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

Article abstract of DOI:10.1016/j.ejmech.2011.02.010

Naphthalenic analogs of MCA-NAT (5-methoxycarbonylamino-N-acetyltryptamine) have been synthesized and evaluated as melatonin receptor ligands. Introduction of a methoxycarbonylamino substituent at the C-7 position of the naphthalenic nucleus yields MT

Full text of DOI:10.1016/j.ejmech.2011.02.010

European Journal of Medicinal Chemistry 46 (2011) 1622e1629
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design and synthesis of naphthalenic derivatives as new ligands at the melatonin
binding site MT3
,
,
,
,
Véronique Leclerc a b, Mohamed Ettaoussi a b, Marouan Rami a b, Amaury Farce a b, Jean Albert Boutin d,
Philippe Delagrange c, Daniel-Henri Caignard c, Pierre Renard c, Pascal Berthelot a b, Saïd Yous a
,
,b,
*
a Univ Lille Nord de France, F-59000 Lille, France
b UDSL, EA GRIIOT, UFR Pharmacie, F-59000 Lille, France
c Département des Sciences Expérimentales, Institut de Recherches Servier, 92150 Suresnes, France
d Institut de Recherches Servier, 78290 Croissy-sur-Seine, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Naphthalenic analogs of MCA-NAT (5-methoxycarbonylamino-N-acetyltryptamine) have been synthe-
sized and evaluated as melatonin receptor ligands. Introduction of a methoxycarbonylamino substituent
at the C-7 position of the naphthalenic nucleus yields MT3 selective ligands. This selectivity can be
modulated with suitable variations of the C-7 position and the acyl group on the C-1 side chain. We
identified new series of compounds with affinity for the MT3 binding site in the nanomolar range, and
singled out a selective ligand, (N-[2-(7-methylsulfamoyl-naphth-1-yl)ethyl]acetamide (17), with a Ki of
4.9 nM and selectivity of 1024 and 2040 versus MT1 and MT2 receptors respectively.
Received 1 October 2010
Received in revised form
3 February 2011
Accepted 8 February 2011
Available online 15 February 2011
Keywords:
Melatonin
Ó 2011 Elsevier Masson SAS. All rights reserved.
MCA-NAT
MT3 binding site
Naphthalenic ligands
Binding
Quinone reductase 2
1. Introduction
melatonin’s effects is still uncertain [11]. Nonetheless, MT3 has
shown to be involved in acute inflammatory responses in the rat [12]
N-acetyl-5-methoxytryptamine (melatonin) is a neurohormone
synthesized and secreted following a circadian rhythm with the
higher levels being released at night [1] by the pineal gland. The
regulation of its production is achieved by a photoperiodic mecha-
nism and therefore, melatonin plays an important part in the
adaptation of mammalian circadian rhythms and reproduction
functions to the environment. It is also implicated in several phys-
iopathological states. These biological effects have hinted to
a possible therapeutic use of melatonin in some disorders [2e5].
Melatonin binds to two kinds of sites. High affinity binding sites
belong to the G-Protein Coupled Receptors (GPCR) super family and
have been divided into MT1 and MT2 [6,7]. The low affinity binding
site, MT3 [8,9], which has been identified as the quinone reductase 2
(QR2 EC 1.6.99.2) [10]. Although it is closely related to the detoxi-
fying enzyme quinone reductase 1, its exact biological relevance in
and in the regulation of intraocular pressure in the rabbit [13]. It has
proved to be a target worthy of more in depth investigations, leading
to ligand-based in silico [14,15] and crystallographic studies [16,17].
An accurate characterization of MT3 mediated functions in native
tissues can only be made using specific ligands. Unfortunately, only
a few selective ligands have been reported to date (Chart 1). Among
them, 5-methoxycarbonylamino-N-acetyltryptamine (MCA-NAT)
has been the first to show a selectivity toward this subtype and has
a good affinity (IC50 ¼ 2.7 nM) [18]. Prazosine, an a1-adrenoceptor
antagonist, also acts as a MT3 selective ligand (IC50 ¼ 7.8 nM) [19].
Nitroindole derivative (S27533) [20] (Ki ¼ 0.3 nM), and DMHMIO (8-
Hydroxy-2,3-dimethoxy-5-methyl-5H-indeno[1,2-b]indol-10-one)
[21] (Ki ¼ 0.19 nM) have been described. Recently, we have
published novel benzofuranic derivatives (MCA-B) as MT3 selective
ligands (Ki ¼ 24 nM) [22]. We have further studied the MT3 binding
sites requirements by noting that MCA-NAT includes a methox-
ycarbonylamino group in the 5-position instead of the melatonin’s
methoxy. We replaced the indolic cycle of MCA-NAT with
naphthalene (4, S26553). Furthermore, in the hope of better
modulating the fit to the MT3 binding site, we replaced the
* Corresponding author. UDSL, EA GRIIOT, UFR Pharmacie, F-59000 Lille, France.
Tel.: þ33 3 2096 4375; fax: þ33 3 2096 4913.
E-mail address: said.yous@univ-lille2.fr (S. Yous).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.02.010

V. Leclerc et al. / European Journal of Medicinal Chemistry 46 (2011) 1622e1629
1623
NHCOCH3
NHCOCH3
For all these compounds, the synthesis, the binding data for the
CH3
O
CH3
O
human MT1 and MT2 receptors and MT3 binding site are reported.
H
N
2. Chemistry
O
N
N
H
H
Compounds listed in Table 1 were synthesized according to
Schemes 1e5. The synthesis of carbamate 4 (Scheme 1) was elabo-
rated in four steps from the starting material, i.e. N-[2-(7-hydroxy-
naphth-1-yl)ethyl]acetamide, whichsynthesisisdescribedpreviously
[23]. The hydroxyl group was activated by trifluoromethanesulfonic
anhydrideinthepresenceoftriethylamineindichloromethanetolead
in the triflate 1 with a 65% yield. The replacement of the triflate
substituent was accomplished in a weak yield (40%) by reacting
compound 1 with 4-methoxybenzylamine, in a sealed tube in
microwave (10 min at 100 W), in the presence of palladium acetate
and cesium carbonate in dry N,N-dimethylformamide. Then the
compound 2 was debenzylated under hydrogene atmospheric pres-
sure in presence of palladium on charcoal catalyst to obtain the crude
coumpound 3, which was engaged in the next step without further
purification. Finally the carbamate 4 was obtained from 3 by reaction
of methyl chloroformate in a biphasic mixture in the presence of
potassium carbonate.
The synthesis of the methylsulfide (11) was conceived in four
steps from 7-methylsulfanyl-3,4-dihydro-2H-naphthalen-1-one
(7), which was obtained from thioanisole by adapted and opti-
mizated methods described by Cagniant [24] and Buu-Hoi [25]
(Scheme 2). The naphthyl acetonitrile derivative 9 was prepared
from compound 7 with good yields by a WadswortheEmmons’s
reaction using diethyl cyanomethyl phosphonate followed by
heating the intermediate acrylonitrile 8 at fusion with sulfur. The
amino compound 10 was obtained by reduction with borane-THF
complex and condensated with various acetyl chlorides to give
compound 11 with moderate yields.
Melatonin
MCA-NAT
O
NHCOCH3
O
N
CH3
CH3 NO2
O
N
O
N
I
N
O
N
CH3
CH3
NH2
S27533
Prazosine
O
CH3
O
O
H
N
OH
CH3
H
O
N
O
N
CH3
O
CH3
O
DMHMIO
MCA-B
Chart 1. Chemical Structures of Melatonin and MT3 Derivatives.
methoxycarbonylamino group of 4, with sulfite, sulfone, sulfoxide
and sulfonamide functions. In order to explore the role of the N-acyl
side chain on the binding affinityand the selectivity, we replaced the
methyl of the acetamido function with furyl group (Table 1).
Table 1
MT1, MT2 and MT3 binding affinities of naphthalenic compounds.
NHCOR2
NHCOCH3
CH3
H
O
N
R1
O
N
H
.
Compd.
R1
R2
IC50 (nM)
MT1
IC50 (nM)
MT2
IC50 (nM)
MT3
S
MT1/MT3
MT2/MT3
Melatonin
MCA-NAT
e
e
e
e
0.20 ꢀ 0.03
1000 ꢀ 44
0.53 ꢀ 0.06
4000 ꢀ 53
64.6 ꢀ 0.9
58.0 ꢀ 0.1
1/323 1/122
17
69
4 (S26553)
11 (S24203)
12 (S26805)
13 (S26716)
16 (S26799)
17 (S26695)
19 (S27784)
NHCO2CH3
SCH3
CH3
CH3
CH3
CH3
CH3
CH3
furyl
85.4 ꢀ 3
0.875 ꢀ 0.07
77.6 ꢀ 7
26.3 ꢀ 11
0.955 ꢀ 0.04
97.0 ꢀ 16
0.39 ꢀ 0.1
18.0 ꢀ 1
37.0 ꢀ 6
21 ꢀ 4
219
67
1/20
1/19
2
3
23
42
10
SOCH3
SO2CH3
477 ꢀ 13
879 ꢀ 272
371 ꢀ 31.5
>10 000
SO2NH2
SO2NHCH3
SO2NHCH3
310 ꢀ 50
32 ꢀ 3
12
5000 ꢀ 1730
2610 ꢀ 45
4.9 ꢀ 0.3
9.1 ꢀ 0.2
1020
>2040
287
752
6840 ꢀ 130

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V. Leclerc et al. / European Journal of Medicinal Chemistry 46 (2011) 1622e1629
O
NHCOCH3
NHCOCH3
NHCOCH3
H3C
ii
HO
TfO
HN
i
2
1
NHCOCH3
NHCOCH3
CO2CH3
HN
H2N
iv
iii
3
4
Scheme 1. Synthesis of carbamate 4. Reagents : (i) (TfO)2O, CH2Cl2, Et3N, ꢂ20 ꢁC, 3 h (65%); (ii) (4-OCH3)C6H4CH2NH2, Pd(AcO)2, Xantphos, Cs2CO3, DMF, microwave, 100 W, 10 min
(40%); (iii) CH3OH, Pd/C, r.t., 12 h (62%); (iv) CH3CO2Cl, K2CO3, EtOAc/H2O, 1 h (68%).
Oxidation using 1 or 3 equivalents of m-CPBA of the sulfide
compound 11 led to the sulfoxide derivative 12 and the sulfone
derivative 13 respectively with good yields (Scheme 3). Sulfon-
amides 16-17 were prepared in three steps from the starting mate-
rial N-[2-(7-hydroxy-naphth-1-yl)ethyl]acetamide (Scheme 4).
The substitution of the hydroxy group with benzylthiol in the
presence of trifluoromethanesulfonic acid at 60 ꢁC [26] readily took
place to give sulfide compound 14. Sulfonyl chloride 15 was syn-
thesized in one-step from benzylsulfide 14 by crushing and grinding
it with a pestle in presence of a mixture of HCl-treated silica gel and
freshly prepared iodosobenzene with a 54% yield [27]. Reaction of
15 with a 28% aqueous ammoniac or methylamine in presence of
triethylamine gave the corresponding sulfonamides 16-17 respec-
tively with very good yields. The derivative 19 (Scheme 5) was
prepared with good yields by heating compound 16 with 6 M HCl
aqueous solution followed by acylating the intermediate amine
18 with 2-furoyl chloride in the presence of triethylamine in
dichloromethane.
MT3 binding site, which is able to accommodate larger moieties in
position 5 than the more restricted GPCR-type binding sites.
Previous studies of our group have showed that melatoninergic
affinity was retained when the indolic cycle of melatonin was
replaced with naphthalene. Our first guess to overcome this lack of
selectivity was to reproduce the same indol-naphthalen isostery
with MCA-NAT, leading to compound 4. This compound has
noticeably lower affinities for the GPCRs, while it has a sub-
nanomolar affinity for MT3, endowing it with fairly good selectiv-
ities of respectively more than 219 and 67 against MT1 and MT2.
These results are similar to those we have already described for
benzofuranic compounds [22]. Another possibility was to take
advantage of the larger steric tolerance of MT3 at the 5 position by
replacing the methoxy group with larger moieties. The first func-
tion we tried was a sulfite (11). This compound yields affinities for
the GPCR sites that are nearly identical to those of melatonin itself
but a 4-fold better affinity for MT3, although it is not sufficient to
give it any selectivity for this subtype. A first oxidation step yields
the sulfonyl 12. This slightly larger function brings a 100-fold drop
in GPCR binding, but also a 2-fold worse affinity for MT3, thus giving
it a mediocre 2 to 3 selectivity for this subtype. A further oxidation
affords the sulfoxide 13, which loses again a factor 10 in its GPCR
binding sites affinities but keeps an MT3 affinity similar to that of
the sulfite. The net result was selectivity close to that of MCA-NAT. A
second series of compounds was derived from the sulfoxide, with
3. Results and discussion
Although MCA-NAT has the same affinity for MT3 as melatonin,
it displays a modest but fairly interesting selectivity for this subtype
as its MT1 and MT2 affinities are about 4000-fold worse than those
of melatonin. This is a clear clue about the steric tolerance of the
CH3
S
CH3
S
CH3
S
O
CH3
S
OH
OH
iii
i
ii
O
O
O
7
5
6
NH2, HCl
NHCOCH3
CN
CN
CH3
S
CH3
CH3
S
CH3
S
S
vi
vii
iv
v
10
11
9
8
Scheme 2. Synthesis of compound 11. Reagents : (i) AlCl3, succinic anhydride, C2H2Cl4, 60 ꢁC, 3 h (67%); (ii) Et3SiH, TFA, 0 ꢁC, 17 h (94%); (iii) PPA, 70 ꢁC, 2 h (66%); (iv) NaH,
(EtO)2P(O)CH2CN, 0 ꢁC then r.t., 3 h (89%); (v) S, >230 ꢁC (fusion), 10 h (64%); (vi) BH3-THF, THF, N2, reflux, 5 h, then HClgas-saturated Et2O (75%); (vii) : CH3COCl, K2CO3, CH2Cl2/H2O,
30 min (57%).

V. Leclerc et al. / European Journal of Medicinal Chemistry 46 (2011) 1622e1629
1625
NHCOCH3
CH3
S
i
ii
11
NHCOCH3
NHCOCH3
CH3
S
O
H3C
O
S
O
12
13
Scheme 3. Synthesis of compounds 12 and 13. Reagents : (i) m-CPBA (1 eq), CH2Cl2, 2 h (88%); (ii) m-CPBA (3 eq), CH2Cl2, 2 h (63%).
the introduction of a sulfonamide group. Compound 16 is the direct
4. Conclusions
analog of 13. While the MT1 affinity of this last compound was
conserved, its MT2 affinity is nearly 2-fold better and its MT3 affinity
one third worse, therefore lowering drastically its selectivity.
Adding a methyl to the sulfonamide in order to increase its volume
leads to 17 and nearly abolishes high affinity sites binding, but in
the meantime improves the MT3 affinity to a great extend, with
a 10-fold better value than MCA-NAT, yielding selectivity values of
1020 for MT1 and up to 2040 for MT2. This makes 17 the most
selective compound of this series and an interesting pharmaco-
logical tool for the elucidation of MT3 biological relevance. Taking
into account the structure of Prazosine, we have introduced a 2-
furyl on the amidoethyl chain of 17, affording compound 19.
However, compared to its parent, this leads to 2-fold better affinity
for MT1 and a slight improvement of MT2 affinity as well, but also
a nearly 2-fold loss in MT3 affinity. Although 19 is still about 300-
fold more selective for MT3 against MT1 and 750-fold against MT2, it
is far from being as selective as its methylated counterpart.
Replacement of the indolic cycle of the MCA-NAT by a naph-
thalenic nucleus led to new series of MT3 ligands. Introduction of
a methoxycarbonylamino group in the C-7 position of the naph-
thalene allows access to MT3 selective ligands. The most selective
compounds 17 and 19, obtained by substitution of the methox-
ycarbonylamino group by a sulfonamide substituents, show selec-
tivity values upon MT3 noticeably higher than that of MCA-NAT,
respectively of 1020 for MT1 and up to 2040 for MT2 and 300 for
MT1 and 750 MT2.
5. Experimental
5.1. Chemistry
Melting points were determined on a Büchi SMP-20 capillary
apparatus and are uncorrected. IR spectra were recorded on
NHCOCH3
NHCOCH3
NHCOCH3
O
Cl
HO
S
S
i
ii
O
15
14
NHCOCH3
R'
O
HN
S
iii
O
Compound
R'
H
16
17
CH3
Scheme 4. Synthesis of compounds 16 and 17. Reagents : (i) C6H5CH2SH, CF3SO3H, N2, 60 ꢁC, 2e3 h (48%); (ii) C6H5IO, HCleSiO2, 10 min (54%); (iii) R’NH2, Et3N, CH2Cl2, 2 h (87e95%).

1626
V. Leclerc et al. / European Journal of Medicinal Chemistry 46 (2011) 1622e1629
O
NHCOCH3
NH2, HCl
HN
CH3
CH3
CH3
O
O
O
O
HN
HN
HN
S
S
S
i
ii
O
O
O
19
16
18
Scheme 5. Synthesis of the compound 19. Reagents : (i) 6 M HCl, reflux, 16 h (71%); (ii) 2-furoyl chloride, Et3N, CH2Cl2, 3 h (63%).
a Vector 22 Bruker spectrophotometer. 1H and 13C NMR spectra
were recorded on an AC 300 Bruker spectrometer. Chemical shifts
(d, 1H, J ¼ 7.7 Hz, H-4), 7.75 (d, 1H, J ¼ 8.8 Hz, H-5), 8.02 (br s, 1H,
NH), 8.33 (br s, 2H, NH2). MS: m/z ¼ 349 [M þ H]þ.
are reported in
d units (parts per million) relative to TMS. Mass
spectra were performed on a Finnigan MAT SSQ 710 Advantage
spectrometer and were recorded in the APCI positive mode.
Elemental analyses for tested compounds were performed by CNRS
Laboratories (Vernaison, France). Obtained results were within
ꢀ0.4% of the theoretical values.
5.4. N-[2-(7-amino-naphth-1-yl)ethyl]acetamide (3)
To a solution of the free amino compound of 2 (3 g, 8.5 mmol) in
50 ml of methanol was added 0.3 g of 10% activated charcoal-
palladium. The mixture was placed under hydrogen atmosphere
(atmospheric pressure) and stirred for 12 h at room temperature.
The catalyst was then filtrated and the filtrate was evaporated to
dryness under reduced pressure to give 3 as brown oil, yield 62%,
which was engaged without further purification in the next step. IR
(KBr), cmꢂ1: 3408 and 3340 (NH, NH2),1651 (C]O).1H NMR (DMSO-
d6): dH 1.95 (s, 3H, CH3), 3.15 (t, 2H, J ¼ 7.0 Hz, CH2-a), 3.55e3.65 (m,
4H, CH2-b and NH2), 5.60 (br s, 1H, NH), 6.95 (dd, 1H, J ¼ 8.6, 2.2 Hz,
H-6), 7.17e7.25 (m, 3H, H-2, 3 and 8), 7.61 (d,1H, J ¼ 7.9 Hz, H-4), 7.68
(d, 1H, J ¼ 8.6 Hz, H-5). MS: m/z ¼ 229 [M þ H]þ.
5.2. N-[2-(7-trifluoromethansulfonyl-naphth-1-yl)ethyl]
acetamide (1)
To a stirred solution of N-[2-(7-hydroxy-napht-1-yl)ethyl]acet-
amide (7.5 g, 33 mmol) in dichloromethane (200 mL) was added
triethylamine (13.8 mL, 100 mmol). The mixture was cooled to
ꢂ20 ꢁC under nitrogen atmosphere and trifluoromethanesulfonic
anhydride (6 mL, 35 mmol) was slowly added. The reaction mixture
was stirred for 5 h and poured into ice-cold water and then
extracted with ethyl acetate. The organic layer was washed
successively with water, an aqueous solution of sodium hydroxide
(1 M) and water, and then dried over MgSO4. The solvent was
removed and the oily residue was purified by column chromatog-
raphy over silica gel with acetone/cyclohexane (3/7) to give 1 as
a white solid; Yield 65%, mp 82e83 ꢁC, Recrystallized from toluene/
cyclohexane. IR (KBr), cmꢂ1: 3300 (NH), 1620 (C]O). 1H NMR
(DMSO-d6): dH 1.81 (s, 3H, CH3), 3.18 (t, 2H, J ¼ 7.7 Hz, CH2-a), 3.32
(m, 2H, CH2-b), 7.40e7.60 (m, 3H, H-2, 3 and 6), 7.93 (dd, 1H, J ¼ 8.1,
2.2 Hz, H-4), 8.06 (br s, 1H, NH), 8.15 (d, 1H, J ¼ 8.1 Hz, H-5), 8.31 (d,
1H, J ¼ 2.2 Hz, H-8). MS: m/z ¼ 362 [M þ H]þ.
5.5. N-[2-(7-methoxycarbonylamino-naphth-1-yl)ethyl]
acetamide (4)
To a vigourously stirred mixture of 3 (1 g, 4.38 mmol) in ethyl
acetate (70 mL) and water (30 mL) were added potassium carbonate
(908 mg, 6.57 mmol)and methyl chloroformate(0.41 mL, 5.26mmol).
After 1 h, the organic layer was washed with water, dried over MgSO4
and concentrated. The residue was recrystallized from toluene to give
4 as a white solid; Yield 67%, mp 163e164 ꢁC. IR (KBr), cmꢂ1: 3410,
3240 (NH), 1706 (C]O amid), 1650 (C]O carbamate). 1H NMR
(DMSO-d6): dH 1.94 (s, 3H, CH3), 3.14 (t, 2H, J ¼ 7.2 Hz, CH2), 3.38 (m,
2H, CH2), 3.62 (s, 3H, CO2CH3), 6.92 (dd, 1H, J ¼ 8.5, 2.3 Hz, H-6),
7.20e7.30 (m, 3H, H-2, 3 and 8), 7.62 (d,1H, J ¼ 7.9Hz, H-4), 7.71 (d,1H,
J ¼ 8.5 Hz, H-5), 7.96 (br s, 1H, NH), 8.70 (br s, 1H, NH). 13C NMR
(CDCl3): dC 23.03 (CH3), 32.78 (C-b), 40.07 (C-a), 52.28 (C-OCH3),
111.06 (C-8), 118.98 (C-6), 124.20 (C-3), 126.88 (C-4), 127.14 (C-2),
129.65 (C-5), 130.48 (C-10), 132.33 (C-9), 134.25 (C-1), 135.96 (C-7),
154.96 (C]O), 170.55 (C-10). MS: m/z ¼ 287 [M þ H]þ. Anal. Calc. for
C16H18N2O3: C, 67.12;H, 6.34; N, 9.78; Found: C, 67.24; H, 6.38; N, 9.58.
5.3. N-(2-{7-[(4-Methoxybenzyl)amino]naphth-1-yl}ethyl)acetamide
hydrochloride (2)
Compound 1 (1 g, 2.8 mmol), palladium acetate (0.062 g,
0.3 mmol), Xantphos (0.132 g, 0.3 mmol), cesium carbonate (0.9 g,
2.8 mmol) and 4-methoxybenzylamine (0.4 ml, 2.8 mmol) in 10 ml
of dimethylformamide were stirred in a sealed tube and irradiated
for 10 min at 100 W in a microwave. After cooling, the reaction
mixture was poured into water (100 mL), and then extracted with
ethyl acetate (3 ꢃ 100 mL). The organic layer was washed with
water, dried over MgSO4, filtered, and concentrated. The crude
residue was purified by column chromatography over silica gel
with acetone/cyclohexane (5/5). The resulting oil was taken up into
20 mL of diethyl ether and a HCl gas-saturated solution of diethyl
ether was cautiously added to produce a precipitate, which was
collected by filtration and recrystallized from acetonitrile to give 2
as a yellow solid; Yield 40%, mp 194e196 ꢁC. IR (KBr), cmꢂ1: 3304
(NH), 3000e2416 (NH2þClꢂ), 1650 (C]O). 1H NMR (DMSO-d6): dH
1.80 (s, 3H, CH3), 3.05 (t, 2H, J ¼ 6.6 Hz, CH2), 3.30 (m, 2H, CH2-a),
3.70 (s, 3H, OCH3), 4.45 (s, 2H, CH2-b), 6.87 (d, 2H, J ¼ 8.6 Hz, H-20),
7.15e7.28 (m, 3H, H-3, 6 and 8), 7.38e7.44 (m, 3H, H-2 and 30), 7.61
5.6. 4-(Methylsulfanyl-phenyl)-4-oxo-butyric acid (5) [24]
To a cooled solution at 0 ꢁC of thioanisole (20 mL, 170 mmol) in
1,1,2,2-tetrachloroethane (140 mL) were successively added suc-
cinic anhydride (17 g, 170 mmol) and portionwise anhydrous
aluminum chloride (45.5 g, 340 mmol). The reaction mixture was
then stirred and heated at 60 ꢁC for 3 h. After cooling, it was poured
into ice-cold water (500 mL) within 50 mL of concentrated HCl. The
resulting precipitate was filtered, washed with water, dried, and
recrystallized from ethyl acetate to give 5 as a white solid; Yield
67%, mp 153e154 ꢁC (litt. [24] 153 ꢁC). IR (KBr), cmꢂ1: 3300e2400
(OH), 1700 (C]O acid), 1670 (C]O cetone). 1H NMR (DMSO-d6): dH
2.54 (t, 2H, J ¼ 6.2 Hz, CH2-a), 2.59 (s, 3H, SCH3), 3.21 (t, 2H,

V. Leclerc et al. / European Journal of Medicinal Chemistry 46 (2011) 1622e1629
1627
J ¼ 6.2 Hz, CH2-b), 7.36 (d, 2H, J ¼ 8.3 Hz, H), 7.90 (d, 2H, J ¼ 8.3 Hz,
H),12.15 (s,1H, CO2H). Anal. Calc. for C11H12O3S: C, 58.91; H, 5.39; O,
21.40; Found: C, 59.01; H, 5.36; O, 21.36.
was hydrolyzed, and then extracted with ethyl acetate (3 ꢃ 50 mL).
The organic layer was washed with water, dried over MgSO4,
filtered, and concentrated. Purification was accomplished by
column chromatography over silica gel with ethyl acetate/cyclo-
hexane (1:4) to give 9 as a beige solid; Yield 64%, mp 71e72 ꢁC. IR
(KBr), cmꢂ1: 2240 (C^N). 1H NMR (DMSO-d6): dH 2.62 (s, 3H, SCH3),
4.49 (s, 2H, CH2-a), 7.44 (t, 1H, J ¼ 7.6 Hz, H-3), 7.50 (dd, 1H, J ¼ 1.5,
8.8 Hz, H-6), 7.58 (d, 1H, J ¼ 7.2 Hz, H-2), 7.71 (s, 1H, H-8), 7.91 (m,
2H, H-4 and 5). Anal. Calc. for C13H11NS: C, 73.20; H, 5.20; N, 6.57;
Found: C, 73.31; H, 5.26; N, 6.61.
5.7. 4-(4-Methylsulfanyl-phenyl)butyric acid (6)
To a cooled solution of 5 (19.8 g, 88 mmol) at 0 ꢁC in trifluoro-
acetic acid (68 mL, 881 mmol) was added dropwise triethylsilane
(35.2 mL, 220 mmol). After 17 h, the mixture was poured onto ice.
The resulting precipitate was filtered, washed with water then with
cyclohexane, and dried. Purification was accomplished by column
chromatography over silica gel with acetone/toluene/cyclohexane
(3:5:2) to give 6 as white crystals; Yield 94%, mp 53e55 ꢁC (litt. [24]
49e50 ꢁC). IR (KBr), cmꢂ1: 33040e2200 (OH), 1750 (C]O). 1H NMR
(DMSO-d6): dH 1.94 (q, 2H, J ¼ 7.4 Hz, CH2-a), 2.37 (t, 2H, J ¼ 7.4 Hz,
CH2-b), 2.47 (s, 3H, SCH3), 2.64 (t, 2H, J ¼ 7.7 Hz, CH2-c), 7.11 (d, 2H,
J ¼ 8.0 Hz, H-2 and 6), 7.20 (d, 2H, J ¼ 8.0 Hz, H-3 and 5). Anal. Calc.
for C11H14O2S: C, 62.83; H, 6.71; S, 15.25; Found: C, 62.92; H, 6.65; S,
15.15.
5.11. 2-(7-Methylsulfanyl-naphth-1-yl)ethylamine hydrochloride (10)
To a solution of 1 M BH3-THF (27 mL, 27 mmol) was added,
under nitrogen atmosphere, a solution of compound 9 (1.90 g,
9.0 mmol) in anhydrous THF (30 mL). The reaction mixture was
refluxed for 5 h. Then a 1 M HCl solution (18 mL, 108 mmol) was
added cautiously by maintening the reflux for another 30 min. After
cooling the mixture was extracted with ethyl acetate (3 ꢃ 100 mL).
The aqueous layer was basified with a 4 M NaOH solution and
extracted again with ethyl acetate (3 ꢃ 100 mL). The organic layer
was washed with water, dried over MgSO4, filtered, and concen-
trated. Purification of the amine of 10 was accomplished by column
chromatography over silica gel with dichloromethane/methanol
(5:5) then methanol/ammonia (95:5). The residue was taken up
with a solution of HCl gas-saturated diethyl ether, the resulting
precipitate was then filtered and dried to yield 10 as a white solid;
Yield 75%, mp 198e199 ꢁC. IR (KBr), cmꢂ1: 3200e2600 (NH3þ). 1H
NMR (DMSO-d6): dH 2.65 (s, 3H, SCH3), 3.05 (t, 2H, J ¼ 7.8 Hz, CH2-
a), 3.36 (m, 2H, CH2-b), 7.31e7.92 (m, 6H, H-2, 3, 4, 5, 6 and 8), 8.29
(br s, 3H, NH3þ). Anal. Calc. for C13H16ClNS: C, 61.52; H, 6.35; N,
5.52; Found: C, 61.60; H, 6.33; N, 5.45.
5.8. 7-Methylsulfanyl-3,4-dihydro-2H-naphthalen-1-one (7) [25]
A mixture of 6 (10 g, 52 mmol) and PPA (100 g) was mechan-
ically stirred at 70 ꢁC for 2 h. After cooling this reaction mixture was
poured onto ice, and then extracted with diethyl ether
(3 ꢃ 150 mL). The organic layer was washed with water, 1 N K2CO3
solution, and water again. The organic layer was dried over MgSO4,
filtered, and concentrated. Purification was accomplished by
column chromatography over silica gel with dichloromethane to
yield 7 as yellow oil; Yield 66%. IR (KBr), cmꢂ1: 1670 (C]O). 1H NMR
(DMSO-d6): dH 2.14 (q, 2H, J ¼ 6.3 Hz, CH2-a), 2.52 (s, 3H, SCH3), 2.64
(t, 2H, J ¼ 6.5 Hz, CH2-b), 2.93 (t, 2H, J ¼ 6.0 Hz, CH2-c), 7.18 (d, 1H,
J ¼ 8.1 Hz, H-5), 7.38 (dd, 1H, J ¼ 2.1, 8.1 Hz, H-6), 7.90 (d, 1H,
J ¼ 2.1 Hz, H-8). Anal. Calc. for C11H12OS: C, 68.71; H, 6.29; O, 8.32;
Found: C, 68.76; H, 6.25; O, 8.35.
5.12. N-[2-(7-methylsulfanyl-naphth-1-yl)ethyl]acetamide (11)
To a cold solution of 10 (400 mg, 1.84 mmol) in 3 mL of
dichloromethane/water (2:1) were added successively potassium
5.9. (7-Methylsulfanyl-3,4-dihydro-2H-naphth-1-ylidene)
acetonitrile (8)
carbonate (511 mg, 3.68 mmol) and acetyl chloride (144
mL,
2.03 mmol). After stirring vigorously for 30 min at room temper-
ature, the two layers were separated. The organic layer was washed
with water, dried over MgSO4, filtered, and concentrated. The oily
residue was purified by column chromatography over silica gel
with acetone/toluene/cyclohexane (3/5/2) to give 11 as a white
solid; Recrystallized from toluene/cyclohexane, yield 57%, mp
104e106 ꢁC. IR (KBr), cmꢂ1: 3270 (NH), 1620 (C]O). 1H NMR
(DMSO-d6): dH 1.95 (s, 3H, CH3), 2.64 (s, 3H, SCH3), 3.27 (t, 2H,
J ¼ 7.2 Hz, CH2-a), 3.61 (m, 2H, CH2-b), 5.54 (s, 1H, NH), 7.25e7.38
(m, 2H, H-2 and 3), 7.40 (dd, 1H, J ¼ 1.8, 8.6 Hz, H-6), 7.69 (d, 1H,
J ¼ 7.5 Hz, H-4), 7.76 (d,1H, J ¼ 8.6 Hz, H-5), 7.88 (d,1H, J ¼ 1.8 Hz, H-
8). 13C NMR (CDCl3): dC 15.82 (CH3), 23.23 (SCH3), 32.76 (C-b), 40.26
(C-a), 119.37 (C-8), 124.77 (C-6), 125.37 (C-3), 127.07 (C-4), 127.29
(C-2), 129.00 (C-5), 131.62 (C-10), 132.40 (C-9), 133.85 (C-1), 136.70
(C-7), 170.26 (C]O). Anal. Calc. for C15H17NOS: C, 69.46; H, 6.61; N,
5.40; Found: C, 61.78; H, 6.44; N, 5.36.
To a pre-cooled suspension at 0 ꢁC of sodium hydride (2.24 g,
46.8 mmol) in anhydrous THF (50 mL) was added dropwise, under
nitrogen atmosphere, a solution of diethyl cyanomethyl phospho-
nate (7.6 mL, 46.8 mmol) in anhydrous THF (20 mL). The mixture
was kept at 0 ꢁC for another 30 min before adding 7 (6 g, 31.2 mmol)
dissolved in anhydrous THF (30 mL). After stirring at room
temperature for 3 h, this reaction mixture was hydrolyzed, and
then extracted with ethyl acetate (3 ꢃ 100 mL). The organic layer
was washed with water, dried over MgSO4, filtered, and concen-
trated. Purification was accomplished by column chromatography
over silica gel with dichloromethane/petroleum ether (5:5) to give
8 as a yellow oil, yield 89%, which was composed by the two
isomers E/Z in proportions 4:1 [the isomer E could be isolated as
a white solid by trituration in a mixture toluene/hexane (1:5)]; mp
60e61 ꢁC. IR (KBr), cmꢂ1: 2200 (C^N). 1H NMR (DMSO-d6): dH 1.92
(q, 2H, J ¼ 6.3 Hz, CH2-2), 2.49 and 2.54 (2 s, 3H, SCH3 isomers E and
Z respectively), 2.81e2.89 (m, 4H, CH2-1 and 3), 5.28 and 5.72 (2 s,
1H, CH isomers Z and E respectively), 7.11 (d, 1H, J ¼ 8.0 Hz, H-5),
7.24 (dd, 1H, J ¼ 1.8, 8.0 Hz, H-6), 7.43 (d, 1H, J ¼ 1.8 Hz, H-8). Anal.
Calc. for C13H13NS: C, 72.52; H, 6.09; N, 6.51; Found: C, 72.60; H,
6.12; N, 6.61.
5.13. General procedure for oxidation of N-[2-(7-methylsulfanyl-
naphth-1-yl)ethyl]acetamide 11 (12 and 13)
To a cold solution of 11 (0.4 g, 1.54 mmol) in anhydrous
dichloromethane (20 mL) was added dropwise a solution of
m-chloroperoxybenzoic acid (1 or 3 equivalents according to obtain
respectively either 12 or 13) in anhydrous dichloromethane
(10 mL). After 2 h, the reaction mixture was evaporated to dryness
under reduced pressure. The residue was taken up into saturated
5.10. (7-Methylsulfanyl-naphth-1-yl)acetonitrile (9)
A mixture of 8 (2 g, 9.30 mmol) and sulfur (360 mg, 11 mmol)
was carried in fusion (>230 ꢁC) for 10 h. After cooling the residue

1628
V. Leclerc et al. / European Journal of Medicinal Chemistry 46 (2011) 1622e1629
Na2CO3 solution and the resulting precipitate was filtered, washed
with water, dried and, recrystallized from toluene.
J ¼ 9.0 Hz, H-5), 8.82 (s, 1H, H-8). Anal. Calc. for C14H14ClNO3S: C,
53.93; H, 4.53; N, 4.49; Found: C, 53.86; H, 4.65; N, 4.42.
5.13.1. N-[2-(7-methylsulfinyl-naphth-1-yl)ethyl]acetamide (12)
Yield 88%, white solid, mp 101e102 ꢁC. IR (KBr), cmꢂ1: 3420
(NH), 1651 (C]O), 1035 (S]O sulfinyl). 1H NMR (DMSO-d6): dH 1.98
(s, 3H, CH3), 2.83 (s, 3H, SOCH3), 3.35 (t, 2H, J ¼ 7.3 Hz, CH2-a), 3.61
(m, 2H, J ¼ 7.0 Hz, CH2-b), 5.82 (br s, 1H, NH), 7.45 (d, 1H, J ¼ 7.1 Hz,
H-2), 7.53 (t, 1H, J ¼ 7.6 Hz, H-3), 7.65 (dd, 1H, J ¼ 1.5, 8.7 Hz, H-6),
7.82 (d, 1H, J ¼ 8.0 Hz, H-4), 8.02 (d, 1H, J ¼ 8.7 Hz, H-5), 8.46 (s, 1H,
H-8). 13C NMR (CDCl3): dC 23.32 (CH3), 32.65 (SCH3), 40.27 (C-b),
43.97 (C-a), 120.89 (C-a), 124.77 (C-8), 127.00 (C-6), 127.89 (C-3),
128.21 (C-4), 128.91 (C-2), 130.19 (C-5), 130.97 (C-10), 135.85 (C-9),
137.10 (C-1), 137.75 (C-7), 169.87 (C]O). Anal. Calc. for C15H17NO2S:
C, 65.43; H, 6.22; N, 5.09; S, 11.64; Found: C, 65.19; H, 6.04; N, 5.19;
S, 11.46.
5.14. Generalprocedure forthepreparationofN-[2-(7-alkylsulfamoyl-
naphth-1-yl)ethyl]acetamides (16 and 17)
To a stirred solution of 15 (0.25 g, 0.8 mmol) in dichloromethane
(10 mL) was added triethylamine (0.17 mL, 1.2 mmol). The reaction
mixture was cooled with ice bath, and then the appropriate amine
(1.2 mmol) was slowly added. After stirring for 2 h the solvent was
evaporated to dryness under reduced pressure and the resulting
residue was recrystallized from suitable solvents.
5.14.1. N-[2-(7-sulfamoyl-naphth-1-yl)ethyl]acetamide (16)
Recrystallized from ethyl acetate, yield 87%, white solid. mp
194e196 ꢁC. IR (KBr), cmꢂ1: 3371 (NH sulfonamide), 3295 (NH
amide),1654 (C]O),1321 and 1162 (SO2NH). 1H NMR (DMSO-d6): dH
1.80 (s, 3H, CH3), 3.22 (t, 2H, J ¼ 7.0 Hz, CH2-a), 3.41 (m, 2H, CH2-b),
7.48 (s, 2H, NH2), 7.50 (d, 1H, J ¼ 7.4 Hz, H-2), 7.61 (m, 1H, H-3),
7.88e7.93 (m, 2H, H-4 and 6), 8.06 (t, 1H, J ¼ 5.2 Hz, NH), 8.13 (d, 1H,
J ¼ 8.7 Hz, H-5), 8.58 (s, 1H, H-8). 13C NMR (DMSO-d6): dC 22.61
(CH3), 31.97 (C-b), 45.51 (C-a),121.73 (C-8),126.72 (C-6),127.85 (C-3),
128.01 (C-4), 129.84 (C-2), 130.40 (C-5), 130.97 (C-10), 134.43 (C-9),
137.00 (C-1),141.32 (C-7),169.49 (C]O). Anal. Calc. for C14H16N2O3S:
C, 57.52; H, 5.52; N, 9.58; Found: C, 57.31; H, 5.49; N, 9.22.
5.13.2. N-[2-(7-methylsulfonyl-naphth-1-yl)ethyl]acetamide (13)
Yield 63%, white solid, mp 137e142 ꢁC. IR (KBr), cmꢂ1: 3400
(NH), 1671 (C]O), 1297 and 1143 (S]O sulfonyl). 1H NMR (DMSO-
d6): dH 1.99 (s, 3H, CH3), 3.18 (s, 3H, SO2CH3), 3.37 (t, 2H, J ¼ 7.3 Hz,
CH2-a), 3.63 (m, 2H, J ¼ 5.1 Hz, CH2-b), 5.64 (br s, 1H, NH), 7.50 (d,
1H, J ¼ 7.3 Hz, H-2), 7.62 (t, 1H, J ¼ 7.7 Hz, H-3), 7.85 (d, 1H,
J ¼ 8.2 Hz, H-4), 7.94 (dd, 1H, J ¼ 1.7, 8.6 Hz, H-6), 8.05 (d, 1H,
J ¼ 8.6 Hz, H-5), 8.77 (s, 1H, H-8). 13C NMR (CDCl3): dC 23.18 (CH3),
32.61 (SCH3), 40.33 (C-b), 44.39 (C-a), 121.90 (C-8), 124.72 (C-6),
127.20 (C-3), 128.35 (C-4), 128.95 (C-2), 130.59 (C-5), 130.91 (C-10),
135.85 (C-9), 137.02 (C-1), 137.67 (C-7), 170.42 (C]O). Anal. Calc. for
C15H17NO3S: C, 61.83; H, 5.88; N, 4.81; S, 11.00; Found: C, 61.70; H,
5.96; N, 5.79; S, 11.17.
5.14.2. N-[2-(7-methylsulfamoyl-naphth-1-yl)ethyl]acetamide (17)
Recrystallized from toluene, yield 95%, white solid, mp
155e156 ꢁC. IR (KBr), cmꢂ1: 3399 (NH sulfonamide), 3288 (NH
amide), 1671 (C]O), 1315 and 1159 (SO2NH). 1H NMR (DMSO-d6): dH
1.79 (s, 3H, CH3), 2.44 (d, 3H, J ¼ 5.0 Hz, NHCH3), 3.23 (t, 2H, J ¼ 7.1 Hz,
CH2-a), 3.40 (m, 2H, CH2-b), 7.52 (d, 1H, J ¼ 7.1, H-2), 7.56 (q, 1H,
J ¼ 5.0 Hz, NH), 7.64 (m,1H, H-3), 7.82 (dd,1H, J ¼ 1.0, 8.6 Hz, H-6), 7.94
(d,1H, J ¼ 8.0 Hz, H-4), 8.06 (br s,1H, NH), 8.16 (d,1H, J ¼ 8.8 Hz, H-5),
8.53 (s,1H, H-8). 13C NMR (CDCl3): dC 23.09 (CH3), 29.51 (NCH3), 33.15
(C-b), 40.62 (C-a),122.54 (C-8),124.17 (C-6),127.11 (C-3),128.09 (C-4),
128.37 (C-2), 130.00 (C-5), 131.07 (C-10), 135.33 (C-9), 135.97 (C-1),
136.82 (C-7), 170.95 (C]O). Anal. Calc. for C15H18N2O3S: C, 58.80; H,
5.92; N, 9.14; Found: C, 58.46; H, 5.88; N, 8.98.
5.13.3. N-[2-(7-benzylsulfanyl-naphth-1-yl)ethyl]acetamide (14)
To a stirred solution of N-[2-(7-hydroxy-naphth-1-yl)ethyl]
acetamide (1 g, 4.4 mmol) in trifluoromethanesulfonic acid (1.17 mL,
13.2 mmol) was slowlyadded benzyl mercaptan (0.78 mL, 6.6 mmol)
under nitrogen atmosphere. The reaction mixture was heated at
65 ꢁC for 2e3 h. After cooling the mixture was poured into ice-cold
water (50 mL) and then extracted with ethyl acetate. The organic
layer was washed successively with water, 2% aqueous NaOH and
water, and then dried over MgSO4. The solvent was removed and the
oily residue was purified by column chromatography over silica gel
with dichloromethane/ethyl acetate (1:1) to give 14 as a white solid;
Recrystallized fromtoluene/cyclohexane, yield 48%, mp 80e83ꢁC, IR
(KBr), cmꢂ1: 3292 (NH),1638 (C]O). 1H NMR (CDCl3): dH 1.92 (s, 3H,
CH3), 3.13 (t, 2H, J ¼ 6.8 Hz, CH2-a), 3.46 (m, 2H, CH2-b), 4.25 (s, 2H,
SCH2), 5.38 (s, 1H, NH), 7.21e7.43 (m, 8H, H-2,3,4,20,30,40,50 and 60),
7.67 (d, 1H, J ¼ 8.6 Hz, H-6), 7.73 (d, 1H, J ¼ 8.6 Hz, H-5), 8.02 (d, 1H,
J ¼ 1.8 Hz, H-8). Anal. Calc. for C21H21NOS: C, 75.19; H, 6.31; N, 4.18;
Found: C, 75.23; H, 6.41; N, 4.10.
5.15. 2-(7-Methylsulfamoyl-naphth-1-yl)ethylamine
hydrochloride (18)
A solution of 16 (0.43 g, 1.4 mmol) in 6 M HCl (5.8 mL,
35.1 mmol) was refluxed for 16 h and evaporated in vacuo. The
residue was taken up with diisopropyl ether and the resulting
precipitate was filtered, dried, and recrystallized from absolute
ethanol to yield 18 as a white solid; Yield 71%, mp 236e238 ꢁC. IR
(KBr), cmꢂ1: 3300 (NH sulfonamide), 2946e2360 (NH3þ), 1320 and
1137 (SO2NH). 1H NMR (DMSO-d6): dH 2.47 (d, 3H, J ¼ 4.9 Hz,
SO2NHCH3), 3.17 (m, 2H, CH2-a), 3.45 (m, 2H, CH2-b), 7.62 (d, 1H,
J ¼ 7.3 Hz, H-2), 7.69 (m, 1H, H-3), 7.81e7.89 (m, 2H, H-6 and NH),
8.01 (d, 1H, J ¼ 8.3 Hz, H-4), 8.20e8.27 (m, 4H, H-5þ and NH3), 8.64
(s, 1H, H-8). Anal. Calc. for C13H17ClN2O2S: C, 51.91; H, 5.70; N, 9.31;
Found: C, 51.63; H, 5.81; N, 9.11.
5.13.4. [8-(2-acetylamino-ethyl)naphth-2-yl]sulfonyl chloride (15)
A mixture of HClesilica gel [28] (107 g), iodosylbenzene (2.88 g,
13.1 mmol) (freshly prepared from diacetoxyiodobenzene by the
method described by Saltzmann [29]), and 14 (1 g, 3 mmol), all
solid, were placed into a mortar. The mixture was well crushed and
ground with a pestle at room temperature for 10 min. The solid
mixture was washed with dichloromethane (3 ꢃ 200 mL), then
acetone (3 ꢃ 200 mL). The combined organic layers were evapo-
rated in vacuo. The residue was triturated with petroleum ether to
give 15 as a pale yellow solid, yield 54%, which was kept in vacuo
under P2O5 because it was hygroscopic. IR (KBr), cmꢂ1: 3420 (NH),
1652 (C]O), 1370 and 1174 (SO2). 1H NMR (CDCl3): dH 1.98 (s, 3H,
CH3), 3.38 (t, 2H, J ¼ 7.1 Hz, CH2-a), 3.64 (m, 2H, CH2-b), 5.67 (s, 1H,
NH), 7.55 (d, 1H, J ¼ 7.1 Hz, H-2), 7.68 (m, 1H, H-3), 7.86 (d, 1H,
J ¼ 7.8 Hz, H-4), 8.01 (dd, 1H, J ¼ 1.9, 8.4 Hz, H-6), 8.08 (d, 1H,
5.16. N-[2-(7-methylsulfamoyl-naphth-1-yl)ethyl]furan-2-
ylcarboxamide (19)
To a pre-cooled solution at 0 ꢁC of 18 (0.5 g, 1.7 mmol) in
dichloromethane (15 mL) were added successively triethylamine
(0.46 mL, 3.4 mmol) and 2-furoyl chloride (0.18 mL,1.9 mmol). After
3 h, the reaction mixture was evaporated in vacuo. The residue was
purified by column chromatography over silica gel with dichloro-
methane then ethyl acetate and the resulting solid was

V. Leclerc et al. / European Journal of Medicinal Chemistry 46 (2011) 1622e1629
1629
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recrystallized from toluene to give 19 as a white solid; Yield 63%,
mp 117e119 ꢁC. IR (KBr), cmꢂ1: 3363 (NH sulfonamide), 3285 (NH
amide), 1664 (C]O), 1319 and 1162 (SO2NH). 1H NMR (CDCl3): dH
2.70 (d, 3H, J ¼ 5.5, NHCH3), 3.43 (m, 2H, CH2-a), 3.77 (m, 2H, CH2-
b), 5.38 (m, 1H, NH), 6.52 (dd,1H, J ¼ 1.8, 3.6 Hz, H-40), 6.72 (br s,1H,
NH), 7.15 (d, 1H, J ¼ 3.6 Hz, H-30), 7.44 (s, 1H, H-50), 7.50 (d, 1H,
J ¼ 6.9 Hz, H-2), 7.58 (m, 1H, H-3), 7.84 (d, 1H, J ¼ 8.0 Hz, H-4), 7.93
(dd, 1H, J ¼ 1.6, 8.6 Hz, H-6), 8.02 (d, 1H, J ¼ 8.4 Hz, H-5), 8.93 (s, 1H,
H-8). 13C NMR (CDCl3): dC 29.55 (NCH3), 33.28 (C-b), 40.03 (C-a),
112.06 (C-30), 114.34 (C-20), 122.55 (C-8), 124.08 (C-6), 127.18 (C-3),
128.08 (C-4), 128.31 (C-2), 130.05 (C-5), 130.96 (C-10), 135.33 (C-9),
136.11 (C-1),136.35 (C-7),144.02 (C-40),147.65 (C-10), 158.72 (C]O).
Anal. Calc. for C18H18N2O4S: C, 60.32; H, 5.06; N, 7.82; Found: C,
60.24; H, 5.00; N, 7.74.
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