Synthesis, characterization, and hypoglycemic activity of 3-(arylsulfonyl)spiroimidazolidine-2,4-diones

Article abstract of DOI:10.1007/s00706-011-0600-9

Spiroimidazolidine-2,4-diones were prepared from methylcyclohexanones by the Bucherer-Bergs reaction. Synthesis of the target 3-(arylsulfonyl) spiroimidazolidine-2,4-diones was achieved by reaction of arylsulfonyl chlorides with corresponding spiroimidazolidine-2,4-diones. The synthesis was confirmed by spectroanalytical techniques and the crystal structure of 3-(4-methoxyphenylsulfonyl)-6-methyl-1,3-diazaspiro[4.5]decane-2,4-dione, and the purity was checked by GC-MS analysis. The in-vivo hypoglycemic potential of 6-methyl-, 7-methyl-, and 8-methyl-3-(4-methylphenylsulfonyl)-1,3-diazaspiro[4. 5]decane-2,4-dione was investigated on male albino rats. The screened compounds were found to have excellent hypoglycemic activity. 6-Methyl-3-(4- methylphenylsulfonyl)-1,3-diazaspiro[4.5]decane-2,4-dione was found highly active, reducing the blood glucose level by 60.79% compared with 41.60% by the standard (glipizide) at a dose level of 100 mg/kg of the mice body weight. The 8-methyl isomer was also more potent than the standard, with 48.56% reduction in blood glucose level.

Full text of DOI:10.1007/s00706-011-0600-9

Monatsh Chem (2012) 143:497–504
DOI 10.1007/s00706-011-0600-9
ORIGINAL PAPER
Synthesis, characterization, and hypoglycemic activity
of 3-(arylsulfonyl)spiroimidazolidine-2,4-diones
•
Zafar Iqbal Tashfeen Akhtar Arthur D. Hendsbee
•
•
•
Jason D. Masuda Shahid Hameed
Received: 12 May 2010 / Accepted: 15 July 2011 / Published online: 25 August 2011
Ó Springer-Verlag 2011
Abstract Spiroimidazolidine-2,4-diones were prepared
from methylcyclohexanones by the Bucherer–Bergs reac-
tion. Synthesis of the target 3-(arylsulfonyl)spiroimidaz-
olidine-2,4-diones was achieved by reaction of arylsulfonyl
chlorides with corresponding spiroimidazolidine-2,4-diones.
The synthesis was confirmed by spectroanalytical techniques
and the crystal structure of 3-(4-methoxyphenylsulfonyl)-6-
methyl-1,3-diazaspiro[4.5]decane-2,4-dione, and the purity
was checked by GC–MS analysis. The in-vivo hypoglycemic
potential of 6-methyl-, 7-methyl-, and 8-methyl-3-(4-methyl-
phenylsulfonyl)-1,3-diazaspiro[4.5]decane-2,4-dione was
investigated on male albino rats. The screened compounds
were found to have excellent hypoglycemic activity.
6-Methyl-3-(4-methylphenylsulfonyl)-1,3-diazaspiro[4.5]
decane-2,4-dione was found highly active, reducing the
blood glucose level by 60.79% compared with 41.60% by
the standard (glipizide) at a dose level of 100 mg/kg of the
mice body weight. The 8-methyl isomer was also more
potent than the standard, with 48.56% reduction in blood
glucose level.
Keywords Antidiabetic ꢀ Spiro compounds ꢀ
Sulfonyl cyclic ureas ꢀ Imidazolidine-2,4-diones ꢀ
Rearrangement ꢀ Crystal structure
Introduction
Diabetes is one of the main causes of death at present, and
being a chronic disease has played havoc especially with
the people of South East Asia [1]. Approximately 5–10%
of the world’s population has been affected by this disease,
171 million people have been diagnosed to be diabetic [2]
and by the end of 2010 this number is expected to approach
230 million [3]. In addition, a huge number of people is
still unaware of their fatal disease [4]. Although a number
of drugs and many herbal formulations are in use to cure
the disease (Refs. [5–7] and references cited therein), there
is still a rapid increase in the number of diabetic patients.
Imidazolidine-2,4-diones, which have a cyclic urea core,
and spiroimidazolidine-2,4-diones reduce the complica-
tions associated with hyperglycemia [8]. The sulfonyl
derivatives of cyclic ureas, on the other hand, are known to
have enhanced antidiabetic activity [1, 9]. A combined
approach of introducing the spiro and sulfonyl moieties
into the imidazolidine-2,4-dione nucleus may result in a
molecule of choice to treat both diabetes and its associated
complications. Hypothesizing this, we planned the syn-
thesis of N-(arylsulfonyl)spiroimidazolidine-2,4-diones
(Scheme 1). The target molecules have all requirements
suggested in pharmacophoric models for enhanced hypo-
glycemic activity [10] and minimal diabetic complications
[11]. This approach is an extension of our previous work
on the development of antidiabetic agents [12, 13]
including arylsulfonylimidazolidine-2,4-diones and aryl-
sulfonylbenzimidazolone derivatives.
Z. Iqbal ꢀ S. Hameed (&)
Department of Chemistry, Quaid-i-Azam University,
Islamabad 45320, Pakistan
e-mail: shameed@qau.edu.pk; shahidhameed@daad-alumni.de
T. Akhtar
Department of Chemistry, Mirpur University of Science
and Technology, Mirpur, Azad Kashmir, Pakistan
A. D. Hendsbee ꢀ J. D. Masuda
Department of Chemistry, Saint Mary’s University,
Halifax, NS B3H 3C3, Canada
123

498
Z. Iqbal et al.
Scheme 1
O
HN
NH
60% aq. EtOH
Heat
O
H3C
+ KCN + (NH4)2CO3
H3C
O
1
3
-
ArSO2Cl
Et3N, DMAP
O
4a 6a
4b 6b
: Ar = 4-ClC6H4;
4d 6d
- : Ar = 4-NO2C6H4;
HN
-
: Ar = 4-CH3C6H4;
-
SO2Ar
N
4c 6c
-
: Ar = 4-BrC6H4;
4e - 6e: Ar = 4-OCH3C6H4; 4f - 6f: Ar = 2-Naphthyl;
4g 6g
H3C
O
-
: Ar = 2-Anthraquinyl
4a 6g
-
Results and discussion
compounds 4a–6g. A low-intensity molecular ion peak was
observed for all the compounds. The appearance of frag-
ments for [M - SO2Ar] confirmed the presence of the
sulfonamide linkage in the synthesized molecules. The
presence of halogens was confirmed by the appearance of
corresponding [M ? 2] peaks for chloro and bromo sub-
stituents. The base peak for all compounds was observed at
m/z = 95 (except for compounds 4g, 5g, and 6g) corre-
sponding to cleavage of the arylsulfonyl part of the
compounds. A common fragment at m/z = 64 correspond-
ing to SO2 was also observed for all the sulfonyl derivatives.
The synthesis of compounds 4a–6g was further con-
firmed by single-crystal X-ray analysis of the structure of
compound 4e, which was found to crystallize in the
monoclinic space group P21/C. The most significant
structural feature is the intermolecular hydrogen bonding
between the two imidazolidine-2,4-dione rings. More spe-
cifically, the carbonyl and N–H fragments of the rings
interact, resulting in the formation of a hydrogen-bonded
Chemistry
Spiroimidazolidine-2,4-diones 1–3 were synthesized by the
Bucherer–Bergs reaction [14, 15]. The synthesis was con-
firmed by modern spectroscopic techniques. The IR spectra
of compounds 1–3 contained two strong absorption bands
between 3,415 and 3,388 cm-1, assigned to the N–H of the
imide and amide groups. Absorption bands observed
between 1,802 and 1,704 cm-1 indicated the presence of
1
two carbonyl groups. In the H NMR spectra, the N–H
proton at position 3, being more acidic, resonated in the
range d = 10.56–10.58 ppm whereas the second N–H
proton appeared in the range 8.26–8.45 ppm. The ele-
mental composition of compounds 1–3 was in good
agreement to the values calculated for carbon, hydrogen,
and nitrogen. It has already been reported from this
laboratory that the nitrogen atom (position 1) in spiroimi-
dazolidine-2,4-diones occupies the axial position whereas
the carbonyl group is equatorial [16, 17].
˚
dimer with an N2–O4 distance of 2.844(2) A. In addition,
one of the S=O groups and the adjacent carbonyl are nearly
planar with a torsion angle [O3–C8–S1–O1] of 179.4(2)°
(Fig. 1).
The sulfonylation of spiroimidazolidine-2,4-diones 1–3
leading to 3-(arylsulfonyl)spiroimidazolidine-2,4-diones
4a–6d was carried out by coupling with arylsulfonyl chlo-
rides in the presence of triethylamine [18]. Formation of the
products was indicated in the IR spectra by the disappear-
ance of the NH absorption in the range 3,415–3,410 cm-1
.
The absorption bands in the ranges 1,392–1,313 cm-1 and
1,191–1,155 cm-1 were assigned to anti-symmetric and
symmetric sulfonamide (O=S=O) stretching, respectively.
1
Synthesis of 4a–6g was confirmed in the H NMR spectra
by the appearance of new signals in the aromatic region.
The disappearance of the NH signal in the region
d = 10.56–10.58 ppm established the sulfonylation at
position 3 of the spiroimidazolidine-2,4-diones. Mass
spectral analysis further confirmed the synthesis of
Fig. 1 Ortep diagram of compound 4e. Hydrogen atoms have been
removed for clarity
123

Hypoglycemic activity of 3-(arylsulfonyl)spiroimidazolidine-2,4-diones
499
Table 1 Effect of 3-(arylsulfonyl)spiroimidazolidine-2,4-diones on blood glucose level in normal and alloxanized diabetic rats
Drug injected
Dose/mg kg-1
Blood glucose levela/mg/100 cm3
At zero hb
After 2 h
Reduction (after 2 h)
After 5 h
Reduction (after 5 h)
Decrease/%c
4a
5a
6a
100
50
329
330
565
453
383
387
560
121
6
5
8
6
8
9
8
9
241
282
473
402
288
9
7
9
6
4
88
48
92
51
95
5
2
7
3
2
110
261
361
392
178
7
3
6
8
2
219
69
8
9
9
7
6
6
6
2
7
60.79
15.15
32.56
9.27
48.56
19.12
41.60
–
100
50
203
61
100
50
205
93
320 12
67 17
294 14
Glipizide
Normal
100
363
118
6
7
197
3.0
4
5
308
114
562
9
6
5
252
7.0
19
Diabetic control
580 16
–
–
–
a
The results are reported as mean standard deviation. Statistical evaluation was carried out using one-way analysis of variance (ANOVA),
followed by Dunnett’s t test, P-values \ 0.05 were considered to be significant
b
Blood glucose level just before administration of the drug
c
Relative to alloxan-induced diabetic group
The attempted rearrangement of 3-(arylsulfonyl)spiro-
imidazolidine-2,4-diones 4a–6g to the corresponding
1-(arylsulfonyl)spiroimidazolidine-2,4-diones in the pres-
ence of sodium hydride [1] met with failure, despite several
attempts. The probable reason for this failure seems to be
that steric crowding at position 1 prohibits the rearrange-
ment. The N atom at position 1 in compounds 4a–6g
occupies an axial position as indicated by single-crystal
X-ray structural analysis. The arylsulfonyl group after
rearrangement will be exactly above the cyclohexyl ring,
thereby creating steric crowding with the axial protons at
position 7 and 9, thus prohibiting the rearrangement.
However, the blood glucose lowering activity of the tested
compounds was not remarkable at a dose of 50 mg/kg.
Hypoglycemic activity testing of the other compounds is in
progress. The liver function test (LFT) and other data are also
being studied to examine the side-effect profile of the drugs;
the results will be published elsewhere.
Experimental
Melting points were determined on a Stuart SMP3 melting-
point apparatus. IR spectra were recorded on a Shimadzu
model 270 Fourier-transform infrared spectrophotometer
using an ATR facility. Only strong and the most significant
peaks are listed. NMR spectra were acquired on a Bruker
Avance 300 MHz NMR spectrometer and the signals cal-
ibrated with reference to the residual solvent signal. Mass
spectra were recorded on a GC-6890 N; MS-5973 inert
MSD; EI-70 eV instrument (Agilent Technologies). Ele-
mental analyses were performed using a Leco CHNS-932
elemental analyzer; results agreed favorably with the
calculated values. All the reactions were monitored by
thin-layer chromatography on pre-coated silica gel 60 F254
plates (Merck, Germany). The compounds 4-methoxy-
phenylsulfonyl chloride, 4-bromophenylsulfonyl chloride,
naphthalene-2-sulfonylchloride, and 4-nitrophenylsulfonyl
chloride were purchased from Sigma–Aldrich. 3-Methyl-
cyclohexanone, toluene-4-sulfonyl chloride, 4-chloro-
phenylsulfonyl chloride, and 4-dimethylaminopyridine were
the products of Fluka. 2-Methylcyclohexanone was pro-
vided by Merck. Anthraquinone-2-sulfonyl chloride was
prepared according to a procedure described in Ref. [19].
All solvents were distilled before use and dried whenever
required, in accordance with standard procedures.
In-vivo antidiabetic activity
The hypoglycemic efficacy of compounds 4a, 5a, and 6a was
trialed on alloxanized diabetic male albino rats of the Spra-
gue–Dawley strain (180–220 g; six to 8-weeks old) at dose
levels of 50 and 100 mg/kg of the mice body weight. The
blood glucose levels were measured 2 and 5 h after dose
administration. All three screened compounds were highly
active (Table 1); however, the activity was more profound at
the dose level of 100 mg/kg. Glipizide, a classical drug
belonging to the second generation of sulfonylurea com-
pounds, was used as the standard drug under the same
conditions and at a dose of 100 mg/kg. Excellent activity was
observed for 6-methyl-3-(4-methylphenylsulfonyl)-1,3-di-
azaspiro[4.5]decane-2,4-dione (4a). Compound 4a lowered
the blood glucose level by 60.79% which has to be compared
with blood glucose lowering of 41.60% by the standard gil-
ipizide at the same dose level. The potency of compound 6a
(48.56% reduction in serum glucose) was also higher than
that of glipizide whereas compound 5a was found to be
moderately active with blood glucose lowering of 32.56%.
123

500
Z. Iqbal et al.
General method for synthesis of spiroimidazolidine-2,4-
diones 1–3 [20]
(4.8 mmol), triethylamine (4.8 mmol), and a catalytic
amount of 4-(dimethylamino)pyridine in a suitable amount
of dichloromethane at room temperature. Completion of
the reaction was monitored by TLC. After completion
(*15 h), the reaction mixture was neutralized with 1 M
HCl and extracted with dichloromethane (4 9 25 cm3).
The combined organic layers were dried (Na2SO4), filtered,
and concentrated in vacuo. The resulting solid was purified
by recrystallization from ethanol–water.
Methylcyclohexanone (5.05 g, 45 mmol), 5.67 g KCN
(87 mmol), and 16.77 g (NH4)2CO3 (174 mmol) were
added to 100 cm3 50% ethanol in a round-bottomed flask
equipped with an air condenser. The reaction mixture was
heated with stirring in an oil bath at 55–60 °C for 14–16 h
and then cooled to room temperature. The precipitated
solid was filtered and washed with water. To obtain the
maximum amount of product, the aqueous filtrate was
acidified to pH 2–3 by adding 1 M HCl. The crude product
was repeatedly recrystallized from 90% ethanol.
6-Methyl-3-(4-methylphenylsulfonyl)-1,3-diazaspi-
ro[4.5]decane-2,4-dione (4a, C16H20N2O4S)
Yield 56%; m.p.: 152 °C; Rf = 0.78 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.40 (d, 3H, J = 6.3 Hz, CH3), 1.11–1.76 (m, 9H,
cyclohex-H), 2.41 (s, 3H, Ar-CH3), 7.49 (d, 2H,
J = 8.1 Hz, Ar–H), 7.87 (d, 2H, J = 8.4 Hz, Ar–H),
9.17 (bs, 1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 21.0, 21.8, 27.6, 33.5, 33.7, 41.8, 62.6, 128.5, 129.9,
6-Methyl-1,3-diazaspiro[4.5]decane-2,4-dione
(1, C9H14N2O2)
Yield 83%; m.p.: 218 °C (Ref. [20]: 215.5–216 °C);
Rf = 0.56 (petroleum ether–ethyl acetate 6:4); H NMR
1
(300 MHz, DMSO-d6): d = 0.65 (d, 3H, J = 6.6 Hz,
CH3), 1.16–1.72 (m, 9H, cyclohex-H), 8.26 (bs, 1H, NH),
10.57 (bs, 1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 15.8, 21.1, 25.5, 29.6, 34.7, 36.2, 66.3, 157.5,
ꢀ
135.0, 146.2, 150.6, 172.6 ppm; IR (ATR): m = 3,380,
3,012, 1,821, 1,742, 1,313, 1,189 cm-1; MS (70 eV):
m/z = 334 (M?), 179, 155, 91 (100), 65.
ꢀ
178.8 ppm; IR (ATR): m = 3,415, 3,388, 1,765,
3-(4-Chlorophenylsulfonyl)-6-methyl-1,3-diazaspi-
ro[4.5]decane-2,4-dione (4b, C15H17ClN2O4S)
1,705 cm-1; MS (70 eV): m/z = 182 (M?), 139, 113
(100), 96, 68, 54.
Yield 62%; m.p.: 236 °C; Rf = 0.75 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.43 (d, 3H, J = 6.6 Hz, CH3), 1.12–1.77 (m, 9H,
cyclohex-H), 7.80 (d, 2H, J = 8.7 Hz, Ar–H), 8.09 (d, 2H,
J = 8.7 Hz, Ar–H), 9.27 (bs, 1H, NH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 15.4, 20.6, 25.0, 29.3, 34.3,
37.2, 65.7, 130.1, 130.4, 136.8, 140.7, 152.5, 172.9 ppm;
7-Methyl-1,3-diazaspiro[4.5]decane-2,4-dione
(2, C9H14N2O2)
Yield 81%; m.p.: 273 °C (Ref. [20]: 268.5–269 °C);
Rf = 0.52 (petroleum ether–ethyl acetate 6:4); H NMR
1
(300 MHz, DMSO-d6): d = 0.85 (d, 3H, J = 6.6 Hz,
CH3), 1.69–1.95 (m, 9H, cyclohex-H), 8.45 (bs, 1H, NH),
10.58 (bs, 1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 21.3, 22.7, 27.5, 33.2, 33.7, 41.7, 63.3, 156.9,
ꢀ
IR (ATR): m = 3,382, 3,009, 1,804, 1,745, 1,390, 1,377,
1,181 cm-1; MS (70 eV): m/z = 358 (M ? 2), 356 (M?),
292, 288, 181, 175, 111, 95 (100).
ꢀ
178.9 ppm; IR (ATR): m = 3,415, 3,388, 1,768,
1,704 cm-1; MS (70 eV): m/z = 182 (M?), 139, 113
(100), 96, 68, 54.
3-(4-Bromophenylsulfonyl)-6-methyl-1,3-diazaspi-
ro[4.5]decane-2,4-dione (4c, C15H17BrN2O4S)
8-Methyl-1,3-diazaspiro[4.5]decane-2,4-dione
(3, C9H14N2O2)
Yield 53%; m.p.: 218 °C; Rf = 0.74 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.44 (d, 3H, J = 6.0 Hz, CH3), 1.25–1.77 (m, 9H,
cyclohex-H), 7.93 (m, 2H, Ar–H), 7.93 (m, 2H, Ar–H),
9.25 (bs, 1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 15.4, 20.6, 25.0, 29.3, 34.4, 37.2, 65.7, 129.9, 130.0,
Yield 80%; m.p.: 278 °C (Ref. [20]: 279–280 °C);
Rf = 0.55 (petroleum ether–ethyl acetate 6:4); H NMR
1
(300 MHz, DMSO-d6): d = 0.87 (d, 3H, J = 6.3 Hz,
CH3), 1.13–1.66 (m, 9H, cyclohex-H), 8.44 (bs, 1H, NH),
10.56 (bs, 1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 22.6, 29.6, 31.2, 33.6, 62.4, 156.8, 179.2 ppm; IR
ꢀ
133.3, 137.3, 150.5, 172.8 ppm; IR (ATR): m = 3,383,
3,013, 1,810, 1,748, 1,398, 1,376, 1,159 cm-1; MS
(70 eV): m/z = 402 (M ? 2), 400 (M?), 336, 333, 219,
181, 155, 95 (100).
(ATR): m = 3,415, 3,388, 1,802, 1,733 cm-1; MS (70 eV):
ꢀ
m/z = 182 (M?), 139, 113 (100), 96, 68, 54.
6-Methyl-3-(4-nitrophenylsulfonyl)-1,3-diazaspi-
ro[4.5]decane-2,4-dione (4d, C15H17N3O6S)
General method for synthesis of 3-(arylsulfonyl)
spiroimidazolidine-2,4-diones 4a–6g
Yield 49%; m.p.: 223 °C; Rf = 0.58 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.46 (d, 1H, J = 6.0 Hz, CH3), 1.11–1.81 (m, 9H,
cyclohex-H), 7.50 (d, 2H, J = 8.7 Hz, Ar–H), 7.85 (d, 2H,
Arylsulfonyl chloride (5.8 mmol) was added dropwise with
stirring to a mixture of spiroimidazolidine-2,4-dione
123

Hypoglycemic activity of 3-(arylsulfonyl)spiroimidazolidine-2,4-diones
501
J = 8.7 Hz, Ar–H), 9.36 (bs, 1H, NH) ppm; 13C NMR d = 20.9, 27.2, 33.2, 33.3, 41.4, 62.5, 150.1, 172.7 ppm;
ꢀ
(75 MHz, DMSO-d6): d = 15.5, 20.5, 25.3, 29.3, 34.4,
37.3, 65.8, 129.4, 130.3, 130.9, 137.7, 152.4, 172.7 ppm;
IR (ATR): ꢀm = 3,382, 3,014, 1,776, 1,714, 1,356,
1,158 cm-1; MS (70 eV): m/z = 367 (M?), 351, 337,
303, 181, 95 (100).
IR (ATR): m = 3,385, 3,019, 1,805, 1,731, 1,388,
1,186 cm-1; MS (70 eV): m/z = 334 (M?), 179, 155, 95
(100), 65.
3-(4-Chlorophenylsulfonyl)-7-methyl-1,3-diazaspi-
ro[4.5]decane-2,4-dione (5b, C15H17ClN2O4S)
3-(4-Methoxyphenylsulfonyl)-6-methyl-1,3-diazaspi-
ro[4.5]decane-2,4-dione (4e, C16H20N2O5S)
Yield 54%; m.p.: 251 °C; Rf = 0.73 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.83 (d, 3H, J = 6.0 Hz, CH3), 1.24–1.61 (m, 9H,
cyclohex-H), 7.78 (d, 2H, J = 8.7 Hz, Ar–H), 7.99 (d, 2H,
J = 8.7 Hz, Ar–H), 9.39 (bs, 1H, NH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 20.9, 22.4, 27.2, 33.1, 33.3,
Yield 43%; m.p.: 234 °C; Rf = 0. 77 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.40 (d, 3H, J = 6.6 Hz, CH3), 1.10–1.75 (m, 9H,
cyclohex-H), 3.86 (s, 3H, OCH3), 7.20 (m, 2H, Ar–H), 7.92
(m, 2H, Ar–H), 9.17 (bs, 1H, NH) ppm; 13C NMR 41.3, 62.8, 130.3, 136.8, 140.6, 150.0, 172.6 ppm; IR
-1
ꢀ
(ATR): m = 3,384, 3,023, 1,811, 1,732, 1,385, 1,184 cm ;
(75 MHz, DMSO-d6): d = 15.4, 20.6, 25.0, 29.3, 34.5,
37.2, 56.5, 65.5, 115.4, 129.3, 130.6, 150.9, 164.7,
MS (70 eV): m/z = 358 (M ? 2), 356 (M?), 292, 288,
181, 175, 111, 95 (100).
ꢀ
173.0 ppm; IR (ATR): m = 3,381, 3,023, 1,803, 1,735,
1,379, 1,191 cm-1; MS (70 eV): m/z = 352 (M?), 288,
171, 138, 107 (100), 96, 95.
3-(4-Bromophenylsulfonyl)-7-methyl-1,3-diazaspi-
ro[4.5]decane-2,4-dione (5c, C15H17BrN2O4S)
6-Methyl-3-(2-naphthalenylsulfonyl)-1,3-diazaspi-
ro[4.5]decane-2,4-dione (4f, C19H20N2O4S)
Yield 60%; m.p.: 216 °C; Rf = 0.73 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.83 (d, 3H, J = 6.0 Hz, CH3), 1.69–1.95 (m, 9H,
cyclohex-H), 7.92 (m, 4H, Ar–H), 9.41 (bs, 1H, NH) ppm;
13C NMR (75 MHz, DMSO-d6): d = 20.9, 22.4, 27.2,
33.1, 33.3, 41.3, 62.8, 129.8, 130.2, 133.3, 137.2, 150.0,
Yield 57%; m.p.: 245 °C; Rf = 0.69 (petroleum ether–
ethyl acetate; 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.81 (d, 3H, J = 6.3 Hz, CH3), 0.88–1.61 (m, 9H,
cyclohex-H), 7.67–8.74 (m, 7H, Ar–H), 9.27 (bs, 1H, NH)
ppm; 13C NMR (75 MHz, DMSO-d6): d = 20.5, 20.6,
25.0, 29.2, 34.5, 37.1, 65.7, 122.1, 128.5, 128.6, 130.2,
130.3, 130.4, 130.6, 131.8, 135.0, 135.6, 150.7, 173.1 ppm;
ꢀ
172.6 ppm; IR (ATR): m = 3,384, 3,010, 1,811, 1,731,
1,389, 1,178 cm-1; MS (70 eV): m/z = 402 (M ? 2), 400
(M?), 336, 331, 219, 155, 181, 95 (100).
ꢀ
IR (ATR): m = 3,385, 3,021, 1,804, 1,731, 1,380,
7-Methyl-3-(4-nitrophenylsulfonyl)-1,3-diazaspi-
ro[4.5]decane-2,4-dione (5d, C15H17N3O6S)
1,177 cm-1; MS (70 eV): m/z = 372 (M?), 308, 304,
265, 181, 138, 127, 96, 95 (100).
Yield 56%; m.p.: 168 °C; Rf = 0.71 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.83 (d, 3H, J = 6.0 Hz, CH3), 1.25–1.62 (m, 9H,
cyclohex-H), 7.50 (d, 2H, J = 8.7 Hz, Ar–H), 7.85 (d, 2H,
J = 8.7 Hz, Ar–H), 9.43 (bs, 1H, NH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 15.4, 20.5, 25.2, 29.4, 34.5,
37.3, 65.8, 129.4, 130.5, 130.8, 137.6, 152.5, 172.5 ppm;
3-[(9,10-Dihydro-9,10-dioxo-2-anthracenyl)sulfonyl]-6-
methyl-1,3-diazaspiro[4.5]decane-2,4-dione
(4g, C23H22N2O6S)
Yield 55%; m.p.: 238 °C; Rf = 0.75 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.83 (d, 3H, J = 6.3 Hz, CH3), 0.81–1.72 (m, 9H,
cyclohex-H), 7.94–8.40 (m, 7H, Ar–H), 9.31 (bs, 1H, NH)
ppm; 13C NMR (75 MHz, DMSO-d6): d = 21.1, 21.2,
25.2, 29.6, 35.0, 37.3, 65.9, 126.4, 127.4, 128.7, 133.1,
133.2, 133.5, 134.0, 135.2, 137.1, 142.2, 151.1, 173.5,
ꢀ
IR (ATR): m = 3,383, 3,021, 1,811, 1,731, 1,376, 1,188,
1,028 cm-1; MS (70 eV): m/z = 367 (M?), 351, 337, 303,
181, 95 (100).
3-(4-Methoxyphenylsulfonyl)-7-methyl-1,3-diazaspi-
ro[4.5]decane-2,4-dione (5e, C16H20N2O5S)
ꢀ
180.3, 181.7 ppm; IR (ATR): m = 3,384, 3,012, 1,768,
1,714, 1,378, 1,188 cm-1; MS (70 eV): m/z = 452 (M?),
271, 208, 207 (100), 180, 179, 151.
Yield 53%; m.p.: 198 °C; Rf = 0.72 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.83 (d, 3H, J = 6.3 Hz, CH3), 1.02–1.61 (m, 9H,
cyclohex-H), 3.24 (s, 3H, OCH3), 7.20 (m, 2H, Ar–H), 7.92
(m, 2H, Ar–H), 9.31 (bs, 1H, NH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 3.2, 20.0, 27.8, 33.3, 42.2, 56.4,
62.5, 115.3, 129.4, 130.7, 150.3, 164.6, 172.7 ppm; IR
7-Methyl-3-(4-methylphenylsulfonyl)-1,3-diazaspi-
ro[4.5]decane-2,4-dione (5a, C16H20N2O4S)
Yield 54%; m.p.: 251 °C; Rf = 0.73 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.82 (d, 3H, J = 6.3 Hz, CH3), 0.83–1.62 (m, 9H,
cyclohex-H), 2.42 (s, 3H, Ar-CH3), 7.49 (d, 2H,
J = 8.1 Hz, Ar–H), 7.87 (d, 2H, J = 8.4 Hz, Ar–H),
9.34 (bs, 1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6):
(ATR): ꢀm = 3,386, 3,023, 1,803, 1,731, 1,388, 1,180 cm-1
;
MS (70 eV): m/z = 352 (M?), 288, 171, 107 (100), 138,
96, 95 (100).
123

502
Z. Iqbal et al.
7-Methyl-3-(2-naphthalenylsulfonyl)-1,3-diazaspiro-
[4.5]decane-2,4-dione (5f, C19H20N2O4S)
3-(4-Bromophenylsulfonyl)-8-methyl-1,3-diazaspiro-
[4.5]decane-2,4-dione (6c, C15H17BrN2O4S) [21]
Yield 67%; m.p.: 166 °C; Rf = 0.68 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.43 (d, 3H, J = 6.6 Hz, CH3), 1.12–1.77 (m, 9H,
cyclohex-H), 7.67–8.74 (m, 7H, Ar–H), 9.36 (bs, 1H, NH)
ppm; 13C NMR (75 MHz, DMSO-d6): d = 20.9, 22.4,
27.2, 33.3, 33.7, 41.4, 62.7, 126.2, 122.3, 128.5, 129.5,
130.3, 130.4, 130.5, 131.8, 135.1, 135.7, 150.1, 170.8 ppm;
Yield 50%; m.p.: 178 °C; Rf = 0.69 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 1.10 (d, 3H, J = 6.0 Hz, CH3), 1.12–1.63 (m, 9H,
cyclohex-H), 7.91 (m, 4H, Ar–H), 9.41 (bs, 1H, NH) ppm;
13C NMR (75 MHz, DMSO-d6): d = 22.4, 29.0, 30.9,
33.5, 62.0, 129.8, 130.2, 133.3, 137.2, 149.9, 172.9 ppm;
ꢀ
IR (ATR): m = 3,384, 3,080, 1,798, 1,737, 1,342, 1,179,
IR (ATR): m = 3,382, 3,035, 1,808, 1,731, 1,362,
1,030 cm-1; MS (70 eV): m/z = 402 (M ? 2), 400 (M?),
336, 333, 219, 181, 155, 95 (100).
ꢀ
1,155 cm-1; MS (70 eV): m/z = 372 (M?), 308, 304,
265, 181, 138, 127, 96 (100).
3-(4-Nitrophenylsulfonyl)-8-methyl-1,3-diazaspiro-
[4.5]decane-2,4-dione (6d, C15H17N3O6S)
3-[(9,10-Dihydro-9,10-dioxo-2-anthracenyl)sulfonyl]-
7-methyl-1,3-diazaspiro[4.5]decane-2,4-dione
(5g, C23H22N2O6S)
Yield 48%; m.p.: 191 °C; Rf = 0.74 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.84 (d, 3H, J = 6.0 Hz, CH3), 1.11–1.69 (m, 9H,
cyclohex-H), 7.51 (d, 2H, J = 8.7 Hz, Ar–H), 7.85 (d, 2H,
J = 8.7 Hz, Ar–H), 9.42 (bs, 1H, NH) ppm; 13C-NMR
(75 MHz, DMSO-d6): d = 22.4, 25.3, 29.3, 37.3, 65.8,
Yield 55%; m.p.: 238 °C; Rf = 0.75 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.81–1.72 (m, 9H, cyclohex-H), 0.83 (d, 3H,
J = 6.3 Hz, CH3), 7.97–8.56 (m, 7H, Ar–H), 9.31
(bs,1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 21.2, 22.6, 27.7, 33.5, 34.0, 41.6, 62.9, 126.6, 127.5,
128.9, 133.2, 133.3, 133.4, 133.9, 134.2, 135.4, 137.4,
142.6, 150.4, 171.3, 181.3, 181.6 ppm; IR (ATR):
129.4, 130.3, 130.9, 137.7, 152.4, 172.7 ppm; IR (ATR):
-1
ꢀ
m = 3,385, 3,031, 1,776, 1,714, 1,358, 1,145, 1,028 cm
;
MS (70 eV): m/z = 367 (M?), 351, 337, 303, 181, 95
(100).
m = 3,383, 3,012, 1,768, 1,714, 1,378, 1,188 cm-1; MS
ꢀ
3-(4-Methoxyphenylsulfonyl)-8-methyl-1,3-diazaspiro-
[4.5]decane-2,4-dione (6e, C16H20N2O5S)
(70 eV): m/z = 452 (M?), 271, 208, 207 (100), 180, 179,
151.
Yield 59%; m.p.: 208 °C; Rf = 0.71 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.83 (d, 3H, J = 6.3 Hz, CH3), 1.02–1.62 (m, 9H,
cyclohex-H), 3.24 (s, 3H, OCH3), 7.20 (m, 2H, Ar–H), 7.92
(m, 2H, Ar–H), 9.31 (bs, 1H, NH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 22.4, 28.8, 30.8, 33.2, 56.4,
62.4, 115.3, 129.7, 130.7, 150.3, 164.7, 172.7 ppm; IR
8-Methyl-3-(4-methylphenylsulfonyl)-1,3-diazaspiro-
[4.5]decane-2,4-dione (6a, C16H20N2O4S)
Yield 64%; m.p.: 175 °C; Rf = 0.67 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.82 (d, 3H, J = 6.3 Hz, CH3), 1.05–1.63 (m, 9H,
cyclohex-H), 2.54 (s, 3H, Ar-CH3), 7.49 (d, 2H,
J = 8.1 Hz, Ar–H), 7.87 (d, 2H, J = 8.4 Hz, Ar–H),
9.34 (bs, 1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 21.8, 22.4, 23.7, 27.6, 41.4, 66.5, 128.5, 129.9, 135.0,
(ATR): m = 3,383, 3,053, 1,801, 1,728 cm-1; MS (70 eV):
ꢀ
m/z = 352 (M?), 288, 171, 107 138, 96, 95 (100).
8-Methyl-3-(2-naphthalenylsulfonyl)-1,3-diazaspiro-
[4.5]decane-2,4-dione (6f, C19H20N2O4S)
ꢀ
146.2, 151.6, 172.7 ppm; IR (ATR): m = 3,381, 3,085,
Yield 65%; m.p.: 203 °C; Rf = 0.63 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.81 (d, 3H, J = 6.3 Hz, CH3), 0.87–1.68 (m, 9H,
cyclohex-H), 7.70–8.73 (m, 7H, Ar–H), 9.34 (bs,1H, NH)
ppm; 13C NMR (75 MHz, DMSO-d6): d = 22.4, 29.0,
30.9, 33.6, 61.9, 122.3, 128.4, 128.5, 130.3, 130.4, 130.5,
131.8, 135.1, 135.6, 150.1, 173.1 ppm; IR (ATR):
ꢀ
1,795, 1,731, 1,374, 1,175, 1,070 cm-1; MS (70 eV):
m/z = 334 (M?), 179, 155, 95 (100), 65.
3-(4-Chlorophenylsulfonyl)-8-methyl-1,3-diazaspiro-
[4.5]decane-2,4-dione (6b, C15H17ClN2O4S) [18]
Yield 54%; m.p.: 197 °C; Rf = 0.66 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.83 (d, 3H, J = 6.0 Hz, CH3), 1.13–1.62 (m, 9H,
cyclohex-H), 7.78 (d, 2H, J = 8.7 Hz, Ar–H), 7.99 (d, 2H,
J = 8.7 Hz, Ar–H), 9.39 (bs, 1H, NH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 22.4, 23.7, 27.6, 41.3, 62.8,
m = 3,384, 3,105, 1,802, 1,729 cm-1
; MS (70 eV):
m/z = 372 (M?), 308, 304, 265, 181, 138, 127, 95 (100).
3-[(9,10-Dihydro-9,10-dioxo-2-anthracenyl)sulfonyl]-
8-methyl-1,3-diazaspiro[4.5]decane-2,4-dione
(6g, C23H22N2O6S)
128.5, 129.9, 135.0, 146.2, 150.0, 172.6 ppm; IR (ATR):
-1
ꢀ
m = 3,385, 3,100, 1,805, 1,739, 1,392, 1,173, 1,030 cm
;
Yield 68%; m.p.: 219 °C; Rf = 0.71 (petroleum ether–
ethyl acetate 6:4); 1H NMR (300 MHz, DMSO-d6):
d = 0.81–1.72 (m, 9H, cyclohex-H), 0.83 (d, 3H,
MS (70 eV): m/z = 358 (M ? 2), 356 (M?), 292, 288,
181, 175, 111, 95 (100).
123

Hypoglycemic activity of 3-(arylsulfonyl)spiroimidazolidine-2,4-diones
503
J = 6.3 Hz, CH3), 7.84–8.36 (m, 7H, Ar–H), 9.31 (bs, 1H,
NH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 22.6, 29.2,
31.2, 33.8, 62.1, 126.6, 127.5, 128.9, 133.2, 133.3, 133.4,
133.6, 134.2, 135.4, 137.5, 142.7, 150.2 173.3, 181.4,
Table 2 Crystal and structure refinement data for compound 4e
Formula
C16H20N2O5S
352.40
Formula weight
Crystal size/mm3
Space group
0.450 9 0.398 9 0.383
P2(1)/c
ꢀ
181.7 ppm; IR (ATR): m = 3,383, 3,105, 1,802,
1,729 cm-1; MS (70 eV): m/z = 452 (M?), 271, 208,
207 (100), 180, 179, 151.
˚
a/A
7.5928(6)
12.4801(10)
17.7627(15)
99.3390(10)
1660.9(2)
4
˚
b/A
˚
c/A
X-ray crystallography
b/°
3
˚
V/A
Crystals of 4e were grown by the vapor diffusion method.
The compound was dissolved in a small volume of ethanol
in a 50 cm3 beaker. This beaker was half dipped in
petroleum ether contained in a 500 cm3 beaker. Finally, the
500 cm3 beaker was covered with aluminium foil. The
crystals so formed were filtered. Single crystals were
mounted in thin-walled capillaries. Data were collected
using the Bruker APEX2 software package [22] on a Sie-
mens diffractometer equipped with an APEXII CCD
detector, a graphite monochromator, and Mo-Ja radiation
Z
D
calc/g cm-3
1.409
L/mm-1
0.224
F(000)
744
h for data collection
Total number of reflections
No. of unique reflections
R1 (I [ 2r(I))a
2.32–24.99°
10,661
2,918
0.0414
Rw (all data)b
0.0630
P
P
˚
a
(k = 0.71073 A) source. A hemisphere of data was col-
R ¼ ðjFoj ꢁ jFcjÞj= jFoj|
h
i
1=2
ꢀ
ꢁ
P
P
2
4
b
Rw
¼
w Fo2 ꢁ Fc2
=
ðFoÞ
where w = 1/[r2(Fo2) ?
lected in 1,664 frames with 40 s exposure times. Data
processing and absorption correction were performed by
use of the APEX2 software package [22, 23]. The structure
was solved by use of direct methods and all non-H atoms
were refined anisotropically. Hydrogen atoms were placed
in the calculated positions by use of an appropriate riding
model and coupled isotropic temperature factors. The
thermal ellipsoid diagram (30% probability level) was
produced using Ortep-3 for Windows [24] (Table 2).
CCDC 776494 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(0.0324 9 P)2 ? 0.6970 9 P] where P = (Fo2 ? 2F2c)/3
level of each rat was tested. Rats having blood glucose
levels above 300 mg/100 cm3 were selected for further
experiments. The diabetic rats were segregated into groups
of six rats each. Control blood samples were collected from
the tail vein by making snip with a scalpel or sharp scis-
sors. In order to compare glucose-lowering potential, the
synthesized compounds were administered orally at doses
of 50 mg/kg and 100 mg/kg of the mice body weight and
the standard drug was administered at a dose of 100 mg/kg.
Blood samples were obtained for glucose assay 2 h and
5 h after compound administration. An appropriate vehicle
control (DMSO) was also run. One group of diabetic rats
was left intact (untreated diabetic) for comparison. After
six days of treatment the mice were subjected to anesthesia
with diethyl ether and blood samples were collected by
cardiac puncture to conduct the liver function test (LFT)
and to obtain other data to examine the side-effect profile
of the drugs. The results are reported as mean standard
deviation, n = 6 in each group.
Biological assay
The in-vivo hypoglycemic activity of the synthesized
3-(arylsulfonyl)spiroimidazolidine-2,4-diones was deter-
mined by use of a standard procedure [25].
Pharmacological methods
To examine the efficacy of the synthesized arylsulfonyl-
spiroimidazolidine-2,4-diones as hypoglycemic agents, six
to eight-week-old albino rats were purchased from
National Institute of Health (NIH), Islamabad, Pakistan.
The animals were housed in cages with 12-h light/dark
cycles. Adult fasted male rats of the Sprague–Dawley
strain (180–220 g) were made diabetic by intra-abdominal
injection of 225 mg/kg alloxan monohydrate [26] freshly
dissolved in distilled water. Three days later, by use of an
Accu-check blood glucose analyzer, the blood glucose
References
1. Kashif MK, Ahmad I, Hameed S (2008) Arkivoc xvi:311
2. Wild S, Roglic G, Green A, Sicree R, King H (2004) Diabetes
Care 27:1047
3. Hamdan II, Afifi FU (2004) J Ethnopharmacol 93:117
4. Zhang Q, Tang N, Schepmoes AA, Phillips LS, Smith RD, Metz
TO (2008) J Proteome Res 7:2025
123

504
Z. Iqbal et al.
5. Phung OJ, Scholle JM, Talwar M, Coleman CI (2010) J Am Med
Assoc 303:1410
15. Brimelow HC, Carrington HC, Vasey CH, Waring WS (1962)
J Chem Soc 2789
6. Waqar MA, Aijaz S, Shaukat S, Waqar A (2009) J Chem Soc Pak
31:677
16. Gauthier TJ, Yokum TS, Morales GA, McLaughlin ML, Liu YH
(1997) Acta Cryst C53:1659
7. Shaukat S, Waqar A, Waqar MA (2009) J Chem Soc Pak 31:480
and references cited therein
17. Kashif MK, Rauf MK, Bolte M, Hameed S (2009) Acta Cryst
E65:o1893
8. Ono H, Nozawa Y, Hayano S (1982) Nippon Ganka Gakkai
Zasshi 86:1343
9. Varma SD, Kinoshita JH (1976) Biochem Pharmacol 25:2505
18. Meanwell NA, Sing YS, Gao J, Wong HS, Gao Q, Denis R,
Laurent S, Balasubramanian N (1995) J Org Chem 60:1565
19. Feng F, Uno B, Goto M, Zhang Z, An D (2002) Talanta 57:481
20. Henze HR, Speer RJ (1942) J Am Chem Soc 64:522
21. Kashif MK, Rauf MK, Bolte M, Hameed S (2009) Acta Cryst
E65:o1892
´
´
10. Murcia-Soler M, Perez-Gimenez F, Nalda-Molina R, Salabert-
´
´
Salvador MT, Garcıa-March FJ, Cercos-del-Pozo RA, Garrigues
TM (2001) J Chem Inf Comput Sci 41:1345
11. Pandeya SN, Raja AS, Stables JP (2002) J Pharm Pharmaceut Sci
5:266
22. APEX2 Ver. 2008.5 (2008) Bruker AXS, Inc, Madison, Wis-
consin, USA
12. Kashif MK, Hussain A, Rauf MK, Ebihara M, Hameed S (2008)
Acta Cryst E64:o444
13. Ahmad I, Hameed S, Duddeck H, Lenzen S, Rustenbeck I,
Ahmad R (2002) Z Naturforsch 57B:349
14. Mahmoodi NO, Khodaee Z (2007) Arkivoc iii:29
23. Sheldrick GM (2008) Acta Cryst A64:112
24. Farrugia LJ (1997) J Appl Cryst 30:565
25. Brown GR, Foubister AJ (1984) J Med Chem 27:79
26. Shukla R, Barve V, Padhye S, Bhonde R (2004) Bioorg Med
Chem Lett 14:4961
123