Synthesis and evaluation of some new pyrazoline substituted benzenesulfonylureas as potential antiproliferative agents

Article abstract of DOI:10.1016/j.bmcl.2014.02.059

Twenty six new pyrazoline substituted benzenesulfonylureas (2a-z) were synthesized and tested for in vitro anticancer activity. Fourteen derivatives (2i, 2k-2p, 2r, 2s-2x) were screened for their antiproliferative activity towards 60 human cancer cell lin

Full text of DOI:10.1016/j.bmcl.2014.02.059

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1685–1691
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of some new pyrazoline substituted
benzenesulfonylureas as potential antiproliferative agents
Pooja Rathore a, Shafiya Yaseen a, Syed Ovais a, Rafia Bashir a, Raed Yaseen a, Alhamzah D. Hameed a,
Mohammed Samim a, Rakesh Gupta b, Firasat Hussain b, Kalim Javed a,
⇑
a Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi 110 062, India
b Department of Chemistry, University of Delhi, Delhi 110 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Twenty six new pyrazoline substituted benzenesulfonylureas (2a–z) were synthesized and tested for
in vitro anticancer activity. Fourteen derivatives (2i, 2k–2p, 2r, 2s–2x) were screened for their antiprolif-
erative activity towards 60 human cancer cell lines by the National Cancer Institute (USA). Among them
four compounds (2i, 2n, 2v and 2x) exhibited significant growth inhibition and further screened at 10-
Received 6 December 2013
Revised 15 February 2014
Accepted 20 February 2014
Available online 28 February 2014
fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100
and 2x showed effective growth inhibition (GI50 MID) values of 2.62, 3.93, 3.33, 3.74
beside cytostatic activity TGI (MG-MID) values of 8.42, 65.80, 24.00 and 36.06 M respectively. The com-
pound 2i displayed remarkable antiproliferative activity in 8 different cell lines with GI50 less than 2 M.
Compounds 2n, 2v and 2x also displayed good antiproliferative activity against 11, 18 and 14 different
cell lines respectively with GI50 less than 3 M.
l
M). The compounds 2i, 2n, 2v
l
M respectively
Keywords:
Benzenesulfonylureas
Pyrazolines
Anti-cancer
Antiproliferative activity
Sulfonamides
l
l
l
Ó 2014 Elsevier Ltd. All rights reserved.
Cancer is a group of illness that results from cells in the body
growing abnormally. These cells divide and produce new cells in
an uncontrolled way that can spread throughout the body and
cause damage to essential organs. Cancer treatment includes many
strategies and chemotherapy plays a central role.1 Chemotherapy
involves the use of low-molecular-weight drugs to selectively de-
stroy tumour cells or at least limit their proliferation. Despite im-
mense advances in the field of basic and clinical research, which
have resulted in higher cure rates for a number of malignancies,
cancer remains the second leading cause of death after heart disor-
ders in developing as well as advanced countries.2 Although major
advances have been made in the chemotherapeutic management
of some patients, the continued commitment to the difficult task
of discovering new anticancer agents remains critically important.
Among the wide range of compounds tested as potential anti-
cancer agents, derivatives comprising the sulfonamide, N1,N3-
diarylsulfonylurea and -thiourea functionalities have attracted
great attention.3,4 Recently three sulphonamides derivatives
E7010, ER-34410 and E7070 (Fig. 1I–III) have been reported as po-
tent antitumor agents and are in advanced clinical trials.5 Sulofe-
nur (Fig. 1IV) is a sulfonylurea that has been clinically evaluated
in lung, breast, colon, ovarian, pancreatic and gastric cancer.6 The
antitumor properties of the diarylsulfonylurea is due to the uncou-
pling of mitochondria7,8 but other mechanisms, such as inhibition
of the mitochondrial isozyme V of carbonic anhydrase (CA V), have
also been hypothesized, since hydrolysis of the cytotoxic agent,
leading to the formation of unsubstituted sulfonamides as the
principal products, has been reported both in vivo and in vitro.9
However, clinical trials of sulofenur have yielded unsatisfactory re-
sults because of its high protein binding and dosing being limited
by the appearance of anemia due to methemoglobinemia, a side
effect likely associated with its aniline-related metabolites.10
Pyrazol(in)e derivatives have attracting continuing attention
over the years because of their broad spectrum biological activities
and strong efficacy. Some representative of this heterocyclic exi-
hibit antiproliferative,11–13 anti-inflammatory,14–16 anti-infec-
tive,17 antidepressant18 and analgesic19 activity.
Recently, Lv et al.,11 discovered (V) (Fig. 1) displayed the most
potent EGFR TK inhibitory activity with IC50 of 0.06 lM, which
was comparable to positive control Erlotirib. This compound (I)
also showed significant antiproliferative activity against MCF-7
with IC50 of 0.07 lM. The present work is an extension of our ongo-
ing efforts towards developing promising biologically active agents
using a hybrid pharmacophore approach. We made the design
(Fig. 1) and synthesized hybrid compounds by linking pyrazoline
ring system with benzene sulfonylurea. In these derivatives we
⇑
Corresponding author. Tel.: +91 9873463272.
E-mail addresses: kjaved@jamiahamdard.ac.in, kjavedchem@yahoo.co.in (K. Javed).
http://dx.doi.org/10.1016/j.bmcl.2014.02.059
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

1686
P. Rathore et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1685–1691
H
N
HN
SO2
O
S
O2
O
H3C
HN
NH
HN
H3C
E 7070
(III)
E 7010
(I)
HN
O2S
SO2
H2N
F
HN
ER-34410
(II)
Cl
R
HN
(n) Butyl/ Benzyl
HN
SO2
N
O
N
2'
3'
4'
A
6'
Target compounds (2a-z)
5'
A = 2', 4' / 2', 5' dimethyl phenyl
F
Cl
H
N
Cl
HN
SO2
O
N
Sulofenur (LY 186641) Antineoplastic agent
N
S
N
(IV)
F
H
N
H
N
HO
H
O
H3C
O
CH3
HN
NH
Potent EGK inhibitor and anticancer agent
(V)
Hydroxy carbamide
(VII)
O
5-Fluorouracil
(VI)
Figure 1. Structure of some biologically active anticancer drugs and rationally designed template for target compounds (2a–z).
introduced butyl or benzyl group at N3 position in order to avoid
possible side effects associated with aniline-related metabolites
generating from the aryl substituted derivatives.10 As per the pro-
tocol of NCI, only fourteen representative compounds 2i, 2k–2p, 2r,
2s–2x were selected and granted NSC codes Viz; NSC 765376, NSC
772443, NSC 765379, NSC 772444, NSC 765378, NSC 765377, NSC
762442, NSC 765372, NSC 762441,NSC 772440, NSC 765373, NSC
765371, NSC 765375 and NSC 765374 respectively and screened
at NCI for antiproliferative activity at a single high dose (10ꢀ5 M)
in full 60 cell panel. Four compounds namely 2i, 2n, 2v and 2x

P. Rathore et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1685–1691
1687
exhibited good activity at a single dose and were selected for fur-
ther evaluation at five dose concentration level against full NCI
60 cell panel.
In vitro one-dose (10ꢀ5 M) anticancer assay was performed
using full panel of about 60 human tumor cell lines representing
nine different cancer types: Leukemia, melanoma, lung, colon,
CNS, ovarian, renal, prostate and breast cancers, in accordance with
the protocol of the Drug Evaluation Branch, National Cancer Insti-
tute (NCI), Bethesda and described elsewhere.22–24
Out of the synthesized compounds (2a–z), fourteen compounds,
namely 2i, 2k–2p, 2r and 2s–2x were selected by the National Can-
cer Institute (NCI). The compounds 2k–m, 2o, 2p, 2r–u and 2w dis-
played mild sensitivity against few cell lines (Table S1). In the
present study four compounds like 2i, 2n, 2v and 2x possessed
considerable anti-proliferative activity (Table S2) and they were
selected for an advanced assay against a full panel (approximately
60 cell lines) at five concentrations at 10-fold dilution (100, 10, 1,
The synthetic pathway used to synthesize compounds (2a–z) is
outlined in Scheme 1. The substituted benzenesulfonylureas were
obtained by refluxing different pyrazolines (1a–q) with appropri-
ate isocyanates in presence of potassium carbonate as a mild cata-
lyst in dry acetone.21 The pyrazolines were synthesised by reacting
appropriate chalcones with 4-hydrazinobenzenesulphonamide.20
The purity of compounds was checked by TLC. The structures of
2a–z were determined on the basis of elementary analysis (C, H,
N & S) and various spectroscopic methods (IR, 1H NMR, 13C NMR
and MS). Elemental analysis (C, H, N & S) data were within 0.4%
of the theoretical values. Spectral data IR, 1H NMR, 13C NMR and
MS of compounds were found in full agreement with the proposed
structure. In general IR spectrum exhibited two bands at 1395–
1321 cmꢀ1 and 1165–1125 cmꢀ1 due to SO2N group. Carbonyl
group showed absorption at 1705–1628 cmꢀ1 while C@N showed
peak at 1628–1532 cmꢀ1. The spectrum displayed band for the
ureido group (HN-CO-NH) at 3392–3159 cmꢀ1. In 1H NMR spectra,
the pyrazoline ring protons showed characteristics of ABX spin sys-
tem due to germinal-vicinal multiple coupling between two pro-
tons at C-4 and a proton at C-5 of pyrazoline ring. The H-4
(trans) protons of pyrazoline ring showed double doublets at d
2.42-3.28. H-4 (cis) of pyrazoline moiety appeared as double-
doublets at d 3.90–4.13. H-5 proton of pyrazoline ring also
appeared as double doublet at d 5.15–5.78 due to vicinal coupling
with two magnetically non-equivalent protons at C-4 of pyrazo-
line. SO2NHCOA showed a one proton broad singlet at d 7.45–
10.38. The signal for proton attached with nitrogen in CONHCH2
system appeared as triplet or distorted triplet at between d 6.20
and 7.57. The scans of all the spectra (1H and 13C NMR) are given
in the Supplementary data.
0.1 and 0.001 lM). A 48 h continuous drug exposure protocol
was used and sulforhodamine B (SRB)24 protein assay was used
to estimate cell growth. The result of tested compound is given
by three response parameters (GI50, TGI and LC50) for each cell line
from log concentration versus% growth inhibition curves on nine
cancer disease. The GI50 value (growth inhibitory activity)
corresponds to the concentration of the compound causing 50%
decrease in net cell growth, the TGI value (cytostatic activity) is
the concentration of the compound resulting in total growth inhi-
bition and LC50 value (cytotoxic activity) is the concentration of the
compound causing net 50% loss of initial cells at the end of
the incubation period of 48 h. Furthermore, a mean graph midpoint
(MG-MID) is calculated giving an averaged activity parameter over
all cell lines. The compounds 2i, 2n, 2v and 2x exhibited considerable
broad spectrum antitumor activities and showed effective growth
inhibition (GI50 MID) values of 2.62, 3.93, 3.33 and 3.74
tively (Table 1), beside cytostatic activity TGI (MG-MID) values of
8.42, 65.80, 24.00 and 36.06 M respectively, (Table S3). In addi-
lM respec-
l
tion, the active compounds 2i, 2n, 2v and 2x exhibited a variable
R
NH
NH
H3C
N
SO2
O
CH3
N
R1
2a-q
R2
R
(i)
NH2
SO2
H3C
N
N
R
NH
O
R1
NH
(ii)
H3C
N
R2
SO2
N
1a-q
R1
2r-z
R2
1a, 2a, R1=H, R2=CH3, R=H,
1b, 2b, R1=H, R2=CH3, R=2-chloro,
1e, 2e, R1=H, R2=CH3, R=4-methyl,
1c, 2c, R1=H, R2=CH3, R=3-nitro,
1f, 2f, R1=H, R2=CH3, R=4-dimethylamino,
1d, 2d, R1=H, R2=CH3, R=4-chloro,
1g, 2g, R1=H, R2=CH3, R=4-methoxy,
1j, 2j, R1=H, R2=CH3, R=H,
1h, 2h, R1=H, R2=CH3, R=3,4-dimethoxy, 1i, 2i,R1=H, R2=CH3, R=3,4,5-trimethoxy,
1k, 2k, R1=CH3, R2=H, R=2-chloro, 1l, 2l, R1=CH3, R2=H, R=4-chloro,
1n, 2n, R1=CH3, R2=H, R=4-dimethylamino, 1o, 2o, R1=CH3, R2=H, R=4-methoxy,
1m, 2m, R1=CH3, R2=H, R=4-methyl,
1p, 2p, R1=CH3, R2=H, R=3,4-dimethoxy, 1q, 2q, R1=CH3, R2=H, R=3,4,5-trimethoxy, 2r, R1=H, R2=CH3, R=2-chloro,
2s, R1=H, R2=CH3, R=4-chloro,
2t, R1=H, R2=CH3, R=,4-methoxy,
2w, R1=CH3, R2=H, R= 2-chloro,
2z, R1=CH3, R2=H, R= 3,4-dimethoxy.
2u, R1=H, R2=CH3, R=3,4-dimethoxy,
2x, R1=CH3, R2=H, R= 4-dimehtylamino,
2v, R1=H, R2=CH3, R=3,4,5-trimethoxy,
2y, R1=CH3, R2=H, R=4-methoxy,
Scheme 1. Synthesis of pyrazoline substitued benzenesulfonylureas (2a–z). Regents and conditions; (i) @C4H9NCO, acetone/K2CO3, (ii) @C6H5CH2NCO, acetone/K2CO3.

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P. Rathore et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1685–1691
Table 1
CNS, SF-539 (GI50 1.90
l
M), colon, HCC-116 (GI50 1.84
M), leukemia, RPMI-8226 (GI50 1.95
Compound 2v showed activity against non small cell lung cancer,
HOP-92 (GI50 1.96 M), melanoma, MDA-MB-435 (GI50 1.98 M).
Obtained data revealed an obvious sensitivity profile of compound
2n towards melanoma SK-MEL-5 (GI50 2.22 M), breast cancer
MDA-MB-468 (GI50 2.22 M) and compound 2x showed sensitivity
towards cell line like ovarian cancer, OVCAR-3 (GI50 2.24 M), mel-
anoma SK-MEL-5 (GI50 2.32 M) (Table 1).
The ratio obtained by dividing the full panel MG-MID (
the compounds by their individual subpanel MG-MID ( M) is con-
l
M), pros-
Growth inhibitory concentration (GI50, l
M) of compounds 2i, 2n, 2v and 2xa
tate, PC-3 (GI50 1.94
l
l
M).
Panel
Cell line
5FU
9.97 2.2
2.3 2.28 2.48 3.62 3.01
3.58 3.14 3.58 3.51
0.35 2.74 3.61 3.24 3.65
2i
2n
2v
2x
l
l
Leukemia
CCRF-CEM
HL-60
K-562
3.32 3.15 3.19
4
l
MOLT
l
RPMI-8226
0.04
1.95 2.99 2.8
2.88
l
Non-small cell lung
Cancer
l
A549/ATCC
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
COLO 205
HCC-2998
HCC-116
HCC-15
HT29
0.18 2.53 3.2
0.39 3.15 6.86 4.3
77.9 1.27 2.39 1.96 2.64
54.7 3.29 4.54 3.63 3.91
0.33 2.35 4.92 3.37 3.6
3.35 5.19 5.41 4.86
3.31 3.46
lM) of
5.69
l
sidered as a measure of compound selectivity. Ratio of 3–6 refer to
moderate selectivity, ratios greater than six indicate high selectiv-
ity towards the corresponding cell line, while compounds not
meeting either of these criteria are rated as nonselective.25 In this
context, the active compounds in the present study were found to
be nonselective with broad spectrum antitumor activity against
the nine tumor subpanels tested with selectivity ratios ranges of
0.72–1.19 at the GI50 respectively. From the present data it is diffi-
cult to extract any SAR of these compounds.
In conclusion, the present study describes the synthesis of
twenty six pyrazoline substituted benzenesulfonylureas (2a–z).
Fourteen compounds 2i, 2k–2p, 2r, 2s–2x were screened at NCI
for antiproliferative activity. The results of this assay indicated an
activity in the micro-molar range, particularly four compounds
(2i, 2n, 2v and 2x). Therefore, this study has provided meaningful
information for further improving the potency of this class of com-
pound as antiproliferative agents.
0.05
7.27 2.39 3.25 3.55 4.48
0.15 2.6 3.19 2.48 3.71
0.05 2.32 2.25 2.63 2.45
0.22 1.84 3.86 3.21
0.11 2.81 3.09 3.18 3.27
0.17 2.42 4.2 3.87 4.53
2.46 3.33 2.53 3.33
Colon cancer
4
KM12
SW-620
SF-268
0.21 2.25 3.72 3.44 3.49
0.92 3.26 4.14 3.62 3.94
1.62 3.15 5.73 4.9
0.06 1.9 3.22 2.02
CNS cancer
Melonoma
4.37
2.43
SF-539
SNB-19
SNB-75
U251
3.81 2.75 4.59 3.75 4.6
78.7 2.12 3.81 2.33 2.44
0.92 2.11 3.59 3.31 3.53
LOX IMVI
MALME-3M
M14
0.24 2.24 4.4
0.05 2.4 3.08 3.48 2.9
0.98 2.14 4.06 3.04 3.57
0.07 1.75 2.55 2.27 2.51
56.7 2.2 3.13 2.81 3.32
1.03 1.97 2.56 2.26 2.36
0.46 2.54 2.22 2.04 2.32
3.55 3.4 4.04 3.53 4.64
3.79 4.08
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
Crystallographic data for compound 2m has been deposited
with Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 986819. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk/data_request/cif.
0.52 1.83 2.18 1.98 2.5
1.22 3.19 4.87 3.95 4.31
Ovarian cancer
Renal cancer
0.01
2.07 2.5
2.42 2.24
4.43 2.52 5.41 3.28 3.54
10.9 3.39 5.24 4.19 5.4
1.74 3.03 3.68 3.77 3.81
0.31 2.95 4.12 4.18 3.93
21.8 3.53 8.16 4.98 8.43
0.72 3.51 5.45 3.79 4.37
Acknowledgments
The authors are very grateful to the staff members of Depart-
ment of Health and Human Services, National Cancer Institute
(NCI), Bethesda, Maryland, USA, for carrying out in vitro anti cancer
screening of the newly synthesized compounds. One of the
authors, Pooja Rathore is thankful to Hamdard National Founda-
tion India for fellowship. Thanks are due to Jamia Hamdard and
SAIF, CDRI, Lucknow for providing Mass spectra.
A498
ACHN
CAKI-1
RXF 393
SN 12C
TK-10
UO-31
PC-3
0.35 2.31 3.9
0.27 3.69 3.93 3.47 3.97
0.07 3.07 3.38 3.17 3.45
2.61 2.61 4.06 2.9
0.49 3.36 3.07 3.15 3.35
1.12 3.44 5.64 4.74 6.46
1.42 3.07 4.57 3.56 4.27
2.36 1.94 3.34 2.54 3.33
3.09
3.08
3
Supplementary data
Prostrate cancer
Breast cancer
DU-145
MCF7
MDA-MB-231/ATCC 6.6
HS 578T
0.36 3.46 5.75 6.05
4.6
0.07
2.06 2.63 2.58 2.99
2.36 5.36 2.96 4.17
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.
02.059.
9.77 2.2
3.95 2.68 2.48
BT-549
T-47D
MDA-MB-468
60
10.6 2.73 4.11 3.08 3.98
8.12 3.91 5.16 4.19 6.74
2.17 2.22 2.32 2.36
7.14 2.62 3.93 3.33 3.74
References and notes
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l
l
l
With regard to sensitivity against some individual cell lines,
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lM), melanoma, MDA-MB-435 (GI50
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21. General procedure for the synthesis of pyrazoline substituted benzenesulfonylureas
(2a–z): A solution of appropriate pyrazoline (1 mmol) (1a–q) in dry acetone
was refluxed over anhydrous K2CO3 (2 mmol) for 1–1.5 h. At this temperature,
a solution of the appropriate isocyanate (1.2 mmol) in dry acetone 5 ml was
added in a drop wise manner. It was stirrer and refluxed for 24–72 h. Acetone
was removed under reduced pressure. The solid residue thus obtained was
suspended in water and acidified with acetic acid. It was filtered and residue
was washed with plenty of distilled water. It was dried and crystallized with
methanol. The purity of compound was checked on TLC plate.
J = 14.2 Hz, CH3CH2CH2CH2A), 1.20–1.30 (2H, m, CH3CH2CH2CH2A), 1.40–1.47
(2H, m, CH3CH2CH2CH2A), 2.32 (3H, s, CH3, C-50), 2.67 (3H, s, CH3, C-20), 2.86–
2.92 (2H, m, CH3CH2CH2CH2A), 3.15 [1H, dd, J = 7.2 Hz, J = 12.9 Hz, H-4 trans
(pyrazoline)], 4.13 [1H, dd, J = 12.3 Hz, J = 17.1 Hz, H-4 cis (pyrazoline)], 5.72
[1H, dd, J = 4.8 Hz, J = 10.5 Hz, H-5 (pyrazoline)], 6.53 (1H, t, CONHCH2A),
6.89 (2H, d, J = 9.3 Hz, H-200, H-600), 6.97–7.19 (5H, m, H-40, H-30, H-60, H-3, H-
5), 7.32 (2H, d, J = 8.4 Hz, H-2, H-6), 7.64 (2H, d, J = 8.4 Hz, H-300, H-500). ESI-MS
(m/z): 539 [M+], 540 [M+1], 542 [M+2], 538 [Mꢀ1], 537 [Mꢀ2]. 13C NMR;
(100 MHz, CDCl3, d): 13.68, 19.86, 21.22, 23.88, 31.57, 39.95, 45.72, 61.74,
112.43, 121.32, 126.58, 127.38, 128.49, 128.71, 129.62, 131.42, 132.43,
137.83, 139.42, 144.46, 147.64, 148.42, 150.92, 151.23. Elemental Analysis
for: C28H31ClN4O3S. Found (Calculated) C: 62.40 (62.38%), H: 5.76 (5.80%), N:
10.37 (10.39%), S: 5.92 (5.95%).
N-(Butylamino-hydroxy-methyl)-4-[3-(2,5-dimethyl-phenyl)-5-tolyl-4,5-dihydro-
pyrazol-1-yl]-benzenesulfonamide (2e). Light yellow crystals (mp 188–190 °C).
Yield 55%. Rf = 0.76 (toluene/ethylacetate/formic acid, 5:4:1). IR mmax (KBr, in
cmꢀ1): 3197 (NHCONH), 1691 (C@O), 1532 (C@N), 1378 and 1161 (SO2N). 1H
NMR (300 MHz, DMSO, d): 0.79 (3H, t, J = 6.9 Hz, J = 13.2 Hz, CH3CH2CH2CH2A),
1.10–1.17 (2H, m, CH3CH2CH2CH2A), 1.23–1.28 (2H, m, CH3CH2CH2CH2A), 2.24
(3H, s, CH3, C-4), 2.30 (3H, s, CH3, C-50), 2.30 (3H, s, CH3, C-20), 2.90–2.92 (2H,
m, CH3CH2CH2CH2A), 3.18 [1H, dd, J = 7.2 Hz, J = 12.9 Hz, H-4 trans
(pyrazoline)], 4.02 [1H, dd, J = 12.3 Hz, J = 17.1 Hz, H-4 cis (pyrazoline)], 5.50
[1H, dd, J = 4.2 Hz, J = 11.4 Hz, H-5 (pyrazoline)], 6.45 (1H, t, CONHCH2A), 7.00–
7.14 (9H, m, H-30, H-40, H-50, H-200, H-600, H-2, H-3, H-5, H-6), 7.69 (2H, d,
J = 9.3 Hz, H-300, H-500), 10.27 (1H, br s, SO2NHCO–). ESI-MS (m/z): 518 [M+], 519
[M+1], 517 [Mꢀ1]. 13C NMR; (100 MHz, DMSO, d): 14.00, 19.76, 21.11, 21.23,
23.89, 31.79, 39.20, 45.71, 112.09, 126.12, 126.91, 127.06, 127.96, 128.58,
128.94, 129.31, 130.15, 132.18, 137.32, 138.78, 139.14, 147.40, 151.63, 152.00.
Elemental Analysis for: C29H34N4O3S. Found (Calculated) C: 67.44 (67.42%), H:
6.24 (6.24%), N: 10.87 (10.84%), S: 6.25 (6.21%).
N-(Butylamino-hydroxy-methyl)-4-[5-(4-dimethylamino-phenyl)-3-(2,5-dimethyl-
phenyl)-4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2f). Light yellow crystals
(mp 190–192 °C). Yield 65%. Rf = 0.46 (petrolleum ether/acetone, 7:3). IR mmax
(KBr, in cmꢀ1): 3241 and 3202 (NHCONH), 1697 (C@O), 1594 (C@N), 1321 and
1161 (SO2N). 1H NMR (300 MHz, DMSO, d): 0.79 (3H, t, J = 6.9 Hz, J = 13.2 Hz,
CH3CH2CH2CH2A), 1.14–1.17 (2H, m, CH3CH2CH2CH2A), 1.25–1.27 (2H, m,
CH3CH2CH2CH2A), 2.30 (3H, s, CH3, C-50), 2.66 (3H, s, CH3 C-20), 2.84 (6H, s,
(CH3)2N–), 2.90–2.92 (2H, m, CH3CH2CH2CH2A), 3.17 [1H, dd, J = 6.0 Hz,
J = 24 Hz, H-4 trans (pyrazoline)], 3.96 [1H, dd, J = 11.7 Hz, J = 16.8 Hz, H-4 cis
(pyrazoline)], 5.40 [1H, dd, J = 4.2 Hz, J = 11.4 Hz, H-5 (pyrazoline)], 6.45 (1H, t,
CONHCH2), 6.66 (2H, d, J = 7.5 Hz, H-3, H-5), 7.01-7.08 (5H, m, H-200, H-600, H-2,
H-6, H-30), 7.16 (1H, s, H-50), 7.35 (1H, d, J = 6.9 Hz, H-40), 7.62 (2H, d, J = 8.1 Hz,
H-300, H-500), 10.23 (1H, br s, SO2NHCO–). ESI-MS (m/z): 547 [M+], 548 [M+1],
546 [Mꢀ1]. 13C NMR; (100 MHz, DMSO, d): 14.00, 19.77, 21.33, 23.89, 31.87,
40.16, 42.67, 43.04, 61.46, 112.11, 113.2, 126.45, 126.93, 127.08, 127.53,
128.15, 128.32, 129.21, 129.46, 132.79, 137.41, 138.90, 140.26, 150.27, 151.73.
Elemental Analysis for: C30H37N5O3S. Found (Calculated) C: 65.76 (65.79%), H:
6.80 (6.81%), N: 12.77 (12.79%), S: 5.84 (5.85%).
N-(Butylamino-hydroxy-methyl)-4-[3-(2,5-dimethyl-phenyl)-5-phenyl-4,5-
dihydro-pyrazol-1-yl]-benzenesulfonamide (2a). Off white crystals (mp 145-
146 °C). Yield 65%. Rf = 0.65, (toluene/ethylacetate/formic acid, 5:4:1). IR
mmax (KBr, in cmꢀ1): 3221 and 3208 (NHCONH), 1702 (C@O), 1598 (C@N),
1334 and 1165 (SO2N). 1H NMR (300 MHz, DMSO, d): 0.79 (3H,
t, CH3CH2CH2CH2A), 1.12–1.18 (2H, m, CH3CH2CH2CH2A), 1.24–1.29
(2H, m, CH3CH2CH2CH2A), 2.27 (3H, s, CH3, C-50), 2.75 (3H, s, CH3, C-20),
2.89–2.91 (2H, m, CH3CH2CH2CH2A), 3.21 [1H, dd, J = 4.2 Hz, J = 17.1 Hz,
H-4 trans (pyrazoline)], 4.0 [1H, dd, J = 8.3 Hz, J = 17.3 Hz, H-4 cis
(pyrazoline)], 5.51 [1H, dd, J = 7.5 Hz, J = 19.1 Hz, H-5 (pyrazoline)], 6.29
(1H, t, CONHCH2A), 6.98–7.08 (3H, m, H-200 H-600, H-30), 7.08 (1H, s, H-60),
7.16–7.35 (6H, m, H-2, H-3, H-4, H-5, H-6, H-40), 7.57-7.63 (2H, m, H-300,
H-500). ESI-MS (m/z); 504 [M+], 505 [M+1], 503 [Mꢀ1]. 13C NMR;
(100 MHz, DMSO, d): 13.70, 19.86, 21.20, 23.90, 31.60, 39.91, 45.78,
62.38, 112.36, 125.62, 126.48, 126.89, 127.61, 127.95, 128.43, 128.59,
129.36, 132.78, 137.78, 138.84, 141.30, 147.75, 150.60, 152.89.
Elemental Analysis for:
C28H32N4O3S, Found (Calculated) C: 66.61
(66.64%), H: 6.41 (6.39%), N: 11.11 (11.10%), S: 6.39 (6.35%).
N-(Butylamino-hydroxy-methyl)-4-[5-(2-chloro-phenyl-3-(2,5-dimethyl-phenyl)-
4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2b). Light yellow crystals (mp
180–182 °C). Yield 60%. Rf = 0.82, (toluene/ethylacetate/formic acid, 5:4:1). IR
m
max (KBr, in cmꢀ1): 3204 and 3153 (NHCONH), 1693 (C@O), 1599 (C@N), 1381
and 1156 (SO2N). 1H NMR (300 MHz, DMSO, d): 0.77–0.85 (3H, m,
CH3CH2CH2CH2A), 0.90–0. 91 (2H, m, CH3CH2CH2CH2A), 1.22–1.29 (2H, m,
CH3CH2CH2CH2A), 2.27 (3H, s, CH3, C-50), 2.66 (3H, s, CH3, C-20), 2.86–2.92 (2H,
m, CH3CH2CH2CH2A), 3.15 [1H, dd, J = 8.6 Hz, J = 17.2 Hz, H-4 trans
(pyrazoline)], 4.13 [1H, dd, J = 12.9 Hz, J = 17.1 Hz, H-4 cis (pyrazoline)], 5.72
[1H, dd, J = 4.2 Hz, J = 11.1 Hz, H-5 (pyrazoline)], 6.20 (1H, t, CONHCH2A), 6.89
(2H, d, J = 9.38 Hz, H-200, H-600), 7.05–7.40 [6H, m, aromatic protons (H-3, H-4,
H-5, H-40, H-60) and SO2NHCO–], 7.56 (1H, d, J = 7.8 Hz, H-30), 7.61 (2H, d,
J = 8.4 Hz, H-300, H-500). ESI-MS (m/z): 539 [M+], 540 [M+1], 541 [M+2], 538
[Mꢀ1], 537 [Mꢀ2]. 13C NMR; (100 MHz, DMSO, d): 14.02, 19.77, 21.33, 23.87,
31.79, 39.21, 45.72, 61.74, 112.08, 112.56, 121.42, 123.16, 126.19, 127.06,
127.93, 128.11, 128.82, 129.38, 129.48, 129.61, 132.18, 138.81, 142.15, 147.39,
151.39, 152.11. Elemental Analysis for: C28H31ClN4O3S, Found (Calculated) C:
62.40 (62.38%), H: 5.76 (5.80%), N: 10.38 (10.39%), S: 5.58 (5.59%).
N-(Butylamino-hydroxy-methyl)-4-[3-(2,5-dimethyl-phenyl-5-(3-nitro-phenyl)-
4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2c). Light yellow crystals (mp
182–185 °C). Yield 60%. Rf = 0.55, (toluene/ethylacetate/formic acid,
7.5:2:0.5). IR mmax (KBr, in cmꢀ1): 3259 and 3181 (NHCONH), 1704 (C@O),
1596 (C@N), 1374 and 1161 (SO2N). 1H NMR (300 MHz, DMSO, d): 0.78 (3H, t,
J = 7.5 Hz, J = 13.2 Hz, CH3CH2CHCH2A), 1.10–1.17 (2H, m, CH3CH2CH2CH2A),
1.23–1.28 (2H, m, CH3CH2CH2CH2A), 2.31 (3H, s, CH3, C-50), 2.68 (3H, s, CH3,
C-20), 2.90–2.92 (2H, m, CH3CH2CH2CH2A), 2.78 [1H, dd, J = 6.3 Hz, J = 17.6 Hz,
H-4 trans (pyrazoline)], 4.07 [1H, dd, J = 5.7 Hz, J = 17.4 Hz, H-4 cis
(pyrazoline)], 5.78 [1H, dd, J = 4.2 Hz, J = 6.9 Hz, H-5 (pyrazoline)], 6.40 (1H,
t, CONHCH2A), 7.05–7.10 (3H, m, H-30, H-200, H-600), 7.18 (1H, s, H-60), 7.36
(1H, o, m coupled doublet H-40), 7.65–7.68 (4H, m, H-300, H-500, H-5, H-6), 8.15
(1H, d, J = 6.0 Hz, H-4), 8.19 (1H, s, H-2), 10.28 (1H, br s, SO2NH–). ESI-MS (m/
z): 549 [M+], 550 [M+1], 548 [Mꢀ1]. 13C NMR; (100 MHz, DMSO, d): 13.97,
19.74, 21.23, 23.82, 31.76, 40.63, 45.41, 60.97, 112.23, 121.42, 123.18, 126.18,
127.06, 127.73, 129.19, 129.15, 129.56, 131.31, 132.88, 137.36, 139.03,
144.26, 147.19, 148.67, 151.84, 151.94. Elemental Analysis for: C28H31N5O5S,
Found (Calculated) C: 61.19 (61.19%), H: 5.66 (5.68%), N: 12.75 (12.74%), S:
5.86 (5.83%).
N-(Butylamino-hydroxy-methyl)-4-[3-(2,5-dimethyl-phenyl)-5-(4-methoxy-phenyl)-
4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2g). Light yellow crystals (mp 188–
190 °C). Yield 55%. Rf = 0.76 (toluene/ethylacetate/formic acid, 5:4:1). IR mmax
(KBr, in cmꢀ1): 3319 (NHCONH), 1693 (C@O), 1597 (C@N), 1369 and 1162
(SO2N). 1H NMR (300 MHz, CDCl3, d): 0.84–0.94 (3H, m, CH3CH2CH2CH2A), 1.20–
1.30 (2H, m, CH3CH2CH2CH2A), 1.52–1.65 (2H, m, CH3CH2CH2CH2A), 2.35 (3H, s,
CH3, C-50), 2.72 (3H, s, CH3 C-20), 3.18–3.22 (2H, m, CH3CH2CH2CH2A), 3.26 [1H,
dd, J = 5.7 Hz, J = 14.4 Hz, H-4 trans (pyrazoline)], 3.78 (3H, s, OCH3), 3.92 [1H, dd,
J = 12.0 Hz, J = 17.1 Hz, H-4 cis (pyrazoline)], 5.23 [1H, dd, J = 5.7 Hz, J = 12.0 Hz,
H-5 (pyrazoline)], 6.53 (1H, t, CONHCH2A), 6.86 (2H, d, J = 8.4 Hz, H-3, H-5), 7.00–
7.04 (3H, m, H-200, H-600, H-40), 7.14–7.26 (4H, m, H-30, H-60, H-2, H-6), 7.62 (2H, d,
J = 7.8 Hz, H-300, H-500). ESI-MS (m/z): 534 [M+], 535 [M+1], 533 [Mꢀ1]. 13C NMR;
(100 MHz, CDCl3, d): 13.67, 19.88, 21.23, 23.95, 31.58, 39.89, 45.84, 55.31, 61.87,
112.38, 112.74, 126.53, 126.91, 127.41, 128.23, 128.73, 128.89, 132.81, 133.29,
137.28, 138.88, 147.91, 150.81, 152.64, 159.23. Elemental Analysis for:
C29H34N4O4S. Found (Calculated) C: 65.17 (65.14%), H: 6.44 (6.41%), N: 10.47
(10.48%), S: 6.01 (6.00%).
N-(Butylamino-hydroxy-methyl)-4-[5-(3,4-dimethoxy-phenyl)-3-(2,5-dimethyl-
phenyl)-4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2h). Off white crystals
(mp 158–160 °C). Yield 65%. Rf = 0.49 (toluene/ethylacetate/formic acid, 7.5:
2: 0.5). IR mmax (KBr, in cmꢀ1): 3262 and 3219 (NHCONH), 1693 (C@O), 1596
(C@N), 1376 and 1161 (SO2N). 1H NMR (300 MHz, CDCl3, d): 0.87 (3H, t,
J = 7.2 Hz, J = 14.4 Hz, CH3CH2CH2CH2A), 0.92–1.24 (2H, m, CH3CH2CH2CH2A)
1.26–1.33 (2H, m, CH3CH2CH2CH2A), 2.36 (3H, s, CH3, C-50), 2.72 (3H, s, CH3,
C-20), 3.23(3H, s, OCH3), 3.12–3.23 (2H, m, CH3CH2CH2CH2A) 3.28 [1H, dd,
J = 6 Hz, J = 17.4 Hz, H-4 trans (pyrazoline)], 3.58 (3H, s, OCH3), 3.93 [1H, dd,
J = 12.3 Hz, J = 17.4 Hz, H-4 cis (pyrazoline)], 5.20 [1H, dd, J = 6.0 Hz,
J = 11.7 Hz, H-5 (pyrazoline)], 6.54 (1H, s, H-2), 6.55 (1H, t, CONHCH2A),
6.56–6.68 (2H, m, H-5, H-6), 6.87 [3H, d, J = 20.1 Hz, superimposed 2 doublet
(H-40), (H-200, H-600)], 7.05 (1H, s, H-60), 7.17 (1H, d, J = 16.2 Hz, H-30), 7.67 (2H,
d, J = 9.0 Hz, H-300, H-500). ESI-MS (m/z): 564 [M+], 565 [M+1], 563 [Mꢀ1]. 13C
NMR; (100 MHz, CDCl3, d): 14.60, 19.77, 21.23, 23.81, 31.80, 40.62, 45.46,
55.80, 56.05, 61.73, 110.12, 112.17, 114.41, 117.90, 127.07, 129.35, 132.77,
134.38, 135.15, 137.12, 138.77, 144.42, 148.63, 149.57, 151.73, 152.46.
Elemental Analysis for: C30H36N4O5S, Found (Calculated) C: 63.84 (63.81%),
H: 6.42 (6.43%), N: 9.95 (9.92%), S: 5.67 (5.68%).
N-(Butylamino-hydroxy-methyl)-4-[5-(4-chloro-phenyl)-3-(2,5-dimethyl-phenyl)-
4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2d). Off white crystals (mp
188–190 °C). Yield 60%. Rf = 0.73, (toluene/ethylacetate/formic acid, 5:4:1).
IR mmax (KBr, in cmꢀ1): 3392 and 3170 (NHCONH), 1695 (C@O), 1596 (C@N),
1381 and 1156 (SO2N). 1H NMR (300 MHz, CDCl3, d): 0.87 (3H, t, J = 7.2 Hz,
N-(Butylamino-hydroxy-methyl)-4-[3-(2,5-dimethyl-phenyl)-5-(3,4,5-trimethoxy-
phenyl)-4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2i). White crystals (mp

1690
P. Rathore et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1685–1691
200–204 °C). Yield 65%. Rf = 0.81(toluene/ethylacetate/formic acid, 5:4:1). IR
max (KBr, in cmꢀ1): 3325 and 3265 (NHCONH), 1690 (C@O), 1595 (C@N), 1348
147.90, 150.93. Elemental Analysis for: C29H34N4O3S. Found (Calculated) C:
67.17 (67.15%), H: 6.62 (6.61%), N: 10.83 (10.80%), S: 6.15 (6.18%).
m
and 1131 (SO2N). 1H NMR (300 MHz, DMSO, d): 0.78 (3H, t, CH3CH2CH2CH2A),
1.11–1.12 (2H, m, CH3CH2CH2CH2A), 1.25–1.29 (2H, m, CH3CH2CH2CH2A), 2.31
(3H, s, CH3, C-50), 2.66 (3H, s, CH3, C-20), 2.89–2.95 (2H, m, CH3CH2CH2CH2A),
3.24 [1H, dd, J = 5.6 Hz, J = 17.4 Hz, H-4 trans (pyrazoline)], 3.58 (3H, s, OCH3,C-
4), 3.69 (6H, s, 2 ꢁ OCH3, C-3, C-5), 4.0 [1H, dd, J = 5.1 Hz, J = 17.4 Hz, H-4 cis
(pyrazoline)], 5.43 [1H, dd, J = 5.4 Hz, J = 11.1 Hz, H-5 (pyrazoline)], 6.32 (1H, t,
CONHCH2A), 6.57 (2H, s, H-2, H-6), 7.05-7.10 (3H, m, H-40, H-200, H-600), 7.17
(1H, s, H-60), 7.36 (1H, d, J = 8.1 Hz, H-30), 7.67 (2H, d, J = 9.0 Hz, H-300, H-500).
ESI-MS (m/z): 594 [M+], 595 [M+1], 593 [Mꢀ1]. 13C NMR; (100 MHz, DMSO, d):
14.00, 19.75, 21.33, 23.78, 32.41, 40.61, 45.41, 55.59, 56.24, 61.45, 103.22,
112.41, 126.41, 127.54, 128.26, 129.14, 131.41, 132.05, 134.41, 136.47, 137.19,
147.40, 147.91, 150.25, 151.80, 153.80. Elemental Analysis for: C31H38N4O6S,
Found (Calculated) C: 62.64 (62.61%), H: 6.45 (6.44%), N: 9.41 (9.42%), S: 5.37
(5.39%).
N-(Butylamino-hydroxy-methyl)-4-[5-(4-dimethyamino-phenyl)-3-(2,4-dimethyl-
phenyl)-4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2n). Light brown
crystals (mp 194–195 °C). Yield 60%. Rf = 0.64 (petroleum ether/acetone, 6:
4). IR m
max (KBr, in cmꢀ1): 3245 and 3182 (NHCONH), 1688 (C@O), 1596 (C@N),
1337 and 1162 (SO2N). 1H NMR (300 MHz, CDCl3, d):, d): 0.85–0.92 (3H, m,
CH3CH2CH2CH2A), 1.23–1.33 (2H, m, CH3CH2CH2CH2A), 1.39–1.49 (2H, m,
CH3CH2CH2CH2A), 2.35 (3H, s, CH3, C-40), 2.72 (3H, s, CH3, C-20), 2.92 [6H, s,
N(CH3)2], 3.16–3.24 (2H, m, CH3CH2CH2CH2A), 3.28 [1H, dd, J = 5.4 Hz,
J = 17.1 Hz, H-4 cis (pyrazoline)], 5.19 [1H, dd, J = 5.7 Hz, J = 12.0 Hz, H-5
(pyrazoline)], 6.53 (1H, t, CONHCH2A), 6.66 (2H, J = 8.7 Hz, H-200, H-600), 7.02–
7.13 (6H, m, H-50, H-2, H-6, H-30, H-3, H-5), 7.20 (1H, d, J = 8.1 Hz, H-60), 7.62
(2H, d, J = 9.0 Hz, H-300, H-500). ESI-MS (m/z): 547 [M+], 548 [M+1], 546 [Mꢀ1].
13C NMR; (100 MHz, CDCl3, d): 14.00, 19.77, 21.33, 23.89, 31.87, 40.16, 42.67,
43.04, 61.46, 112.11, 113.2, 126.45, 126.93, 127.08, 127.53, 128.15, 128.32,
129.21, 129.46, 132.79, 137.41, 138.90, 140.26, 150.27, 151.73. Elemental
N-(Butylamino-hydroxy-methyl)-4-[3-(2,4-dimethyl-phenyl)-5-phenyl-4,5-dihydro-
pyrazol-1-yl]-benzenesulfonamide (2j). Off white crystals (mp 155–158 °C). Yield
60%. Rf = 0.55 (toluene/ethylacetate/formic acid, 5:4:1). IR mmax (KBr, in cmꢀ1):
Analysis for:
C30H37N5O3S. Found (Calculated) C: 65.77 (65.79%), H: 6.82
(6.81%), N: 12.78 (12.79%), S: 5.84 (5.85%).
N-(Butylamino-hydroxy-methyl)-4-[3-(2,4-dimethyl-phenyl)-5-(4-methoxy-phenyl)-
3221 and 3160 (NHCONH), 1696 (C@O), 1596 (C@N), 1390 and 1159 (SO2N). 1
H
NMR (300 MHz, CDCl3, d): 0.84 (3H, t, CH3CH2CH2CH2A), 1.24–1.36 (2H, m,
CH3CH2CH2CH2A), 1.39–1.43 (2H, m, CH3CH2CH2CH2A), 2.35 (3H, s, CH3, C-40),
2.79 (3H, s, CH3 C-20), 3.12 (2H, d, J = 6.6 Hz, CH3CH2CH2CH2A), 3.26 [1H, dd,
J = 6.0 Hz, J = 12.8 Hz, H-4 trans (pyrazoline)], 3.90 [1H, dd, J = 11.1 Hz,
J = 18.2 Hz, H-4 cis (pyrazoline)], 5.23 [1H, dd, J = 6.6 Hz, J = 11.1 Hz, H-5
(pyrazoline)], 6.44 (1H, t, CONHCH2), 6.98–7.04 (3H, m, H-50, H-200, H-600),
7.13–7.16 (2H, m, H-4, H-30), 7.19–7.34 (5H, m, H-4’, H-2, H-3, H-5, H-6), 7.65
(2H, d, J = 9.0 Hz, H-300, H-500). ESI-MS (m/z): 504 [M+], 505 [M+1], 503 [Mꢀ1]. 13C
NMR; (100 MHz, CDCl3, d): 13.70, 19.86, 21.20, 23.90, 31.60, 39.91, 45.78, 62.38,
112.36, 125.62, 126.48, 126.89, 127.61, 127.95, 128.43, 128.59, 129.36, 132.78,
137.78, 138.84, 141.30, 147.75, 150.60, 152.89. Elemental Analysis for:
4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2o). Light yellow crystals (mp 170–
172 °C). Yield 62%. Rf = 0.88 (petroleum ether/acetone, 6:4). IR
m
max (KBr, in cmꢀ1):
3245 and 3182 (NHCONH), 1688 (C@O), 1596 (C@N), 1337 and 1162 (SO2N). 1
H
NMR (300 MHz, CDCl3, d): 0.89–0.94 (3H, m, CH3CH2CH2CH2A), 1.23–1.33 (2H, m,
CH3CH2CH2CH2A), 1.36–1.49 (2H, m, CH3CH2CH2CH2A), 2.17 (3H, s, CH3, C-40),
2.72 (3H, s, CH3, C-20), 3.16–3.20 (2H, m, CH3CH2CH2CH2A), 3.26 [1H, dd,
J = 5.7 Hz, J = 17.1 Hz, H-4 trans (pyrazoline)], 3.78 (3H, s, OCH3), 3.92 [1H, dd,
J = 12.0 Hz, J = 16.8 Hz, H-4 cis (pyrazoline)], 5.24 [1H, dd, J = 5.7 Hz, 12.3 Hz, H-5
(pyrazoline)], 6.53 (1H, t, CONHCH2A), 6.86 (2H, d, J = 8.4 Hz, H-3, H-5), 7.00–7.03
(3H, m, H-200, H-600, H-50), 7.14–7.22 (4H, m, H-2, H-6, H-30, H-60), 7.62 (2H, d,
J = 8.7 Hz, H-300, H-500). ESI-MS (m/z): 534 [M+], 535 [M+1], 533 [Mꢀ1]. 13C NMR;
(100 MHz, CDCl3, d): 13.70, 19.86, 21.23, 23.93, 31.57, 39.94, 45.85, 55.29, 61.84,
112.40, 114.72, 126.52, 126.83, 127.58, 127.64, 128.84, 128.60, 129.41, 132.81,
133.16, 138.95, 147.94, 150.92, 152.16, 159.22. Elemental Analysis for:
C28H32N4O3S, Found (Calculated) C: 66.62 (66.64%), H: 6.37 (6.39%), N: 11.13
(11.10%), S: 6.37 (6.35%).
N-(Butylamino-hydroxy-methyl)-4-[5-(2-chloro-phenyl)-3-(2,4-dimethyl-phenyl)-
4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2k). Off white crystals (mp 178–
180 °C). Yield 60%. Rf = 0.50 (toluene/ethylacetate/formic acid, 5: 4: 1). IR mmax
(KBr, in cmꢀ1): 3197 (NHCONH), 1692 (C@O), 1598 (C@N), 1334 and 1158
(SO2N). 1H NMR (300 MHz, DMSO, d): 0.79 (3H, t, J = 7.2 Hz, J = 14.1 Hz,
CH3CH2CH2CH2A), 1.11–1.18 (2H, m, CH3CH2CH2CH2A), 1.25–1.29 (2H, m,
CH3CH2CH2CH2A), 2.30 (3H, s, CH3, C-40), 2.66 (3H, s, CH3 C-20), 2.90–2.93 (2H,
m, CH3CH2CH2CH2A), 3.20 [1H, dd, J = 6.0 Hz, J = 18.3 Hz, H-4 trans
(pyrazoline)], 4.13 [1H, dd, J = 12.0 Hz, J = 17.4 Hz, H-4 cis (pyrazoline)], 5.73
[1H, dd, J = 4.5 Hz, J = 12.0 Hz, H-5 (pyrazoline)], 6.33 (1H, t, CONHCH2A), 6.93
(2H, d, J = 14.7, H-200, H-600), 7.05–7.16 (2H, m, H-50, H-6), 7.16 (1H, s, H-30),
7.24–7.38 (3H, m, H-2, H-3, H-5), 7.56 (1H, d, J = 9.0 Hz, H-60), 7.68 (2H, d,
J = 9.0, H-300, H-500), 10.23 (1H, br s, SO2NHCO–). ESI-MS (m/z): 539 [M+], 540
[M+1], 542 [M+2], 537 [Mꢀ2]. 13C NMR; (75 MHz, DMSO, d): 13.68, 19.86,
21.22, 23.86, 31.59, 40.01, 44.56, 59.25, 112.34, 112.47, 126.54, 126.76, 127.04,
127.89, 128.57, 128.73, 129.28, 130.16, 137.81, 132.83, 137.69, 137.85, 139.20,
C29H34N4O4S. Found (Calculated) C: 65.43 (65.40%), H: 6.42 (6.41%), N: 10.50
(10.48%), S: 6.02 (6.00%).
N-(Butylamino-hydroxy-methyl)-4-[5-(3,4-dimethoxy-phenyl)-3-(2,4-dimethyl-
phenyl)-4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2p). White crystals
(mp 168–169 °C). Yield 70%. Rf = 0.73 (toluene/ethylacetate/formic acid,
5:4:1). IR mmax (KBr, in cmꢀ1): 3261 and 3183 (NHCONH), 1699 (C@O),
1596 (C@N), 1333 and 1161 (SO2N). 1H NMR (300 MHz, CDCl3, d): 0.87 (3H, t,
J = 7.2 Hz, J = 14.4 Hz, CH3CH2CH2CH2A), 0.92–1.24 (2H, m, CH3CH2CH2CH2A)
1.26–1.33 (2H, m, CH3CH2CH2CH2A), 2.36 (3H, s, CH3, C-40), 2.72 (3H, s, CH3
C-20), 3.23 (3H, s, OCH3), 3.12–3.23 (2H, m, CH3CH2CH2CH2A), 3.28 [1H, dd,
J = 6.0 Hz, J = 17.4 Hz, H-4 trans (pyrazoline)], 3.58 (3H, s, OCH3), 3.93 [1H, dd,
J = 12.3 Hz, J = 17.4 Hz, H-4 cis (pyrazoline)], 5.20 [1H, dd, J = 6.0 Hz,
J = 11.7 Hz, H-5 (pyrazoline)], 6.54 (1H, s, H-2), 6.55 (1H, t, CONHCH2A),
6.56–6.68 (2H, m, H-5, H-6), 6.87 [3H, d, J = 20.1 Hz, superimposed 2 doublet
(H-40), (H-200, H-600)], 7.05 (1H, s, H-60), 7.17 (1H, d, J = 16.2 Hz, H-30), 7.67 (2H,
d, J = 9.0 Hz, H-300, H-500). ESI-MS (m/z): 564 [M+], 565 [M+1]. 13C NMR;
(100 MHz, CDCl3, d): 14.03, 19.77, 21.24, 23.90, 31.80, 39.94, 45.71, 55.29,
55.76, 61.72, 101.65, 111.69, 126.19, 127.09, 127.93, 128.49, 129.61, 132.81,
133.14, 137.25, 138.82, 142.15, 147.38, 148.46, 151.63, 153.35. Elemental
Analysis for: C30H36N4O5S. Found (Calculated) C: 63.82 (63.81%), H: 6.42
(6.43%), N: 9.90 (9.92%), S: 5.55 (5.58%).
147.69, 151.44, 152.24. Elemental Analysis for:
C28H31ClN4O3S. Found
(Calculated) C: 62.48 (62.47%), H: 5.83 (5.80%), N: 10.37 (10.39%), S: 5.97
(5.95%).
N-(Butylamino-hydroxy-methyl)-4-[5-(4-chloro-phenyl)-3-(2,4-dimethyl-phenyl)-
4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2l). Light yellow crystals (mp
164–166 °C). Yield 60%. Rf = 0.84 (toluene/ethylacetate/formic acid, 5: 4: 1). IR
m
max (KBr, in cmꢀ1): 3235 (NHCONH), 1700 (C@O), 1596 (C@N), 1364 and 1156
N-(Butylamino-hydroxy-methyl)-4-[3-(2,4-dimethyl-phenyl)-5-(3,4,5-trimethoxy-
phenyl)-4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2q). White crystals (mp
200–202 °C). Yield 72%. Rf = 0.74 (toluene/ethylacetate/formic acid, 5:4:1). IR
(SO2N). 1H NMR (300 MHz, DMSO, d): 0.79 (3H, t, J = 7.2 Hz, J = 14.1 Hz,
CH3CH2CH2CH2A), 1.10–1.18 (2H, m, CH3CH2CH2CH2A), 1.24–1.29 (2H, m,
CH3CH2CH2CH2A), 2.31 (3H, s, CH3, C-40), 2.67 (3H, s, CH3, C-20), 2.88–2.98 (2H,
m, CH3CH2CH2CH2A), 3.23 [1H, dd, J = 6.0 Hz, J = 18.0 Hz, H-4 trans
(pyrazoline)], 4.03 [1H, dd, J = 12.0 Hz, J = 17.4 Hz, H-4 cis (pyrazoline)], 5.58
[1H, dd, J = 4.5 Hz, J = 11.5 Hz, H-5 (pyrazoline)], 6.33 (1H, t, CONHCH2), 7.01
(2H, d, J = 9.0 Hz, H-200, H-600), 7.08 (1H, d, J = 7.8 Hz, H-50), 7.17 (1H, s, H-30),
7.25 (2H, d, J = 14.7 Hz, H-200, H-600), 7.35 (1H, d, J = 9.0 Hz, H-60), 7.41 (2H, d,
J = 7.5 Hz, H-3, H-5), 7.65 (2H, d, J = 9.0 Hz, H-300, H-500),10.23 (1H, br s,
SO2NHCO–). ESI-MS (m/z): 539 [M+], 540 [M+1], 542 [M+2], 537 [Mꢀ2]. 13C
NMR; (100 MHz, DMSO, d): 13.70, 21.25, 23.94, 31.56, 39.95, 45.72, 61.71,
112.43, 116.40, 126.58, 126.79, 127.34, 127.54, 128.72, 128.76, 129.54, 129.62,
131.25, 132.87, 133.84, 137.86, 139.68, 147.76, 150.64. Elemental Analysis for:
m
max (KBr, in cmꢀ1): 3251 and 3162 (NHCONH), 1690 (C@O), 1595 (C@N), 1347
and 1131 (SO2N). 1H NMR (300 MHz, CDCl3, d): 0.87 (3H, t, J = 7.2 Hz,
J = 14.4 Hz, CH3CH2CH2CH2A), 1.25–1.32 (2H, m, CH3CH2CH2CH2A) 1.41–1.56
(2H, m, CH3CH2CH2CH2A), 2.36 (3H, s, CH3, C-40), 2.72 (3H, s, CH3, C-20), 3.80
(6H, s, 2 ꢁ OCH3), 3.83 (3H, s, OCH3), 3.17–3.24 (2H, m, CH3CH2CH2CH2A) 3.30
[1H, dd, J = 6.0 Hz, J = 17.1 Hz, H-4 trans (pyrazoline)], 3.93 [1H, dd, J = 11.7 Hz,
J = 15.8 Hz, H-4 cis (pyrazoline)], 5.16 [1H, dd, J = 6.3 Hz, J = 11.7 Hz, H-5
(pyrazoline)], 6.44 (2H, s, H-2, H-6), 7.05 (3H, doublet of H-50 merged with 2
proton doublet, J = 8.7 Hz, H-200, H-600), 6.55 (1H, t, CONHCH2A), 7.18 (2H, d,
J = 1.8 Hz, H-30, H-60), 7.66 (2H, d, J = 9.0 Hz, H-300, H-500). ESI-MS (m/z): 594
[M+], 595 [M+1], 593 [Mꢀ1]. 13C NMR; (100 MHz, CDCl3, d): 14.03, 19.77, 21.24,
23.90, 31.80, 39.94, 45.71, 55.29, 55.76, 61.72, 101.65, 111.69, 126.19, 127.09,
127.93, 128.49, 129.61, 132.81, 133.14, 137.25, 138.82, 142.15, 147.38, 148.46,
151.63, 153.35. Elemental Analysis for: C31H38N4O6S. Found (Calculated) C:
62.65 (62.61%), H: 6.45 (6.44%), N: 9.43 (9.42%), S: 5.40 (5.39%).
C28H31ClN4O3S. Found (Calculated) C: 62.36 (62.38%), H: 5.83 (5.80%), N: 10.38
(10.39%), S: 5.97 (5.95%).
N-(Butylamino-hydroxy-methyl)-4-[3-(2,4-dimethyl-phenyl)-5-p-tolyl-4,5-dihydro-
pyrazol-1-yl]-benzenesulfonamide (2m). Light yellow crystals (mp 158–159 °C).
Yield 60%. Rf = 0.79 (toluene/ethylacetate/formic acid, 5:4:1). IR mmax (KBr, in
cmꢀ1): 3159 (NHCONH), 1699 (C@O), 1595 (C@N), 1336 and 1158 (SO2N). 1H
NMR (300 MHz, CDCl3, d): 0.92–0.94 (3H, m, CH3CH2CH2CH2A), 1.21–1.33 (2H,
m, CH3CH2CH2CH2A), 1.36–1.48 (2H, m, CH3CH2CH2CH2A), 2.31 (3H, s, CH3, C-4),
2.35 (3H, s, CH3, C-40), 2.72 (3H, s, CH3, C-20), 3.14–3.20 (2H, m, CH3
CH2CH2CH2A), 3.25 [1H, dd, J = 5.7 Hz, J = 17.1 Hz, H-4 trans (pyrazoline)], 3.92
[1H, dd, J = 12.0 Hz, J = 17.1 Hz, H-4 cis (pyrazoline)], 5.23 [1H, dd, J = 5.7 Hz,
J = 12.0 Hz, H-5 (pyrazoline)], 6.50 (1H, t, CONHCH2), 6.99–7.04 (3H, m, H-2, H-
200, H-600), 7.08 (1H, d, J = 7.8 Hz, H-50), 7.13–7.17 (5H, m, H-3, H-5, H-6, H-60),
7.19 (1H, d, J = 12.6 Hz, H-30), 7.62 (2H, d, J = 9.0 Hz, H-300, H-500). ESI-MS (m/z):
518 [M+], 519 [M+1], 517 [Mꢀ1]. 13C NMR; (100 MHz, CDCl3, d): 13.67, 19.85,
21.10, 21.21, 23.88, 31.59, 39.95, 45.86, 62.16, 112.56, 125.54, 126.51, 127.12,
127.59, 128.46, 128.59, 129.32, 129.64, 130.06, 132.79, 137.79, 138.18, 138.94,
N-(Benzylamino-hydroxy-methyl)-4-[5-(2-chloro-phenyl)3-(2,5-dimethyl-phenyl)-
4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2r). White crystals (mp 190–
192 °C). Yield 70%. Rf = 0.53 (toluene/ethylacetate/formic acid, 7.5:2:0.5). IR
m
max (KBr, in cmꢀ1): 3197 (NHCONH), 1691 (C@O), 1597 (C@N), 1335 and 1156
(SO2N). 1H NMR (300 MHz, CDCl3, d): 2.34 (3H, s, CH3, C-50), 2.76 (3H, s, CH3, C-
20), 2.42 [1H, dd, J = 14.0 Hz, J = 17.1 Hz, H-4 trans (pyrazoline)], 4.09 [1H, dd,
J = 11.7 Hz, J = 17.4 Hz, H-4 cis (pyrazoline)], 5.68 [1H, dd, J = 5.7 Hz, J = 12.6 Hz,
H-5 (pyrazoline)], 6.9–7.7 (16H, m, H-30, H-40, H-60, H-3, H-4, H-5, H-6, H-200, H-
300, H-5’00, H-600, H-2000, H-3000, H-4000, H-5000, H-6000). ESI-MS (m/z): 573 [M+], 574
[M+1], 575 [M+2], 571 [Mꢀ2]. 13C NMR; (100 MHz, CDCl3, d): 21.27, 23.94,
43.30, 59.32, 111.88, 126.77, 127.19, 127.33, 127.51, 128.06, 128.51, 128.76,
128.91, 129.32, 129.52, 130.33, 131.79, 132.74, 135.24, 137.46, 138.16, 138.82,
139.67, 142.41, 147.21, 151.28, 152.12. Elemental Analysis for: C31H29ClN4O3S.

P. Rathore et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1685–1691
1691
Found (Calculated) C: 64.97 (64.97%), H: 5.13 (5.10%), N: 9.77 (9.78%), S: 5.60
(5.59%).
phenyl)-4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2w). Off white crystals
(mp 170–173 °C). Yield 50%. Rf = 0.62 (toluene/ethylacetate/formic acid,
7.5:2:0.5). IR mmax (KBr, in cmꢀ1): 3189 and 3197 (NHCONH), 1692 (C@O),
1598 (C@N), 1335 and 1156 (SO2N). 1H NMR (400 MHz, DMSO, d) 2.17 (3H, s,
CH3, C-40), 2.40 (3H, s, CH3, C-20), 3.02 [1H, dd, J = 5.2 Hz, J = 17.2 Hz, H-4 trans
(pyrazoline)], 3.91[1H, dd, J = 12.4 Hz, J = 17.6 Hz, H-4 cis (pyrazoline)], 4.77
(2H, d, J = 7.0 Hz, CH2C6H5), 5.50 [1H, dd, J = 6.5 Hz, J = 12.5 Hz, H-5
(pyrazoline)], 6.43 (1H, t, CONHCH2A), 6.76 (2H, d, H-200, H-600), 6.85–7.56
(14H, m, H-300, H-500, H-2, H-3, H-4, H-5, H-30, H-50, H-60, H-2000, H-3000, H-4000, H-
5000, H-6000), 10.24 (1H, br s, SO2NHCO–). ESI-MS (m/z): 573 [M+], 574 [M+1], 575
[M+2], 572 [Mꢀ1]. 13C NMR; (100 MHz, DMSO, d): 21.25, 23.93, 43.13, 44.32,
54.19, 111.96, 127.11, 127.27, 127.67, 128.24, 128.51, 128.35, 128.61, 129.26,
129.50, 129.64, 130.01, 131.22, 135.21, 132.81, 137.33, 138.40, 139.73, 142.61,
N-(Benzylamino-hydroxy-methyl)-4-[5-(4-chloro-phenyl)-3-(2,5-dimethyl-phenyl)-
4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2s). Off white crystals (mp 148–
152 °C). Yield 70%. Rf = 0.64 (toluene/ethylacetate/formic acid, 7.5:2:0.5). IR mmax
(KBr, in cmꢀ1): 3225 and 3168 (NHCONH), 1705 (C@O), 1596 (C@N), 1363 and
1
1125 (SO2N). H NMR (300 MHz, DMSO, d): 2.30 (3H, s, CH3, C-50), 2.66 (3H, s,
CH3, C-20), 3.19 [1H, dd, J = 12.6 Hz, J = 17.7 Hz, H-4 trans (pyrazoline)], 3.97 [1H,
dd, J = 18.0 Hz, J = 20.1 Hz, H-4 cis (pyrazoline)], 4.07 (2H, s, CH2C6H5), 5.48 [1H,
dd, J = 5.7 Hz, J = 12.6 Hz, H-5 (pyrazoline)], 6.87 (2H, d, J = 6.0 Hz, H-200, H-600),
6.88–7.04 (1H, t, CONHCH2A) 7.04–7.41 (12H, m, H-2, H-3, H-5, H-6, H-30, H-40,
H-60, H-2000, H-3000, H-4000, H-5000, H-6000), 7.18 (1H, d, J = 1.8 Hz, H-60), 7.53 (2H, d,
J = 9.0 Hz, H-300, H-500). ESI-MS (m/z): 573[M+], 574[M+1], 575[M+2],
571[Mꢀ2].13C NMR; (100 MHz, DMSO, d): 21.46, 23.75, 39.62, 43.59, 54.26,
112.21, 126.24, 126.76, 127.18, 127.38, 128.18, 128.56, 129.34, 130.32, 131.81,
132.73, 135.11, 137.24, 138.12, 138.81, 139.24, 142.02, 147.19, 151.14, 153.24.
Elemental Analysis for: C31H29ClN4O3S. Found (Calculated) C: 64.97 (64.97%), H:
5.12 (5.10%), N: 9.77 (9.78%), S: 5.57 (5.59%).
147.23, 151.23, 154.21. Elemental Analysis for:
C31H29ClN4O3S. Found
(Calculated) C: 64.98 (64.97%), H: 5.13 (5.10%), N: 9.75 (9.78%), S: 5.60 (5.59%).
N-(Benzylamino-hydroxy-methyl)-4-[5-(4-dimethylamino-phenyl)-3-(2,4-dimethyl-
phenyl)-4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2x). White crystals (mp
180–182 °C). Yield 55%. Rf = 0.41 (toluene/ethylacetate/formic acid, 5:4:1). IR
N-(Benzylamino-hydroxy-methyl)-4-[3-(2,5-dimethyl-phenyl)-5-(4-methoxy-
phenyl)-4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2t). Off white
crystals (mp 136–137 °C). Yield 65%. Rf = 0.41 (toluene/ethylacetate/
formic acid, 5:4:1). IR mmax (KBr, in cmꢀ1): 3225 and 3268 (NHCONH),
1697 (C@O), 1594 (C@N), 1395 and 1159 (SO2N). 1H NMR (300 MHz, DMSO,
d): 2.28 (3H, s, CH3, C-50), 2.72 (3H, s, CH3, C-20), 3.21 [1H, dd, J = 7.5 Hz,
J = 16.9 Hz, H-4 trans (pyrazoline)], 3.70 (3H, s, OCH3, C-4), 3.98 [1H, dd,
J = 11.7 Hz, J = 17.8 Hz, H-4 cis (pyrazoline)], 4.12 (2H, d, J = 5.7 Hz,
CH2C6H5), 5.48 [1H, dd, J = 5.7 Hz, J = 12.6 Hz, H-5 (pyrazoline)], 6.44–6.46
(1H, t, CONHCH2), 6.80–7.05 (5H, m, H-200, H-600, H-3, H-5 + SO2NHCO–),
7.06–7.36 (10H, m, H-2, H-6, H-30, H-40, H-60, H-2000, H-3000, H-4000, H-5000, H-
6000), 7.60 (2H, d, J = 1.8 Hz, H-300, H-500). ESI-MS (m/z): 568 [M+], 569 [M+1],
570 [M+2], 567 [Mꢀ1]. 13C NMR; (100 MHz, DMSO, d): 21.23, 23.76, 39.76,
43.71, 55.24, 58.32, 112.29, 112.73, 126.89, 126.91, 127.32, 128.44, 128.61,
128.74, 129.46, 129.62, 132.41, 135.25, 138.24, 138.37, 139.41, 141.41,
m
max (KBr, in cmꢀ1): 3218 (NHCONH), 1699 (C@O), 1594 (C@N), 1376 and 1158
(SO2N). 1H NMR (400 MHz, DMSO, d): 2.36 (3H, s, CH3,C-40), 2.74 (3H, s, CH3, C-
20), 2.95 [6H, s, N(CH3)2, C-4], 3.27 [1H, dd, J = 5.2 Hz, J = 17.2 Hz, H-4 trans
(pyrazoline)], 3.91 [1H, dd, J = 12.0 Hz, J = 17.2 Hz, H-4 cis (pyrazoline)], 434–4.46
(2H, m, CH2C6H5), 5.22 [1H, dd, J = 5.2 Hz,0 J = 11.6 Hz, H-5 (pyrazoline)],
6.84–7.57 [18H, m, all aromatic protons (H-3 , H-50, H-60, H-2, H-3, H-5, H-6,
H-200, H-300, H-5000
, , , , , ) + (SO2NHCO–
H-600, H-2000 H-3000 H-4000 H-5000 H-6000
) + (CONHCH2A)]. ESI-MS (m/z): 581 [M+], 582 [M+1], 583 [M+2], 580 [Mꢀ1].
13C NMR; (100 MHz, DMSO, d): 21.23, 23.79, 43.28, 44.12, 45.78, 55.43, 61.23,
112.17, 114.78, 127.10, 127.25, 127.44, 127.47, 128.01, 128.44, 128.68, 129.40,
132.82, 134.03, 137.45, 138.70, 139.50, 147.50, 151.72, 152.20, 159.13. Elemental
Analysis for: C33H35N5O3S. Found (Calculated) C: 68.12 (68.13%), H: 6.03 (6.06%),
N: 12.01 (12.04%), S: 5.52 (5.51%).
N-(Benzylamino-hydroxy-methyl)-4-[3-(2,4-dimethyl-phenyl)-5-(4-methoxy-phenyl)-
4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2y). Light yellow crystals (mp 179–
146.55, 147.24, 151.25, 153.29. Elemental Analysis for:
Found (Calculated) C: 64.97 (64.97%), H: 5.09 (5.10%), N: 9.77 (9.78%), S:
5.61 (5.59%).
C
32H32N4O4S.
183 °C). Yield 65%. Rf = 0.66 (toluene/ethylacetate/formic acid, 5:4:1). IR mmax (KBr,
in cmꢀ1): 3209 and 3171 (NHCONH), 1699 (C@O), 1593 (C@N), 1386 and 1158
(SO2N). 1H NMR (300 MHz, CDCl3, d): 2.48 (3H, s, CH3, C-40), 2.66 (3H, s, CH3, C-20),
3.17 [1H, dd, J = 4.8 Hz, J = 17.2 Hz, H-4 trans (pyrazoline)], 3.69 (3H, s, OCH3, C-4),
3.99 [1H, dd, J = 12.0 Hz, J = 17.2 Hz, H-4 cis (pyrazoline)], 4.12 (2H, s, CH2C6H5),
5.47 [1H, dd, J = 4.4 Hz, J = 11.8 Hz, H-5 (pyrazoline)], 6.84–6.90 (3H, m, H-3, H-5,
CONHCH2A), 7.01 (2H, d, J = 8.8 Hz, H-200, H-600), 7.06–7.09 (3H, m, H-30, H-5,
H-2000), 7.16–7.22 (6H, m, H-2, H-6, H-3000, H-4000 H-5000, H-6000), 7.34 (1H, d, J = 8.0 Hz,
H-60), 7.63 (2H, d, J = 9.2 Hz, H-300, H-500), 10.38 (1H, br s, SO2NHCO–). ESI-MS (m/z):
568 [M+], 569 [M+1], 567 [Mꢀ1]. 13C NMR; (100 MHz, CDCl3, d): 21.23, 23.79,
43.28, 44.12, 45.78, 55.43, 61.23, 112.17, 114.78, 127.10, 127.25, 127.44, 127.47,
128.01, 128.44, 128.68, 129.40, 132.82, 134.03, 137.45, 138.70, 139.50, 147.50,
151.72, 152.20, 159.13. Elemental Analysis for: C32H32N4O4S. Found (Calculated) C:
64.97 (64.97%), H: 5.14 (5.10%), N: 9.77 (9.78%), S: 5.60 (5.59%).
N-(Benzylamino-hydroxy-methyl)-4-[5-(3,4-dimethoxy-phenyl)-3-(2,5-dimethyl-
phenyl)-4,5- dihydro-pyrazol-1-yl]-benzenesulfonamide (2u). Light yellow
crystals (mp 181–183 °C). Yield 65%. Rf = 0.82 (toluene/ethylacetate/formic
acid, 5:4:1). IR mmax (KBr, in cmꢀ1): 3366 and 3271 (NHCONH), 1694 (C@O),
1594 (C@N), 1398 and 1156 (SO2N). 1H NMR (400 MHz, DMSO, d): 2.30 (3H, s,
CH3, C-50), 2.66 (3H, s, CH3, C-20), 3.20 [1H, dd, J = 4.8 Hz, J = 17.6 Hz, H-4 trans
(pyrazoline)], 3.68 (3H, s, OCH3, C-3), 3.70 (3H, s, OCH3, C-4), 3.99 [1H, dd,
J = 12.0 Hz, J = 17.6 Hz, H-4 cis (pyrazoline)], 4.33 (2H, d, J = 6.0 Hz, CH2C6H5),
5.19 [1H, dd, J = 5.3 Hz, J = 11.6 Hz, H-5 (pyrazoline)], 6.72 (2H, d, J = 8.4 Hz, o,
m coupling H-6), 6.81 (1H, t, CONHCH2A), 6.84–7.22 (10H, m, H-2, H-5, H-40,
H-60, H-200, H-600, H-2000, H-3000, H-5000, H-6000), 7.35 (1H, d, J = 7.6 Hz, H-30), 7.64
(2H, d, J = 8.8 Hz, H-300, H-500), 10.38 (1H, br s, SO2NHCO–). ESI-MS (m/z): 598
[M+], 599 [M+1], 600 [M+2], 597 [Mꢀ1]. 13C NMR; (100 MHz, DMSO, d): 21.24,
23.82, 43.13, 45.84, 55.90, 56.24, 61.75, 110.12, 112.31, 112.76, 117.93,
127.10, 127.25, 127.43, 128.06, 128.45, 128.67, 129.40, 132.80, 134.43, 137.22,
138.81, 139.70, 147.73, 148.05, 149.60, 151.84, 152.17. Elemental Analysis for:
N-(Benzylamino-hydroxy-methyl)-4-[5-(3,4-dimethoxy-phenyl)-3-(2,4-dimethyl-
phenyl)-4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2z). Light yellow
crystals (mp 170–172 °C). Yield 55%. Rf = 0.66 (toluene/ethylacetate/formic
acid, 5:4:1). IR mmax (KBr, in cmꢀ1): 3224 and 3170 (NHCONH), 1694 (C@O),
1628 (C@N), 1386 and 1158 (SO2N). 1H NMR (300 MHz, CDCl3, d): 0.36 (3H, s,
CH3, C-40), 2.74 (3H, s, CH3, C-20), 3.27 [1H, dd, J = 5.7 Hz, J = 17.1 Hz, H-4 trans
(pyrazoline)], 3.82 (3H, s, OCH3, C-3), 3.85 (3H, s, OCH3, C-4), 3.94 [1H, dd,
J = 12.0 Hz, J = 16.8 Hz, H-4 cis (pyrazoline)], 4.41 (2H, s, CH2C6H5), 5.20 [1H,
dd, J = 5.7 Hz, J = 12.0 Hz, H-5 (pyrazoline)], 6.74 (1H, s, H-2), 6.58 (2H, d,
J = 9.0 Hz, H-300, H-500), 6.82–7.31 [10H, m, H-3, H-5, H-6, H-30, H-50, H-60, H-200,
H-600 + (SO2NHCO–) + (CONHCH2A)]. ESI-MS (m/z): 598 [M+], 599 [M+1], 600
[M+2], 597 [Mꢀ1]. 13C NMR; (100 MHz, CDCl3, d): 21.29, 23.87, 44.09, 44.64,
55.96, 56.00, 62.46, 108.36, 111.79, 112.54, 117.87, 126.59, 127.04, 127.50,
128.54, 128.63, 128.68, 128.74, 132.35, 133.70, 137.71, 137.79, 139.10, 148.32,
148.81, 149.88, 151.16, 152.91. Elemental Analysis for: C33H34N4O5S. Found
(Calculated) C: 66.22 (66.20%), H: 5.75 (5.72%), N: 9.40 (9.36%), S: 5.33 (5.36%).
22. Grever, M. R.; Schepartz, S. A.; Chabner, B. A. Semin. Oncol. 1992, 19, 622.
23. Boyd, M. R.; Paull, K. D. Drug Rev. Res. 1995, 34, 91.
C
33H34N4O5S. Found (Calculated) C: 64.17 (66.20%), H: 5.75 (5.72%), N: 9.37
(9.36%), S: 5.33 (5.36%).
N-(Benzylamino-hydroxy-methyl)-4-[3-(2,5-dimethyl-phenyl-5-(3,4,5,trimethoxy-
phenyl)-4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2v). Off white crystals
(mp 140–142 °C). Yield 65%. Rf = 0.81 (toluene/ethylacetate/formic acid, 5:4:1).
IR mmax (KBr, in cmꢀ1): 3238 and 3192 (NHCONH), 1690 (C@O), 1594 (C@N),
1330 and 1157 (SO2N). 1H NMR (400 MHz, CDCl3, d) 2.37 (3H, s, CH3, C-5’), 2.73
(3H, s, CH3, C-20), 3.81 (6H, s, 2 ꢁ OCH3, C-3, C-5), 3.82 (3H, s, OCH3, C-4), 3.31
[1H, dd, J = 6.4 Hz, J = 17.2 Hz, H-4 trans (pyrazoline)], 3.94 [1H, dd, J = 12.4 Hz,
J = 17.6 Hz, H-4 cis (pyrazoline)], 4.33 (2H, s, CH2C6H5), 5.15 [1H, dd, J = 6.4 Hz,
J = 12.0 Hz, H-5 (pyrazoline)], 6.31 (2H, s, H-2, H-6), 6.81 (1H, t, CONHCH2A),
7.01–7.33 (10H, m, H-3, H-4, H-6, H-200, H-600, H-2000, H-3000, H-4000, H-5000, H-6000),
7.45 (1H, br s, SO2NH), 7.60 (2H, d, J = 8.8 Hz, H-300, H-500). ESI-MS (m/z): 528
[M+], 529 [M+1], 527 [Mꢀ1]. 13C NMR; (100 MHz, CDCl3, d): 21.23, 23.81, 39.41,
44.76, 56.22, 60.87, 102.12, 102.18, 112.58, 126.62, 127.28, 127.36, 127.51,
128.57, 128.63, 128.68, 128.74, 128.81, 132.86, 137.04, 137.70, 137.78, 138.21,
148.45, 151.27, 151.76, 154.12. Elemental Analysis for: C34H36N4O6S. Found
(Calculated) C: 64.94 (64.95%), H: 5.75 (5.77%), N: 8.88 (8.91%), S: 5.13 (5.10%).
N-(Benzylamino-hydroxy-methyl)-4-[5-(2-chloro-phenyl)3-(2,4-dimethyl-
24. Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.; Vistica, D.; Hose,
C.; Jangley, J.; Cronisie, P.; Viagro-Wolff, A.; Gray-Goodrich, M.; Campell, H.;
Boyd, M. J. Natl Cancer Inst. 1991, 83, 757.
25. Acton, E. M.; Narayanan, V. L.; Risbood, P. A.; Shoemaker, R. H.; Vistica, D. T.;
Boyd, M. R. J. Med. Chem. 1994, 37, 2185.