N-arylsulfonyl-benzimidazolones as potential hypoglycemic agents

Article abstract of DOI:10.1515/znb-2002-0315

1,3-Bis(arylsulfonyl)-benzimidazolones 1a-d were synthesized by reacting benzimidazolones with arenesulfonyl chlorides in the presence of NaOH. Mono(arylsulfonyl)-benzimidazolone derivatives 5a-c were prepared from benzimidazolone by protecting one of the

Full text of DOI:10.1515/znb-2002-0315

N-Arylsulfonyl-benzimidazolones as Potential Hypoglycemic Agents
Iftikhar Ahmada, Shahid Hameeda, Helmut Duddeckb, Sigurd Lenzenc,
Ingo Rustenbeckd, and Roshan Ahmada
a
Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan
b
Institute of Organic Chemistry, University of Hannover, Schneiderberg 1B,
D-30167 Hannover, Germany
c
Institute of Clinical Biochemistry, Hannover Medical School, D-30643 Hannover, Germany
d
Institute of Pharmacology, Technical University of Braunschweig, D-38106 Braunschweig,
Germany
Reprint request to Prof. Dr. Roshan Ahmad. E-mail: roshan@hudson.isb.sdnpk.org
Z. Naturforsch. 57b, 349Ð354 (2002); received December 7, 2001
Arylsulfonyl-benzimidazolones, Insulin Release, Antidiabetic Activity
1,3-Bis(arylsulfonyl)-benzimidazolones 1a-d were synthesized by reacting benzimidazo-
lones with arenesulfonyl chlorides in the presence of NaOH. Mono(arylsulfonyl)-benzimida-
zolone derivatives 5a-c were prepared from benzimidazolone by protecting one of the N-
atoms with a tert-butoxycarbonyl group followed by arylsulfonylation and deprotection in
acidic medium. The antidiabetic activity of three compounds 1a, 1c and 5a has been deter-
mined.
Introduction
enesulfonyl chlorides with benzimidazolones in
basic medium using sodium hydroxide in acetone.
Benzimidazolones for this purpose were prepared
by two methods known in the literature. In the
first method [12] o-phenylenediamines were
treated with urea at 20Ð140∞ C under inert atmo-
sphere and in the second method [13] methyl
anthranilates were converted into azides via hy-
drazides, which on heating resulted in the forma-
tion of benzimidazolones.
In order to synthesize the monosulfonylated de-
rivatives 5a-c, one of the benzimidazolone nitro-
gens was protected with a tert-butoxycarbonyl
group [14] by treatment with NaH/DMF and di-
tert-butyldicarbonate. The nitrobenzimidazolone
gave two regioisomers, 2b and 3, which were iso-
lated and identified by spectroscopic methods. The
major product, 2b (33% yield) was taken for fur-
ther studies. The protected benzimidazolones were
sulfonylated in the presence of triethylamine and
dimethylaminopyridine (DMAP) and the resulting
compounds 4aÐ4c deprotected with dilute acid to
give the target molecules. The structures of all in-
termediates and final products were elucidated by
spectroscopic methods and the purity determined
by elemental analysis.
Benzimidazolones are a class of cyclic urea de-
rivatives demonstrating a wide variety of biochem-
ical and pharmacological properties. They antago-
nize neurotransmitters [1], inhibit aldose reductase
[2], show antiulcer and antisecretory properties
[3], enhance pulmonary surfactant secretion [4]
and modulate ion channels [5]. Several of these
compounds show activity against leukemia [6]. A
number of such compounds with different substi-
tution patterns have been synthesized [7Ð10] to
check their medicinal properties.
In continuation of our work [11] on arylsulfonyl
cyclic urea derivatives as hypoglycemic agents, we
synthesized 1,3-bis(arylsulfonyl)-benzimidazolone
derivatives 1a-d and mono(arylsulfonyl)-benzimi-
dazolone derivatives 5aÐc (Scheme 1). The syn-
thesis and spectroscopic characterization of the in-
termediate compounds and the final products is
presented in this work. The antidiabetic activity of
compounds 1a, 1c and 5a only is reported because
the other compounds were either less soluble or
showed no significant effects.
Results and Discussion
Syntheses
1,3-Bis(arylsulfonyl)-benzimidazolones
1a-d
were synthesized in 62Ð97 % yield by reacting ar-
0932Ð0776/2002/0300Ð0349 $06.00 ” 2002 Verlag der Zeitschrift für Naturforschung, Tübingen · www.znaturforsch.com
D
Brought to you by | University of California
Authenticated
Download Date | 1/15/16 10:02 AM

350
I. Ahmad et al. · N-Arylsulfonyl-benzimidazolones as Potential Hypoglycemic Agents
Scheme 1. Formula and reaction scheme.
Antidiabetic activity
ulated insulin release under the same conditions
as used to measure the effect of the test agents. At
Imidazolone derivatives 1a, 1c and 5a were 800 µm, tolbutamide increased the insulin content
tested for their ability to stimulate insulin release in the medium to 16.5 ng/ml which has to be com-
using concentrations of 10 and 100 µm. At these pared with 24.6 ð 1.4 ng/ml produced by 100 µm
concentrations of the test agents, the correspond- of the least efficient compound, 1a. There was no
ing concentrations of solvent from the stock solu- increase in insulin release, when the incubation
tions were 0.2 and 2%. The static incubation of was performed at 20 ∞C rather than at 37 ∞C.
insulin-secreting INS-1 cells showed that at 100 µm
All test agents proved to be stimulators of insu-
all of the selected test agents stimulated insulin lin release when used at a concentration of 100 µm.
release. However, at 10 µm 1a had a small but sig- Since the stimulatory effect could be inhibited by
nificant effect (Table 1). 2% Methanol, but not incubation at room temperature, a nontoxic mech-
0.2% methanol alone also increased insulin re- anism of action can be assumed. The insulin-re-
lease, but the effect was clearly smaller than that leasing potency is only moderate, because only
of the test agents. Tolbutamide, a classical pharma- one compound was effective at 10 µm. This has to
cological stimulator of insulin secretion belonging be compared with a maximally effective concen-
to the class of sulfonylurea compounds [15], stim- tration of 1 µm for glibenclamide, a prototypic se-
Brought to you by | University of California
Authenticated
Download Date | 1/15/16 10:02 AM

I. Ahmad et al. · N-Arylsulfonyl-benzimidazolones as Potential Hypoglycemic Agents
351
with water and recrystallized from chloroform and
methanol (3:1).
cond-generation sulfonylurea compound. How-
ever, the magnitude of the effect was impressive.
The least effective compound produced a more
marked increase in insulin release than tolbuta-
mide, a fast acting first-generation sulfonylurea at
a maximally effective concentration. Thus, it seems
worthwhile to investigate the mechanism of action
of these compounds and to look for more potent
derivatives by setting up a complete structure-ac-
tivity relationship.
2,3-Dihydro-1,3-bis(4-tolylsulfonyl)-1H-
benzimidazol-2-one (1a):
M. p. = 187∞ C; yield = 84%. Ð IR (KBr, cmÐ1):
ν˜ = 3052, 2956, 2924, 1760, 1596, 1468, 1384, 1340,
1260, 1192, 1152, 1084, 812, 664. Ð 1H NMR
(CDCl3):
4H, 3Ј/5Ј-H, J = 8.5 Hz), 7.26 (dd, 2H, 4/7-H), 2.4
(s, 6H, CH3). Ð 13C NMR (CDCl3):
= 21.8 (C-
Ն = 7.95 (m, 6H, 2Ј/6Ј/5/6-H), 7.31 (d,
Ն
CH3), 113.4 (C-3Ј/5Ј), 125.2 (C-4/7), 126.3 (C-4Ј),
128.4 (C-5/6), 130.1 (C-2Ј/6Ј), 134.2 (C-1Ј), 146.9
(C-8/9), 147.6 (CO). Ð MS (EI, 70 eV): m/z (%) =
442 (45)[M+], 378 (6), 287 (40), 223 (10), 208 (4),
Table 1. Measurement of insulin release by compounds
1a, 1c and 5aa.
Compound
1a
1c
5a
180 (4), 155 (94), 139 (15), 91 (100).
Ð
10 µm
100 µm
13.6 ð 1.0b 8.2 ð 0.4
8.0 ð 0.4
24.6 ð 1.4c 31.0 ð 0.7c 45.6 ð 7.0c
C21H18N2O5S2 (442.51): calcd. C 57.00, H 4.10, N
6.33; found C 56.84, H 4.03, N 6.26.
a Insulin release by INS-1 cells during a 1 h incubation
at 37 ∞C. The insulin content of the incubation medium
is expressed as ng/ml. All data are given as mean ð SEM
of three experiments. The insulin content after control
incubation with 0.2% methanol was 9.3 ð 0.7 ng/ml and
after control incubation with 2% methanol 13.4 ð 0.6
ng/ml. Significance of the differences in comparison with
the respective control was calculated using Student’s un-
paired two-tailed t-test; b P < 0.05; c P < 0.01.
2,3-Dihydro-1,3-bis(naphth-2-ylsulfonyl)-1H-
benzimidazol-2-one (1b):
M. p. = 186Ð188∞ C; yield = 62%. Ð IR (KBr,
cmÐ1): ν = 3056, 2928, 1756, 1588, 1304, 1184, 1156,
˜
1152, 1072, 816, 784. Ð 1H NMR (CDCl3):
Ն = 8.00
(m, 2H, 5/6-H), 7.94 (d, 4H, 1Ј/3Ј-H), 7.82 (m, 6H,
4Ј/5Ј/8Ј-H), 7.75 (t, 2H, 6Ј-H), 7.68 (t, 2H, 7Ј-H),
7.30 (dd, 2H, 4/7-H, J7Ð6 = 6.2 Hz, J7Ð5 = 3.5
Experimental Section
Hz). Ð 13C NMR (CDCl3):
Ն = 113.6 (C-6Ј), 122.0
(C-3Ј/4Ј/7Ј), 125.3 (C-4/7), 128.1 (C-5/6), 129.5 (C-
5Ј), 130.5 (C-2Ј/8Ј), 131.7 (C-9Ј/10Ј), 133.9 (C-1Ј),
135.5 (C-8/9), 147.5 (CO). Ð MS (EI, 70 eV): m/z
(%) = 514 (21)[M+], 450 (7), 323 (8), 259 (14), 231
(2), 191 (48), 127 (100), 77 (5). Ð C27H18N2O5S2
(514.458): calcd. C 63.02, H 3.52, N 5.44; found C
62.18, H 3.46, N 5.19.
The melting points were determined on a Gal-
lenkamp digital melting point apparatus MFB-
1
595Ð010m and are uncorrected. H and 13C NMR
spectra were recorded on a Bruker DPX-400 in-
strument. Solvents used for NMR are given in the
experimental part. All chemical shifts are refer-
enced to TMS. The mass spectra were recorded on
a Varian MAT CH-5 spectrometer.
2,3-Dihydro-5-nitro-1,3-bis(4-tolylsulfonyl)-1H-
benzimidazol-2-one (1c):
General method for arylsulfonylation of
benzimidazolones (1aÐd)
M. p. = 219Ð220∞ C; yield = 97%. Ð IR (KBr,
cmÐ1): ν˜ = 3068, 2952, 1772, 1528, 1444, 1344, 1192,
The standard procedure was as follows [16]:
Benzimidazolone (0.01 mol) was suspended in ac-
etone (60 ml) in a three-neck round bottomed
flask fitted with an air condenser and two drop-
ping funnels. In one dropping funnel was taken
1 N NaOH solution (20 ml) and in the other a so-
lution of 4-toluene- or naphthalene-2-sulfonyl
chloride (0.02 mol) in acetone. To the suspension
of benzimidazolone in acetone was added 1 N
NaOH solution and 4-tolyl- or naphthylsulfonyl
chloride, respectively, dropwise with constant stir-
ring. The temperature was maintained at 20Ð
30∞ C. The mixture was stirred for one hour. Ace-
tone was removed in vacuo, the residue washed
1152, 1084, 856, 812. Ð 1H NMR (CDCl3):
Ն
= 8.80
(d, 1H, 4-H, J4Ð6 = 2.0 Hz), 8.08 (d, 1H, 7-H, J7Ð6
=
9.0 Hz), 8.22 (dd, 1H, 6-H, J6Ð7 = 9.0 Hz, J6Ð4 = 2.0
Hz), 7.98 (m, 4H, 2Ј/6Ј-H), 7.37 (d, 4H, 3Ј/5Ј-H, J =
8.0 Hz), 2.5 (s, 6H, 2 ¥ CH3). Ð 13C NMR (CDCl3):
Ն
= 22.0 (CH3), 109.3 (C-7), 113.2 (C-4), 121.4 (C-
5), 126.6 (C-4Ј), 128.3 (C-2Ј/6Ј), 130.4 (C-9), 130.9
(C-3Ј/5Ј), 133.3 (C-1Ј), 144.8 (C-8), 147.1 (CO),
147.2 (C-6). Ð MS (EI, 70 eV): m/z (%) = 487
(26)[M+], 423 (6), 156 (10), 155 (100), 139 (9), 121
(00), 92 (10), 91 (77), 65 (11). Ð C21H17N3O7S2
(487.51): calcd. C 51.73, H 3.51, N 8.61; found C
51.32, H 3.38, N 8.48.
Brought to you by | University of California
Authenticated
Download Date | 1/15/16 10:02 AM

352
I. Ahmad et al. · N-Arylsulfonyl-benzimidazolones as Potential Hypoglycemic Agents
2,3-Dihydro-1,3-bis(naphth-2-ylsulfonyl)-5-nitro-
2-oxo-1H-benzimidazol-2-one (1d):
122 (2). Ð C12H13N3O5 (279.25): calcd. C 51.61, H
4.69, N 15.04; found C 50.91, H 4.31, N 14.95.
M. p. = 206∞ C; yield = 73%. Ð IR (KBr, cmÐ1):
2,3-Dihydro-5-nitro-2-oxo-1H-benzimidazole-1-
carboxylic acid, 1,1-dimethylethyl ester (3):
ν = 3056, 2928, 1528, 1488, 1344, 1184, 1152, 1068,
˜
1
888, 860. Ð H NMR (CDCl3):
Ն = 8.87 (d, 1H, 4-
M. p. = 327∞ C; yield = 29%. Ð IR (KBr, cmÐ1):
H, J4Ð6 = 2.0 Hz), 8.67 (distort. d, 2H, 1Ј-H), 8.25
(dd, 1H, 6-H, J6Ð7 = 9.0 Hz, J6Ð4 = 2.0 Hz), 8.16
(d, 1H, 7-H, J7Ð6 = 9.0 Hz), 8.00 (d, 2H, 3Ј-H,
J3Ј/4Ј = 8.9 Hz), 7.86 (m, 6H, 4Ј/5Ј/8Ј-H), 7.71 (t,
2H, 6Ј-H), 7.64 (t, 2H, 7Ј-H). Ð 13C NMR
ν = 3365, 3195, 2975, 1779, 1740, 1521, 1390, 1365,
˜
1
1110, 871, 627. Ð H NMR (CDCl3):
Ն = 9.48 (s,
1H, N-H), 8.10 (dd, 1H, 6-H, J6Ð7 = 8.7 Hz, J6Ð4
=
2.1 Hz), 8.00 (d, 1H, 4-H, J4Ð6 = 2.3 Hz), 7.87 (d,
1H, 7-H, J7Ð6 = 8.7 Hz), 1.25 (s, 9H, 3 ¥ CH3). Ð
MS (EI, 70 eV): m/z (%) = 279 (7) [M+], 235 (9),
206 (4), 179 (100), 178 (4), 151 (10), 150 (3), 123
(4), 122 (2). Ð C12H13N3O5 (279.25): calcd. C
51.61, H 4.69, N 15.04; found C 51.95, H 4.23, N
14.95.
(CDCl3):
Ն = 113.8 (C-4), 121.4 (C-5), 122.0 (C3Ј/
4Ј/7Ј), 126.9 (C-9), 128.7 (C-6Ј), 130.1 (C-9Ј/10Ј),
130.4 (C-7), 130.9 (C-8), 131.2 (C-5Ј), 131.5 (C-2Ј/
8Ј), 145.2 (C-6), 197.3 (C-CO). Ð MS (EI, 70 eV):
m/z (%) = 559 (10)[M+], 495 (9), 369 (2), 305 (2),
304 (2), 149 (2), 127 (100), 115 (5), 77 (5). Ð
C27H17N3O7S2 (559.58): calcd. C 57.95, H 3.06, N
7.50; found C 57.60, H 2.97, N 7.39.
General method for arylsulfonylation of t-butylcar-
boxybenzimidazolone [14] (4aÐc):
Generalmethod for t-butoxycarbonyal tion of ben-
To the mono-protected benzimidazolone (0.01
mol) dry dichloromethane (500 ml) was added fol-
lowed by triethylamine as a base and dimethylami-
nopyridine as a catalyst. To this well-stirred solu-
tion 4-toluene- or naphthalene-2-sulfonyl chloride
(0.11 mol) was added portionwise and stirring con-
tinued at 20 ∞C for further 3 h. Then, the mixture
was diluted with 1 N HCl and extracted with di-
chloromethane. The solvent was removed in vacuo
and the crude product was recrystallized from cho-
loroform-n-hexane (1 : 3).
zimidazolones [14] (2a, 2b, and 3):
The standard procedure was as follows [14]: To
the solution of benzimidazolone (0.01 mol) in dry
DMF was added sodium hydride (0.1 mol) under
argon. The solution was stirred for 30 minutes. To
this solution di-tert-butyldicarbonate (0.1 mol) was
added dropwise from a dropping funnel with con-
stant stirring. The solution was stirred for 24 h at
20 ∞C. DMF was removed in vacuo, the residue
treated with saturated ammonium chloride solu-
tion and extracted with ethyl acetate. Ethyl acetate
was removed in vacuo and purification carried out
by flash column chromatography using ethyl ace-
tate : n-hexane (1 : 4) as eluent. In case of nitro-
benzimidazolone two isomers were obtained,
which were separated by column chromatography.
2,3-Dihydro-2-oxo-3-(4-tolylsulfonyl)-1H-
benzimidazole-1-carboxylic acid, 1,1-dimethylethyl
ester (4a):
M. p. = 130Ð132∞ C; yield = 88%. Ð IR (KBr,
cmÐ1): ν = 3195, 2975, 2950, 1790, 1765, 1595, 1390,
˜
1
1345, 1193, 1152, 890. Ð H NMR (CDCl3):
Ն =
2,3-Dihydro-2-oxo-1H-benzimidazole-1-carboxylic
acid, 1,1-dimethylethyl ester (2a):
8.03 (dd, 2H, 2Ј/6Ј-H, J2ЈÐ6Ј = 1.2 Hz, J2ЈÐ3Ј = 8.
Hz), 7.83 (dd, 1H, 4-H, J4Ð6 = 1.0 Hz, J4Ð5 = 1.6
Hz), 7.34 (d, 2H, 3Ј/5Ј-H, J3ЈÐ2Ј = 8.0 Hz), 7.28Ð
7.20 (m, 3H, 5/6/7-H), 2.4 (s, 3H, Ar-CH3), 1.6 (s,
9H, 3 ¥ CH3). Ð MS (EI, 70 eV): m/z (%) = 388
(9) [M+], 288 (100), 224 (15), 155 (50), 133 (73),
106 (13), 91 (48), 77 (4), 65 (8). Ð C19H20N2O5S
(388.44): calcd. C 58.75, H 5.18, N 7.21; found C
59.06, H 5.29, N: 7.31.
M. p. = 305Ð307∞ C (lit. 313Ð315∞ C [14]);
yield = 68%. Spectroscopic data were identical
with the reported ones.
2,3-Dihydro-6-nitro-2-oxo-1H-benzimidazole-1-
carboxylic acid, 1,1-dimethylethyl ester (2b):
M. p. = 320∞ C; yield = 33%. Ð IR (KBr, cmÐ1):
ν˜ = 3365, 3195, 2975, 2850, 1777, 1740, 1520, 1394,
2,3-Dihydro-3-(naphth-2-yl-sulfonyl)-2-oxo-1H-
benzimidazole-1-carboxylic acid, 1,1-dimethylethyl
ester (4b):
1365, 1110, 888, 832. Ð 1H NMR (CDCl3):
Ն = 9.70
(s, 1H, N-H), 8.70 (d, 1H, 7-H, J7Ð5 = 2.3 Hz), 8.18
(dd, 1H, 5-H, J5Ð4 = 8.7 Hz, J5Ð7 = 2.5 Hz), 7.18
(d, 1H, 4-H, J4Ð5 = 8.7 Hz), 1.25 (s, 9H, 3 ¥
M. p. = 127∞ C; yield = 75%. Ð IR (KBr, cmÐ1):
CH3). Ð MS (EI, 70 eV): m/z (%) = 279 (9) [M+], ν = 3190, 1791, 1770, 1391, 1345, 1340, 1190, 1152,
˜
1
179 (100), 178(6), 151 (9), 150 (3), 135 (2), 123 (3), 891. Ð H NMR (CDCl3):
Ն = 8.01 (dd, 2H, 5/6-
Brought to you by | University of California
Authenticated
Download Date | 1/15/16 10:02 AM

I. Ahmad et al. · N-Arylsulfonyl-benzimidazolones as Potential Hypoglycemic Agents
353
H, J6Ð7 = 6.2 Hz, J6Ð4 = 3.4 Hz), 7.87Ð7.59 (m, 7H, 2,3-Dihydro-1-(naphth-2-ylsulfonyl)-1H-
naphthyl-H), 7.32 (dd, 2H, 4/7-H, J7Ð6 = 6.2 Hz, benzimidazol-2-one (5b):
J7Ð5 = 3.2 Hz), 2.24 (s, 9H, 3 ¥ CH3). Ð MS (EI,
M. p. = 206∞ C; yield = 70%. Ð IR (KBr, cmÐ1):
70 eV): m/z (%) = 424 (9)[M+], 324 (48), 260 (13),
232 (3), 105 (12), 77 (4), 191 (35), 127 (100), 189
(2), 90 (11). Ð C22H20N2O5S (424.47): calcd. C
62.25, H 4.74, N 6.59; found C 62.12, H 4.31, N
6.54.
ν = 3182, 2770, 1770, 1765, 1380, 1340, 1180, 1152. Ð
˜
1H NMR (CDCl3):
Ն = 9.7 (s, 1H, N-H), 8.98 (m,
3H, 4Ј/5Ј/8Ј-H), 8.67 (d, 2H, 1Ј/3Ј-H, J3ЈÐ4Ј = 8.7 Hz),
7.93 (d, 1H, 7-H, J7Ð6 = 8.0 Hz), 7.71 (t,1H, 7Ј-H),
7.64 (t, 1H, 6Ј-H), 7.20Ð7.13 (m, 3H, 4/5/6-H). Ð MS
(EI, 70 eV): m/z (%) = 324 (36) [M+], 260 (15), 259
(3), 232 (3), 191 (15), 133 (78), 127 (100), 105 (10),
90 (11). Ð C17H12N2O3S (324.35): calcd. C 62.95, H
2,3-Dihydro-3-(naphth-2-yl-sulfonyl)-6-nitro-2-
oxo-1H-benzimidazole-1-carboxylic acid, 1,1-di- 3.72, N 8.63; found C 62.01, H 3.59, N 8.54.
methylethyl ester (4c):
2,3-Dihydro-1-(naphth-2-ylsulfonyl)-5-nitro-1H-
M. p. = 295Ð297∞ C; yield = 56%. Ð IR (KBr,
benzimidazol-2-one (5c):
cmÐ1): ν˜ = 3125, 2925, 1761, 1715, 1515, 1374, 1345,
M. p. = 325∞ C; yield = 62%. Ð IR (KBr, cmÐ1):
1
1331, 1182, 1152, 902, 806. Ð H NMR (CDCl3):
ν˜ = 3128, 2925, 1767, 1761, 1552, 1375, 1346, 1333,
Ն
= 8.71 (d, 1H, 7-H, J7Ð5 = 2.2 Hz), 8.21 (dd, 1H, 5-
1183, 1152, 902. Ð 1H NMR (CDCl3):
Ն = 8.87 (m,
H, J5Ð4 = 8.6 Hz, J5Ð7 = 2.3 Hz), 7.90 (d, 2H, 1Ј/3Ј-
H, J = 3.2 Hz), 7.83 (m, 3H, 4Ј/5Ј/8Ј-H), 7.72 (t, 1H,
6Ј-H), 7.60 (t, 1H, 7Ј-H), 7.36 (d, 1H, 4-H, J4Ð5 = 8.0
Hz), 1.6 (s, 9H, 3 ¥ CH3). Ð MS (EI, 70 eV): m/z
(%) = 469 (8) [M+], 425 (3), 369 (45), 305 (12),
277 (2), 236 (32), 186 (11), 172 (100), 158 (4). Ð
C22H19N3O7S (469.47): calcd. 56.28, H 4.07, N
8.95; found C 56.02, H 4.01, N 8.89.
3H, 4Ј/5Ј/8Ј-H), 8.71 (d, 1H, 4-H, J4Ð6 = 2.1 Hz),
8.70 (d, 2H, 1Ј/3Ј-H, J3ЈÐ4Ј = 8.2 Hz), 8.35 (dd, 1H,
6-H, J6Ð7 = 8.2 Hz), 8.10 (d, 1H, 7-H, J7Ð6 = 8.0
Hz), 7.69 (t, 1H, 7Ј-H), 7.63 (t, 1H, 6Ј-H), 7.27 (s,
1H, N-H). Ð MS (EI, 70 eV): m/z (%) = 369
(34)[M+], 305 (17), 304 (2), 277 (5), 236 (13), 178
(53), 172 (100), 150 (9), 122 (7). C17H11N3O5S
(369.35): calcd. C 55.28, H 3.00, N 11.37; found C
55.31, H 2.95, N 11.31.
Generalmethod for deprotection [14] (5a-c):
Measurement of the insulin-releasing property
In a 100 ml round bottomed flask, 0.0013 mol
of monoprotected sulfonylated benzimidazolones
were dissolved in CH3CN (5 ml). To this conc. HCl
(2.5 ml) in diethyl ether (6 ml) was added. The
mixture was stirred at 20 ∞C for 3 h and concen-
trated using a rotary evaporator and triturated
with diethyl ether to give the monosulfonylated
benzimidazolones.
To prepare a 5 mm stock solution, Ic was dis-
solved in ethyl acetate and Ia and Va were dis-
solved in methanol. Measurement of insulin secre-
tion was performed by static incubation of ca. 0.5 ¥
106 insulin-secreting cells of the INS-1 permanent
tissue culture cell line in 12-well dishes. The incu-
bation medium was a Krebs-Ringer buffer con-
taining 5 mm glucose. After incubation for 1 h at
37∞ C, 500 µl of the incubation medium were aspi-
rated from each well and centrifuged to pellet as-
pirated cells. The insulin content in the superna-
tant was determined by a sandwich ELISA
according to the instruction of the manufacturer
(Mercodia AB, Uppsala, Sweden).
2,3-Dihydro-1-(4-tolylsulfonyl)-1H-benzimidazol-
2-one (5a):
M. p. = 208Ð210∞ C (lit. 198Ð200∞ C [14]);
yield = 81%. Ð IR (KBr, cmÐ1): ν = 3166, 2975,
˜
1771, 1760, 1389, 1340, 1190, 1152, 888. Ð 1H NMR
Acknowledgements
(CDCl3):
Ն = 9.87 (s, 1H, N-H), 7.98 (d, 2H, 2Ј/6Ј-
R. Ahmad wants to thank DAAD for a short-
term revisit scholarship to carry out part of the
work in Germany. This work has been performed
within the project “Biologically Active Natural
Products: Synthetic Diversity“ and was supported
by the Deutsche Forschungsgemeinschaft. Finan-
cial support of the Fonds der Chemischen In-
dustrie is also acknowledged.
H, J2ЈÐ6Ј = 2.1 Hz, J2ЈÐ3Ј = 8.2 Hz), 7.90 (d, 1H, 7-
H, J7Ð6 = 8.0 Hz), 7.28 (d, 2H, 3Ј/5Ј-H, J3ЈÐ2Ј = 8.1
Hz, J3ЈÐ5Ј = 2.0 Hz), 7.22Ð7.11 (m, 3H, 4/5/6-H),
2.4 (s, 3H, CH3). Ð MS (EI, 70 eV): m/z (%) =
288 (65) [M+], 224 (16), 195 (4), 155 (41), 133
(100), 105 (13), 91 (59), 77 (6), 65 (14). Ð
C14H12N2O3S (288.32): calcd. C 58.32, H 4.19, N
9.71; found C 58.22, H 4.24, N 9.72.
Brought to you by | University of California
Authenticated
Download Date | 1/15/16 10:02 AM

354
I. Ahmad et al. · N-Arylsulfonyl-benzimidazolones as Potential Hypoglycemic Agents
[1] M. Turconi, M. Nicola, M. G. Qunitero, L. Maiocchi, [10] M. R. Grimmett, in A. R. Katritzky, C. W. Rees,
R. Micheletti, E. Giraldo, A. Donetti, J. Med.
Chem. 33, 2101 (1990).
K. T. Potts (eds.): Comprehensive Heterocyclic
Chemistry, Vol. 5, 345, Pergamon Press, Oxford
(1984).
[2] H. R. Howard, R. Sarges, T. W. Siegel, T. A. Beyer,
Eur. J. Med. Chem. 27, 779 (1992).
[11] R. Ahmad, R. Jabeen, M. Zia-ul-haq, H. Nadeem,
H. Duddeck, E. J. Verspohl, Z. Naturforsch. 55B,
203 (2000).
[12] O. Kym, M. Rig, Ber. Dtsch. Chem. Ges. 48, 1675
(1915).
[3] M. Bianchi, A. Butti, S. Rossi, F. Barzaghi, V. Marc-
aria, Eur. J. Med. Chem.-Chim. Ther. 18, 495, 501
(1983).
[4] H. Hara, T. Maruyama, M. Saito, M. Takeuchi, T.
Mase, Eur. Pat. 454330, Apr. 12, (1991); Chem. [13] G. Heller, A. Siller, J. Prakt. Chem. 9, 116 (1927).
Abstr. 72, 55348.
[14] N. A. Meanwell, Y. S. Sing, J. Gao, H. S. Wong, Q.
Gao, R. Denis, S. Laurent, N. Balasubramanian, J.
Org. Chem. 60, 1565 (1995).
[15] U. Panten, M. Schwanstecher, C. Schwanstecher,
Exp. Clin. Endocrinol. Diab. 104, 1 (1996).
[16] S. Umemoto, A. Kobayashi, Y. Nakamura, Yaku-
gaku Zasshi 89, 1545 (1969); Chem. Abstr. 72,
55348.
[5] M. C. McKay, S. I. Dworetzky, N. A. Meanwell, S-P.
Olesen, P. H. Reinhart, I. B. Levitan, J. P. Adelman,
V. K. Gribkoff, J. Neurophysiol. 71, 1873 (1994).
[6] R. L. Clark, A. A. Pessolano, J. Am. Chem. Soc. 80,
1657 (1958).
[7] J. B. Wright, Chem. Rev. 48, 397 (1951).
[8] P. N. Preston, Chem. Rev. 74, 279 (1974).
[9] D. M. Smith, in P. M. Preston (ed.). Chemistry of
Heterocyclic Compounds, Vol. 40, Part I, p. 331. Wi-
ley Interscience, New York (1981).
Brought to you by | University of California
Authenticated
Download Date | 1/15/16 10:02 AM