Synthesis and molecular structure of novel 2-(alkylthio)-4-chloro-N-(4,5- dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamides with potential anticancer activity

Article abstract of DOI:10.1007/s00706-012-0849-7

Aseries of novel 4-chloro-N-(4,5-dihydro-5-oxo- 1-R2-1H-1,2,4-triazol-3-yl) -5-methyl-2-(R¹-methylthio)benzenesulfonamide derivatives have been synthesized as potential anticancer agents. The in vitro antitumor activity of some compounds was ev

Full text of DOI:10.1007/s00706-012-0849-7

Monatsh Chem (2012) 143:1705–1718
DOI 10.1007/s00706-012-0849-7
ORIGINAL PAPER
Synthesis and molecular structure of novel 2-(alkylthio)-4-chloro-
N-(4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-5-methylbenzene-
sulfonamides with potential anticancer activity
_
Jarosław Sławinski Beata Zołnowska
•
•
´
Czesława Orlewska Jarosław Chojnacki
•
Received: 1 March 2012 / Accepted: 22 August 2012 / Published online: 25 September 2012
Ó The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract Aseriesofnovel4-chloro-N-(4,5-dihydro-5-oxo-
1-R2-1H-1,2,4-triazol-3-yl)-5-methyl-2-(R1-methylthio)ben-
zenesulfonamide derivatives have been synthesized as
potential anticancer agents. The in vitro antitumor activity of
some compounds was evaluated in the US National Cancer
Institute (NCI) against the NCI-60 cell line panel. The most
prominent compound showed remarkable activity against 13
human tumor cell lines representing lung, colon, CNS, mel-
anoma, ovarian, renal, prostate, and breast at low micromolar
GI50 level in the range of 1.9–3.0 lM.
It has been known that aryl/heteroarylsulfonamides may
act as antitumor agents through a variety of mechanisms such
as cell cycle perturbation in the G1 phase, disruption of
microtubules, angiogenesis inhibition, and functional sup-
pression of the transcriptional activator NF-Y. The most
prominent mechanism was the inhibition of carbonic anhy-
drase isozymes [18–22]. Recently, a host of structurally novel
arylsulfonamide derivatives have been reported to show
substantial anticancer activities in vitro and/or in vivo
[23–26]. We have reported the synthesis and anticancer
activityof2-mercaptobenzenesulfonamides and subsequently
extendedourstudytoanalogueswithvariousheterocyclicring
systems attached to the benzenesulfonamide scaffold [4–6, 8,
10, 15] (Fig. 1 structure A [4–6, 8, 15], B [8], C [10]).
Keywords Sulfonamide Á Anticancer Á Isocyanate Á
Cyclization Á Triazolone
In this article we investigated new sulfonamide deriva-
tives containing a triazolone ring in their structure.
Triazolones are described in the literature as biologically
active compounds, including anti-inflammatories [27], Nki
antagonists [28], inhibitors of tumor necrosis factor-a-con-
verting enzyme (TACE) [29], checkpoint kinase-1 inhibitor
[30], anti-tumor agents [31–34], and molecular chaperone
Hsp90 inhibitor, which is currently in clinical trials for a
number of human cancers [35]. Taking into account the
interesting properties of triazolones, we have synthesized
novel compounds of general structure D (Fig. 1).
Introduction
The aryl- and heteroarylsulfonamides are widely described
compounds revealing a broad spectrum of applications in bio-
logical and pharmacological areas [1]. For many years,
2-mercaptobenzenesulfonamide derivatives (MBSAs) have
been of interest because of the various biological properties
including antitumor [2–10], antimicrobial [11, 12], and antiviral
activities [13, 14], and inhibition of carbonic anhydrase [15–17].
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-012-0849-7) contains supplementary
material, which is available to authorized users.
Results and discussion
_
´
J. Sławinski (&) Á B. Zołnowska Á C. Orlewska
Chemistry
Department of Organic Chemistry, Medical University of
´ ´
Gdansk, Gen. J. Hallera Str. 107, 80416 Gdansk, Poland
e-mail: jaroslaw@gumed.edu.pl
The main goal of this study was to synthesize and investigate the
anticancer activity of the new 2-(alkylthio)benzenesulfonamides
containing diverse substituted 1,2,4-triazol-5-one moieties.
Thus, we propose a synthetic route leading to the target
J. Chojnacki
Department of Chemistry, Gdansk University of Technology,
´
Narutowicza 11/12, 80233 Gdansk, Poland
´
123

´
J. Sławinski et al.
1706
R4
Fig. 1 General structures of
2-mercaptobenzenesulfonamides
A, B, C, and D
Het:
R3
N
O
N
N
Ar
Ar
R2
N
X
Z
NH
HN
Z
HN
N
O
Cl
R1
S
S
N
Z
X = O, S, NH
H
N
Z = aromatic or
heteroaromatic ring
Het
O
O
A
R2
S
Ph
R1
R3
R2
Cl
R1
Cl
R1
S
S
Cl
Me
S
S
H
R2
N
N
H
N
H
S
O
R3
N
N
N
N
O
O
HN
O
O
O
NH2
O
N
O
NO2
N
N
R2
B
C
D
R1
R2
H
Cl
S
S
NH2
Scheme 1
Compounds
3, 11, 26
3, 12, 27
3, 13, 28
3, 14, 29
3, 15, 30
4, 16, 31
5, 17, 32
6, 18, 33
6, 19, 34
7, 20, 35
8, 21, 36
8, 22, 37
8, 23, 38
N
Ph
Ph
Ph
Ph
Ph
Me
O
O
Me
Ph
1
K2CO3
excess
4-O2NPhSO2
4-MePhSO2
4-MePh
Ph
PhCH2Cl,
K2CO3 excess,
THF
COOEt
O
Cl
SK
K
N
O
Me
S
3-CF3Ph
Ph
N
O
O
2
3-CF3Ph
4-CF3Ph
4-MePhSO2
Ph
R1CH2X,
(X = Cl or Br)
1-naphthyl
1-naphthyl
1-naphthyl
Ph
4-ClPh
4-MePhSO2
R1
R1
Cl
S
Cl
S
S
NH2NH2xHCl
K
N
9, 24, 39
NH
Ph
Ph
N
NH2
Me
S
Me
N
O
O
O
O
O
HN
O
3-10
11
NH2
10, 25, 40
R2NHNH2xHCl or
O
route A
route B
R2NHNH2,
4-MePhSO2OH
R1
TsCl, pyridine
R1
Cl
S
S
Cl
S
H
TsNCO
(3 equiv.)
H
N
H
N
O
N
NH
Me
Me
S
O
O
O
O
HN
N
N
R2
NH
R2
26-40
12-25
2-(alkylthio)-4-chloro-N-(4,5-dihydro-5-oxo-1-R2-1H-1,2,-
4-triazol-3-yl)-5-methylbenzenesulfonamides as shown in
Scheme 1.
salts 3 and 4, according to the reported procedure for prepa-
ration of N-(phenylsulfonyl)cyanamide potassium salts [36].
Novel potassium salts 5–10 were prepared by the reaction of 2
with the corresponding halomethyl electrophiles such as
aryl/cycloalkyl/methyl chlorides in methanol or ethanol.
Starting 3-aminobenzodithiazine 1 could be readily con-
verted to the corresponding dipotassium 2 and potassium
123

Synthesis and molecular structure of sulfonamide derivatives
1707
Subsequent reaction of salts 3–10 with either hydrazine
monohydrochloride, methylhydrazine, p-toluenesulfonyl
hydrazide, or various 4-substituted phenylhydrazine hydro-
chlorides led to the formation of the desired 3-(R2-amino)-1-
[4-chloro-5-methyl-2-(R1-methylthio)phenylsulfonyl]guanidine
derivatives 11–25 as depicted in Scheme 1. It is pertinent to
know, however, that aminoguanidine 15 was chosen for the
synthesis in two different ways (route A and B in Scheme 1).
This was supposed to explain some arising synthetic aspects:
whether the usefulness of the potassium salt, i.e., 3 with tosyl
hydrazide (route A), is higher than the reaction of amino-
guanidine11 with tosyl chloride (TsCl, route B), and whether
the reaction proceeds on the N-terminal nitrogen atom of the
sulfonylhydrazide moiety or on the second nitrogen atom
neighboring the sulfonyl group. As it turned out, both
methods products 15 were identical, with structures (IR,
NMR) having a N’-substituted sulfonylhydrazide fragment
and obtained in almost equal yields.
Fig. 2 Molecular structure of 31Pyr showing the atom-labeling
scheme. Displacement ellipsoids drawn at the 50 % probability level,
with the solvating water molecule omitted
Many methods are known for the synthesis of 1,2,4-triazol-
5-ones. Triazol-5-ones can be prepared for instance by the
reaction of the corresponding nitriles via imidates with
semicarbazide [37], from 4-substituted semicarbazides under
alkaline conditions [32], by heating of N1,N4-substituted hy-
drazinecarboxamides in alkaline media [38], by cyclization of
semicarbazide with an excess of phosgene [39], from the
reaction of N-acylureas with arylhydrazines [40], N-acylure-
thaneswithphenylhydrazinesasanEinhorn–Brunnerreaction
extension, as well as from C-halobenzylidenephenylhy-
drazones via nitrilimines with phenyl isocyanates [41, 42].
In the present study we utilized a new method for the synthesis
of 1,2,4-triazol-5-ones in the reaction of the corresponding
aminoguanudines 11–25 with an excess of p-toluenesulfonyl
isocyanate(TsNCO, Scheme 1). The isocyanates are wellknown
as carbonyl precursors [43] and electrophilic agents whose
reactions with hydrazines lead to intramolecular cyclization to
five-membered heterocyclic rings [44] or reagents in cycload-
dition reactions with various compounds having C=Nbonds [45].
Our experiments demonstrated that the proposed synthetic
route was an efficient way to prepare the desired N-(4,5-dihy-
dro-5-oxo-1H-1,2,4-triazol-3-yl)benzenesulfonamides 26–40
when an excess of three molar equivalents of tosyl isocyanate
was applied in the reaction with the corresponding aminogua-
nidines 11–25 in anhydrous tetrahydrofuran (THF) for at least
9 h at reflux. It is noteworthy, however, when 2 equivalents of
tosyl isocyanate were used, no cyclization product was
observed and a complex mixture of products was formed, even
after considerable extending of the reaction time.
Fig. 3 Hydrogen bonds in structure of 31Pyr. Blue lines represent
hydrogen bonds; transparent yellow balls denote inversion centers in
the crystal (generated using Mercury CSD 2.4 [46])
Molecular structure
Details on data collection, structure solution, and refine-
ment are given in Table 1. Compound 31Pyr crystallizes in
the monoclinic space group C2/c with (typical for this
symmetry) eight molecules in the unit cell. The molecule,
being a secondary benzenesulfonamide, is deprotonated at
the N1 atom and in the crystal structure is present in the
anionic form (Fig. 2). The proton is accepted by pyridine
so a pyridinium ion acts as a counterion. Additionally the
The structure of the new compounds was confirmed by
elemental analyses(C, H, N) and spectral(NMR, IR, MS) data
presented in the experimental section. Moreover, X-ray
analysis was undertaken to confirm proposed structures on the
representative compound 31, which crystallized as pyridini-
um salt (further specified as 31Pyr, Figs. 2 and 3).
123

´
J. Sławinski et al.
1708
Table 1 Crystal data and structure refinement for compound 31Pyr
Table 2 Hydrogen bond geometry in crystal structure of 31Pyr
˚
D–H/A
˚
˚
Empirical formula
Formula weight
Temperature/K
C20H20ClN4O5S2ÁC5H6NÁ0.08(O)
577.42
D–HÁÁÁA
N4–H4ÁÁÁO5i
N5–H5ÁÁÁN1
HÁÁÁA/A
DÁÁÁA/A
D–HÁÁÁA/°
0.88
0.88
1.89
1.90
2.765 (2)
2.767 (2)
171
169
120(2)
˚
Wavelength/A
0.71073
Monoclinic
C2/c
Symmetry code: (i) -x ? 1/2, -y ? 1/2, -z
Crystal system
Space group
Table 3 Main p–p stacking interaction geometry in crystal structure
of 31Pyr
Unit cell dimensions
˚
a/A
14.1490(3)
14.0574(4)
28.1211(6)
90
ii a
ab/°
bc/°
Perp.d
˚
b/A
˚
Cg(1)ÁÁÁCg(1 ) /A
˚
c/A
3.8513(10)
17
15.5
3.7104(7)
a/°
b/°
c/°
Ring (1) is composed from C5–C10 carbon atoms
102.107(2)
90
Symmetry code: (ii) -x, y, 1/2-z
a
Distance between centroids
3
˚
Volume/A
5,468.8 (2)
8
b
Dihedral angle between the rings
Z
c
Density (calculated)/mg m-3
Absorption coefficient/mm-1
F(000)
1.403
Angle between the vector span on the centroids and normal to
ring(1)
d
0.338
Perpendicular distance of Cg(I) on the other ring
2405
Crystal size/mm3
h range for data collection/°
Index ranges
0.20 9 0.13 9 0.10
2.3–26.0
p–p stacking interactions between adjacent aromatic rings
C5–C10 whose centers of gravity (Cg or centroids) are
˚
distant at 3.8513(10) A. The geometry of the interaction is
-17 B h B 17, -12 B k B 17,
-25 B l B 34
more precisely characterized in Table 3.
Reflections collected
12,491
Independent reflections
Completeness to h = 26.0°
Absorption correction
Refinement method
5,374 [R(int) = 0.02]
99.6 %
Biological assay
Numerical
Full-matrix least-squares on F2
Compounds 27, 28, and 30–39 were initially tested at a single
dose (10-5 M) in the full NCI-60 cell panel, and the results
are shown in Table 4. The methodology of the in vitro cancer
screen is described at the website http://www.dtp.nci.nih.
gov/branches/btb/ivclsp.html.
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I [ 2r(I)]
R indices (all data)
5,374/0/349
1.04
R1 = 0.0405, wR2 = 0.1015
R1 = 0.0469, wR2 = 0.1074
0.43 and -0.31
The relatively highest sensitivity to the compounds
described here was found for the cell lines of non-small cell
lung cancer NCI-H522 cell line to compounds 27, 28, 31,
and 38 (46 % \ IGP \ 84 %), leukemia RPMI-8226 to
compounds 27, 28, 30, and 31 (36 % \ IGP \ 45 %),
HL-60(TB) to 30, 31, 36, and 39 (22 % \ IGP \ 91 %), and
K-562 to compounds 30, 31, and 38 (37 % \ IGP \ 66 %)
as well as breast MCF7 to 30, 36, and 38 (38 % \ IGP \
83 %) (Table 4).
-3
˚
Largest diff. peak and hole/eÁA
solid contains solvating molecules of water that reside on
twofold rotation axes, and these positions are not fully
occupied by them (s.o.f. = 0.079). Actually, only ca. 1/8 of
the H2O molecules suffice to fit to the observed electron
density in this region.
The following conclusions can be drawn from the
structure–activity relationship study (Table 4):
The two ions are linked by a charge-assisted hydrogen
bond of the (?)NHÁÁÁN(-) type; pyridinium N(5) is a
donor, and sulfonamide N(1) is an acceptor. Bonds N(4)–
H(4) interact with carbonyl oxygen atoms O5 from the
triazolone moiety of the neighboring molecules forming
intermolecular hydrogen bonds NHÁÁÁO. These interactions
arranged in pairs can be described by the R22(8) motifs
situated about local inversion centers (see Fig. 3). Detailed
information on hydrogen bonds is given in Table 2.
Packing of molecules in the solid state is reinforced also by
1. The susceptibility of the non-small cell lung NCI-H522
cell line against 2-(benzylthio)-N-(2,5-dihydro-5-oxo-1-
R2-1H-1,2,4-triazol-3-yl)benzenesulfonamide derivatives
(27, 28, 30) was remarkable and increased when the
methyl group (R2 = Me, 27, IGP = 46 %) was
replaced by aromatic moieties such as phenyl (R2 = Ph,
28, IGP = 69 %) or tosyl (R2 = 4-MePhSO2, 30,
IGP = 71 %). The compounds mentioned above showed
similar potency for RPMI-8226 (27, IGP = 36 %; 28,
123

Synthesis and molecular structure of sulfonamide derivatives
1709
Table 4 Inhibition growth percent (IGP [%]). One-dose screening data of in vitro tumor growth inhibition for compounds 27, 28, 30–39 at a
dose of 10 lM
Panel
Cell line
Compound
27
28
30
31
32
33
34
35
36
37
38
39
Non-small cell
Lung cancer
A549/ATCC
NCI-H522
HOP-92
26
46
21
36
7
62
69
6
*
*
3
*
2
3
58
NT
NT
NT
NT
91
52
NT
73
36
61
77
49
41
75
65
88
68
71
79
83
31
3a
*
5
*
71
29
45
57
27
22
49
*
84
18
39
31
26
16
37
1
NT
NT
NT
NT
*
5
5
*
*
83
19
*
*
NT
7
20
13
19
*
NT
11
NT
NT
22
NT
*
5
NT
*
Leukemia
RPMI-8226
SR
45
28
13
10
17
46
18
*
7
NT
15
7
NT
*
78
*
NT
22
17
NT
*
HL-60(TB)
MOLT-4
K-562
19
2
*
7
*
21
66
16
23
19
3
14
2
NT
*
NT
*
*
9
Renal cancer
CNS cancer
RXF 393
UO-31
*
2
15
23
*
14
15
*
26
18
*
3
3
11
12
1
10
10
2
24
4
11
*
SNB-75
7
2
SF-295
*
*
4
8
*
SF-539
*
*
*
*
*
*
*
*
*
*
*
Colon cancer
HCC-2998
HCT-116
HCT-15
1
*
*
*
*
*
*
*
*
66
62
38
53
55
NT
1
4
3
6
6
*
*
1
*
4
*
*
4
*
7
*
*
5
*
4
1
2
HT29
*
*
4
*
*
*
1
*
*
*
SW-620
1
*
9
5
*
6
4
*
2
*
COLO 205
KM12
*
*
*
*
*
NT
*
*
NT
*
*
NT
*
*
*
5
*
*
*
*
Breast cancer
MCF7
*
*
38
20
NT
24
8
*
2
*
2
*
3
51
41
61
*
*
T-47D
8
3
9
*
*
*
1
6
1
MDA-MB-468
HS 578T
OVCAR-3
NCI/ADR-RES
UACC-257
UACC-62
MALME-3M
SK-MEL-2
MDA-MB-435
PC-3
NT
11
*
NT
*
NT
5
*
NT
NT
*
3
NT
NT
*
NT
12
*
*
*
2
46
5a
NT
Ovarian cancer
Melanoma
1
*
*
1
65
32
21
*
NT
*
NT
33
7
NT
*
NT
*
*
2
5
9
64
21
55
43
26
29a
59
*
*
*
4
*
*
*
9
2
*
*
6
3
15
5
7
*
10
12
*
*
7
4
5
NT
*
*
*
13
19
*
4
16
*
25
NT
69
7
*
*
9
*
*
NT
9
NT
6
NT
16
NT
8
1
9
1
*
Prostate cancer
5
8
5
12
*
Data obtained from NCI-60 DTP human tumor cell line screening
NT not tested
* Not active
a
Cytotoxic effect (lethality)
IGP = 45 %; 30, IGP = 45 %) and SR (27,
IGP = 7 %; 28, IGP = 28 %; 30, IGP = 57 %) lines
of leukemia. It should be noted, moreover, that replace-
ment of R2 = Ph (28) for R2 = 4-MePhSO2 (30) caused
loss of activity against non-small cell lung cancer
(A549/ATCC) and renal (RXF 393) cell lines.
2-position of benzenesulfonamide has an impact on the
antiproliferative activity against some cancer cell
lines: exchange for instance of R1 = 1-naphthyl in
36 into R1 = Ph (28), 1,3-dioxolan-1-yl (32), 3-CF3Ph
(34), 4-CF3Ph (35), and 1,2-dihydro-2-oxoquinolin-4-
yl (39) decreased activity against the leukemia HL-
60(TB) cell line, as well as the leukemia MOLT-4 cell
line; replacing R1 = 1-naphthyl or Ph for R1 = 3-
CF3Ph, 4-CF3Ph or 1,2-dihydro-2-oxoquinolin-4-yl
2. For the series of N-(4,5-dihydro-5-oxo-1-phenyl-1H-
1,2,4-triazol-3-yl)-2-(R1-methylthio)benzenesulfona-
mides the substituent at the sulfur atom S-2 at the
123

´
J. Sławinski et al.
1710
Table 5 The in vitro tumor growth inhibition data for compound 36
Table 5 continued
Panel
Cell line
GIa50
/
TGIb/
LCc50
/
Panel
Cell line
GIa50
/
TGIb/
LCc50
/
lM
lM
lM
lM
lM
lM
Leukemia
CCRF-CEM
HL-60(TB)
K-562
3.2
3.1
3.6
5.7
3.6
4.4
4.6
7.1
7.5
3.6
3.1
8.3
2.8
2.5
2.3
3.5
3.4
4.0
3.5
3.2
4.6
3.7
3.0
3.2
4.8
2.9
5.3
4.8
8.9
3.2
1.9
5.8
6.0
3.6
7.9
4.0
4.9
2.4
4.2
6.3
5.0
2.7
3.9
7.9
1.9
5.8
4.2
2.5
13.2
9.2
[100
58.7
[100
[100
[100
[100
[100
49.3
57.0
53.0
42.8
[100
[100
44.1
11.1
40.0
43.0
47.8
41.9
46.1
48.9
48.2
[100
44.1
95.3
85.1
54.9
48.8
92.2
64.9
32.0
60.2
54.2
36.6
[100
48.5
97.0
23.6
55.1
46.8
[100
[100
[100
54.3
38.0
68.7
[100
32.2
SN12C
10.3
4.6
18.2
56.8
45.9
17.1
8.6
52.7
TK-10
24.2
18.7
3.6
13.9
37.2
28.1
27.8
23.3
20.8
23.0
16.1
11.7
32.9
11.7
8.3
UO-31
5.5
MOLT-4
RPMI-8226
A549/ATCC
EKVX
Prostate cancer
PC-3
73.7
32.6
DU-145
MCF7
2.9
Non-small cell lung
cancer
Breast cancer
3.8
15.3
20.5
[100
60.4
MDA-MB-231/
ATCC
5.6
HOP-62
HS 578T
BT-549
2.9
19.6
26.0
35.9
12.3
[100
60.4
HOP-92
11.2
6.1
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
COLO 205
HCC-2998
HCT-116
HCT-15
T-47D
[100
49.9
MDA-MB-468
3.0
Data obtained from NCI-60 DTP human tumor cell line screening
a
GI50: molar concentration that inhibits 50 % net cell growth
b
Colon cancer
4.9
TGI: molar concentration giving total growth inhibition
c
12.6
12.6
15.3
11.7
12.5
18.6
15.5
13.9
9.4
LC50: molar concentration causing 50 % net cell death
HT29
resulted in loss of activity against cell lines non-small
cell lung A549/ATCC and renal RXF 393.
KM12
SW-620
3. The significant susceptibility of almost the entire colon
cancer subpanel against N-(4,5-dihydro-5-oxo-1-R2-1H-
1,2,4-triazol-3-yl)-2-(naphthalen-1-ylmethylthio)ben-
zenesulfonamides 36 and 38 should be pointed out.
Moreover, the exchange of R2 = Ph (36) or 4-MePh-
SO2 (38) for 4-ClPh (37) led to a lack of susceptibil-
ity of HCC-2998, HTC-116, HTC-15, HT29, and
SW-620.
CNS cancer
SF-268
SF-295
SF-539
SNB-19
23.5
15.5
19.9
18.3
29.4
11.5
5.5
SNB-75
U251
Melanoma
LOX IMVI
MALME-3 M
M14
Further anticancer evaluation was performed at five-dose
assay on the distinctive compound 36. The anticancer activity
of the tested compound was reported for each cell line by the
parameters GI50 (molar concentration of the compounds that
inhibit 50 % net cell growth), TGI (molar concentration of the
compounds leading to total inhibition), and LC50 (molar
concentration of the compounds causing 50 % net cell death).
The susceptibility of individual subpanels indicates the fol-
lowing order: prostate, colon, CNS, leukemia, ovarian, non-
small cell lung, melanoma, renal, and breast cancer (Table 5).
As shown in Table 5, compound 36 exhibited remarkable
activity at low GI50 level\11.2 lM (MID GI50 = 4.2 lM)
over a number of cancer cell lines, acting effectively against
13 human tumor cell lines with GI50 values in the low
micromolar range of 1.9–3.0 lM with selectivity toward
melanoma MDA-MB-435 (GI50 = 1.9 lM, TGI = 5.5) and
renal A498 (GI50 = 1.9 lM, TGI = 10.5) cell lines. It is
worth mentioning that lines HL-60(TB), NCI-H522, COLO
205, SF-539, MDA-MB-435, OVCAR-3, A498, RXF 393,
DU-145, and MDA-MB-468 were characterized by the
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
786-0
20.7
20.1
13.1
33.6
16.1
21.9
6.2
Ovarian cancer
16.5
19.4
33.0
8.6
18.1
22.0
10.5
21.9
25.9
7.6
Renal cancer
A498
ACHN
CAKI-1
RXF 393
123

Synthesis and molecular structure of sulfonamide derivatives
1711
triturated with 90 cm3 diethyl ether to give a second fraction
of precipitate. The product was extracted from the combined
fractions of solid with hot ethanol to give 2.99 g (86 %) 5.
M.p.: 224–225 °C; TLC: Rf = 0.74 (CHCl3:MeOH = 3:1);
IR (KBr): vꢀ = 2,924 (CH3, CH2), 2,854 (CH3, CH2), 2,179
relatively low parameters GI50 (1.9–3.2 lM), TGI (4.9–12.3
lM), and LC50 below 58.7 lM.
A COMPARE [47] analysis at the NCI of compound 36
showed a moderate Pearson’s correlation coefficient
(PCC = 0.473–0.425) with agents disrupting microtubule
formation such as maytansine and rhizoxin [48].
1
(C:N), 1,339, 1,145 (SO2) cm-1; H NMR (200 MHz,
DMSO-d6): d = 2.31 (s, 3H, CH3), 3.21 (d, 2H, S–CH2),
3.79–4.00 (m, 4H, CH2–O), 5.11 (t, 1H, CH–O), 7.46 (s, 1H,
H-3), 7.77 (s, 1H, H-6) ppm; 13C NMR (50 MHz, DMSO-
d6): d = 19.22, 36.04, 64.96, 102.34, 117.50, 127.42,
130.74, 131.36, 135.75, 135.97, 140.86 ppm.
Conclusion
We have developed a new method for the synthesis of a series
of2-(alkylthio)-4-chloro-N-(4,5-dihydro-5-oxo-1-R2-1H-1,2,
4-triazol-3-yl)-5-methylbenzenesulfonamides 26–40. The
prominent compound 36 showed high (GI50 = 1.9–3.0 lM)
activity against 13 of the tumor cell lines and reasonable
activity at level GI50\11.2 lM (MID GI50 = 4.2 lM) over a
number cell lines, suggesting that 36 may be a useful lead
compound for the search for more powerful anticancer agents
with low toxicity against normal cells.
General procedure for the preparation of N-[4-chloro-
5-methyl-2-(R1-methylthio)phenylsulfonyl]cyanamide
potassium salts 6–10
To a suspension of 3.05 g 5-chloro-2-(cyanoaminosulfo-
nyl)-4-methylthiophenolate dipotassium salt (2, 9 mmol) in
methanol or ethanol the appropriate halomethyl electro-
phile was added. The reaction mixture was stirred at room
temperature or at 65 °C. The precipitate was collected by
filtration. The product was separated from inorganic salts
by extraction with 200 cm3 hot ethanol.
Experimental
The following instruments and parameters were used:
melting points: Boetius apparatus; IR spectra: KBr pellets,
400–4,000 cm-1, Thermo Mattson Satellite FTIR spec-
trometer; 1H NMR and 13C NMR: Varian Gemini 200
apparatus or Varian Unity Plus 500 MHz, chemical shifts are
expressed as d values relative to Me4Si as standard; LC–MS
analyses: Shimadzu LCMS-IT-TOF LC-20A mass spec-
trometer with an electrospray ionization, capillary voltage in
N-[4-Chloro-5-methyl-2-[3-(trifluoromethyl)-
benzylthio]phenylsulfonyl]cyanamide potassium
salt (6, C16H11ClF3KN2O2S2)
Starting from 2 in 45 cm3 ethanol and 1.3 cm3 3-(trifluoro-
methyl)benzyl chloride (9 mmol) for 2 h at room temperature,
compound 6 was obtained. Yield: 3.46 g (84 %); m.p.: 158
–160 °C; TLC: Rf = 0.87 (CHCl3:MeOH = 2:1); IR (KBr):
vꢀ = 2,924 (CH3, CH2), 2,174 (C:N), 1,332, 1,132 (SO2)
cm-1;1H NMR (200 MHz, DMSO-d6): d = 2.31 (s, 3H, CH3),
4.41 (s, 2H, S–CH2), 7.41 (s, 1H, H-3), 7.58-7.62 (m, 2H, Ar),
7.76–7.81 (m, 3H, H-6, Ar) ppm; 13C NMR (50 MHz, DMSO-
d6): d = 19.23, 35.73, 117.46, 124.12, 124.20, 125.95, 126.03,
127.78, 129.77, 130.85, 131.89, 133.49, 134.82, 135.94,
138.57, 141.12 ppm.
˚
positive ion mode ?4.5 kV, column: Jupiter 4 u Proteo 90 A,
4.0 9 150 mm, 4 lm, mobile phase: A—water with 0.1 %
formic acid, B—0.1 % formic acid in acetonitrile, linear
gradient 50–100 % B in 45 min, flow rate: 0.2 cm3 min-1
.
The results of elemental analyses for C, H, and N were in
agreement with the calculated values within 0.3 % range.
Thin-layer chromatography (TLC) was performed on Merck
Kieselgel 60F254 plates and visualized with UV. N-(5-
Methylphenylsulfonyl)cyanamide potassium salts 3, 4 and
aminoguanidines 11–14 and 16 were obtained in accordance
with the previously described procedures [2, 36].
N-[4-Chloro-5-methyl-2-[4-(trifluoromethyl)-
benzylthio]phenylsulfonyl]cyanamide potassium
salt (7, C16H11ClF3KN2O2S2)
Starting from 2 in 45 cm3 ethanol and 1.3 cm3 4-(trifluoro-
methyl)benzyl chloride (9 mmol) for 4 h at room temperature,
compound 7 was obtained. Yield: 3.64 g (88 %); m.p.: 177
–178 °C; TLC: Rf = 0.69 (ethyl acetate:isopropanol = 2:1);
IR (KBr): vꢀ = 2,921 (CH3, CH2), 2,176 (C:N), 1,327, 1,137
N-[4-Chloro-2-(1,3-dioxolan-2-ylmethylthio)-
5-methylphenylsulfonyl]cyanamide potassium
salt (5, C12H12ClKN2O4S2)
To a suspension of 3.05 g 5-chloro-2-(cyanoaminosulfo-
nyl)-4-methylthiophenolate dipotassium salt (2, 9 mmol) in
9 cm3 methanol 2.4 cm3 2-(bromomethyl)-1,3-dioxolane
(23 mmol) was added dropwise for 5 min. The reaction
mixture was stirred at 65 °C for 6.5 h, then 12 h at room
temperature. The precipitate was collected by filtration.
The filtrate was evaporated to dryness, and the residue was
(SO2) cm-1 1H NMR (500 MHz, DMSO-d6): d = 2.29
;
(s, 3H, CH3), 4.38 (s, 2H, S–CH2), 7.38 (s, 1H, H-3), 7.66 (d,
2H, Ar), 7.68 (d, 2H, Ar), 7.73 (s, 1H, H-6) ppm; 13C NMR
(50 MHz, DMSO-d6): d = 19.23, 35.78, 117.50, 125.41, 125.
49, 125.56, 127.57, 130.13, 130.87, 131.84, 134.93, 135.96,
141.06, 142.02 ppm.
123

´
J. Sławinski et al.
1712
N-[4-Chloro-5-methyl-2-(naphthalen-1-ylmethylthio)-
phenylsulfonyl]cyanamide potassium
General procedure for the preparation of 1-[4-chloro-
5-methyl-2-(R1-methylthio)phenylsulfonyl]-3-
(R2-amino)guanidines 15, 17–25
salt (8, C19H14ClKN2O2S2)
Starting from 2 in 10 cm3 ethanol and 1.3 cm3 1-(chloro-
methyl)naphthalene (9 mmol) for 1 h at room temperature,
compound 8 was obtained. Yield: 3.09 g (78 %); m.p.:
223–225 °C; TLC: Rf = 0.63 (ethyl acetate:isopropa-
nol = 2:1); IR (KBr): vꢀ = 2,922 (CH3, CH2), 2,175
To a suspension of the appropriate N-(phenylsulfo-
nyl)cyanamide potassium salt (3, 5–10, 3.5 mmol) in dry
toluene was added the corresponding phenylhydrazine
hydrochloride derivative (3.5 mmol) or p-toluenesulfonyl
hydrazide (3.5 mmol) in the presence of p-toluenesulfonic
acid monohydrate (PTSA, 3.5 mmol). The reaction mixture
was stirred at reflux for 1–8 h, and left overnight at 0 °C.
The precipitate was filtered off, and dried, then treated with
20 cm3 of water. After vigorously stirring for 30 min the
precipitate was collected by filtration, dried, and crystal-
lized from ethanol (15, 17, 19, 21-23, 25), ethyl acetate/
hexane (18), or ethyl acetate (20, 24).
1
(C:N), 1,341, 1,140 (SO2) cm-1; H NMR (500 MHz,
DMSO-d6): d = 2.32 (s, 3H, CH3), 4.72 (s, 2H, S–CH2),
7.44–7.47 (m, 1H, Ar), 7.51 (s, 1H, H-3), 7.52–7.59 (m,
2H, Ar), 7.61 (d, 1H, Ar), 7.76 (s, 1H, H-6), 7.87 (d, 1H,
Ar), 7.95 (d, 1H, Ar), 8.24 (d, 1H, Ar) ppm; 13C NMR
(50 MHz, DMSO-d6): d = 19.29, 34.68, 117.49, 124.62,
125.78, 126.20, 126.52, 127.76, 128.20, 128.36, 128.76,
130.80, 131.60, 131.71, 132.20, 133.68, 136.04, 136.15,
140.76 ppm.
1-[2-(Benzylthio)-4-chloro-5-methylphenylsulfonyl]-3-
(4-methylphenylsulfonylamino)guanidine
(15, C22H23ClN4O4S3)
N-[4-Chloro-2-(1,2-dihydro-2-oxoquinolin-4-ylmethyl-
thio)-5-methylphenylsulfonyl]cyanamide potassium
salt (9, C18H13ClKN3O3S2)
Method A. According to the general procedure, starting from
1.37 g 3, 0.65 g p-toluenesulfonyl hydrazide, and 0.66 g
PTSA in 40 cm3 of dry toluene for 1 h, the title compound 15
was obtained. Yield: 1.62 g (86 %); m.p.: 242–244 °C;
TLC: Rf = 0.38 (CHCl3:pentane:acetone = 1:1:0.5); IR
(KBr): vꢀ = 3,469, 3,361 (NH), 2,922, 2,832 (CH3, CH2),
1,384, 1,340, 1,172, 1,141 (SO2) cm-1; 1H NMR (500 MHz,
DMSO-d6): d = 2.30 (s, 3H, CH3), 2.39 (s, 3H, CH3), 4.29
(s, 2H, S–CH2), 7.18 (brs, 1H, NH=), 7.25–7.28 (m, 1H, Ar),
7.32–7.38 (m, 4H, Ar), 7.42–7.43 (m, 4H, H-3, NH, Ar), 7.66
(d, 2H, Ar), 7.79 (s, 1H, H-6), 9.23 (s, 1H, N–NHSO2), 9.89
(s, 1H, SO2NH) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 19.20, 21.35, 36.60, 127.51, 128.04, 128.15, 128.74,
129.41, 129.89, 130.58, 132.09, 134.71, 135.86, 136.48,
136.74, 139.64, 144.17, 158.47 ppm.
Starting from 2 in 42 cm3 ethanol and 2.1 g 4-(bromo-
methyl)quinolin-2(1H)-one (9 mmol) for 4 h at room
temperature, compound 9 was obtained. Yield: 3.60 g
(88 %); m.p.: 199–201 °C; TLC: Rf = 0.61 (ethyl ace-
tate:isopropanol:acetic acid = 1:1:0.02); IR (KBr): vꢀ =
2,922 (CH3, CH2), 2,181 (C:N), 1,668 (CO), 1,341, 1,142
1
(SO2) m-1; H NMR (500 MHz, DMSO-d6): d = 2.31 (s,
3H, CH3), 4.52 (s, 2H, S-CH2), 6.57 (s, 1H, Ar), 7.21 (t,
1H, Ar), 7.32 (d, 1H, Ar), 7.40 (s, 1H, H-3), 7.51 (t, 1H,
Ar), 7.77 (s, 1H, H-6), 7.93 (d, 1H, Ar), 11.74 (s, 1H,
NH) ppm; 13C NMR (50 MHz, DMSO-d6): d = 19.30,
33.33, 115.88, 117.50, 118.47, 121.99, 122.08, 125.42,
128.14, 130.82, 132.21, 134.60, 136.04, 139.22, 141.24,
146.29, 161.59 ppm.
Method B. To a cooled mixture of 1.35 g 11 (3.5 mmol) in
5 cm3 dry pyridine was added 0.67 g tosyl chloride
(3.5 mmol). The ice bath was removed and the mixture
was stirred at room temperature for 4 h, then at 60–65 °C for
5 h. After standing overnight, the mixture was added
dropwise to 12 cm3 slush and vigorously stirred for 2 h.
The solid was filtered off, washed with water (5 9 20 cm3),
1 % HCl (2 9 20 cm3), water (2 9 20 cm3) and dried.
Purification from MeOH yielded 15 (86 %); m.p.
242–244 °C (dec.); IR and 1H NMR spectra were identical
with an authentic sample of 15.
N-[4-Chloro-2-(2,3-dihydrobenzo[b][1,4]dioxin-2-
ylmethylthio)-5-methylphenylsulfonyl]cyanamide
potassium salt (10, C17H14ClKN2O4S2)
Starting from 2 in 23 cm3 methanol and 1.7 cm3 2-(bro-
momethyl)-1,4-benzodioxane (12 mmol) for 6 h at 65 °C,
compound 10 was obtained. Yield: 3.2 g (78 %); m.p.:
98–100 °C; TLC: Rf = 0.86 (CHCl3:pentane:acetone =
1:1:0.5); IR (KBr): vꢀ = 2,923 (CH3, CH2), 2,176 (C:N),
1,343, 1,143 (SO2) cm-1; 1H NMR (200 MHz, DMSO-d6):
d = 2.33 (s, 3H, CH3), 3.34 (d, 2H, S–CH2), 4.04–4.13 (m,
2H, CH2–O), 4.29–4.43 (m, 1H, CH–O), 6.80–6.91 (m, 4H,
Ar), 7.57 (s, 1H, H-3), 7.78 (s, 1H, H-6) ppm; 13C NMR
(50 MHz, DMSO-d6): d = 19.30, 32.96, 66.34, 71.91,
107.38, 117.23, 117.37, 121.61, 121.79, 128.34, 130.85,
132.24, 134.60, 136.20, 141.72, 142.81, 143.13 ppm.
1-[4-Chloro-2-(1,3-dioxolan-2-ylmethylthio)-
5-methylphenylsulfonyl]-3-(phenylamino)guanidine
(17, C18H21ClN4O4S2)
Starting from 1.36 g 5 and 0.51 g phenylhydrazine hydro-
chloride in 5 cm3 dry toluene for 1 h, the title compound
123

Synthesis and molecular structure of sulfonamide derivatives
1713
17 was obtained. Yield: 0.80 g (50 %); m.p.: 173–175 °C;
TLC: Rf = 0.59 (CHCl3:pentane:acetone = 1:1:0.5); IR
(KBr): vꢀ = 3,447 (NH), 2,923 (CH3, CH2), 1,393, 1140
(SO2) cm-1; 1H NMR (500 MHz, DMSO-d6): d = 2.32 (s,
3H, CH3), 3.28 (d, 2H, S-CH2), 3.79–3.85 (m, 2H, CH2–O),
3.92–3.98 (m, 2H, CH2–O), 5.14 (t, 1H, CH–O), 6.69 (d,
2H, Ar), 6.79 (t, 1H, Ar), 7.02 (s, 1H, NH=), 7.17 (t, 2H,
Ar), 7.38 (s, 1H, NH-Ph), 7.56 (s, 1H, H-3), 7.86 (s, 1H,
H-6), 7.88 (s, 1H, NH-NH-Ph), 9.07 (s, 1H, NHSO2) ppm;
13C NMR (50 MHz, DMSO-d6): d = 19.22, 36.44, 65.06,
102.35, 112.99, 120.01, 128.16, 129.09, 130.56, 132.04,
136.00, 136.64, 140.28, 148.23, 159.25 ppm.
was obtained. Yield: 1.04 g (56 %); m.p.: 161–164 °C; TLC:
Rf = 0.71 (CHCl3:pentane:acetone = 1:1:0.5); IR (KBr):
vꢀ = 3,433 (NH), 2,924 (CH3, CH2), 1,325, 1,129 (SO2)
1
cm-1; H NMR (500 MHz, DMSO-d6): d = 2.29 (s, 3H,
CH3), 4.46 (s, 2H, S–CH2), 6.65 (d, 2H, Ar), 6.76 (t, 1H, Ar),
7.04 (s, 1H, NH=), 7.11 (t, 2H, Ar), 7.40 (s, 1H, NH-Ph), 7.46
(s, 1H, H-3), 7.62–7.72 (m, 4H, H-6, Ar, NH-NH-Ph), 7.89 (d,
2H, Ar), 9.06 (s, 1H, NHSO2) ppm; 13C NMR (50 MHz,
DMSO-d6): d = 19.21, 35.81, 112.94, 119.96, 125.48, 125.
56, 125.63, 128.03, 129.04, 130.12, 130.79, 132.39, 135.04,
136.65, 140.29, 141.74, 148.15, 159.21 ppm.
1-[4-Chloro-5-methyl-2-(naphthalen-1-ylmethylthio)-
phenylsulfonyl]-3-(phenylamino)guanidine
(21, C25H23ClN4O2S2)
1-[4-Chloro-5-methyl-2-[3-(trifluoromethyl)-
benzylthio]phenylsulfonyl]-3-(phenylamino)-
guanidine (18, C22H20ClF3N4O2S2)
Starting from 1.54 g 8 and 0.5 g phenylhydrazine hydrochlo-
ride in 10 cm3 dry toluene for 1 h, the title compound 21 was
obtained. Yield: 0.82 g (40 %); m.p.: 145–150 °C; TLC: Rf =
0.71(CHCl3:pentane:acetone = 1:1:0.5); IR (KBr): vꢀ = 3,331
(NH), 2,922 (CH3, CH2), 1,391, 1,137 (SO2) cm-1; 1H NMR
(200 MHz, DMSO-d6): d = 2.33 (s, 3H, CH3), 4.79 (s, 2H,
S–CH2), 6.62 (d, 2H, Ar), 6.75 (t, 1H, Ar), 6.96 (s, 1H, NH=),
7.07–7.10 (m, 2H, Ar), 7.33 (s, 1H, NH-Ph), 7.43–7.46 (m, 1H,
Ar), 7.52–7.61 (m, 4H, H-3, Ar), 7.84–7.96 (m, 4H, H-6, Ar,
Staring from 1.61 g 6 and 0.50 g phenylhydrazine hydro-
chloride in 11 cm3 dry toluene for 1 h, the title compound 18
was obtained. Yield: 1.26 g (68 %); m.p.: 184–185 °C;
TLC: Rf = 0.67 (CHCl3:pentane:acetone = 1:1:0.5); IR
(KBr): vꢀ = 3,444 (NH), 2,925 (CH3, CH2), 1,330, 1,120
(SO2) cm-1; 1H NMR (200 MHz, DMSO-d6): d = 2.30 (s,
3H, CH3), 4.46 (s, 2H, S–CH2), 6.66 (d, 2H, Ar), 6.77 (t, 1H,
Ar), 7.04 (s, 1H, NH=), 7.13 (t, 2H, Ar), 7.40 (s, 1H, NH-Ph),
7.47 (s, 1H, H-3), 7.55–7.68 (m, 2H, Ar), 7.74 (s, 1H, H-6),
7.97 (s, 1H, NH-NH-Ph), 7.88–7.97 (m, 2H, Ar), 9.08 (s, 1H,
NHSO2) ppm; 13C NMR (50 MHz, DMSO-d6): d = 19.22,
35.90, 112.94, 119.97, 124.20, 124.27, 126.01, 126.08,
128.42, 129.05, 129.89, 130.77, 132.49, 133.44, 134.90,
136.59, 138.39, 140.47, 148.16, 159.19 ppm.
NH-NH-Ph), 8.25 (d, 1H, Ar), 9.05 (s, 1H, NHSO2) ppm; 13
C
NMR (50 MHz, DMSO-d6): d = 19.28, 34.82, 112.92, 119.
97, 124.50, 125.82, 126.24, 126.60, 128.22, 128.41, 128.80, 12
8.89, 129.06, 130.73, 131.71, 132.00, 132.24, 133.69, 136.19,
136.72, 140.13, 148.13, 159.19 ppm.
1-[4-Chloro-5-methyl-2-(naphthalen-1-ylmethylthio)-
phenylsulfonyl]-3-(4-chlorophenylamino)guanidine
(22, C25H22Cl2N4O2S2)
1-[4-Chloro-5-methyl-2-[3-(trifluoromethyl)-
benzylthio]phenylsulfonyl]-3-(4-methylphenylsulfonyl-
amino)guanidine (19, C23H22ClF3N4O4S3)
Starting from 1.54 g 8 and 0.63 g 4-chlorophenylhydrazine
hydrochloride in 10 cm3 dry toluene for 3 h, the title
compound 22 was obtained. Yield: 1.34 g (70 %); m.p.: 148
–149 °C; TLC: Rf = 0.68 (CHCl3:pentane:acetone = 1:1:
0.5); IR (KBr): vꢀ = 3,448, 3,318 (NH), 2,923 (CH3, CH2),
1,340, 1,140 (SO2) cm-1; 1H NMR (200 MHz, DMSO-d6):
d = 2.33 (s, 3H, CH3), 4.80 (s, 2H, S–CH2), 6.60 (d, 2H, Ar),
6.98 (s, 1H, NH=), 7.07 (d, 2H, Ar), 7.35–7.64 (m, 6H, Ar,
NH), 7.84–8.10 (m, 4H, Ar, NH), 8.50 (d, 1H, Ar), 9.05 (s,
1H, NHSO2) ppm; 13C NMR (50 MHz, DMSO-d6): d =
19.27, 34.77, 114.35, 123.23, 124.51, 125.81, 126.25, 126.
60, 128.27, 128.45, 128.78, 130.72, 131.73, 131.98, 132.22,
133.68, 136.22, 136.77, 139.97, 147.18, 159.01 ppm.
Starting from 1.61 g 6, 0.65 g p-toluenesulfonyl hydrazide,
and 0.66 g PTSA in 40 cm3 dry toluene for 1.5 h, the title
compound 19 was obtained. Yield: 1.49 g (70 %); m.p.:
190–191 °C; TLC: Rf = 0.65 (CHCl3:MeOH = 16:3); IR
(KBr): vꢀ = 3,459, 3,360, 3,310 (NH), 2,926 (CH3, CH2),
1
1,635 (C=N), 1,333, 1,174, 1,126 (SO2) cm-1; H NMR
(200 MHz, DMSO-d6): d = 2.29 (s, 3H, CH3), 2.38 (s, 3H,
CH3), 4.40 (s, 2H, S–CH2), 7.24 (brs, 1H, NH), 7.36 (d, 2H,
Ar tosyl), 7.43 (s, 1H, NH), 7.50–7.77 (m, 7H, Ar, Ar
tosyl), 7.78 (s, 1H, H-6), 9.22 (s, 1H, SO2NH), 9.90 (s, 1H,
SO2NH) ppm; 13C NMR (50 MHz, DMSO-d6): d = 19.22,
21.32, 36.01, 124.31, 124.39, 126.00, 126.08, 128.13,
128.89, 129.51, 129.89, 130.59, 132.68, 133.46, 134.69,
134.73, 136.69, 138.41, 140.23, 144.18, 158.46 ppm.
1-[4-Chloro-5-methyl-2-(naphthalen-1-ylmethylthio)-
phenylsulfonyl]-3-(4-methylphenylsulfonylamino)-
guanidine (23, C26H25ClN4O4S3)
1-[4-Chloro-5-methyl-2-[4-(trifluoromethyl)-
benzylthio]phenylsulfonyl]-3-(phenylamino)guanidine
(20, C22H20ClF3N4O2S2)
Starting from 1.54 g 8, 0.65 g p-toluenesulfonyl hydrazide,
and 0.66 g PTSA in 70 cm3 dry toluene for 2.5 h, the title
compound 23 was obtained. Yield: 1.61 g (78 %); m.p.:
203–206 °C; TLC: Rf = 0.32 (CHCl3:pentane:acetone
Starting from 1.61 g 7 and 0.51 g phenylhydrazine hydro-
chloride in 13 cm3 dry toluene for 2 h, the title compound 20
123

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J. Sławinski et al.
1714
= 1:1:0.5); IR (KBr): vꢀ = 3,475, 3,370, 3,310 (NH), 2,923
General procedure for the preparation of 4-chloro-5-
(CH3, CH2), 1633 (C=N), 1,339, 1,172, 1,146 (SO2) cm-1
;
methyl-2-(R1-methylthio)-N-(1-R2-4,5-dihydro-5-oxo-
1H-1,2,4-triazol-3-yl)benzenesulfonamide derivatives
26–40
1H NMR (200 MHz, DMSO-d6): d = 2.33 (s, 3H, CH3), 2.
36 (s, 3H, CH3), 4.74 (s, 2H, S–CH2), 7.20 (brs, 1H, NH),
7.31 (d, 2H, Ar tosyl), 7.44 (s, 1H, NH), 7.48–7.74 (m, 6H,
Ar naphth, tosyl), 7.66 (s, 1H, H-3), 7.82 (s, 1H, H-6), 7.8
4–8.02 (m, 2H, Ar naphth), 8.24 (d, 1H, Ar naphth), 9.20
(s, 1H, SO2NH), 9.86 (s, 1H, SO2NH) ppm; 13C NMR
(50 MHz, DMSO-d6): d = 19.28, 21.33, 34.97, 124.49, 12
5.79, 126.24, 126.58, 128.12, 128.22, 128.41, 128.80, 128.
96, 129.86, 130.57, 131.67, 132.07, 132.46, 133.68, 134.6
5, 135.97, 136.79, 139.94, 144.13, 158.45 ppm.
The reaction was carried out in a two-neck round-bottom
flask (capacity 5 cm3) with drying tube protection. To the
cooled (0 °C) mixture of the corresponding aminoguani-
dines 11–25 (1 mmol) in dry THF, 0.46 cm3 TsNCO
(3 mmol) was added dropwise, and the reaction mixture was
stirred at room temperature for 1 h, then at reflux for 8–36 h.
After cooling (0 °C, overnight) the reaction product was
isolated in precipitate state (27–31, 34–40) or in oil form
(26, 32, and 33) and purified by crystallization from ethanol
(26-31, 33–39), ethyl acetate (32), or acetonitrile (40).
1-[4-Chloro-2-(1,2-dihydro-2-oxoquinolin-4-ylmethylthio)-
5-methylphenylsulfonyl]-3-(phenylamino)guanidine
(24, C24H22ClN5O3S2)
2-(Benzylthio)-4-chloro-N-(4,5-dihydro-5-oxo-1H-1,2,4-
triazol-3-yl)-5-methylbenzenesulfonamide
Starting from 1.6 g 9 and 0.51 g phenylhydrazine hydro-
chloride in 15 cm3 dry toluene for 8 h, the title compound
24 was obtained. Yield: 1.06 g (58 %); m.p.: 171–173 °C;
TLC: Rf = 0.70 (CHCl3:MeOH = 16:3); IR (KBr): vꢀ =
3,343 (NH), 2,922 (CH3, CH2), 1,663 (CO), 1,386, 1,143
(SO2) cm-1; 1H NMR (500 MHz, DMSO-d6): d = 2.31 (s,
3H, CH3), 4.62 (s, 2H, S–CH2), 6.66 (d, 2H, Ar), 6.69
(s, 1H, Ar), 6.76 (t, 1H, Ar), 7.00 (s, 1H, NH =), 7.13
(t, 2H, Ar), 7.22 (t, 1H, Ar), 7.32 (d, 1H, Ar), 7.39 (s, 1H,
NH-Ph), 7.50 (t, 1H, Ar), 7.52 (s, 1H, H-3), 7.88 (s, 1H,
H-6), 7.90 (s, 1H, NH-NH-Ph), 7.94 (d, 1H, Ar), 9.14 (s,
1H, NHSO2), 11.78 (s, 1H, NH-quinol) ppm; 13C NMR
(50 MHz, DMSO-d6): d = 19.03, 33.16, 112.69, 115.69,
118.31, 119.75, 121.67, 121.83, 125.01, 128.46, 128.85, 13
0.51, 130.61, 132.64, 134.39, 136.49, 138.90, 140.48, 14
6.08, 147.88, 158.91, 161.55 ppm.
(26, C16H15ClN4O3S2)
Starting from 0.385 g 11 (1 mmol) in 1.5 cm3 THF, the
reaction mixture was refluxed for 8 h. After cooling to room
temperature, the oily solution was treated with 30 cm3 diethyl
ether. The ether solution was decanted from the solid,
evaporated to dryness, and the residue crystallized from ethanol
to obtain 0.065 g (16 %) of 26. The deposit after decantation
was treated with 20 cm3 diethyl ether, filtered off, and purified
by crystallization from ethanol to give 0.123 g (30 %) as a
second fraction of 26. M.p.: 278–279 °C; TLC: Rf = 0.44
(benzene:EtOH = 2:1); IR (KBr): vꢀ = 3,346 (NH), 2,929
(CH3, CH2), 1,688 (CO), 1,355, 1,161 (SO2) cm-1; 1H NMR
(500 MHz, DMSO-d6): d = 2.32 (s, 3H, CH3), 4.36 (s, 2H,
S–CH2), 7.26 (t, 1H, Ar), 7.32 (t, 2H, Ar), 7.43 (d, 2H, Ar), 7.54
(s, 1H, H-3), 7.86 (s, 1H, H-6), 11.19 (s, 1H, NH), 11.50 (s, 1H,
NH) ppm; 13C NMR (50 MHz, DMSO-d6): d = 19.29, 36.81,
125.89, 127.63, 128.73, 129.49, 132.02, 132.78, 136.05,
136.29, 138.29, 154.50 ppm; LC–MS (IT-TOF): m/z = 410
(M?), tR = 5 min.
1-[4-Chloro-2-(2,3-dihydrobenzo[b][1,4]dioxin-2-
ylmethylthio)-5-methylphenylsulfonyl]-3-(phenylamino)-
guanidine (25, C23H23ClN4O4S2)
Starting from 1.57 g 10 and 0.53 g phenylhydrazine
hydrochloride in 8 cm3 dry toluene for 1 h, the title
compound 25 was obtained. Yield: 1.12 g (62 %); m.p.:
175–177 °C; TLC: Rf = 0.70 (CHCl3:pentane:acetone =
1:1:0.5); IR (KBr): vꢀ = 3,442 (NH), 2,923 (CH3, CH2),
1,399, 1,145 (SO2) cm-1; 1H NMR (500 MHz, DMSO-d6):
d = 2.33 (s, 3H, CH3), 3.32-3.48 (m, 2H, S–CH2), 4.06
–4.10 (m, 1H, CH–O), 4.37 (d, 2H, CH2–O), 6.68 (d, 2H,
Ar), 6.77 (t, 1H, Ar), 6.81–6.87 (m, 4H, Ar), 7.03 (s, 1H, N
H=), 7.15 (t, 2H, Ar), 7.41 (s, 1H, NH-Ph), 7.64 (s, 1H,
H-3), 7.88 (s, 1H, H-6), 7.90 (s, 1H, NH-NH-Ph), 9.09 (s,
1H, NHSO2) ppm; 13C NMR (50 MHz, DMSO-d6): d =
19.29, 33.19, 66.32, 72.02, 112.96, 117.23, 117.41, 120.03,
121.66, 121.83, 128.87, 129.11, 130.74, 132.78, 134.89,
136.86, 140.95, 142.77, 143.10, 148.19, 159.23 ppm.
2-(Benzylthio)-4-chloro-N-(4,5-dihydro-1-methyl-5-
oxo-1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamide
(27, C17H17ClN4O3S2)
Starting from 0.399 g 12 (1 mmol) in 1.5 cm3 THF, the
reaction mixture was refluxed for 8 h. The product was
purified to give 0.263 g (62 %) of 27. M.p.: 226–228 °C;
TLC: Rf = 0.22 (benzene:EtOH = 2:1); IR (KBr): vꢀ = 3,
102 (NH), 2,924 (CH3, CH2), 1,764 (CO), 1,319, 1,131
1
(SO2) cm-1; H NMR (500 MHz, DMSO-d6): d = 2.31 (s,
3H, CH3), 3.19 (s, 3H, CH3), 4.32 (s, 2H, S–CH2), 7.25 (t, 1H,
Ar), 7.31 (t, 2H, Ar), 7.37 (d, 2H, Ar), 7.51 (s, 1H, H-3), 7.94
(s, 1H, H-6), 11.75 (brs, 1H, NH) ppm; 13C NMR (50 MHz,
DMSO-d6): d = 19.21, 32.66, 36.38, 127.51, 128.04, 128.71,
129.20, 130.93, 132.18, 135.60, 136.67, 136.84, 139.58,
123

Synthesis and molecular structure of sulfonamide derivatives
1715
147.70, 152.49 ppm; LC–MS (IT-TOF): m/z = 424 (M?),
tR = 6 min.
2, 138.77, 143.34, 145.82, 151.67 ppm; LC–MS (IT-TOF):
m/z = 564 (M?), tR = 12 min.
2-(Benzylthio)-4-chloro-N-(4,5-dihydro-5-oxo-1-phenyl-
1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamide
(28, C22H19ClN4O3S2)
4-Chloro-N-[4,5-dihydro-1-(4-methylphenyl)-5-oxo-1H-
1,2,4-triazol-3-yl]-2-(ethoxycarbonylmethylthio)-5-methyl-
benzenesulfonamide (31, C20H21ClN4O5S2)
Starting from 0.461 g 13 (1 mmol) in 1.5 cm3 THF, the
reaction mixture was refluxed for 9 h. The product was
purified to give 0.362 g (74 %) of 28. M.p.: 212–214.5 °C;
TLC: Rf = 0.61 (benzene:EtOH = 2:1); IR (KBr): vꢀ =
3,240 (NH), 2,923 (CH3, CH2), 1,702 (CO), 1,354, 1,173
(SO2) cm-1; 1H NMR (200 MHz, DMSO-d6): d = 2.36 (s,
3H, CH3), 4.34 (s, 2H, S–CH2), 7.12–7.24 (m, 4H, Ar), 7.
30–7.44 (m, 4H, Ar), 7.58 (s, 1H, H-3), 7.66 (d, 2H, Ar), 7.98
(s, 1H, H-6), 11.98 (s, 1H, NH) ppm; 13C NMR (50 MHz,
DMSO-d6): d = 19.21, 36.70, 117.66, 124.74, 127.60, 128.
49, 128.63, 129.19, 129.44, 132.80, 133.21, 135.55, 135.85,
136.71, 137.91, 138.92, 139.52, 151.52 ppm; LC–MS
(IT-TOF): m/z = 486 (M?), tR = 13 min.
Starting from 0.471 g 16 (1 mmol) in 1.5 cm3 THF, the
reaction mixture was refluxed for 8 h. The precipitate of by-
products was filtered off. The filtrate was evaporated to
dryness under reduced pressure and purified to give 0.343 g
(69 %) of 31. M.p.: 190–191 °C; TLC: Rf = 0.42 (ben-
zene:EtOH = 2:1); IR (KBr): vꢀ = 3,255 (NH), 2,978, 2,801
(CH3, CH2), 1,726 (CO), 1,336, 1,171 (SO2) cm-1; 1H NMR
(200 MHz, DMSO-d6): d = 1.04 (t, 3H, CH3), 2.26 (s, 3H,
CH3), 2.38 (s, 3H, CH3), 3.97-4.08 (m, 4H, S–CH2, CH2),
7.18 (d, 2H, Ar), 7.52 (d, 2H, Ar), 7.60 (s, 1H, H-3), 8.01 (s,
1H, H-6), 11.98 (s, 1H, NH) ppm; 13C NMR (50 MHz,
DMSO-d6): d = 14.10, 19.23, 20.66, 35.15, 61.43, 117.76,
129.14, 129.54, 133.20, 133.51, 133.90, 135.33, 135.51,
136.11, 138.90, 139.23, 151.40, 168.89 ppm; LC–MS
(IT-TOF): m/z = 496 (M?), tR = 12 min.
2-(Benzylthio)-4-chloro-N-[4,5-dihydro-1-
(4-nitrophenylsulfonyl)-5-oxo-1H-1,2,4-triazol-3-yl]-5-
methylbenzenesulfonamide (29, C22H18ClN5O7S3)
Starting from 0.596 g 14 (1 mmol) in 2 cm3 THF, the
reaction mixture was refluxed for 9 h. The product was
purified to give 0.30 g (50 %) of 29. M.p.: 211–214 °C;
TLC: Rf = 0.59 (benzene:ethanol = 2:1); IR (KBr): vꢀ = 3,
429, 3,269 (NH), 1,764 (CO), 1,536, 1,350 (NO2), 1,403,
4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-
triazol-3-yl)-2-(1,3-dioxolan-2-ylmethylthio)-5-
methylbenzenesulfonamide (32, C19H19ClN4O5S2)
Starting from 0.458 g 17 (1 mmol) in 3 cm3 THF, the
reaction mixture was refluxed for 5 h. After cooling to room
temperature, the oily residue was treated with diethyl ether to
obtain a white solid. The crude product was purified to give
0.159 g (33 %) of 32. M.p.: 214–217 °C; TLC: Rf = 0.36
(benzene:EtOH = 2:1); IR (KBr): vꢀ = 3,414 (NH), 2,972
(CH3, CH2), 1,716 (CO), 1,382, 1,165 (SO2) cm-1; 1H NMR
(500 MHz, DMSO-d6): d = 2.37 (s, 3H, CH3), 3.28 (d, 2H,
S–CH2), 3.71-3.75 (m, 2H, CH2–O), 3.83–3.88 (m, 2H,
CH2–O), 5.05 (t, 1H, CH–O), 7.13 (t, 1H, Ar), 7.36 (t, 2H,
Ar), 7.64 (d, 2H, Ar), 7.68 (s, 1H, H-3), 7.97 (s, 1H, H-6),
11.97 (s, 1H, NH) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 19.22, 36.70, 64.96, 102.10, 117.69, 124.73, 129.18,
129.31, 129.83, 132.98, 136.13, 136.74, 137.89, 138.87,
139.64, 151.54 ppm; LC–MS (IT-TOF): m/z = 482 (M?),
tR = 9 min.
1,391, 1,184, 1,167 (SO2) cm-1 1H NMR (200 MHz,
;
DMSO-d6): d = 2.32 (s, 3H, CH3), 4.28 (s, 2H, S–CH2), 7.
10–7.21 (m, 3H, Ar), 7.30 (d, 2H, Ar), 7.50 (s, 1H, H-3), 7.78
(d, 2H, J = 8.8 Hz, Ar), 7.89 (s, 1H, H-6), 8.24 (d, 2H,
J = 8.8 Hz, Ar) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 19.19, 36.41, 124.92, 127.42, 128.30, 128.40, 128.47,
128.82, 129.16, 132.48, 133.47, 135.98, 136.15, 138.37,
141.76, 144.95, 150.91, 151.71 ppm; LC–MS (IT-TOF):
m/z = 596 (M?), tR = 15 min.
2-(Benzylthio)-4-chloro-N-[4,5-dihydro-1-(4-methyl-
phenylsulfonyl)-5-oxo-1H-1,2,4-triazol-3-yl]-5-methyl-
benzenesulfonamide (30, C23H21ClN4O5S3)
Starting from 0.539 g 15 (1 mmol) in 1.5 cm3 THF, the
reaction mixture was refluxed for 8 h. The product was
purified to give 0.405 g (72 %) of 30. M.p.: 202–204 °C;
TLC: Rf = 0.60 (benzene:EtOH = 2:1); IR (KBr): vꢀ = 3,3
71 (NH), 2,922 (CH3, CH2), 1,755 (CO), 1,387, 1,191, 1,176
4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-
triazol-3-yl)-5-methyl-2-[3-(trifluoromethyl)benzyl-
thio]benzenesulfonamide (33, C23H18ClF3N4O3S2)
Starting from 0.506 g 18 (1 mmol) in 1 cm3 THF, the
reaction mixture was refluxed for 9 h. After cooling to room
temperature, the oily residue was treated with diethyl ether to
obtain a white solid. The crude product was purified to give
0.210 g (38 %) of 33. M.p.: 195–198 °C; TLC: Rf = 0.45
(benzene:EtOH = 2:1); IR (KBr): vꢀ = 3,425 (NH), 2,924
(CH3, CH2), 1,702 (CO), 1,334, 1,170 (SO2) cm-1; 1H NMR
(200 MHz, DMSO-d6): d = 2.36 (s, 3H, CH3), 4.48 (s, 2H,
(SO2) cm-1 1H NMR (500 MHz, DMSO-d6): d = 2.34
;
(s, 3H, CH3), 2.37 (s, 3H, CH3), 4.28 (s, 2H, S–CH2), 7.20
(t, 1H, Ar), 7.26 (d, 2H, Ar), 7.33 (d, 2H, Ar), 7.36 (d, 2H,
Ar), 7.51 (d, 2H, Ar), 7.54 (s, 1H, H-3), 7.89 (s, 1H, H-6),
11.93 (s, 1H, NH) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 19.23, 21.46, 36.67, 127.32, 127.60, 128.52, 128.66, 12
9.32, 130.18, 132.69, 133.33, 133.95, 135.42, 135.86, 136.4
123

´
J. Sławinski et al.
1716
S-CH2), 7.14 (t, 1H, Ar), 7.27–7.58 (m, 4H, Ar), 7.58 (s, 1H,
H-3), 7.62–7.76 (m, 4H, Ar), 7.98 (s, 1H, H-6), 12.00 (s, 1H,
NH) ppm; 13C NMR (50 MHz, DMSO-d6): d = 19.20,
36.05, 117.62, 124.20, 124.29, 124.71, 126.08, 126.16,
128.93, 129.14, 129.32, 129.56, 133.24, 133.33, 133.43,
135.44, 136.33, 137.85, 138.81, 139.48, 151.49 ppm;LC–MS
(IT-TOF): m/z = 554 (M?), tR = 17 min.
(SO2) cm-1; 1H NMR (500 MHz, DMSO-d6): d = 2.39 (s,
3H, CH3), 4.80 (s, 2H, S–CH2), 7.15 (t, 1H, Ar), 7.32–7.42
(m, 3H, Ar), 7.51–7.53 (m, 3H, Ar), 7.62–7.73 (m, 3H, H-3,
Ar), 7.83 (d, 1H, Ar), 7.92 (d, 1H, Ar), 8.00 (s, 1H, H-6), 8.20
(d, 1H, Ar), 11.90 (s, 1H, NH) ppm; 13C NMR (50 MHz,
DMSO-d6): d = 19.26, 35.02, 117.70, 124.41, 124.78,
125.69, 126.25, 126.62, 128.44, 128.58, 128.78, 129.21,
129.56, 131.43, 131.61, 132.95, 133.11, 133.64, 135.66,
137.08, 137.91, 138.95, 139.51, 151.50 ppm; LC–MS
(IT-TOF): m/z = 536 (M?), tR = 18 min.
4-Chloro-N-[4,5-dihydro-1-(4-methylphenylsulfonyl)-
5-oxo-1H-1,2,4-triazol-3-yl]-5-methyl-2-[3-(trifluoro-
methyl)benzylthio]benzenesulfonamide
(34, C24H20ClF3N4O5S3)
4-Chloro-N-[1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-
1,2,4-triazol-3-yl]-5-methyl-2-(naphthalen-1-ylmethyl-
thio)benzenesulfonamide (37, C26H20Cl2N4O3S2)
Starting from 0.607 g 19 (1 mmol) in 2 cm3 THF, the reaction
mixture was refluxed for 36 h. The product was purified to give
0.443 g (71 %) of 34. M.p.: 99–100 °C; TLC: Rf = 0.62
(benzene:EtOH = 2:1); IR (KBr): vꢀ = 3,284 (NH), 2,924 (CH3,
CH2), 1,716 (CO), 1,331, 1,347, 1,170, 1,194 (SO2) cm-1; 1H
NMR (500 MHz, DMSO-d6): d = 2.32 (s, 3H, CH3), 2.34 (s,
3H, CH3), 4.38 (s, 2H, S–CH2), 7.30 (d, 2H, Ar), 7.43–7.52 (m,
4H, Ar), 7.55–7.69 (m, 3H, Ar), 7.86 (s, 1H, H-6), 11.90 (brs, 1H,
NH) ppm; 13C NMR (50 MHz, DMSO-d6): d = 19.24, 21.36,
36.03, 127.34, 127.79, 129.03, 129.78, 129.85, 130.14, 133.12,
133.29, 133.98, 135.36, 136.18, 136.55, 137.83, 138.61, 143.63,
144.62, 145.77, 148.09, 151.75 ppm; LC–MS (IT-TOF):
m/z = 632 (M?), tR = 20 min.
Starting from 0.545 g22 (1 mmol) in 2 cm3 THF, thereaction
mixture was refluxed for 9 h. The product was purified to give
0.224 g (39 %) of 37. M.p.: 205–206 °C; TLC: Rf = 0.59
(benzene:EtOH = 2:1); IR (KBr): vꢀ = 3,251 (NH), 2,924
(CH3, CH2), 1,722 (C=O), 1,352, 1,166 (SO2) cm-1; 1H NMR
(200 MHz, DMSO-d6): d = 2.39 (s, 3H, CH3), 4.81 (s, 2H,
S-CH2), 7.31–7.58 (m, 6H, Ar), 7.62–7.72 (m, 3H, Ar),
7.80–7.94 (m, 2H, Ar), 8.01 (s, 1H, H-6), 8.20 (d, 1H, Ar),
11.99 (s, 1H, NH) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 19.27, 34.99, 119.09, 124.41, 125.89, 126.24, 126.61,
128.41, 128.56, 128.77, 129.17, 129.56, 131.43, 131.60,
132.96, 133.09, 133.64, 135.59, 136.76, 137.08, 138.98,
139.92, 142.10, 151.42 ppm; LC–MS (IT-TOF): m/z = 570
(M?), tR = 22 min.
4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-
3-yl)-5-methyl-2-[4-(trifluoromethyl)benzylthio]benzene-
sulfonamide (35, C23H18ClF3N4O3S2)
Starting from 0.529 g 20 (1 mmol) in 1 cm3 THF, the
reaction mixture was refluxed for 9 h. The product was
purified to give 0.29 g (52 %) of 35. M.p.: 208–210 °C;
TLC: Rf = 0.40 (benzene:EtOH = 2:1); IR (KBr):
vꢀ = 3,253 (NH), 2,923 (CH3, CH2), 1,701 (CO), 1,327,
4-Chloro-N-[4,5-dihydro-1-(4-methylphenylsulfonyl)-5-
oxo-1H-1,2,4-triazol-3-yl]-5-methyl-2-(naphthalen-1-
ylmethylthio)benzenesulfonamide (38, C27H23ClN4O5S3)
Starting from 0.589 g 23 (1 mmol) in 2 cm3 THF, the
reaction mixture was refluxed for 11 h. The product was
purified to give 0.438 g (70 %) of 38. M.p.: 118–120 °C;
TLC: Rf = 0.60 (benzene:EtOH = 2:1); IR (KBr):
vꢀ = 3,530 (NH), 2,973 (CH3, CH2), 1,726 (CO), 1,388,
1,127 (SO2) cm-1
;
1H NMR (500 MHz, DMSO-d6):
d = 2.35 (s, 3H, CH3), 4.46 (s, 2H, S–CH2), 7.14 (t, 1H,
Ar), 7.36 (t, 2H, Ar), 7.50 (d, 2H, Ar), 7.56 (d, 2H, Ar),
7.59 (s, 1H, H-3), 7.63 (d, 2H, Ar), 7.97 (s, 1H, H-6), 11.99
(s, 1H, NH) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 19.21, 35.92, 117.62, 124.70, 125.36, 125.43,
127.76, 129.15, 129.83, 130.11, 133.17, 133.25, 135.78,
135.97, 137.88, 138.89, 139.63, 144.53, 151.51 ppm;
LC–MS (IT-TOF): m/z = 554 (M?), tR = 17 min.
1,370, 1,193, 1,177 (SO2) cm-1 1H NMR (500 MHz,
;
DMSO-d6): d = 2.31 (s, 3H, CH3), 2.37 (s, 3H, CH3), 4.70
(s, 2H, S–CH2), 7.32 (d, 2H, Ar), 7.38 (t, 1H, Ar),
7.48–7.53 (m, 5H, Ar), 7.63 (s, 1H, H-3), 7.84 (d, 1H, Ar),
7.90 (s, 1H, H-6), 7.94 (d, 1H, Ar), 8.08 (d, 1H, Ar), 11.90
(brs, 1H, NH) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 19.29, 21.42, 35.06, 124.28, 125.76, 126.27, 126.64,
127.37, 128.27, 128.56, 128.79, 128.96, 130.19, 131.38,
131.59, 132.90, 133.27, 133.64, 133.91, 135.68, 136.75,
138.77, 143.56, 145.85, 151.78 ppm; LC–MS (IT-TOF):
m/z = 614 (M?), tR = 23 min.
4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-
3-yl)-5-methyl-2-(naphthalen-1-ylmethylthio)benzenesul-
fonamide (36, C26H21ClN4O3S2)
Starting from 0.513 g 21 (1 mmol) in 1 cm3 THF, the
reaction mixture was refluxed for 9 h. After cooling to room
temperature, the reaction mixture was treated with petroleum
ether to obtain a white solid. The crude product was purified
to give 0.166 g (31 %) of 36. M.p.: 214–216 °C; TLC:
Rf = 0.55 (CHCl3:MeOH = 16:3); IR (KBr): vꢀ = 3,258
(NH), 2,922 (CH3, CH2), 1,720 (CO), 1,349, 1,168
4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-
3-yl)-2-(1,2-dihydro-2-oxoquinolin-4-ylmethylthio)-5-
methylbenzenesulfonamide (39, C25H20ClN5O4S2)
Starting from 0.528 g24 (1 mmol) in 3 cm3 THF, thereaction
mixture was refluxed for 9 h. The product was purified to give
123

Synthesis and molecular structure of sulfonamide derivatives
1717
0.161 g (29 %) of 39. M.p.: 185–188 °C; TLC: Rf = 0.12
(CHCl3:MeOH = 16:3), Rf = 0.19 (CHCl3:MeCN:AcOH
= 2:1:0.05); IR (KBr): vꢀ = 3,467 (NH), 2,923 (CH3, CH2),
All hydrogen atoms were refined using isotropic model
with Uiso (H) values fixed to be 1.2 times Ueq of C atoms
for CH and CH2 and 1.5 times Ueq for CH3. Bond lengths
1,692, 1,655 (CO), 1,383, 1,127 (SO2) cm-1 1H NMR
;
˚
˚
C–H were fixed at 0.98 A for methyl groups, and 0.95 A
for methylene and methine groups; distances N–H were set
(500 MHz, DMSO-d6): d = 2.37 (s, 3H, CH3), 4.59 (s, 2H,
S–CH2),6.58(s, 1H, Ar),7.10(t, 1H, Ar),7.16(t, 1H, Ar), 7.30
(d, 1H, Ar), 7.34 (t, 2H, Ar), 7.49 (t, 1H, Ar), 7.55 (s, 1H, H-3),
7.65 (d, 2H, Ar), 7.88 (d, 1H, Ar), 8.01 (s, 1H, H-6), 11.73 (s,
2H, NH-quinolin, NH-triazolone) ppm; 13C NMR (50 MHz,
DMSO-d6): d = 19.27, 33.74, 115.88, 117.75, 118.29,
121.90, 122.48, 124.75, 125.28, 129.17, 129.46, 130.83,
133.17, 133.53, 135.51, 136.33, 137.84, 138.90, 139.23,
139.47, 145.59, 151.51, 161.49 ppm; LC–MS (IT-TOF):
m/z = 554 (M?), tR = 17 min.
˚
to 0.88 A. Solvating water molecules generated an electron
density peak of ca. 1.7 e A-3. Because the electron density
˚
maximum is placed at a special position (‘, y, ) locali-
zation of hydrogen atoms is additionally uncertain so we
did not attempt to find H atoms. The occupation factor of
oxygen atom O10 was refined freely to obtain 0.079. One
incorrect reflection (-1 1 17) was omitted.
Crystallographic data for the structure of 31Pyr reported
in this article have been deposited with the Cambridge
Crystallographic Data Center as supplementary publication
no. CCDC868805. Copies of the data can be obtained free
of charge on application to CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK [Fax: (?44) 1223-336-033; email:
deposit@ccdc.cam.ac.uk].
4-Chloro-2-(2,3-dihydrobenzo[b][1,4]dioxin-2-ylmethyl-
thio)-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-
yl)-5-methylbenzenesulfonamide (40, C24H21ClN4O5S2)
Starting from 0.519 g 25 (1 mmol) in 3 cm3 THF, the
reaction mixture was refluxed for 9 h. The product was
purified to give 0.262 g (48 %) of 40. M.p.: 185–188 °C;
TLC: Rf = 0.53 (benzene:ethanol = 2:1); IR (KBr):
vꢀ = 3,311 (NH), 2,922 (CH3, CH2), 1,697 (CO), 1,334,
Acknowledgments The authors are very grateful to Dr. Joel Morris,
Ph.D., Chief Drug Synthesis & Chemistry Branch, National Cancer
Institute (Bethesda, MD), for the in vitro anticancer screening.
1,165 (SO2) cm-1
;
1H NMR (500 MHz, DMSO-d6):
Open Access This article is distributed under the terms of the
Creative Commons Attribution License which permits any use, dis-
tribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
d = 2.38 (s, 3H, CH3), 3.36 (dd, 1H, S–CH2), 3.46 (dd,
1H, S–CH2), 4.00 (dd, 1H, O–CH2), 4.26 (dd, 1H, O–CH2),
4.31–4.35 (m, 1H, O–CH), 6.70–6.81 (m, 4H, Ar), 7.12 (t,
1H, Ar), 7.34 (t, 2H, Ar), 7.64 (d, 2H, Ar), 7.76 (s, 1H,
H-3), 8.01 (s, 1H, H-6), 12.01 (s, 1H, NH) ppm; 13C NMR
(50 MHz, DMSO-d6): d = 19.29, 33.64, 66.26, 72.02,
117.15, 117.29, 117.69, 121.61, 121.70, 124.74, 129.14,
129.83, 133.09, 133.61, 135.83, 136.62, 137.83, 139.12,
139.50, 142.61, 142.99, 151.54 ppm; LC–MS (IT-TOF):
m/z = 545 (M?), tR = 21 min.
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