6-Sulfonylbenzothiazolones as potential scaffolds for the design of 5-HT6 ligands

Article abstract of DOI:10.1016/j.ejmech.2015.01.052

5-HT₆ Receptors are relatively recently discovered receptors that interact with cholinergic, glutamatergic, GABAergic and dopaminergic transmission systems. These receptors have been implicated in the CNS system as therapeutic targets in applications such as psychosis, reduction of body weight or Alzheimer's disease. As part of our efforts to develop 5-HT₆ antagonists, we explored the benzothiazolone scaffold substituted in position 3 or 6 respectively with ethylamino chains and an aromatic ring connected through a sulfonyl linker. Final compounds were evaluated in radioligand binding assays for their ability to interact with 5-HT₆ receptors. Their potential cytotoxic effects were determined on the human neuroblastoma cell line SY5Y. They showed very low cytotoxicity, and one of them has submicromolar affinity for 5-HT₆ receptors.

Full text of DOI:10.1016/j.ejmech.2015.01.052

European Journal of Medicinal Chemistry 92 (2015) 807e817
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
6-Sulfonylbenzothiazolones as potential scaffolds for the design of 5-
HT6 ligands
,
b
,
c
,
, e
ꢀ a
, Vincent Ultre d, Delphine Le Broc a
Paul-Emmanuel Larchanche a
,
Celine Ballandone , Christophe Furman e, Patrick Dallemagne f, Patricia Melnyk a
,
f
a,
, b, c, *
ꢀ
, b, *
Pascal Carato a
a
ꢀ
Universite de Lille, F-59000 Lille, France
b UDSL, EA 4481, UFR Pharmacie, F-59000 Lille, France
c Inserm UMR-S1172, Jean-Pierre Aubert Research Center, F-59000 Lille, France
d UDSL, Laboratoire de RMN, UFR Pharmacie, F-59000 Lille, France
e UDSL, EA 4483, UFR Pharmacie, F-59000 Lille, France
f CERMN, EA 4258, UFR des Sciences Pharmaceutiques, UNICAEN, F-14032 Caen, France
a r t i c l e i n f o
a b s t r a c t
Article history:
5-HT6 Receptors are relatively recently discovered receptors that interact with cholinergic, glutamatergic,
GABAergic and dopaminergic transmission systems. These receptors have been implicated in the CNS
system as therapeutic targets in applications such as psychosis, reduction of body weight or Alzheimer's
disease. As part of our efforts to develop 5-HT6 antagonists, we explored the benzothiazolone scaffold
substituted in position 3 or 6 respectively with ethylamino chains and an aromatic ring connected
through a sulfonyl linker. Final compounds were evaluated in radioligand binding assays for their ability
to interact with 5-HT6 receptors. Their potential cytotoxic effects were determined on the human neu-
roblastoma cell line SY5Y. They showed very low cytotoxicity, and one of them has submicromolar af-
finity for 5-HT6 receptors.
Received 2 December 2014
Received in revised form
23 January 2015
Accepted 24 January 2015
Available online 26 January 2015
Keywords:
5-HT6 ligand
Benzothiazolone
© 2015 Elsevier Masson SAS. All rights reserved.
1. Introduction
appetite control [12,13], learning, memory impairment [14], and
related CNS diseases such as Alzheimer's disease [15,16].
Serotonin (5-hydroxytryptamine, 5-HT) mediates a wide range
of physiological functions. This neurotransmitter interacts with
seven serotoninergic receptor families (5-HT1 to 5-HT7) sub-
divided into 14 subpopulations [1e5]. One of them, the 5-HT6
receptor (5-HT6R), was most recently identified by molecular
biology in the early 1990s [6e8]. The 5-HT6R belongs to G-protein
coupled receptors, and is positively linked to adenylyl cyclase via
Gs-protein [9,10]. Extensive investigation has shown that 5-HT6R
is almost exclusively localised in the central nervous system (CNS),
and is associated with psychosis [11], convulsive disorders,
Numerous studies have shown that 5-HT6Rs regulate several
neurotransmitter pathways including cholinergic, noradrenergic,
glutamatergic and dopaminergic systems. Blockade of 5-HT6R
function specifically increases cholinergic and glutamatergic
neurotransmission [17,18], and improves cognition in rodent
behavioural models [19].
Crystallographic data are presently unavailable, and the struc-
tural requirements of 5-HT6R are unknown, but
a three-
dimensional pharmacophore model has been reported for 5-HT6
antagonists [20e22]. The structural features hypothesis, for high
potency of 5-HT6 ligands, entails the following three key elements
on an aromatic hydrophobic site (AR): a positive ionisable atom (PI,
usually secondary or tertiary amino group), a hydrogen bond
acceptor group (HBA, usually a sulfone or sulfonamide group)
connected to a hydrophobic site (HYD) (aromatic or heteroaromatic
ring). The amino group could interact with the sulfonyl group by an
intramolecular hydrogen bond to stabilise and afford an advanta-
geous binding conformation [23]. However, no publications
* Corresponding authors. UFR Pharmacie, 3 rue du Pr Laguesse, BP83, 59006 Lille,
France.
E-mail addresses: paul-emmanuel.larchanche@univ-lille2.fr (P.-E. Larchanche),
ꢀ
vincent.ultre@univ-lille2.fr (V. Ultre), delphine.lebroc@univ-lille2.fr (D. Le Broc),
celine.ballandone@unicaen.fr (C. Ballandone), christophe.furman@univ-lille2.fr
(C. Furman), patrick.dallemagne@unicaen.fr (P. Dallemagne), patricia.melnyk@
univ-lille2.fr (P. Melnyk), pascal.carato@univ-poitiers.fr (P. Carato).
http://dx.doi.org/10.1016/j.ejmech.2015.01.052
0223-5234/© 2015 Elsevier Masson SAS. All rights reserved.

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P.-E. Larchanche et al. / European Journal of Medicinal Chemistry 92 (2015) 807e817
convincingly demonstrate the need for a basic side chain for
effective interaction with 5-HT6R. In recent work, the replacement
of the N-methylamino group by a methylthio or a methyl group
established that the basic side chain is not essential for the high
affinity binding of ligands to 5-HT6Rs [24,25].
Eaton's reagent. For the second step, substitution of chloroalkyl- or
cycloalkylamine with potassium carbonate in DMF with derivative
5 afforded final products 6e7 (Yield: 17e36%).
For the synthesis of retrosulfonylamide derivatives 16e21
(Scheme 2), we again took advantage of the reactivity of this het-
erocycle and the possibility of easily performing a selective elec-
trophilic aromatic substitution in position 6. Benzothiazolone 1
reacted in 70% nitric acid to give 6-nitro benzothiazolone 8 [27,31],
which was allowed to react in DMF with potassium carbonate and
the corresponding 2-chloroethylalkylamine derivatives to yield
compounds 9e11 with moderate yields (35e42%). Reduction of the
nitro group of derivatives 9e11 in methanol with Pd/C under
hydrogen atmosphere gave compounds 12e14 in good yields
(73e82%). A first attempt at nucleophilic reaction of the amino
derivatives (1 eq) with phenyl sulfonylchloride (1.5 eq) in ethyl
acetate with triethylamine or a solution of potassium carbonate in
ethyl acetate/water gave a mixture of mono- and disubstituted
sulfonyl compounds 15, 17. Indeed, the presence of a base, such as
triethylamine or potassium carbonate, generated a second reaction
of the in situ formed sulfonamide derivatives with phenyl sulfo-
nylchloride to afford disubstituted sulfonyl compound 15. In a
second attempt, the reaction was performed in pyridine with amino
derivatives and the desired chlorosulfonyl products, to afford only
monosubstituted compounds 16e21 with reasonable yields
(53e78%).
In our laboratory, we previously explored imidazopyridine as
the aromatic hydrophobic site (AR) of the 5-HT6R pharmacophore
[26], and introduced various ethylamino chains at position 3, and
sulfonyl or sulfamide aromatic rings at position 6 of the hetero-
cycle. Given the low affinity of these compounds, we turned our
attention to the benzothiazolone heterocycle as a potential scaffold.
In the present study, three series were successively studied with
sulfonyl, sulfamide and retrosulfonylamide groups as the linker
between the heterocycle core and the aryl ring. A few variations
were envisaged with dimethylamino, pyrrolidino and piperidino
ethyl chains as the R1 group. Phenyl and naphthyl were introduced
as R2 groups. These two aryl rings have already been successfully
introduced into 5-HT6R antagonists [20]. In Fig. 1, the key elements
(HYD, HBA and PI) and the benzothiazolone as aromatic site (AR)
are represented with an example of a synthesised compound. Three
different schemes were developed to synthesise these three series
of compounds.
2. Chemistry
For the synthesis of sulfonylamide derivatives 28e33 (Scheme
3), again an electrophilic substitution of benzothiazolone 1 was
used as the first step. Using chlorosulfonic acid, 6-chlorosulfonic
benzothiazol-2-one 22 was obtained with 82% yield. Starting
from compound 22, two routes were envisaged. A first route (route
A) was attempted by introducing 1-amino naphthalene in pyridine
to afford derivative 23 with 59% yield, which was placed in dry THF
with methyl iodide to afford only the N-methyl benzothiazol-2-one
derivative 24, and not the expected N-methylsulfonamide deriva-
tive. In the literature, substitution reaction of halogenoalkyl ben-
zothiazolone derivatives with amino reagent was performed in
acetone or acetonitrile in the presence of triethylamine [32]. In
these conditions no substitution reaction was observed at the free
NH benzothiazolone compound. Substitution reaction at this 3
position could be performed in DMF with potassium carbonate
[28].
By the second route B, N-methylsulfonamide compounds 28e33
were prepared in two steps starting from commercially available N-
methylaniline and synthesised N-methyl-1-amino naphthalene. In
a first step, N-methyl-1-amino naphthalene was synthesised in two
steps [33]. A reaction in absolute ethanol with 1-amino naphtha-
lene and benzotriazole, followed by a reduction in dry THF with
sodium borohydride, gave the N-methyl-1-amino naphthalene.
Reaction of the 6-chlorosulfonic benzothiazol-2-one 22 with N-
methylaniline or N-methyl-1-amino naphthalene in pyridine gave
the N-methylsulfonamide derivatives 25e26 with 65e70% yields. It
was observed that compound 22 also reacted with pyridine, used as
solvent and base, to give the pyridinium derivative 27, as a sec-
ondary product with a 16% yield. Final compounds 28e33 were
obtained in DMF with potassium carbonate and the corresponding
2-chloroethylalkylamine reagents with satisfactory yields
Sulfone series could be synthesised according to two different
synthetic pathways (Scheme 1). In the first method, benzothiazo-
lone 1 was brominated in CHCl3 with Br2 to afford the corresponding
6-bromobenzothiazolone 2 [27], with good yield (85%), which was
allowed to react in DMF with potassium carbonate [28] and the
corresponding 2-chloroethylalkylamine derivatives to yield the N-
substituted compounds 3e4. The Stille reaction [29,30] was then
performed in two steps to furnish final compounds. Reaction in dry
toluene under inert atmosphere with tetrakis(triphenylphosphine)
palladium and hexabutylditin provided the expected tributyltin
intermediates. The subsequent coupling reaction with 5-tri-n-
butyltin derivatives in dry toluene under inert atmosphere with
dichloro(diphenylphosphine) palladium and the desired chlor-
osulfonyl reagent never afforded the expected compounds, but only
the N-substituted benzothiazolones corresponding to destanny-
lated compounds. Modification of the experimental conditions
never allowed us to obtain sulfonylbenzothiazolones 6 and 7.
The second pathway was based on FriedeleCrafts reaction fol-
lowed by alkylation of the thiocarbamate function. Using a mixture
of AlCl3-DMF [28], the FriedeleCrafts acid-catalysed acylation of
benzothiazol-2-one
1 with the corresponding phenylsulfonyl
chloride afforded 6-phenylsulfonylbenzothiazol-2-one 5 in low
yield (15%), with a reaction time of 2 h. The conversion was not
complete, and continuation of the reaction led to the degradation of
the reaction medium. In the presence of Eaton's reagent (P2O5/
CH3SO3H), expected compound 5 was obtained with higher yield
(57%), together with minor degradation products. The synthesis of
the naphthyl derivative was attempted without success. Friedele-
Crafts reaction with a mixture of AlCl3-DMF led to the complete
degradation of the reaction medium, whereas no reaction occurred
between starting benzothiazolone 1, naphthylsulfonyl chloride and
N
N
N
N
R 1
R 2
:
:
R
N
PI
N
S
1
HYD
O
HN
O
S
R
2
S
O
O
AR
X
HBA
SO2, NHSO2, SO2NH, SO2NCH3
X :
Fig. 1. Design of benzothiazolone derivatives.

P.-E. Larchanche et al. / European Journal of Medicinal Chemistry 92 (2015) 807e817
809
R
1
H
N
H
N
N
b
a
3-4
O
O
O
S
S
S
Br
Br
1
2
R 1
Cpd
3 , 6
d
c
N
R
N
1
H
4 , 7
N
b
N
O
O
S
S
S
S
O
O
6-7
O
O
5
Scheme 1. Synthesis of the 6-phenylsulfonyl compounds (6e7). Reagents and conditions: (a) Br2, CHCl3, rt, 3 h, 85%, (b) 2-chloroethylamine derivatives, K2CO3, DMF, 80 ꢀC, 18 h,
17e61%, (c) i: Sn(Bu3)2, Pd(PPh3)4, toluene, ii: phenylsulfonyl chloride, PdCl2(PPh3)2, toluene, (d) phenylsulfonyl chloride, AlCl3, DMF, 80 ꢀC, 2 h, 15% or P2O5/CH3SO3H (1/10), 110 ꢀC,
24 h, 57%.
R 1
Cpd
9, 12
R
N
1
H
N
H
N
b
a
N
O
O
O
S
S
S
NO2
NO2
R
9-11
8
1
10, 13
11, 14
N
N
R
N
1
1
N
c
e
O
O
O
O
S
S
d
S
NH2
N
R
2
H
16-21
12-14
R 2
N
R 1
16
17
19
20
N
N
S
O
O
O
S
N
N
O
S
15
O
21
18
N
Scheme 2. Synthesis of the 6-retrosulfonylamide compounds (16e21). Reagents and conditions: (a) HNO3 70%, rt, 3 h, 90%, (b) 2-chloroethylamine derivatives, K2CO3, DMF, 80 ꢀC,
18 h, 35e42%, (c) H2, Pd/C, MeOH, rt, 4 h, 73e82%, (d) arylsulfonyl chloride, Et3N, AcOEt or arylsulfonyl chloride, K2CO3, H2O, AcOEt, rt, 24 h, 68%, (e) arylsulfonyl chloride, pyridine,
rt, 24 h, 53e78%.
(42e63%).
The NH analogue derivatives 37e42 (Scheme 3) could not be
[34], on membranes of HEK-293 cells transiently expressing the
human 5-HT6 receptors.
obtained by route A. Indeed, after chlorosulfonyl reaction to afford
compound 23, reaction in DMF, with chloroethylamine and potas-
sium carbonate, furnished the corresponding N,N-disubstituted
compound at the N-3 and N-sulfonamide positions. These final
compounds 37e42 were prepared in two steps. A reaction in DMF
with potassium carbonate with benzothiazolone 1 and the desired
chloroethylamine reagents furnished the corresponding com-
pounds 34e36. A chlorosulfonyl reaction of compounds 34e36 in
CHCl3 with chlorosulfonic acid gave chlorosulfonyl intermediates
which were reacted in situ with triethylamine, and addition of the
corresponding arylamine derivatives afforded final compounds
37e42, with low yield for the two steps (6e26%). It could be noticed
that attempts were made to isolate the chlorosulfonyl derivatives,
but the intermediates could not be extracted or isolated in acid
medium, and sulfonyl acid derivatives were obtained in basic
medium.
Starting from benzothiazolone as a scaffold for the aromatic
hydrophobic site, we introduced into position 3, dimethylamino,
pyrrolidino and piperidino ethyl chains (R1) and into position 6,
sulfonyl (6e7), sulfamide (28e33, 37e42) and retrosulfonylamide
(16e21) functions substituted by phenyl and naphthyl as the aro-
matic ring (R2). Derivative 15, with an ethylpyrrolidino chain and
disubstituted with a phenylsulfonyl group, was also evaluated. The
percentage inhibition of specific control binding was determined at
a concentration of 100 nM and the inhibition constant Ki was then
calculated (Table 1).
The evaluated derivatives showed disappointing results with
respect to affinity for 5-HT6 receptors. Only one derivative (40)
showed a Ki value of 100 nM. For the other compounds, with in-
hibition of less than 50% at 100 nM of the evaluated compound, the
affinity for 5-HT6 receptors was not determined.
The disubstituted compound 15 also showed low inhibition
(20%) for 5-HT6 receptors. For the two series of sulfonyl and ret-
rosulfonylamide compounds, respectively 6e7 and 16e21, the in-
hibition was less than 22%. In the sulfonylamide series, derivatives
28e31, 33, 37, 39, 41e42 provided low inhibition (0e21%) and
moderate inhibition for compounds 32, 38 (respectively 40 and
37%). The sulfonylamide compound 40, with dimethylamino chain
as R1 and a naphthyl ring as R2, showed a moderate Ki of 100 nM.
3. Results and discussion
3.1. Biological evaluations and SAR
Receptor affinities were investigated in competition experi-
ments with [3H]-LSD, according to the methods of Monsma et al.

810
P.-E. Larchanche et al. / European Journal of Medicinal Chemistry 92 (2015) 807e817
Route A
H
N
H
N
H
N
b
N
S
c
a
O
O
O
O
H
H
N
N
S
S
S
SO2Cl
S
S
O
O
1
O
O
22
23
24
e
R 1
d
Cpd
Route B
34
35
N
N
R
N
R 2
1
Cpd
25
H
N
-
Cl
H
N
O
O
+
N
O
S
S
S
N
R
2
S
O
S
O
36
O
N
O
26
f
e
27
R
N
R
N
1
1
O
O
H
N
N
S
S
S
S
R
R
2
2
O
O
O
O
R 2
R 2
R 1
R 1
28
29
31
32
37
40
41
N
N
N
38
39
N
30
33
42
N
N
Scheme 3. Synthesis of the 6-sulfonylamide compounds (28e33, 37e42). Reagents and conditions: (a): chlorosulfonic acid, reflux, 2 h, 82% (b): aniline, pyridine, rt, 24 h, 59% (c):
CH3I, Et3N, CH3CN, rt, 30 min, 18% (d): N-methylarylamine derivatives, pyridine, rt, 24 h, 65e70% (e): chloroethylamine derivatives, K2CO3, DMF, 80 ꢀC, 18 h, 42e68% (f): i:
chlorosulfonic acid, CHCl3, reflux, 1 h ii: arylamine derivatives, Et3N, rt, 1 h, 6e26%.
3.2. Evaluation of cytotoxic effects
possible to understand the relation-structure-affinity for these
compounds in the three series. Furthermore, these studies will
allow us to optimise and generate new series of 5-HT6 ligands.
To determine the potential cytotoxic effects of our synthetic
derivatives, the human neuroblastoma cell line SY5Y was treated
with all the compounds at different concentrations up to 100
Cell viability was calculated using a colorimetric MTT assay.
mM.
All compounds exhibited moderate to low cytotoxicity (Table 1).
In particular, the retrosulfonylamide series, with derivatives 15e21,
5. Experimental section
showed very low cytotoxicity (6e39% at 100
sulfonylamide series, with compounds 6e7, 28e33, 38e42, showed
moderate cytotoxicity, with IC50 in the 10e102 M range. In the
mM). The sulfonyl and
5.1. Chemistry
m
5.1.1. General
sulfonylamide series, compound 37 exhibited no cytotoxicity on the
Chemicals and solvents were obtained from commercial sour-
ces, and used without further purification unless otherwise stated.
Reactions were monitored by TLC performed on MachereyeNagel
Alugram® Sil 60/UV254 sheets (thickness 0.2 mm). Products were
purified using column chromatography. Column chromatography
was carried out using MachereyeNagel silica gel (230e400 mesh).
NMR spectra were recorded on a Bruker DRX 300 spectrometer
(operating at 300 MHz for 1H and 75 MHz for 13C). Chemical shifts
are expressed in ppm relative to either tetramethylsilane (TMS) or
to residual proton signal in deuterated solvents. Chemical shifts are
human neuroblastoma cell line SY5Y.
4. Conclusion
The 5-HT6 receptors have been implicated in several therapeutic
targets with agonist and antagonist ligands, as potential antide-
pressant, cognitive effects, decrease of body weight and food
intake. We synthesised compounds with a benzothiazolone scaf-
fold, and introduced an alkylamino chain and an aromatic ring
respectively at positions 3 and 6 of this heterocycle according to the
previously published pharmacophore. These compounds were
evaluated for their affinity for 5-HT6 receptors and their cytotoxic
effect on neuronal cells. Unfortunately, most of them showed an
inhibition inferior to 50% at 100 nM, compared to derivative SB
271046, which has an excellent Ki of 1.7 nM. Compound 40, with a
dimethylamino chain in position 3 and naphthylsulfonylamide in
position 6, exhibited the best affinity of the sulfonylamide series
(Ki ¼ 100 nM). The 3D pharmacophore model described in the
literature, and molecular modelling techniques will make it
reported as position
(d
in ppm), multiplicity (s
¼
singlet,
d ¼ doublet, t ¼ triplet, q ¼ quartet, p ¼ pentet, dd ¼ double
doublet, br ¼ broad and m ¼ multiplet), coupling constant (J in Hz),
relative integral and assignment. The attributions of protons and
carbons were made by analysis of 2D experiments (COSY, HSQC and
HMBC). Mass spectra were recorded on a Varian triple quadrupole
1200W mass spectrometer equipped with a non-polar C18 TSK-gel
Super ODS (4.6 ꢁ 50 mm) column, using electrospray ionisation
and a UV detector (diode array). All compounds were found to be
>96% pure by HPLC analysis.

P.-E. Larchanche et al. / European Journal of Medicinal Chemistry 92 (2015) 807e817
811
Table 1
Evaluation of 5-HT6R affinity and cytotoxicity of target compounds.
Compound
Structure
R1
R2
5-HT6 affinity
Cytotoxicity (SY5Y)
% Inhibition of specific
Ki (nM)
% Inhibition
IC50 (mM)
control bindinga
of cell growingb
SB 271046
6
e
e
e
e
e
1.7
e
e
16%
86.9
7
e
e
11%
20%
e
e
44.1
15
e
19%
16
17
18
5%
11%
6%
e
e
e
20%
25%
39%
19
20
21
22%
0%
e
e
e
17%
28%
5%
4%
28
29
30
5%
10%
0%
e
e
e
91.0
49.5
50.0
31
32
33
0%
40%
14%
e
e
e
29.0
102
91.9
37
38
39
21%
37%
7%
e
e
e
0%
10.0
17.4
40
41
42
e
100
e
45.7
68.6
25.2
0%
3%
e
Mean IC50 or Ki values for 2-3 independent experiments are shown with less than 10% deviation.
a
Competition binding assay at 100 nM giving the displacement (%) of compounds (radioligand: [3H]-LSD, n ¼ 3).
b
Determination of the potential cytotoxic effects at the concentration of 100 mM.
5.1.2. General procedure for the synthesis of N-substituted-3H-
benzothiazol-2-one derivatives
form.
To DMF (20 mL) were added potassium carbonate (0.4 g,
3 mmol), 3H-benzothiazol-2-one derivative (1 mmol) and the
corresponding chloroethylamine derivative (1 mmol). The mixture
was warmed at 80 ꢀC for 18 h. The mineral was filtered and the
solution evaporated under reduced pressure. The resulting crude
product was purified by chromatography on silica gel
(40e63 mesh), eluting with dichloromethane/methanol (95/5, v/v).
The hydrochloride product was obtained by solubilising the free
base in dry ethyl acetate and treated with gaseous hydrochloric acid
in diethyl ether (20 mL). The precipitate obtained was filtered and
washed with ethyl acetate (2 ꢁ 20 mL) to afford the desired com-
pound. Compounds were described as free base or hydrochloride
5.1.2.1. 6-Bromo-3-dimethylaminoethyl-3H-benzothiazol-2-one
3.
Yield 61%; 1H NMR (300 MHz, CDCl3)
d: 2.20 (s, 6H, N(CH3)2), 2.58
(t, J ¼ 7.1 Hz, 2H, NCH2), 4.01 (t, J ¼ 7.2 Hz, 2H, CH2), 6.95 (d,
J ¼ 8.6 Hz, 1H, H4), 7.41 (dd, J ¼ 8.5 Hz, J ¼ 1.9 Hz, 1H, H5), 7.53 (d,
J ¼ 2.0 Hz, 1H, H7). 13C NMR (75 MHz, CDCl3)
d: 41.1 (CH2), 45.7 (2
CH3), 56.1 (CH2), 111.8 (CH), 115.8 (Caro), 124.5 (Caro), 125.2 (CH),
129.4 (CH), 136.1 (Caro), 169.2 (CO). LCMS (ESIþ): calc for [MþHþ]:
301.0e303.0; found: 301.0e302.9.
5.1.2.2. 6-Bromo-3-piperidino
Yield 58%; 1H NMR (300 MHz, CDCl3)
4H, CH2), 2.50 (m, 4H, NCH2), 2.62 (t, J ¼ 7.3 Hz, 2H, CH2), 4.05 (t,
ethyl-3H-benzothiazol-2-one
4.
d: 1.40 (m, 2H, CH2), 1.60 (m,

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P.-E. Larchanche et al. / European Journal of Medicinal Chemistry 92 (2015) 807e817
J ¼ 7.3 Hz, 2H, CH2), 7.00 (d, J ¼ 8.5 Hz, 1H, H4), 7.41 (dd, J ¼ 8.6 Hz,
J ¼ 1.9 Hz, 1H, H5), 7.53 (d, J ¼ 1.9 Hz, 1H, H7). 13C NMR (75 MHz,
N(CH3)2), 3.17 (s, 3H, NCH3), 3.39 (m, 2H, NCH2), 4.39 (t, J ¼ 6.8 Hz,
2H, NCH2), 7.17 (m, 2H, HAr), 7.26e7.40 (m, 3H, HAr), 7.44 (dd,
J ¼ 8.6 Hz, J ¼ 1.9 Hz, 1H, H5), 7.68 (d, J ¼ 8.6 Hz, 1H, H4), 8.08 (d,
J ¼ 1.9 Hz, 1H, H7), 10.46 (m, 1H, NHþ). 13C NMR (75 MHz, DMSO-d6)
CDCl3) d: 24.2 (CH2), 25.9 (2 CH2), 40.9 (CH2), 54.9 (2 CH2), 55.7
(CH2), 112.0 (CH), 115.3 (Caro), 124.5 (Caro), 125.1 (CH), 129.2 (CH),
136.3 (Caro), 169.1 (CO). LCMS (ESIþ): calc for [MþHþ]: 341.0-343.0;
found: 340.9e343.0.
d
: 38.1 (CH2), 38.5 (CH3), 42.6 (2 CH3), 53.1 (CH2), 112.1 (CH), 123.2
(CH), 123.4 (Caro), 126.5 (CH), 126.7 (2 CH), 127.8 (CH), 129.5 (2 CH),
131.4 (Caro),140.5 (Caro),141.5 (Caro),170.4 (CO). LCMS (ESIþ): calc for
[MþHþ]: 392.1; found: 392.0.
5.1.2.3. 6-Benzenesulfonyl-3-(2-dimethylaminoethyl)-3H-benzothia-
zol-2-one hydrochloride 6. Yield 17%; mp 236e238 ꢀC; 1H NMR
(300 MHz, DMSO-d6)
d: 2.82 (m, 6H, N(CH3)2), 3.38 (m, 2H, CH2),
5.1.2.9. 3-Methyl-2-oxo-3-(2-pyrrolidin-1-ylethyl)-2,3-dihydro-ben-
4.39 (t, J ¼ 6.3 Hz, 2H, CH2), 7.56 - 7.23 (m, 3H, HAr), 7.76 (d,
J ¼ 8.5 Hz, 1H, H4), 7.95 (dd, J ¼ 8.5 Hz, J ¼ 1.8 Hz, 1H, H5), 7.98 (m,
2H, HAr), 8.46 (d, J ¼ 1.8 Hz, 1H, H7), 10.75 (m, 1H, NHþ). 13C NMR
zothiazole-6-sulfonic acid methylphenylamide hydrochloride 29.
Yield 42%; mp > 240 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d: 1.86 (m,
2H, 2 CH2), 2.01 (m, 2H, 2 CH2), 3.09 (m, 2H, 2 NCH2), 3.18 (s, 3H,
NCH3), 3.50 (m, 2H, NCH2), 3.59 (m, 2H, 2 NCH2), 4.37 (t, J ¼ 6.3 Hz,
2H, NCH2), 7.14 (m, 2H, HAr), 7.26e7.40 (m, 3H, HAr), 7.45 (dd,
J ¼ 8.5 Hz, J ¼ 1.8 Hz, 1H, H5), 7.65 (d, J ¼ 8.5 Hz, 1H, H4), 8.09 (d,
J ¼ 1.8 Hz, 1H, H7), 10.45 (m, 1H, NHþ). 13C NMR (75 MHz, DMSO-d6)
(75 MHz, DMSO-d6) d: 38.1 (CH2), 42.6 (2 CH3), 53.2 (CH2), 112.7
(CH), 123.3 (CH), 123.9 (Caro), 126.6 (CH), 127.7 (2 CH), 130.3 (2 CH),
134.2 (CH), 136.1 (Caro), 140.9 (Caro), 141.9 (Caro), 170.4 (CO). LCMS
(ESIþ): calc for [MþHþ]: 363.1; found: 363.0.
d: 23.2 (2 CH2), 38.5 (CH3), 39.1 (CH2), 50.4 (CH2), 53.5 (2 CH2), 112.0
5.1.2.4. 6-Benzenesulfonyl-3-(2-piperidin-1-ylethyl)-3H-benzothia-
(CH), 123.2 (CH), 123.4 (Caro), 126.5 (CH), 126.7 (2 CH), 127.8 (CH),
129.4 (2CH), 131.3 (Caro), 140.4 (Caro), 141.5 (Caro), 170.3 (CO). LCMS
(ESIþ): calc for [MþHþ]: 418.1; found: 418.0.
zol-2-one hydrochloride 7. Yield 36%; mp > 240 ꢀC; 1H NMR
(300 MHz, DMSO-d6) d: 1.36 (m, 1H, CH2), 1.62e1.88 (m, 6H, 3 CH2),
2.93 (m, 2H, 2 NCH2), 3.30 (m, 2H, NCH2), 3.53 (m, 2H, 2 NCH2), 4.43
(t, J ¼ 6.8 Hz, 2H, NCH2), 7.58e7.73 (m, 3H, HAr), 7.81 (d, J ¼ 8.9 Hz,
1H, H4), 7.95 (dd, J ¼ 8.9 Hz, J ¼ 1.8 Hz, 1H, H5), 7.98 (m, 2H, HAr),
8.46 (d, J ¼ 1.8 Hz, 1H, H7), 10.66 (m, 1H, NHþ). 13C NMR (75 MHz,
5.1.2.10. 3-Methyl-2-oxo-3-(2-piperidin-1-ylethyl)-2,3-dihydro-ben-
zothiazole-6-sulfonic acid methylphenylamide hydrochloride 30.
Yield 58%; mp > 240 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d: 1.37 (m,
DMSO-d6)
d: 21.7 (CH2), 22.8 (2 CH2), 37.5 (CH2), 52.2 (CH2), 52.5 (2
1H, CH2), 1.76e1.88 (m, 5H, 3CH2), 2.96 (m, 2H, 2 NCH2), 3.17 (s, 3H,
NCH3), 3.32 (m, 2H, NCH2), 3.56 (m, 2H, 2 NCH2), 4.44 (t, J ¼ 7.0 Hz,
2H, NCH2), 7.14 (m, 2H, HAr), 7.26e7.40 (m, 3H, HAr), 7.44 (dd,
J ¼ 8.6 Hz, J ¼ 1.9 Hz, 1H, H5), 7.73 (d, J ¼ 8.6 Hz, 1H, H4), 8.08 (d,
J ¼ 1.9 Hz, 1H, H7), 10.45 (m, 1H, NHþ). 13C NMR (75 MHz, DMSO-d6)
CH2), 112.7 (CH), 123.3 (CH), 123.8 (Caro), 126.6 (CH), 127.7 (CH),
130.3 (CH), 134.2 (CH), 136.1 (Caro), 140.8 (Caro), 141.9 (Caro), 170.2
(CO). LCMS (ESIþ): calc for [MþHþ]: 403.1; found: 403.0.
5.1.2.5. 3-(2-Dimethylaminoethyl)-6-nitro-3H-benzothiazol-2-one
d: 21.7 (CH2), 22.8 (2 CH2), 37.6 (CH2), 38.5 (CH3), 52.1 (CH2), 52.4 (2
hydrochloride 9. Yield 37%; mp > 240 ꢀC; 1H NMR (300 MHz, CDCl3)
CH2), 112.1 (CH), 123.3 (Caro), 123.3 (CH), 126.5 (CH), 126.7 (2 CH),
127.8 (CH), 129.4 (2 CH), 131.4 (Caro), 140.4 (Caro), 141.5 (Caro), 170.1
(CO). LCMS (ESIþ): calc for [MþHþ]: 432.1; found: 432.2.
d
: 2.85 (d, J ¼ 4.2 Hz, 6H, N(CH3)2), 3.42 (m, 2H, CH2), 4.45 (t,
J ¼ 6.7 Hz, 2H, CH2), 7.79 (d, J ¼ 9.0 Hz, 1H, H4), 8.29 (dd, J ¼ 9.0 Hz,
J ¼ 2.4 Hz, 1H, H5), 8.78 (d, J ¼ 2.4 Hz, 1H, H7), 10.78 (m, 1H, NHþ).
13C NMR (75 MHz, CDCl3)
d: 38.3 (CH2), 42.7 (2 CH3), 53.3 (CH2),
5.1.2.11. 3-(2-Dimethylaminoethyl)-2-oxo-2,3-dihydro-benzothia-
112.2 (CH), 119.8 (CH), 123.1 (CH), 123.6 (Caro), 142.2 (Caro), 143.5
(Caro), 170.7 (CO). LCMS (ESIþ): calc for [MþHþ]: 268.3; found:
268.0.
zole-6-sulfonic acid methylnaphthalen-1-yl amide hydrochloride 31.
Yield 63%; mp > 240 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d: 2.88 (m,
6H, N(CH3)2), 3.28 (s, 3H, NCH3), 3.44 (m, 2H, NCH2), 4.43 (t,
J ¼ 6.3 Hz, 2H, NCH2), 6.95 (dd, J ¼ 7.4 Hz, J ¼ 1.0 Hz, 1H, HAr), 7.43
(dd, J ¼ 8.3 Hz, J ¼ 7.4 Hz, 1H, HAr), 7.55e7.68 (m, 2H, HAr), 7.68 (dd,
J ¼ 8.4 Hz, J ¼ 1.8 Hz, 1H, H5), 7.74 (d, J ¼ 8.4 Hz, 1H, H4), 7.96 (d,
J ¼ 8.4 Hz, 1H, HAr), 8.00 (m, 1H, HAr), 8.16 (m, 1H, HAr), 8.25 (d,
J ¼ 1.8 Hz, 1H, H7), 10.23 (m, 1H, NHþ). 13C NMR (75 MHz, DMSO-d6)
5.1.2.6. 6-Nitro-3-(2-pyrrolidin-1-ylethyl)-3H-benzothiazol-2-one
hydrochloride 10. Yield 35%; mp > 240 ꢀC; 1H NMR (300 MHz,
DMSO-d6) d: 1.87 (m, 2H, 2 CH2), 2.01 (m, 2H, 2 CH2), 3.09 (m, 2H, 2
NCH2), 3.50 (m, 2H, NCH2), 3.58 (m, 2H, 2 NCH2), 4.42 (t, J ¼ 6.4 Hz,
2H, NCH2), 7.74 (d, J ¼ 9.0 Hz, 1H, H4), 8.29 (dd, J ¼ 9.0 Hz, J ¼ 2.4 Hz,
1H, H5), 8.78 (d, J ¼ 2.4 Hz, 1H, H7), 10.67 (m, 1H, NHþ). 13C NMR
d: 38.1 (CH2), 40.2 (CH3), 42.7 (2 CH3), 53.2 (CH2), 112.2 (CH), 123.5
(CH), 123.6 (Caro), 124.0 (CH), 125.3 (CH), 126.0 (CH), 126.8 (CH),
127.1 (CH), 127.3 (CH), 128.5 (CH), 129.1 (CH), 132.1 (Caro), 132.2
(Caro), 134.7 (Caro), 138.4 (Caro), 140.5 (Caro), 170.5 (CO). LCMS (ESIþ):
calc for [MþHþ]: 442.1; found: 442.0.
(75 MHz, DMSO-d6) d: 23.1 (2 CH2), 39.5 (CH2), 50.7 (CH2), 53.7 (2
CH2), 112.1 (CH), 119.8 (CH), 123.1 (CH), 123.6 (Caro), 142.2 (Caro),
143.5 (Caro),170.8 (CO). LCMS (ESIþ): calc for [MþHþ]: 294.3; found:
294.0.
5.1.2.12. 3-Methyl-2-oxo-3-(2-pyrrolidin-1-ylethyl)-2,3-dihydro-
benzothiazole-6-sulfonic acid methylnaphthalen-1-yl amide hydro-
chloride 32. Yield 48%; mp > 240 ꢀC; 1H NMR (300 MHz, DMSO-d6)
5.1.2.7. 6-Nitro-3-(2-piperidin-1-ylethyl)-3H-benzothiazol-2-one
hydrochloride 11. Yield 42%; mp > 240 ꢀC; 1H NMR (300 MHz,
DMSO-d6)
d: 1.38 (m, 1H, CH2), 1.65e1.78 (m, 3H, 3 CH2), 1.84 (m,
d: 1.88 (m, 2H, 2 CH2), 2.03 (m, 2H, 2 CH2), 3.12 (m, 2H, 2 NCH2), 3.28
2H, 2 CH2), 2.97 (m, 2H, 2 NCH2), 3.40 (m, 2H, NCH2), 3.58 (m, 2H, 2
NCH2), 4.47 (t, J ¼ 7.0 Hz, 2H, NCH2), 7.78 (d, J ¼ 9.0 Hz, 1H, H4), 8.30
(dd, J ¼ 9.0 Hz, J ¼ 2.4 Hz, 1H, H5), 8.79 (d, J ¼ 2.4 Hz, 1H, H7), 10.20
(s, 3H, NCH3), 3.54 (m, 2H, NCH2), 3.61 (m, 2H, 2 NCH2), 4.42 (t,
J ¼ 6.3 Hz, 2H, NCH2), 6.95 (dd, J ¼ 7.4 Hz, J ¼ 1.0 Hz, 1H, HAr), 7.43
(dd, J ¼ 8.2 Hz, J ¼ 7.4 Hz, 1H, HAr), 7.56e7.67 (m, 2H, HAr), 7.67 (dd,
J ¼ 8.4 Hz, J ¼ 1.8 Hz, 1H, H5), 7.74 (d, J ¼ 8.4 Hz, 1H, H4), 7.96 (d,
J ¼ 8.4 Hz, 1H, HAr), 8.00 (m, 1H, HAr), 8.16 (m, 1H, HAr), 8.25 (d,
J ¼ 1.8 Hz, 1H, H7), 10.48 (m, 1H, NHþ). 13C NMR (75 MHz, DMSO-d6)
(m, 1H, NHþ). 13C NMR (75 MHz, DMSO-d6),
d
¼ 21.7 (CH2), 22.9 (2
CH2), 37.8 (CH2), 52.5 (CH2), 52.7 (2 CH2), 112.1 (CH), 119.8 (CH),
123.1 (CH), 123.6 (Caro), 142.1 (Caro), 143.5 (Caro), 170.7 (CO). LCMS
(ESIþ): calc for [MþHþ]: 308.1; found: 307.9.
d
: 23.2 (2 CH2), 39.2 (CH2), 40.2 (CH3), 50.6 (CH2), 53.6 (2 CH2),112.2
(CH), 123.5 (CH), 123.6 (Caro), 124.0 (CH), 125.3 (CH), 126.0 (CH),
126.8 (CH), 127.1 (CH), 127.3 (CH), 128.5 (CH), 129.1 (CH), 132.1
(Caro), 132.2 (Caro), 134.7 (Caro), 138.4 (Caro), 140.6 (Caro), 170.5 (CO).
LCMS (ESIþ): calc for [MþHþ]: 468.1; found: 468.0.
5.1.2.8. 3-(2-Dimethylaminoethyl)-2-oxo-2,3-dihydro-benzothia-
zole-6-sulfonic acid methylphenylamide hydrochloride 28. Yield
68%; mp 203e204 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d: 2.85 (m, 6H,

P.-E. Larchanche et al. / European Journal of Medicinal Chemistry 92 (2015) 807e817
813
5.1.2.13. 3-Methyl-2-oxo-3-(2-piperidin-1-ylethyl)-2,3-dihydro-ben-
zothiazole-6-sulfonic acid methylnaphthalen-1-yl amide hydrochlo-
atmosphere until complete homogeneity was obtained. Phenyl-
sulfonyl chloride (3.0 g,17.0 mmol) and benzothiazol-2-one 1 (3.8 g,
25.5 mmol) were then added to Eaton's reagent. The mixture was
heated at 110 ꢀC under inert atmosphere for 24 h. After cooling at
20 ꢀC, the reaction medium was hydrolysed in cooled water
(200 mL) and stirred for 1 h. The precipitate obtained was filtered
and recrystallised in absolute ethanol (yield: 57%).
ride 33. Yield 57%; mp > 240 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d:
1.39 (m, 1H, CH2), 1.66e1.91 (m, 5H, 3 CH2), 2.98 (m, 2H, 2 NCH2),
3.27 (s, 3H, NCH3), 3.32 (m, 2H, NCH2), 3.59 (m, 2H, 2 NCH2), 4.44 (t,
J ¼ 6.8 Hz, 2H, NCH2), 6.95 (dd, J ¼ 7.4 Hz, J ¼ 1.0 Hz, 1H, HAr), 7.43
(dd, J ¼ 8.2 Hz, J ¼ 7.4 Hz, 1H, HAr), 7.56e7.68 (m, 2H, HAr), 7.67 (dd,
J ¼ 8.4 Hz, J ¼ 1.8 Hz, 1H, H5), 7.84 (d, J ¼ 8.4 Hz, 1H, H4), 7.96 (d,
J ¼ 8.4 Hz, 1H, HAr), 8.00 (m, 1H, HAr), 8.16 (m, 1H, HAr), 8.24 (d,
5.1.3.3. 6-Benzenesulfonyl-3H-benzothiazol-2-one
5. Mp
J ¼ 1.8 Hz, 1H, H7), 10.48 (m, 1H, NHþ). 13C NMR (75 MHz, CDCl3)
d:
225e227 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
: 7.26 (d, J ¼ 8.4 Hz,1H,
21.8 (CH2), 22.8 (2 CH2), 37.6 (CH2), 38.5 (CH3), 52.3 (CH2), 52.6 (2
CH2), 112.2 (CH), 123.5 (CH), 123.6 (Caro), 124.0 (CH), 125.3 (CH),
126.0 (CH), 126.8 (CH), 127.1 (CH), 127.3 (CH), 128.5 (CH), 129.1 (CH),
132.1 (Caro), 132.2 (Caro), 134.7 (Caro), 138.4 (Caro), 140.5 (Caro), 170.3
(CO). LCMS (ESIþ): calc for [MþHþ]: 482.1; found: 482.0.
H4), 7.57e7.70 (m, 3H, HAr), 7.80 (dd, J ¼ 8.4 Hz, J ¼ 1.9 Hz, 1H, H5),
7.93 (m, 2H, HAr), 8.30 (d, J ¼ 1.9 Hz, 1H, H7), 12.40 (br s, 1H, NH). 13
C
NMR (75 MHz, DMSO-d6) d: 112.4 (CH), 123.3 (CH), 125.3 (Caro),
126.7 (CH), 127.6 (2 CH), 130.2 (2 CH), 134.0 (CH), 135.2 (Caro), 141.1
(Caro), 142.0 (Caro), 170.8 (CO). LCMS (ESIꢂ): calc for [MꢂHþ]: 290.0;
found: 290.0.
5.1.2.14. 3-(2-Dimethyaminoethyl)-3H-benzothiazol-2-one
chloride 34. Yield 45%; mp 218e220 ꢀC; 1H NMR (300 MHz, DMSO-
d6)
hydro-
5.1.4. 6-Nitro-3H-benzothiazol-2-one 8 [27,31]
d
: 2.84 (d, J ¼ 3.8 Hz, 6H, N(CH3)2), 3.36 (m, 2H, NCH2), 4.40 (t,
To 70% HNO3 (20 mL) was added 3H-benzothiazol-2-one (10 g,
66 mmol) and the mixture stirred at 20 ꢀC for 3 h. The precipitate
was filtered and washed with water. The product was recrystallised
in absolute ethanol. Yield 90%; mp 228e229 ꢀC; 1H NMR (300 MHz,
J ¼ 7.2 Hz, 2H, NCH2), 7.24 (ddd, J ¼ 8.1 Hz, J ¼ 7.8 Hz, J ¼ 1.0 Hz, 1H,
H6), 7.41 (ddd, J ¼ 8.1 Hz, J ¼ 7.8 Hz, J ¼ 1.3 Hz, 1H, H5), 7.60 (dd,
J ¼ 8.1 Hz, J ¼ 0.6 Hz, 1H, H4), 7.70 (dd, J ¼ 7.8 Hz, J ¼ 1.0 Hz, 1H, H7),
11.26 (m, 1H, NHþ). 13C NMR (75 MHz, DMSO-d6)
d: 37.7 (CH2), 42.5
DMSO-d6)
d
: 7.28 (d, J ¼ 8.9 Hz, 1H, H4), 8.18 (dd, J ¼ 8.9 Hz,
(2 CH3), 53.0 (CH2), 112.1 (CH), 122.1 (Caro), 123.5 (CH), 124.0 (CH),
127.2 (CH), 136.7 (Caro), 169.7 (CO). LCMS (ESIþ): calc for [MþHþ]:
223.1; found: 222.9.
J ¼ 2.4 Hz, 1H, H5), 8.65 (d, J ¼ 2.5 Hz, 1H, H7), 12.54 (br s, 1H, NH).
13C NMR (75 MHz, DMSO-d6)
d: 111.9 (CH), 119.6 (CH), 123.2 (CH),
125.0 (Caro), 142.5 (Caro), 142.9 (Caro), 171.0 (CO). LCMS (ESIꢂ): calc
for [MꢂHþ]: 195.0; found: 195.0.
5.1.2.15. 3-(2-Pyrrolidin-1-ylethyl)-3H-benzothiazol-2-one
chloride 35. Yield 43%; mp 215e217 ꢀC; 1H NMR (300 MHz, DMSO-
d6) : 1.80 (m, 2H, CH2), 2.01 (m, 2H, CH2), 3.06 (m, 2H, 2 NCH2),
hydro-
5.1.5. General procedure for the synthesis of compounds 12e14
To a solution of compounds (10 mmol) in methanol was added
10% Pd/C (100 mg). The resulting solution was stirred at 20 ꢀC under
atmospheric pressure of hydrogen for 4 h. The solution was filtered
and concentrated to dryness. The residue was purified by column
chromatography using dichloromethane/methanol (95/5, v/v) as
eluent to afford the corresponding oily compounds.
d
3.46 (m, 2H, NCH2), 3.59 (m, 2H, 2 NCH2), 4.37 (t, J ¼ 7.0 Hz, 2H,
NCH2), 7.25 (td, J ¼ 7.7 Hz, J ¼ 1.1 Hz, 1H, H6), 7.41 (ddd, J ¼ 8.1 Hz,
J ¼ 7.7 Hz, J ¼ 1.3 Hz, 1H, H5), 7.58 (dd, J ¼ 8.1 Hz, J ¼ 1.1 Hz, 1H, H4),
7.70 (dd, J ¼ 7.7 Hz, J ¼ 1.3 Hz, 1H, H7), 11.25 (m, 1H, NHþ). 13C NMR
(75 MHz, DMSO-d6) d: 23.1 (2 CH2), 38.7 (CH2), 50.4 (CH2), 53.4 (2
CH2), 112.0 (CH), 122.1 (Caro), 123.5 (CH), 124.0 (CH), 127.2 (CH),
136.7 (Caro) 169.7 (CO). LCMS (ESIþ): calc for [MþHþ]: 249.1; found:
249.0.
5.1.5.1. 6-Amino-3-(2-dimethylaminoethyl)-3H-benzothiazol-2-one
12. Yield 73%; 1H NMR (300 MHz, CDCl3)
d: 2.30 (s, 6H, NCH3), 2.60
(t, J ¼ 6.7 Hz, 2H, NCH2), 3.65 (br s, 2H, NH2), 4.00 (t, J ¼ 6.7 Hz, 2H,
5.1.2.16. 3-(2-Piperidin-1-ylethyl)-3H-benzothiazol-2-one
chloride 36. Yield 51%; mp 226e227 ꢀC; 1H NMR (300 MHz, DMSO-
d6) : 1.38 (m, 1H, CH2), 1.72 (m, 1H, CH2), 1.77-1.85 (m, 4H, 2 CH2),
hydro-
NCH2), 6.65 (dd, J ¼ 8.5 Hz, J ¼ 2.1 Hz, 1H, H5), 6.78 (d, J ¼ 2.0 Hz,1H,
H7), 6.86 (d, J ¼ 8.6 Hz, 1H, H4). 13C NMR (75 MHz, CDCl3)
d: 40.9
d
(CH2), 45.7 (2 CH3), 56.1 (CH2), 109.1 (CH), 111.2 (CH), 113.8 (CH),
123.9 (Caro), 129.5 (Caro), 142.7 (Caro), 169.4 (CO). LCMS (ESIþ): calc
for [MþHþ]: 237.1; found: 238.0.
2.97 (m, 2H, 2 NCH2), 3.30 (m, 2H, NCH2), 3.55 (m, 2H, 2 NCH2), 4.45
(t, J ¼ 7.5 Hz, 2H, NCH2), 7.25 (ddd, J ¼ 7.8 Hz, J ¼ 7.5 Hz, J ¼ 1.0 Hz,
1H, H6), 7.42 (ddd, J ¼ 8.2 Hz, J ¼ 7.5 Hz, J ¼ 1.3 Hz, 1H, H5), 7.66 (dd,
J ¼ 8.2 Hz, J ¼ 1.0 Hz, 1H, H4), 7.71 (dd, J ¼ 7.8 Hz, J ¼ 1.3 Hz, 1H, H7),
11.03 (m, 1H, NHþ). 13C NMR (75 MHz, DMSO-d6)
d: 21.8 (CH2), 22.8
5.1.5.2. 6-Amino-3-(2-pyrrolidin-1-ylethyl)-3H-benzothiazol-2-one
13. Yield 79%; 1H NMR (300 MHz, CDCl3)
d: 1.83 (m, 4H, 2 CH2),
(2 CH2), 37.2 (CH2), 52.2 (CH2), 52.5 (2 CH2), 112.1 (CH), 122.1 (Caro),
123.6 (CH), 124.0 (CH), 127.2 (CH), 136.7 (Caro), 169.6 (CO). LCMS
(ESIþ): calc for [MþHþ]: 263.1; found: 263.0.
2.63 (m, 4H, 2 NCH2), 2.80 (t, J ¼ 6.6 Hz, 2H, NCH2), 3.65 (br s, 2H,
NH2), 4.05 (m, J ¼ 6.6 Hz, 2H, NCH2), 6.65 (dd, J ¼ 8.7 Hz, J ¼ 2.2 Hz,
1H, H5), 6.78 (d, J ¼ 2.2 Hz, 1H, H7), 6.93 (d, J ¼ 8.7 Hz, 1H, H4). 13
C
NMR (75 MHz, CDCl3) d: 23.6 (2CH2), 41.9 (CH2), 52.9 (CH2), 54.4
5.1.3. General procedures for Friedel Crafts reaction for the
synthesis of compound 5
(2CH2), 109.1 (CH), 111.4 (CH), 113.9 (CH), 123.6 (Caro), 129.2 (Caro),
142.7 (Caro), 169.2 (CO). LCMS (ESIþ): calc for [MþHþ]: 264.1; found:
264.0.
5.1.3.1. Procedure in the presence of aluminium chloride reagent.
To aluminium chloride (36 g, 264 mmol) in DMF (8.5 mL) were
added benzothiazol-2-one 1 (5 g, 33 mmol) and phenylsulfonyl
chloride (66 mmol). The mixture was warmed at 80 ꢀC for 2 h. The
solution was hydrolysed in cooled water (200 mL). The precipitate
obtained was filtered and recrystallised in absolute ethanol (yield:
15%).
5.1.5.3. 6-Amino-3-(2-piperidin-1-ylethyl)-3H-benzothiazol-2-one
14. Yield 82%; 1H NMR (300 MHz, CDCl3)
d: 1.36 (m, 2H, CH2), 1.54
(m, 4H, 2 CH2), 2.40 (m, 4H, 2 NCH2), 2.55 (t, J ¼ 6.7 Hz, 2H, NCH2),
3.63 (br s, 2H, NH2), 3.95 (t, J ¼ 6.8 Hz, 2H, NCH2), 6.58 (dd,
J ¼ 8.8 Hz, J ¼ 2.0 Hz, 1H, H5), 6.69 (d, J ¼ 2.0 Hz, 1H, H7), 6.83 (d,
5.1.3.2. Procedure in the presence of Eaton's reagent. Eaton's reagent
was prepared from phosphorus pentoxide (1.0 g, 7.0 mmol) and
methanesulfonic acid (11.0 g, 114.6 mmol) (weight ratio P2O5/
CH3SO3H 1:10). The mixture was heated at 60 ꢀC under nitrogen
J ¼ 8.8 Hz, 1H, H4). 13C NMR (75 MHz, CDCl3)
d: 21.8 (CH2), 22.8 (2
CH2), 38.1 (CH2), 52.2 (CH2), 52.5 (2 CH2), 112.7 (CH), 117.1 (CH),
120.9 (CH), 123.4 (Caro), 130.5 (Caro), 135.1 (Caro), 169.6 (CO). LCMS
(ESIþ): calc for [MþHþ]: 278.1; found: 278.0.

814
P.-E. Larchanche et al. / European Journal of Medicinal Chemistry 92 (2015) 807e817
5.1.6. Diphenylsulfonic acid-(3-(2-pyrrolidin-1-ylethyl)-2-oxo-2,3-
dihydro-benzothiazol-6-yl)amide hydrochloride 15
J ¼ 1.2 Hz, 1H, HAr), 7.14 (m, 2H, HAr), 7.23 (m, 2H, HAr), 7.76 (m, 2H,
H4, H5), 8.22 (m, 1H, H7), 10.45 (s, 1H, NH), 10.58 (m, 1H, NHþ). 13
NMR (75 MHz, DMSO-d6) : 21.7 (CH2), 22.8 (2 CH2), 37.3 (CH2), 52.2
(CH2), 52.5 (2 CH2), 112.4 (CH), 116.3 (CH), 120.4 (CH), 122.9 (Caro),
127.2 (2 CH), 129.8 (2 CH), 133.4 (CH), 133.6 (Caro), 133.8 (Caro), 139.8
(Caro), 169.4 (CO). LCMS (ESIþ): calc for [MþHþ]: 418.1; found: 418.1.
C
To AcOEt (20 mL) with triethylamine (0.3 mL, 2.2 mmol) or a
solution of AcOEt/H2O (10/10 v/v) with potassium carbonate (0.3 g,
2.2 mmol) were added 6-amino-3-(2-pyrrolidin-1-ylethyl)-3H-
benzothiazol-2-one (13) (0.3 g, 1.1 mmol) and chlorosulfonylphenyl
(0.3 mL, 1.9 mmol). The reaction mixture was stirred for 24 h. Water
(10 mL) was added. The organic layer was evaporated under
reduced pressure. The product was purified by chromatography on
silica gel using dichloromethane/methanol (95/5, v/v). The product
was solubilised in dry ethyl acetate and treated with gaseous hy-
drochloric acid in diethyl ether (20 mL). The precipitate obtained
was filtered and washed with ethyl acetate (2 ꢁ 20 mL) to afford
the desired compound. Yield 68%; mp 238e239 ꢀC; 1H NMR
d
5.1.7.4. Naphthalen-2-sulfonic acid-(3-(2-dimethylaminoethyl)-2-
oxo-2,3-dihydro-benzothiazol-6-yl)amide
hydrochloride
19.
: 2.80
Yield 65%; mp 228e229 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
(d, J ¼ 4.3 Hz, 6H, N(CH3)2), 3.30 (m, 2H, CH2), 4.22 (t, J ¼ 6.7 Hz, 2H,
CH2), 7.08 (dd, J ¼ 8.7 Hz, J ¼ 2.1 Hz, 1H, H5), 7.34 (d, J ¼ 8.7 Hz, 1H,
H4), 7.51 (d, J ¼ 2.1 Hz, 1H, H7), 7.61e7.74 (m, 2H, HAr), 7.81 (dd,
J ¼ 8.7 Hz, J ¼ 1.8 Hz, 1H, HAr), 8.02 (d, J ¼ 8.1 Hz, 1H, HAr), 8.11 (d,
J ¼ 8.3 Hz, 1H, HAr), 8.13 (d, J ¼ 8.2 Hz, 1H, HAr), 8.45 (d, J ¼ 1.8 Hz,
1H, HAr), 10.15 (m, 1H, NHþ), 10.53 (s, 1H, NH). 13C NMR (75 MHz,
(300 MHz, DMSO-d6) d: 1.87 (m, 2H, 2 CH2), 2.02 (m, 2H, 2 CH2),
3.09 (m, 2H, 2 NCH2), 3.48 (m, 2H, NCH2), 3.60 (m, 2H, 2 NCH2), 4.36
(t, J ¼ 6.4 Hz, 2H, CH2), 6.95 (dd, J ¼ 8.6 Hz, J ¼ 2.2 Hz, 1H, H5), 7.57
(d, J ¼ 8.6 Hz, 1H, H4), 7.63 (d, J ¼ 2.2 Hz, 1H, H7), 7.71 (m, 4H, HAr),
7.84 (m, 4H, HAr), 7.85 (m, 2H, HAr), 10.83 (m, 1H, NHþ). 13C NMR
DMSO-d6) d: 37.8 (CH2), 42.7 (2 CH3), 53.4 (CH2), 112.4 (CH), 116.3
(CH), 120.3 (CH), 122.5 (CH), 123.0 (Caro), 128.2 (CH), 128.3 (CH),
128.5 (CH), 129.5 (CH), 129.7 (CH), 130.0 (CH), 132.0 (Caro), 133.7 (2
(75 MHz, DMSO-d6)
d: 23.2 (2 CH2), 39.0 (CH2), 50.4 (CH2), 53.5 (2
C
aro), 134.7 (Caro), 136.8 (Caro), 169.8 (CO). LCMS (ESIþ): calc for
CH2), 112.3 (CH), 123.2 (Caro), 126.9 (CH), 128.5 (4 CH), 128.7 (Caro),
130.1 (4 CH), 130.3 (CH), 135.3 (2 CH), 138.4 (Caro), 138.8 (Caro), 170.1
(CO). LCMS (ESIþ): calc for [MþHþ]: 544.1; found: 543.8.
[MþHþ]: 428.1; found: 428.0.
5.1.7.5. Naphthalen-2-sulfonic acid-(3-(2-pyrrolidin-1-ylethyl)-2-
oxo-2,3-dihydro-benzothiazol-6-yl)amide
hydrochloride
20.
: 1.82
5.1.7. General procedure for the synthesis of compounds 16e21
To pyridine (20 mL) were added 6-aminobenzothiazol-2-one
(1 g, 6 mmol) and the corresponding chlorosulfonylaryl (9 mmol).
The reaction mixture was stirred at 20 ꢀC for 24 h. The solution was
evaporated under reduced pressure. The product was purified by
chromatography on silica gel using dichloromethane/methanol
(96/4, v/v). The product was solubilised in dry ethyl acetate and
treated with gaseous hydrochloric acid in diethyl ether (20 mL). The
precipitate obtained was filtered and washed with ethyl acetate
(2 ꢁ 20 mL) to afford the desired compound.
Yield 53%; mp 221e222 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
(m, 2H, 2 CH2), 1.96 (m, 2H, 2 CH2), 3.00 (m, 2H, 2 NCH2), 3.36 (m,
2H, NCH2), 3.60 (m, 2H, 2 NCH2), 4.23 (t, J ¼ 6.7 Hz, 2H, NCH2), 7.10
(dd, J ¼ 8.7 Hz, J ¼ 2.2 Hz, 1H, H5), 7.40 (d, J ¼ 8.7 Hz,1H, H4), 7.52 (d,
J ¼ 2.2 Hz, 1H, H7), 7.60ꢂ7.72 (m, 2H, HAr), 7.84 (dd, J ¼ 8.7 Hz,
J ¼ 1.9 Hz, 1H, HAr), 8.00 (dd, J ¼ 7.9 Hz, J ¼ 1.2 Hz, 1H, HAr), 8.10 (d,
J ¼ 8.7 Hz, 1H, HAr), 8.12 (dd, J ¼ 7.3 Hz, J ¼ 1.2 Hz, 1H, HAr), 8.45 (d,
J ¼ 1.9 Hz, 1H, HAr), 10.61 (s, 1H, NH), 10.96 (m, 1H, NHþ). 13C NMR
(75 MHz, DMSO-d6) d: 23.1 (2 CH2), 38.8 (CH2), 50.4 (CH2), 53.4 (2
CH2), 112.4 (CH), 116.3 (CH), 120.3 (CH), 122.6 (CH), 122.9 (Caro),
128.2 (CH), 128.3 (CH), 128.5 (CH), 129.5 (CH), 129.7 (CH), 130.0
(CH), 132.0 (Caro), 133.6 (Caro), 133.8 (Caro), 134.7 (Caro), 136.8 (Caro),
170.1 (CO). LCMS (ESIꢂ): calc for [MꢂHþ]: 452.1; found: 451.9.
5.1.7.1. Phenyl-1-sulfonic acid-(3-(2-dimethylaminoethyl)-2-oxo-2,3-
dihydro-benzothiazol-6-yl)amide hydrochloride 16. Yield 78%;
mp > 240 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
: 2.86 (d, J ¼ 4.6 Hz,
6H, N(CH3)2), 3.35 (m, 2H, CH2), 4.26 (t, J ¼ 6.5 Hz, 2H, CH2), 7.06
(dd, J ¼ 8.7 Hz, J ¼ 2.2 Hz, 1H, H5), 7.37 (d, J ¼ 8.7 Hz, 1H, H4), 7.46 (d,
J ¼ 2.2 Hz, 1H, H7),7.52e7.66 (m, 3H, HAr), 7.78 (m, 2H, HAr), 10.13
5.1.7.6. Naphthalen-2-sulfonic acid-(3-(2-piperidin-1-ylethyl)-2-
oxo-2,3-dihydro-benzothiazol-6-yl)amide
hydrochloride
21.
Yield 58%; mp > 240 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d: 1.20e1.88
(m, 1H, NHþ), 10.41 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6)
d: 37.8
(m, 6H, 3 CH2), 2.90 (m, 2H, 2 NCH2), 3.26 (m, 2H, NCH2), 3.52 (m,
2H, 2 NCH2), 4.25 (t, J ¼ 6.7 Hz, 2H, NCH2), 7.08 (dd, J ¼ 8.9 Hz,
J ¼ 2.1 Hz, 1H, H5), 7.35 (d, J ¼ 8.9 Hz, 1H, H4), 7.52 (d, J ¼ 2.1 Hz, 1H,
H7), 7.62e7.74 (m, 2H, HAr), 7.81 (dd, J ¼ 8.7 Hz, J ¼ 1.8 Hz, 1H, HAr),
8.02 (d, J ¼ 8.2 Hz, 1H, HAr), 8.11 (d, J ¼ 8.7 Hz, 1H, HAr), 8.14 (d,
J ¼ 8.2 Hz, 1H, HAr), 8.45 (d, J ¼ 1.8 Hz, 1H, HAr), 9.74 (m, 1H, NHþ),
(CH2), 42.6 (2 CH3), 53.1 (CH2), 112.4 (CH), 116.3 (CH), 120.4 (CH),
122.9 (Caro), 127.2 (2 CH), 129.8 (2 CH), 133.4 (CH), 133.6 (Caro), 133.8
(Caro), 139.8 (Caro), 169.5 (CO). LCMS (ESIþ): calc for [MþHþ]: 378.1;
found: 378.0.
5.1.7.2. Phenyl-1-sulfonic
2,3-dihydro-benzothiazol-6-yl)amide hydrochloride 17. Yield 65%;
mp 164e165 ꢀC; 1H NMR (300 MHz, DMSO-d6)
: 1.83 (m, 2H, 2
acid-(3-(2-pyrrolidin-1-ylethyl)-2-oxo-
10.51 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6)
d: 21.7 (CH2), 22.8 (2
CH2), 37.3 (CH2), 52.2 (CH2), 52.5 (2 CH2), 112.4 (CH), 116.3 (CH),
120.3 (CH), 122.5 (CH), 122.9 (Caro), 128.2 (CH), 128.3 (CH), 128.5
(CH), 129.5 (CH), 129.7 (CH), 130.0 (CH), 132.0 (Caro), 133.6 (Caro),
133.8 (Caro), 134.7 (Caro), 136.8 (Caro), 169.4 (CO). LCMS (ESIþ): calc
for [MþHþ]: 468.1; found: 468.1.
d
CH2), 2.00 (m, 2H, 2 CH2), 3.06 (m, 2H, 2 NCH2), 3.43 (m, 2H, NCH2),
3.57 (m, 2H, 2 NCH2), 4.24 (t, J ¼ 6.1 Hz, 2H, NCH2), 7.05 (dd,
J ¼ 8.7 Hz, J ¼ 2.2 Hz, 1H, H5), 7.35 (d, J ¼ 8.7 Hz, 1H, H4), 7.46 (d,
J ¼ 2.2 Hz, 1H, H7),7.52e7.66 (m, 3H, HAr), 7.77 (m, 2H, HAr), 10.12
(m, 1H, NHþ), 10.39 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6)
d: 23.1
5.1.8. 2-Oxo-2,3-dihydro-benzothiazole-6-sulfonic acid
(2 CH2), 38.9 (CH2), 50.4 (CH2), 53.6 (2 CH2), 112.4 (CH), 116.3 (CH),
120.4 (CH), 122.9 (Caro), 127.2 (2 CH), 129.8 (2 CH), 133.4 (CH), 133.7
(Caro), 133.8 (Caro), 139.8 (Caro), 169.6 (CO). LCMS (ESIþ): calc for
[MþHþ]: 404.1; found: 404.0.
naphthalen-1-ylamide 23
To pyridine (20 mL) were added 6-chlorosulfonylbenzothiazol-
2-one (4.0 g, 16 mmol) and naphthalen-1-ylamine (3.1 g, 22 mmol).
The reaction mixture was stirred at 20 ꢀC for 24 h. The solution was
evaporated under reduced pressure. The resulting crude product
was washed with diethyl ether, CH2Cl2 and water. The solid product
was recrystallised in absolute ethanol. Yield 59%; mp 210e211 ꢀC;
5.1.7.3. Phenyl-1-sulfonic acid-(3-(2-piperidin-1-ylethyl)-2-oxo-2,3-
dihydro-benzothiazol-6-yl)amide hydrochloride 18. Yield 59%;
mp > 240 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d: 1.36 (m, 1H, CH2),
1H NMR (300 MHz, DMSO-d6)
d
: 7.14 (d, J ¼ 7.7 Hz, 1H, HAr), 7.17 (d,
1.55e1.90 (m, 5H, 3CH2), 2.93 (m, 2H, 2 NCH2), 3.29 (m, 2H, NCH2),
3.53 (m, 2H, 2 NCH2), 4.40 (t, J ¼ 7.0 Hz, 2H, CH2), 7.01 (tt, J ¼ 7.2 Hz,
J ¼ 8.4 Hz, 1H, H4), 7.40 (dd, J ¼ 8.0 Hz, J ¼ 7.7 Hz, 1H, HAr), 7.41e7.52
(m, 2H, HAr), 7.58 (dd, J ¼ 8.4 Hz, J ¼ 1.8 Hz, 1H, H5), 7.78 (d,

P.-E. Larchanche et al. / European Journal of Medicinal Chemistry 92 (2015) 807e817
815
J ¼ 8.0 Hz, 1H, HAr), 7.89 (m,1H, HAr), 7.96 (d, J ¼ 1.8 Hz,1H, H7), 8.04
2-one (1 g, 4 mmol) and naphthalen-1-ylamine (0.8 mL, 6 mmol).
The reaction mixture was stirred for 24 h and the solution evapo-
rated under reduced pressure. The resulting crude product was
washed with diethyl ether and CH2Cl2. Yield 16%; mp 216e217 ꢀC;
(m, 1H, HAr), 10.19 (br s, 1H, NH), 12.30 (br s, 1H, NH). 13C NMR
(75 MHz, DMSO-d6) d: 112.0 (CH),122.3 (CH),123.6 (CH),123.7 (CH),
124.5 (Caro), 126.0 (CH), 126.1 (CH), 126.5 (CH), 126.7 (CH), 127.2
(CH), 128.4 (CH), 129.9 (Caro), 132.8 (Caro), 134.3 (Caro), 134.4 (Caro),
140.2 (Caro), 170.7 (CO). LCMS (ESIꢂ): calc for [MꢂH]: 355.0; found:
355.0.
1H NMR (300 MHz, DMSO-d6)
d
: 7.05 (d, J ¼ 8.2 Hz,1H, H4), 7.52 (dd,
J ¼ 8.2 Hz, J ¼ 1.7 Hz, 1H, H5), 7.76 (d, J ¼ 1.7 Hz, 1H, H7), 8.03 (dd,
J ¼ 7.8 Hz, J ¼ 6.5 Hz, 2H, HAr), 8.55 (tt, J ¼ 7.8 Hz, J ¼ 1.5 Hz,1H, HAr),
8.91 (dd, J ¼ 6.5 Hz, J ¼ 1.5 Hz, 2H, HAr), 11.94 (s, 1H, NH). 13C NMR
5.1.9. 3-Methyl-2-oxo-2,3-dihydro-benzothiazole-6-sulfonic acid
naphthalen-1-ylamide 24
(75 MHz, DMSO-d6) d: 111.0 (CH), 120.6 (CH), 123.0 (Caro), 124.6
(CH), 127.6 (2CH), 136.8 (Caro), 142.8 (2CH), 143.5 (Caro), 146.6 (CH),
170.8 (CO).
To acetonitrile (10 mL) were added 2-oxo-2,3-dihydro-benzo-
thiazole-6-sulfonic acid naphthalen-1-ylamide (0.3 g, 0.9 mmol),
triethylamine (0.2 mL, 1.4 mmol) and methyl iodide (0.06 mL,
1.1 mmol). The reaction mixture was stirred at 20 ꢀC for 30 min. The
solution was stirred for 24 h and evaporated under reduced pres-
sure. The reaction was quenched with water (50 mL), the product
extracted with dichloromethane, and the organic layer evaporated
under reduced pressure. The product was purified by chromatog-
raphy on silica gel using dichloromethane/methanol (95/5, v/v).
5.1.12. General procedure for the synthesis of compounds 37e42
To CHCl3 (15 mL) were added 3-(2-alkyl or cyclo-
alkylaminoethyl)-3H-benzothiazol-2-one (1.1 mmol) and chlor-
osulfonic acid (0.3 mL, 5.8 mmol). The reaction mixture was
refluxed for 1 h. After cooling the mixture, the corresponding
arylamine (3.5 mmol) and Et3N (1.2 mL, 8.1 mmol) were added and
the mixture stirred at 20 ꢀC for 1 h. An aqueous solution of 1% so-
dium hydroxide (100 mL) was added. The solution was extracted
with dichloromethane, and the organic layer evaporated under
reduced pressure. The product was purified by chromatography on
silica gel using dichloromethane/methanol (98/2, v/v). The product
was solubilised in dry ethyl acetate and treated with gaseous hy-
drochloric acid in diethyl ether (20 mL). The precipitate obtained
was filtered and washed with ethyl acetate (2 ꢁ 20 mL) to afford
desired compound.
Yield 18%; mp 227e228 ꢀC; 1H NMR (300 MHz, acetone-d6)
d: 3.47
(s, 3H, NCH3), 7.32 (d, J ¼ 8.4 Hz, 1H, H4), 7.35 (dd, J ¼ 7.4 Hz,
J ¼ 1.4 Hz, 1H, HAr), 7.42 (dd, J ¼ 8.0 Hz, J ¼ 7.4 Hz, 1H, HAr),
7.42e7.53 (m, 2H, HAr), 7.74 (dd, J ¼ 8.4 Hz, J ¼ 1.9 Hz, 1H, H5), 7.81
(d, J ¼ 8.0 Hz, 1H, HAr), 7.90 (m, 1H, HAr), 7.99 (d, J ¼ 1.9 Hz, 1H, H7),
8.18 (m, 1H, HAr), 9.05 (br s, 1H, NH). 13C NMR (75 MHz, acetone-d6)
d: 28.7 (CH3), 110.8 (CH), 121.9 (CH), 122.6 (Caro), 122.9 (CH), 123.3
(CH), 125.4 (CH), 126.0 (CH), 126.1 (CH), 126.2 (CH), 127.0 (CH), 128.1
(CH), 129.7 (Caro), 132.5 (Caro), 134.5 (Caro), 134.8 (Caro), 141.3 (Caro),
168.9 (CO). LCMS (ESIþ): calc for [MꢂHþ]: 369.0; found: 369.0.
5.1.12.1. 3-(2-Dimethylaminoethyl)-2-oxo-2,3-dihydro-benzothia-
zole-6-sulfonic acid phenylamide hydrochloride 37. Yield 26%;
5.1.10. General procedure for the synthesis of compounds 25e26
To pyridine (20 mL) were added 6-chlorosulfonylbenzothiazol-
2-one (1 g, 4 mmol) and the corresponding arylamine derivative
(6 mmol). The reaction mixture was stirred at 20 ꢀC for 24 h. The
solution was evaporated under reduced pressure. The resulting
crude product was hydrolysed in aqueous HCl 5% (20 mL), extracted
with dichloromethane, and the organic layer evaporated under
reduced pressure. The precipitate obtained was recrystallised in the
appropriate solvent.
mp > 240 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
: 2.83 (d, J ¼ 2.8 Hz,
6H, N(CH3)2), 3.37 (m, 2H, NCH2), 4.37 (t, J ¼ 6.8 Hz, 2H, NCH2), 7.02
(tt, J ¼ 7.3 Hz, J ¼ 1.1 Hz, 1H, HAr), 7.15 (dd, J ¼ 8.4 Hz, J ¼ 1.1 Hz, 2H,
H
Ar), 7.24 (dd, J ¼ 8.4 Hz, J ¼ 7.3 Hz, 2H, HAr), 7.71 (d, J ¼ 8.7 Hz, 1H,
H4), 7.78 (dd, J ¼ 8.7 Hz, J ¼ 1.9 Hz, 1H, H5), 8.23 (d, J ¼ 1.9 Hz, 1H,
H7), 10.49 (s, 1H, NH), 10.74 (m, 1H, NHþ). 13C NMR (75 MHz, DMSO-
d6) d: 38.1 (CH2), 42.6 (2 CH3), 53.2 (CH2), 112.4 (CH), 120.2 (2 CH),
122.6 (CH), 123.1 (Caro), 124.4 (CH), 125.8 (CH), 129.7 (2 CH), 134.9
(Caro), 138.1 (Caro), 140.1 (Caro), 170.3 (CO). LCMS (ESIþ): calc for
[MþHþ]: 378.1; found: 377.8.
5.1.10.1. 2-Oxo-2,3-dihydro-benzothiazole-6-sulfonic acid methyl-
phenylamide 25. Yield 70% (absolute ethanol); mp 177e178 ꢀC; 1H
5.1.12.2. 2-Oxo-3-(2-pyrrolidin-1-ylethyl)-2,3-dihydro-benzothia-
NMR (300 MHz, DMSO-d6)
d
: 3.14 (s, 3H, CH3), 7.12 (m, 2H, HAr),
zole-6-sulfonic acid phenylamide hydrochloride 38. Yield 6%;
7.21 (d, J ¼ 8.4 Hz, 1H, H4), 7.25e7.38 (m, 4H, H5, HAr), 7.90 (d,
mp > 240 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d: 1.80 (m, 2H, 2 CH2),
J ¼ 1.9 Hz, 1H, H7), 12.37 (br s, 1H, NH). 13C NMR (75 MHz, DMSO-d6)
2.00 (m, 2H, 2 CH2), 3.06 (m, 2H, 2 NCH2), 3.46 (m, 2H, NCH2), 3.57
(m, 2H, 2 NCH2), 4.34 (t, J ¼ 6.5 Hz, 2H, NCH2), 7.02 (tt, J ¼ 7.2 Hz,
J ¼ 1.3 Hz, 1H, HAr), 7.14 (dd, J ¼ 8.6 Hz, J ¼ 1.3 Hz, 2H, HAr), 7.24 (dd,
J ¼ 8.6 Hz, J ¼ 7.2 Hz, 2H, HAr), 7.68 (d, J ¼ 8.6 Hz, 1H, H4), 7.77 (dd,
J ¼ 8.6 Hz, J ¼ 1.9 Hz, 1H, H5), 8.23 (d, J ¼ 1.9 Hz, 1H, H7), 10.45 (s, 1H,
d: 38.4 (CH3), 111.9 (CH), 123.0 (CH), 124.7 (Caro), 126.7 (CH), 126.8 (2
CH), 127.7 (CH), 129.4 (2 CH), 130.3 (Caro), 140.6 (Caro), 141.6 (Caro),
170.8 (CO). LCMS (ESIꢂ): calc for [MꢂHþ]: 319.0; found: 319.0.
5.1.10.2. 2-Oxo-2,3-dihydro-benzothiazole-6-sulfonic acid methyl-
NH), 10.76 (m, 1H, NHþ). 13C NMR (75 MHz, DMSO-d6)
d: 23.1 (2
naphthalen-1-yl amide 26. Yield 65% (absolute ethanol); mp
CH2), 39.2 (CH2), 50.6 (CH2), 53.6 (2 CH2), 112.3 (CH), 120.1 (2 CH),
122.6 (CH), 123.2 (Caro), 124.4 (CH), 125.7 (CH), 129.7 (2 CH), 134.8
(Caro), 138.1 (Caro), 140.2 (Caro), 170.3 (CO). LCMS (ESIþ): calc for
[MþHþ]: 404.1; found: 404.0.
219e220 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d: 3.25 (s, 3H, NCH3),
6.95 (dd, J ¼ 7.4 Hz, J ¼ 1.0 Hz, 1H, HAr), 7.30 (d, J ¼ 8.4 Hz, 1H, H4),
7.43 (dd, J ¼ 8.3 Hz, J ¼ 7.4 Hz, 1H, HAr), 7.55 (dd, J ¼ 8.4 Hz,
J ¼ 1.9 Hz, 1H, H5), 7.55e7.65 (m, 2H, HAr), 7.94 (d, J ¼ 8.3 Hz, 1H,
H
Ar), 7.99 (m, 1H, HAr), 8.08 (d, J ¼ 1.9 Hz, 1H, H7), 8.15 (m, 1H, HAr),
5.1.12.3. 2-Oxo-3-(2-piperidin-1-ylethyl)-2,3-dihydro-benzothiazole-
12.41 (br s, 1H, NH). 13C NMR (75 MHz, DMSO-d6)
d
: 40.1 (CH3),
6-sulfonic acid phenylamide hydrochloride 39. Yield 8%;
112.0 (CH), 123.3 (CH), 124.0 (CH), 124.9 (Caro), 125.3 (CH), 126.0
(CH), 127.0 (2 CH), 127.2 (CH), 128.5 (CH), 129.0 (CH), 131.2 (Caro),
132.1 (Caro), 134.6 (Caro), 138.5 (Caro), 140.8 (Caro), 170.9 (CO). LCMS
(ESIꢂ): calc for [MꢂHþ]: 369.0; found: 369.0.
mp > 240 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d: 1.36 (m, 1H, CH2),
1.62e1.86 (m, 5H, 3CH2), 2.93 (m, 2H, 2 NCH2), 3.29 (m, 2H, NCH2),
3.53 (m, 2H, 2 NCH2), 4.40 (t, J ¼ 7.0 Hz, 2H, NCH2), 7.01 (tt,
J ¼ 7.2 Hz, J ¼ 1.2 Hz, 1H, HAr), 7.14 (m, 2H, HAr), 7.23 (m, 2H, HAr),
7.71e7.80 (m, 2H, H4, H5), 8.22 (m, 1H, H7), 10.45 (s, 1H, NH), 10.58
5.1.11. 6-(Pyridinium-1-sulfonyl)-3H-benzothiazol-2-one chloride
(m, 1H, NHþ). 13C NMR (75 MHz, DMSO-d6)
d: 21.7 (CH2), 22.8 (2
27
CH2), 37.6 (CH2), 52.2 (CH2), 52.5 (2 CH2), 112.3 (CH), 120.1 (2 CH),
122.6 (CH), 123.1 (Caro), 124.4 (CH), 125.8 (CH), 129.7 (2 CH), 134.9
To pyridine (20 mL) were added 6-chlorosulfonylbenzothiazol-

816
P.-E. Larchanche et al. / European Journal of Medicinal Chemistry 92 (2015) 807e817
(Caro), 138.1 (Caro), 140.1 (Caro), 170.2 (CO). LCMS (ESIꢂ): calc for
of the drugs under study.
[MꢂHþ]: 416.1; found: 416.1.
The method was validated from saturation studies: 6 concen-
trations of [3H]-LSD were used to give final concentrations of
0.25e8 nM, and non-specific binding of [3H]-LSD was defined in the
5.1.12.4. 3-(2-Dimethylaminoethyl)-2-oxo-2,3-dihydro-benzothia-
zole-6-sulfonic acid naphthylamide hydrochloride 40. Yield 7%;
presence of 100 mM serotonin to determine the Kd and the Bmax.
mp > 240 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d: 2.62 (m, 6H,
N(CH3)2), 3.10 (m, 2H, NCH2), 4.25 (t, J ¼ 5.6 Hz, 2H, NCH2), 7.16 (dd,
5.2.2. Cell culture and cytotoxicity assay
The human neuroblastoma cell line (SY5Y) was cultured in
DMEM (Dulbecco's Modified Eagle Medium) (Gibco) supplemented
J ¼ 7.4 Hz, J ¼ 1.0 Hz, 1H, HAr), 7.39 (dd, J ¼ 8.2 Hz, J ¼ 7.4 Hz, 1H,
H
Ar), 7.42 - 7.53 (m, 2H, HAr), 7.58 (d, J ¼ 8.5 Hz, 1H, H4), 7.71 (dd,
J ¼ 8.5 Hz, J ¼ 1.9 Hz,1H, H5), 7.78 (dd, J ¼ 8.2 Hz, J ¼ 1.0 Hz,1H, HAr),
with 2 mM L-glutamine, 172 mM streptomycin, 100 IU/mL penicillin,
7.89 (m, 1H, HAr), 8.07 (m, 1H, HAr), 8.10 (d, J ¼ 1.9 Hz, 1H, H7), 10.35
1 mM non-essential amino acids and 10% (v/v) heat-inactivated
foetal bovine serum (Sigma Aldrich), and grown at 37 ꢀC in a hu-
midified incubator with 5% CO2.
Cells were seeded at 2000 cells per well onto 96-well plates in
DMEM medium. Cells were starved for 24 h to obtain synchronous
cultures, and were then incubated in culture medium that con-
tained various concentrations of test compounds, each dissolved in
less than 0.1% DMSO. After 72 h of incubation, cell growth was
estimated by the colorimetric MTT (thiazolyl blue tetrazolium
bromide) assay.
(m, 2H, NH, NHþ). 13C NMR (75 MHz, DMSO-d6)
d: 39.0 (CH2), 43.7
(2 CH3), 54.3 (CH2), 112.1 (CH), 122.5 (CH), 122.9 (Caro), 123.3 (CH),
123.6 (CH),125.9 (CH),126.0 (CH),126.5 (CH),126.7 (CH),127.1 (CH),
128.4 (CH), 129.8 (Caro), 132.8 (Caro), 134.4 (Caro), 135.2 (Caro), 140.2
(Caro), 170.2 (CO). LCMS (ESIþ): calc for [MþHþ]: 428.1; found:
428.0.
5.1.12.5. 2-Oxo-3-(2-pyrrolidin-1-ylethyl)-2,3-dihydro-benzothia-
zole-6-sulfonic acid naphthylamide hydrochloride 41. Yield 7%;
mp > 240 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d: 1.80 (m, 2H, 2 CH2),
2.00 (m, 2H, 2 CH2), 3.06 (m, 2H, 2 NCH2), 3.46 (m, 2H, NCH2), 3.57
Acknowledgements
(m, 2H, 2 NCH2), 4.35 (t, J ¼ 6.4 Hz, 2H, NCH2), 7.17 (d, J ¼ 7.4 Hz, 1H,
H
Ar), 7.40 (dd, J ¼ 8.2 Hz, J ¼ 7.4 Hz, 1H, HAr), 7.46e7.54 (m, 2H, HAr),
ꢀ
The 300 MHz NMR facilities were funded by the Region Nord-
Pas de Calais (France), the Ministere de la Jeunesse, de l’Education
Nationale et de la Recherche (MJENR), and the Fonds Europeen de
7.65 (d, J ¼ 8.6 Hz, 1H, H4), 7.74 (dd, J ¼ 8.6 Hz, J ¼ 1.8 Hz, 1H, H5),
7.79 (d, J ¼ 8.2 Hz, 1H, HAr), 7.90 (m, 1H, HAr), 8.11 (m, 1H, HAr), 8.14
(d, J ¼ 1.8 Hz, 1H, H7), 10.35 (s, 1H, NH), 10.72 (m, 1H, NHþ). 13C NMR
ꢁ
ꢀ
ꢀ
ꢀ
Developpement Regional (FEDER).
(75 MHz, DMSO-d6) d: 23.1 (2 CH2), 39.2 (CH2), 50.6 (CH2), 53.7 (2
CH2), 112.1 (CH), 122.6 (CH), 123.1 (Caro), 123.1 (CH), 123.6 (CH),
125.9 (CH),126.0 (CH),126.6 (CH),126.7 (CH),127.1 (CH),128.4 (CH),
129.8 (Caro), 132.8 (Caro), 134.4 (Caro), 135.4 (Caro), 140.0 (Caro), 170.4
(CO). LCMS (ESIþ): calc for [MþHþ]: 454.1; found: 454.0.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2015.01.052.
5.1.12.6. 2-Oxo-3-(2-piperidin-1-ylethyl)-2,3-dihydro-benzothiazole-
References
6-sulfonic acid naphthylamide hydrochloride 42. Yield 5%; mp
172e174 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d: 1.36 (m, 1H, CH2), 1.71
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