Synthesis and blood glucose lowering activity of some novel benzenesulfonylthiourea derivatives substituted with 6-aryl-4,5-dihyropyridazin- 3(2H)-ones

Article abstract of DOI:10.1007/s00044-010-9539-3

Some new benzenesulfonylthiourea derivatives substituted with pyridazinone (2a-o) were synthesized by refluxing the appropriate 6-aryl-2-(p-sulfamylphenyl) -4,5-dihydropyridazine-3(2H)-ones with isothiocyanate in dry acetone over anhydrous K₂CO

Full text of DOI:10.1007/s00044-010-9539-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:428–436
DOI 10.1007/s00044-010-9539-3
ORIGINAL RESEARCH
Synthesis and blood glucose lowering activity of some novel
benzenesulfonylthiourea derivatives substituted
with 6-aryl-4,5-dihyropyridazin-3(2H)-ones
•
Rafia Bashir Shafiya Yaseen
•
•
Syed Ovais Hinna Hamid M. S. Alam
•
•
•
Mohammad Samim Kalim Javed
Received: 15 September 2010 / Accepted: 8 December 2010 / Published online: 14 January 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Some new benzenesulfonylthiourea derivatives
substituted with pyridazinone (2a–o) were synthesized by
refluxing the appropriate 6-aryl-2-(p-sulfamylphenyl)-4,5-
dihydropyridazine-3(2H)-ones with isothiocyanate in dry
acetone over anhydrous K2CO3. All the synthesized com-
utilization of insulin (Sakurai, 2002; WHO, 1985). NIDDM
is the most common form of diabetes constituting nearly
90% of the diabetes population in any country.
Over the last 40 years oral therapy for type II DM has
focused on sulfonylureas (SU) and biguanides (Kecskemeti
et al., 2002). SU drugs improve glucose levels by stimu-
lating insulin secretion by the pancreatic b-cells. The SU
were discovered accidentally. Some sulphonamides were
demonstrated to induce hypoglycemia in experimental
animals. This observation led to the development of a
group of substituted arylsulphonylureas differing at the
para position of the benzene ring at one nitrogen residue of
the urea moiety. Some of these have been marketed for the
treatment of NIDDM (Fig. 1).
1
pounds were characterized on the basis of IR, H NMR,
13C NMR, DEPT and MS data, and elemental analysis.
These compounds at the dose of 20 mg/kg were tested for
blood glucose lowering activity in glucose-fed hypergly-
cemic normal rats. Five compounds (2a, 2d, 2l, 2m, and
2n) markedly reduced the content of glucose in rat blood
(by more than 25%). Compound 2d showed the maximum
reduction (38.8%).
Keywords Sulfonylthiourea ꢀ Pyridazinone ꢀ
Diabetes ꢀ Antihyperglycemic
Chronic diabetes is accompanied by complications such as
neuropathy, cataracts, and retinopathy, which are not con-
trolled by insulin. These complications are considerably
caused by accumulation of sorbitol, which is produced from
glucose by aldose reductase (AR) in polyol pathway. AR
converts glucose to sorbitol only at high glucose levels in
plasma and tissue in diabetes (Dvornik, 1987a, b; Kinoshita
and Nishimura, 1988). Recently, compounds containing pyr-
idazine nucleus have beenreportedasARinhibitors(Courdert
et al., 1991; Costantino et al., 1996, 2000). Therefore, it has
been considered worthwhile to attach pyridazinone ring to
benzenesulfonylthiourea derivatives (Fig. 2).
Introduction
Diabetes mellitus (DM) is a metabolic disorder, which
affects the people of all age groups and from all walks of
life. There are estimated 150 million people worldwide
sufferings from diabetes (Marx, 2002), which is almost five
times more than the estimated number 10 years ago. Gen-
erally DM is classified as Type I insulin dependent diabetes
mellitus (IDDM) caused by low or insufficient secretion of
insulin by pancreas and Type II non-insulin dependent
diabetes mellitus (NIDDM) caused due to insufficient
In the present study, 15 novel benzenesulfonylthiourea
derivatives substituted with pyridazinone were synthesized
by condensing appropriate 6-aryl-2-(p-sulfamylphenyl)-4,5-
dihydropyridazine-3(2H)-one with isothiocyanate. These
were characterized by elemental analysis and various spec-
troscopic methods viz. IR, 1H NMR, 13C NMR, DEPT, and
MS. Oral antihyperglycemic activity of these compounds
were assessed using an oral glucose tolerance test in normal
rat model.
R. Bashir ꢀ S. Yaseen ꢀ S. Ovais ꢀ H. Hamid ꢀ
M. S. Alam ꢀ M. Samim ꢀ K. Javed (&)
Department of Chemistry, Faculty of Science, Jamia Hamdard
(Hamdard University), New Delhi 110062, India
e-mail: kjavedchem@yahoo.co.in; kjaved@jamiahamdard.ac.in
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Med Chem Res (2012) 21:428–436
429
Fig. 1 Clinically used
sulfonylureas
O
SO2NHCNHR2
R1
R1
R2
C4H9
C3H7
Tolbutamide
CH3
Cl
Chloropropamide
Tolazamide
CH3
N
C6H11
Acetohexamide
CH3CO
Cl
Glyburide
(Glibenclamide)
CONHCH2CH2-
CONHCH2CH2-
C6H11
OMe
N
H3C
C6H11
Glipizide
N
CH3
N
Gliclazide
H3C
CONHCH2CH2-
Glimepride
CH3
H3C
O
Result and discussion
NMR, DEPT, and MS. Elemental analysis (C, H, N, and S)
data were within 0.4% of the theoretical values.
Chemistry
In the IR spectra of 2a–o, five bands characteristic
of sulfonylthiourea moiety out of which two bands for
thioureido group were observed (1585–1490 cm-1 and
The synthetic route used to synthesize title compounds
(2a–o) is outlined in Scheme 1. The pyridazinone substi-
tuted benzenesulfonamide derivatives (1a–f) synthesized
through reported method (Ahmad et al., 2010, Bashir,
2010) were converted to sulfonylthioureas by refluxing
with different isothiocyanates in dry acetone containing
K2CO3.
S
SO2NHCNHR2
R1
R1 = Pyridazinone moiety
The structures of sulfonylthiourea derivatives (2a–o)
were determined on the basis of elemental analysis and
1
various spectroscopic methods such as IR, H NMR, 13C
Fig. 2 Sulfonylthiourea
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Med Chem Res (2012) 21:428–436
Scheme 1 Reagents and
conditions: isothiocynate,
K2CO3, dry acetone, reflux
24–72 h
R
O
1
R
O
1
N N
N N
Isothiocyanate
O S O
HN
O S O
NH
R
2
NH
2
C
S
(1a-g)
(2a-o)
1a, 2a, 2k: R1= -C6H5
1b, 2b, 2l: R1 = -C6H5CH3
2a-2g: R2 = CH2C6H5
2h-2j: R2 = C6H5
1c, 2c, 2h, 2m: R1 = C6H5OCH3
1d, 2d, 2i, 2n: R1 = C6H5Cl
1e, 2e: R1 = C6H5C2H5
2k- 2o: R2 = C3H7
1f, 2f, 2o: R1 = C6H5OC6H5
1g, 2g, 2j: R1 = C6H5C6H5
1545–1488 cm-1
3040 cm-1 3287–2955 cm-1
)
and three bands for NH (3347–
and 2964–2922 cm-1).
Experimental
Chemistry
,
,
Apart from these a band for carbonyl of pyridazinone
(1686–1588 cm-1), a band for C=N of pyridazinone
(1639–1586 cm-1) and two bands for SO2NH2 (1378–
1315 cm-1 and 1170–1136 cm-1) were also observed. The
structure was further established by proton NMR spectral
data. The pyridazinone ring protons were appeared as two
triplets at d 2.70–2.83 and d 3.05–3.19. Proton attached with
nitrogen of thioureido group appeared as singlet at d
4.30–8.90. DEPT spectra indicate the presence of CH3, CH2,
and CH carbons.
Melting points were determined by open capillary tubes
and are uncorrected. All the Fourier transform infra red
(FTIR) spectra were recorded on a Brukers Vector 22
spectrophotometer in film; mmax values are given in cm-1
.
1H NMR spectra were recorded on a Bruker Spectrospin
DPX 300-MHz spectrometer using deuterated DMSO as a
solvent and tetramethyl silane (TMS) as an internal stan-
dard. Chemical shifts are given in d (ppm) scale and cou-
pling constants (J values) are expressed in Hz. Mass
spectra (MS) were scanned by affecting FAB ionization
JEOL-JMS-DX 303 system, equipped with direct inlet
probe system and ESI Bruker Esquire 3000. The m/z values
of the more intense peaks are mentioned. 13C NMR and
DEPT spectra were recorded on Bruker spectrospin DPX
400 MHz and 500 MHz using deuterated DMSO as a
solvent and tetramthyl silane (TMS) as internal standard.
Purity of the compounds was checked on TLC plates (silica
gel G) which were visualized by exposing to iodine vapors.
Elemental analysis was carried out on CHNS Elementar
(Vario EL III).
Antihyperglycemic activity
In the present study, oral antihyperglcemic effect of 15
compounds (2a–o) was assessed in glucose-fed hypergly-
cemic normal rats. The marketed sulfonylurea drug gliben-
clamide was selected as positive control. Five compounds
(2a, 2d, 2l, 2m, and 2n) prevented the rise in the blood
glucose level by 25% or more (Table 1). Compound 2d
showed maximum prevention (38.8%). With regard to the
SAR it seems impossible to extract an obvious structure–
activity relationship from the data shown in Table 1.
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Med Chem Res (2012) 21:428–436
431
General procedure for the synthesis of sulfonylthiourea
4-(6-Oxo-3-phenyl-5,6-dihydropyridazin-1(4H)-yl)-N-
(benzylcarbamothioyl) benzenesulfonamide (2a)
(2a–o)
A solution of appropriate pyridazinone (1 mmol) in dry
acetone was refluxed over anhydrous K2CO3 for 1–1.5 h.
At this temperature, a solution of the isothiocyanate
(1.2 mmol) in dry acetone 5 mL was added in a drop wise
manner. Refluxing was continued for 24–72 h. Acetone
was removed under reduced pressure and the residue was
suspended in water. The suspension acidified with acetic
acid. It was filtered, washed and dried residue was crys-
tallized by appropriate solvent.
Yield = 50%, m.p 180–181°C, IR tmax: 3330, 2955 and
2924 (NH–CS–NH), 1665 (C=O), 1589 (C=N), 1536 and
1492 (C=S of thioureido group), 1378 and 1157 cm-1
(SO2N).1H NMR: 2.75 (2H, t, –CH2–CH2–), 3.14 (2H, t,
–CH2–CH2–), 4.39 (2H, s, –CH2–C6H5), 7.01–8.15 (14H, m,
N-phenyl, benzyl amine, 6-aryl protons), 10.00 (1H, s, NH).
ESI–MS (m/z): 477 (M-1), 501 (M?Na). 13C NMR: d 22.72
(–CH2 of pyridazinone), d 28.03 (–CH2 of pyridazinone), d
48.15 (–CH2NH), d 153.89 (C=N of pyridazinone), d 166.38
Table 1 Effect of
sulfonylthiourea derivatives in
glucose (3 g/kg) fed
hyperglycemic normal rats
Blood glucose level
Blood glucose level
Compound
R1
R2
(mg/dl) at zero
hour
(mg/dl) at one hour
R
1
___
___
Control
92.1 4.1
48.5 5.3
149.3 6.3
94.3 7.6*
N
O
N
Glibanclamide
O
S
O
97.0 5.6
91.5 5.3
98.0 5.6
93.5 4.6
93.0 4.1
139.0 4.6 *
(26.6%)
2a
2b
2c
2d
2e
HN
NH
C
R2
S
136.0 6.1 *
(21.3%)
Me
152.0 6.6
(5.6%)
OMe
Cl
128.5 5.3 *
(38.8%)
148.0 6.6
(3.8%)
C H
2
5
147.5 7.1
(3.0%)
92.0 4.3
94.5 5.6
O
2f
137.5 6.1 *
(24.8%)
2g
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Med Chem Res (2012) 21:428–436
Table 1 continued
Blood glucose level
Blood glucose level
(mg/dl) at one hour
Compound
R1
R2
(mg/dl) at zero
hour
91.5 3.3
93.5 5.1
94.0 3.1
87.5 9.3
95.0 6.5
96.0 5.6
94.0 4.3
170.5 4.1
(No activity)
148.0 7.3
(4.7%)
OMe
2h
2i
Cl
166.0 6.6
(No activity)
160.0 8.3
(No activity)
134.5 7.6 *
(30.9%)
2j
2k
2l
C3H7
C3H7
C3H7
C3H7
Me
132.0 3.6 *
(37.1%)
OMe
2m
2n
132.5 4.6 *
(32.7%)
Cl
* P \ 0.05 compared to control
(one-way ANOVA followed by
Dunnett’s test). Values are
presented as mean S.E.M.
(n = 6). Values in parentheses
represent inhibition of the rise
of blood glucose level in rats
152.0 5.6
(No activity)
91.0 4.1
O
2o
C3H7
(C=O), d 179.04 (C=S). Anal. Calcd. for C24H22N4O3S2:
C = 60.23, H = 4.63, N = 11.71, S = 13.40. Found:
C = 60.18, H = 4.60, N = 11.70, S = 13.37.
(7H, m, aromatic protons), 8.31 (1H, s, –NH–CH2–C6H5).
FAB-MS (m/z): 494 (M?2, base peak), 491 (M-1). Anal.
Calcd. for C25H24N4O3S2: C = 60.95, H = 4.91, N =
11.37, S = 13.02. Found: C = 60.90, H = 4.87, N =
11.36, S = 12.99.
4-(6-Oxo-3-(40-methylphenyl)-5,6-dihydropyridazin-
1(4H)-yl)-N-(benzylcarbamothioyl)
benzenesulfonamide (2b)
4-(6-Oxo-3(40-methoxyphenyl)-5,6-dihydropyridazin-
1(4H)-yl)-N-(benzylcarbamothioyl)
benzenesulfonamide (2c)
Yield = 42%, m.p 190–191°C, IR tmax: 3330 (NH–CS–
NH), 1671 (cyclic carbonyl), 1589 (C=N), 1540 and 1490
(C=S of thiourea), 1322 and 1161 cm-1 (SO2N). 1H NMR:
2.35 (3H, s, CH3), 2.77 (2H, t, –CH2–CH2), 3.05 (2H, t,
–CH2–CH2–), 4.72 (2H, d, J = 4.83 Hz, –CH2–C6H5),
7.65–8.00 (6H, m, aromatic protons system), 7.14–7.30
Yield = 52%, m.p 200–202°C; IR tmax: 3322, 2956, and
2925 (NH–CS–NH), 1676 (cyclic carbonyl), 1588 (C=N),
1536 and 1513 (C=S of thiourea), 1315 and 1168 (SO2N),
1
1084 cm-1 (OCH3). H NMR: 2.75 (2H, t, –CH2–CH2–),
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Med Chem Res (2012) 21:428–436
433
3.12 (2H, t –CH2–CH2–), 3.79 (3H, s, OCH3), 4.68 (2H, s,
–CH2–C6H5), 7.00–7.34 (7H, m, H-30, H-50, H-2000, H-3000,
H-4000, H-5000, H-6000), 7.82–7.94 (6H, m, H-200, H-300, H-500,
H-600, H-20, H-60), 8.90 (1H, s, NH–CH2–C6H5). FAB-MS
(m/z): 510 (M??2), 509 (M??1). 13C NMR: d 22.81
(–CH2 of pyridazinone), d 28.71 (–CH2 of pyridazinone), d
48.33 (–NH–CH2), d 55.85 (–OCH3), d 153.75 (C=N of
pyridazinone), d 166.35 (C=O), d 179.20 (C=S). DEPT: d
22.11 (–CH2 of pyridazinone), d 27.67 (–CH2 of pyridaz-
inone), d 47.70 (–CH2NH), d 55.32 (–OCH3). Anal. Calcd.
for C25H24N4O4S2: C = 59.04, H = 4.76, N = 11.02,
S = 12.61. Found: C = 58.98, H = 4.72, N = 11.01,
S = 12.58.
DEPT (DMSO, d): d 15.92 (–CH2CH3), d 22.75 (–CH2 of
pyridazinone), d 28.13 (–CH2CH3), d 28.49 (–CH2 of py-
ridazinone), d 48.21 (–CH2NH). Anal. Calcd. for C26H26
N4O3S2: C = 61.64, H = 5.17, N = 11.10, S =
12.71. Found: C = 61.66, H = 5.14, N = 11.08, S =
12.67.
4-(6-Oxo-3-(40-phenoxyphenyl)-5,6-dihydropyridazin-1
(4H)-yl)-N-(benzylcarbamothioyl) benzenesulfonamide
(2f)
Yield = 50%, m.p 186–188°C; IR tmax: 3330, 2955, and
2924 (NH–CS–NH), 1588 (cyclic carbonyl), 1490 (C=S of
1
thiourea), 1377 and 1157 cm-1 (SO2N). H NMR: 2.78
4-(6-Oxo-3-(40-chlorophenyl)-5,6-dihydropyridazin-1
(4H)-yl)-N-(benzylcarbamothioyl) benzenesulfonamide
(2d)
(2H, t, –CH2–CH2), 3.05 (2H, t, –CH2–CH2–), 4.73 (2H, s,
–CH2–C6H5), 7.75-7.90 (6H, m, aromatic protons), 6.99-
7.32 (12H, m, aromatic protons). FAB-MS (m/z): 411
(Base Peak). Anal. Calcd. for C30H26N4O4S2: C = 63.14,
H = 4.59, N = 9.82, S = 11.24. Found: C = 63.09,
H = 4.56, N = 9.81, S = 11.22.
Yield = 45%, m.p 200–202°C; IR tmax: 3320 (NH–CS–
NH), 1671 (cyclic carbonyl), 1639 (C=N), 1585, 1545
(C=S of thiourea), 1335 and 1146 cm-1 (SO2N). 1H NMR:
2.79 (2H, t, –CH2–CH2–), 3.17 (2H, t, –CH2–CH2–), 4.67
(2H, d, –CH2–C6H5), 7.10–7.95 (13H, m, N-phenyl, benzyl
amine, 6-aryl protons), 8.90 (1H, s, –NH–CH2–C6H5),
11.69 (1H, brs s, –NH–SO2). ESI–MS (m/z): 511 (M?-1),
536 (M??Na). 13C NMR (DMSO, d): d 22.16 (–CH2 of
pyridazinone), d 27.35 (–CH2 of pyridazinone), d 47.67
(–CH2NH), d 152.24 (C=N of pyridazinone), d 165.76
(C=O), d 178.52 (C=S). DEPT (DMSO, d): d 22.15 (–CH2
of pyridazinone), d 27.35 (–CH2 of pyridazinone), d 47.67
(–CH2NH). Anal. Calcd. for C24H21ClN4O3S2: C = 56.19,
H = 4.13, N = 10.92, S = 12.50. Found: C = 56.14,
H = 4.09, N = 10.91, S = 12.47.
4-((6-Biphenyl-4-yl) 6-oxo-)-5,6-dihydropyridazin-
1(4H)-yl)-N-(benzylcarbamothioyl)
benzenesulfonamide (2g)
Yield = 52%, m.p 192–194°C; IR tmax: 3316, 3095, and
2922 (NH–CS–NH), 1656 (cyclic carbonyl), 1586 (C=N),
1
1542 (C=S of thiourea), 1327 and 1137 cm-1 (SO2N). H
NMR: 2.81 (2H, t, –CH2–CH2–), 3.21 (2H, t, –CH2–CH2–),
4.68 (2H, s, –CH2–C6H5), 7.10–7.98 (18H, m, aromatic
hydrogens), 8.90 (1H, s, NH–CH2–C6H5), 11.75 (1H, s,
SO2NH). FAB-MS (m/z): 555 (M?1), 556 ((M?2), base
peak).13C NMR (DMSO, d): d 22.22 (–CH2 of pyridazi-
none), d 27.58 (–CH2 of pyridazinone)), d 47.71 (–NH–
CH2), d 153.00 (C=N of pyridazinone), d 165.87 (C=O),
d 178.55 (C=S). DEPT (DMSO, d): d 22.29 (–CH2 of
pyridazinone), d 27.65 (–CH2 of pyridazinone)), d 47.78
(–CH2NH). Anal. Calcd. for C30H26N4O3S2: C = 64.96,
H = 4.72, N = 10.10, S = 11.56. Found: C = 64.98,
H = 4.69, N = 10.13, S = 11.58.
4-(6-Oxo-3-(40-ethylphenyl)-5,6-dihydropyridazin-1
(4H)-yl)-N-(benzylcarbamothioyl) benzenesulfonamide
(2e)
Yield = 60%, m.p.: 201–202°C; IR tmax: 3347, 3067 and
2962 (NH–CS–NH), 1653 (cyclic carbonyl), 1587 (C=N),
1547 (C=S of thiourea), 1330 and 1141 cm-1 (SO2N). H
1
NMR: 1.18 (3H, t, –CH2–CH3), 2.64 (2H, q, –CH2–CH3),
2.76 (2H, t, –CH2–CH2–), 3.14 (2H, t, –CH2–CH2–), 4.67
(2H, d, J = 5.1 Hz, –CH2–C6H5), 7.09–7.26 (5H, m, –CH2–
C6H5), 7.30 (2H, d, J = 8.1 Hz, H-20, H-50), 7.79 (2H, d,
J = 8.1 Hz, H-30, H-50), 7.86 (d, J = 9.00, H-300, H-500),
7.94 (2H, d, J = 8.7 Hz, H-200, H-600), 8.90 (1H, t,
–NH–CH2–C6H5), 11.70 (1H, s, SO2NH). FAB-MS (m/z):
506 (M?), 508 (M??2). 13C NMR (DMSO, d): d 15.40
(–CH2CH3), d 22.25 (–CH2 of pyridazinone), d 27.63
(–CH2CH3), d 27.98 (–CH2 of pyridazinone), d 47.70
(–NH–CH2), d 146.19 (C=N of pyridazinone), d 153.48
(C-40), d 165.90 (C=O of pyridazinone), d 178.00 (C=S).
4-(6-Oxo-3-(40-methoxyphenyl)-5,6-dihydropyridazin-
1(4H)-yl)-N-phenylcarbamothioyl)
benzenesulfonamide (2h)
Yield = 37%, m.p 184–186°C; IR tmax: 3282 (NH–CS–
NH), 1662 (cyclic carbonyl), 1590 (C=N), 1512 and 1494
(C=S of thiourea), 1322 and 1170 cm-1 (SO2N). 1H NMR:
2.73 (2H, t, –CH2–CH2–), 3.11 (2H, t, –CH2–CH2–), 3.79
(3H, s, OCH3), 4.30 (1H, s, –NH–C6H5), 6.71–7.86 (14H,
m, aromatic hydrogens), 6.68 (1H, s, SO2NH). FAB-MS
(m/z): 495 (M??1), 493 (M?-1). Anal. Calcd. for
C24H20N4O4S2: C = 58.28, H = 4.48, N = 11.33,
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Med Chem Res (2012) 21:428–436
S = 12.97. Found: C = 58.29, H = 4.45, N = 11.34, S =
d 145.27 (C=N of pyridazinone), d 153.39 (C=O of py-
ridazinone), d 165.78 (C=S). DEPT (DMSO, d): d 11.09
(–CH2CH2CH3), d 20.93 (–CH2CH2CH3), d 22.23 (–CH2
of pyridazinone), d 27.48 (–CH2 of pyridazinone), d 46.08
(–NHCH2CH2CH3). Anal. Calcd. for C20H22N4O3S2: C =
55.79, H = 5.15, N = 13.01, S = 14.90. Found: C =
55.75, H = 5.13, N = 13.00, S = 14.88.
12.95.
4-(6-Oxo-3-(40-chlorophenyl)-5,6-dihydropyridazin-
1(4H)-yl)-N-(phenylcarbamothioyl)
benzenesulfonamide (2i)
Yield = 57%, m.p 187–188°C; IR tmax: 3040 (NH–CS–
NH), 1656 (cyclic carbonyl), 1587 (C=N), 1358 and
4-(6-Oxo-3-(40-methylphenyl)-5,6-dihydropyridazin-
1(4H)-yl)-N-(propylcarbamothioyl)
benzenesulfonamide (2l)
1
1166 cm-1 (SO2N). H NMR: 2.74 (2H, t, –CH2–CH2–),
3.13 (2H, t, –CH2–CH2–), 7.36–7.88 (13H, m, 6-aryl, N-
phenyl, aniline protons). ESI–MS (m/z): 498 (M?). Anal.
Calcd. for C23H19ClN4O3S2: C = 55.36, H = 3.84,
N = 11.23, S = 12.85. Found: C = 55.31, H = 3.81,
N = 11.22 S = 12.82.
Yield = 50%, m.p 188–189°C; IR tmax (Solvent, in cm-1):
3328, 3123, and 2965 (NH–CS–NH), 1669 (cyclic car-
bonyl), 1587 (C=N), 1542 and 1489 (C=S of thiourea),
1322 and 1154 cm-1 (SO2N). 1H NMR (400 MHz,
DMSO,d) : 0.80 (2H, t, –CH2–CH2–CH3), 1.49 (2H, m,
–CH2–CH2–CH3), 2.31 (3H, s, –CH3), 2.70 (2H, t, –CH2–
CH2-), 3.05 (2H, t, -CH2-CH2-), 3.37 (2H, m, –CH2–CH2–
CH3), 7.17 (2H, d, J = 8.00 Hz, H-20, H-60), 7.65 (2H, d,
J = 8.00 Hz, H-30, H-50), 7.83 (2H, d, N-phenyl,
J = 8.7 Hz, H-200, H-600), 7.88 (2H, d, N-phenyl,
J = 8.8 Hz, H-300, H-5000), 8.17 (1H, t, NH–CH2–CH2–
CH3), 11.35 (1H, s, SO2NH). FAB-MS (m/z): 443 (M?-1),
445 (M??1). 13C NMR (DMSO, d): d 11.61 (–CH2
CH2CH3), d 21.42 (–CH2CH2CH3, –CH3), d 22.63 (–CH2
of pyridazinone), d 28.02 (–CH2 of pyridazinone), d 46.66
(–CH2CH2CH3), d 153.87 (C=N of pyridazinone), d 166.39
(C=O), d 178.41 (C=S). DEPT (DMSO,d): d 11.61 (–CH2
CH2CH3), d 21.40 (–CH3), d 21.44 (–CH2CH2CH3),
d 22.63 (–CH2 of pyridazinone), d 28.02 (–CH2 of pyrid-
azinone), d 46.66 (–NHCH2CH2CH3). Anal. Calcd. for
C21H24N4O3S2: C = 56.73, H = 5.44, N = 12.60, S =
14.43. Found: C = 56.69, H = 5.40, N = 12.59, S =
14.40.
4-((3-Biphenyl-4-yl) 6-oxo-)-5,6-dihydropyridazin-1
(4H)-yl)-N-(phenylcarbamothioyl) benzenesulfonamide
(2j)
Yield = 36%, m.p 191–192°C; IR tmax (Solvent, in cm-1):
3362 and 3287 (NH–CS–NH), 1662 (cyclic carbonyl),
1588 (C=N), 1509 and 1496 (C=S of thiourea), 1326 and
1
1136 cm-1 (SO2N). H NMR (300 MHz, DMSO, d): 2.79
(2H, t, –CH2–CH2–), 3.19 (2H, t, –CH2–CH2–), 7.15–7.51
(8H, m, aromatic protons), 7.71–7.79 (4H, m, aromatic
protons), 7.95–7.99 (5H, m, N-phenyl protons), 7.87 (2H,
d, J = 8.70 Hz, H-20, H-60), 10.15 (1H, s, SO2NH). FAB-
MS (m/z): 476 (M?-SO2), 442 (base peak). 13C NMR
(DMSO, d): d 22.18 (–CH2 of pyridazinone), d 27.57
(–CH2 of pyridazinone), d 152.94 (C=N of pyridazinone), d
165.86 (C=O), d 177.49 (C=S). DEPT (DMSO, d): d 22.18
(-CH2 of pyridazinone), d 27.57 (–CH2 of pyridazinone).
Anal. Calcd. for C29H24N4O3S2: C = 64.42, H = 4.47,
N = 10.36, S = 11.86. Found: C = 64.44, H = 4.44,
N = 10.37, S = 11.85.
4-(6-Oxo-3-(40-methoxyphenyl)-5,6-dihydropyridazin-
1(4H)-yl)-N-(propylcarbamothioyl)
benzenesulfonamide (2m)
4-(6-Oxo-3-(phenyl)-5,6-dihydropyridazin-1(4H)-yl)-
N-(propylcarbamothioyl) benzene sulfonamide (2k)
Yield = 63.3%, m.p, 192-193°C; IR tmax (Solvent, in
cm-1): 3335, 2958 and 2924 (NH–CS–NH), 1686 (cyclic
carbonyl), 1543 and 1491 (C=S of thiourea), 1589 (C=N),
1318 and 1154 cm-1 (SO2N). 1H NMR (300 MHz,
DMSO,d) : 0.91 (3H, t, CH3–CH2–CH2–N), 1.58 (2H, m,
CH3–CH2–CH2–N), 2.83 (2H, t, –CH2–CH2–), 3.16 (2H,
t, –CH2–CH2–), 3.47 (2H, m, CH3–CH2–CH2–NH),
7.46–7.98 (9H, m, 6-aryl, N-phenyl protons), 8.21 (1H, t,
–CO–NH-propyl), 11.39 (1H, brs s, SO2–NH). ESI–MS
(m/z): 429 (M-1), 453 (M??Na). 13C NMR (DMSO, d): d
10.97 (–CH2CH2CH3), d 20.93 (–CH2CH2CH3), d 22.48
(–CH2 of pyridazinone), d 27.66 (–CH2 of pyridazinone),
Yield = 78%, m.p 184–185°C; IR tmax (Solvent, in cm-1):
3323, 3126, 2964 (NH–CO–NH), 1668 (cyclic carbonyl),
1545 and 1514 (C=S of thiourea), 1588 (C=N), 1327 and
1
1155 cm-1 (SO2N). H NMR (300 MHz, DMSO,d): 0.78
(3H, t, NH–CH2–CH2–CH3), 1.46 (2H, q, NH–CH2–CH2–
CH3), 2.76 (2H, t, –CH2–CH2–), 3.11 (2H, t, –CH2–CH2–),
3.79 (3H, s, OCH3), 7.01 (2H, d, J = 9.00 Hz, H-30, H-50),
7.82–7.94 (6H, m, H-200, H-300, H-500, H-600, H-20, H-60),
8.45 (1H, t, NH), 11.50 (1H, s, SO2NH). FAB-MS (m/z):
461 (M?1). 13C NMR (DMSO, d): d 10.98 (–CH2
CH2CH3), d 20.96 (–CH2CH2CH3), d 22.34 (–CH2 of
pyridazinone), d 27.78 (–CH2 of pyridazinone), d 46.24
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Med Chem Res (2012) 21:428–436
435
(–NHCH2CH2CH3), d 55.33 (–OCH3), d 153.22 (C=N of
pyridazinone), d 165.83 (C=O), d 178.23 (C=S). DEPT
(DMSO, d): d 11.08 (–CH2CH2CH3), d 20.93 (–CH2
CH2CH3), d 22.10 (–CH2 of pyridazinone), d 27.66 (–CH2
of pyridazinone), d 46.16 (–NHCH2CH2CH3), d 55.30
(–OCH3). Anal. Calcd. for C21H24N4O4S2: C = 54.76,
H = 5.25, N = 12.16, S = 13.92. Found: C = 54.72,
H = 5.21, N = 12.16, S = 13.89.
Effect of synthesized compounds on oral glucose
tolerance in normal rats
Albino rats (either sex) of Wistar strain weighing
150–200 g were fasted overnight and classified into groups
of six animals each. Animals of group I received only
vehicle (10 ml/kg) to serve as control, while animals of
given II were given glibenclamide 20 mg/kg suspended in
the vehicle. The test compounds in the dose of 20 mg/kg
suspended in the vehicle were administered to respective
groups. All the animals were given glucose (3 g/kg, p.o.)
30 min after dosing. Blood samples were collected from
retro-orbital plexus (under mild condition) just prior to and
60 min after the glucose loading and blood glucose levels
were measured with an autoanalyser by using AccuCheck
Advantage II glucose kit.
4-(6-Oxo-3-(40-chlorophenyl)-5,6-dihydropyridazin-1
(4H)-yl)-N-(propylcarbamothioyl) benzenesulfonamide
(2n)
Yield = 52%, m.p 195–196°C; IR tmax (Solvent, in cm-1):
3326 and 3129 (NH–CS–NH), 1670 (cyclic carbonyl),
1587 (C=N), 1540 (C=S of thiourea), 1324 and 1154 cm-1
(SO2N). 1H NMR (300 MHz, DMSO,d) : 0.78 (3H, t, CH3–
CH2–CH2–NH), 1.47 (2H, m, CH3–CH2–CH2–NH), 2.79
(2H, t, –CH2–CH2–), 3.14 (2H, t, –CH2–CH2–), 7.53 (2H,
d, H-30, H-50), 7.77–7.96 (6H, m, N-phenyl protons, H-20,
H-60), 8.48 (1H, s, NH-propyl), 11.48 (1H, brs s, SO2–NH–).
ESI–MS (m/z): 464 (M?), 487 (M??Na). DEPT (DMSO,
d): d 18.51 (–CH2CH2CH3), d 22.16 (–CH2 of pyridazi-
Statistics and calculation
All the results were expressed as mean standard error
mean (SEM). The data of all the groups were analyzed
using one-way ANOVA followed by Dunnett’s t-test.
Percent reduction was calculated by considering the dif-
ferences between the sugar level at 0 and 60 min of control
animals as 100% rise in the blood sugar. A 100% reduction
indicates that there is no rise in the level of blood sugar,
while 0% reduction indicates that there is no reduction in
the level of blood sugar.
none),
d 27.15 (–CH2 of pyridazinone), d 56.00
(–NHCH2CH2CH3). Anal. Calcd. for C20H21ClN4O3S2:
C = 51.66, H = 4.55, N = 12.05, S = 13.79. Found:
C = 51.62, H = 4.50, N = 12.04, S = 13.70.
Acknowledgments This work was supported by Grant No. 32-228/
2006 (SR) from the University Grants Commission, New Delhi, India.
One of the authors, Rafia Bashir is thankful to UGC for fellowship.
Thanks are due to SAIF, CDRI, Lucknow, for providing Mass spectra.
4-(6-Oxo-3-(40-phenoxyphenyl)-5,6-dihydropyridazin-
1(4H)-yl)-N-(propylcarbamothioyl)
benzenesulfonamide (2o)
Yield = 42%, m.p 183–184°C; IR tmax (Solvent, in cm-1):
3327, 3019 and 2926 (NH–CS–NH), 1664 (cyclic carbonyl),
1536 and 1488 (C=S of thiourea), 1587 (C=N), 1326 and
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