ( 0.13
>10000
1.26 ( 0.53
10 ( 3
19 ( 9
>10000
0.096 ( 0.001
0.17 ( 0.06
0.39 ( 0.04
100
<10
25 ( 1
30 ( 1
<10
13 ( 1
41 ( 4
25 ( 2
<10
100 ( 1
20 ( 3
44 ( 1
ND
10a
10b
10c
10d
10f
10j
10n
10o
10q
18
0.21 ( 0.04
0.88 ( 0.45
1.65 ( 0.44
0.42 ( 12
2.4 ( 0.71
7 ( 1
>10000
37 ( 21
>10000
>10000
481 ( 63
>10000
>10000
0.17 ( 0.05
25 ( 5
26 ( 6
26 ( 5
35 ( 8
89 ( 10
242.4 ( 116
266 ( 50
27 ( 9
ND
25 ( 11
<10
<10
41 ( 10
<10
18 ( 2
<10
12 ( 3
100 ( 5
35 ( 3
43 ( 9
ND
ND
57 ( 17
0.16 ( 0.06
0.24 ( 0.02
19
138 ( 11
Sch em e 5a
ligand melatonin has an efficacy (Emax) of 100%. Full
agonists stimulate [35S]GTPγS binding with a maximum
efficacy, close to that of melatonin itself. If Emax is
between 30% and 70%, the compound is considered a
partial agonist. Whereas if Emax is inferior to 30%, the
compound is considered an antagonist. In this last case
the antagonist potency (KB) is determined against 30
or 3 nM melatonin for MT1 or MT2, respectively.
Resu lts a n d Discu ssion
The chemical structures, binding affinities, and MT1/
MT2 selectivity ratios of the new compounds are re-
ported in Table 1. The intrinsic activities of the most
interesting ones are shown in Table 2.
The benzofuran bioisostere of melatonin (1b) can be
considered a very interesting lead compound: (i) its
affinity values for both MT1 and MT2 receptors are
nearly the same as those of melatonin (Table 1), and
(ii) its predicted bioavailability is different and better
than that of melatonin.21
a
Reagents: (a) BBr3/Me2S, methylene chloride; (b) R-I, K2CO3,
acetonitrile.
Starting from this benzofuran bioisostere, we decided
to incorporate changes at the C-2 and C-5 positions and
in the acyl side chain to investigate structure-affinity
(selectivity) and structure-activity relationships for
MT1 and MT2 subtypes.
(a ) 2-P h en ylben zofu r a n s. The positive effect of a
2-phenyl substitution already described for melatonin
itself and some analogues in displacing 2-[125I]iodo-
melatonin from different tissues31,32 is also observed in
our series and affects both MT1 and MT2 subtypes,
The activity and efficacy of the most interesting
compounds were evaluated on [35S]guanosine-5′-O-(3-
thiotriphosphate) ([35S]GTPγS) binding in Chinese ham-
ster ovarian (CHO) cells, stably transfected with human
MT1 and MT2 receptors. This test measures the interac-
tion between the melatonin receptors and the G pro-
teins.
An agonist stimulates [35S]GTPγS binding, and this
stimulation is proportional to the efficacy and intrinsic
activity of the molecule. By convention, the natural

2792 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 13
Wallez et al.
(i) Va r ia tion s of th e 2-Ben zyl Gr ou p . The presence
of various substituents on the 2-benzyl moiety allows
the MT2 selectivity to be modulated. This selectivity is
better for the compounds bearing a methoxy group
(10b-10d ) than for the unsubstituted derivative (10a ).
Moreover, it depends on the position of this group on
the aromatic ring, the meta position being the most
favorable: compound 10c (MT1/MT2 ratio 123) is about
5-fold more selective for MT2 than the lead 10a and
3-fold more selective than its isomers 10b and 10d .
Moreover, this selective compound presents an affinity
for MT2 similar to that of melatonin itself and acts as
an MT2 and MT1 antagonist (Figure 1). Replacement of
the methoxy group on the meta position by a trifluo-
romethyl (10f) or a chlorine (10g) decreases the MT2
selectivity, which totally disappears with the fluoro
derivative (10e). On the other hand, introduction of two
substituents on the aromatic ring in the ortho (10h ) or
meta (10i) position is particularly unfavorable for both
affinity and selectivity. All these results show that steric
and electronic parameters are probably involved in the
influence of the 2-benzyl moiety on affinity and selectiv-
ity. Replacement of the phenyl group by a pyridin-3-yl
heterocycle (10k ) decreases the MT2 affinity more
strongly than the MT1 affinity and therefore the selec-
tivity, whereas lengthening the side chain from one to
three methylene groups (10l) leads to the same selectiv-
ity ratio as that for the phenyl but with a decrease in
binding affinity. The substitution of the aromatic phenyl
ring in the 2 position with a cyclohexyl group (10j)
causes a decrease in both MT1 and MT2 binding affini-
ties and a partial loss of the antagonist potency;
compound 10j acts as a partial agonist with an MT2
selectivity ratio of 27.
F igu r e 1. Comparison of the [35 S]GTPγS binding curves of
1a (b), 10q (0), 10c (O), and 19 (9) tested on hMT1 and hMT2
expressed in CHO cells. Agonist stimulation of [35 S]GTPγS
binding (0.1 nM) is expressed as the percentage of basal
binding taken at 0% in the presence of various logarithmic
concentrations of ligands (1 pM to 0.1 µM).
These results confirm the previously reported hypoth-
esis that both MT1 and MT2 subtypes possess a second-
ary binding site around the C-2 position.34 This binding
site could be a hydrophobic pocket, and the main
difference between the two subtypes lies in the size of
this pocket, which is smaller in the case of the MT1
subtype. Moreover, considering the role of the substitu-
ent position on the aromatic nucleus, it seems that
electronic parameters also contribute to the selectivity
and to the antagonist activity.
leading to one of the most potent agonist melatonin
receptor ligands reported to date (10q; Figure 1). This
result is in agreement with previous studies concerning
the indole series31,32 and confirms the hypothesis of a
secondary binding site around the C-2 position, but it
also allows the specification that this secondary binding
site is present in both MT1 and MT2 receptor subtypes.
Structural variations at the N-alkylamido group were
found to be less important than in other series of
melatonin analogues.20,33 Replacement of the methyl
group of the amide side chain by a vinyl (16), allyl (20),
or methylamino (23) does not modify the binding affinity
for each of the two receptor subtypes, all these com-
pounds therefore being devoid of selectivity. Neverthe-
less, methylvinyl (21) and furyl (17) substituents de-
crease the binding affinity for MT1 more than for MT2.
(ii) Va r ia tion s of th e Acyl Gr ou p on th e C-3 Sid e
Ch a in . Substitution of the methyl group of 10a with
iodomethyl (11), propyl (12), vinyl (14), or methylamino
(22) causes a slight decrease in both MT1 and MT2
binding affinities, leading to MT1/MT2 ratios between
15 (22) and 78 (14). On the other hand, substitution with
a furyl substituent (13) sharply decreases the MT1 and
MT2 affinities but does not affect the MT1/MT2 selectiv-
ity ratio (MT1/MT2 ) 19). The most interesting results
are obtained with the allyl substituent (18, 19). The MT2
binding affinity of these two compounds is better than
that of melatonin itself, and the best MT1/MT2 selectiv-
ity ratio (192) is observed for 19, which bears a 2-(m-
methoxybenzyl) substitution and is 8-fold more selective
than the lead 10a . Nevertheless, compound 19 behaves
as an MT1 and MT2 partial agonist (Figure 1) whereas
its N-acetamido analogue 10c is an antagonist (Figure
1).
(b) 2-Ben zylben zofu r a n s. Introduction of a benzyl
group in the C-2 benzofuran position (10a ) slightly
increases the MT2 binding affinity but decreases the
MT1 binding affinity 10-fold, leading to a quite interest-
ing selectivity ratio (MT1/MT2 ) 23). Moreover, this
compound behaves as an MT2 antagonist and an MT1
partial agonist. We therefore decided to select this
compound (10a ) as a lead in the search for MT2 selective
agents.
These results also show that the N-acyl side chain
can modulate affinity and selectivity but that its role is

Benzofuran Derivatives as Melatonin Receptor Ligands
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 13 2793
abundantly with methylene chloride. The filtrate was then
different according to the presence or not of a substitu-
tion in the C-2 benzofuran position. The unsaturated
allyl substituent seems to be the most favorable for MT2
affinity and selectivity but not for the antagonist
potency.
concentrated to afford crude 5a , which was recrystallized from
1
methanol to give 3.4 g (75%) of pure 5a : mp 133-135 °C; H
NMR (300 MHz, DMSO-d6) δ 7.95-7.90 (m, 2H), 7.45-7.40
(m, 3H), 7.25-7.20 (m, 3H), 6.90 (s, 1H), 3.85 (s, 3H).
Da ta for 5-Meth oxy-2-(2-m eth oxyp h en yl)m eth ylid en e-
3-oxo-2,3-d ih yd r oben zo[b]fu r a n (5b): recrystallized from
methanol; yield 80%; mp 164-166 °C; 1H NMR (300 MHz,
DMSO-d6) δ 7.60-7.40 (m, 5H), 7.30 (d, J ) 2.7 Hz, 1H), 7.05
(dd, J ) 2.7 and 8.3 Hz, 1H), 6.95 (s, 1H), 3.85 (s, 6H).
Da ta for 5-Meth oxy-2-(3-m eth oxyp h en yl)m eth ylid en e-
3-oxo-2,3-d ih yd r oben zo[b]fu r a n (5c): recrystallized from
ethanol (95%); yield 76%; mp 121-123 °C; 1H NMR (300 MHz,
DMSO-d6) δ 7.50-7.20 (m, 6H), 6.95-6.90 (m, 1H), 6.85 (s,
1H), 3.90 (s, 3H), 3.85 (s, 3H).
(iii) Va r ia tion s of th e 5-Meth oxy Gr ou p . Deletion
of the 5-methoxy group (10o, 10p ) causes a sharp
decrease in the MT1 and MT2 binding affinities, a
finding that parallels previous results in other se-
ries.20,33 It seems possible that the MT1/MT2 ratios of
these compounds (15 and 12, respectively) point out a
less important role of the methoxy group in the MT2
versus MT1 selectivity. This hypothesis is strengthened
by the fact that the same results are obtained by
substitution of the methoxy with an ethyl (10m , 10n )
or a hydroxy (24). On the other hand, lengthening the
alkyl chain of the ether function to five (25) or six (26)
carbon atoms more strongly decreases the MT2 binding
affinity than the MT1 binding affinity and therefore
appears unfavorable for MT2 selectivity.
Da ta for 5-Meth oxy-2-(4-m eth oxyp h en yl)m eth ylid en e-
3-oxo-2,3-d ih yd r oben zo[b]fu r a n (5d ): recrystallized from
methanol; yield 84%; mp 173-175 °C; 1H NMR (300 MHz,
DMSO-d6) δ 7.95 (d, J ) 8.8 Hz, 2H), 7.50 (d, J ) 9.1 Hz, 1H),
7.40 (dd, J ) 2.6 and 9.1 Hz, 1H), 7.25 (d, J ) 2.6 Hz, 1H),
7.05 (d, J ) 8.8 Hz, 2H), 6.95 (s, 1H), 3.85 (s, 3H), 3.80 (s,
3H).
Da t a for 2-(3-F lu or op h en yl)m et h ylid en e-5-m et h oxy-
3-oxo-2,3-d ih yd r oben zo[b]fu r a n (5e): recrystallized from
methanol; yield 70%; mp 144-146 °C; 1H NMR (300 MHz,
DMSO-d6) δ 7.85-7.80 (m, 2H), 7.60-7.50 (m, 2H), 7.40 (dd,
J ) 2.8 and 9.1 Hz, 1H), 7.35-7.30 (m, 1H), 7.25 (d, J ) 2.8
Hz, 1H), 7.00 (s, 1H), 3.85 (s, 3H).
All these results clearly confirm the crucial role
played by the 5-methoxy group, in agreement with
previous studies.20,33
Con clu sion s
Da ta for 5-Meth oxy-3-oxo-2-(3-tr iflu or om eth ylp h en yl)-
m eth ylid en e-2,3-d ih yd r oben zo[b]fu r a n (5f): recrystallized
from ethanol; yield 87%; mp 147-149 °C; 1H NMR (300 MHz,
DMSO-d6) δ 8.35-8.30 (m, 2H), 7.85-7.75 (m, 2H), 7.55 (d,
J ) 9.0 Hz, 1H), 7.40 (dd, J ) 2.7 and 9.0 Hz, 1H), 7.30 (d,
J ) 2.7 Hz, 1H), 7.10 (s, 1H), 3.85 (s, 3H).
Da ta for 2-(3-Ch lor op h en yl)m eth ylid en e-5-m eth oxy-
3-oxo-2,3-d ih yd r oben zo[b]fu r a n (5g): recrystallized from
ethanol; yield 80%; mp 123-125 °C; 1H NMR (300 MHz,
DMSO-d6) δ 8.05-7.95 (m, 2H), 7.55-7.50 (m, 3H), 7.40 (dd,
J ) 2.5 and 8.9 Hz, 1H), 7.25 (d, J ) 2.5 Hz, 1H), 6.95 (s, 1H),
3.85 (s, 3H).
The results of this study confirm that the benzofuran
heterocycle can be considered a good bioisostere of indole
in the search for melatonin receptor ligands. Most of
the structure-affinity relationships previously de-
scribed17 from tissue binding studies are consistent with
MT1 and/or MT2 subtypes in, for example, the roles
played by the 5-methoxy group, the N-acyl substituent,
and a 2-phenyl substitution, this last modification
leading to a compound, 10q, which binds more strongly
that melatonin itself to both MT1 and MT2 subtypes and
behaves as a full agonist.
Introduction of a 2-benzyl group in the C-2 benzofuran
position allows access to MT2 selective antagonists, and
modulation of the selectivity and of the intrinsic activity
can be obtained with suitable modification on the N-acyl
and the 2-benzyl substituents.
Da ta for 2-(2,6-Dich lor op h en yl)m eth ylid en e-5-m eth -
oxy-3-oxo-2,3-d ih yd r oben zo[b]fu r a n (5h ): recrystallized
from methanol; yield 91%; mp 163-165 °C; 1H NMR (300 MHz,
DMSO-d6) δ 7.65 (d, J ) 7.9 Hz, 2H), 7.50 (t, J ) 7.9 Hz, 1H),
7.40-7.35 (m, 3H), 6.95 (s, 1H), 3.85 (s, 3H).
Da ta for 5-Meth oxy-3-oxo-2-(3,5-bistr iflu or om eth yl-
p h en yl)m eth ylid en e-2,3-d ih yd r oben zo[b]fu r a n (5i): re-
crystallized from ethyl acetate; yield 80%; mp 202-204 °C; 1H
NMR (300 MHz, DMSO-d6) δ 8.65 (s, 2H), 8.20 (s, 1H), 7.60
(d, J ) 9.0 Hz, 1H), 7.45 (dd, J ) 2.7 and 9.0 Hz, 1H), 7.30 (d,
J ) 2.7 Hz, 1H), 7.20 (s, 1H), 3.85 (s, 3H).
The most selective compounds 10c and 19 show MT1/
MT2 selectivity ratios of 123 and 192, respectively, and
are also very good MT2 ligands with affinities as strong
as that of melatonin itself (0.1 nM), but these two
compounds differ in their intrinsic activities (antagonist
and partial agonist, respectively).
Da ta for 2-Cycloh exylm eth ylid en e-5-m eth oxy-3-oxo-
2,3-d ih yd r oben zo[b]fu r a n (5j): recrystallized from ethanol
1
(95%); yield 82%; mp 68-70 °C; H NMR (300 MHz, DMSO-
d6) δ 7.45 (d, J ) 9.0 Hz, 1H), 7.35 (dd, J ) 2.2 and 9.0 Hz,
1H), 7.20 (d, J ) 2.2 Hz, 1H), 6.00 (s, 1H), 3.80 (s, 3H), 2.65-
2.60 (m, 1H), 1.75-1.25 (m, 10H).
Exp er im en ta l Section
Ch em istr y. Melting points were determined on a Buchi
SMP-20 capillary apparatus and are uncorrected. IR spectra
were recorded on a Perkin-Elmer 297 or a Vector 22 Bruker
Da ta for 5-Meth oxy-3-oxo-2-(p yr id in -3-yl)m eth ylid en e-
2,3-d ih yd r oben zo[b]fu r a n (5k ): recrystallized from ethanol
(95%); yield 72%; mp 157-159 °C; 1H NMR (300 MHz, DMSO-
d6) δ 9.10 (d, J ) 1.6 Hz, 1H), 8.60 (dd, J ) 1.6 and 8.1 Hz,
1H), 8.40 (d, J ) 8.1 Hz, 1H), 7.55 (m, J ) 8.1 and 8.9 Hz,
2H), 7.45 (dd, J ) 2.8 and 8.9 Hz, 1H), 7.30 (d, J ) 2.8 Hz,
1H), 7.00 (s, 1H), 3.85 (s, 3H).
1
spectrophotometer. H NMR spectra were recorded on an 80
SY or an AC 300 Bruker spectrometer. Chemical shifts are
reported in δ units (parts per million) relative to that of
(CH3)4Si. Elemental analyses for new substances were per-
formed by CNRS Laboratories (Vernaison, France). The results
obtained are within 0.4% of the theoretical values.
Data for 5-Meth oxy-3-oxo-2-(3-ph en ylpr open -2-yliden e)-
2,3-d ih yd r oben zo[b]fu r a n (5l): recrystallized from metha-
nol; yield 80%; mp 163-165 °C; 1H NMR (300 MHz, CDCl3) δ
7.55-7.15 (m, 9H), 7.05 (d, J ) 15.4 Hz, 1H), 6.80-6.75 (m,
1H), 3.85 (s, 3H).
Gen er a l P r oced u r e for th e Syn th esis of 2-Ar yl(cyclo-
h exyl)a lk ylid en e-3-oxo-2,3-d ih yd r oben zo[b]fu r a n s 5a -
5p . The method adopted for the synthesis of 5-methoxy-3-oxo-
2-phenylmethylidene-2,3-dihydrobenzo[b]furan (5a) is described.
Benzaldehyde (2.33 g, 0.022 mol) and activated basic alumi-
num oxide (66 g) were added to a vigorously stirred solution
of 3 g (0.018 mol) of 2 in 100 mL of methylene chloride. After
15 min of stirring, aluminum oxide was filtered and washed
Da ta for 5-Eth yl-3-oxo-2-p h en ylm eth ylid en e-2,3-d ih y-
d r oben zo[b]fu r a n (5m ): recrystallized from ethanol (95%);
1
yield 75%; mp 70-72 °C; H NMR (300 MHz, CDCl3) δ 7.70

2794 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 13
Wallez et al.
(dd, J ) 1.2 and 8.3 Hz, 2H), 7.65-7.60 (m, 1H), 7.45-7.35
(m, 5H), 6.90 (s, 1H), 2.70 (q, J ) 7.5 Hz, 2H), 1.25 (t, J ) 7.5
Hz, 3H).
Da ta for 5-Eth yl-3-oxo-2-(3-m eth oxyp h en yl)m eth yli-
d en e-2,3-d ih yd r oben zo[b]fu r a n (5n ): recrystallized from
ethanol (95%); yield 72%; mp 130-132 °C; 1H NMR (300 MHz,
DMSO-d6) δ 7.70-7.40 (m, 6H), 7.05 (dd, J ) 2.3 and 8.0 Hz,
1H), 6.90 (s, 1H), 3.85 (s, 3H), 2.70 (q, J ) 7.6 Hz, 2H), 1.20 (t,
J ) 7.6 Hz, 3H).
Da ta for 2-(2,6-Dich lor oben zyl)-5-m eth oxy-3-oxo-2,3-
d ih yd r oben zo[b]fu r a n (6h ): recrystallized from ethanol
(95%); yield 82%; mp 133-135 °C; 1H NMR (300 MHz, DMSO-
d6) δ 7.55 (d, J ) 7.9 Hz, 2H), 7.40-7.35 (m, 2H), 7.20 (d, J )
9.0 Hz, 1H), 7.10 (d, J ) 3.0 Hz, 1H), 5.00 (dd, J ) 4.5 and
10.3 Hz, 1H), 3.80 (s, 3H), 3.35 (dd, J ) 4.5 and 14.1 Hz, 1H),
3.25 (dd, J ) 10.3 and 14.1 Hz, 1H).
Da ta for 5-Meth oxy-3-oxo-2-(3,5-bistr iflu or om eth yl-
ben zyl)-2,3-d ih yd r oben zo[b]fu r a n (6i): recrystallized from
ethanol; yield 90%; mp 120-122 °C; 1H NMR (300 MHz,
DMSO-d6) δ 8.05 (s, 2H), 8.00 (s, 1H), 7.35 (dd, J ) 2.7 and
9.1 Hz, 1H), 7.20 (d, J ) 9.1 Hz, 1H), 7.05 (d, J ) 2.7 Hz, 1H),
5.30 (dd, J ) 4.3 and 8.8 Hz, 1H), 3.75 (s, 3H), 3.35 (dd, J )
4.3 and 14.8 Hz, 1H), 3.25 (dd, J ) 8.8 and 14.8 Hz, 1H).
Da ta for 2-Cycloh exylm eth yl-5-m eth oxy-3-oxo-2,3-d i-
h yd r oben zo[b]fu r a n (6j): recrystallized from ethanol (95%);
yield 80%; mp 65-67 °C; 1H NMR (300 MHz, DMSO-d6) δ 7.35
(dd, J ) 2.9 and 8.7 Hz, 1H), 7.20 (d, J ) 8.7 Hz, 1H), 7.05 (d,
J ) 2.9 Hz, 1H), 4.85 (dd, J ) 3.2 and 9.9 Hz, 1H), 3.80 (s,
3H), 1.85-0.90 (m, 13H).
Da ta for 3-Oxo-2-p h en ylm eth ylid en e-2,3-d ih yd r oben -
zo[b]fu r a n (5o): recrystallized from ethanol (95%); yield 75%;
1
mp 112-114 °C; H NMR (300 MHz, CDCl3) δ 7.95-7.90 (m,
2H), 7.80-7.75 (m, 1H), 7.70-7.65 (m, 1H), 7.50-7.20 (m, 5H),
6.90 (s, 1H).
Da ta for 2-(3-Meth oxyp h en yl)m eth ylid en e-3-oxo-2,3-
d ih yd r oben zo[b]fu r a n (5p ): recrystallized from ethanol
(95%); yield 78%; mp 119-121 °C; 1H NMR (300 MHz, CDCl3)
δ 7.80-7.75 (m, 1H), 7.65-7.60 (m, 1H), 7.55-7.45 (m, 2H),
7.40-7.30 (m, 2H), 7.20-7.15 (m, 1H), 7.00-6.95 (m, 1H), 6.85
(s, 1H), 3.90 (s, 3H).
Da ta for 5-Meth oxy-3-oxo-2-(p yr id in -3-ylm eth yl)-2,3-
d ih yd r oben zo[b]fu r a n (6k ): purified by column chroma-
tography (SiO2, acetone/toluene/cyclohexane (5:3:2)); yield 94%;
oil; 1H NMR (300 MHz, CDCl3) δ 8.50-8.25 (m, 3H), 7.30-
7.05 (m, 4H), 5.15 (dd, J ) 4.4 and 7.7 Hz, 1H), 3.75 (s, 3H),
3.30 (dd, J ) 4.4 and 14.5 Hz, 1H), 3.05 (dd, J ) 7.7 and 14.5
Hz, 1H).
Gen er a l P r oced u r e for th e Syn th esis of 3-Oxo-2-a r yl-
(cycloh exyl)a lk yl-2,3-d ih yd r oben zo[b]fu r a n s 6a -6p . The
method adopted for the synthesis of 2-benzyl-5-methoxy-3-oxo-
2,3-dihydrobenzo[b]furan (6a ) is described. A solution of 1.95
g (0.007 mol) of 5a in 400 mL of methanol and 100 mL of
dioxane was hydrogenated over 10% Pd/C (0.2 g) at atmo-
spheric pressure for 1 h. After filtration and evaporation, the
residue was purified by column chromatography (SiO2, ethyl
acetate/petroleum ether (2:8)) to give 1.8 g (92%) of pure 6a :
oil; 1H NMR (300 MHz, CDCl3) δ 7.30-7.20 (m, 6H), 7.05-
7.00 (m, 2H), 4.80 (dd, J ) 3.3 and 8.6 Hz, 1H), 3.80 (s, 3H),
3.35 (dd, J ) 3.3 and 14.6 Hz, 1H), 3.00 (dd, J ) 8.6 and 14.6
Hz, 1H).
Da ta for 5-Meth oxy-3-oxo-2-(3-p h en ylp r op -1-yl)-2,3-
d ih yd r oben zo[b]fu r a n (6l): purified by column chromatog-
raphy (SiO2, ethyl acetate/petroleum ether (2:8)); yield 93%;
1
oil; H NMR (300 MHz, DMSO-d6) δ 7.35-7.10 (m, 8H), 4.80
(s, 1H), 3.80 (s, 3H), 2.65-2.55 (m, 4H), 1.70-1.65 (m, 2 H).
Da ta for 2-Ben zyl-5-eth yl-3-oxo-2,3-d ih yd r oben zo[b]-
fu r a n (6m ): purified by column chromatography (SiO2, ethyl
acetate/petroleum ether (2:8)); yield 90%; oil; 1H NMR (300
MHz, CDCl3) δ 7.45-7.40 (m, 2H), 7.35-7.25 (m, 5H), 7.00
(d, J ) 7.2 Hz, 1H), 4.80 (dd, J ) 3.6 and 8.7 Hz, 1H), 3.35
(dd, J ) 3.6 and 14.8 Hz, 1H), 2.95 (dd, J ) 8.7 and 14.8 Hz,
1H), 2.55 (q, J ) 7.6 Hz, 2H), 1.20 (t, J ) 7.6 Hz, 3H).
Da ta for 5-Eth yl-2-(3-m eth oxyben zyl)-3-oxo-2,3-d ih y-
d r oben zo[b]fu r a n (6n ): purified by column chromatography
Da ta for 5-Meth oxy-2-(2-m eth oxyben zyl)-3-oxo-2,3-d i-
h yd r oben zo[b]fu r a n (6b): purified by column chromatog-
raphy (SiO2, ethyl acetate/petroleum ether (2:8)); yield 92%;
1
mp 100-102 °C; H NMR (300 MHz, CDCl3) δ 7.30-7.20 (m,
4H), 7.10-6.90 (m, 3H), 4.95 (dd, J ) 3.6 and 10.1 Hz, 1H),
3.85 (s, 3H), 3.80 (s, 3H), 3.50 (dd, J ) 3.6 and 14.4 Hz, 1H),
2.75 (dd, J ) 10.1 and 14.4 Hz, 1H).
Da ta for 5-Meth oxy-2-(3-m eth oxyben zyl)-3-oxo-2,3-d i-
h yd r oben zo[b]fu r a n (6c): purified by column chromatog-
raphy (SiO2, ethyl acetate/petroleum ether (2:8)); yield 91%;
oil; 1H NMR (300 MHz, CDCl3) δ 7.30-7.20 (m, 2H), 7.10-
6.75 (m, 5H), 4.80 (dd, J ) 3.4 and 8.8 Hz, 1H), 3.85 (s, 3H),
3.80 (s, 3H), 3.30 (dd, J ) 3.4 and 14.7 Hz, 1H), 2.95 (dd, J )
8.8 and 14.7 Hz, 1H).
1
(SiO2, ethyl acetate/petroleum ether (2:8)); yield 80%; oil; H
NMR (300 MHz, DMSO-d6) δ 7.55-6.80 (m, 7H), 5.10 (dd,
J ) 3.9 and 8.5 Hz, 1H), 3.75 (s, 3H), 3.20 (dd, J ) 3.9 and
14.6 Hz, 1H), 2.90 (dd, J ) 8.5 and 14.6 Hz, 1H), 2.30 (q, J )
7.6 Hz, 2H), 1.15 (t, J ) 7.6 Hz, 3H).
Data for 2-Ben zyl-3-oxo-2,3-dih ydr oben zo[b]fu r an (6o):
purified by column chromatography (SiO2, ethyl acetate/
petroleum ether (2:8)); yield 88%; oil; 1H NMR (300 MHz,
CDCl3) δ 7.60-7.50 (m, 2H), 7.40-7.00 (m, 7H), 4.75 (dd, J )
3.6 and 8.8 Hz, 1H), 3.40 (dd, J ) 3.6 and 14.5 Hz, 1H), 2.90
(dd, J ) 8.8 and 14.5 Hz, 1H).
Da ta for 5-Meth oxy-2-(4-m eth oxyben zyl)-3-oxo-2,3-d i-
h yd r oben zo[b]fu r a n (6d ): purified by column chromatog-
raphy (SiO2, ethyl acetate/petroleum ether (2:8)); yield 79%;
1
mp 81-83 °C; H NMR (300 MHz, DMSO-d6) δ 7.30 (dd, J )
2.7 and 9.1 Hz, 1H), 7.20-7.15 (m, 3H), 7.00 (d, J ) 2.7 Hz,
1H), 6.80 (d, J ) 8.8 Hz, 2H), 5.00 (dd, J ) 4.0 and 7.7 Hz,
1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.20 (dd, J ) 4.0 and 14.7 Hz,
1H), 2.90 (dd, J ) 7.7 and 14.7 Hz, 1H).
Da ta for 2-(3-Meth oxyben zyl)-3-oxo-2,3-d ih yd r oben zo-
[b]fu r a n (6p ): recrystallized from propan-2-ol; yield 85%; mp
1
89-91 °C; H NMR (300 MHz, CDCl3) δ 7.65-7.55 (m, 2H),
Da ta for 2-(3-F lu or oben zyl)-5-m eth oxy-3-oxo-2,3-d ih y-
d r oben zo[b]fu r a n (6e): purified by column chromatography
(SiO2, ethyl acetate/petroleum ether (2:8)); yield 75%; mp 74-
76 °C; 1H NMR (300 MHz, DMSO-d6) δ 7.35-7.05 (m, 7H),
5.10 (dd, J ) 4.2 and 8.3 Hz, 1H), 3.75 (s, 3H), 3.25 (dd, J )
4.2 and 14.8 Hz, 1H), 2.95 (dd, J ) 8.3 and 14.8 Hz, 1H).
Da ta for 5-Meth oxy-3-oxo-2-(3-tr iflu or om eth ylben zyl)-
2,3-d ih yd r oben zo[b]fu r a n (6f): recrystallized from ethanol;
yield 78%; mp 93-95 °C; 1H NMR (300 MHz, DMSO-d6) δ
7.65-7.50 (m, 4H), 7.30 (dd, J ) 2.7 and 8.9 Hz, 1H), 7.20 (d,
J ) 8.9 Hz, 1H), 7.05 (d, J ) 2.7 Hz, 1H), 5.20 (dd, J ) 4.2
and 8.4 Hz, 1H), 3.75 (s, 3H), 3.35 (dd, J ) 4.2 and 14.8 Hz,
1H), 3.10 (dd, J ) 8.4 and 14.8 Hz, 1H).
Da ta for 2-(3-Ch lor oben zyl)-5-m eth oxy-3-oxo-2,3-d i-
h yd r oben zo[b]fu r a n (6g): recrystallized from ethanol; yield
92%; mp 90-92 °C; 1H NMR (300 MHz, DMSO-d6) δ 7.40-
7.20 (m, 6H), 7.05 (d, J ) 2.5 Hz, 1H), 5.15 (dd, J ) 3.8 and
8.5 Hz, 1H), 3.75 (s, 3H), 3.30 (dd, J ) 3.8 and 14.6 Hz, 1H),
3.00 (dd, J ) 8.5 and 14.6 Hz, 1H).
7.25-7.20 (m, 1H), 7.10-7.00 (m, 2H), 6.95-6.85 (m, 2H), 6.75
(dd, J ) 2.2 and 8.2 Hz, 1H), 4.75 (dd, J ) 3.6 and 8.8 Hz,
1H), 3.75 (s, 3H), 3.35 (dd, J ) 3.6 and 14.6 Hz, 1H), 2.95 (dd,
J ) 8.8 and 14.6 Hz, 1H).
Gen er a l P r oced u r e for th e Syn th esis of 2-(2-Ar yl-
(cycloh exyl)a lk ylben zo[b]fu r a n -3-yl) Aceton itr iles 8a -
8p . The method adopted for the synthesis of 2-(2-benzyl-5-
methoxybenzo[b]furan-3-yl) acetonitrile (8a) is described. Under
stirring and N2, a solution of 2.65 g (0.015 mol) of diethyl
cyanomethylphosphonate in 10 mL of anhydrous THF was
added dropwise to a mixture of 0.6 g (0.015 mol) of NaH (60%
in oil) in 30 mL of anhydrous THF cooled to -10 °C. After 30
min in these conditions and addition of 10 mL of HMPT, a
solution of 2.54 g (0.010 mol) of 6a in 50 mL of anhydrous THF
was added dropwise, and the mixture was stirred at room
temperature for 1 h and 30 min. The mixture was then poured
into water and extracted with ether. The organic phase was
washed with brine, dried over MgSO4, filtered, and concen-
trated under reduced pressure to afford crude 8a , which was

Benzofuran Derivatives as Melatonin Receptor Ligands
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 13 2795
1
purified by column chromatography (SiO2, ethyl acetate/
petroleum ether (2:8)) to give 2.02 g (73%) of pure 8a : mp 68-
70 °C; 1H NMR (300 MHz, CDCl3) δ 7.40-7.20 (m, 6H), 7.00-
6.85 (m, 2 H), 4.10 (s, 2H), 3.75 (s, 3H), 3.60 (s, 2H).
oil; H NMR (300 MHz, DMSO-d6) δ 7.45-6.80 (m, 7H), 4.20
(s, 4H), 3.70 (s, 3H), 2.70 (q, J ) 7.6 Hz, 2H), 1.20 (t, J ) 7.6
Hz, 3H).
Da ta for 2-(2-Ben zylben zo[b]fu r a n -3-yl) Aceton itr ile
(8o): purified by column chromatography (SiO2, ethyl acetate/
petroleum ether (2:8)); yield 73%; oil; 1H NMR (300 MHz,
CDCl3) δ 7.50-7.45 (m, 1H),7.30-7.25 (m, 1H), 6.90-6.70 (m,
7H), 4.20 (s, 4H).
Da ta for 2-[5-Meth oxy-2-(2-m eth oxyben zyl)ben zo[b]-
fu r a n -3-yl] Aceton itr ile (8b): purified by column chroma-
tography (SiO2, ethyl acetate/ petroleum ether (2:8)); yield 83%;
1
mp 121-123 °C; H NMR (300 MHz, CDCl3) δ 7.30-7.25 (m,
4H), 7.00-6.85 (m, 3H), 4.10 (s, 2H), 3.85 (s, 6H), 3.75 (s, 2H).
Da ta for 2-[5-Meth oxy-2-(3-m eth oxyben zyl)ben zo[b]-
fu r a n -3-yl] Aceton itr ile (8c): recrystallized from toluene/
cyclohexane (3:1); yield 83%; mp 80-82 °C; 1H NMR (300 MHz,
DMSO-d6) δ 7.40 (dd, J ) 2.0 and 9.1 Hz, 1H), 7.30-7.20 (m,
2H), 6.90-6.80 (m, 4H), 4.20 (s, 4H), 3.80 (s, 3H), 3.75 (s, 3H).
Da ta for 2-[5-Meth oxy-2-(4-m eth oxyben zyl)ben zo[b]-
fu r a n -3-yl] a ceton itr ile (8d ): purified by column chroma-
tography (SiO2, ethyl acetate/petroleum ether (3:7)); yield 70%;
Da ta for 2-[2-(3-Meth oxyben zyl)ben zo[b]fu r a n -3-yl]
Aceton itr ile (8p ): purified by column chromatography (SiO2,
ethyl acetate/petroleum ether (2:8)); yield 73%; oil; H NMR
(300 MHz, CDCl3) δ 7.50-7.45 (m, 1H), 7.30-7.25 (m, 1H),
7.20-7.10 (m, 3H), 6.80-6.70 (m, 3H), 4.10 (s, 4H), 3.70 (s,
3H).
1
2-(5-Meth oxy-2-p h en ylben zo[b]fu r a n -3-yl) Aceton itr ile
(8q). Under stirring and N2, 0.085 g (0.0005 mol) of AIBN and
1.87 g (0.0105 mol) of NBS were added to a solution of 2.5 g
(0.0105 mol) of 7 in 50 mL of CCl4, and the mixture was
refluxed for 2 h and 30 min. After cooling and filtration, the
filtrate was concentrated and the residue was dissolved in 5
mL of DMSO and added to a solution of 0.565 g (0.0115 mol)
of sodium cyanide in 5 mL of DMSO at 60 °C. After 4 h at this
temperature, the mixture was poured into ice water, giving a
precipitate which was filtered, purified by column chromatog-
raphy (SiO2, cyclohexane/ethyl acetate (8:2)), and recrystallized
from cyclohexane to give 1.24 g (45%) of pure 8q: mp 105-
1
mp 82-84 °C; H NMR (300 MHz, DMSO-d6) δ 7.40 (d, J )
8.7 Hz, 1H), 7.25-6.80 (m, 6H), 4.20 (s, 2H), 4.15 (s, 2H), 3.80
(s, 3H), 3.70 (s, 3H).
Da ta for 2-[2-(3-F lu or oben zyl)-5-m eth oxyben zo[b]fu -
r a n -3-yl] Aceton itr ile (8e): recrystallized from ethanol/
water (1:1); yield 70%; mp 66-68 °C; 1H NMR (300 MHz,
DMSO-d6) δ 7.45-7.35 (m, 2H), 7.20-7.05 (m, 4H), 6.90 (m,
J ) 8.6 Hz, 1H), 4.25 (s, 2H), 4.20 (s, 2H), 3.80 (s, 3H).
Da ta for 2-[5-Meth oxy-2-(3-tr iflu or om eth ylben zyl)ben -
zo[b]fu r a n -3-yl] a ceton itr ile (8f): recrystallized from ethyl
1
107 °C; H NMR (300 MHz, DMSO-d6) δ 7.75-7.40 (m, 6H),
1
acetate/petroleum ether (2:8); yield 70%; mp 115-117 °C; H
7.10 (d, J ) 2.7 Hz, 1H), 7.00 (dd, J ) 2.7 and 8.9 Hz, 1H),
NMR (300 MHz, DMSO-d6) δ 7.65-7.55 (m, 4H), 7.40 (d, J )
8.9 Hz, 1H), 7.20 (d, J ) 2.7 Hz, 1H), 6.90 (dd, J ) 2.7 and 8.9
Hz, 1H), 4.35 (s, 2H), 4.25 (s, 2H), 3.80 (s, 3H).
3.95 (s, 3H), 3.90 (s, 2H).
Gen er a l P r oced u r e A for th e Syn th esis of 2-(Ben zo-
[b]fu r a n -3-yl) Eth yla m in e Hyd r och lor id es 9a -9d , 9i, 9k ,
9l, 9m , a n d 9o-9q. The method adopted for the synthesis of
2-(2-benzyl-5-methoxybenzo[b]furan-3-yl) ethylamine hydro-
chloride (9a ) is described. An NH3-oversaturated solution of
2.77 g (0.010 mol) of 8a in 100 mL of ethanol was hydrogenated
over Raney nickel under pressure (50 bar) at 60 °C for 4 h
and 30 min. After filtration and evaporation, the oil was
dissolved in dry ether and treated with HCl gas to give, after
filtration, 2 g (65%) of 9a , which was of sufficient purity to be
used in subsequent reactions: mp 174-176 °C; 1H NMR (300
MHz, DMSO-d6) δ 8.40 (s, 3H), 7.50-7.10 (m, 7H), 6.80 (dd,
J ) 2.5 and 8.9 Hz, 1H), 4.20 (s, 2H), 3.80 (s, 3H), 3.20-2.90
(m, 4H).
Da ta for 2-[5-Meth oxy-2-(2-m eth oxyben zyl)ben zo[b]-
fu r a n -3-yl] Eth yla m in e Hyd r och lor id e (9b): yield 74%;
mp 181-183 °C; 1H NMR (300 MHz, DMSO-d6) δ 8.20 (s, 3H),
7.35-6.80 (m, 7H), 4.05 (s, 2H), 3.80 (s, 6H), 3.00 (s, 4H).
Da ta for 2-[5-Meth oxy-2-(3-m eth oxyben zyl)ben zo[b]-
fu r a n -3-yl] Eth yla m in e Hyd r och lor id e (9c): yield 67%; mp
135-137 °C; 1H NMR (300 MHz, DMSO-d6) δ 8.20 (s, 3H),
7.45-6.80 (m, 7H), 4.10 (s, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 3.05-
3.00 (m, 4H).
Da ta for 2-[2-(3-Ch lor oben zyl)-5-m eth oxyben zo[b]fu -
r a n -3-yl] Aceton itr ile (8g): recrystallized from cyclohexane;
yield 60%; mp 81-83 °C; 1H NMR (300 MHz, DMSO-d6) δ
7.45-7.25 (m, 6H), 6.90 (dd, J ) 2.5 and 9.0 Hz, 1H), 4.25 (s,
4H), 3.80 (s, 3H).
Da ta for 2-[2-(2,6-Dich lor oben zyl)-5-m eth oxyben zo[b]-
fu r a n -3-yl] Aceton itr ile (8h ): recrystallized from cyclohex-
1
ane/toluene (1:3); yield 69%; mp 185-187 °C; H NMR (300
MHz, DMSO-d6) δ 7.55 (d, J ) 8.1 Hz, 2H), 7.40-7.35 (m, 2H),
7.20 (d, J ) 2.6 Hz, 1H), 6.85 (dd, J ) 2.6 and 8.8 Hz, 1H),
4.50 (s, 2H), 4.20 (s, 2H), 3.80 (s, 3H).
Da ta for 2-[5-Meth oxy-2-(3,5-bistr iflu or om eth ylben -
zyl)ben zo[b]fu r a n -3-yl] Aceton itr ile (8i): recrystallized
1
from cyclohexane; yield 80%; mp 111-113 °C; H NMR (300
MHz, DMSO-d6) δ 8.00 (s, 3H), 7.45 (d, J ) 9.0 Hz, 1H), 7.25
(d, J ) 2.7 Hz, 1H), 6.90 (dd, J ) 2.7 and 9.0 Hz, 1H), 4.50 (s,
2H), 4.25 (s, 2H), 3.80 (s, 3H).
Da ta for 2-(2-Cycloh exylm eth yl-5-m eth oxyben zo[b]-
fu r a n -3-yl) Aceton itr ile (8j): recrystallized from cyclohex-
ane; yield 70%; mp 72-74 °C; 1H NMR (300 MHz, DMSO-d6)
δ 7.40 (d, J ) 9.2 Hz, 1H), 7.15 (d, J ) 2.9 Hz, 1H), 6.85 (dd,
J ) 2.9 and 9.2 Hz, 1H), 4.00 (s, 2H), 3.80 (s, 3H), 2.65 (d,
J ) 6.8 Hz, 2H), 1.60-0.95 (m, 11H).
Da ta for 2-[5-Meth oxy-2-(p yr id in -3-ylm eth yl)ben zo[b]-
fu r a n -3-yl] Aceton itr ile (8k ): recrystallized from toluene;
yield 63%; mp 122-124 °C; 1H NMR (300 MHz, CDCl3) δ 8.55
(d, J ) 1.6 Hz, 1H), 8.45 (dd, J ) 1.6 and 5.5 Hz, 1H), 7.70 (d,
J ) 5.5 Hz, 1H), 7.45-7.35 (m, 2H), 7.20 (d, J ) 2.7 Hz, 1H),
6.90 (dd, J ) 2.7 and 9.1 Hz, 1H), 4.30 (s, 2H), 4.25 (s, 2H),
3.80 (s, 3H).
Da ta for 2-[5-Meth oxy-2-(4-m eth oxyben zyl)ben zo[b]-
fu r a n -3-yl] Eth yla m in e Hyd r och lor id e (9d ): yield 72%;
mp 110-112 °C; 1H NMR (300 MHz, DMSO-d6) δ 8.10 (s, 3H),
7.30-6.70 (m, 7H), 4.00 (s, 2H), 3.75 (s, 3H), 3.65 (s, 3H), 2.95
(s, 4H).
Da ta for 2-[5-Meth oxy-2-(3,5-bistr iflu or om eth ylben -
zyl)ben zo[b]fu r a n -3-yl] Eth yla m in e Hyd r och lor id e (9i):
1
yield 87%; mp 209-211 °C; H NMR (300 MHz, DMSO-d6) δ
8.20 (s, 3H), 8.05 (s, 2H), 8.00 (s, 1H), 7.40 (d, J ) 8.9 Hz,
1H), 7.30 (d, J ) 2.7 Hz, 1H), 6.85 (dd, J ) 2.7 and 8.9 Hz,
1H), 4.45 (s, 2H), 3.80 (s, 3H), 3.15-3.05 (m, 4H).
Da ta for 2-[5-Meth oxy-2-(3-p h en ylp r op -1-yl)ben zo[b]-
fu r a n -3-yl] Aceton itr ile (8l): purified by column chroma-
tography (SiO2, ethyl acetate/petroleum ether (2:8)); yield 75%;
1
Da ta for 2-[5-Meth oxy-2-(p yr id in -3-ylm eth yl)ben zo[b]-
fu r a n -3-yl] Eth yla m in e Dih yd r och lor id e (9k ): yield 67%;
mp 217-219 °C; 1H NMR (300 MHz, DMSO-d6) δ 8.95 (s, 1H),
8.80 (s, 1H), 8.40 (s, 1H), 8.20 (s, 3H), 7.95 (s, 1H), 7.35 (d,
J ) 8.8 Hz, 1H), 7.30 (s, 1H), 6.85 (dd, J ) 2.4 and 8.8 Hz,
1H), 4.45 (s, 2H), 3.80 (s, 3H), 3.10 (s, 4H).
Da ta for 2-[5-Meth oxy-2-(3-p h en ylp r op -1-yl)ben zo[b]-
fu r a n -3-yl] Eth yla m in e Hyd r och lor id e (9l): yield 56%; mp
121-123 °C; 1H NMR (300 MHz, DMSO-d6) δ 8.10 (s, 3H),
7.40-7.15 (m, 7H), 6.85 (dd, J ) 2.2 and 8.9 Hz, 1H), 3.80 (s,
oil; H NMR (300 MHz, CDCl3) δ 7.35-6.85 (m, 8H), 3.85 (s,
3H), 3.55 (s, 2H), 2.80-2.65 (m, 4H), 2.10-2.05 (m, 2H).
Da ta for 2-(2-Ben zyl-5-eth ylben zo[b]fu r a n -3-yl) Aceto-
n itr ile (8m ): purified by column chromatography (SiO2, ethyl
acetate/petroleum ether (2:8)); yield 50%; oil; 1H NMR (300
MHz, CDCl3) δ 7.45-6.90 (m, 8H), 4.15 (s, 2H), 3.65 (s, 2H),
2.75 (q, J ) 7.5 Hz, 2H), 1.30 (t, J ) 7.5 Hz, 3H).
Da t a for 2-[5-E t h yl-2-(3-m et h oxyb en zyl)b en zo[b]fu -
r a n -3-yl] Aceton itr ile (8n ): purified by column chromatog-
raphy (SiO2, ethyl acetate/petroleum ether (2:8)); yield 68%;

2796 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 13
Wallez et al.
3H), 3.00-2.95 (m, 4H), 2.80 (t, J ) 7.5 Hz, 2H), 2.65 (t, J )
7.5 Hz, 2H), 1.95 (m, J ) 7.5 Hz, 2H).
Da t a for 2-(2-Ben zyl-5-et h ylb en zo[b]fu r a n -3-yl) E t h -
yla m in e Hyd r och lor id e (9m ): yield 63%; mp 147-149 °C;
1H NMR (300 MHz, DMSO-d6) δ 8.20 (s, 3H), 7.45-6.80 (m,
8H), 4.10 (s, 2H), 3.05-3.00 (m, 4H), 2.70 (q, J ) 7.4 Hz, 2H),
1.20 (t, J ) 7.4 Hz, 3H).
Da ta for 2-Ben zylben zo[b]fu r a n -3-yl Eth yla m in e Hy-
d r och lor id e (9o): yield 65%; mp 193-195 °C; 1H NMR (300
MHz, DMSO-d6) δ 8.25 (s, 3H), 7.70 (s, 1H), 7.45 (s, 1H), 7.30-
7.20 (m, 7H), 4.20 (s, 2H), 3.10-3.00 (m, 4H).
Da ta for 2-[2-(3-Meth oxyben zyl)ben zo[b]fu r a n -3-yl]
Eth yla m in e Hyd r och lor id e (9p ): yield 72%; mp 153-155
°C; 1H NMR (300 MHz, DMSO-d6) δ 8.20 (s, 3H), 7.65 (s, 1H),
7.50 (s, 1H), 7.30-6.25 (m, 3H), 6.90-6.80 (m, 3H), 4.10 (s,
2H), 3.70 (s, 3H), 3.10-2.90 (m, 4H).
benzyl-5-methoxybenzo[b]furan-3-yl) ethylamine (10a ) is de-
scribed. A solution of 2.77 g (0.010 mol) of 8a in 80 mL of acetic
anhydride was hydrogenated over Raney nickel under pressure
(50 bar) at 60 °C for 6 h. After filtration and evaporation, the
oil was cooled and 10 mL of a 10% NaOH solution was added.
After 10 min under stirring, the mixture was extracted with
ethyl acetate. The organic phase was washed with brine, dried
over MgSO4, filtered, and concentrated under reduced pressure
to afford crude 10a , which was recrystallized from toluene to
give 2.81 g (87%) of pure 10a : mp 112-114 °C; 1H NMR (300
MHz, DMSO-d6) δ 8.00 (s, 1H), 7.35-7.20 (m, 6H), 7.15 (d,
J ) 2.6 Hz, 1H), 6.80 (dd, J ) 2.6 and 9.0 Hz, 1H), 4.10 (s,
2H), 3.80 (s, 3H), 3.30 (m, J ) 6.7 Hz, 2 H), 2.85 (t, J ) 6.7
Hz, 2H), 1.75 (s, 3H). Anal. (C20H21NO3) C, H, N.
Da ta for N-Acetyl-2-[5-m eth oxy-2-(2-m eth oxyben zyl)-
ben zo[b]fu r a n -3-yl] Eth yla m in e (10b): recrystallized from
toluene/hexane (1:1); yield 65%; mp 102-104 °C; 1H NMR (300
MHz, DMSO-d6) δ 8.00 (s, 1H), 7.30-6.85 (m, 6H), 6.80 (dd,
J ) 2.5 and 8.9 Hz, 1H), 4.00 (s, 2H), 3.80 (s, 3H), 3.75 (s,
3H), 3.30 (m, J ) 6.7 Hz, 2 H), 2.80 (t, J ) 6.7 Hz, 2H), 1.75
(s, 3H). Anal. (C21H23NO4) C, H, N.
Data for 2-(5-Meth oxy-2-ph en ylben zo[b]fu r an -3-yl] Eth -
yla m in e Hyd r och lor id e (9q): yield 77%; mp 255-257 °C;
1H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 3H), 7.90-7.40 (m,
7H), 6.95 (dd, J ) 2.3 and 8.8 Hz, 1H), 3.85 (s, 3H), 3.40-3.05
(m, 4H).
Da ta for N-Acetyl-2-[5-m eth oxy-2-(3-m eth oxyben zyl)-
ben zo[b]fu r a n -3-yl] Eth yla m in e (10c): recrystallized from
toluene/hexane (1:1); yield 55%; mp 109-111 °C; 1H NMR (300
MHz, DMSO-d6) δ 8.00 (s, 1H), 7.35-6.80 (m, 7H), 4.05 (s, 2H),
3.80 (s, 3H), 3.70 (s, 3H), 3.25 (m, J ) 6.7 Hz, 2 H), 2.80 (t,
J ) 6.7 Hz, 2H), 1.75 (s, 3H). Anal. (C21H23NO4) C, H, N.
Da ta for N-Acetyl-2-[5-m eth oxy-2-(4-m eth oxyben zyl)-
ben zo[b]fu r a n -3-yl] Eth yla m in e (10d ): recrystallized from
toluene; yield 67%; mp 101-103 °C; 1H NMR (300 MHz,
DMSO-d6) δ 8.00 (s, 1H), 7.30 (d, J ) 9.0 Hz, 1H), 7.15 (m,
J ) 8.7 Hz, 3H), 6.85 (m, J ) 8.7 and 9.0 Hz, 3H), 4.00 (s,
2H), 3.80 (s, 3H), 3.70 (s, 3H), 3.25 (br q, 2 H), 2.80 (s, 2H),
1.75 (s, 3H). Anal. (C21H23NO4) C, H, N.
Gen er a l P r oced u r e B for th e Syn th esis of 2-(Ben zo-
[b]fu r a n -3-yl) Eth yla m in e Hyd r och lor id es 9e-9h , 9j, a n d
9n . The method adopted for the synthesis of 2-[2-(3-fluoroben-
zyl)-5-methoxybenzo[b]furan-3-yl] ethylamine hydrochloride
(9e) is described. Under N2, a solution of 2.95 g (0.010 mol) of
8e in 15 mL of anhydrous THF was added dropwise to 30 mL
(0.03 mol) of borane-tetrahydrofuran complex, 1 M solution
in THF. After 2 h and 30 min at reflux, 20 mL (0.12 mol) of a
6 N HCl solution was added very slowly and the mixture was
refluxed for 30 min. After evaporation, the solid residue was
poured into a 12% NaOH solution and the resulting amine
was extracted with ethyl acetate. The organic phase was dried
over MgSO4, filtered, and concentrated under reduced pressure
to afford an oil which was dissolved in dry ether and treated
with HCl gas to give, after filtration, 2 g (65%) of 9e, which
was of sufficient purity to be used in subsequent reactions:
mp 171-173 °C; 1H NMR (300 MHz, DMSO-d6) δ 8.25 (s, 3H),
7.40-7.05 (m, 6H), 6.85 (dd, J ) 2.6 and 8.8 Hz, 1H), 4.20 (s,
2H), 3.80 (s, 3H), 3.05-3.00 (m, 4H).
Data for N-Acetyl-2-[5-m eth oxy-2-(3,5-bistr iflu or om eth -
ylben zyl)ben zo[b]fu r an -3-yl] Eth ylam in e (10i): recrystal-
lized from toluene/petroleum ether (1:1); yield 54%; mp 124-
1
126 °C; H NMR (300 MHz, DMSO-d6) δ 8.00-7.95 (m, 4H),
7.35 (d, J ) 9.1 Hz, 1H), 7.15 (d, J ) 2.5 Hz, 1H), 6.80 (dd,
J ) 2.5 and 9.1 Hz, 1H), 4.35 (s, 2H), 3.80 (s, 3H), 3.30 (m,
J ) 6.6 Hz, 2 H), 2.85 (t, J ) 6.6 Hz, 2H), 1.70 (s, 3H). Anal.
(C22H19F6NO3) C, H, F, N.
Da ta for 2-[5-Meth oxy-2-(3-tr iflu or om eth ylben zyl)ben -
zo[b]fu r a n -3-yl] Eth yla m in e Hyd r och lor id e (9f): recrys-
tallized from toluene/cyclohexane (1:1); yield 60%; mp 127-
Da ta for N-Acetyl-2-(2-cycloh exylm eth yl-5-m eth oxy-
ben zo[b]fu r a n -3-yl] Eth yla m in e (10j): purified by column
chromatography (SiO2, ethyl acetate/methylene chloride (1:1));
1
129 °C; H NMR (300 MHz, DMSO-d6) δ 8.35 (s, 3H), 7.70-
7.60 (m, 4H), 7.40 (d, J ) 9.0 Hz, 1H), 7.30 (s, 1H), 6.85 (dd,
J ) 2.3 and 9.0 Hz, 1H), 4.35 (s, 2H), 3.85 (s, 3H), 3.10-3.05
(m, 4H).
1
yield 62%; oil; H NMR (300 MHz, DMSO-d6) δ 7.95 (s, 1H),
7.35 (d, J ) 9.1 Hz, 1H), 7.05 (d, J ) 2.4 Hz, 1H), 6.80 (dd,
J ) 2.4 and 9.1 Hz, 1H), 3.75 (s, 3H), 3.20 (m, J ) 6.8 Hz, 2
H), 2.70 (t, J ) 6.8 Hz, 2H), 2.55 (d, J ) 6.7 Hz, 2H), 1.75 (s,
3H), 1.65-1.00 (m, 11H). Anal. (C20H27NO3) C, H, N.
Da ta for 2-[2-(3-Ch lor oben zyl)-5-m eth oxyben zo[b]fu -
r a n -3-yl] Eth yla m in e Hyd r och lor id e (9g): yield 75%; mp
140-142 °C; 1H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 3H),
7.40-7.30 (m, 6H), 6.80 (dd, J ) 2.8 and 8.5 Hz, 1H), 4.20 (s,
2H), 3.80 (s, 3H), 3.05-3.00 (m, 4H).
Da ta for 2-[2-(2,6-Dich lor oben zyl)-5-m eth oxyben zo[b]-
fu r a n -3-yl] Eth yla m in e Hyd r och lor id e (9h ): yield 55%;
mp 244-246 °C; 1H NMR (300 MHz, DMSO-d6) δ 8.05 (s, 3H),
7.55 (d, J ) 7.6 Hz, 2H), 7.35 (m, J ) 7.6 and 8.9 Hz, 2H),
7.25 (d, J ) 2.6 Hz, 1H), 6.80 (dd, J ) 2.6 and 8.9 Hz, 1H),
4.45 (s, 2H), 3.80 (s, 3H), 3.10 (s, 4H).
Da ta for N-Acetyl-2-[5-m eth oxy-2-(3-p h en ylp r op -1-yl)-
ben zo[b]fu r a n -3-yl] Eth yla m in e (10l): recrystallized from
1
toluene/petroleum ether (1:1); yield 60%; mp 101-103 °C; H
NMR (300 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.35-7.15 (m, 6H),
7.05 (d, J ) 2.2 Hz, 1H), 6.80 (dd, J ) 2.2 and 8.6 Hz, 1H),
3.80 (s, 3H), 3.25 (m, J ) 6.7 Hz, 2H), 2.65 (m, J ) 6.7 and 7.5
Hz, 6H), 1.95 (m, J ) 7.5 Hz, 2H), 1.75 (s, 3H). Anal. (C22H25
NO3) C, H, N.
-
Da ta for N-Acetyl-2-(2-ben zyl-5-eth ylben zo[b]fu r a n -3-
yl) Eth yla m in e (10m ): recrystallized from toluene; yield
Da ta for 2-(2-Cycloh exylm eth yl-5-m eth oxyben zo[b]-
fu r a n -3-yl) Eth yla m in e Hyd r och lor id e (9j): recrystallized
from cyclohexane; yield 45%; mp 194-196 °C; H NMR (300
MHz, DMSO-d6) δ 7.95 (s, 3H), 7.40 (d, J ) 8.8 Hz, 1H), 7.15
(d, J ) 2.4 Hz, 1H), 6.80 (dd, J ) 2.4 and 8.8 Hz, 1H), 3.80 (s,
3H), 3.00-2.90 (m, 4H), 2.65 (d, J ) 6.8 Hz, 2H), 1.65-1.00
(m, 11H).
1
1
65%; mp 100-102 °C; H NMR (300 MHz, DMSO-d6) δ 7.90
(s, 1H), 7.35-7.20 (m, 7H), 7.05 (d, J ) 8.7 Hz, 1H), 4.05 (s,
2H), 3.30-3.25 (m, 2H), 2.80 (t, J ) 6.9 Hz, 2H), 2.65 (q, J )
7.6 Hz, 2H), 1.75 (s, 3H), 1.95 (t, J ) 7.6 Hz, 3H). Anal. (C21H23
NO2) C, H, N.
-
Da ta for N-Acetyl-2-(2-ben zylben zo[b]fu r a n -3-yl) Eth -
yla m in e (10o): recrystallized from toluene/cyclohexane (1:
1); yield 55%; mp 98-100 °C; H NMR (300 MHz, CDCl3) δ
Da t a for 2-[5-E t h yl-2-(3-m et h oxyb en zyl)b en zo[b]fu -
r a n -3-yl] Eth yla m in e Hyd r och lor id e (9n ): recrystallized
from ethyl acetate; yield 57%; mp 152-154 °C; H NMR (300
1
1
7.50 (d, J ) 7.0 Hz, 1H), 7.45-7.40 (m, 1H), 7.35-7.30 (m,
7H), 5.40 (s, 1H), 4.10 (s, 2H), 3.50-3.45 (m, 2 H), 2.90-2.85
(t, J ) 6.6 Hz, 2H), 1.70 (s, 3H). Anal. (C19H19NO2) C, H, N.
Da ta for N-Acetyl-2-[2-(3-m eth oxyben zyl)ben zo[b]fu -
r a n -3-yl] Eth yla m in e (10p ): recrystallized from cyclohexane;
MHz, DMSO-d6) δ 8.20 (s, 3H), 7.45-6.85 (m, 7H), 4.10 (s, 2H),
3.75 (s, 3H), 3.05 (s, 4H), 2.70 (q, J ) 7.4 Hz, 2H), 1.20 (t, J )
7.4 Hz, 3H).
Gen er a l P r oced u r e A for th e Syn th esis of th e N-
Acyla ted Der iva tives 10a -10d , 10i, 10j, 10l, 10m , 10o, a n d
10p . The method adopted for the synthesis of N-acetyl-2-(2-
1
yield 63%; mp 99-101 °C; H NMR (300 MHz, DMSO-d6) δ

Benzofuran Derivatives as Melatonin Receptor Ligands
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 13 2797
8.00 (t, J ) 5.4 Hz, 1H), 7.60-7.55 (m, 1H), 7.45-7.40 (m, 1H),
7.25-7.20 (m, 3H), 6.85-6.80 (m, 3H), 4.10 (s, 2H), 3.50 (s,
3H), 3.30-3.25 (m, 2 H), 2.90 (t, J ) 7.1 Hz, 2H), 1.75 (s, 3H).
Anal. (C20H21NO3) C, H, N.
2H), 3.30 (t, J ) 7.0 Hz, 2H), 2.80 (t, J ) 7.0 Hz, 2H). Anal.
(C20H20NIO3) C, H, N.
Da ta for N-Bu ta n oyl-2-(2-ben zyl-5-m eth oxyben zo[b]-
fu r a n -3-yl) E t h yla m in e (12): recrystallized from hexane;
yield 40%; mp 85-87 °C; 1H NMR (300 MHz, DMSO-d6) δ 7.95
(t, J ) 5.4 Hz, 1H), 7.40-7.20 (m, 6H), 7.15 (d, J ) 2.4 Hz,
1H), 6.80 (dd, J ) 2.4 and 8.6 Hz, 1H), 4.05 (s, 2H), 3.75 (s,
3H), 3.30 (dt, J ) 5.4 and 6.8 Hz, 2H), 2.80 (t, J ) 6.8 Hz,
2H), 2.05 (t, J ) 7.2 Hz, 2H), 1.50-1.45 (m, 2H), 0,80 (t, J )
7.2 Hz, 3H). Anal. (C22H25NO3) C, H, N.
Gen er a l P r oced u r e B for th e Syn th esis of th e N-
Acyla ted Der iva tives 10e-10h , 10k , 10n , 10q, a n d 11-
17. The method adopted for the synthesis of N-acetyl-2-[2-(3-
fluorobenzyl)-5-methoxybenzo[b]furan-3-yl] ethylamine (10e)
is described. Potassium carbonate (1.38 g, 0.010 mol) was
added to a solution of 1.68 g (0.005 mol) of 9e in 20 mL of
water and 60 mL of methylene chloride. After the mixture was
stirred for 20 min at 0 °C, 0.78 g (0.010 mol) of acetyl chloride
was added dropwise at the same temperature. The reaction
mixture was stirred at room temperature for 2 h. The organic
phase was separated, washed with water, a 1 N HCl solution,
and water until pH 7 was reached, dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was
recrystallized from toluene to give 1.2 g (71%) of pure 10e:
mp 136-138 °C; 1H NMR (300 MHz, DMSO-d6) δ 8.00 (s, 1H),
7.40-7.05 (m, 6H), 6.80 (dd, J ) 2.5 and 8.9 Hz, 1H), 4.10 (s,
2H), 3.80 (s, 3H), 3.30 (m, J ) 6.7 Hz, 2 H), 2.80 (t, J ) 6.7
Hz, 2H), 1.75 (s, 3H). Anal. (C20H20FNO3) C, H, F, N.
Da ta for N-F u r oyl-2-(2-ben zyl-5-m eth oxyben zo[b]fu -
r a n -3-yl) Eth yla m in e (13): recrystallized from toluene/
1
cyclohexane; yield 68%; mp 120-122 °C; H NMR (300 MHz,
DMSO-d6) δ 8.55 (s, 1H), 7.85 (s, 1H), 7.75-7.20 (m, 6H), 7.15
(d, J ) 2.2 Hz, 1H), 7.05 (d, J ) 3.3 Hz, 1H), 6.80 (dd, J ) 2.2
and 8.8 Hz, 1H), 6.60 (q, J ) 3.3 Hz, 1H), 4.10 (s, 2H), 3.75 (s,
3H), 3.50 (q, J ) 6.7 Hz, 2H), 2.95 (t, J ) 6.7 Hz, 2H). Anal.
(C23H21NO4) C, H, N.
Da ta for N-P r op en -2-oyl-2-(2-ben zyl-5-m eth oxyben zo-
[b]fu r a n -3-yl) Eth yla m in e (14): purified by column chro-
matography (SiO2, ethyl acetate/methylene chloride (1:1));
1
yield 54%; mp 107-109 °C; H NMR (300 MHz, DMSO-d6) δ
8.30 (t, J ) 5.8 Hz, 1H), 7.40-7.20 (m, 6H), 7.10 (d, J ) 2.4
Hz, 1H), 6.80 (dd, J ) 2.4 and 8.9 Hz, 1H), 6.20 (dd, J ) 9.7
and 17.1 Hz, 1H), 6.10 (dd, J ) 2.5 and 17.1 Hz, 1H), 5.55
(dd, J ) 2.5 and 9.7 Hz, 1H), 4.05 (s, 2H), 3.80 (s, 3H), 3.30
(dt, J ) 5.8 and 6.9 Hz, 2H), 2.85 (t, J ) 6.9 Hz, 2H). Anal.
(C21H21NO3) C, H, N.
Da ta for N-Acetyl-2-[5-m eth oxy-2-(3-tr iflu or om eth yl-
ben zyl)ben zo[b]fu r a n -3-yl] Eth yla m in e (10f): recrystal-
lized from toluene; yield 71%; mp 123-125 °C; H NMR (300
MHz, DMSO-d6) δ 8.00 (s, 1H), 7.65-7.55 (m, 4H), 7.35 (d,
J ) 9.0 Hz, 1H), 7.15 (d, J ) 2.6 Hz, 1H), 6.80 (dd, J ) 2.6
and 9.0 Hz, 1H), 4.20 (s, 2H), 3.80 (s, 3H), 3.30 (m, J ) 6.5
Hz, 2 H), 2.85 (t, J ) 6.5 Hz, 2H), 1.75 (s, 3H). Anal. (C21H20F3-
NO3) C, H, F, N.
1
Da ta for N-P r op en -2-oyl-2-[5-m eth oxy-2-(3-m eth oxy-
ben zyl)ben zo[b]fu r a n -3-yl] Eth yla m in e (15): recrystal-
1
lized from toluene; yield 73%; mp 113-115 °C; H NMR (300
Da ta for N-Acetyl-2-[2-(3-ch lor oben zyl)-5-m eth oxyben -
zo[b]fu r a n -3-yl] Eth yla m in e (10g): recrystallized from
toluene/cyclohexane (3:1); yield 51%; mp 114-116 °C; 1H NMR
(300 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.65-7.55 (m, 4H), 7.35
(d, J ) 9.0 Hz, 1H), 7.15 (d, J ) 2.6 Hz, 1H), 6.80 (dd, J ) 2.6
and 9.0 Hz, 1H), 4.20 (s, 2H), 3.80 (s, 3H), 3.30 (m, J ) 6.5
MHz, DMSO-d6) δ 8.30 (t, J ) 5.6 Hz, 1H), 7.35-6.80 (m, 7H),
6.20 (dd, J ) 9.5 and 17.0 Hz, 1H), 6.10 (dd, J ) 2.7 and 17.0
Hz, 1H), 5.60 (dd, J ) 2.7 and 9.5 Hz, 1H), 4.05 (s, 2H), 3.80
(s, 3H), 3.70 (s, 3H), 3.40 (m, J ) 6.8 Hz, 2 H), 2.90 (t, J ) 6.8
Hz, 2H). Anal. (C22H23NO4) C, H, N.
Da ta for N-P r op en -2-oyl-2-(5-m eth oxy-2-p h en ylben zo-
[b]fu r a n -3-yl) Eth yla m in e (16): recrystallized from cyclo-
hexane; yield 86%; mp 116-118 °C; 1H NMR (300 MHz,
DMSO-d6) δ 8.40 (t, J ) 5.8 Hz, 1H), 7.85-7.40 (m, 6H), 7.20
(d, J ) 2.6 Hz, 1H), 6.90 (dd, J ) 2.6 and 9.0 Hz, 1H), 6.20
(dd, J ) 9.2 and 17.1 Hz, 1H), 6.10 (dd, J ) 3.3 and 17.1 Hz,
1H), 5.60 (dd, J ) 3.3 and 9.2 Hz, 1H), 3.80 (s, 3H), 3.50 (m,
J ) 7.0 Hz, 2 H), 3.05 (t, J ) 7.0 Hz, 2H). Anal. (C20H19NO3)
C, H, N.
Da ta for N-F u r oyl-2-(5-m eth oxy-2-p h en ylben zo[b]fu -
r a n -3-yl) Eth yla m in e (17): recrystallized from ethanol
(95%); yield 58%; mp 122-124 °C; 1H NMR (300 MHz, DMSO-
d6) δ 8.65 (t, J ) 5.9 Hz, 1H), 7.85-7.80 (m, 3H), 7.55-7.40
(m, 4H), 7.25 (d, J ) 2.6 Hz, 1H), 7.05 (d, J ) 3.6 Hz, 1H),
6.90 (dd, J ) 2.6 and 8.7 Hz, 1H), 6.60 (q, J ) 3.6 Hz, 1H),
3.80 (s, 3H), 3.55 (q, J ) 7.0 Hz, 2 H), 3.10 (t, J ) 7.0 Hz, 2H).
Anal. (C22H19NO4) C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of th e N-Bu t-1-
en -3-oyl-2-(5-m et h oxyb en zo[b]fu r a n -3-yl) E t h yla m in es
18-20. The method adopted for the synthesis of N-but-1-en-
3-oyl-2-(2-benzyl-5-methoxybenzo[b]furan-3-yl) ethylamine (18)
is described. The amine hydrochloride 9a (0.5 g, 0.0016 mol)
was dissolved in 50 mL of water with 0.67 g (0.0048 mol) of
K2CO3, and after 2 h under stirring, the mixture was extracted
with ether. The organic phase was dried over MgSO4, filtered,
and concentrated under reduced pressure. The resulting amine
was dissolved in 20 mL of methylene chloride at -20 °C. At
this temperature, 0.2 g (0.0023 mol) of vinylacetic acid and
0.45 g (0.0023 mol) of EDCI were dissolved in 30 mL of
methylene chloride. After 30 min, the solution of the amine
was added dropwise to the mixture of the acid and EDCI. The
reaction mixture was stirred at -20 °C for 2 h and at room
temperature for 24 h; then, it was washed with a 6 N HCl
solution, water, a 10% NaOH solution, and water until pH 7
was reached. The organic phase was dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue
was purified by column chromatography (SiO2, ethyl acetate/
methylene chloride (1:1)), and recrystallized from ethanol/
Hz, 2 H), 2.85 (t, J ) 6.5 Hz, 2H), 1.75 (s, 3H). Anal. (C20H20
ClNO3) C, H, Cl, N.
-
Da ta for N-Acetyl-2-[2-(2,6-d ich lor oben zyl)-5-m eth oxy-
ben zo[b]fu r a n -3-yl] Eth yla m in e (10h ): recrystallized from
ethanol/water (1:1); yield 64%; mp 165-167 °C; 1H NMR (300
MHz, DMSO-d6) δ 8.05 (s, 1H), 7.50 (d, J ) 8.2 Hz, 2H), 7.35
(m, J ) 8.2 and 8.9 Hz, 2H), 7.15 (d, J ) 2.6 Hz, 1H), 6.80 (dd,
J ) 2.6 and 8.9 Hz, 1H), 4.35 (s, 2H), 3.80 (s, 3H), 3.30 (m,
J ) 6.7 Hz, 2 H), 2.85 (t, J ) 6.7 Hz, 2H), 1.80 (s, 3H). Anal.
(C20H19Cl2NO3) C, H, Cl, N.
Da ta for N-Acetyl-2-[5-m eth oxy-2-(p yr id in -3-ylm eth -
yl)ben zo[b]fu r a n -3-yl] Eth yla m in e (10k ): recrystallized
from toluene/cyclohexane (1:1); yield 45%; mp 116-118 °C; 1H
NMR (300 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.45 (d, J ) 5.7 Hz,
1H), 8.00 (s, 1H), 7.65 (d, J ) 5.7 Hz, 1H), 7.35-7.30 (m, 2H),
7.10 (d, J ) 2.3 Hz, 1H), 6.80 (dd, J ) 2.3 and 8.7 Hz, 1H),
4.10 (s, 2H), 3.75 (s, 3H), 3.25 (m, J ) 6.7 Hz, 2 H), 2.85 (t,
J ) 6.7 Hz, 2H), 1.70 (s, 3H). Anal. (C19H20N2O3) C, H, N.
Da ta for N-Acetyl-2-[5-eth yl-2-(3-m eth oxyben zyl)ben -
zo[b]fu r a n -3-yl] Eth yla m in e (10n ): recrystallized from
toluene/cyclohexane (9:1); yield 66%; mp 101-103 °C; 1H NMR
(300 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.40-6.80 (m, 7H), 4.05
(s, 2H), 3.70 (s, 3H), 3.25 (m, J ) 6.8 Hz, 2 H), 2.80 (t, J ) 6.8
Hz, 2H), 2.70 (q, J ) 7.6 Hz, 2H), 1.75 (s, 3H), 1.20 (t, J ) 7.6
Hz, 3H). Anal. (C22H25NO3) C, H, N.
Da ta for N-Acetyl-2-(5-m eth oxy-2-p h en ylben zo[b]fu -
r a n -3-yl) Eth yla m in e (10q): recrystallized from toluene/
1
cyclohexane (1:1); yield 68%; mp 114-116 °C; H NMR (300
MHz, DMSO-d6) δ 8.00 (s, 1H), 7.90-7.40 (m, 6H), 7.20 (d,
J ) 2.2 Hz, 1H), 6.95 (dd, J ) 2.2 and 8.8 Hz, 1H), 3.80 (s,
3H), 3.45-3.30 (m, 2 H), 3.00 (t, J ) 7.2 Hz, 2H), 1.75 (s, 3H).
Anal. (C19H19NO3) C, H, N.
Da ta for N-Iod oa cetyl-2-(2-ben zyl-5-m eth oxyben zo[b]-
fu r a n -3-yl) Eth yla m in e (11): recrystallized from toluene;
1
yield 83%; mp 110-112 °C; H NMR (300 MHz, DMSO-d6) δ
7.95 (s, 1H), 7.35-7.20 (m, 6H), 7.10 (d, J ) 2.5 Hz, 1H), 6.80
(dd, J ) 2.5 and 8.8 Hz, 1H), 4.10 (s, 2H), 3.75 (s, 3H), 3.55 (s,

2798 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 13
Wallez et al.
1
water (1:3) to give 0.2 g (36%) of pure 18: mp 90-92 °C; H
washed with a 1 N NaHCO3 solution, and then extracted with
a 20% NaOH solution. The aqueous phases were combined,
acidified with a 1 N HCl solution, and extracted with ethyl
acetate. The organic phase was dried over MgSO4, filtered, and
concentrated under reduced pressure to afford crude 24, which
was recrystallized from toluene to give 0.6 g (63%) of pure 24:
mp 160-162 °C; 1H NMR (300 MHz, DMSO-d6) δ 9.10 (s, 1H),
8.00 (t, J ) 5.3 Hz, 1H), 7.40-7.15 (m, 6H), 6.90 (d, J ) 1.7
Hz, 1H), 6.65 (dd, J ) 1.7 and 8.7 Hz, 1H), 4.10 (s, 2H), 3.30
(q, J ) 6.7 Hz, 2H), 2.80 (t, J ) 6.7 Hz, 2H), 1.80 (s, 3H). Anal.
(C19H19NO3) C, H, N.
NMR (300 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.35-7.20 (m, 6H),
7.10 (d, J ) 2.5 Hz, 1H), 6.70 (dd, J ) 2.5 and 8.9 Hz, 1H),
5.90-5.75 (m, 1H), 5.10-5.00 (m, 2H), 4.10 (s, 2H), 3.80 (s,
3H), 3.30-3.25 (m, 2H), 2.90-2.80 (m, 4H). Anal. (C22H23NO3)
C, H, N.
Da ta for N-Bu t-1-en -3-oyl-2-[5-m eth oxy-2-(3-m eth oxy-
ben zyl)ben zo[b]fu r a n -3-yl] Eth yla m in e (19): recrystal-
lized from cyclohexane; yield 46%; mp 98-100 °C; 1H NMR
(300 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.35-7.20 (m, 2H), 7.10
(d, J ) 1.9 Hz, 1H), 6.90-6.70 (m, 4H), 5.90-5.85 (m, 1H),
5.10-5.00 (m, 2H), 4.10 (s, 2H), 3.80 (s, 3H), 3.70 (s, 3H), 3.30-
3.25 (m, 2 H), 2.90-2.80 (m, 4H). Anal. (C23H25NO4) C, H, N.
Da ta for N-Bu t-1-en -3-oyl-2-(5-m eth oxy-2-p h en ylben -
zo[b]fu r a n -3-yl) Eth yla m in e (20): recrystallized from cy-
clohexane; yield 53%; mp 99-101 °C; 1H NMR (300 MHz,
DMSO-d6) δ 8.10 (s, 1H), 7.85-7.40 (m, 6H), 7.20 (d, J ) 2.3
Hz, 1H), 6.95 (dd, J ) 2.3 and 9.1 Hz, 1H), 5.90-5.75 (m, 1H),
5.10-5.00 (m, 2H), 3.80 (s, 3H), 3.40-3.35 (m, 2 H), 3.05 (t,
J ) 7.0 Hz, 2H), 2.85 (d, J ) 6.9 Hz, 2H). Anal. (C21H21NO3)
C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of th e Eth er s 25
a n d 26. The method adopted for the synthesis of N-acetyl-2-
(2-benzyl-5-pentoxybenzo[b]furan-3-yl) ethylamine (25) is de-
scribed. A 2.6 mL (0.02 mol) portion of iodopentane was added
to a solution of 3.09 g (0.01 mol) of 24 in 100 mL of acetonitrile
in the presence of 2.76 g (0.02 mol) of K2CO3, and the mixture
was refluxed for 18 h. After cooling and filtration, the filtrate
was concentrated and the residue was dissolved in ethyl
acetate and washed with a 10% NaOH solution and then with
brine. The organic phase was dried over MgSO4, filtered, and
concentrated under reduced pressure to afford crude 25, which
was recrystallized from toluene/petroleum ether (1:1) to give
2.6 g (68%) of pure 25: mp 71-73 °C; 1H NMR (300 MHz,
DMSO-d6) δ 8.00 (s, 1H), 7.35-7.20 (m, 6H), 7.10 (d, J ) 2.6
Hz, 1H), 6.80 (dd, J ) 2.6 and 8.8 Hz, 1H), 4.05 (s, 2H), 3.95
(t, J ) 7.0 Hz, 2H), 3.25 (q, J ) 6.8 Hz, 2H), 2.80 (t, J ) 6.8
Hz, 2H), 1.75-1.70 (m, 5H), 1.45-1.30 (m, 4H), 0.90 (t, J )
7.0 Hz, 3H). Anal. (C24H29NO3) C, H, N.
N-Bu t-2-en -3-oyl-2-(5-m eth oxy-2-p h en ylben zo[b]fu r a n -
3-yl) eth yla m in e (21). A solution of vinylacetic acid (0.36 g,
0.0042 mol) in 10 mL of methylene chloride was stirred at -10
°C for 20 min. Then, triethylamine (0.32 g, 0.0032 mol), HOBt
(0.43 g, 0.0032 mol), and EDCI (0.61 g, 0.0032 mol) were added,
and the mixture was stirred at -10 °C for 30 min. A solution
of 0.64 g (0.0021 mol) of 9q in 10 mL of methylene chloride
was cooled at -10 °C and added dropwise. After 18 h of stirring
at room temperature, the reaction mixture was washed with
water, a 1 N HCl solution, water, a 10% NaOH solution, and
water until pH 7 was reached. The organic phase was dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. The residue was precipitated in petroleum ether and
recrystallized from ethanol/water (1:1) to give 0.4 g (57%) of
pure 21: mp 118-120 °C; 1H NMR (300 MHz, DMSO-d6) δ
8.20 (t, 1H), 7.85-7.45 (m, 6H), 7.20 (s, 1H), 6.95 (d, J ) 8.8
Hz, 1H), 6.65-6.60 (m, 1H), 5.85 (d, J ) 15.3 Hz, 1H), 3.80 (s,
3H), 3.50-3.45 (m, 2 H), 3.05 (t, J ) 6.7 Hz, 2H), 1.80 (d, J )
6.5 Hz, 3H). Anal. (C21H21NO3) C, H, N.
Da ta for N-Acetyl-2-(2-ben zyl-5-h exyloxyben zo[b]fu -
r a n -3-yl) eth yla m in e (26): recrystallized from ethanol/water
(1:1); yield 60%; mp 64-66 °C; 1H NMR (300 MHz, DMSO-d6)
δ 8.00 (s, 1H), 7.35-7.20 (m, 6H), 7.10 (d, J ) 2.4 Hz, 1H),
6.80 (dd, J ) 2.4 and 9.0 Hz, 1H), 4.05 (s, 2H), 3.95 (t, J ) 6.9
Hz, 2H), 3.25 (q, J ) 6.8 Hz, 2H), 2.80 (t, J ) 6.8 Hz, 2H),
1.75-1.70 (m, 5H), 1.50-1.25 (m, 6H), 0.90 (t, J ) 6.9 Hz, 3H).
Anal. (C25H31NO3) C, H, N.
P h a r m a cology. Rea gen ts a n d Ch em ica ls. 2-[125I]Iodo-
melatonin (2200 Ci/mmol) was purchased from NEN (Boston,
MA). Other drugs and chemicals were purchased from Sigma-
Aldrich (Saint Quentin, France).
Gen er a l P r oced u r e for th e Syn th esis of th e Ur ea s 22
a n d 23. The method adopted for the synthesis of N-[2-(2-
benzyl-5-methoxybenzo[b]furan-3-yl)ethyl]-N′-methylurea (22)
is described. A 0.15 g (0.0028 mol) portion of methyl isocyanate
was added dropwise to a solution of the amine hydrochloride
9a (0.754 g, 0.0024 mol) in 10 mL of pyridine. After being
stirred for 1 h and 30 min at room temperature, the mixture
was poured into ice-water and extracted with ethyl acetate.
The organic phase was washed with a 3 N HCl solution and
then with water, dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was recrystallized from
ethanol/water (1:3) to give 0.24 g (31%) of pure 22: mp 133-
Cell Cu ltu r e. HEK (provided by A.D. Strosberg, Paris,
France) and CHO cell lines stably expressing the human
melatonin MT1 or MT2 receptor were grown in DMEM medium
supplemented with 10% fetal calf serum, 2 mM glutamine, 100
IU/mL penicillin, and 100 µg/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
(95000g, 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 -80 °C
until use.
Bin d in g Assa ys. 2-[125I]Iodomelatonin binding assay condi-
tions were essentially as previously described.35 Briefly, bind-
ing was initiated by addition of membrane preparations from
stable transfected HEK cells (40 µg/mL) diluted in binding
buffer (50 mM TRIS-HCl buffer, pH 7.4, containing 5 mM
MgCl2) to 2-[125I]iodomelatonin (0.025 and 0.2 nM, respectively,
for MT1 and MT2 receptors) and the tested drug. Nonspecific
binding was defined in the presence of 1 µM 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) poly-
ethylenimine. The filters were washed three times with 1 mL
of ice-cold 50 mM TRIS-HCl buffer, pH 7.4.
1
135 °C; H NMR (300 MHz, DMSO-d6) δ 7.50-7.20 (m, 6H),
7.10 (d, J ) 2.4 Hz, 1H), 6.80 (dd, J ) 2.4 and 8.9 Hz, 1H),
5.95 (t, J ) 5.8 Hz, 1H), 5.75 (q, J ) 4.7 Hz, 1H), 4.10 (s, 2H),
3.80 (s, 3H), 3.25 (td, J ) 5.8 and 6.9 Hz, 2 H), 2.80 (t, J ) 6.9
Hz, 2H), 2.55 (d, J ) 4.7 Hz, 3H). Anal. (C20H22N2O3) C, H, N.
Da ta for N-[2-(5-Meth oxy-2-p h en ylben zo[b]fu r a n -3-yl)
eth yl]-N′-m eth ylu r ea (23): recrystallized from toluene; yield
56%; mp 153-155 °C; 1H NMR (300 MHz, DMSO-d6) δ 7.95-
7.35 (m, 6H), 7.25 (d, J ) 2.7 Hz, 1H), 6.90 (dd, J ) 2.7 and
8.9 Hz, 1H), 6.10 (t, J ) 5.5 Hz, 1H), 5.80 (q, J ) 4.6 Hz, 1H),
3.85 (s, 3H), 3.40-3.25 (m, 2H), 3.00 (t, J ) 7.2 Hz, 2H), 2.55
(d, J ) 4.6 Hz, 3H). Anal. (C19H20N2O3) C, H, N.
N-Acetyl-2-(2-ben zyl-5-h ydr oxyben zo[b]fu r an -3-yl) Eth -
yla m in e (24). Under N2, a solution of 1.9 g (0.006 mol) of the
complex BBr3/Me2S in 100 mL of methylene chloride was
stirred at room temperature for 15 min. A solution of 1 g (0.003
mol) of 10a in 50 mL of methylene chloride was added
dropwise, and the mixture was refluxed for 18 h. After cooling,
the mixture was carefully hydrolyzed and concentrated under
reduced pressure. The residue was taken off with ethyl acetate,
[35S]GTPγS binding assay was performed according to
published methodology.36 Briefly, membranes from CHO trans-
fected cells and peptides were diluted in binding buffer (20
mM HEPES, pH 7.4, 100 mM NaCl, 3 µM GDP, 3 mM MgCl2,
and 20 µg/mL saponin). Incubation was started by the addition
of 0.2 nM [35S]GTPγS to the membranes (20 µg/mL) and drugs,

Benzofuran Derivatives as Melatonin Receptor Ligands
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 13 2799
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and further followed for 1 h at room temperature. For
experiments with antagonists, the membranes were preincu-
bated with both the melatonin and the antagonist for 30 min
prior to the addition of [35S]GTPγS. Nonspecific binding was
defined using cold GTPγS (10 µM). Reaction was stopped by
rapid filtration through GF/B filters followed by three succes-
sive washes with ice-cold buffer.
The usual levels of [35S]GTPγS binding (expressed in dpm)
were, respectively, for CHO-MT1 and CHO-MT2 membranes
1000 and 2000 for basal activity, 4800 and 8000 in the presence
of melatonin (1 µM), and 160 and 180 in the presence of GTPγS
10 µM, which defined the nonspecific binding.
Data were analyzed 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 pKB ) -(log KB), with
KB ) IC50/(1 + [Ago]/EC50(ago)), where IC50 is the inhibitory
concentration of antagonist that gives 50% inhibition of [35S]-
GTPγS binding in the presence of a fixed concentration of
melatonin ([Ago]) and EC50(ago) is the EC50 of the molecule
when tested alone.
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