Synthesis and blood glucose lowering activity of novel benzenesulfonyl-urea derivatives

Article abstract of DOI:10.1080/10426500802467187

Treatment of the pyridazinone derivatives (1a, 1b) with ethyl chloroformate afforded novel carbamates (2a, 2b). Subsequent treatment of 2a, 2b with appropriate amines gave novel benzenesulfonylurea derivatives (3a-i). All these compounds were characterize

Full text of DOI:10.1080/10426500802467187

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Synthesis and Blood Glucose
Lowering Activity of Novel
Benzenesulfonyl-Urea
Derivatives
Shamim Ahmad a , Kalim Javed a , I. G. Rathish a ,
Sameena Bano a & M. S. Alam a
a Department of Chemistry, Faculty of Science,
Jamia Hamdard (Hamdard University), New Delhi,
India
Version of record first published: 21 Sep 2009.
To cite this article: Shamim Ahmad , Kalim Javed , I. G. Rathish , Sameena Bano
& M. S. Alam (2009): Synthesis and Blood Glucose Lowering Activity of Novel
Benzenesulfonyl-Urea Derivatives, Phosphorus, Sulfur, and Silicon and the Related
Elements, 184:10, 2516-2524
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Phosphorus, Sulfur, and Silicon, 184:2516–2524, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802467187
Synthesis and Blood Glucose Lowering Activity of Novel
Benzenesulfonyl-Urea Derivatives
Shamim Ahmad, Kalim Javed, I. G. Rathish,
Sameena Bano, and M. S. Alam
Department of Chemistry, Faculty of Science, Jamia Hamdard
(Hamdard University), New Delhi, India
Treatment of the pyridazinone derivatives (1a, 1b) with ethyl chloroformate af-
forded novel carbamates (2a, 2b). Subsequent treatment of 2a, 2b with appropri-
ate amines gave novel benzenesulfonylurea derivatives (3a–i). All these compounds
1
were characterized on the basis of H NMR, IR, Mass spectral data and elemen-
tal analysis results. Preliminary biological testing of urea derivatives revealed that
some compounds possess significant blood sugar lowering activity. Four compounds
(3c, 3f, 3g, and 3h) were found to have promising blood glucose lowering activity
and may be used as lead compounds for developing new antidiabetic drugs.
Keywords Benzenesulfonylurea; carbamates; diabetes; pyridazinones
INTRODUCTION
Diabetes mellitus is one of the most daunting challenges posed by
chronic diseases. Recent data show that approximately 135 million
people suffer from diabetes mellitus worldwide, and that this number
will rise to almost 300 million by the year 2025. Thus, a more than
twofold rise is projected to occur because of population ageing, un-
healthy diets, obesity, and a sedentary lifestyle. Though the rise will
be of the order of 45% in developed countries, it will be almost 200%
in developing countries.1 India has 35 million diabetics. As per World
Health Organization data, the number will reach 50 million in 2020.2
Diabetes mellitus is generally classified as Type-I insulin-dependent
diabetes mellitus (IDDM), caused by low or insufficient secretion of
Received 9 July 2008; accepted 9 September 2008.
One of the authors (SA) is thankful to Hamdard National Foundation India for pro-
viding fellowship. Thanks are due to SAIF, CDRI, Lucknow, for providing mass spectra.
Address correspondence to Dr. Kalim Javed, Department of Chemistry, Faculty of
Science, Jamia Hamdard (Hamdard University), New Delhi 110 062, India. E-mail:
kjavedchem@yahoo.co.in
2516

Benzenesulfonyl-Urea Derivatives
2517
insulin by the pancreas, and Type-II non-insulin-dependent diabetes
mellitus (NIDDM), caused due to insufficient utilization of insulin.1,3
NIDDM is the most common form of diabetes, constituting nearly 90%
of the diabetic population in any country.
Chronic diabetes is accompanied by complications such as neuropa-
thy, nephropathy, cataracts, and retinopathy, which are not controlled
by insulin. These complications are caused by accumulation of sorbitol,
which is produced from glucose by aldose reductase (AR) in polyol
pathway.4,5 Over the last 40 years, oral therapy for Type-2 DM has
focused on sulfonylureas and biguanides.6 Sulfonylureas, which are
widely used as hypoglycemic agents for NIDDM, strongly inhibit ATP-
sensitive K+ channel activity by binding to sulfonylurea receptors in
pancreatic β-cells.7,8 The result of clinical trials justifies the importance
of improved glycemic control in diabetic patients in order to prevent or
at least delay long-term complications. There is need to develop antidi-
abetic agents provided with aldose reductase inhibitor (ARI).
Recently, compounds containing pyridazine nucleus have been re-
ported as AR inhibitors.9–11 Therefore, it has been considered worth-
while to attach a pyridazinone ring to benzenesulfonylurea derivatives.
In the present study, nine novel pyridazinone-substituted benzene-
sulfonylurea derivatives and six novel carbamates were synthesized.
These were characterized by elemental analysis and various spectro-
scopic methods, viz. IR, 1H NMR, and MS. Oral antihyperglycemic
efficacy of sulfonylurea derivatives were assessed using an oral glucose
tolerance test in a normal rat model.
RESULTS AND DISCUSSION
Synthesis of Compounds
The synthetic route used to prepare the title compounds (3a–i) is out-
lined in Scheme 1. The pyridazinone derivatives (1a, 1b) were con-
verted to the corresponding carbamates (2a, 2b) by refluxing with ethyl
chloroformate in dry acetone containing anhydrous K2CO3. The carba-
mates were subsequently condensed with the desired primary amines
in toluene to give the corresponding pyridazinone-substituted benzene-
sulfonylurea derivatives (3a–i). The pyridazinone derivatives (1a, 1b)
were synthesized through a reported method.12
The structures of sulfonylurea derivatives were determined on the
basis of their elemental analysis and various spectroscopic methods
such as IR, 1H NMR, and MS, whereas the carbamates were character-
ized by 1H NMR, IR, and elemental analysis. Elemental analysis (C, H,
N, and S) data were within 0.4% of the theoretical values.

2518
S. Ahmad et al.
SCHEME 1
Support for the structures 2a, 2b is evidenced by the presence of
prominent bands in the IR spectra for C O of carbamates (1754–1752
cm−1), cyclic carbonyl (1681–1672 cm−1), and SO2N < (1343–1338 cm−1
and 1164–1160 cm−1). The 1H NMR spectra revealed a triplet at δ 1.06
and a quartet at δ 4.36 for -OCH2CH3. Similarly, two triplets in the
range of δ 2.78 and δ 3.16–3.17 can be attributed to the dihydropyridazi-
none ring protons. A broad singlet for NH at δ 4.10 was also observed.
The aromatic protons were observed in the region of δ 7.36–7.90.
In the IR spectra of 3a–i a band for NH (3385–3357 cm−1) and two
bands for carbonyl group of urea (1729–1687 cm−1) and carbonyl func-
tion of pyridazinone (1680–1658 cm−1) were identified. Two bands for
SO2N < (1347–1310 cm−1 and 1161–1156 cm−1) were also observed.
The structures were further established by proton NMR spectral data.
Two triplets at δ 2.78–2.83 and δ 3.10–3.18 were observed for dihy-
dropyridazinone ring protons. A singlet for R-NH was observed at
δ 6.08–8.93. The aromatic protons were observed in the region of δ

Benzenesulfonyl-Urea Derivatives
2519
TABLE I Effect of Sulfonylurea Derivatives on Glucose Tolerance
Test on Normal Rats
Group no.
Sample
0 Min
30 Min
60 Min
I
II
Control
Standard
(3a)
(3c)
(3e)
(3f)
(3g)
84.3 4.4
70.0 3.2
70.2 6.1
78.2 4.2
67.7 5.2
70.2 3.2
73.7 3.2
72.4 7.0
140.6 6.6
164.0 7.3
102 7.2 (43.2%)
139.3 10.2 (0%)
89.9∗ 5.7 (79.2%)
124.0 7.9 (0%)
115.5 8.3 (42.9%)
135.8 11.7 (17.7%)
135.0 9.4 (28.7%)
144.2 11.7(4.0 %)
142 7.7 (9.9%)
III
IV
V
VI
VII
VIII
88.0∗ 4.7 (68.4%)
82.7∗ 6.7 (84.0%)
80.0∗ 2.3 (86.5%)
124.7 8.8 (36.0%)
135 7.7 (21.5%)
(3h)
Values are mean SEM of six animals; values in parentheses indicate percentage
reduction.
∗Indicates statistical difference in respect to the vehicle (P < 0.01).
6.89–8.03. SO2NH signal was observed in the case of two compounds
3f (δ 10.17) and 3h (δ 10.77).
Biological Activity
The blood glucose lowering effect of urea derivative was evaluated in
glucose-fed hyperglycemic rats. As shown in Table I, blood glucose lev-
els in control were increased after the administration of glucose up
to 60 min. Test compounds 3c, 3f, 3g, and 3h significantly prevented
the elevation of blood glucose level at 30 min after glucose loading,
whereas test compounds 3a and 3e failed to inhibit the rise of blood
glucose levels. Structure activity relationship studies (SARs) suggest
that increment of carbon number at N1 enhances the blood sugar low-
ering activity of the sulfonylureas derived from 2b.
EXPERIMENTAL
Melting points were determined by open capillary tubes and are uncor-
rected. All Fourier transform infrared (FTIR) spectra were recorded on
a Jasco FT/IR-55000 spectrophotometer using KBr pellets; νmax values
1
are given in cm−1. H NMR spectra were recorded on a Bruker Spec-
trospin DPX 300-MHz spectrometer using either CDCl3 or DMSO as
a solvent and trimethyl silane (TMS) as an internal standard. Chem-
ical shifts are given in δ (ppm) scale and coupling constants (J val-
ues) are expressed in Hz. Mass spectra (MS) were scanned by using a
FAB ionization JEOL-JMS-DX 303 system equipped with a direct inlet
probe system. The m/z values of the more intense peaks are mentioned.
Purity of the compounds was checked on TLC plates (silica gel G) that

2520
S. Ahmad et al.
were visualized by exposing to iodine vapors. Elemental analysis was
carried out on a CHNS Elementar (Vario EL III).
General Procedure for the Preparation of Carbamates (2a, 2b)
A mixture of desired pyridazinone (1a, 1b) (0.1 mol), ethyl chlorofor-
mate (0.13 mol), and anhydrous potassium carbonate (20 g) in dry
acetone (150 mL) was refluxed for 18 h. Acetone was removed under
reduced pressure, the residue was stirred in water (150 mL) and neu-
tralized with acetic acid, and the product formed was separated and
crystallized from methanol as colorless crystals.
Ethyl{[4-(6-oxo-3-phenyl-5,6-dihydropyridazin-1(4H)yl)
phenyl]sulfonyl}Carbamate (2a)
mp 186◦C; yield = 61%; IR υmax (KBr): 1754 (C O of carbamate), 1681
(cyclic carbonyl), 1338 and 1164 cm−1 (SO2N). 1H NMR (300 MHz,
DMSO, δ): 1.06 (3H, t, -O-CH2- CH3), 2.78 and 3.17 (t each 2 x -CH2-
pyridazinone), 4.10 (1H, broad singlet, NH), 4.36 (2H, q, -O-CH2-CH3),
7.36–7.89 (9H, m, Ar-H). FAB-MS (m/z): 402 [M+1], 401 [M+].
Ethyl({4-[3-(4-chlorophenyl)-6-oxo-5,6-dihydropyridazin-1(4H)
yl]phenyl}sulfonyl) Carbamate (2b)
mp 182◦C; yield = 66%; IR υmax (KBr): 1752 (C O of carbamate), 1672
(cyclic carbonyl), 1343 and 1160 cm−1 (SO2N). 1H NMR (300 MHz,
DMSO, δ): 1.06 (3H, t, -O-CH2- CH3), 2.78 and 3.16 (t each 2 x -CH2-
pyridazinone), 4.10 (1H, broad singlet, 4.36 (2H, q, -O-CH2-CH3), NH),
7.53 (2H, d, J = 8.39 Hz, Ar-H), 7.78 (2H, d, J = 8.49 Hz, Ar-H), 7.87–
7.90 (4H, m, Ar-H). FAB-MS (m/z): 435 [M+].
General Method for the Preparation of Pyridazinone
Substituted Benzenesulfonylurea (3a–i)
To a warm solution of carbamate (2a, 2b) (0.02 mol) in toluene (75
mL), a solution of the desired amine (0.022 mol) in toluene (25 mL) was
added dropwise with stirring. The mixture was refluxed for 3 h and then
allowed to cool at room temperature. If the product crystallized out,
it was separated; otherwise, the toluene was removed under reduced
pressure. The product was then crystallized from methanol.
N-[(Butylamino)carbonyl]-4-(6-oxo-3-phenyl-5,
6-dihydropyridazin-1(4H)-yl) Benzenesulfonamide (3a)
mp 158◦C; yield 58%; IR υmax (KBr): 3385 (NH), 1716 (C O of urea),
1658 (cyclic carbonyl), 1334 and 1156 cm−1 (SO2N). 1H NMR (400 MHz,

Benzenesulfonyl-Urea Derivatives
2521
CDCl3, δ): 0.89 (3H, t, CH3), 1.30 (2H, q, -CH2-CH2-CH2-CH3) 1.47
(2H, m, -CH2-CH2-CH2-CH3), 2.81 and 3.11 (4H, t, each -CH2-CH2-
/pyridazine ring), 3.21 (2H, q, HN-CH2-CH2-CH2-CH3), 6.55 (1H, s,
NH-C4H9), 7.45 (3H, m, Ar-H), 7.79–7.94 (6H, m, Ar-H), signal for
SO2NH- could not be picked out. FAB-MS (m/z): 428 [M+], 429 [M+1],
330, 313, 297, 266, 249.
N-[(Cyclohexylamino)carbonyl]-4-(6-oxo-3-phenyl-5,
6-dihydropyridazin-1(4H)-yl) Benzenesulfonamide (3b)
mp 190◦C; yield = 56%; IR υmax (KBr): 1679 (C O), 1328 and 1159 cm−1
(SO2NH). 1H NMR (400 MHz, CDCl3, δ): 1.18–1.87 (10H, m, cyclohex-
ane), 3.60 (1H, 2, axial-H at C-1 of cyclohexane), 2.80 and 3.10 (4H,
t, each 2 x -CH2-) 6.47 (1H, NH-C6H11), 7.45 (3H, m, Ar-H), 7.79–7.94
(6H, m, Ar-H). FAB-MS (m/z): 455 [M+1], 454 [M+], 330, 313, 297, 266,
249.
N-[(Propylamino)carbonyl]-4-(6-oxo-3-phenyl-5,
6-dihydropyridazin-1(4H)-yl) Benzenesulfonamide (3c)
mp 188◦C, yield = 49%; IR υmax (KBr): 3368 (NH), 1680 (C O), 1347
and 1161 cm−1 (SO2N). 1H NMR (300 MHz, CDCl3, δ): 0.91 (3H, t, CH3),
1.54 (2H, m, N-CH2-CH2-CH3) 2.83 and 3.13 (4H, t, each -CH2-CH2-
/pyridazinone ring) 3.20 (2H, q, N-CH2-CH2-CH3), 6.59 (1H, NH-C3H7),
7.47 (3H, closely packed multiplet, Ar-H), 7.82–7.93 (6H, m, Ar-H).
FAB-MS (m/z): 415 [M+1], 414 [M+].
N-[(Phenylamino)carbonyl]-4-(6-oxo-3-phenyl-5,
6-dihydropyridazin-1(4H)-yl) Benzenesulfonamide (3d)
mp 228–230◦C, yield = 55%; IR υmax (KBr): 3357 (NH), 1729 (C O of
1
urea), 1666 (cyclic carbonyl), 1342 and 1157 cm−1 (SO2N). H NMR
(300 MHz, DMSO, δ): 2.79 and 3.17 (4H, t, each 2 x -CH2-) 7.01 (1H, t,
H-4 aniline unit), 7.23–7.36 (4H, m, aromatic protons of aniline unit),
7.48 (3H, compact multiplet, Ar-H), 7.89–8.03 (6H, m, Ar-H), 8.93 (1H,
s, NH-Ar). FAB-MS (m/z): 448 [M+].
N-[(Benzylamino)carbonyl]-4-(6-oxo-3-phenyl-5,
6-dihydropyridazin-1(4H)-yl) Benzenesulfonamide (3e)
mp 192–194◦C, yield = 47%; IR υmax (KBr): 1677 (C O), 1335 and 1160
cm−1 (SO2N). 1H NMR (300 MHz, DMSO, δ): 2.79 and 3.18 (4H, t, each
2 x -CH2-), 4.17 (2H, d, J = 5.76 Hz), 7.00 (1H, t, H-4 benzyl unit),

2522
S. Ahmad et al.
7.13–7.30 (4H, m, aromatic protons of benzyl unit), 7.48 (3H, compact
multiplet, Ar-H), 7.83–7.97 (6H, m, Ar-H). FAB-MS (m/z): 462 [M+].
4-[3-(4-Chlorophenyl)-6-oxo-5,6-dihydropyridazin-1(4H)-yl]-
N-[(propylamino) carbonyl]benzenesulfonamide (3f)
mp 184◦C, yield = 53%; IR υmax (KBr): 1726 (C O of urea), 1666 (cyclic
carbonyl), 1333 and 1158 cm−1 (SO2N). 1H NMR (300 MHz, CDCl3, δ):
0.86 (3H, t, CH3), 1.45 (2H, heptet, CH2/C-2 of propyl chain), 2.83 (2H, t,
-CH2- of pyridazinone ring), 3.03–3.15 (4H, m, one CH2 of pyridazinone
and one CH2/C-1 of propyl chain), 6.08 (1H, t, NH-C3H7), 7.42 (2H, d,
J = 8.36 Hz, Ar-H), 7.78 (2H, d, J = 8.40 Hz, Ar-H), 7.84 (2H, d, J =
8.61 Hz, Ar-H), 8.02 (2H, d, J = 8.62, Ar-H), 10.17 (1H, broad singlet,
SO2NH-). FAB-MS (m/z): 448 [M+].
4-[3-(4-Chlorophenyl)-6-oxo-5,6-dihydropyridazin-1(4H)-yl]-
N-[(butylamino) carbonyl]benzenesulfonamide (3g)
mp 202◦C; yield = 59%; IR υmax (KBr): 3358 (NH), 1699 (C O of urea),
1680 (cyclic carbonyl), 1310 and 1161 cm−1 (SO2N). 1H NMR (400 MHz,
CDCl3, δ): 0.91 (3H, t, CH3), 1.30 and 1.46 (each multiplet 2 x -CH2-/
n-butyl chain), 3.27 (2H, quartet, CH2/C-1/butyl chain) 2.83 and 3.10
(each t, 2 x CH2-/pyridazinone ring), 7.42 (2H, d, J = 8.4 Hz, Ar-H),
7.75 (2H, d, J = 8.4 Hz, Ar-H), 7.89 (2H, d, J = 6.9 Hz, Ar-H) and 7.92
(2H, d, J = 6.9 Hz, Ar-H). FAB-MS (m/z): 462 [M+].
4-[3-(4-Chlorophenyl)-6-oxo-5,6-dihydropyridazin-1(4H)-yl]-
N-[(phenylamino) carbonyl]benzenesulfonamide (3h)
mp 198–200◦C; yield = 62%; IR υmax (KBr): 3359 (NH), 1726 (C O of
1
urea), 1666 (cyclic carbonyl), 1334 and 1157 cm−1 (SO2N). H NMR
(300 MHz, DMSO, δ): 2.78 and 3.16 (4H, t, each 2 x -CH2-), 7.02 (1H, t,
H-4ꢀꢀꢀ), 7.23–7.35 (4H, m, Ar-H), 7.53 (2H, d, J = 8.48 Hz, Ar-H), 7.86
(2H, d, J = 8.84 Hz, Ar-H), 7.90 (2H, d, J = 8.64 Hz, Ar-H), 8.00 (2H,
d, J = 8.68 Hz, Ar-H), 8.86 (1H, s, NH-Ar), 10.77 (1H, broad singlet,
SO2NH). FAB-MS (m/z): 482 [M+].
4-[3-(4-Chlorophenyl)-6-oxo-5,6-dihydropyridazin-1(4H)-yl]-N-
[(benzylamino)carbonyl]benzenesulfonamide (3i)
mp 204◦C; yield = 57%; IR υmax (KBr): 1687 (C O of urea), 1663 (cyclic
carbonyl), 1316 and 1161 cm−1 (SO2N). 1H NMR (400 MHz, CDCl3, δ):
2.83 and 3.10 (4H, t, each 2 x -CH2-), 4.41 (2H, d, J = 5.6 Hz, CH2- of
benzyl), 6.89 (1H, t, Ar-H), 7.17–7.29 (4H, m, Ar-H), 7.42 (2H, d, 8.4

Benzenesulfonyl-Urea Derivatives
2523
Hz, Ar-H), 7.75 (2H, d, J = 8.8 Hz, Ar-H) 7.84 (2H, d, J = 7.2 Hz, Ar-H),
7.86 (2H, J = 6.9 Hz, Ar-H). FAB-MS (m/z): 496 [M+].
Biological Activity
Albino rats of either sex (Wistar strain), weighing 150–200 g, that
fasted overnight (16 h) were divided into eight groups. Group I was fed
with vehicle (1% CMC in distilled water) in volume of 10 mL/kg and
served as the control. The reference drug glibenclamide (10 mg/kg) and
the test compounds (3a, 3c, 3e–h) in the dose of 20 mg/kg suspended
in the vehicle were administered p.o. in volume of 10 mL/kg to groups
II–VIII, respectively. All the animals were given glucose (2 g/kg, p.o.) 30
min after dosing. Blood samples were collected from the retro-orbital
plexus just prior to and 30 and 60 min after the glucose loading and
glucose levels were measured by Dubowski’s method.13
Results of the blood glucose estimation are presented in the form of
SEM and percentage reduction by the test drug (Table I). The per-
centage reduction was calculated by considering the difference between
the blood glucose levels at 0 and 30 and 0 and 60 min of respective con-
trol animal as 100% rise in the blood sugar. A 100% reduction indicates
that there is no rise in the level of blood sugar, whereas 0% reduction
indicates that there is no reduction in the level of blood sugar.
CONCLUSION
The structures proposed to the synthesized compounds (2a, 2b, and
3a–i) are well supported by spectroscopic data and elemental analysis.
Four compounds (3c, 3f, 3g, and 3h) were found to have promising
blood glucose lowering activity and may be used as lead compounds for
developing new antidiabetic drugs.
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