Design and synthesis of benzofuranic derivatives as new ligands at the melatonin-binding site MT3

Article abstract of DOI:10.1016/j.bmc.2008.03.036

Benzofuranic analogues of MCA-NAT (5-methoxycarbonylamino-N-acetyltryptamine) have been synthesized and evaluated as melatonin receptor ligands. Introduction of a methoxycarbonylamino substituent in the C-5 position of the benzofurane nucleus obtains MT

Full text of DOI:10.1016/j.bmc.2008.03.036

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 4954–4962
Design and synthesis of benzofuranic derivatives as new ligands
at the melatonin-binding site MT3
a
a
a
c
Mohamed Ettaoussi, Basile P e´ res, Fr e´ derique Klupsch, Philippe Delagrange,
b
c
c
Jean-A. Boutin, Pierre Renard, Daniel-H. Caignard,
Philippe Chavatte, Pascal Berthelot, Daniel Lesieur and Sa ¨ı d Yous
a
a
a
a,
*
a
Laboratoire de Chimie Th e´ rapeutique (EA 1043), Facult e´ des Sciences Pharmaceutiques et Biologiques, Universit e´ de Lille, 3,
rue du professeur Laguesse, 2, BP 83, 59006 Lille Cedex, France
b
Division de Pharmacologie Mol e´ culaire et Cellulaire, Institut de Recherches Servier, 125 Chemin de Ronde,
78290 Croissy-sur-Seine, France
Institut de Recherches Servier, 11 rue des Moulineaux, 92150 Suresnes, France
c
Received 10 January 2008; revised 4 March 2008; accepted 14 March 2008
Available online 17 March 2008
Abstract—Benzofuranic analogues of MCA-NAT (5-methoxycarbonylamino-N-acetyltryptamine) have been synthesized and eval-
uated as melatonin receptor ligands. Introduction of a methoxycarbonylamino substituent in the C-5 position of the benzofurane
nucleus obtains MT selective ligands. This selectivity can be modulated with suitable variations of the C-5 position and the acyl
3
group on the C-3 side chain.
Ó 2008 Elsevier Ltd. All rights reserved.
9
1. Introduction
the quinone reductase 2 (QR2 EC 1.6.99.2) an enzyme
closely related to quinone reductase 1.
Melatonin
(
(N-acetyl-5-methoxytryptamine,
MLT)
Chart 1) is synthesized and released by the pineal gland
Recent works suggest that the MT melatonin-binding
3
in a circadian fashion, with high levels occurring during
the night. Indeed its synthesis is regulated by the day–
night alternation and by the way MLT transmits to
site is involved in acute inflammatory responses in the
1
rat and in the regulation of intraocular pressure in
0
1
1
the rabbit. The physiological importance of the MT3/
QR2 site is still unknown and therefore is of particular
interest to design and synthesize new selective ligands
which will provide pharmacological tools to assess and
better characterize the role of this melatonin-binding
1
the organism information about the photoperiod.
Melatonin appears to play an important role in the reg-
ulation of mammalian circadian rhythms and reproduc-
tion functions and has been implicated in a number of
pathological states suggesting its therapeutic application
1
2,13
site.
2
–5
in several disorders.
An accurate characterization of this binding site mediat-
ing specific functions in native tissues can only be made
using specific ligands. Unfortunately, only a few MT3
selective ligands have been reported to date (Chart 1).
To date, two mammalian MLT receptors have been
,7
6
cloned (MT and MT ). Both are G-protein coupled
1
2
8
14
receptors. Another melatonin-binding site with low
affinity, referred to as MT , was recently identified as
Among them, prazosin, familiarly known as an a1-
adrenoceptor antagonist, acts as an MT selective ligand
5-methoxycarbonylamino-N-acetyl-
3
3
(IC50 = 7.8 nM),
tryptamine (MCA-NAT), has been described as a
1
5
selective MT ligand (IC = 2.7 nM), nitroindole deriv-
3
50
Keywords: Melatonin; MCA-NAT; MT
ligands; Binding; Quinone reductase 2.
3
binding site; Benzofuranic
20964375; e-mail:
1
6
ative (S27533) (K ꢀ 0.3 nM), and recently, DMHMIO
i
*
Corresponding author. Tel./fax: +33
said.yous@univ-lille2.fr
3
(2,3-dimethoxy 7-hydroxy 10-methyl 5H 10H inde-
no(1,2-b)indol-10-one) (K = 0.19 nM).
1
7
i
0
968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.03.036

M. Ettaoussi et al. / Bioorg. Med. Chem. 16 (2008) 4954–4962
4955
CH3
O
H
NHCOCH3
H3CO
N
NHCOCH3
O
NH
NH
Melatonin
MCA-NAT
O
O
CH3
O
N
CH3 NO2
O
N
N
NHCOCH3
I
N
N
O
CH3
CH3
NH2
S27533
Prazosine
CH3
O
O
OH
O
N
CH3
CH3
DMHMIO
Chart 1. Chemical structures of melatonin and MT
3
ligands.
The known MT ligand MCA-NAT includes a methoxy-
3
into benzofuranone was achieved by treatment with
potassium carbonate in acetone, and then nitrile 4 was
obtained employing Horner-Emmons olefination with
diethyl cyanomethylphosphonate. Hydrogenation of
nitrile 4 in the presence of platinum oxide in chloroform
and methanol led to amine 5. The N-acyl derivatives 6a–e
were prepared from 5 by treatment with the appropriate
carbonylamino group in the 5-position. It appeared to
us therefore desirable to synthesize its benzofuranic bio-
isostere (10a) as it has been reported that the benzofura-
ne analogues of melatonin are not only metabolically
more stable but also very potent for the melatonin
2
1
1
8,19
receptors.
lating the fit to the MT binding site, we replaced the
Furthermore, in the hope of better modu-
acid chlorides in the presence of N(Et) as base.
3
3
methoxycarbonylamino group of 10a with ester function
6a) and amide groups (7a, 8a, 11).
(
Compounds 7(a, c, e) and 8(a, c, d) were synthesized
from the corresponding esters 6(a, c–e) according to
Scheme 2. Introduction of the carboxamido group was
achieved using aqueous ammonia (method A) or form-
amide and sodium methanolate (method B), whereas
treatment with methylamine afforded secondary amide
In order to explore the role of the N-acyl side chain on
the binding affinity and the selectivity, we replace the
methyl of the acetamido function with, isopropyl, cyclo-
propyl, cyclopentyl, furyl, and allyl (Table 1).
8
(a, c, d).
For all these compounds, the synthesis, the binding data
for the human MT and MT receptors and MT bind-
ing site are reported.
The synthetic sequences used for the transformation of
esters 6a–e into targeted compounds 10a–e and 11 were
as follows (Scheme 3): (1) saponification of the ester
group, producing the corresponding acid derivatives
9(a–e), (2) preparation of the azide intermediates by
reaction with ethyl chloroformate then with sodium
azide, and (3) treatment with methanol or trifluoroacetic
acid, resulting in carbamates 10(a–e) and amide 11,
respectively.
1
2
3
2
. Results and discussion
2
.1. Chemistry
The synthetic pathway for compounds 6a-e is outlined
in Scheme 1.
Synthesis of the vinylacetamide 10f was carried out as
illustrated in Scheme 4. Ester 4 was saponified to give
acid 12, which was converted into carbamate 13 as pre-
viously described. Hydrogenation of the cyano group
over Raney nickel in methanol provided amine 14. A
peptide coupling reaction type in the presence of 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochlo-
ride (EDCI) between the amine 14 and vinylacetic acid
gave the amide 10f.
Commercially available 4-acetoxybenzoic acid was con-
verted to acid 1 by treatment with aluminium trichloride
2
0
in nitrobenzene. First attempts to form bromoacetyl
compound 2 using bromine in dichloromethane afforded
its dibromated analogue as the major product. Replac-
ing dichloromethane by acetic acid furnished the desired
monobrominated compound 2, which reacted with thio-
nyl chloride and methanol to give ester 3. Cyclization

4956
M. Ettaoussi et al. / Bioorg. Med. Chem. 16 (2008) 4954–4962
Table 1. MT
1
, MT
2
, and MT
3
receptor-binding affinities of benzofuranic compounds
H
H3CO
N
NHCOCH3
R1
NHCOR2
O
NH
O
MCANAT
Compound
Melatonin
R
1
R
2
IC50 (nM) MT
3
IC50 (nM) MT
1
IC50 (nM) MT
2
MT
1/323
/122
17
1
/ MT
3
MT
2
/MT
3
—
—
—
64.6 ± 0.9
0.2 ± 0.03
0.53 ± 0.06
1
MCA-NAT
S21767
—
58 ± 0.1
64 ± 1
1000 ± 44
0,6 ± 0.02
4000 ± 53
0,7 ± 0.01
7
0
OCH
3
CH
3
3
1/103
/92
1
a
a
nd
6
6
6
6
7
7
8
8
8
1
1
1
1
1
1
1
a
COOCH
COOCH
COOCH
COOCH
3
3
3
3
CH
14 ± 0.9
65 ± 1
nd
—
—
a
a
nd
b
CH(CH
c-C
2-Furyl
CH
2-Furyl
CH
3
)
2
nd
—
—
d
5
H
9
18 ± 1.1
53 ± 1
3880 ± 42
>10,000
>10,000
>10,000
189 ± 5
389 ± 6
>10,000
1000 ± 41
>10,000
>1000
215
2
1.6
>188
188
122
e
>
a
CONH
2
2
3
82 ± 0.5
67 ± 0.8
12 ± 0.3
41 ± 1.1
1
2
e
CONH
>149
149
16
>
a
CONHCH
CONHCH
CONHCH
3
3
3
3
>
83
c
c-C
3
5
H
5
9
1220 ± 10
>10,000
>10,000
>10,000
>29
>
244
a
nd
d
c-C
H
—
—
—
—
232
a
a
nd
0a
0b
0c
0d
0e
0f
1
NHCOOCH
NHCOOCH
NHCOOCH
NHCOOCH
NHCOOCH
NHCOOCH
3
3
3
3
3
3
CH30
CH(CH
16 ± 0.4
23 ± 0.3
24 ± 1.1
nd
3
)
2
5350 ± 32
8180 ± 5
5320 ± 19
>10,000
4580 ± 12
5900 ± 22
5320 ± 29
>10,000
1
99
340
45
c-C
3
5
H
5
9
2
a
nd
c-C
H
—
—
2-Furyl
56 ± 1.5
11 ± 0.9
>178
>178
244
CH
2
3
CH@CH
2
2690 ± 21
>10,000
560 ± 11
2000 ± 54
5
1
a
nd
NHCOCF
3
CH
—
—
a
nd, not determined.
2
.2. Pharmacology
MT binding site are nearly the same as those of mela-
3
tonin (Table 1), and (ii) its predicted bioavailability is
better than that of melatonin.
The affinities of the compounds for the melatonin recep-
tor subtypes were evaluated in vitro in binding assays
1
25
using 2-[ I]-iodomelatonin, human embryonic kidney
cell line HEK293 stably expressing MT or MT human
melatonin receptors, and hamster brain membrane prep-
Starting from this benzofuranic bioisostere, we
decided to incorporate changes at the C-5 positions
and in the acyl side chain to investigate structure–
affinity-selectivity relationships for MT , MT , and
1
2
arations for the MT binding site according to a previ-
3
1
2
2
2
ously described method.
MT subtypes.
3
The chemical structures, binding affinities (MT , MT ,
1
and MT ), and selectivity ratios of the new compounds
3
The positive effect of a 5-methoxycarbonylamino (car-
bamate) substitution toward MT selectivity has already
2
3
are reported in Table 1.
been described for melatonin itself. It is also observed in
our series and affects both MT , MT , and MT sub-
1
2
3
The benzofurane bioisostere of melatonin (S21767) can
be considered a very interesting lead compound: (i) its
affinity values for both MT and MT receptors and
types, leading to a MT selective ligand (10a; Table 1).
3
Further structural variations at the N-acyl group were
found to be important. Replacement of the methyl
1
2

M. Ettaoussi et al. / Bioorg. Med. Chem. 16 (2008) 4954–4962
4957
O
O
O
O
O
Br
HO
O
a
HO
CH3
b
HO
O
O
CH3
OH
OH
O
1
2
c
O
CN
O
O
O
H C
3
H C
H C
Br
O
3
3
e
O
d
O
O
OH
4
3
f
NH , HCl
NHCOR
2
O
O
H C
H3C
3
g
O
O
O
O
5
6a, R = CH3
6
6
6
6
b, R = CH(CH3)2
c, R = c-C H5
3
d, R = c-C H9
5
e, R = 2-furyl
a
Scheme 1. Synthesis of esters 6a–e. Reagents: (a) AlCl
3
, C
6
H
5
NO
2
; (b) Br
OH; (g) ClCOR, N(Et)
2
, CH
3
COOH; (c) SOCl
Cl
2
, CH
3
OH; (d) K
2
CO
3
, acetone; (e)
(C
2
H
5
O)
2
P(O)CH
2
CN, NaH, THF; (f) H
2
, PtO
2
, CHCl /CH
3
3
3
, CH
2
2
.
3. Conclusions
NHCOR
O
Introduction of a methoxycarbonylamino group in the
C-5 benzofuran position allows access to MT selective
H C
3
O
3
ligands, and modulation of the selectivity can be ob-
tained with suitable modification on the N-acyl
substituents.
O
6
(a, c-e)
The most selective compounds 10b and 10c show MT1/
MT and MT /MT selectivity ratios of 232/199 and
340/245, respectively. These ratios are noticeably higher
a
b
3
2
3
NHCOR
NHCOR
O
than that of MCANAT itself (S = 17/70).
O
H CHN
H N
3
2
O
4. Experimental
O
8
8
8
a, R = CH3
7
7
7
a, R = CH3
4.1. Chemistry
c, R = c-C H
c, R = c-C H
3
5
3
5
d, R = c-C H
9
e, R = 2-furyl
5
Melting points were determined on a Buchi SMP-20
capillary apparatus and are uncorrected. IR spectra
were recorded on a Vector 22 Bruker spectrophotome-
ter. H NMR spectra were recorded on a AC 300 Bruker
spectrometer. Chemical shifts are reported in d units
a
Scheme 2. Synthesis of amides 7(a, c, e) and 8(a, c, d). Reagents: (a)
NH OH 20%/H O (Method A) or (i) HCONH , DMF, (ii) CH ONa
Method B); (b) CH NH , CH OH.
4
2
2
3
1
(
3
2
3
(parts per million) relative to (Me) Si. HR-FAB/MS
were recorded on a JEOL LMS-SX/SX 102A.
4
group of the amide side chain by an isopropyl (10b),
cyclopropyl (10c), furyl (10e) or allyl (10f) does not
modify the binding affinity for the MT binding site.
3
Compound purity and Mass spectra were performed on
Surveyor MSQ Thermoelectron spectrometer (+cAPCI
corona sid = 30.00, det = 1400.00 Full ms [100.00–
1000.00]) Elemental analyses for final substances were
performed by CNRS Laboratories (Vernaison, France).
Obtained results were within 0.4% of the theoretical
values.
Nevertheless, these modifications sharply decrease the
binding affinity for both MT and MT , thus increasing
1
2
the MT selectivity.
3
Replacement of the carbamate group on the 5-posi-
tion by ester group (6), primary or secondary amide
group (7, 8) decreases the MT3 selectivity except
when a furyl heterocycle is grafted on the N-acyl
chain (6e, 7e).
4.1.1. 3-Bromoacetyl-4-hydroxybenzoic acid (2). Com-
pound 1 (5.8 g, 0.032 mol) was added to a solution of

4958
M. Ettaoussi et al. / Bioorg. Med. Chem. 16 (2008) 4954–4962
NHCOR
NHCOR
O
O
H C
3
a
O
HO
O
O
6
(a-e)
9
(a-e)
R = CH3
b, c
b, d
NHCOCH3
NHCOR
H
N
F3C
H
O
N
H C
3
O
O
O
O
1
1
1
1
1
1
1
0a, R = CH3
0b, R = CH(CH3)2
0c, R = c-C H5
3
0d, R = c-C H9
5
0e, R = 2-furyl
a
Scheme 3. Synthesis of compounds 10 (a–e) and 11. Reagents: (a) i—NaOH, CH
NaN , H O; (c) CH OH/Toluene, reflux; (d) TFA, CH Cl
3
OH, H
2 3
O; ii—6 M HCl; (b) i—ClCOOEt, N(Et) , acetone; ii—
3
2
3
2
2
.
O
CN
CN
H
N
O
a
HO
b
H C
3
4
O
O
O
12
13
c
NH ,HCl
NHCOCH CH=CH
2
2
2
H
H
O
N
O
N
d
H C
H C
3
3
O
O
O
O
10f
14
a
Scheme 4. Synthesis of compound 10f. Reagents: (a) i—NaOH, MeOH, H
2
O; ii—6 M HCl; (b) i—ClCOOEt, N(Et)
3
3 2
, acetone; ii—NaN , H O; iii—
CH OH/Toluene, reflux; (c) i—H , Raney nickel, CH OH; ii—HCl(g); (d) CH
3
2
3
2
@CHCH COOH, EDCI, HOBT, CH
2
2
Cl .
2
À1
bromine (2.5 mL, 0.048 mol) in 40 mL of glacial acetic
acid. After stirring at 80 °C for 2 h, the reaction mixture
was poured into ice-cold water. The precipitate was fil-
tered, washed with water, dried, and crystallized from
274; IR (neat, cm ) 3580–3250, 1710, 1662, 1220,
1
1174, 1114; H NMR (300 MHz, CDCl ) d 3.94 (s,
3
3H), 4.54 (s, 2H), 7.08 (d, J = 8.9 Hz, 1H), 8.19 (dd,
J = 8.9 and 2.2 Hz, 1H), 8.50 (d, J = 2.2 Hz, 1H), 9.45
(s, 1H).
ethanol 95° to give 6.7 g (80% yield) of 2; mp 174–175
+
C; MS (APCI, pos. 30 V) m/z: [M+H] 260; IR (neat,
°
cm
À1
1
)
3502–3400, 1689, 1653, 1224;
H
NMR
4.1.3. (5-Methoxycarbonyl-3-benzo[b]furan-3-yl)acetoni-
trile (4). A mixture of 3 (4.1 g, 0.015 mol) and K CO
3
(
DMSO-d ) d 4.94 (s, 2H), 7.09 (d, J = 8.7 Hz, 1H),
6
2
8
1
.02 (dd, J = 8.7 and 1.8 Hz, 1H), 8.33 (d, J = 1.8 Hz,
H), 11.80 (s, 1H), 12.23 (s, 1H).
(4.1 g, 0.030 mol) in 35 mL of acetone was stirred at
room temperature for 2 h. The precipitate was filtered
and washed with acetone. The filtrate was then concen-
trated under reduced pressure to give an intermediate
benzofuranone which was not isolated.
4
.1.2. Methyl-(3-bromoacetyl-4-hydroxy)benzoate (3).
Thionyl chloride (4.0 mL, 0.055 mol) was added drop-
wise to a solution of 2 (7.1 g, 0.027 mol) in 70 mL of
methanol cooled to 0 °C. After stirring at room temper-
ature for 1 h, the reaction mixture was refluxed for 2 h,
then concentrated under reduced pressure. The residue
was extracted off with ethyl acetate, washed with water,
dried over MgSO , filtered, and concentrated under re-
4
duced pressure to afford a residue which was recrystal-
lized from isopropanol to give 5.3 g (70% yield) of 3;
Under stirring and N , diethyl cyanomethylphospho-
2
nate (3.5 mL, 0.023 mol) in 30 mL of anhydrous THF
was added dropwise at À10 °C to a mixture of NaH
(0.9 g, 0.023 mol) (60% in mineral oil) in 40 mL of anhy-
drous THF. After 1 h, the intermediate benzofuranone
in 70 mL of anhydrous THF was added dropwise at
À10 °C, then the stirring was continued at room temper-
ature for 2 h. The mixture was poured into cold water
+
mp 93–94 °C; MS (APCI, pos. 30 V) m/z: [M+H]

M. Ettaoussi et al. / Bioorg. Med. Chem. 16 (2008) 4954–4962
4959
1
1709, 1643, 1325, 1253, 1182; H NMR (300 MHz,
and extracted with diethyl ether. The organic phase was
dried over MgSO , filtered, and concentrated under re-
DMSO-d ) d 0.58–0.79 (m, 4H), 1.47 (m, 1H), 3.10–
4
6
duced pressure. The oily residue was purified by column
chromatography (SiO , CH Cl ) to afford a yellow solid.
Recrystallization from absolute ethanol gave 1.6 g (50%
3.32 (m, 4H), 3.86 (s, 3H), 7.67 (d, J = 8.6 Hz, 1H),
7.92 (dd, J = 8.6 and 1.3 Hz, 1H), 7.93 (m, 1H), 8.21
(t, J = 5.6 Hz, 1H), 8.26 (d, J = 1.3 Hz, 1H). Anal. Calcd
for C H NO : C,66.89; H, 5.96; N, 4.87. Found: C,
2
2
2
yield) of 4; mp 125–126 °C; MS (APCI, pos. 30 V) m/z:
1
6
17
4
+
M+H] 216; IR (neat, cm ) 2250, 1717, 1287, 1259,
À1
[
66.78; H, 5.92; N 4.75.
1
1
190; H NMR (300 MHz, CDCl ) d 3.80 (s, 2H), 3.96
3
(
(
s, 3H), 7.55 (d, J = 8.5 Hz, 1H), 7.75 (s, 1H), 8.09
dd, J = 8.5 and 1.7 Hz, 1H), 8.31 (d, J = 1.7 Hz, 1H).
4.2.4. N-(2-(5-Methoxycarbonyl-benzo[b]furan-3-yl)ethyl)-
cyclopentylcarboxamide (6d). Recrystallized from tolu-
1
ene; yield 67%; mp 122–123 °C; H NMR (300 MHz,
4
.1.4. N-2-(5-Methoxycarbonyl-benzo[b]furan-3-yl)ethyl-
amine hydrochloride (5). A solution of 4 (0.70 g,
.003 mol) in 30 mL of methanol and 3 mL of chloro-
DMSO-d ) d 1.43–1.75 (m, 8H), 2.50 (s, 1H), 2.84 (t,
6
J = 6.9 Hz, 2H), 3.36 (m, 2H), 3.90 (s, 3H), 7.68 (d,
J = 8.5 Hz, 1H), 7.80–8.00 (m, 3H), 8.30 (d,
0
À1
form was hydrogenated over PtO (0.11 g, 0.004 mol)
2
J = 1.1 Hz, 1H). IR (neat, cm ) 3258, 1718, 1631. Anal.
Calcd for C H NO : C, 68.55; H, 6.71; N, 4.44.
Found: C,68.42; H,6.72; N, 4.36.
under pressure (35 bars) at room temperature for 48 h.
After filtration and evaporation, the residue was recrys-
tallized from acetonitrile to give 0.72 g (86% yield) of 5;
mp 210–211 °C; MS (APCI, pos. 30 V) m/z: [M+H]
2
1
8
21
4
+
4.2.5. N-(2-(5-Methoxycarbonyl-benzo[b]furan-3-yl)ethyl)-
furoylamide (6e). Recrystallized from isopropanol; yield
À1
20; IR (neat, cm ) 3500–3400, 1710, 1300, 1249,
1
À1
1
J = 4.5 Hz, 2H), 3.36 (m, 2H), 3.89 (s, 3H), 7.71 (d,
188; H NMR (300 MHz, DMSO-d ) d 3.07 (t,
70%; mp 116–118 °C; IR (neat, cm ) 3275, 1713, 1660,
6
1
1645; H NMR (300 MHz, DMSO-d ) d 2.93 (t,
6
J = 8.7 Hz, 1H), 7.97 (dd, J = 8.7 and 1.8 Hz, 1H),
.06 (s, 1H), 8.10–8.23 (br s, 3H), 8.35 (d, J = 1.8 Hz,
J = 7.1 Hz, 2H), 3.51 (m, 2H), 3.85 (s, 3H), 6.60 (m,
1H), 7.05 (d, J = 3.2 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H),
7.81 (m, 1H), 7.92 (dd, J = 8.6 and 1.6 Hz, 1H), 7.97
8
1
H).
(s, 1H), 8.31 (m, 1H), 8.56 (t, J = 5.6 Hz, 1H). Anal.
Calcd for C H NO : C, 65.17; H,4.83; N, 4.47. Found:
C, 64.80; H, 4.84; N, 4.50.
4
e)
.2. General procedure for the preparation of amides (6a–
1
7
15
5
Triethylamine (0.002 mol) was added to a solution of 5
(
4.2.6. N-(2-(5-Carboxamido-benzo[b]furan-3-yl)ethyl)-
acetamide (7a)
0.001 mol) in 30 mL of anhydrous methylene chloride.
After stirring for 10 min at 0 °C, 0.001 mol of the appro-
priate acid chloride was added dropwise at this temper-
ature. The reaction mixture was stirred at room
temperature for 20 min. The organic phase was sepa-
rated, washed with a 1 M HCl solution and water, dried
4.2.6.1. Method A. A solution of 6a (26.2 g, 0.1 mol)
in 50 mL of aqueous 20% ammonia was refluxed under
stirring for 5 h. The reaction mixture was cooled and
concentrated under reduced pressure. Recrystallization
from ethanol gave 10.6 g (43% yield) of 7a.
over MgSO , filtered and concentrated under reduced
4
pressure to give the desired amides (6a–e).
4.2.6.2. Method B. Formamide (0.68 mL, 0.015 mol)
was added to a solution of 6a (0.39 g, 0.0015 mol) in
DMF (10 mL). After 15 min of stirring at 80 °C, a
30% solution of sodium (0.006 at.gr) in methanol was
added, and then the mixture was refluxed overnight.
After cooling, the reaction mixture was poured into
water and extracted with ethyl acetate. The organic
4.2.1. N-(2-(5-Methoxycarbonyl-benzo[b]furan-3-yl)ethyl)-
acetamide (6a). Recrystallized from cyclohexane; yield
À1
4
1
2
7
1
3%; mp 121–122 °C; IR (neat, cm ) 3260, 1705,
1
640; H NMR (300 MHz, DMSO-d ) d 1.80 (s, 3H),
6
.73 (t, J = 6.9 Hz, 2H), 3.32 (m, 2H), 3.92 (s, 3H),
.32 (dd, J = 8.8 and 1.7 Hz, 1H), 7.45 (d, J = 8.8 Hz,
H), 7.77 (s, 1H), 7.79 (d, J = 1.7 Hz, 1H), 8.01 (t,
phase was dried over MgSO , filtered, and concentrated
4
under reduced pressure. The residue was recrystallized
from ethanol 95° to afford 0.19 g (50% yield) of 7a;
J = 5.4 Hz, 1H); Anal. Calcd for C H NO : C, 64,36;
4
1
4
15
À1
1
H, 5.79; N, 5.36. Found: C, 64.14; H, 5.81; N, 5.28.
mp 206–208 °C; IR (neat, cm ) 3288, 1662, 1620; H
NMR (300 MHz, DMSO-d ) d 1.79 (s, 3H), 2.81 (t,
6
4
.2.2. N-(2-(5-Methoxycarbonyl-benzo[b]furan-3-yl)ethyl)-
isopropylcarboxamide (6b). Recrystallized from cyclo-
2H, J = 6.6 Hz), 3.39 (m, 2H), 7.35 (s, 1H), 7.61 (d,
J = 8.5 Hz, 1H), 7.83–7.87 (m, 2H), 8.01 (m, 2H), 8.22
(d, J = 1.5 Hz, 1H). Anal. Calcd for C H N O : C,
63.40; H, 5.73; N, 11.38. Found: C, 63.23; H, 5.89; N,
11.17.
hexane/toluene (1:3); yield 65%; mp 98–100 °C; IR (neat,
cm ) 3290, 1710, 1633; H NMR (300 MHz, CDCl ) d
1
3
14
2
3
À1
1
3
1
.13 (d, J = 6.7 Hz, 6H), 2.30 (m, 1H), 2.94 (t,
J = 6.8 Hz, 2H), 3.61 (m, 2H), 3.94 (s, 3H), 5.57 (t,
J = 5.6 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.52 (s, 1H),
4.2.7. N-(2-(5-Methylcarbamoyl-benzo[b]furan-3-yl)ethyl)-
furylcarboxamide (7e). This compound was prepared
from 6e according to the procedure (Method A) de-
8
.04 (dd, J = 8.7 and 1.8 Hz, 1H), 8.29 (d, J = 1.8 Hz,
H). Anal. Calcd for C H NO : C, 66.42; H, 6.62;
1
N, 4.84. Found: C, 66.38; H, 6.40; N, 4.62.
1
6
19
4
scribed for 7a. Recrystallized from ethyl acetate; yield
À1
4
0%; mp 110–112 °C; IR (neat, cm ) 3350, 3426,
1
4.2.3. N-(2-(5-Methoxycarbonyl-benzo[b]furan-3-yl)ethyl)-
cyclopropylcarboxamide (6c). Recrystallized from etha-
1664, 1624; H NMR (300 MHz, DMSO-d ) d 2.94 (t,
6
J = 6.7 Hz, 2H), 3.57 (m, 2H), 6.62 (m, 1H), 7.09 (m,
1H), 7.36 (s, 1H), 7.59 (dd, J = 8.1 and 1.2 Hz, 1H),
À1
nol; yield 55%; mp 154–155 °C; IR (neat, cm ) 3257,

4960
M. Ettaoussi et al. / Bioorg. Med. Chem. 16 (2008) 4954–4962
7.84–7.93 (m, 3H), 8.02 (s, 1H), 8.28 (m, 1H), 8.57 (t,
J = 5.5 Hz, 1H). Anal. Calcd for C H N O : C,
7.30 (dd, J = 8.8 and 1.8 Hz, 1H), 7.43 (d, J = 8.8 Hz,
1H), 7.78 (s, 1H), 7.81 (d, J = 1.8 Hz, 1H), 8.05 (br s,
1H), 12.40 (br s, 1H).
1
6
14
2
4
6
9
4.42; H, 4.73; N, 9.39. Found: C, 64.23; H, 4.98; N,
.25.
4
.2.12. N-(2-(5-Carboxy-benzo[b]furan-3-yl)ethyl)isopro-
4
.2.8. N-(2-(5-Methylcarbamoyl-benzo[b]furan-3-yl)ethyl)-
pylcarboxamide (9b). This compound was prepared from
6b according to the procedure described for 9a. Recrys-
tallized from ethanol 95°/water (1:1); yield 96%; mp
acetamide (8a). A 40% aqueous solution of methylamine
1.6 mmol) was added to a solution of ester 6a (0.26 g,
.001 mol) in 40 mL of methanol. The mixture was re-
(
0
+
200–202 °C; MS (APCI, pos. 30 V) m/z: [M+H] 276;
À1
1
IR (neat, cm ) 3490, 3298, 1683, 1641; H NMR
fluxed for 2 h, cooled to room temperature, concen-
trated under reduced pressure, then extracted with
ethyl acetate. The organic phase was dried over MgSO4,
filtered, and concentrated under reduced pressure. The
(300 MHz, DMSO-d ) d 0.97 (d, J = 6.8 Hz, 6H), 2.30
6
(m, 1H), 2.82 (t, J = 6.9 Hz, 2H), 3.34 (m, 2H), 7.64
(d, J = 8.3 Hz, 1H), 7.90 (m, 2H), 8.28 (m, 1H), 8.05
(br s, 1H), 12.88 (br s, 1H).
residue was recrystallized from toluene to give 0.11 g
(
À1
43% yield) of 8a; mp 158–159 °C; IR (neat, cm
)
1
3
1
262, 1665, 1630; H NMR (300 MHz, DMSO-d ) d
4.2.13. N-(2-(5-Carboxy-benzo[b]furan-3-yl)ethyl)cyclo-
propylcarboxamide (9c). This compound was prepared
from 6c according to the procedure described for 9a.
Recrystallized from ethanol 95°; yield 93%; mp 128–
6
.80 (s, 3H), 2.79–2.83 (m, 5H), 3.36 (m, 2H), 7.60 (d,
J = 8.5 Hz, 1H), 7.81 (dd, J = 8.5 and 1.9 Hz, 1H),
.89 (s, 1H), 8.00 (t, J = 5.1 Hz, 1H), 8.16 (d,
J = 1.9 Hz, 1H), 8.48 (q, J = 3.1 Hz, 1H). Anal. Calcd
7
+
130 °C; MS (APCI, pos. 30 V) m/z: [M+H] 274; IR
À1
1
(neat, cm ) 3497, 2462, 1691, 1645; H NMR
for C H N O : C, 64.60; H,6.20; N, 10.76. Found:
2
1
4
16
3
C, 64.27; H, 6.13; N, 10.44.
(300 MHz, DMSO-d ) d 0.62–0.68 (m, 4H), 1.51 (m,
6
1H), 3.37–3.42 (m, 4H), 7.66 (d, J = 8.8 Hz, 1H), 7.78
(d, J = 8.8 Hz, 1H), 7.95 (s, 1H), 8.25 (t, J = 6.0 Hz,
1H), 8.29 (m, 1H), 12.88 (br s, 1H).
4
.2.9. N-(2-(5-Methylcarbamoyl-benzo[b]furan-3-yl)ethyl)-
cyclopropylcarboxamide (8c). This compound was pre-
pared from 6c according to the procedure described
for 8a. Recrystallized from water; yield 41%; mp 188–
4.2.14. N-(2-(5-Carboxy-benzo[b]furan-3-yl)ethyl)cyclo-
pentylcarboxamide (9d). This compound was prepared
from 6d according to the procedure described for 9a.
Recrystallized from ethanol 95°/water (1:1); yield 95
%; mp 208–210 °C; MS (APCI, pos. 30 V) m/z:
À1
1
1
89 °C; IR (neat, cm ) 3265, 1659, 1629; H NMR
(
300 MHz, DMSO-d ) d 0.58–0.69 (m, 4H), 1.50 (m,
6
1
H), 2.80–2.82 (m, 5H), 3.41 (m, 2H), 7.60 (d,
J = 8.2 Hz, 1H), 7.80 (dd, J = 8.2 and 1.5 Hz, 1H),
.87 (s, 1H), 8.15 (d, J = 1.5 Hz, 1H), 8.22 (t,
+
À1
7
[M+H] 302; IR (neat, cm ) 3500, 3290, 1680, 1630;
1
J = 5.5 Hz, 1H), 8.47 (q, J = 4.2 Hz, 1H). Anal. Calcd
for C H N O : C, 67.12; H, 6.34; N, 9.78. Found: C,
H NMR (300 MHz, DMSO-d ) d 1.42–1.80 (m, 8H),
6
2.50 (m, 1H), 2.82 (t, J = 6.9 Hz, 2H), 3.35 (m, 2H),
7.63 (d, J = 8.6 Hz, 1H), 7.90–7.95 (m, 3H), 8.27 (d,
J = 1.7 Hz, 1H), 12.87 (s, 1H).
1
6
18
2
3
6
7.00; H, 6.34; N, 9.77.
4
.2.10. N-(2-(5-Methylcarbamoyl-benzo[b]furan-3-yl)ethyl)-
cyclopentylcarboxamide (8d). This compound was pre-
pared from 6d according to the procedure described
for 8a. Recrystallized from toluene; yield 40%; mp
4.2.15. N-(2-(5-Carboxy-benzo[b]furan-3-yl)ethyl)furyl-
carboxamide (9e). This compound was prepared from
6e according to the procedure described for 9a. Recrys-
tallized from ethanol 95°/water (1:1); yield 90 %; mp
À1
1
1
70–171 °C; IR (neat, cm ) 3265, 1652, 1630;
H
+
NMR (300 MHz, DMSO-d ) d 1.46–1.71 (m, 8H), 2.50
220–222 °C; MS (APCI, pos. 30 V) m/z: [M+H] 300;
6
À1
1
(
(
s, 1H), 2.81 (m, 2H), 3.34 (m, 3H), 3.39 (m, 2H), 7.59
d, J = 8.7 Hz, 1H), 7.80 (dd, J = 8.7 and 1.4 Hz, 1H),
IR (neat, cm
)
3913, 1696, 1646;
H
NMR
(300 MHz, DMSO-d ) d 2.93 (t, J = 6.9 Hz, 2H), 3.53
6
7
J = 1.4 Hz, 1H), 8.47 (q, J = 4.5 Hz, 1H). Anal. Calcd
.86 (s, 1H), 7.91 (t, J = 5.4 Hz, 1H), 8.15 (d,
(m, 2H), 6.60 (m, 1H), 7.06 (d, J = 3.3 Hz, 1H), 7.63
(d, J = 8.4 Hz, 1H), 7.81 (m, 1H), 7.92 (dd, J = 8.4 and
1.5 Hz, 1H), 7.95 (s, 1H), 8.32 (d, J = 1.5 Hz, 1H),
8.57 (t, J = 5.7 Hz, 1H), 12.87 (s, 1H). Anal. Calcd for
C H NO : C, 64.21; H, 4.38; N, 4.68. Found: C,
for C H N O : C, 68.77; H, 7.05; N, 8.91. Found: C,
1
8
22
2
3
6
8.54; H, 7.10; N, 8.88.
1
6
13
5
4.2.11. N-(2-(5-Carboxy-benzo[b]furan-3-yl)ethyl)acetamide
64.12; H, 4.52, N, 4.55.
(
9a). A 30% NaOH aqueous solution (30 mL) was added
to a solution of ester 6a (0.52 g, 0.002 mol) in 90 mL of
methanol. The mixture was stirred overnight at room
temperature, then the solvent was evaporated under re-
duced pressure. The aqueous residue was cooled to 0 °C,
acidified with a 6 M HCl solution and extracted with
ethyl acetate. The organic phase was dried over MgSO4,
filtered, and concentrated under reduced pressure. The
residue was recrystallized from ethanol 95° to give
4.2.16. N-(2-(5-Methoxycarbonylamino-benzo[b]furan-3-
yl)ethyl)acetamide (10a). Triethylamine (0.2 mL,
0.015 mol) and ethyl chloroformate (1.5 mL, 0.015 mol)
were added at 0 °C to a stirred solution of acid 9a
(2.47 g, 0.01 mol) in 50 mL of acetone. After 1 h of stirring
at 0 °C, sodium azide (1 g, 0.015 mol) dissolved in 1 mL of
water was added, then the mixture was stirred at room
temperature for 1 h, poured into water and extracted with
ethyl acetate. The organic phase was dried over MgSO4,
filtered, and concentrated under reduced pressure, afford-
ing the intermediate N-(2-(5-azidocarbonyl-benzo[b]fur-
an-3-yl)ethyl) acetamide. This crude azide was dissolved
0
.46 g (93% yield) of 9a; mp 210–211 °C; MS (APCI,
+
pos. 30 V) m/z: [M+H] 248; IR (neat, cm ) 3536,
À1
1
2
1
440, 1688, 1637; H NMR (300 MHz, DMSO-d ) d
6
.80 (s, 3H), 2.71 (t, J = 6.1 Hz, 2H), 3.34 (m, 2H),

M. Ettaoussi et al. / Bioorg. Med. Chem. 16 (2008) 4954–4962
4961
À1
in 50 mL of absolute ethanol and 50 mL of toluene. The
solution was refluxed overnight, then the solvents were
evaporated under reduced pressure. The residue was
26%; mp 119–121 °C; IR (neat, cm ) 3260, 3254,
1713, 1647, 1240, 1076; H NMR (300 MHz, DMSO-
1
d6) d 2.85 (t, J = 6.7 Hz, 2H), 3.51 (m, 2H), 6.67 (s,
3H), 6.61 (m, 1H), 7.07 (d, J = 3.2 Hz, 1H), 7.29 (d,
J = 8.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.80 (m,
3H), 8.56 (t, J = 4.9 Hz, 1H), 9.64 (s, 1H). Anal. Calcd
for C H N O : C, 62.19; H, 4.91; N, 8.53. Found: C,
recrystallized from toluene to give 0.72 g (26% yield) of
À1
1
1
3
7
7
0a; mp 138–140 °C; IR (neat, cm ) 3312, 1704, 1635,
1
248, 1057; H NMR (300 MHz, DMSO-d ) d 1.81 (s,
6
H), 2.73 (t, J = 6.9 Hz, 2H), 3.35 (m, 2H), 3.67 (s, 3H),
.31 (d, J = 9.0 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 7.76–
.80 (m, 2H), 8.01 (t, J = 5.9 Hz, 1H), 9.65 (s, 1H). Anal.
1
7
16
2
5
62.05; H, 4.85; N, 8.44.
Calcd for C H N O : C, 60.86; H, 5.84; N, 10.14.
1
Found: C, 60.92; H, 5.74; N, 10.24.
4.2.21. N-(2-(5-Trifluoroacetamido-benzo[b]furan-3-yl)ethyl)-
acetamide (11). Triethylamine (0.4 mL, 0.030 mol) and
ethyl chloroformate (3.0 mL, 0.030 mol) were added at
0 °C to a stirred solution of acid 9a (4.94 g, 0.020 mol)
in 80 mL of acetone. After 1 h of stirring at 0;°C, so-
dium azide (2 g, 0.030 mol) dissolved in 2 mL of water
was added, then the mixture was stirred at room temper-
ature for 1 h, poured into water and extracted with ethyl
4
16
2
4
4
.2.17. N-(2-(5-Methoxycarbonylamino-benzo[b]furan-3-
yl)ethyl)isopropylcarboxamide (10b). This compound
was prepared from 9b according to the procedure de-
scribed for 10a. The intermediate azide was not iso-
lated. Recrystallized from toluene/cyclohexane (2:1);
À1
yield 65%; mp 122–124 °C; IR (neat, cm ) 3314,
acetate. The organic phase was dried over MgSO , fil-
4
1
1
703, 1639; H NMR (300 MHz, DMSO-d ) d 0.98
tered, and concentrated under reduced pressure, afford-
ing the intermediate azide which was immediately
dissolved in 70 mL of methylene chloride. Trifluoroace-
tic acid (18.2 mL, 0.023 mol) was added and the mixture
was stirred at room temperature overnight, washed with
6
(
d, J = 6.6 Hz, 6H), 2.28–2.35 (m, 1H), 2.73 (t,
J = 6.9 Hz, 2H), 3.32 (m, 2H), 3.68 (s, 3H), 7.30 (dd,
J = 8.4 and 1.1 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.74
(
s, 1H), 7.79 (d, J = 1.1 Hz, 1H), 7.89 (t, J = 5.5 Hz,
1
6
9
H), 9.64 (s, 1H). Anal. Calcd for C H N O : C,
4
3.14; H, 6.62; N, 9.20. Found: C, 63.59; H, 6.62; N,
.26.
water and with a 10% NaHCO solution. The organic
3
phase was dried over MgSO , filtered, and concentrated
4
1
6
20
2
under reduced pressure. The oily residue was purified by
column chromatography (SiO , ethyl acetate) to afford a
brown solid. Recrystallization from ethyl acetate gave
2
4
.2.18. N-(2-(5-Methoxycarbonylamino-benzo[b]furan-3-
yl)ethyl)cyclopropylcarboxamide (10c). This compound
was prepared from 9c according to the procedure de-
scribed for 10a. The intermediate azide was not isolated.
Purified by column chromatography (SiO , CH Cl /
3.27 g (65% yield) of 11; mp 152–154 °C; IR (neat,
cm ) 3340, 1695, 1645, 1150; H NMR (300 MHz,
À1
1
DMSO-d ) d 1.79 (s, 3H), 2.76 (t, J = 6.9 Hz, 2H),
6
3.32 (m, 2H), 7.52 (dd, J = 8.1 and 1.9 Hz, 1H), 7.60
(d, J = 8.1 Hz, 1H), 7.86 (s, 1H), 7.95 (d, J = 1.9 Hz,
1H), 8.01 (t, J = 5.4 Hz, 1H), 11.32 (s, 1H). Anal. Calcd
for C H F N O : C, 53.51; H, 4.17; N, 8.91. Found:
2
2
2
ethyl acetate 1:1) and recrystallized from toluene; yield
À1
2
1
0
2
1
1
6
9
6%; mp 153–155 °C; IR (neat, cm ) 3329, 1705,
1
642, 1244, 1055; H NMR (300 MHz, DMSO-d ) d
6
14 13
3
2
3
.58–0.69 (m, 4H), 1.52 (m, 1H), 2.75 (t, J = 7.2 Hz,
H), 3.36 (m, 2H), 3.68 (s, 3H), 7.29 (d, J = 8.9 Hz,
H), 7.46 (d, J = 8.9 Hz, 1H), 7.76 (m, 2H), 8.22 (m,
H), 9.64 (s, 1H). Anal. Calcd for C H N O : C,
C, 53.23; H, 4.22; N, 9.05.
4.2.22. N-(2-(5-Carboxy benzo[b]furan-3-yl)ethyl)aceto-
nitrile (12). A 10% K CO aqueous solution (40 mL) was
1
6
18
2
4
2
3
3.57; H, 6.00; N, 9.27. Found: C, 63.27; H, 6.02; N,
.14.
added to a solution of nitrile 4 (0.73 g, 0.0034 mol) in
60 mL of methanol. The mixture was stirred 48 h at
room temperature, then the solvent was evaporated un-
der reduced pressure. The aqueous residue was cooled to
0 °C, acidified with a 6 M HCl solution and extracted
with ethyl acetate. The organic phase was dried over
4
.2.19. N-(2-(5-Methoxycarbonylamino-benzo[b]furan-3-
yl)ethyl)cyclopentylcarboxamide (10d). This compound
was prepared from 9d according to the procedure de-
scribed for 10a. The intermediate azide was not isolated.
MgSO , filtered, and concentrated under reduced pres-
4
Purified by column chromatography (SiO , ethyl ace-
2
sure. The residue was recrystallized from ethanol 95°/
water (1:1) to give 0.58 g (85% yield) of 12; mp 199–
tate) and recrystallized from toluene/cyclohexane (2:1);
yield 70%; mp 147–148 °C; IR (neat, cm ) 3329,
À1
+
201 °C; MS (APCI, pos. 30 V) m/z: [M+H] 202; IR
1
705, 1642, 1244, 1055; H NMR (300 MHz, DMSO-
À1
1
1
(neat, cm
)
3400–3250, 2250, 1680;
H NMR
d6) d 1.42–1.72 (m, 8H), 2.50 (m, 1H), 2.72 (t,
J = 7.0 Hz, 2H), 3.33 (m, 2H), 3.68 (s, 3H), 7.27 (dd,
J = 9.0 and 2.0 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 7.74
(300 MHz, DMSO-d ) d 4.21 (m, 2H), 7.73 (d,
J = 8.8 Hz, 1H), 7.99 (dd, J = 8.8 and 1.4 Hz, 1H),
8.14 (s, 1H), 8.37 (d, J = 1.4 Hz, 1H), 13.03 (s, 1H).
6
(
s, 1H), 7.77 (m, 1H), 7.92 (t, J = 5.5 Hz, 1H), 9.63 (s,
H). Anal. Calcd for C H N O : C, 65.44; H, 6.71;
N, 8.48. Found: C, 65.50; H, 6.72; N, 8.26.
1
4.2.23. N-(2-(5-Methoxycarbonylamino-benzo[b]furan-3-yl)
ethyl)acetonitrile (13). Triethylamine (0.6 mL, 0.0045 mol)
and ethyl chloroformiate (0.4 mL, 0.0045 mol) were added
at 0 °C to a stirred solution of acid 12 (0.6 g, 0.003 mol) in
50 mL of acetone. After 1 h of stirring at 0 °C, sodium
azide (0.3 g, 0.0045 mol) dissolved in 1 mL of water was
added, then the mixture was stirred at room temperature
for 1 h, poured into water and extracted with ethyl ace-
1
8
22
2
4
4
.2.20. N-(2-(5-Methoxycarbonylamino-benzo[b]furan-3-
yl)ethyl)furylcarboxamide (10e). This compound was
prepared from 9e according to the procedure described
for 10a. The intermediate azide was not isolated. Puri-
fied by column chromatography (SiO , ethyl acetate)
2
and recrystallized from toluene/cyclohexane (3:1); yield
tate. The organic phase was dried over MgSO , filtered,
4

4962
M. Ettaoussi et al. / Bioorg. Med. Chem. 16 (2008) 4954–4962
and concentrated under reduced pressure, affording the
intermediate azide which was not isolated. It was dis-
solved immediately in 40 mL of methanol and 40 mL of
toluene. The solution was heated at 80 °C overnight, then
the solvents were evaporated under reduced pressure. The
residue was purified by column chromatography (SiO2,
ethyl acetate) to afford 0.49 g (72% yield) of 13 as a yellow
solid; mp 102–104 °C; MS (APCI, pos. 30 V) m/z:
References and notes
1. Reiter, R. J. Endocr. Rev. 1991, 12, 151–180.
. Cagnacci, A. J. Pineal Res. 1996, 21, 200–213.
. Li, P.-K.; Witt-Enderby, P. A. Drugs Future 2000, 25, 945–
2
3
9
57.
4
5
. Miles, A.; Philbrick, D. R. S.; Thompson, C.; Melatonin,
Clinical Perspectives. Oxford: Oxford University Press,
1
988.
+
À1
1
H
[
M+H] 231; IR (neat, cm ) 3342, 2250, 1717;
. Tamarkin, L.; Baird, C. J.; Almeida, O. F. X. Science
1985, 227, 714–720.
NMR (300 MHz, DMSO-d ) d 3.67 (s, 3H), 4.10 (s,
6
2H), 7.35 (dd, J = 8.8 and 1.3 Hz, 1H), 7.54 (d,
J = 8.8 Hz, 1H), 7.88 (d, J = 1.3 Hz, 1H), 7.96 (s, 1H),
6. Reppert, S. M.; Weaver, D. R.; Ebisawa, T. Neuron 1994,
13, 1177–1185.
9
.74 (s, 1H).
7. Dubocovich, M. L.; Yun, K.; Al-Ghoul, W. M.; Benlou-
cif, S.; Masana, M. I. FASEB J. 1998, 12, 1211–1220.
8
. Ebisawa, T.; Karne, S.; Lerner, M.; Reppert, S. M. Proc.
Natl. Acad. Sci. U.S.A. 1994, 91, 6133–6137.
. Nosjean, O.; Ferro, M.; Coge, F.; Beauverger, P.; Henlin,
J. M.; Lefoulon, F.; Fauch e` re, J. L.; Delagrange, P.;
Canet, E.; Boutin, J. A. J. Biol. Chem. 2000, 275, 31311–
4
.2.24. N-2-(5-Methoxycarbonylamino-benzo[b]furan-3-
yl)ethylamine hydrochloride (14). A solution of 13
0.50 g, 0.0022 mol) in 30 mL of methanol and 3 mL
of chloroforme was hydrogenated over PtO (0.10 g,
9
(
2
0
.0003 mol) under pressure (35 bars) at room tempera-
3
1317.
ture for 24 h. After filtration and evaporation, the resi-
due was recrystallized from acetonitrile to give 0.40 g
1
0. Lotufo, C. M. C.; Lopes, C.; Dubocovich, M. L.; Farsky,
S. H. P.; Markus, R. P. Eur. J. Pharmacol. 2001, 430, 351–
357.
(
m/z: [M+H] 235; IR (neat, cm ) 3420–3200, 1700;
68% yield) of 14; mp > 230°C; MS (APCI, pos. 30 V)
+
À1
11. Pintor, J.; Martin, L.; Pelaez, T.; Hoyle, C. H. V.; Peral,
A. Eur. J. Pharmacol. 2001, 416, 251–254.
1
H NMR (300 MHz, DMSO-d ) d 2.95 (t, J = 7.8 Hz,
6
1
1
1
1
2. Vella, F.; Ferry, G.; Delagrange, P.; Boutin, J. A.
Biochem. Pharmacol. 2005, 71, 1–12.
3. Boutin, J. A.; Audinot, V.; Ferry, G.; Delagrange, P.
Trends Pharmacol. Sci. 2005, 26, 412–419.
4. Pickering, D. S.; Niles, L. P. Eur. J. Pharmacol. 1990, 175,
2H), 3.09 (s, 2H), 3.68 (s, 3H), 7.29 (dd, J = 8.7 and
2.0 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.80–7.89 (m,
2H), 8.15 (br s, 3H), 9.70 (s, 1H).
4
.2.25. N-(2-(5-Methoxycarbonylamino-benzo[b]furan-3-
7
1–77.
yl)ethyl)vinylacetamide (10f). A solution of vinylacetic
acid (0.1 mL, 0.0013 mol) in 50 mL of methylene chloride
was stirred at À10 °C for 20 min. Then, triethylamine
5. Molinari, E. J.; North, P.; Dubocovich, M. L. Eur. J.
Pharmacol. 1996, 301, 159–168.
16. Leclerc, V.; Depreux, P.; Lesieur, D.; Caignard, D. H.;
Renard, P.; Delagrange, P.; Guardiola-Lema ˆı tre, B.;
Morgan, P. J. Med. Chem. 2002, 45, 1853–1859.
(
0.023 mL, 0.0017 mol), EDCI (0.3 g, 0.0014 mol) and
HOBt (0.2 g, 0.0014 mol) were added, and the mixture
was stirred at À10 °C for 30 min. A solution of 14
1
7. Boussard, M. F.; Truche, S.; Rousseau-Rojas, A.; Briss,
S.; Descamps, S.; Droual, M.; Wierzbicki, M.; Ferry, G.;
Audinot, V.; Delagrange, P.; Boutin, J. A. Eur. J. Med.
Chem. 2006, 41, 306–320.
8. Depreux, P.; Lesieur, D.; Mansour, H. A.; Morgan, P.;
Howell, H. E.; Renard, P.; Caignard, D.-H.; Pfeiffer, B.;
Delagrange, P.; Guardiola, B.; Yous, S.; Demarque, A.;
Adam, G.; Andrieux, J. J. Med. Chem. 1994, 37, 3231–
3239.
(
0.50 g, 0.0019 mol) in 10 mL of methylene chloride was
cooled at À10 °C and added dropwise. After 4 days of
stirring at room temperature, the reaction mixture was
washed with water, a 1 M HCl solution, water, a 10%
NaOH solution, and water until pH 7 was reached. The
1
organic phase was dried over MgSO , filtered, and con-
4
centrated under reduced pressure. The residue was puri-
fied by column chromatography (SiO , ethyl acetate) to
19. Wallez, V.; Durieux-Poissonnier, S.; Chavatte, P.; Boutin,
J. A.; Audinot, V.; Nicolas, J. P.; Bennejean, C.; Delag-
range, P.; Renard, P.; Lesieur, D. J. Med. Chem. 2002, 45,
2788–2800.
2
2
2
2
afford a white solid. Recrystallization from toluene/cyclo-
hexane (2:1) gave 0.12 g (20% yield) of 10f; mp 145–
À1
1
1
(
46 °C; IR (neat, cm ) 3420–3200, 1700; H NMR
0. Shah, B. L.; Desai, C. M. J. Indian Chem. Soc. 1984, 61,
51.
1. Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc.
961, 83, 1733–1738.
300 MHz, DMSO-d ) d 2.74 (t, J = 7.2 Hz, 2H), 2.88
6
6
(
d, J = 7.0 Hz, 2H), 3.39 (t, J = 7.2 Hz, 2H), 3.67 (s,
3
1
H), 5.07 (m, 2H), 5.86 (m, 1H), 7.29 (d, J = 8.9 Hz,
H), 7.46 (d, J = 8.7 Hz, 1H), 7.74–7.79 (m, 2H), 8.02 (t,
J = 4.8 Hz, 1H), 9.64 (s, 1H). Anal. Calcd for
1
2. Mailliet, F.; Ferry, G.; Vella, F.; Berger, S.; Cog e´ , F.;
Chomarat, P.; Mallet, C.; Gu e´ nin, S. P.; Guillaumet, G.;
Viaud-Massuard, M. C.; Yous, S.; Delagrange, D.;
Boutin, J. A. Biochem. Pharmacol. 2005, 71, 74–88.
C H N O : C, 63.57; H, 6.00; N, 9.27. Found: C,
1
6
18
2
4
6
3.22; H, 5.91; N, 9.04.