Chiral aryl sulfonyl hydantoins as hypoglycemic agents

Article abstract of DOI:10.1515/znb-2000-0212

Some novel chiral sulfonyl hydantoin derivatives 2a-e and 3a-e have been prepared. p-Toluenesulfonyl chloride on treatment with L-amino acids in presence of K₂CO₃/H₂O yielded N-(p-toluensulfonyl-)amino acids 1a-e which were cyclized in presence of NH₄SCN / Ac₂O to afford 1-(p-toluenesulfonyl)-5-substituted-2-thiohydantoins 2a-e. These compounds were oxidized with HNO₃ to yield 1-(p-toluenesulfonyl)-5-substituted hydantoins 3a-e. The enantiomeric ratios of 3a-e were determined by ¹H NMR spectroscopy using Eu(hfc)₃. The antidiabetic activity of 3a-d has been determined.

Full text of DOI:10.1515/znb-2000-0212

Chiral Aryl Sulfonyl Hydantoins as Hypoglycemic Agents
Roshan Ahm ad3*, Rukhsana Jabeen3, M ohammad Zia-ul-H aq3,
Humaira Nadeem3 Helmut D uddeckb, and Eugen J. Verspohl0
a Department of Chemistry, Quaid-I-Azam University Islamabad, Islamabad, Pakistan
b Institute of Organic Chemistry, Hannover University, Schneiderberg 1B,
D-30167 Hannover, Germany
c Institute of Pharmaceutical Chemistry, University of Münster. Hittorfstr. 58-62,
D-48149 Münster, Germany
Reprint request to Prof. Dr. Roshan Ahmad. E-mail: roshan@hudson.sdnpk.undp.org
Z. Naturforsch. 55b, 203-207 (2000); received September 2, 1999
Hydantoins, Antidiabetic Activity, NMR Data
Some novel chiral sulfonyl hydantoin derivatives 2a-e and 3a-e have been prepared.
p-Toluenesulfonyl chloride on treatment with L-amino acids in presence of K2C 0 3/H20
yielded /V-(/7-toluensulfonyl-)amino acids la -e which were cyclized in presence of NH4SCN /
Ac20 to afford l-(p-toluenesulfonyl)-5-substituted-2-thiohydantoins 2a-e. These compounds
were oxidized with H N 0 3 to yield l-(p-toluenesulfonyl)-5-substituted hydantoins 3a-e. The
enantiomeric ratios of 3a-e were determined by 'H NMR spectroscopy using Eu(hfc)3. The
antidiabetic activity of 3a-d has been determined.
cally pure amino acids. The spectroscopy of the
Introduction
interm ediate compounds and the final products is
discussed. The enantiom eric ratios of compounds
3 a -e have been determ ined by 'H NM R method
using lanthanide shift reagent Eu(hfc)3. The anti-
diabetic activity of compounds 3 a -e is also re-
ported.
Besides biguanides and a-glucosidase inhibitors
another class of oral hypoglycemic agents is seen
in the m arket, the sulfonylureas. Tolbutamide, Gli-
benclamide, and Tolazamide are im portant drugs
used for the treatm ent of non-insulin dependent
diabetes mellitus. During the last two decades, lit-
erature is overloaded with the synthesis and anti-
diabetic activity of many acyclic aryl heterocyclic
sulfonyl ureas. Little attention has been paid to
cyclic urea derivatives.
Results and Discussion
Syntheses
Many researchers concentrated their attention
to the synthesis of sulfonyl hydantoin derivatives
[1-3]. It was proved that the arylsulfonyl group at
1-position of hydantoins greatly effects the physi-
All the desired compounds la - e to 3 a -e were
synthesized using standard methods. N -(p-tolu-
enesulfonyl) amino acids l a - e were successfully
prepared in 82-85% yield starting from /?-tolu-
ochemical properties and intestinal absorption of enesulfonyl chloride and the respective L-amino
the drugs, and they are much more active than
those where the 3-position is substituted by aryl-
sulfonyl group [4], A num ber of aryl/heteroaryl
sulfonyl hydantoin derivatives were prepared and
tested against aldose reductase inhibitor and for
acid [5, 6]. Surprisingly, only the NM R data of lc
have been reported before [6b, 6c] so that we in-
clude them in the Experim ental Part. Novel thio-
hydantoin derivatives 2a - e were obtained under
anhydrous conditions in 77-79% yield by treating
treatm ent of glucose and galactose induced cata- the sulfonyl amino acids l a - e with NH 4SCN in
ract. The synthesis of 3-arylsulfonyl hydantoins by
coupling of corresponding sulfonyl chlorides with
substituted hydantoins has been reported which
the presence of acetic anhydride and pyridine
(Scheme 1) [7], The NM R data (Experimental
Part) meet the expectations; the assignment of C-
on rearrangem ent in the presence of sodium hy- 2 and C-4 is based on well-known strong deshield-
dride lead to 1-sulfonyl derivatives [5]. In the pre- ings of thiocarbonyl carbons. On treatm ent with
sent work we report the synthesis of chiral 1-p-
toluenesulfonyl hydantoins starting from the opti-
50% (w/v) nitric acid, 2 a -e were transformed into
the corresponding novel (except 3d [8]) hydantoin
0932-0776/2000/0200-0203 $06.00 © 2000 Verlag der Zeitschrift für Naturforschung, Tübingen • www.znaturforsch.com
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204
R. Ahm ad et al. ■Chiral Aryl Sulfonyl Hvdantoins as Hypoglycemic Agents
COOH
/ /
ff
H,C
<'
^ — s —CI
+
h 2n
o
NH4SCN
Ac20/Py
H,C-
2a-2e
a: R = H
b: R = CH3‘
c: R = CH,1Ph
d: R = CHr(CH2’)2
e: R = CH1'CH2(CH,3’),
below 100 °C and the reaction time should not ex-
derivatives 3 a -e in 69-75% yield (Scheme 1) [7a],
Purification was mainly achieved by recrystalliza- ceed 2.5 hours to avoid total racemization.
tion using methanol or ethanol/w ater mixture.
NMR spectra of various hydantoin derivatives
have been reported, and the dependence of NM R
parameters on various structural features were dis-
cussed [7a, 8, 9].
Antidiabetic activity
INS-1 cells were grown in plastic culture or
microwells for 4 -6 days (half confluence: 1 -2 x
106 cells m l“1) in RPMI medium supplemented
with 10% (v/v) fetal calf serum, 100 U of pencillin
m l-1 and 0.1 mg of streptomycin m l-1. Prior to the
experim ent cells were washed and incubated in
Krebs-Ringer containing 10 mM HEPES and
0.5% bovine serum albumin (KRBH). To measure
insulin secretion, half-confluent cells in microwells
were incubated for 90 min at 37 °C in the afore-
m entioned KRBH buffer. Insulin released into the
medium was assayed with a radioimmunoassay
using rat insulin (Novo Nordisk, Denmark) as a
Determination o f the enantiomeric ratio o f the
hydantoin derivatives 3 a -e using 1H N M R
spectroscopy in the presence o f a chiral
lanthanide shift reagent
The enantiomeric ratio of compounds 3 a -e was
determined by 'H NMR using the lanthanide shift
reagent Eu(hfc)3 (Aldrich). In most cases, ratios
were found to be 70-76 : 30-34 although enantio-
merically pure amino acids have been employed.
It turned out that the tem perature during the nit- standard, porcin insulin as the labelled compound
ric acid reaction (2 to 3) has to be kept carefully [(m ono-,25I-Tyr A 14)-porcine insulin; Hoechst,
Table I. Effects of various compounds (3a-d ) on insulin release from INS-1 cells in the presence of 5.6 mM glucose.
The low glucose concentration (0.3 mM) and glibenclamide (= glyburide) served as negative and positive controls.
INS-1 cells in multiwells were washed three times and incubated in KRBH-buffer for 90 minutes. The results are
expressed as % secreted insulin at 5.6 mM glucose alone. Each value represents the mean (x) ± S. E. M. of experi-
ments (n).
Glucose
3 mM
Glucose
5.6 mM
3c
IO"3 M
3d
1 0 4 M
Glibenclamide
10~3 M
none
none
3a
IO’ 4 M
3a
W~-
3b
10 4 M
3b
10“3 M
3c
10-4 M
3d
10~? M
M
92.60
4
268.4
4
X
n
66.97
5
100.00
141.98
4
118.75
6
89.51
4
30.11
6
59.50
4
46.40
4
181.00
4
6
14.27
44.87
7.150
0
26.78
20.04
7.560
2.282
32.63
8.460
6.480
S. E M
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R. Ahm ad et al. • Chiral Aryl Sulfonyl Hydantoins as Hypoglycemic Agents
N-(p-ToluenesulphonyI)alanine (lb)
M.p. 133 °C (lit. 132-133 °C [5]).
83%. - 'H NM R (CD 3OD): <3 = 1.30 (d, H -l'),
2.40 (s, A r-CH 3), 3.90 (q, H-2), 5.10 (bs, NH), 7.35
(d, H-3"), 7.75 (d, H-2"). - 13C NM R (CD ,O D ):
Ö = 19.4 (C -l') 21.4 (A r-CH 3), 52.6 (C-2), 127.9
(C-2"), 130.6 (C-3"), 139.0 (C-l"), 144.6 (C-4"),
Germany] and insulin antibodies from Linco
(U. S. A.).
-
Yield
Com pounds 3a -d were dissolved in ethanol and
tested for their antidiabetic activity in the presence
of 5.6 mM glucose (Table I). It can be stated that
compounds 3b and 3d possessed a clear inhibitory
effect on insulin release at either 10-4 or 10~3 M
concentration and thus showed no antidiabetic ac-
tivity while compounds 3a and 3c exhibited antidi-
abetic activity only at lower concentrations. How-
ever, it requires further confirmatory evidence
from in vivo studies in animal experiments in or-
der to ascertain their margin of safety and free-
dom from undesireable toxic manifestation on vi-
tal functions in the host.
175.3 (C -l).
-
EI-MS, C 10H 13NO 4S (243), m /z
(% ): 243 (M +, 2), 242 (1), 199 (5), 198 (87), 189
(5),183 (3), 178 (5),155 (71), 106 (5), 96 (5), 91
(100), 79 (6). - [ct]P89 = -3.8° (MeOH).
N-(p-ToluenesulphonyI)phenylalanine (lc)
M.p. 134 °C (lit. 134-135 °C [5]).
-
Yield
83%. - !H NM R (CD 3OD): ö = 2.40 (s, Ar-CH3),
2.85 and 3.05 (each dd, 2 H -l'), 4.00 (t, H-2), 4.90
(bs, NH), 7.00-7.30 (m, Ph), 7.35 (d, H-3")), 7.75
(d, H-2"). - EI-MS, C 16H 17N 0 4S (319), m /z (%):
319 (M +, 1), 274 (5), 228 (10), 227 (1), 173 (10),
164 (2), 157 (3), 155 (48), 149 (3), 148 (25), 147
(3), 118 (5), 117 (4), 91 (100), 90 (3), 77 (6), 65
(21). - [a]P89 = +63.9° (MeOH).
Experim ental
The melting points were determ ined on a Gal-
lenkam p digital melting point apparatus MFB-
595-010M and are uncorrected. !H and 13C NMR
spectra were recorded on a Bruker AM-400 in-
strum ent (*H: 400.1 MHz and 13C: 100.6 MHz),
and mass spectra on a Varian MAT CH-5 spec-
trom eter. Solvents are noted in the Experimental
Part. All chemical shifts are referenced to TMS.
Optical rotations were determ ined on Jasco J-20A
autom atic recording spectropolarimeter.
N-(p-ToluenesulphonyI)valine (Id)
M.p. 147 °C (lit. 147 °C [5]). - Yield 82%. - lU
NM R (CD 3OD): <5 = 0.87 and 0.95 (each d, 2 H-
2'), 2.40 (s, A r-CH 3), 2.50 (m, H -l'), 3.65 (d, H-2),
4.95 (bs, NH), 7.35 (d, H-3"), 7.75 (d, H-2"). - EI-
MS, C 12H 17N 0 4S (271), m /z (% ): 271 (M+, 2), 228
(6), 227 (7), 226 (49), 173 (7), 157 (6), 156 (8), 155
(62),139 (5), 92 (19), 91 (100). - [a]?89 = +59°
(MeOH).
General m ethod for the preparation o f
N -(p-toluenesulphonyl) amino acids la - e
An equim olar mixture of potassium carbonate
(0.01 mol) and an a-am ino acid (0.01 mol) in water
(50 ml) was heated at 60 °C for 30 minutes. To this
mixture was added p-toluenesulphonyl chloride
(0.01 mol) in dioxane (20 ml). The mixture was
heated under reflux for 30 minutes. A fter cooling
to room tem perature the resultant solution was
acidified with 2 N hydrochloric acid to a pH = 1 -
2. The precipitates obtained were filtered, washed
with w ater and recrystallised from methanol.
N-(p-Toluenesulphonyl)leucine (le)
M.p. 125 °C (lit. 121-122 °C [5]).
-
Yield
82%. - 'H NM R (CD 3OD): (3 = 0.75 and 0.95
(each d, 2 H -3'), 1.45 (ddd, H -2'), 2.40 (s, Ar-
CH 3), 1.75 (m, H -l'), 3.80 (t, H-2), 4.95 (bs, NH),
7.35 (d, H-3"), 7.75 (d, H-2").
-
EI-MS,
C13H 19N 0 4S (285), m /z (% ): 285 (M+, 2), 279 (1),
242 (3), 241 (8), 229 (5), 184 (14), 171 (5), 157
(3),156 (6), 155 (64), 139 (4), 107 (4), 92 (14), 91
(100), 90 (4), 89 (8), 86 (8). - [a]_?89 = +21.0°
(MeOH).
N-(p-Toluenesulphonyl)glycine (la)
M.p. 147 °C (lit. 147; 149-150 °C [5]). - Yield
85%. - JH NM R (CD3OD): d = 2.40 (s, Ar- CH 3),
3.70 (s, H-2), 5.40 (bs, NH), 7.35 (d, H-3"), 7.75 (d,
H-2"). - 13C NM R (CD3OD): <5 = 21.5 (Ar-CH3),
44.7 (C-2), 128.0 (C-2"), 130.6 (C-3"), 138.2 (C-l"),
144.7 (C-4"), 172.2 (C-l). - EI-MS, C9H n N 0 4S
(229), m /z (% ): 229 (M+, 3); 225 (1), 185 (3), 184
(8), 156 (6),155 (47), 92 (18), 91 (100), 90 (3), 89
General m ethod fo r the preparation o f (p-toluene-
sulphonyl)-2-thiohydantoins 2a - e
A solution containing jY-(/?-toluenesulphonyl)-
amino acid (2 mmol), N H 4SCN (2.4 mmol) and
acetic anhydride (4 mmol) in anhydrous pyridine
(1 ml) was heated with stirring at 90 °C for 1 hour,
then cooled to room tem perature. Cold water
(50 ml) was added to the solution and the mixture
(9).
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206
was stirred for 1 h at room tem perature. The pre- z (% ): 312 (M +, 1), 260 (2), 258 (8), 256 (21), 250
R. Ahm ad et al. ■Chiral Aryl Sulfonyl Hydantoins as Hypoglycemic A gents
cipitates were filtered off, washed with water to
remove excess of pyridine and recrystallized from
EtO H : H 20 (1:1).
(3), 249 (10), 248 (44), 247 (22), 208 (5), 207 (8),
206 (58), 205 (44), 193 (8), 192 (6), 162 (6), 160
(14), 156 (3), 155 (12), 150 (27). 146 (7), 139 (10),
128 (28), 124 (37), 123 (17), 119 (6), 118 (11), 97
(9), 96 (13), 93 (6), 92 (64), 91 (100), 90 (5). 89
(10). - [ a ] i9 = +51.3° (MeOH).
l-(p-Toluenesulphonyl)-2-thiohydantoin (2a)
M.p. 270 °C. - Yield 78%. - 'H NM R (DMSO-
d6): ö = 2.40 (s, Ar-CH3), 4.80 (s, H-5), 7.5 (d, H-
l-(p -Toluenesulphonyl) -5-isobutyl-2-
thiohydantoin (2e)
3"), 8.00 (d, H-2"). 12.7 (bs, NH).
-
13C NMR
(DM SO-d6): d = 21.1 (A r-CH3), 54.1 (C-5), 128.8
and 129.5 (C-273"), 133.9 (C-l"), 145.5 (C-4"),
M.p. 226 °C. - Yield 79%. - lH NMR (acetone-
169.8 (C-4), 180.6 (C-2). - EI-MS, C 10H 10N2O 3S2 d6): (3 = 2.45 (s, Ar-CH^), 0.95-1.08 ( each d. H-
(270), m /z (%): 270 (M +, 1), 209 (4), 208 (11), 207
(57), 206 (52), 178 (8), 156 (4), 155 (5), 139 (4),
135 (7), 125 (5), 124 (9), 120 (20), 119 (5), 106 (10),
3'), 2.00-2.25 (m, H -l' and H-2'), 5.07 (dd, H-5),
7.45 (d, H-3"), 8.05 (d, H-2"). EI-MS,
C 14H 18N ,0 4S (310), m /z (%): 310 (M +, 2), 263 (5),
-
92 (12), 91 (100), 90 (4), 89 (9). C 10H 10N2O 3S2 262 (23), 261 (4), 221 (5), 220 (16), 219 (100), 207
(270): Calcd.C 44.44, H 3.70. N 10.37, S 23.70;
Found C 44.70, H 3.65, N 10.40, S 23.53%.
(23), 205 (4), 170 (4), 155 (10), 124 (29), 118 (4). -
M?89 = +32.1° (MeOH).
C 14H 18N .O ,S2 (326): Calcd. C 51.53, H 5.52, N
8.58, S 19.63; Found C 51.23, H 5.60, N 8.60, S
19.53%.
1-(p-Toluenesulphonyl)-5-m ethyl-2-thiohydantoin
(2b)
M.p. 284 °C. - Yield 78%. - >H NM R (acetone-
d6): (3 = 1.80 (d, H -l'), 2.45 (s, A r-CH 3), 5.05 (q.
General procedure for the preparation o f
1-(p-toluenesulphonyl) -2-hydantoins 3a - e
H-5), 7.45 (d, H-3"), 8.05 (d, H-2").
-
EI-MS,
To
l-(/>-toluenesulphonyl)-2-thiohydantoins
C n H 12N20 3S, (284), m /z (% ): 284 (M +, 1), 224
(4), 221 (13), 220 (75), 219 (79), 205 (3), 199 (9),
190 (3), 150 (4), 149 (4), 136 (5), 135 (14), 133 (12),
125 (5), 124 (58), 123 (7), 119 (15), 118 (9), 95 (3),
92 (15), 91 (100), 90 (6), 89 (10). - [ot]?89 = -10.6°
(MeOH). Cn H 12N ,0 3S, (284): Calcd. C 46.47, H
4.22, N 9.85, S 22.53; Found C 46.35, H 4.29, N 10.00,
S 22.39%.
(5 mmol) was added 50% (w/v) nitric acid (20 ml),
and the mixture was heated with stirring on a boil-
ing water bath for 30 minutes, and 60% (w/v) nitric
acid (10 ml) was added again. Then, the reaction
mixture was heated with stirring on a boiling water
bath for 2 hours. The resultant solution was then
cooled, evaporated and treated with ice-cooled
water. The precipitates formed were filtered,
washed successively with water, methanol and di-
chloromethane and recrystallized from ethanol /
water.
1-(p-Toluenesulphonyl)-5-benzyl-2-thiohy dantoin
(2c)
M.p. 360 °C. - Yield 77%. - XH NM R (acetone-
d6): d = 2.45 (s, A r-CH 3), 3.40 and 3.70 (each dd,
2 H -l'), 5.35 (dd, H-5), 7.05-7.35 (m, Ph), 7.46
(d. H-3"), 8.05 (d, H-2"). - EI-MS, C 17H 16N20 3S,
(360), m /z (% ): 360 (M+, 1), 298 (2), 297 (3), 296
(32), 207 (4), 206 (12), 205 (84), 204 (5), 173 (4),
171 (4), 155 (7), 150 (22), 128 (6), 124 (5), 123 (9),
118 (6), 117 (8), 92 (14), 90 (100), 89 (7). - [a]?89 =
l-(p-Toluenesulphonyl)-2-hydantoin (3a)
M.p. 268 °C. - Yield 75%. - lH NMR (acetone-
d6): (3 = 2.40 (s, A r-CH3), 4.60 (s, H-5), 7.50 (d,
H-3"), 8.00 (d, H-2"), 11.7 (bs, NH). - 13C NM R
(DM SO-d6): (3 = 21.1 (Ar-CH3), 54.2 (C-5), 127.8
(C-2"), 129.4 (C-3"), 134.8 (C-l"), 145.4 (C-4"),
152.8 (C-2), 170.2 (C-4). - EI-MS, C10H 10N 2O 4S
(254), m /z (% ): 254 (M+, 31), 253 (29), 252 (19).
251 (18), 250 (18), 190 (12). 184 (10), 172 (5), 156
(5), 155 (13), 119 (5), 91 (100). C 10H 10N2O 4S
(254): Calcd. C 47.24, H 3.93, N 11.02, S 12.59;
Found C 47.29, H 3.89, N 10.96, S 12.65%.
+ 1.4° (M eOH). C 17H 16N20 ,S 2 (360): Calcd.
56.66. H 4.44. N 7.77, S 17.77; Found C 56.36, H
4.52, N 7.67, S 17.70%.
C
l-(p-Toluenesulphonyl)-5-isopropyl-2-
thiohydantoin (2d)
M.p. 312 °C. - Yield 78%. - 'H NM R (acetone-
d6): d = 0.90 and 1.25 (each d. 2 H-2'), 2.45 (s, Ar-
C H ,). 2.85 (m. H -l'), 4.95 (d. H-5), 7.46 (d. H-3"),
l-(p-Toluenesulphonyl)-5-methyl-2-hydantoin (3b)
M.p. 254 °C. - Yield 69%. - 'H NMR (acetone-
8.05 (d. H-2"). - EI-MS. C 13H 16N20 3S2 (312), m / d6): (3 = 1.70 (d. H -l'), 2.45 (s, Ar-CH3), 4.80 (q.
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R. Ahmad et al. • Chiral Aryl Sulfonyl Hydantoins as Hypoglycemic Agents
207
H-5), 7.50 (d, H-3"), 8.00 (d, H-2"), 10.4 (bs,
NH). - 13C NMR (DM SO-d6): (3 = 17.9 (C -l'),
21.5 (Ar-CH,), 59.8 (C-5), 129.1 and 130.5 (C-2'7
3"), 136.8 (C-l"), 146.2 (C-4"), 153.0 (C-2), 172.3
(C-4). - EI-MS, C n H p N ,0 4S (268), m /z (% ): 268
(M+, 1), 205 (9), 204 (68), 190 (4), 189 (20), 155
(20), 149 (5), 146 (6), 134 (4), 133 (28), 119
(13),118 (5), 108 (5), 91 (100), 90 (5).
C n H 12N20 4S (268): Calcd. C 49.25, H 4.47, N
10.44, S 11.94; Found C 49.29, H 4.52, N 10.53,
S 11.70%.
d6): ö = 15.3 and 18.1 (C-2'), 21.5 (A r-CH 3), 31.4
(C -l'), 68.2 (C-5), 129.1 and 130.5 (C-2'73"), 136.8
(C-l"), 146.3 (C-4"), 153.2 (C-2), 170.6 (C-4). - EI-
MS, C 13H 16N20 4S (296), m /z (%): 296 (M +, 1), 254
(5), 232 (45). 191 (6), 190 (40), 189 (9), 156 (24),
155 (27), 146 (5), 139 (7), 137 (6), 118 (6), 108
(8), 100 (4),99 (36), 91 (100), 90 (8). C 17H 16N20 4S
(344): Calcd. C 59.30, H 4.65, N 8.13, S 9.30; Found
C 58.99, H 4.75. N 8.02, S 9.35%.
1-(p -Toluenesulphonyl)-5-isobutyl-2-hydantoin
(3e)
1-(p-Toluenesulphonyl) -5-benzyl-2-hydantoin (3c)
M.p. 176-177 °C. - Yield 71%. - ’H NM R (ac-
etone-d6): (3 = 0.95-1.05 (m, H-3'), 2.05-2.25 (m,
H -l72'), 2.45 (s, A r-CH 3), 4.85 (dd, H-5), 7.50 (d,
H-3"), 8.00 (d, H-2"), 13.0 (bs, NH). - 13C NMR
(DM SO-d6): ö = 21.6 (Ar-CH3), 22.2 and 23.8 (C-
3'), 24.8 (C-2'), 41.0 (C -l'), 62.49 (C-5), 129.2 and
130.6 (C-2"/3"), 136.7 (C-l"), 146.4 (C-4"), 153.3
(C-2), 172.1 (C-4). - EI-MS, C 14H 18N20 4S (310),
m /z (%): 310 (M +, 1), 255 (3), 247 (3), 203 (52),
190 (10), 155 (38), 139 (4), 127 (4), 108 (11), 107
(3), 91 (100), 90 (5), 89 (5). C 14H 18N20 4S (310).
Calcd. C 54.19, H 5.80, N 9.03, S 10.32; Found C
54.03, H 5.89, N 9.23, S 10.25%.
M.p. 344 °C. - Yield 70%. - 'H NM R (acetone-
d6): d = 2.45 (s, A r-CH3), 3.50 and 3.70 (each dd,
H -l'), 7.05-7.50 (m, Ph), 8.00 (d, H-3"), 8.30 (d,
H-2"), 10.3 (bs, NH). - 13C NM R q(DM SO-d6):
d = 21.6 (Ar-CH,), 37.1 (C -l'), 62.4 (C-5), 129.4
and 130.5 (C-2'73"), 129.5-137.40 (5 signals of Ph),
135.1 (C-l"), 146.7 (C-4"), 152.9 (C-2), 170.7 (C-
4). - EI-MS, C 17H 16N20 4S (344), m /z (% ): 344
(M+, 9), 189 (11), 155 (20), 139 (4), 127 (3), 118
(4), 117 (3), 97 (6) ,91 (100), 90 (6), 89 (6).
C 17H 16N ,0 4S (344): Calcd. C 59.30, H 4.65, N
8.13, S 9.30; Found C 58.99, H 4.75, N 8.02, S
9.35%.
A ckno wledgem ents
l-(p-Toluenesulphonyl)-5-isopropyl-2-hydantoin
(3d)
M.p. 296 °C. - Yield 72%. - ‘H NM R (acetone-
d6): ö = 0.85 and 1.30 (each d, 2 H -2'), 2.45 (s, Ar-
CH-O, 2.75 (m, H -l'), 4.75 (d, H-5), 7.50 (d, H-3"),
8.00 (d, H-2"), 10.4 (bs, NH). - 13C NM R (DMSO-
The authors are thankful to Pakistan Science
Foundation for financial assistance. This work was
supported by Deutscher Akadem ischer Austausch-
dienst and Fonds der Chemischen Industrie. They
thank Hoechst AG (Germany) for supplying
(m ono-12:T-TyrA14)-porcine insulin.
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