Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies

Article abstract of DOI:10.1016/j.ejmech.2012.02.049

The combination of antagonism at histamine H₃ receptor and the stimulation of insulin secretion have been proposed as an approach to new dual therapeutic agents for the treatment of type 2 diabetes mellitus associated with obesity. We have desi

Full text of DOI:10.1016/j.ejmech.2012.02.049

European Journal of Medicinal Chemistry 52 (2012) 1e13
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies
*
Javier Ceras, Nuria Cirauqui, Silvia Pérez-Silanes, Ignacio Aldana, Antonio Monge, Silvia Galiano
Unidad en Investigación y Desarrollo de Medicamentos, Centro de Investigación en Farmacobiología Aplicada (CIFA), Universidad de Navarra, c/Irunlarrea, 1,
E-31008 Pamplona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The combination of antagonism at histamine H3 receptor and the stimulation of insulin secretion have
been proposed as an approach to new dual therapeutic agents for the treatment of type 2 diabetes
mellitus associated with obesity. We have designed and synthesized a new series of non-imidazole
derivatives, based on a basic amine ring connected through an alkyl spacer of variable length to a phe-
noxysulfonylurea moiety. These compounds were initially evaluated for histamine H3 receptor binding
affinities, suggesting that a propoxy chain linker between the amine and the core ring could be essen-
tial for optimal binding affinity. Compound 56, 1-(naphthalen-1-yl)-3-[(p-(3-pyrrolidin-1-ylpropoxy)
benzene)]sulfonylurea exhibited the best H3 antagonism affinity. However, since all these derivatives
failed to block KATP channels, the link of these two related moieties should not be considered a good
pharmacophore for obtaining new dual H3 antagonists with insulinotropic activity, suggesting the
necessity to propose a new chemical hybrid prototype.
Received 14 January 2011
Received in revised form
24 February 2012
Accepted 25 February 2012
Available online 3 March 2012
Keywords:
Histamine H3 receptor
Obesity
Sulfonylurea
Type 2 diabetes mellitus
Ó 2012 Elsevier Masson SAS. All rights reserved.
1. Introduction
be useful for the treatment of a variety of CNS disorders affecting
cognition, sleep and energy homeostasis [12].
Obesity is one of today’s major health problems, affecting 400
million people throughout the world. Its alarming rising prevalence
and the health risks associated with this disease warrant obesity as
one of the most challenging therapeutic areas in the 21st century.
Closely linked to obesity is the wide spread increase of type 2
diabetes [1], emerging as a new epidemic: diabesity [2]. The lack of
efficacious drugs for this new disease makes this field one of the
most attractive targets.
The histamine H3 receptor has been known to play a critical role
in homeostasis regulatory functions, such as control of food intake
and maintenance of body weight [3]. The histamine H3 receptor is
an important G protein-coupled receptor, identified in 1983 by
Arrang et. al. [4] and cloned and characterized in 1999 [5]. The
histamine H3 receptor has been described as a presynaptic auto-
receptor [6e8] mainly expressed in the central nervous system
(CNS), regulating histamine biosynthesis and release, as well as
a heteroreceptor on non-histaminergic neurons, where it is capable
of inhibiting the release of other important neurotransmitters, such
as acetylcholine, noradrenaline, dopamine and serotonin [6,9e11].
The blockade of this negative feedback mechanism with histamine
H3 receptor antagonists/inverse agonists suggests that they would
Many classes of potent H3 receptor antagonists have been
reported in the reference literature. Imidazole-based compounds
such as ciproxifan, clobenpropit, thioperamide and SCH79687
[13e16] were the first published H3 receptor antagonists/inverse
agonists derived from the endogenous neurotransmitter histamine
andcontaining the classical structure in the form of an imidazole ring
connected by a spacer to a polar group, which is attached to a lipo-
philic end group [17]. The potential liability of imidazole-containing
compounds with respect to cytochrome P450 inhibition and
drugedrug interactions led to the development of potent and
selective non-imidazole derivatives, including compounds such
ABT-239, UCL 1972, JNJ-5207852, GSK-189254, Novo Nordisk’s and
Merck’s (Fig. 1) [18e22]. These intense efforts made by numerous
pharmaceutical companies led to the development of a new refined
H3 antagonist pharmacophore model which contains three parts:
a basic amine moiety (western part) able to interact with ASP3.32, an
amino acid of the receptor [23], linked via a variable alkyl spacer to
a central core, and an additional eastern part displaying a high
chemical diversity (Fig. 2) [24]. A chemical template containing these
structural features is depicted by the generic structure (Fig. 2), based
on a phenoxyalkylamine skeleton, common to the many reported
non-imidazole H3 antagonists shown in Fig. 1.
Stimulation of glucose-mediated insulin secretion has been the
first pharmacological approach for the treatment of type 2 diabetes
[25], heralded by the introduction of sulfonylureas in the anti-
diabetic pharmacopoeia more than 50 years ago. The sulfonylurea
Abbreviations: N.T., Not Tested; SEM, standard error of the media.
* Corresponding author. Tel.: þ34 948 425653; fax: þ34 948 425652.
E-mail address: sgaliano@unav.es (S. Galiano).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2012.02.049

2
J. Ceras et al. / European Journal of Medicinal Chemistry 52 (2012) 1e13
CN
NO2
N
N
O
N
N
O
O
N
CH3
ABT-239
UCL 1972
JNJ-5207852
N
N
O
CF3
O
N
NH
N
CF3
O
O
O
N
N
5s
GSK-189254
NNC 38-1202
Fig. 1. Non-imidazole histamine H3 receptor antagonists/inverse agonists.
receptor-1 (SUR1) is the molecular target for the sulfonylurea class
of anti-hyperglycemic drugs such as chlorpropamide [26], glipizide
[27], glimepiride [28], which have been widely used in the treat-
ment of type 2 diabetes mellitus and are maintained as the front-
line therapy in the most recent 2005 IDF Global Guidelines for
Type 2 Diabetes [29] (Fig. 3). These compounds are antagonists of
and KATP channel binding affinities and preliminary SAR of several
members of this novel series of non-imidazole derivatives.
Historically, many of the reported H3 antagonists have shown
substantial hERG channel inhibition which represents a potential
safety liability [30,31]. Drugs that block hERG have been associated
with QT interval prolongation as well as serious, and sometimes
fatal, cardiac arrhythmias (including torsade de pointes) [32].
Blockade of the hERG channel poses a risk of cardiac toxicity and
has become a critical issue for regulatory agencies and the phar-
maceutical industry [33]. This problem has recently been addressed
[34]. In an attempt to overcome hERG channel inhibition related to
H3 antagonists, we decided to evaluate all of the synthesized
compounds for the hERG ion channel inhibitory affinity.
the
b
-cell ATP-dependent Kþ channel (KATP) and they promote
insulin secretion. All of them share a phenylsulfonylurea group
with para-substitution on the phenyl ring in their structure.
Therefore, this sulfonylurea moiety was incorporated into our
molecules with the goal of providing antagonism of KATP channels
and anti-diabetic activity.
These observations suggested to us that the combination of H3
receptor antagonism and the stimulation of insulin secretion might
result in synergistic improvements in type 2 diabetes associated
with obesity. In this report, we describe our initial hit-finding
proposal towards new pharmacodynamic hybrids with dual
mechanisms of action. Our strategy towards these dual acting
compounds was the multiple target approach designing one new
drug by combining two related pharmacophore elements in one
structure (Fig. 4). This approach has been carried out by linking the
known H3R antagonist template to a phenylsulfonylurea moiety
(sulfonylurea drug structure related to the insulinotropic effect).
Based on this strategy and as part of our ongoing program to
develop new anti-obesity drugs, we report the synthesis, human H3
2. Chemistry
Forty-four sulfonylurea and ten sulfonamide derivatives were
synthesized using the four-step protocol outlined in Scheme 1.
Dropwise addition of chlorosulfonic acid to an ice-cooled solution
of the corresponding bromoalkoxyphenyl derivatives (1e3) dis-
solved in dichloromethane (DCM) gave chlorosulfonyl compounds
4e6, substituted only at the para position due to steric impedi-
ments ortho to the alkoxy group.
Conversion of derivatives 4e6 to the corresponding sulfon-
amides (7e9) was accomplished via treatment with ammonia in
Western part
Eastern part
2nd basic moiety
1st basic
moiety
Central
core
N
Polar group
Linker
Lipophilic residue
2nd basic moiety
Polar group
Lipophilic residue
N
O
n
Fig. 2. The H3 pharmacophore model and the derived chemical H3 antagonist template based on a phenoxyalkylamine skeleton.

J. Ceras et al. / European Journal of Medicinal Chemistry 52 (2012) 1e13
3
O
O
O
O
O
O
O
O
O
O
S
S
N
S
N
H
N
H
N
H
N
H
N
H
NH
N
H
O
O
N
Cl
N
N
H
Chlorpropamide
Glipizide
Glimepiride
3rd generation sulfonylurea
1st generation sulfonylurea
2nd generation sulfonylurea
Fig. 3. Some selective sulfonylureas for the treatment of type 2 diabetes.
dichloromethane (DCM) at 0 ꢀC. Condensation of amines with
compounds 7e9 under reflux in ethanol (EtOH) provided
compounds 10e19. Treatment of the resulting sulfonamides with
the appropriate isocyanates in acetone yielded the desired sulfo-
nylurea derivatives 20e64.
In general, compounds having a para-substituted phenyl group
in R showed better affinity to the human histamine H3 receptor
than the corresponding meta and ortho-substituted phenyl analogs.
The 4-trifluoromethylphenyl analog (compound 40) was signifi-
cantly more potent than compound 59 (10.40
(20.90 M) (6e12-fold improvement in potency).
mM) and 60
m
Comparing the different electronic effects caused by the substi-
tuents on the phenyl rest, no substantial differences were observed.
Steric effect seems to be more important for these compounds.
Compound 56, substituted with a 1-naphthyl group, was the
3. Results and discussion
The first objective of this preliminary study was to evaluate
the synthesized compounds as H3 receptor antagonists. Initially, we
synthesized a series of sulfonylurea derivatives with five different
substituents in the eastern part of the molecules in order to evaluate
the influence of the substituent on the urea rest. The substituents
were both aliphatic (isopropyl and cyclohexyl), and aromatic
(phenyl, 2,5-dichlorophenyl and 4-trifluoromethylphenyl). At the
same time, a series of sulfonamide derivatives was obtained as the
precursors of the sulfonylurea compounds. The in vitro H3 receptor
binding data for these compounds is summarized in Tables 1 and 2.
In general, compounds with an aromatic moiety for R exhibited
lower IC50 values than the aliphatic substituents, as exemplified by
entries 20 versus 21 and 31 versus 32. Among all of the aromatic
derivatives tested, compounds 32 and 37 were the most potent
most potent sulfonylurea for the H3 receptor with an IC50 ¼ 0.08
mM.
In addition, we examined the effects of these synthesized
compounds on the ATP-sensitive Kþ channel (KATP) channel. Unfor-
tunately, no KATP channel blocker activity was observed. Therefore,
these compounds are unlikely to play a role in the stimulation of
insulin secretion from pancreatic b-cells and consequently, we are
not able to assert that they could exert insulinotropic activity.
Furthermore, in the [3H]dofetilide membrane binding assay, all
of the sulfonylureas exhibited low affinity for the hERG channel. In
addition, we have observed that the sulfonylureas have less hERG
affinity than the corresponding sulfonamides.
In summary, in an approach to finding new dual therapeutic
agents for the treatment of type 2 diabetes associated with obesity,
we have designed and synthesized a new series of non-imidazole
H3 antagonists, based on a basic amine ring connected through
an alkyl spacer of variable length to a phenoxysulfonylurea moiety.
SAR was explored, indicating that a propoxy chain linker between
the amine and an aromatic ring is optimal in the binding to the H3
receptor. Compound 56, 1-(naphthalen-1-yl)-3-(p-(3-pyrrolidin-1-
ylpropoxy)benzene)sulfonylurea, exhibited the best H3 antago-
nism affinity. However, since all these derivatives did not block KATP
channels, the combination of these two related moieties should not
be considered a good pharmacophore for obtaining new dual H3
antagonists with insulinotropic activity, suggesting the necessity to
propose a new chemical hybrid prototype.
sulfonylureas, with IC50 ¼ 0.16 and 0.83
mM, respectively, at H3R.
Introduction of a propoxy chain linker between the basic amine
(pyrrolidine and piperidine) and the core ring led to an increase
in the H3 affinity (compounds 32 and 37). The shortening or
lengtheningof the chainlinkerresulted in asignificant lossofaffinity
(compounds 21 and 43 vs. 32). Introduction of an ethoxycarbonyl
group on the cyclic amine showed a dramatic loss of affinity.
Use of either pyrrolidine or piperidine as the basic amine on the
western part of molecule provided similar H3 affinity, as demons-
trated by compounds 32 and 37.
The sulfonamide intermediates, compounds 10e19, were first
screened as an early proof-of-concept. Many of these derivatives, as
well as their aromatic sulfonylurea derivatives, displayed good
affinity as H3 receptor antagonists. Although good H3 receptor
affinity was observed with sulfonamides 10e19, we were more
interested in compounds containing a sulfonylurea group since
these compounds have the potential for anti-diabetic activity.
In an attempt to improve the H3R in vitro affinity, further analogs
of the propoxy phenylsulfonylurea 32 and 37 were examined,
introducing different aromatic rests as R. The SAR of compounds
53e64 is summarized in Table 3.
4. Experimental protocols
4.1. General methods
All reagents and solvents were purchased from commercial
sources. E. Merck (Darmstadt, Germany), Scharlau (F E R.O.S.A.,
Barcelona, Spain), Panreac Química S.A. (Montcada
i Reixac,
sulfonylurea moiety for
anti-diabetic drugs
H receptor antagonism
3
template
O
S
O
O
O
O
O
R
S
R
N
N
H
N
N
H
H
H
N
N
O
O
n
n
proposed general structure for compounds
with dual activity as H receptor antagonists
3
and KATP blockers
Fig. 4. Drug design of the general structure for a new dual H3 receptor antagonist and KATP channel inhibitor.

4
J. Ceras et al. / European Journal of Medicinal Chemistry 52 (2012) 1e13
O
NH2
O
O
O
S
S
a
b
Cl
Br
Br
Br
O
O
O
n
n
n
1-3
4-6
7-9
c
O
O
O
O
O
S
S
R
d
N
H
N
NH2
H
A
A
N
N
O
O
n
n
10-19
20-64
Scheme 1. Reagents and conditions: (a) chlorosulfonic acid, DCM, ꢁ10 ꢀC, 2 h, 60%; (b) NH3, DCM, 0 ꢀC, 1 h, 78%; (c) pyrrolidine, EtOH, reflux, 20 h, 86%; (d) i) acetone, 10% NaOH,
10 min; ii) acetone, phenyl isocyanate, reflux, 4 h, 71% in two steps.
Barcelona, Spain), SigmaeAldrich Química, S.A., (Alcobendas,
Madrid), Acros Organics (Janssen Pharmaceuticalaan 3a, 2440 Geel,
België), and Lancaster (Bischheim-Strasbourg, France).
Melting points were determined with a Mettler FP82 þ FP80
apparatus (Greifense, Switzerland) and have not been corrected.
The 1H NMR spectra were recorded on a Bruker 400 UltrashieldÔ
(Bruker BioSpin GmbH, Rheinstetten, Germany), using TMS as the
internal standard and DMSO-d6 as the solvent; the chemical shifts
(strong), m (medium), and w (weak). Elemental micro-analyses
were obtained on an Elemental Analyzer LECO CHN-900 (Michi-
gan, USA) from vacuum-dried samples. The analytical results for C,
H, and N were within ꢂ0.4 of the theoretical values. Mass spectra
were measured on an Agilent Technologies Model MSD/DS 5973N
(mod. G2577A) mass spectrometer with direct insertion probe
(DIP) (Waldbronn, Germany) and the ionization method was elec-
tron impact (EI, 70 eV).
(
d
) are reported in ppm and the coupling constant (J) values are
The progress of the reactions was followed by thin-layer chro-
matography and silica gel 60 (0.040e0.063 mm) AlugramÒ SIL G/
UV254 (Layer: 0.2 mm) (MachereyeNagel GmbH & Co. KG. Postfach
101352. D-52313 Düren, Germany). Flash column chromatography
was carried out using flash silica gel (Merck, Germany).
given in Hertz (Hz). Signal multiplicities are represented by: s
(singlet), bs (broad singlet), d (doublet), dd (double doublet), t
(triplet), q (quadruplet), and m (multiplet). Infrared spectra (IR)
were recorded on Thermo Nicolet FT-IR Nexus Euro (Madison, USA)
using potassium bromide pellets for solid products and sodium
chloride plates for oil products; the frequencies are expressed in
cmꢁ1. Signal intensities are expressed by: vs (very strong), s
4.2. General procedure for the preparation of 4-(bromoalkoxy)
benzenesulfonyl chloride derivatives (4e6)
Table 1
Chlorosulfonic acid (20.00 mmol) was added dropwise to an ice-
salt bath solution of the appropriate bromoalkoxyphenyl (1e3)
(10.00 mmol) dissolved in dichloromethane (25 ml) at ꢁ10 ꢀC.
After stirring for 2 h, the reaction mixture was allowed to warm to
room temperature, and was stirred for an additional hour. The
reaction mixture was then poured into 200 g of cracked ice and
extracted with dichloromethane. The organic layer was washed
with brine, dried over anhydrous sodium sulfate and filtered. The
solvent was removed under reduced pressure to afford the
corresponding 4-(bromoalkoxy)benzenesulfonyl chloride deriva-
tives (4e6).
Binding affinities of sulfonamide derivatives (10e19) at histamine H3 receptor and
hERG channel.
O
O
S
NH2
A
N
O
n
4.2.1. 4-(2-bromoethoxy)benzenesulfonyl chloride (4)
a
Compound
n
A
H3R IC50
hERG
IC50
>102
White solid. Yield: 60%. M.p.: 51e53 ꢀC. IR (KBr, cmꢁ1): 1374 (s,
b
(
m
M) ꢂ SEM
(
m
M)
nSO2N); 1258 (s, nCeOeC). 1H NMR (400 MHz, DMSO-d6)
d
ppm: 3.70
10
11
12
13
14
15
16
17
18
19
1
1
1
2
2
2
2
3
3
3
pyrrolidine
piperidine
7.06 ꢂ 2.42
(t, 2H, BreCH2, JCH2eCH2
¼
6.1 Hz); 4.42 (t, 2H, OeCH2,
10.00 ꢂ 8.96 24.00
ethyl piperidine-4-carboxylate >104
22.90
N.T.
JCH2eCH2 ¼ 6.1 Hz); 7.09 (d, 2H, H3þH5, J3,5-2,6 ¼ 9.1 Hz); 8.02 (d,
2H, H2þH6, J2,6-3,5 ¼ 9.0 Hz). Anal. Calcd for C8H8BrClO3S: C, 32.06%;
H, 2.67%; N, 0.00%. Found: C, 32.19%; H, 2.60%; N, 0.00%.
pyrrolidine
piperidine
0.25 ꢂ 0.50
0.13 ꢂ 0.33
93.20
76.50
N.T.
ethyl piperidine-4-carboxylate >104
morpholine
pyrrolidine
piperidine
0.40
0.70 ꢂ 0.39
>102
13.60
18.80
4.2.2. 4-(3-bromopropoxy)benzenesulfonyl chloride (5)
Rose solid. Yield: 62%. M.p.: 47e50 ꢀC. IR (KBr, cmꢁ1): 1370 (vs,
0.39 ꢂ 0.14
ethyl piperidine-4-carboxylate >104
nSO2N); 1264 (s, nCeOeC). 1H NMR (400 MHz, DMSO-d6)
d ppm:
SEM is the standard error of the mean. n is the number of experiments. N.T, not
2.21e2.25 (m, 2H, BreCH2eCH2); 3.64 (t, 2H, BreCH2,
JCH2eCH2 ¼ 6.5 Hz); 4.07 (t, 2H, OeCH2, JCH2eCH2 ¼ 6.0 Hz); 6.90
(d, 2H, H3þH5, J3,5-2,6 ¼ 8.8 Hz); 7.55 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.8 Hz).
Anal. Calcd for C9H10BrClO3S: C, 34.46%; H, 3.19%; N, 0.00%. Found:
C, 34.77%; H, 3.16%; N, 0.00%.
tested.
a
All experiments were performed in duplicate (n ¼ 2).
b
hERG1(h)/[3H]Dofetilide/HEK293 IC50 is the concentration of antagonist that
displaces 50% of [3H]Dofetilide in a competitive binding assay. All experiments were
performed in duplicate (n ¼ 2).

J. Ceras et al. / European Journal of Medicinal Chemistry 52 (2012) 1e13
5
Table 2
Binding affinities of sulfonylurea derivatives (20e52) at histamine H3 receptor and hERG channel.
O
O
O
S
R
N
H
N
H
A
N
O
n
a
b
Compound
n
A
R
H3R IC50
>105
(m
M) ꢂ SEM
hERG IC50 (mM)
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
3
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
piperidine
piperidine
piperidine
piperidine
piperidine
ethyl piperidine-4-carboxylate
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
piperidine
piperidine
piperidine
piperidine
piperidine
ethyl piperidine-4-carboxylate
pyrrolidine
pyrrolidine
isopropyl
phenyl
cyclohexyl
2,5-dichlorophenyl
4-trifluoromethylphenyl
isopropyl
phenyl
cyclohexyl
2,5-dichlorophenyl
4-trifluoromethylphenyl
phenyl
isopropyl
phenyl
cyclohexyl
2,5-dichlorophenyl
4-trifluoromethylphenyl
isopropyl
phenyl
cyclohexyl
>102
>102
>102
>102
>102
26.10
27.60
>102
>102
>102
>102
>102
N.T.
88.60 ꢂ 3.40
>104
>104
107.00 ꢂ 2.87
16.60 ꢂ 6.36
10.00 ꢂ 2.75
53.80 ꢂ 15.50
93.60
82.00 ꢂ 2.24
77.90 ꢂ 18.00
13.40 ꢂ 2.63
0.164 ꢂ 0.24
6.06 ꢂ 0.62
8.31 ꢂ 1.45
16.50 ꢂ 2.57
1.33 ꢂ 0.52
0.83 ꢂ 0.004
N.T.
2.57 ꢂ 0.91
1.74 ꢂ 0.08
91.10 ꢂ 6.53
19.60 ꢂ 4.26
18.00 ꢂ 5.20
29.90 ꢂ 4.49
17.50 ꢂ 3.24
22.60 ꢂ 1.65
18.50 ꢂ 1.17
4.85 ꢂ 3.50
>104
>102
>102
>102
>102
>102
N.T.
2,5-dichlorophenyl
4-trifluoromethylphenyl
phenyl
isopropyl
phenyl
>102
>102
78.70
>102
>102
>102
>102
49.10
>102
>102
>102
>102
>102
>102
pyrrolidine
pyrrolidine
pyrrolidine
piperidine
piperidine
piperidine
piperidine
piperidine
cyclohexyl
2,5-dichlorophenyl
4-trifluoromethylphenyl
isopropyl
phenyl
cyclohexyl
2,5-dichlorophenyl
4-trifluoromethylphenyl
phenyl
13.20 ꢂ 5.62
10.00 ꢂ 1.70
>105
ethyl piperidine-4-carboxylate
SEM is the standard error of the mean. n is the number of experiments. N.T., not tested.
a
All experiments were done in duplicate (n ¼ 2).
b
hERG1(h)/[3H]Dofetilide/HEK293 IC50 is the concentration of antagonist that displaces 50% of [3H]Dofetilide in a competitive binding assay. All experiments were done in
duplicate (n ¼ 2).
4.2.3. 4-(4-bromobutoxy)benzenesulfonyl chloride (6)
2H, OeCH2, JCH2eCH2 ¼ 5.4 Hz); 7.12 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.9 Hz);
7.22 (s, 2H, NH2); 7.76 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.9 Hz). Anal. Calcd
for C8H10BrNO3S: C, 34.54%; H, 3.60%; N, 5.04%. Found: C, 34.42%; H,
3.36%; N, 4.69%.
Beige oil. Yield: 56%. IR (NaCl, cmꢁ1): 1370 (s, nSO2N); 1261 (s,
nCeOeC). 1H NMR (400 MHz, DMSO-d6)
d ppm: 2.03e2.10 (m, 4H,
BreCH2eCH2eCH2); 3.52 (t, 2H, BreCH2, JCH2eCH2 ¼ 6.3 Hz); 4.13 (t,
2H, OeCH2, JCH2eCH2 ¼ 5.8 Hz); 7.05 (d, 2H, H3þH5, J3,5-2,6 ¼ 9.0 Hz);
7.99 (d, 2H, H2þH6, J2,6-3,5 ¼ 9.0 Hz).
4.3.2. 4-(3-bromopropoxy)benzenesulfonamide (8)
White solid. Yield: 90%. M.p: 110e112 ꢀC. IR (KBr, cmꢁ1): 3401
4.3. General procedure for the preparation of 4-(bromoalkoxy)
(m, nNH2); 1333 (vs, nSO2N); 1262 (vs, nCeOeC). 1H NMR (400 MHz,
benzenesulfonamide derivatives (7e9)
DMSO-d6)
d
ppm: 2.27 (q, 2H, BreCH2eCH2, JCH2eCH2 ¼ 6.3 Hz and
JCH2eCH2 ¼ 6.2 Hz); 3.68 (t, 2H, BreCH2, JCH2eCH2 ¼ 6.5 Hz); 4.16 (t,
2H, OeCH2, JCH2eCH2 ¼ 6.0 Hz); 7.11 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.8 Hz);
7.22 (s, 2H, NH2); 7.75 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.8 Hz). Anal. Calcd
for C9H12BrNO3S: C, 37.00%; H, 4.11%; N, 4.80%. Found: C, 37.10%; H,
3.98%; N, 4.70%.
The corresponding 4-(bromoalkoxy)benzenesulfonyl chloride
(4e6) (30.00 mmol) was dissolved in 80 ml of dichloromethane and
cooled to 0 ꢀC. Next, the reaction mixture was stirred under
ammonia gas atmosphere for 45 min. The obtained precipitate was
filtered off and the solvent was removed under vacuum to yield 4-
(bromoalkoxy)benzenesulfonamide derivatives (7e9).
4.3.3. 4-(4-bromobutoxy)benzenesulfonamide (9)
Beige oil. Yield: 66%. IR (NaCl, cmꢁ1): 3354 (vs, nNeH); 1321 (vs,
4.3.1. 4-(2-bromoethoxy)benzenesulfonamide (7)
nSO2N); 1251 (s, nCeOeC). 1H NMR (400 MHz, DMSO-d6)
d ppm:
White solid. Yield: 78%. M.p: 112e114 ꢀC. IR (KBr, cmꢁ1): 3338
1.97e2.12 (m, 4H, BreCH2eCH2eCH2); 3.61 (t, 2H, BreCH2,
JCH2eCH2 ¼ 6.0 Hz); 4.09 (t, 2H, OeCH2, JCH2eCH2 ¼ 6.3 Hz); 4.81
(s, 2H, NH2); 7.08 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.9 Hz); 7.74 (d, 2H,
(vs, nNH2); 1388 (vs, nSO2N); 1296 (vs, nCeOeC). 1H NMR (400 MHz,
DMSO-d6)
d
ppm: 3.83 (t, 2H, BreCH2, JCH2eCH2 ¼ 5.4 Hz); 4.41 (t,

6
J. Ceras et al. / European Journal of Medicinal Chemistry 52 (2012) 1e13
Table 3
Binding affinities of sulfonylurea derivatives (53e64) at histamine H3 receptor and hERG channel.
O
O
O
S
R
N
H
N
H
A
N
O
n
a
Compound
n
A
R
H3R IC50
M) ꢂ SEM
hERG
IC50
b
(
m
(
mM)
53
54
55
56
57
58
59
60
61
62
63
64
2
2
2
2
2
2
2
2
2
2
2
2
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
piperidine
piperidine
piperidine
piperidine
piperidine
piperidine
3-trifluoromethylphenyl
4-acetylphenyl
4-methylphenyl
1-naphthyl
4-(dimethylamino)-phenyl
benzhydryl
2-trifluoromethylphenyl
3-trifluoromethylphenyl
4-methoxyphenyl
4-acetylphenyl
11.80 ꢂ 2.60
>102
>102
>102
>102
>102
N.T.
0.40
0.32
0.08
0.50
0.50
10.40 ꢂ 1.12
20.90 ꢂ 0.97
29.80 ꢂ 1.19
0.32
0.40
0.50
>102
N.T.
>102
>102
>102
>102
4-methylphenyl
benzhydryl
SEM is the standard error of the mean. n is the number of experiments. N.T., no tested.
a
All experiments were done in duplicate (n ¼ 2).
b
hERG1(h)/[3H]Dofetilide/HEK293 IC50 is the concentration of antagonist that displaces 50% of [3H]Dofetilide in a competitive binding assay. All experiments were done in
duplicate (n ¼ 2).
H2þH6, J2,6-3,5 ¼ 8.9 Hz). Anal. Calcd for C10H14BrNO3S: C, 38.96%; H,
4.4.3. 4-{2-[(4-ethoxycarbonyl)piperidin-1-yl]ethoxy}
benzenesulfonamide (12)
4.54%; N, 4.54%. Found: C, 39.02%; H, 4.41%, N, 4.45%
White solid. Yield: 85%. M.p: 129e132 ꢀC. IR (KBr, cmꢁ1): 3296
(s, nNeH); 1727 (vs, nC]O); 1327 and 1156 (vs, nSO2N); 1260 (s,
4.4. General procedure for the preparation of 4-(aminealkoxy)
benzenesulfonamide derivatives (10e19)
nCeOeC). 1H NMR (400 MHz, DMSO-d6)
d ppm: 1.17 (t, 3H, CH3,
JCH3eCH2 ¼ 7.1 Hz); 1.51e1.61 (m, 2H, H3eqþH5eq-pip); 1.79 (d, 2H,
The appropriate amine (31.50 mmol) was added to the corres-
ponding 4-(bromoalkoxy)benzenesulfonamide (7e9) (9.00 mmol)
dissolved in 25 ml of ethanol. The mixture reaction was heated
under reflux for 20 h. The solvent was removed under reduced
pressure and the obtained residue was dissolved in dichloro-
methane and quenched with water. The organic phase was dried
with anhydrous sodium sulfate and filtered. The solvent was
removed in vacuo and the resultant solid was precipitated with
diethyl ether in order to obtain 4-(aminealkoxy)benzenesulfona-
mide derivatives (10e19).
H3axþH5ax-pip); 2.11 (t, 2H, H2eqþH6eq-pip); 2.24e2.31 (m, 1H, H4-
pip); 2.69 (t, 2H, NeCH2, JCH2eCH2 ¼ 5.8 Hz); 2.87 (d, 2H, H2axþH6ax
-
pip); 4.06 (q, 2H, CH3-CH2, JCH2eCH3 ¼ 7.1 Hz); 4.14 (t, 2H, OeCH2,
JCH2eCH2 ¼ 5.8 Hz); 7.09 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.8 Hz); 7.20 (s,
2H, NH2); 7.74 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.7 Hz). Anal. Calcd for
C16H24N2O5S: C, 53.93%; H, 6.74%; N, 7.86%. Found: C, 53.90%; H,
6.82%; N, 7.57%.
4.4.4. 4-[(3-(pyrrolidin-1-yl)propoxy)]benzenesulfonamide (13)
White solid. Yield: 55%. M.p: 163e165 ꢀC. IR (KBr, cmꢁ1): 3293
(s, nNeH); 1255 (s, nCeOeC); 1153 (vs, nSO2N). 1H NMR (400 MHz,
4.4.1. 4-[(2-(pyrrolidin-1-yl)ethoxy)]benzenesulfonamide (10)
White solid. Yield: 86%. M.p: 130e135 ꢀC. IR (KBr, cmꢁ1): 3299
(m, nNeH); 1321 and 1154 (vs, nSO2N); 1262 (s, nCeOeC). 1H NMR
DMSO-d6)
d
ppm: 1.67 (d, 4H, H3þH4-pyr); 1.89 (bs, 2H,
NeCH2eCH2); 2.40e2.45 (m, 4H, H2þH5-pyr); 2.51e2.55 (m, 2H,
NeCH2); 4.09 (t, 2H, OeCH2, JCH2eCH2 ¼ 5.9 Hz); 7.07 (d, 2H, H3þH5,
J3,5-2,6 ¼ 8.9 Hz); 7.19 (s, 2H, NH2); 7.74 (d, 2H, H2þH6, J2,6-
(400 MHz, DMSO-d6)
d
ppm: 1.58e1.69 (m, 4H, H3þH4-pyr);
2.49e2.54 (m, 4H, H2þH5-pyr); 2.80 (t, 2H, NeCH2,
JCH2eCH2 ¼ 6.0 Hz); 4.15 (t, 2H, OeCH2, JCH2eCH2 ¼ 6.0 Hz); 6.96
(d, 2H, H3þH5, J3,5-2,6 ¼ 8.9 Hz); 7.20 (s, 2H, NH2); 7.85 (d, 2H,
H2þH6, J2,6-3,5 ¼ 8.9 Hz). Anal. Calcd for C12H18N2O3S$ ½ H2O: C,
51.61%; H, 6.81%; N, 10.03%. Found: C, 52.00%; H, 6.73%; N, 9.79%.
¼ 8.9 Hz) ppm. Anal. Calcd for C13H20N2O3S $1/6H2O: C, 54.35%;
3,5
H, 6.97%; N, 9.75%. Found: C, 54.49%; H, 6.93%; N, 9.44%. MS (EI,
70eV): m/z (%) ¼ 284 ([M$]þ, 10); 110 (5); 84 (100).
4.4.5. 4-[(3-(piperidin-1-yl)propoxy)]benzenesulfonamide (14)
Beige solid. Yield: 83%. M.p: 160e162 ꢀC. IR (KBr, cmꢁ1): 3288
(m, nNeH); 1325 and 1158 (vs, nSO2N); 1255 (vs, nCeOeC). 1H
4.4.2. 4-[(2-(piperidin-1-yl)ethoxy)]benzenesulfonamide (11)
White solid. Yield: 64%. M.p: 139e141 ꢀC. IR (KBr, cmꢁ1): 3292
(m, nNeH); 1326 and 1146 (s, nSO2N); 1257 (s, nCeOeC). 1H NMR
NMR (400 MHz, DMSO-d6)
d ppm: 1.38 (d, 2H, H4-pip); 1.47e1.52
(m, 4H, H3þH5-pip); 1.84e1.90 (m, 2H, NeCH2eCH2); 2.34e2.40
(m, 6H, H2þH6-pip and NeCH2); 4.07 (t, 2H, OeCH2,
JCH2eCH2 ¼ 6.4 Hz); 7.08 (d, 2H, H3þH5, J3,5-2,6 ¼ 6.8 Hz); 7.19
(bs, 2H, NH2); 7.72e7.74 (m, 2H, H2þH6). Anal. Calcd for
C14H22N2O3S: C, 56.38%; H, 7.38%; N, 9.40%. Found: C, 56.61%; H,
7.21%; N, 9.01%. MS (EI, 70eV): m/z (%) ¼ 298 ([M$]þ, 14); 124 (5);
113 (2); 98 (100).
(400 MHz, DMSO-d6) d ppm: 1.39 (t, 2H, H4-pip); 1.47e1.52 (m, 4H,
H3þH5-pip); 2.41e2.45 (m, 4H, H2þH6-pip); 2.67 (t, 2H, NeCH2,
JCH2eCH2 ¼ 5.9 Hz); 4.14 (t, 2H, OeCH2, JCH2eCH2 ¼ 5.9 Hz); 7.09
(d, 2H, H3þH5, J3,5-2,6 ¼ 8.9 Hz); 7.21 (bs, 2H, NH2); 7.73 (d, 2H,
H2þH6, J2,6-3,5 ¼ 8.9 Hz). Anal. Calcd for C13H20N2O3S$ 2/3H2O: C,
52.70%; H, 7.09%; N, 9.46%. Found: C, 52.57%; H, 6.64%; N, 9.08%.

J. Ceras et al. / European Journal of Medicinal Chemistry 52 (2012) 1e13
7
4.4.6. 4-{3-[(4-ethoxycarbonyl)piperidin-1-yl]propoxy}
benzenesulfonamide (15)
was added dropwise and the mixture was stirred at reflux for 4 h.
The solvent was concentrated to dryness in vacuo and the obtained
residue was purified by flash column chromatography (CH2Cl2/
MeOH 95:5) in order to afford 20e64 derivatives.
White solid. Yield: 96%. M.p: 153e155 ꢀC. IR (KBr, cmꢁ1): 3326
(m, nNeH); 1727 (vs, nC]O); 1327 (vs, nSO2N); 1260 (s, nCeOeC).1H NMR
(400 MHz, DMSO-d6)
d
ppm: 1.17 (t, 3H, CH3, JCH3eCH2 ¼ 7.1 Hz); 1.55
(t, 2H, NeCH2eCH2); 1.78 (d, 2H, H3eqþH5eq-pip); 1.87 (t, 2H,
H3axþH5ax-pip); 1.96 (t, 2H, H2eqþH6eq-pip); 2.27 (s, 1H, H4-pip);
2.40 (t, 2H, NeCH2, JCH2eCH2 ¼ 7.0 Hz); 2.79 (d, 2H, H2axþH6ax-pip);
4.03e4.08 (m, 4H, CH3eCH2 and OeCH2); 7.07 (d, 2H, H3þH5,
4.5.1. 1-Isopropyl-3-[4-(2-pyrrolidin-1-ylethoxy)benzene]
sulfonylurea (20)
White solid. Yield: 53%. M.p: 73e75 ꢀC. IR (KBr, cmꢁ1): 3374 (w,
nNeH); 1704 (s, nC]O); 1326 and 1119 (s, nSO2N); 1249 (vs, nCeOeC). 1H
J3,5-2,6
¼
8.8 Hz); 7.20 (s, 2H, NH2); 7.73 (d, 2H, H2þH6,
NMR (400 MHz, DMSO-d6) d ppm: 1.00 (d, 6H, (CH3)2CH,
J2,6-3,5 ¼ 8.8 Hz). Anal. Calcd for C17H26N2O5S: C, 55.14%; H, 7.03%; N,
JCH3eCH ¼ 6.5 Hz); 1.72 (bs, 4H, H3þH4-pyr); 2.66 (bs, 4H, H2þH5-
pyr); 2.94 (t, 2H, NeCH2, JCH2eCH2 ¼ 5.6 Hz); 3.53e3.62 (m, 2H,
(CH3)2CH and NHeSO2); 4.19 (t, 2H, OeCH2, JCH2eCH2 ¼ 5.6 Hz); 6.25
7.57%. Found: C, 54.76%; H, 7.24%; N, 7.24%.
4.4.7. 4-(3-morpholinopropoxy)benzenesulfonamide (16)
(d, 1H, NHeCH, JNHeCH
¼ 7.2 Hz); 7.10 (d, 2H, H3þH5,
White solid. Yield: 37%. M.p: 153e155 ꢀC. IR (KBr, cmꢁ1): 3327
J3,5-2,6 ¼ 8.8 Hz); 7.80 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.8 Hz). Anal. Calcd for
C16H25N3O4S.1/2H2O: C, 52.75%; H, 7.14%; N, 11.54%. Found: C,
53.01%; H, 7.30%; N, 11.31%.
(m, nNeH); 1304 and 1156 (vs, nSO2N); 1260 (s, nCeOeC). 1H NMR
(400 MHz, DMSO-d6)
d ppm: 1.86e1.92 (m, 2H, NeCH2eCH2);
2.36e2.43 (m, 6H, H3þH5-morp and NeCH2); 3.56e3.58 (m, 4H,
H2þH6-morp); 4.08 (t, 2H, OeCH2, JCH2eCH2 ¼ 8.9 Hz); 7.12 (d, 2H,
H3þH5, J3,5-2,6 ¼ 8.9 Hz); 7.20 (s, 2H, NH2); 7.74 (d, 2H, H2þH6,
J2,6-3,5 ¼ 8.9 Hz). Anal. Calcd for C13H20N2O4S: C, 52.00%; H, 6.67%;
N, 9.33%. Found: C, 52.10%; H, 6.89%; N, 9.32%.
4.5.2. 1-Phenyl-3-[4-(2-pyrrolidin-1-ylethoxy)benzene]
sulfonylurea (21)
White solid. Yield: 71%. M.p: 103e104 ꢀC. IR (KBr, cmꢁ1): 3350
(w, nNeH); 1717 (s, nC]O); 1312 and 1131 (s, nSO2N); 1241 (vs,
nCeOeC). 1H NMR (400 MHz, DMSO-d6)
d
ppm: 1.87 (t, 4H, H3þH4-
4.4.8. 4-[(4-(pyrrolidin-1-yl)butoxy)]benzenesulfonamide (17)
White solid. Yield: 45%. M.p: 142 ꢀC. IR (KBr, cmꢁ1): 3280 (s,
nNeH); 1260 (s, nCeOeC); 1150 (vs, nSO2N). 1H NMR (400 MHz, DMSO-
pyr); 3.15 (s, 4H, H2þH5-pyr); 3.40 (t, 2H, NeCH2,
JCH2eCH2 ¼ 5.0 Hz); 3.69 (s, 1H, NHeSO2); 4.28 (t, 2H, OeCH2,
JCH2eCH2 ¼ 5.6 Hz); 6.81 (t, 1H, H4-ph-NH, J4-3, ¼ 7.2 Hz); 7.01
5
d6)
d
ppm: 1.54e1.61 (m, 2H, NeCH2eCH2); 1.67 (d, 4H, H3þH4-
(d, 2H, H3þH5, J3,5-2,6 ¼ 8.6 Hz); 7.13 (t, 2H, H3þH5-ph-NH
,
pyr); 1.72e1.76 (m, 2H, OeCH2eCH2); 2.38e2.42 (m, 6H, H2þH5-
pyr and NeCH2); 4.05 (t, 2H, OeCH2, JCH2eCH2 ¼ 6.3 Hz); 7.07 (d, 2H,
H3þH5, J3,5-2,6 ¼ 8.5 Hz); 7.20 (s, 2H, NH2); 7.74 (d, 2H, H2þH6, J2,6-
J3,5-2,6 ¼ 7.8 Hz); 7.38 (d, 2H, H2 þ H6-ph-NH, J2,6-3,5 ¼ 8.4 Hz); 7.79
(d, 2H, H2þH6, J2,6-3,5 ¼ 8.7 Hz); 9.52 (s, 1H, NH-ph). Anal. Calcd for
C19H23N3O4S.1/2H2O: C, 57.29%; H, 6.03%; N, 10.55%. Found: C,
57.32%; H, 6.05%; N, 10.35%.
¼ 8.1 Hz). Anal. Calcd for C14H22N2O3S $ ½ H2O: C, 54.73%; H,
3,5
7.49%; N, 9.10%. Found: C, 55.12%; H, 7.29%; N, 8.84%.
4.5.3. 1-Cyclohexyl-3-[4-(2-pyrrolidin-1-ylethoxy)benzene]
sulfonylurea (22)
4.4.9. 4-[(4-(piperidin-1-yl)butoxy)]benzenesulfonamide (18)
White solid. Yield: 55%. M.p: 147e149 ꢀC. IR (KBr, cmꢁ1): 3290 (vs,
nNeH); 1325 and 1157 (s, nSO2N); 1259 (s, nCeOeC). 1H NMR (400 MHz,
White solid. Yield: 10%. M.p: 87e88 ꢀC. IR (KBr, cmꢁ1): 3371 (w,
nNeH); 1595 (s, nC]O); 1356 and 1123 (s, nSO2N); 1251 (vs, nCeOeC). 1H
DMSO-d6)
d
ppm: 1.37e1.38 (m, 2H, H4-pip); 1.46e1.49 (m, 4H,
NMR (400 MHz, DMSO-d6)
d
ppm: 1.07e1.13 (m, 4H, H3þH5-cyc); 1.21
H3þH5-pip); 1.54e1.59 (m, 2H, NeCH2eCH2); 1.69e1.76 (m, 2H,
OeCH2eCH2); 2.27e2.31 (m, 6H, H2þH6-pip and NeCH2); 4.01e4.05
(m, 2H, OeCH2);7.06 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.8 Hz); 7.19 (s, 2H, NH2);
7.74 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.8 Hz). Anal. Calcd for C15H24N2O3S: C,
57.69%; H, 7.69%; N, 8.97%. Found: C, 57.39%; H, 7.49%; N, 8.61%.
(d,1H, H4eq-cyc);1.49(d,1H, H4ax-cyc);1.57e1.63 (m, 4H, H2þH6-cyc);
1.71e1.75 (m, 4H, H3þH4-pyr); 2.69 (bs, 4H, H2þH5-pyr); 2.97 (t, 2H,
NeCH2, JCH2eCH2 ¼ 5.6 Hz); 3.54e3.59 (m, 1H, H1-cyc); 3.69 (s, 1H,
NHeSO2); 4.20 (t, 2H, OeCH2, JCH2eCH2 ¼ 5.6 Hz); 6.32 (d, 1H, NH-
CHcyc, JNHeCH ¼ 7.5 Hz); 7.10 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.9 Hz); 7.80 (d,
2H, H2þH6, J2,6-3,5 ¼ 8.9 Hz). Anal. Calcd for C19H29N3O4S: C, 57.72%; H,
7.34%; N, 10.63%. Found: C, 57.41%; H, 7.45%; N, 10.26%.
4.4.10. 4-{4-[4-(ethoxycarbonyl)piperidin-1-yl]butoxy}
benzenesulfonamide (19)
White solid. Yield: 71%. M.p: 132e134 ꢀC. IR (KBr, cmꢁ1): 3297
(m, nNeH); 1733 (vs, nC]O); 1328 and 1155 (vs, nSO2N); 1260 (s,
4.5.4. 1-(2,5-dichlorophenyl)-3-[4-(2-pyrrolidin-1-ylethoxy)
benzene]sulfonylurea (23)
nCeOeC). 1H NMR (400 MHz, DMSO-d6)
d
ppm: 1.17 (t, 3H, CH3,
White solid. Yield: 54%. M.p: 101e102 ꢀC. IR (KBr, cmꢁ1): 3419 (w,
JCH3eCH2 ¼ 7.1 Hz); 1.49e1.57 (m, 4H, NeCH2eCH2eCH2); 1.69e1.78
(m, 4H, H3þH5-pip); 1.92 (t, 2H, H2eqþH6eq-pip); 2.23e2.31 (m, 3H,
H4-pip and NeCH2); 2.78 (d, 1H, H2axþH6ax-pip); 3.99e4.11 (m, 4H,
CH3eCH2 and OeCH2); 7.07 (d, 2H, H3þH5, J3,5-2,6 ¼ 6.9 Hz); 7.19 (s,
2H, NH2); 7.73 (d, 2H, H2þH6, J2,6-3,5 ¼ 6.9 Hz) Anal. Calcd for
C18H28N2O5S.1/2H2O: C, 54.96%; H, 7.34%; N, 7.12%. Found: C,
54.81%; H, 7.38%; N, 6.91%.
nNeH); 1593 (s, nC]O); 1405 and 1134 (s, nSO2N); 1251 (vs, nCeOeC). 1H
NMR (400 MHz, DMSO-d6)
d
ppm: 1.91e1.96 (m, 4H, H3þH4-pyr);
3.26 (bs, 4H, H2þH5-pyr); 3.51 (bs, 2H, NeCH2); 4.30 (t, 2H, OeCH2,
JCH2eCH2 ¼ 5.5 Hz); 6.90, 6.92 (dd,1H, H4-2,5-diClph-NH, J4e3 ¼ 8.5 Hz
and J4e6 ¼ 2.6 Hz); 7.00 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.9 Hz); 7.36, 7.38
(dd, 1H, H3-2,5-diClph-NH, J3e4 ¼ 8.6 Hz and J3e6 ¼ 0.5 Hz); 7.68 (d,
1H, NH-2,5-diClph, JNHeH6
¼ 8.9 Hz); 7.76 (d, 2H, H2þH6,
J2,6-3,5 ¼ 8.5 Hz); 8.30 (d, 1H, H6-2,5-diClph-NH, J4e6 ¼ 2.6 Hz); 10.05
(bs, 1H, NHeSO2). Anal. Calcd for C19H21Cl2N3O4S: C, 49.78%; H,
4.58%; N, 9.17%. Found: C, 49.57%; H, 4.80%; N, 8.93%.
4.5. General procedure for the preparation of 4-(aminealkoxy)
benzenesulfonylurea derivatives (20e64)
A solution of 10% of NaOH (5.00 mmol) was added to a solution
of the corresponding 4-(aminealkoxy)benzenesulfonamide 10e19
(5.00 mmol) in acetone (25 ml). After 10 min of stirring, the
solvent was removed under reduced pressure. The solid was
redissolved in acetone (30 ml) and the reaction mixture was stirred
under reflux. The appropriate isocyanate derivative (10.00 mmol)
4.5.5. 1-(4-trifluoromethylphenyl)-3-[4-(2-pyrrolidin-1-ylethoxy)
benzene]sulfonylurea (24)
White solid. Yield: 81%. M.p: 128e130 ꢀC. IR (KBr, cmꢁ1): 3329
(w, nNeH); 1595 (s, nC]O); 1324 (vs, nSO2N); 1241 (vs, nCeOeC). 1H
NMR (400 MHz, DMSO-d6)
3.27 (bs, 4H, H2þH5-pyr); 3.52 (s, 2H, NeCH2); 3.71 (bs, 1H,
d
ppm: 1.90e1.95 (m, 4H, H3þH4-pyr);

8
J. Ceras et al. / European Journal of Medicinal Chemistry 52 (2012) 1e13
NHeSO2); 4.29 (t, 2H, OeCH2, JCH2eCH2 ¼ 4.9 Hz); 6.98 (d, 2H,
H3þH5, J3,5-2,6 ¼ 8.8 Hz); 7.43 (d, 2H, H2þH6-4-CF3ph-NH, J2,6-
1.68 (s, 4H, H3þH5-pip); 3.06 (bs, 4H, H2þH6-pip); 3.31 (bs, 2H,
NeCH2); 4.31 (t, 2H, OeCH2, JCH2eCH2 ¼ 4.7 Hz); 6.98 (d, 2H, H3þH5,
J3,5-2,6 ¼ 8.8 Hz); 7.43 (d, 2H, H3þH5-4-CF3ph-NH, J3,5-2,6 ¼ 8.6 Hz);
7.60 (d, 2H, H2þH6-4-CF3ph-NH, J2,6-3,5 ¼ 8.6 Hz); 7.76 (d, 2H,
H2þH6, J2,6-3,5 ¼ 8.8 Hz); 8.89 (bs, 1H, NHeSO2). Anal. Calcd for
C21H24F3N3O4S.1/2H2O: C, 52.50%; H, 5.00%; N, 8.75%. Found: C,
52.32%; H, 5.09%; N, 8.25%.
¼ 8.8 Hz); 7.60 (d, 2H, H3þH5-4-CF3ph-NH, J3,5-2,6 ¼ 8.6 Hz); 7.77
3,5
(d, 2H, H2þH6, J2,6-3,5 ¼ 8.8 Hz). Anal. Calcd for C20H22F3N3O4S.1/
2H2O: C, 51.50%; H, 4.93%; N, 9.01%. Found: C, 51.43%; H, 4.71%; N,
8.89%.
4.5.6. 1-Isopropyl-3-[4-(2-piperidin-1-ylethoxy)benzene]
sulfonylurea (25)
4.5.11. 1-Phenyl-3-[4-(2-(4-ethoxycarbonylpiperidin-1-yl)ethoxy)
benzene]sulfonylurea (30)
Beige solid. Yield: 43%. M.p: 80e82 ꢀC. IR (KBr, cmꢁ1): 3375 (w,
nNeH); 1596 (s, nC]O); 1327 and 1154 (vs, nSO2N); 1250 (vs, nCeOeC).
White solid. Yield: 61%. M.p: 100e101 ꢀC. IR (KBr, cmꢁ1): 3349
(m, nNeH); 1727 (vs, nC]O ester); 1597 (m, nC]O urea); 1311 and 1131
1H NMR (400 MHz, DMSO-d6)
d ppm: 0.99 (d, 6H, (CH3)2CH,
JCH3eCH ¼ 6.6 Hz); 1.39 (d, 2H, H4-pip); 1.48e1.54 (m, 4H, H3þH5-
pip); 2.50 (bs, 4H, H2þH6-pip); 2.74 (t, 2H, NeCH2,
JCH2eCH2 ¼ 5.8 Hz); 3.53e3.62 (m, 1H, (CH3)2CH); 4.17 (t, 2H,
OeCH2, JCH2eCH2 ¼ 5.8 Hz); 6.25 (d, 1H, NHeCH, JNHeCH ¼ 6.9 Hz);
7.10 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.9 Hz); 7.80 (d, 2H, H2þH6,
J2,6-3,5 ¼ 8.9 Hz). Anal. Calcd for C17H27N3O4S: C, 55.28%; H, 7.32%; N,
11.38%. Found: C, 54.91%; H, 7.24%; N, 11.30%.
(vs, nSO2N); 1249 (s, nCeOeC). 1H NMR (400 MHz, DMSO-d6)
d ppm:
1.17 (t, 3H, CH3, JCH3eCH2 ¼ 7.0 Hz); 1.57 (dq, 2H, H3eqþH5eq-pip);
1.79 (d, 2H, H3axþH5ax-pip); 2.10 (dt, 2H, H2eqþH6eq-pip); 2.27 (t,
1H, H4-pip); 2.67 (t, 2H, NeCH2, JCH2eCH2 ¼ 5.8 Hz); 2.86 (dt, 2H,
H2axþH6ax-pip); 4.02e4.09 (m, 4H, CH3eCH2, OeCH2); 6.70 (t, 1H,
H4-ph-NH, J4-3, 5 ¼ 7.2 Hz); 6.89 (ddd, 2H, H3þH5, J3,5-2,6 ¼ 8.8 Hz,
J3-5,
¼ 2.8 Hz, J3-6,5-2 ¼ 1.8 Hz); 7.06 (d, 2H, H3 þ H5-ph-NH
,
5-3
J3,5-2,6 ¼ 8.0 Hz); 7.41 (ddd, 2H, H2 þ H6-ph-NH, J2,6-3,5 ¼ 7.6 Hz,J2-
4.5.7. 1-Phenyl-3-[4-(2-piperidin-1-ylethoxy)benzene]sulfonylurea
(26)
¼ 3.0 Hz, J2-5,6-3 ¼ 2.0 Hz); 7.69 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.0 Hz).
6,6-2
Anal. Calcd for C23H29N3O6S.1/4H2O: C, 57.56%; H, 6.15%; N, 8.76%.
Found: C, 57.39%; H, 6.26%; N, 7.42%.
Beige solid. Yield: 50%. M.p: 99e101 ꢀC. IR (KBr, cmꢁ1): 3324 (w,
nNeH); 1593 (s, nC]O); 1311 and 1127 (vs, nSO2N); 1229 (vs, nCeOeC).
1H NMR (400 MHz, DMSO-d6)
d
ppm: 1.42 (s, 2H, H4-pip); 1.54e1.58
4.5.12. 1-Isopropyl-3-[4-(3-pyrrolidin-1-ylpropoxy)benzene]
sulfonylurea (31)
(m, 4H, H3þH5-pip); 2.50 (bs, 4H, H2þH6-pip); 2.69 (bs, 2H,
NeCH2); 4.18 (t, 2H, OeCH2, JCH2eCH2 ¼ 5.3 Hz); 6.77 (t, 1H, H4-
ph-NH, J4-3, 5 ¼ 7.3 Hz); 6.85e6.96 (d, 2H, H3þH5, J3,5-2,6 ¼ 7.9 Hz);
7.10 (t, 2H, H3þH5-ph-NH, J3,5-4 ¼ 7.4 Hz,J3,5-2,6 ¼ 7.1 Hz); 7.39e7.46
(m, 2H, H2þH6-ph-NH); 7.75 (d, 2H, H2þH6, J2,6-3,5 ¼ 7.9 Hz); 8.45 (s,
1H, NHeSO2). Anal. Calcd for C20H25N3O4S: C, 59.55%; H, 6.20%; N,
10.42%. Found: C, 59.89%; H, 6.24%; N, 10.30%. MS (EI, 70eV): m/z
(%) ¼ 401 (0.5); 212 (13); 119 (19); 98 (100).
White solid. Yield: 2%. M.p: 74e78 ꢀC. IR (KBr, cmꢁ1): 3369 (w,
nNeH); 1701 (s, nC]O); 1254 (vs, nCeOeC); 1119 (s, nSO2N). 1H NMR
(400 MHz, DMSO-d6)
d
ppm: 0.97 (d, 6H, (CH3)2CH,
JCH3eCH
¼
6.6 Hz); 1.72 (bs, 4H, H3þH4-pyr); 1.93 (q, 2H,
NeCH2eCH2, JCH2eCH2 ¼ 6.9 Hz); 2.61 (bs, 4H, H2þH5-pyr); 2.67 (bs,
2H, NeCH2); 3.57 (q, 1H, (CH3)2CH, JCHeCH3 ¼ 6.5 Hz); 3.90 (s, 1H,
NHeSO2); 4.07 (s, 2H, OeCH2); 6.16 (s, 1H, NHeCH); 7.03 (d, 2H,
H3þH5, J3,5-2,6 ¼ 8.9 Hz); 7.74 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.9 Hz). Anal.
Calcd for C17H27N3O4S.1/2H2O: C, 53.97%; H, 7.41%; N,11.11%. Found:
C, 53.90%; H, 7.32%; N, 10.96%. MS (EI, 70eV): m/z (%) ¼ 369 (4); 284
(7); 203 (8); 84 (100).
4.5.8. 1-Cyclohexyl-3-[4-(2-piperidin-1-ylethoxy)benzene]
sulfonylurea (27)
Beige solid. Yield: 7%. M.p: 67e70 ꢀC. IR (KBr, cmꢁ1): 3376 (w,
nNeH); 1595 (s, nC]O); 1325 and 1156 (vs, nSO2N); 1252 (vs, nCeOeC).
1H NMR (400 MHz, DMSO-d6)
d
ppm: 1.08e1.26 (m, 6H,
4.5.13. 1-Phenyl-3-[4-(3-pyrrolidin-1-ylpropoxy)benzene]
sulfonylurea (32)
H3þH4þH5-cyc); 1.40 (d, 2H, H4-pip); 1.50e1.66 (m, 8H, H3þH5-
pip, H2þH6-cyc); 2.55 (s, 4H, H2þH6-pip); 2.79 (t, 2H, NeCH2,
JCH2eCH2 ¼ 5.6 Hz); 3.27 (bs, 1H, H1-cyc); 4.16e4.21 (m, 2H,
OeCH2); 6.35 (d, 1H, NH-CHcyc, JNHeCH ¼ 7.5 Hz); 7.11 (t, 2H,
H3þH5, J3,5-2,6 ¼ 8.9 Hz); 7.80 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.9 Hz). Anal.
Calcd for C20H31N3O4S.1/2H2O: C, 57.42%; H, 7.66%; N, 10.05%.
Found: C, 57.10%; H, 7.39%; N, 9.72%.
White solid. Yield: 70%. M.p: 159 ꢀC. IR (KBr, cmꢁ1): 3434 (vs,
nNeH); 1693 (s, nC]O); 1258 (vs, nCeOeC); 1148 (vs, nSO2N). 1H NMR
(400 MHz, DMSO-d6)
d
ppm: 1.93 (bs, 4H, H3þH4-pyr); 2.15 (bs, 2H,
NeCH2eCH2); 2.51 (bs, 2H, NeCH2); 3.26 (bs, 5H, H2þH5-pyr,
NHeSO2); 4.16 (t, 2H, OeCH2, JCH2eCH2 ¼ 5.5 Hz); 6.97 (t, 1H, H4-
ph-NH, J4-3, 5 ¼ 7.0 Hz); 7.12 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.9 Hz); 7.23 (t,
2H, H3þH5-ph-NH, J3,5-2,6 ¼ 7.5 Hz); 7.33 (t, 2H, H2þH6-ph-NH
,
4.5.9. 1-(2,5-dichlorophenyl)-3-[4-(2-piperidin-1-ylethoxy)
benzene]sulfonylurea (28)
J2,6-3,5 ¼ 7.6 Hz); 7.89 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.9 Hz); 9.26 (s, 1H,
NH-ph); 10.57 (bs, 1H, NH$HCl). Anal. Calcd for C20H25N3O4S.2HCl:
C, 50.42%; H, 5.68%; N, 8.84%. Found: C, 50.16%; H, 5.86%; N, 8.70%.
MS (EI, 70eV): m/z (%): 476 ([M$]þ, 10); 368 (30); 312 (10); 191(45);
57 (100).
White solid. Yield: 53%. M.p: 112e114 ꢀC. IR (KBr, cmꢁ1): 3361
(m, nNeH); 1629 (vs, nC]O); 1409 and 1179 (s, nSO2N); 1253 (vs,
nCeOeC). 1H NMR (400 MHz, DMSO-d6)
d ppm: 1.50 (s, 2H, H4-pip);
1.69 (bs, 4H, H3þH5-pip); 2.50e2.52 (m, 4H, H2þH6-pip); 3.06 (bs,
2H, NeCH2); 4.32 (t, 2H, OeCH2, JCH2eCH2 ¼ 5.3 Hz); 6.91 (dd, 1H,
H4-2,5-diClph-NH, J4e3 ¼ 8.6 Hz, J4e6 ¼ 2.6 Hz); 7.02 (d, 2H, H3þH5,
J3,5-2,6 ¼ 8.6 Hz); 7.38 (d, 1H, H3-2,5-diClph-NH, J3e4 ¼ 8.6 Hz); 7.77
(d, 2H, H2þH6, J2,6-3,5 ¼ 8.8 Hz); 8.18 (s, 1H, H6-3,5-diClph-NH); 8.27
(d, 1H, NH-2,5-diClph). Anal. Calcd for C20H23Cl2N3O4S: C, 50.85%;
H, 4.87%; N, 8.90%. Found: C, 50.93%; H, 5.08%; N, 8.83%.
4.5.14. 1-Cyclohexyl-3-[4-(3-pyrrolidin-1-ylpropoxy)benzene]
sulfonylurea (33)
White solid. Yield: 3%. M.p: 89e90 ꢀC. IR (KBr, cmꢁ1): 3379 (s,
nNeH); 1595 (s, nC]O); 1254 (s, nCeOeC); 1124 (vs, nSO2N). 1H NMR
(400 MHz, DMSO-d6)
d
ppm: 1.07e1.21 (m, 6H, H3þH4þH5-cyc);
1.58e1.64 (t, 4H, H2þH6-cyc); 1.91 (bs, 4H, H3þH4-pyr); 2.15 (bs,
2H, NeCH2eCH2); 3.19e3.26 (m, 8H, H2þH5-pyr, NeCH2, H1-cyc,
NHeSO2); 4.16 (t, 2H, OeCH2, JCH2eCH2 ¼ 5.9 Hz); 6.62 (d, 1H, NH-
CHcyc, JNHeCH ¼ 7.2 Hz); 7.10 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.8 Hz);
7.82 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.8 Hz). Anal. Calcd for C20H31N3O4S:
C, 58.65%; H, 7.63%; N, 10.26%. Found: C, 58.32%; H, 7.45%; N,
9.86%.
4.5.10. 1-(4-trifluoromethylphenyl)-3-[4-(2-piperidin-1-ylethoxy)
benzene]sulfonylurea (29)
Beige solid. Yield: 22%. M.p: 124e126 ꢀC. IR (KBr, cmꢁ1): 3321
(w, nNeH); 1595 (s, nC]O); 1324 and 1107 (vs, nSO2N); 1242 (vs,
nCeOeC). 1H NMR (400 MHz, DMSO-d6)
d ppm: 1.48 (s, 2H, H4-pip);

J. Ceras et al. / European Journal of Medicinal Chemistry 52 (2012) 1e13
9
4.5.15. 1-(2,5-dichlorophenyl)-3-[4-(3-pyrrolidin-1-ylpropoxy)
benzene]sulfonylurea (34)
NH-CHcyc, JNHeCH ¼ 7.6 Hz); 7.10 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.8 Hz);
8.8 Hz). Anal. Calcd for
C21H33N3O4S$H2O: C, 58.33%; H, 7.87%; N, 9.72%. Found: C, 57.90%;
7.80 (d, 2H, H2þH6, J2,6-3,5
¼
White solid. Yield: 2%. M.p: 166e167 ꢀC. IR (KBr, cmꢁ1): 3426 (m,
nNeH); 1626 (s, nC]O); 1252 (vs, nCeOeC); 1133 (vs, nSO2N). 1H NMR
H, 8.13%; N, 9.50%.
(400 MHz, DMSO-d6)
d
ppm: 1.91 (bs, 4H, H3þH4-pyr); 2.10 (bs, 2H,
NeCH2eCH2); 3.20e3.40 (m, 7H, H2þH5-pyr, NeCH2, NHeSO2);
4.09 (t, 2H, OeCH2, JCH2eCH2 ¼ 6.4 Hz); 6.86, 6.89 (dd, 1H, H4-2,5-
diClph-NH, J4e3 ¼ 8.6 Hz and J4e6 ¼ 2.6 Hz); 6.91 (d, 2H, H3þH5,
J3,5-2,6 ¼ 8.8 Hz); 7.36 (d, 1H, H3-2,5-diClph-NH, J3e4 ¼ 8.5 Hz); 7.60
(s, 1H, NH-2,5-diClph); 7.74 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.8 Hz); 8.30 (s,
1H, H6-2,5-diClph-NH). Anal. Calcd for C20H23Cl2N3O4S.1/2H2O: C,
49.89%; H, 4.99%; N, 8.73%. Found: C, 49.51%; H, 4.88%; N, 8.59%. MS
(EI, 70eV): m/z (%) ¼ 481 ([M$]þ, 10); 310 (7); 284 (14); 187 (100);
161 (81).
4.5.20. 1-(2,5-dichlorophenyl)-3-[4-(3-piperidin-1-ylpropoxy)
benzene]sulfonylurea (39)
White solid. Yield: 46%. M.p: 180e182 ꢀC. IR (KBr, cmꢁ1): 3429
(m, nNeH); 1630 (vs, nC]O); 1231 (vs, nCeOeC); 1142 (s, nSO2N). 1H
NMR (400 MHz, DMSO-d6)
d ppm: 1.51 (bs, 2H, H4-pip); 1.68 (bs,
4H, H3þH5-pip); 2.06e2.10 (m, 2H, NeCH2eCH2); 2.50e2.52 (m,
2H, NeCH2); 3.07 (bs, 4H, H2þH6-pip); 4.06e4.13 (m, 2H, OeCH2);
6.88e6.96 (m, 3H, H3þH5, H4-2,5-diClph-NH); 7.37 (d, 1H, H3-2,5-
diClph-NH, J3e4
¼
8.5 Hz); 7.58 (s, 1H, H6-2,5-diClph-NH);
7.71e7.74 (m, 2H, H2þH6); 8.32 (s, 1H, NH-2,5-diClph). Anal. Calcd
for C21H25Cl2N3O4S: C, 51.85%; H, 5.14%; N, 8.64%. Found: C, 51.46%;
H, 5.16%; N, 8.56%.
4.5.16. 1-(4-trifluoromethylphenyl)-3-[4-(3-pyrrolidin-1-
ylpropoxy)benzene]sulfonylurea (35)
White solid. Yield: 14%. M.p: 89e90 ꢀC. IR (KBr, cmꢁ1): 3322 (vs,
nNeH); 1645 (s, nC]O); 1229 (s, nCeOeC); 1133 (s, nSO2N). 1H NMR
4.5.21. 1-(4-trifluoromethylphenyl)-3-[4-(3-piperidin-1-ylpropoxy)
benzene]sulfonylurea (40)
(400 MHz, DMSO-d6)
NeCH2eCH2); 2.50 (bs, 2H, NeCH2); 3.23 (bs, 4H, H2þH5-pyr); 4.08
(t, 2H, OeCH2, JCH2eCH2
d
ppm: 1.91 (bs, 4H, H3þH4-pyr); 2.08 (bs, 2H,
Beige solid. Yield: 40%. M.p: 150e152 ꢀC. IR (KBr, cmꢁ1): 3328
(w, nNeH); 1594 (m, nC]O); 1313, 1133 (vs, nSO2N); 1249 (vs, nCeOeC).
¼
6.0 Hz); 6.92 (d, 2H, H3þH5,
J3,5-2,6 ¼ 8.9 Hz); 7.41 (d, 2H, H3þH5-4-CF3ph-NH, J3,5-2,6 ¼ 8.8 Hz);
7.60 (t, 2H, H2þH6-4-CF3ph-NH, J2,6-3,5 ¼ 8.7 Hz); 7.74 (d, 2H, H2þH6,
J2,6-3,5 ¼ 8.8 Hz); 8.84 (s, 1H, NH-4-CF3ph-NH); 9.70 (bs, 1H,
NHeSO2). Anal. Calcd for C21H24F3N3O4S.H2O: C, 51.53%; H, 5.31%;
N, 8.59%. Found: C, 51.74%; H, 4.97%; N, 8.72%. MS (EI, 70eV): m/z
(%) ¼ 368 (40); 312 (13); 191 (100); 175 (69).
1H NMR (400 MHz, DMSO-d6)
d ppm: 1.51 (bs, 2H, H4-pip); 1.68 (bs,
4H, H3þH5-pip); 2.08 (bs, 2H, NeCH2eCH2); 3.06 (bs, 6H, H2þH6-
pip, NeCH2); 4.06 (t, 2H, OeCH2, JCH2eCH2 ¼ 5.9 Hz); 5.79 (bs, 1H,
NHeSO2); 6.91 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.7 Hz); 7.41 (d, 2H, H3þH5-
4-CF3ph-NH, J3,5-2,6 ¼ 8.7 Hz); 7.60 (d, 2H, H2þH6-4-CF3ph-NH
,
J2,6-3,5 ¼ 8.5 Hz); 7.74 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.8 Hz); 8.83 (s, 1H,
NH-4-CF3ph-NH). Anal. Calcd for C22H26F3N3O4S: C, 54.43%; H,
5.36%; N, 8.66%. Found: C, 54.57%; H, 5.21%; N, 8.72%.
4.5.17. 1-Isopropyl-3-[4-(3-piperidin-1-ylpropoxy)benzene]
sulfonylurea (36)
White solid. Yield: 34%. M.p: 122e124 ꢀC. IR (KBr, cmꢁ1): 3526,
3372 (m, nNeHCOeNeH); 1592 (vs, nC]O); 1316, 1151 (vs, nSO2N); 1261
4.5.22. 1-Phenyl-3-[4-(3-(4-ethoxycarbonylpiperidin-1-yl)
propoxy)benzene]sulfonylurea (41)
(vs, nCeOeC). 1H NMR (400 MHz, DMSO-d6)
d
ppm: 0.99 (d, 6H,
Beige solid. Yield: 25%. M.p: 91e93 ꢀC. IR (KBr, cmꢁ1): 3352 (w,
nNeH); 1727 (vs, nC]Oester); 1596 (m, nC]Ourea); 1311, 1131 (vs,
(CH3)2CH, JCH3eCH ¼ 6.5 Hz); 1.42 (d, 2H, H4-pip); 1.54e1.58 (m, 4H,
H3þH5-pip); 1.92e1.98 (m, 2H, NeCH2eCH2); 2.52e2.62 (m, 6H,
H2þH6-pip, NeCH2); 3.53e3.62 (m, 1H, (CH3)2CH); 4.08 (t, 2H,
OeCH2, JCH2eCH2 ¼ 6.3 Hz); 6.33 (bs, 1H, NHeCH); 7.07 (d, 2H,
H3þH5, J3,5-2,6 ¼ 8.9 Hz); 7.79 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.9 Hz). Anal.
Calcd for C18H29N3O4S$H2O: C, 53.86%; H, 7.73%; N, 10.47%. Found:
C, 53.54%; H, 7.76%; N, 10.13%.
nSO2N); 1244 (s, nCeOeC). 1H NMR (400 MHz, DMSO-d6)
d ppm: 1.18
(t, 3H, CH3, J
¼ 7.1 Hz); 1.69 (d, 2H, NeCH2eCH2,
CH3eCH2
JCH2eCH2 ¼ 10.0 Hz); 2.01 (d, 4H, H3þH5-pip); 2.27 (s, 1H, H4-pip);
2.56 (bs, 2H, NeCH2); 2.83 (s, 2H, H2eqþH6eq-pip); 3.17 (bs, 2H,
H2axþH6ax-pip); 4.05e4.10 (m, 4H, CH3eCH2, OeCH2); 6.83 (bs, 1H,
H4-ph-NH); 6.96e7.02 (m, 2H, H3þH5); 7.16 (d, 2H, H3þH5-ph-NH
,
J3,5-2,6 ¼ 7.5 Hz); 7.37 (d, 2H, H2þH6-ph-NH, J2,6-3,5 ¼ 7.8 Hz);
7.70e7.81 (m, 2H, H2þH6); 8.60 (bs, 1H, NHeSO2). Anal. Calcd for
C24H31N3O6S$1/2H2O: C, 57.83%; H, 6.42%; N, 8.43%. Found: C,
57.54%; H, 6.17%; N, 8.32%.
4.5.18. 1-Phenyl-3-[4-(3-piperidin-1-ylpropoxy)benzene]
sulfonylurea (37)
White solid. Yield: 25%. M.p: 106e108 ꢀC. IR (KBr, cmꢁ1): 3336
(w, nNeH); 1592 (s, nC]O); 1308, 1129 (vs, nSO2N); 1228 (vs, nCeOeC).
1H NMR (400 MHz, DMSO-d6)
d
ppm: 1.48 (bs, 2H, H4-pip); 1.65 (t,
4.5.23. 1-Isopropyl-3-[4-(4-pyrrolidin-1-ylbutoxy)benzene]
sulfonylurea (42)
4H, H3þH5-pip); 2.04 (bs, 2H, NeCH2eCH2); 2.81 (bs, 2H, NeCH2);
2.93 (bs, 4H, H2þH6-pip); 4.05e4.12 (m, 2H, OeCH2); 6.77 (t, 1H,
H4-ph-NH, J4-3, 5 ¼ 7.3 Hz); 6.93 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.6 Hz);
7.07e7.12 (m, 2H, H3þH5-ph-NH); 7.22 (s, 1H, NHeSO2); 7.39 (d, 2H,
H2þH6-ph-NH, J2,6-3,5 ¼ 7.6 Hz); 7.75 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.8 Hz);
8.44 (s, 1H, NH-ph-NH). Anal. Calcd for C21H27N3O4S$H2O: C, 57.93%;
H, 6.67%; N, 9.65%. Found: C, 58.19%; H, 7.06%; N, 9.25%. MS (EI,
70eV): m/z (%) ¼ 435 ([M$]þ, 5); 324 (1); 298 (25); 119 (19); 98
(100).
White solid. Yield: 17%. M.p: 135e137 ꢀC. IR (KBr, cmꢁ1): 3369
(w, nNeH); 1702 (w, nC]O); 1267 (s, nCeOeC); 1118 (s, nSO2N). 1H NMR
(400 MHz, DMSO-d6)
d
ppm: 0.98 (d, 6H, (CH3)2CH,
JCH3eCH ¼ 6.6 Hz); 1.62e1.68 (m, 4H, NeCH2eCH2eCH2); 1.76 (bs,
4H, H3þH4-pyr); 2.70e2.75 (m, 6H, H2þH5-pyr, NeCH2); 3.54e3.57
(m, 1H, (CH3)2CH); 3.90 (s, 1H, NHeSO2); 4.02 (t, 2H, OeCH2,
JCH2eCH2 ¼ 6.2 Hz); 6.20 (s, 1H, NHeCH); 7.02 (d, 2H, H3þH5,
J3,5-2,6 ¼ 8.9 Hz); 7.74 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.9 Hz). Anal. Calcd for
C18H29N3O4S: C, 56.40%; H, 7.57%; N, 10.97%. Found: C, 56.01%; H,
7.52%; N, 10.59%. MS (EI, 70eV): m/z (%) ¼ 383 ([M$]þ, 10); 171 (34);
126 (10); 84 (100).
4.5.19. 1-Cyclohexyl-3-[4-(3-piperidin-1-ylpropoxy)benzene]
sulfonylurea (38)
White solid. Yield: 13%. M.p: 138 ꢀC. IR (KBr, cmꢁ1): 3378 (w,
nNeH); 1705 (s, nC]O); 1334, 1124 (vs, nSO2N); 1255 (s, nCeOeC). 1H
4.5.24. 1-Phenyl-3-[4-(4-pyrrolidin-1-ylbutoxy)benzene]
sulfonylurea (43)
NMR (400 MHz, DMSO-d6)
d
ppm: 1.10e1.19 (m, 6H, H3þH4þH5-
cyc); 1.46 (bs, 2H, H4-pip); 1.64 (bs, 8H, H2þH6-cyc, H3þH5-pip);
2.04 (bs, 2H, NeCH2eCH2); 2.80 (bs, 6H, H2þH6-pip, NeCH2); 3.28
(m, 2H, H1-cyc, NHeSO2); 4.11 (bs, 2H, OeCH2); 6.57 (d, 1H,
White solid. Yield: 19%. M.p: 91e92 ꢀC. IR (KBr, cmꢁ1): 3352 (m,
nNeH); 1716 (w, nC]O); 1249 (s, nCeOeC); 1176 (s, nSO2N). 1H NMR
(400 MHz, DMSO-d6)
d ppm: 1.73 (bs, 4H, NeCH2eCH2eCH2); 1.89

10
J. Ceras et al. / European Journal of Medicinal Chemistry 52 (2012) 1e13
(bs, 4H, H3þH4-pyr); 3.11 (s, 2H, NeCH2); 3.20 (bs, 4H, H2þH5-pyr);
3.29 (s, 1H, NHeSO2); 4.01 (t, 2H, OeCH2, JCH2eCH2 ¼ 6.2 Hz); 6.76
(400 MHz, DMSO-d6) d ppm: 1.49 (s, 2H, H4-pip); 1.66e1.73 (m, 8H,
H3þH5-pip, NeCH2eCH2eCH2); 2.91e2.95 (m, 6H, H2þH6-pip,
NeCH2); 4.02 (s, 2H, OeCH2); 6.77 (t, 1H, H4-ph-NH, J4-3, 5 ¼ 7.3 Hz);
6.90e6.94 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.7 Hz); 7.10 (t, 2H, H3þH5-
(t, 1H, H4-ph-NH, J4-3,
¼ 7.0 Hz); 6.96 (t, 2H, H3þH5-ph-NH
,
5
J3,5-2,6 ¼ 7.6 Hz); 7.10 (t, 2H, H2þH6-ph-NH, J2,6-3,5 ¼ 7.6 Hz); 7.39 (d,
2H, H3þH5, J3,5-2,6
¼
8.9 Hz); 7.73 (d, 2H, H2þH6, H2þH6,
ph-NH, J3,5-2,6 ¼ 8.7 Hz, J3,5-4 ¼ 7.3 Hz); 7.39 (d, 2H, H2þH6-ph-NH
,
J2,6-3,5 ¼ 8.9 Hz); 8.43 (s, 1H, NH-ph). Anal. Calcd for C21H27N3O4S.3/
2H2O: C, 56.76%; H, 6.76%; N, 9.46%. Found: C, 56.89%; H, 6.69%; N,
9.27%. MS (EI, 70eV): m/z (%) ¼ 417 (0.5); 298 (1); 119 (45); 84 (100).
J2,6-3,5 ¼ 8.4 Hz); 7.73 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.7 Hz); 8.41 (s, 1H,
NH-ph). Anal. Calcd for C22H29N3O4S: C, 61.25%; H, 6.73%; N, 9.74%.
Found: C, 61.42%; H, 7.38%; N, 9.99%.
4.5.25. 1-Cyclohexyl-3-[4-(4-pyrrolidin-1-ylbutoxy)benzene]
sulfonylurea (44)
4.5.30. 1-Cyclohexyl-3-[4-(4-piperidin-1-ylbutoxy)benzene]
sulfonylurea (49)
White solid. Yield: 28%. M.p: 96e97 ꢀC. IR (KBr, cmꢁ1): 3275 (m,
White solid. Yield: 22%. M.p: 160e162 ꢀC. IR (KBr, cmꢁ1): 1592
nNeH); 1705 (s, nC]O); 1258 (s, nCeOeC); 1155 (vs, nSO2N). 1H NMR
(m, nC]O); 1312, 1117 (m, nSO2N); 1253 (vs, nCeOeC). 1H NMR
(400 MHz, DMSO-d6)
d
ppm: 1.09e1.23 (m, 6H, H3þH4þH5-cyc);
(400 MHz, DMSO-d6)
d
ppm: 1.07e1.22 (m, 6H, H3þH4þH5-cyc);
1.48 (t, 4H, H2þH6-cyc); 1.61 (bs, 4H, NeCH2eCH2eCH2); 1.80 (bs,
4H, H3þH4-pyr); 2.97 (s, 2H, NeCH2); 3.16 (bs, 4H, H2þH5-pyr);
3.28 (s, 1H, H1-cyc); 4.01 (s, 2H, OeCH2); 6.86 (d, 1H, NH-CHcyc,
JNHeCH ¼ 8.8 Hz); 7.10 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.7 Hz); 7.81 (d, 2H,
H2þH6, J2,6-3,5 ¼ 8.7 Hz); 10.51 (s, 1H, NH$HCl) ppm. Anal. Calcd for
C21H33N3O4S$HCl$H2O: C, 52.77%; H, 7.12%; N, 8.80%. Found: C,
52.40%; H, 6.93%; N, 8.50%. MS (EI, 70eV): m/z (%) ¼ 423 (10); 368
(48); 191 (90); 84 (100).
1.40 (s, 2H, H4-pip); 1.51e1.62 (m, 10H, H3þH5-pip, NeCH2eCH2,
H2þH6-cyc); 1.69e1.74 (m, 2H, OeCH2eCH2); 2.44e2.51 (m, 6H,
H2þH6-pip, NeCH2); 3.26 (s, 1H, H1-cyc); 4.05 (t, 2H, OeCH2,
JCH2eCH2 ¼ 6.4 Hz); 6.23 (s, 1H, NH-cyc); 7.05 (d, 2H, H3þH5,
J3,5-2,6 ¼ 8.6 Hz); 7.78 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.7 Hz). Anal. Calcd for
C22H35N3O4S$½ H2O: C, 59.19%; H, 8.07%; N, 9.41%. Found: C,
59.41%; H, 7.98%; N, 9.30%.
4.5.31. 1-(2,5-dichlorophenyl)-3-[4-(4-piperidin-1-ylbutoxy)
benzene]sulfonylurea (50)
4.5.26. 1-(2,5-dichlorophenyl)-3-[4-(4-pyrrolidin-1-ylbutoxy)
benzene]sulfonylurea (45)
White solid. Yield: 64%. M.p: 153e155 ꢀC. IR (KBr, cmꢁ1): 3422
(w, nNeH); 1585 (m, nC]O); 1351, 1134 (s, nSO2N); 1253 (vs, nCeOeC).
White solid. Yield: 31%. M.p: 162e164 ꢀC. IR (KBr, cmꢁ1): 3322
(w, nNeH); 1705 (s, nC]O); 1250 (s, nCeOeC); 1134 (vs, nSO2N). 1H NMR
1H NMR (400 MHz, DMSO-d6)
d ppm: 1.49 (s, 2H, H4-pip); 1.66
(400 MHz, DMSO-d6)
d
ppm: 1.75 (bs, 4H, NeCH2eCH2eCH2); 1.90
(bs, 4H, H3þH5-pip); 1.74 (bs, 4H, NeCH2eCH2eCH2); 2.93 (bs, 6H,
H2þH6-pip, NeCH2); 4.03e4.09 (m, 2H, OeCH2); 6.89e6.93 (dd,
1H, H4-2,5-diClph-NH, J4e3 ¼ 8.5 Hz, J4e6 ¼ 2.6 Hz); 7.08 (d, 2H,
(bs, 4H, H3þH4-pyr); 3.00e3.30 (m, 7H, H2þH5-pyr, NeCH2,
NHeSO2); 4.00 (m, 2H, OeCH2); 6.90e6.97 (m, 1H, H4-2,5-
diClph-NH); 6.95 (bs, 2H, H3þH5); 7.40 (bs, 1H, H3-2,5-diClph-NH);
7.55 (s,1H, NH-2,5-diClph-NH); 7.70 (bs, 2H, H2þH6); 8.30 (s,1H, H6-
2,5-diClph-NH). Anal. Calcd for C21H25Cl2N3O4S: C, 51.85%; H, 5.14%;
N, 8.64%. Found: C, 52.12%; H, 5.26%; N, 8.45%.
H3þH5, J3,5-2,6
¼
8.5 Hz); 7.36 (d, 1H, H3-2,5-diClph-NH,
J3e4 ¼ 8.5 Hz); 7.53 (s, 1H, H6-2,5-diClph-NH); 7.73 (d, 2H, H2þH6,
J2,6-3,5 ¼ 8.6 Hz); 8.28 (d, 1H, NH-2,5-diClph-NH). Anal. Calcd for
C22H27Cl2N3O4S.1/2H2O: C, 51.87%; H, 5.50%; N, 8.25%. Found: C,
51.54%; H, 5.24%; N, 8.11%.
4.5.27. 1-(4-trifluoromethylphenyl)-3-[4-(4-pyrrolidin-1-ylbutoxy)
benzene]sulfonylurea (46)
4.5.32. 1-(4-trifluoromethylphenyl)-3-[4-(4-piperidin-1-ylbutoxy)
benzene]sulfonylurea (51)
Yellowish solid. Yield: 13%. M.p: 136e138 ꢀC. IR (KBr, cmꢁ1): 3430
(m, nNeH); 1629 (s, nC]O); 1242 (vs, nCeOeC); 1105 (vs, nSO2N).1H NMR
White solid. Yield: 9%. M.p: 115e117 ꢀC. IR (KBr, cmꢁ1): 3430 (w,
(400 MHz, DMSO-d6)
d ppm: 1.77 (bs, 4H, NeCH2eCH2eCH2); 1.90
nNeH); 1622 (s, nC]O); 1242 (vs, nCeOeC); 1107 (s, nSO2N). 1H NMR
(bs, 4H, H3þH4-pyr); 3.14e3.60 (m, 6H, H2þH5-pyr, NeCH2); 4.02 (s,
2H, OeCH2); 6.92 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.6 Hz); 7.42 (d, 2H,
H3þH5-4-CF3ph-NH, J3,5-2,6 ¼ 8.5 Hz); 7.60 (d, 2H, H2þH6-4-
CF3ph-NH, J2,6-3,5 ¼ 8.5 Hz); 7.73 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.6 Hz);
8.87 (s, 1H, NH-4-CF3ph-NH). Anal. Calcd for C22H26F3N3O4S: C,
54.43%; H, 5.36%; N, 8.66%. Found: C, 54.09%; H, 5.11%; N, 8.71%. MS
(EI, 70eV): m/z (%): 429 (3); 187 (57); 161 (85); 84 (100).
(400 MHz, DMSO-d6) d ppm: 1.23e1.28 (m, 2H, H4-pip); 1.72e1.76
(m, 8H, H3þH5-pip, NeCH2eCH2eCH2); 3.02 (bs, 6H, H2þH6-pip,
NeCH2); 3.57 (s, 1H, NHeSO2); 4.04 (t, 2H, OeCH2,
JCH2eCH2 ¼ 5.5 Hz); 6.92 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.7 Hz); 7.42 (d,
2H, H3þH5-4-CF3ph-NH, J3,5-2,6 ¼ 8.6 Hz); 7.60 (d, 2H, H2þH6-4-
CF3ph-NH, J2,6-3,5 ¼ 8.7 Hz); 7.73 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.8 Hz);
8.87 (s, 1H, NH-4-CF3ph-NH). Anal. Calcd for C23H28F3N3O4S$H2O: C,
53.37%; H, 5.61%; N, 8.41%. Found: C, 53.57%; H, 5.70%; N, 8.03%.
4.5.28. 1-Isopropyl-3-[4-(4-piperidin-1-ylbutoxy)benzene]
sulfonylurea (47)
4.5.33. 1-Phenyl-3-{4-[4-(4-ethoxycarbonylpiperidin-1-yl)butoxy]
benzene}sulfonylurea (52)
White solid. Yield: 98%. M.p: 117e119 ꢀC. IR (KBr, cmꢁ1): 3378
(m, nNeH); 1597 (vs, nC]O); 1388, 1146 (vs, nSO2N); 1258 (vs, nCeOeC).
White solid. Yield: 50%. M.p: 93e94 ꢀC. IR (KBr, cmꢁ1): 3351 (m,
nNeH); 1727 (vs, nC]Oester); 1596 (m, nC]Ourea); 1311, 1131 (vs,
1H NMR (400 MHz, DMSO-d6)
d ppm: 0.98 (d, 6H, (CH3)2CH,
JCH3eCH ¼ 6.5 Hz); 1.40 (s, 2H, H4-pip); 1.54 (t, 4H, H3þH5-pip); 1.62
(bs, 2H, NeCH2eCH2); 1.73 (bs, 2H, OeCH2eCH2); 2.46e2.49 (m,
6H, H2þH6-pip, NeCH2); 3.55e3.57 (m, 1H, (CH3)2CH); 4.06 (t, 2H,
OeCH2, JCH2eCH2 ¼ 6.3 Hz); 6.20 (s, 1H, NHeCH); 7.05 (d, 2H,
H3þH5, J3,5-2,6 ¼ 8.8 Hz); 7.77 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.8 Hz). Anal.
Calcd for C19H31N3O4S.1/2H2O: C, 56.16%; H, 7.88%; N, 10.34%.
Found: C, 56.34%; H, 7.74%; N, 9.98%.
nSO2N); 1249 (s, nCeOeC). 1H NMR (400 MHz, DMSO-d6)
d
ppm: 1.17
(t, 3H, CH3, J
¼ 7.0 Hz); 1.49 (bs, 4H, NeCH2eCH2eCH2);
CH3eCH2
1.57 (dq, 2H, H3eqþH5eq-pip); 1.79 (dd, 2H, H3axþH5ax-pip); 2.10
(dt, 2H, H2eqþH6eq-pip); 2.27 (t, 1H, H4-pip); 2.67 (bs, 2H, NeCH2);
2.86 (dt, 2H, H2axþH6ax-pip); 4.06 (m, 4H, CH3eCH2, OeCH2); 6.70
(t, 1H, H4-ph-NH, J4-3, 5 ¼ 7.2 Hz); 6.87, 6.89, 6.71 (ddd, 2H, H3þH5,
J3,5-2,6 ¼ 8.8 Hz, J3-5,
¼ 2.8 Hz, J3-6,5-2 ¼ 1.8 Hz); 7.06 (t, 2H,
5-3
H3þH5-ph-NH, J3,5-2,6 ¼ 7.2 Hz); 7.39, 7.41, 7.44 (ddd, 2H, H2þH6-
ph-NH, J2,6-3,5 ¼ 7.6 Hz, J2-6,6,2 ¼ 3.0 Hz, J2-5,6-3 ¼ 2.0 Hz); 7.69 (d, 2H,
H2þH6, J2,6-3,5 ¼ 8.8 Hz); 8.26 (s, 1H, NH-ph). Anal. Calcd for
C25H33N3O6S.H2O: C, 57.58%; H, 6.72%; N, 8.06%. Found: C, 57.71%;
H, 6.39%; N, 8.10%.
4.5.29. 1-Phenyl-3-[4-(4-piperidin-1-ylbutoxy)benzene]
sulfonylurea (48)
White solid. Yield: 25%. M.p: 105e107 ꢀC. IR (KBr, cmꢁ1): 1591
(m, nC]O); 1309, 1127 (s, nSO2N); 1249 (vs, nCeOeC). 1H NMR

J. Ceras et al. / European Journal of Medicinal Chemistry 52 (2012) 1e13
11
4.5.34. 1-(3-trifluoromethylphenyl)-3-[4-(3-pyrrolidin-1-
ylpropoxy)benzene]sulfonylurea (53)
NH-4eN(CH3)2eph). Anal. Calcd for C22H30N4O4S.1/2H2O: C,
58.02%; H, 6.81%; N, 12.31%. Found: C, 57.91%; H, 6.64%; N, 12.34%.
MS (EI, 70eV): m/z (%) ¼ 455 ([M$]þ, 10); 327 (12); 284 (10); 239
(33); 134 (52); 84 (100).
White solid. Yield: 13%. M.p: 114e116 ꢀC. IR (KBr, cmꢁ1): 3337
(m, nNeH); 1722 (m, nC]O); 1254 (s, nCeOeC); 1125 (vs, nSO2N). 1H
NMR (400 MHz, DMSO-d6)
d
ppm: 1.92 (bs, 4H, H3þH4-pyr); 2.12
(bs, 2H, NeCH2eCH2); 3.26 (bs, 6H, H2þH5-pyr, NeCH2); 4.11 (t, 2H,
OeCH2, JCH2eCH2 ¼ 5.8 Hz); 6.97 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.7 Hz);
7.10 (d, 1H, H5-3-CF3ph-NH, J5e6 ¼ 7.6 Hz); 7.34 (t, 1H, H4-3-
4.5.39. 1-Benzhydryl-3-[4-(3-pyrrolidin-1-ylpropoxy)benzene]
sulfonylurea (58)
White solid. Yield: 3%. M.p: 104 ꢀC. IR (KBr, cmꢁ1): 3374 (m,
CF3ph-NH
,
J4e5
¼
8.1 Hz); 7.52 (d, 1H, H6-3-CF3ph-NH,
nNeH); 1707 (s, nC]O); 1251 (s, nCeOeC); 1155 (s, nSO2N). 1H NMR
J6e5 ¼ 7.8 Hz); 7.76 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.7 Hz); 7.96 (s,1H, H2-3-
CF3ph-NH); 8.98 (s, 1H, NH-3-CF3ph-NH); 10.15 (bs, 1H, NH$HCl).
Anal. Calcd for C21H24F3N3O4S $HCl: C, 49.65%; H, 4.93%; N, 8.28%.
Found: C, 49.49%; H, 4.71%; N, 7.91%.
(400 MHz, DMSO-d6)
(m, 2H, NeCH2eCH2); 2.96 (d, 6H, H2þH5-pyr, NeCH2); 4.07 (t,
2H, OeCH2, JCH2eCH2 5.0 Hz); 5.79 (d, 1H, CHeC12H10
JCHeNH ¼ 8.0 Hz); 7.04 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.2 Hz); 7.20e7.28
(m, 10H, CHeC12 10); 7.62 (d, 1H, NHeCHeC12H10
d
ppm: 1.82 (bs, 4H, H3þH4-pyr); 2.05e2.08
¼
,
H
,
4.5.35. 1-(4-acetylphenyl)-3-[4-(3-pyrrolidin-1-ylpropoxy)
benzene]sulfonylurea (54)
JCHeNH ¼ 7.7 Hz); 7.79 (d, 2H, H2þH6, J2,6-3,5 ¼ 7.7 Hz). Anal. Calcd
for C27H31N3O4S$H2O: C, 63.41%; H, 6.46%; N, 8.22%. Found: C,
63.46%; H, 6.31%; N, 8.26%.
White solid. Yield: 23%. M.p: 161e162 ꢀC. IR (KBr, cmꢁ1): 3286
(m, nNeH); 1695 (s, nC]O ketone); 1664 (s, nC]O urea); 1234 (vs,
nCeOeC); 1135 (s, nSO2N). 1H NMR (400 MHz, DMSO-d6)
d
ppm: 1.67
4.5.40. 1-(2-trifluoromethylphenyl)-3-[4-(3-piperidin-1-ylpropoxy)
benzene]sulfonylurea (59)
(bs, 4H, H3þH4-pyr); 1.87 (bs, 2H, NeCH2eCH2); 2.42 (bs, 6H,
H2þH5-pyr, NeCH2); 2.51 (s, 3H, CH3eCO); 4.03 (t, 2H, OeCH2,
JCH2eCH2 ¼ 6.0 Hz); 6.90 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.4 Hz); 7.54 (d,
2H, H3þH5-COCH3ph-NH, J3,5-2,6 ¼ 8.5 Hz); 7.71 (bs, 4H, H2þH6,
H2þH6-COCH3ph-NH); 8.85 (s, 1H, NH-4-COCH3ph-NH). Anal. Calcd
for C22H27N3O5S.1/2H2O: C, 58.14%; H, 6.17%; N, 9.25%. Found: C,
57.89%; H, 6.19%; N, 8.98%.
White solid. Yield: 20%. M.p: 159e160 ꢀC. IR (KBr, cmꢁ1): 3477
(w, nNeH); 1644 (s, nC]O); 1322, 1138 (vs, nSO2N); 1257 (vs, nCeOeC).
1H NMR (400 MHz, DMSO-d6)
d ppm: 1.48 (bs, 2H, H4-pip); 1.65 (bs,
4H, H3þH5-pip); 2.04 (bs, 2H, NeCH2eCH2); 2.93 (bs, 6H, H2þH6-
pip, NeCH2); 4.05e4.12 (m, 2H, OeCH2); 6.91e6.95 (m, 1H, H4-2-
CF3ph-NH); 7.00e7.10 (m, 1H, H5-2-CF3ph-NH); 7.22e7.32 (m, 2H,
H3þH5); 7.45e7.54 (m, 2H, H3þH6-2-CF3ph-NH); 7.71e7.76 (m, 2H,
H2þH6, J2,6-3,5 ¼ 8.8 Hz); 8.20 (bs, 1H, NH-2-CF3ph-NH). Anal. Calcd
for C22H26F3N3O4S$H2O: C, 52.48%; H, 5.57%; N, 8.35%. Found: C,
52.75%; H, 5.49%; N, 8.04%.
4.5.36. 1-(4-methylphenyl)-3-[4-(3-pyrrolidin-1-ylpropoxy)
benzene]sulfonylurea (55)
White solid. Yield: 15%. M.p: 158e159 ꢀC. IR (KBr, cmꢁ1): 3442
(w, nNeH); 1635 (s, nC]O); 1227 (vs, nCeOeC); 1123 (vs, nSO2N). 1H
NMR (400 MHz, DMSO-d6)
d
ppm: 1.87 (bs, 4H, H3þH4-pyr);
4.5.41. 1-(3-trifluoromethylphenyl)-3-[4-(3-piperidin-1-ylpropoxy)
benzene]sulfonylurea (60)
2.07e2.14 (m, 2H, NeCH2eCH2); 2.17 (s, 3H, CH3-ph); 3.08 (bs, 6H,
H2þH5-pyr, NeCH2); 4.09 (t, 2H, OeCH2, JCH2eCH2 ¼ 6.0 Hz);
6.90e6.96 (m, 4H, H3þH5, H3þH5-4eCH3eph); 7.30 (d, 2H,
White solid. Yield: 34%. M.p: 108e110 ꢀC. IR (KBr, cmꢁ1): 3321
(w, nNeH); 1596 (s, nC]O); 1338, 1169 (vs, nSO2N); 1253 (vs, nCeOeC).
H2þH6-4eCH3eph, J2,6-3,5
¼
8.2 Hz); 7.74 (d, 2H, H2þH6,
1H NMR (400 MHz, DMSO-d6)
d ppm: 1.52 (bs, 2H, H4-pip); 1.70 (bs,
J2,6-3,5 ¼ 8.7 Hz); 8.52 (s, 1H, NH-4-CH3ph-NH). Anal. Calcd for
C21H27N3O4S.2/3H2O: C, 58.74%; H, 6.53%; N, 9.79%. Found: C,
58.54%; H, 6.61%; N, 9.78%.
4H, H3þH5-pip); 2.07e2.11 (m, 2H, NeCH2eCH2); 3.10e3.14 (bs,
6H, H2þH6-pip, NeCH2); 4.07 (t, 2H, OeCH2, JCH2eCH2 ¼ 5.9 Hz);
6.93 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.9 Hz); 7.05 (d, 1H, H5-3-CF3ph-NH
,
J5-4,6 ¼ 8.0 Hz); 7.30 (t, 1H, H4-3-CF3ph-NH, J4e5 ¼ 8.0 Hz); 7.51 (d,
4.5.37. 1-(1-naphthyl)-3-[4-(3-pyrrolidin-1-ylpropoxy)benzene]
sulfonylurea (56)
1H, H6-3-CF3ph-NH J6e5
,
¼ 8.2 Hz); 7.74 (d, 2H, H2þH6,
J2,6-3,5 ¼ 8.8 Hz); 8.00 (s, 1H, H2-3-CF3ph-NH); 8.79 (bs, 1H, NH-3-
CF3ph-NH) ppm. Anal. Calcd for C22H26F3N3O4S: C, 54.43%; H, 5.36%;
N, 8.66%. Found: C, 54.57%; H, 5.41%; N, 8.37%.
White solid. Yield: 15%. M.p: 136e137 ꢀC. IR (KBr, cmꢁ1): 3415
(w, nNeH); 1599 (s, nC]O); 1343, 1134 (vs, nSO2N); 1248 (vs, nCeOeC).
1H NMR (400 MHz, DMSO-d6)
d
ppm: 1.83 (bs, 4H, H3þH4-pyr);
1.97e2.04 (m, 2H, NeCH2eCH2); 3.06 (bs, 6H, H2þH5-pyr, NeCH2);
4.04 (t, 2H, OeCH2, JCH2eCH2 ¼ 6.1 Hz); 6.96 (d, 2H, H3þH5,
J3,5-2,6 ¼ 8.8 Hz); 7.35 (t, 1H, H3-naph, J3-4,2 ¼ 7.9 Hz); 7.45e7.49 (m,
3H, H2þH6þH7-naph); 7.79 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.7 Hz);
7.83e7.85 (m, 1H, H4-naph); 7.90 (d, 1H, H5-naph, J5e6 ¼ 7.5 Hz);
8.03e8.05 (m, 1H, H8-naph); 8.61 (s, 1H, NH-naph). Anal. Calcd
for C24H27N3O4S.1/2H2O: C, 62.34%; H, 6.06%; N, 9.09%. Found: C,
62.32%; H, 6.10%; N, 8.94%. MS (EI, 70eV): m/z (%) ¼ 462 ([M$]þ, 5);
327 (14); 285 (20); 239 (46); 110 (5); 84 (100).
4.5.42. 1-(4-methoxyphenyl)-3-[4-(3-piperidin-1-ylpropoxy)
benzene]sulfonylurea (61)
Beige solid. Yield: 39%. M.p: 85e87 ꢀC. IR (KBr, cmꢁ1): 3351 (w,
nNeH); 1596 (s, nC]O); 1338, 1136 (vs, nSO2N); 1243 (vs, nCeOeC). 1H
NMR (400 MHz, DMSO-d6)
d ppm: 1.47 (bs, 2H, H4-pip); 1.65 (bs,
4H, H3þH5-pip); 2.02e2.07 (m, 2H, NeCH2eCH2); 2.93 (m, 6H,
H2þH6-pip, NeCH2); 3.66 (s, 3H, OCH3); 4.06 (t, 2H, OeCH2,
JCH2eCH2
¼
6.0 Hz); 6.73 (d, 2H, H2þH6-4-OCH3ph-NH
,
J2,6-3,5 ¼ 8.9 Hz); 6.96 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.5 Hz); 7.29 (d, 2H,
H3þH5-4-OCH3ph-NH, J3,5-2,6 ¼ 8.9 Hz); 7.77 (d, 2H, H2þH6,
J2,6-3,5 ¼ 8.5 Hz); 8.79 (s, 1H, NH-4-OCH3ph-NH). Anal. Calcd for
C22H29N3O5S$1/2H2O: C, 57.89%; H, 6.58%; N, 9.21%. Found: C,
57.52%; H, 6.77%; N, 8.86%.
4.5.38. 1-[4-(N,N0-dimethylamino)phenyl]-3-[4-(3-pyrrolidin-1-
ylpropoxy)benzene]sulfonylurea (57)
Purple solid. Yield: 21%. M.p: 142e143 ꢀC. IR (KBr, cmꢁ1): 3465
(w, nNeH); 1601 (s, nC]O); 1312, 1123 (vs, nSO2N). 1H NMR (400 MHz,
DMSO-d6)
d
ppm: 1.84 (bs, 4H, H3þH4-pyr); 2.01e2.07 (m, 2H,
4.5.43. 1-(4-acetylphenyl)-3-[4-(3-piperidin-1-ylpropoxy)benzene]
sulfonylurea (62)
NeCH2eCH2); 2.76 (bs, 6H, N(CH3)2); 3.00e3.04 (m, 6H, H2þH5-
pyr, NeCH2); 4.07 (t, 2H, OeCH2, JCH2eCH2 ¼ 6.4 Hz); 6.56 (d, 2H,
H3þH5-4eN(CH3)2eph, J3,5-2,6 ¼ 8.6 Hz); 6.87 (d, 2H, H3þH5,
White solid. Yield: 64%. M.p: 146e148 ꢀC. IR (KBr, cmꢁ1): 3420
(w, nN-H); 1686 (s, nC]Oketone); 1599 (s, nC]Ourea); 1359, 1173 (vs,
J3,5-2,6
¼
8.9 Hz); 7.24 (d, 2H, H2þH6-4eN(CH3)2eph,
nSO2N); 1232 (vs, nC-O-C). 1H NMR (400 MHz, DMSO-d6)
d
ppm: 1.36
J2,6-3,5 ¼ 8.8 Hz); 7.73 (d, 2H, H2þH6, J2,6-3,5 ¼ 8.8 Hz); 8.27 (s, 1H,
(bs, 2H, H4-pip); 1.46e1.51 (m, 4H, H3þH5-pip); 1.63 (s, 3H,

12
J. Ceras et al. / European Journal of Medicinal Chemistry 52 (2012) 1e13
COeCH3); 1.85 (t, 2H, NeCH2-CH2, JCH2-CH2 ¼ 6.8 Hz); 2.31e2.37 (m,
4H, H2þH6-pip); 2.44 (s, 2H, NeCH2); 4.01 (t, 2H, OeCH2,
JCH2eCH2 ¼ 6.4 Hz); 6.89 (d, 2H, H3þH5, J3,5-2,6 ¼ 8.9 Hz); 7.54 (d,
2H, H2þH6-4-COCH3ph-NH, J2,6-3,5 ¼ 8.8 Hz); 7.69e7.72 (m, 4H,
H2þH6, H3þH5-4-COCH3ph-NH); 8.86 (s, 1H, NH-4-COCH3ph-NH).
Anal. Calcd for C23H29N3O5S$H2O: C, 57.86%; H, 6.50%; N, 8.80%.
Found: C, 58.25%; H, 6.39%; N, 8.40%.
polyethyleneimine, followed by three ice-cold buffer washes
[50 mM Tris}HCl (pH 7.4)]. The binding data were analyzed by
a non-linear regression curve-fitting (single site) procedure using
the computer program PRISM (Graphpad Software Inc., San Diego,
CA, U.S.A.) to yield IC50 values.
4.6.2. KATP channel binding assay
The inhibitory effect on KATP channels of all sulfonylurea
derivatives was studied in rat cerebral cortex membranes as
previously described [36].
4.5.44. 1-(4-methylphenyl)-3-[4 -(3-piperidin-1-ylpropoxy)
benzene]sulfonylurea (63)
Beige solid. Yield: 76%. M.p: 120e122 ꢀC. IR (KBr, cmꢁ1): 3394,
3326 (m, nN-H); 1594 (s, nC]O); 1309,1138 (vs, nSO2N); 1230 (vs, nC-O-
4.6.3. hERG binding assay
C). 1H NMR (400 MHz, DMSO-d6)
d
ppm: 1.37 (d, 2H, H4-pip);
4.6.3.1. Cell culture. HERG-transfected HEK 293 cells were
obtained from the University of Wisconsin. These cells have been
fully characterized [37] and are widely used in functional iso-
lated whole-cell patch clamp assays for measuring hERG current
block. The cells were routinely cultured in T-175 cm2 flasks in
1.45e1.50 (m, 4H, H3þH5-pip); 1.84 (t, 2H, NeCH2-CH2,
JCH2-CH2 ¼ 6.8 Hz); 2.15 (s, 3H, CH3-ph-NH); 2.22 (bs, 2H, NeCH2);
2.31e2.38 (m, 4H, H2þH6-pip); 4.00 (t, 2H, OeCH2,
JCH2-CH2 ¼ 6.4 Hz); 6.87 (d, 4H, H3þH5, H3þH5-4-CH3ph-NH); 7.30
(d, 2H, H2þH6-4-CH3ph-NH, J2,6-3,5 ¼ 8.4 Hz); 7.68 (d, 2H, H2þH6,
J2,6-3,5 ¼ 8.5 Hz); 8.18 (s, 1H, NH-4-COCH3ph-NH). Anal. Calcd for
C22H29N3O4S$1/2H2O: C, 60.00%; H, 6.98%; N, 9.54%. Found: C,
60.14%; H, 6.82%; N, 9.17%.
MEM (Gibco/BRL 11095-080) supplemented with 2 mM L-gluta-
mine (Gibco/BRL 25030-081), 10% fetal bovine serum (Gibco/BRL
16000-036), 0.2 mg/ml geneticin (Gibco/BRL 10131-027), 1%
penicillin/streptomycin (Gibco/BRL 15140-122), 0.1 mM non-
essential amino acids (Gibco/BRL 11140-050), and 1 mM sodium
pyruvate (Gibco/BRL 11360-070) in a 37 ꢀC incubator with
5% CO2.
For membrane preparation, cells from two T-175 flasks were
combined, added to 2 l of complete MEM, seeded into a cell factory
(10 trays/chamber, 6320 cm2 culture area, Nunc catalog #170009),
and incubated at 37 ꢀC, 5% CO2 for 5 days with no media changes.
Six cell factories were typically seeded at the same time. Several
different membrane homogenate preparations and cell passages
(ranging from 17 to 66) were used to generate the data.
4.5.45. 1-Benzhydryl-3-[4-(3-piperidin-1-ylpropoxy)benzene]
sulfonylurea (64)
White solid. Yield: 21%. M.p: 182e184 ꢀC. IR (KBr, cmꢁ1): 3367
(m, nN-H); 1634 (s, nC]O); 1306, 1123 (vs, nSO2N); 1262 (vs, nC-O-C). 1H
NMR (400 MHz, DMSO-d6)
d ppm: 1.41 (bs, 2H, H4-pip); 1.56 (bs,
4H, H3þH5-pip); 1.94 (t, 2H, NeCH2-CH2, JCH2-CH2 ¼ 6.3 Hz); 2.67
(bs, 6H, H2þH6-pip, NeCH2); 4.07 (t, 2H, OeCH2, JCH2-CH2 ¼ 6.4 Hz);
5.81 (d, 1H, CHeC12
H
10, JCHeNH ¼ 7.9 Hz); 7.00 (d, 2H, H3þH5,
J3,5-2,6 ¼ 8.9 Hz); 7.20e7.28 (m, 12H, CHeC12
H10, NHCONH); 7.63 (d,
2H, H2þH6, J2,6-3,5 ¼ 8.0 Hz). Anal. Calcd for C28H33N3O4S$1/2H2O:
C, 65.12%; H, 6.59%; N, 8.14%. Found: C, 65.35%; H, 6.23%; N, 8.28%.
4.6.3.2. Membrane preparations. When the cells were approxi-
mately 80% confluent, the media were aspirated and the cell factory
chambers were washed with 1 l D-PBS (Gibco/BRL 14190-136). Cells
from each cell factory were harvested with 200 ml PBS-based,
enzyme-free cell dissociation buffer and rinsed with 250 ml
DPBS. Cells were then centrifuged at 14000x g for 15 min at 4 ꢀC,
resuspended in cold 0.32 M sucrose (10 ml/g of wet weight), and
homogenized using a Tekmar Tissuemizer. The cell homogenate
was centrifuged at 1000x g at 4 ꢀC for 10 min and the supernatant
was centrifuged at 41,000x g at 4 ꢀC for 30 min. The resulting
membrane pellets were suspended in 6.25 ml of 50 mM Tris (pH
8.5)/5 mM KCl per each gram of wet pellet weight, flash-frozen in
liquid nitrogen and stored at ꢁ80 ꢀC. Protein content was deter-
mined by the Coomasie method using Pierce’s Dry Protein Assay
Plate (cat. # 1856296).
4.6. Pharmacology
4.6.1. [125I]Iodoproxyfan binding assay
All compounds described in this paper were assayed for their
ability to displace radiolabelled
[
125I]Iodoproxyfan from hH3
receptors in a competitive binding assay [35].
CHO-K1 cells (American type culture collection, CCL61) were
maintained in Ham-F12 medium supplemented with 10% (v/v) fetal
calf serum, 2 mM glutamine, 500 units/ml penicillin and 500 mg/ml
streptomycin. The coding regions of the human H3 receptor were
subcloned into the pcDNA-neo expression vector (Invitrogen) and
transfected into CHO-K1 cells using lipofectAMINEÔ, as described
by the manufacturer (Life Technologies). Stably transfected cells
were selected with neomycin (500
mg/ml) and tested for their
ability to bind [125I]Iodoproxyfan.
4.6.3.3. [3H]Dofetilide-isolated membrane binding assay. The assay
conditions for [3H]dofetilide binding in membrane homogenates
were adapted from previously published methods [38]. The incu-
bation temperature was maintained at 37 ꢀC in order to more
accurately correlate our results to those in the reference literature,
and the incubation time for competition assays was 45 min.
Preliminary studies demonstrated that equilibrium binding was
achieved at 15 min and maintained until 90 min. This coincides
fairly well with incubation times ranging from 30 to 60 min
reported in the literature. Astemizole, a selective H1-receptor
antagonist and potent hERG current blocker, was used to determine
nonspecific binding.
Stock solutions of drugs were prepared in dimethylsulfoxide
(DMSO) at 10- or 30-mM concentrations. Serial drug dilutions were
prepared in binding assay buffer containing 1% DMSO for a final
DMSO assay concentration of 0.1%. Each concentration point was
tested in duplicate in each experiment.
Cells grown to confluence were harvested in 2 mM EDTA/PBS
and centrifuged at 1000 g for 5 min (4 ꢀC). The resulting pellet was
suspended in 20 mM Tris}HCl (pH 7.7) containing 5 mM EDTA, and
was homogenized using a Kinematica polytron (Fisher Bioblock
Scientific, Illkirch, France). The homogenate was then centrifuged at
95000 g for 30 min (4 ꢀC) and the pellet was suspended in binding
buffer [50 mM Na/HPO%/KH/PO4 (pH 7.5)]. Aliquots of membrane
preparations were stored at ꢁ80 ꢀC and were used for [125I]iodo-
proxyfan binding experiments.
Membranes (5
receptors were incubated for 1 h at room temperature in binding
buffer in a final volume of 250 l. For competition studies, 25 pM
125I]Iodoproxyfan (2000 Ci/mmol; Amersham Pharmacia Biotech)
was used. Nonspecific binding was determined in the presence
of 1 -methylhistamine. The reaction was stopped by
M R(ꢁ)-
rapid filtration through GF/B unifillters pretreated with 0.1%
mg/ml) obtained from cells stably expressing hH3
m
[
m
a

J. Ceras et al. / European Journal of Medicinal Chemistry 52 (2012) 1e13
13
P. Jacobson, V. Knourek- Segel, K.M. Krueger, M.E. Nuss, J.B. Pan, R. Shapiro,
D.G. Witte, B.B. Yao, Eur. J. Pharmacol. 487 (2004) 183e197;
(d) S. Celanaire, M. Wijtmans, P. Talaga, R. Leurs, I.J.P. de Esch, Drug Discov.
Today 10 (2005) 1613.
hERG-transfected HEK 293 cells were suspended in binding
assay buffer (37 ꢀC) at a concentration of 106 cells/ml. Membrane
aliquots were thawed and homogenized again in a glass Dounce
homogenizer (approximately 10 passes). The following were added
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to each 200-
plate, cat. # 6005290): 20
determination), 1 M astemizole (for nonspecific binding) or test
compound, 50 l of membrane
l of [3H]dofetilide, and 130
g/well). The plates
ml well of a 96-well polystyrene plate (Packard Opti-
ml of assay binding buffer (for total bound
m
m
m
homogenate (final protein concentration ¼ 30
m
were incubated at 37 ꢀC for 45 min, aspirated onto GF/B filter plates,
and washed with 2 ml of cold wash buffer. The radioactivity was
counted in a Packard Topcount Scintillation Counter after adding
[17] M. Mor, F. Bordi, C. Silva, S. Rivara, V. Zuliani, F. Vacondio, M. Rivara,
E. Barocelli, S. Bertoni, V. Ballabeni, F. Magnanini, M. Impicciatore, P.V. Plazzi,
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50 ml of scintillant (Packard Microscint-20, cat. # 6013621). Counts
per minute data from binding experiments were converted to
percent total specific bound (%TSB) using the following formula: %
TSB ¼ [(cpm _NSB)/(TB _NSB)]_100. The data was analyzed with
a four parameter logistic equation (PRISM, Graphpad) and reported
as IC50 where IC50 was the concentration that gives 50% inhibition
of [3H]dofetilide binding. For drugs that failed to displace more
than 50% of labeled dofetilide at the highest concentration tested,
IC50 values were reported as >10 mM. Drugs were typically tested at
seven concentrations, at half-log intervals. Each concentration
point was tested in duplicate.
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Acknowledgments
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J. Med. Chem. 47 (2004) 2833e2838.
We wish to Express our gratitude to the Asociación de Amigos
de la Universidad de Navarra and the Gobierno de Navarra for
grants given to J. Ceras and N. Cirauqui, respectively. We also thank
Carmen Elizalde for her help in the identification assays of this
study.
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