Synthesis and antihyperglycemic activity profiles of novel thiazolidinedione derivatives

Article abstract of DOI:10.1016/j.bmc.2004.08.031

A number of thiazolidine-2,4-diones derivatives having carboxylic ester appendage at N-3 were synthesized and their antihyperglycemic activity was evaluated. Many of these derivatives as well as their corresponding carboxylic acid showed significant impro

Full text of DOI:10.1016/j.bmc.2004.08.031

Bioorganic & Medicinal Chemistry 12 (2004) 5857–5864
Synthesis and antihyperglycemic activity profiles of novel
thiazolidinedione derivativesq
Bashir A. Bhat,a Shashikanth Ponnala,a Devi Prasad Sahu,a,* Priti Tiwari,b
Brajendra K. Tripathib and Arvind K. Srivastavab
aDivision of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226001, India
bBiochemistry Division, Central Drug Research Institute, Lucknow 226001, India
Received 23June 2004; revised 23August 2004; accepted 23August 2004
Available online 15 September 2004
Abstract—A number of thiazolidine-2,4-diones derivatives having carboxylic ester appendage at N-3were synthesized and their
antihyperglycemic activity was evaluated. Many of these derivatives as well as their corresponding carboxylic acid showed signifi-
cant improvement on post-prandial hyperglycemia in normal rats, in contrast to their poor agonist activity at PPARc.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
When recommended dietary medication and exercise fail
to control elevated blood glucose levels, pharmacologi-
cal therapy is required to restore normoglycemia, reduce
the attendant sequelae, and delay the need for insulin
therapy. Pharmacological agents, currently available or
under investigation, include drugs that improve insulin
resistance or increase insulin secretion. Metformin, a
biguanides, acts primarily by decreasing hepatic glucose
output and increasing peripheral glucose utilization.6 It
is a first line therapeutic option for Type 2 DM. Another
class of drugs, that is, sulfonylureas stimulate insulin
secretion by blocking ATP-dependent potassium
channels7 but are associated with a significant risk of
hypoglycemia. Since the pioneer thiazolidinedione
compound, ciglitazone, was reported improving blood
glucose level by increasing insulin sensitivity, several
new thiazolidine-2,4-diones such as pioglitazone, rosig-
litazone,8 were launched into market since 1997.
Diabetes mellitus, long considered a disease of minor
significance to world health, is now taking its place as
one of the main threats to human health in the 21st cen-
tury.1 The incidence of the disease currently is estimated
to reach 210 million by the year 2010 and 300 million by
the year 2025.2 Most cases will be of type 2 diabetes,
which is strongly associated with a sedentary life style
and obesity.3 Early stages of type 2 diabetes mellitus
(Type 2 DM) are characterized by tissue resistance to
the effects of insulin secreted by pancreatic beta cells.
The ability of pancreatic beta cells to continue increased
production of insulin diminishes over time. When insu-
lin production declines in the face of insulin resistance,
glucose disposal from the muscle is diminished and sup-
pression of hepatic glucose output is decreased. The dis-
ease is often associated with obesity, dyslipidemia, and
hypertension leading to cardiovascular risks.4 The
macrovascular (atherosclerotic) complications of Type
2 DM are less closely linked to hyperglycemia but con-
tribute to substantial morbidity. The large vessel compli-
cations directly result from the altered metabolic milieu
in Type 2 DM.5
Thiazolidinedione derivatives though effective therapeu-
tic agents some of them have been reported to have
hepatotoxicity.9 There exist the need for efficient anti-
diabetic agents devoid of hepatotoxicity.
We were interested in developing a series of thiazolidine-
2,4-diones having carboxylic ester appendage at N-3and
benzyl and heteroaryl substituents at C-5, which might
surmount the hepatic toxicity encountered with the
some of the glitazones. Epalrestat, a 5-cinnamylidene-
2-thioxo-4-thiazolidinone N-acetic acid derivative is
the only aldose reductase inhibitor available currently
Keywords: Antihyperglycemic activity; Thiazolidinedione; Diabetes;
SLM; PPARc.
q CDRI Communication No 6534.
*
Corresponding author. Tel.: +91 522 2212411 18 4378; fax: +91 522
223405/223938; e-mail: dpsahu@rediffmail.com
0968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.08.031

5858
B. A. Bhat et al. / Bioorg. Med. Chem. 12 (2004) 5857–5864
on the market, which is devoid of hepatic toxicity.10 The
aldose reductase inhibitory activity of 5-benzylidenethi-
azolidine-2,4-dione-3-acetic acid is found to be higher
than that of N-unsubstituted analogues.11 N-Carboalk-
oxymethylthiazolidine-2,4-diones (A) was selected as
core structure with substituted benzylidene and benzyl
and heteroaryl derivatives of (A) were synthesized and
their hypoglycemic activity were evaluated. We present
herein the hypoglycemic activity evaluated SLM (su-
crose-loaded model) in mice.
presented in Table 1 with reference to rosiglitazone
and metformin.
Following pattern of hypoglycemic activity of the syn-
thesized compounds was observed. The 5-arylmethyl
thiazolidine-2,4-diones with various substituents dis-
played higher hypoglycemic activity than their corre-
sponding precursor 5-arylidenethiazolidine-2,4-dione
derivative. Surprisingly the ethyl ester of thiazolidine-
2,4-dione-3-acetic acid 4a exhibited higher antihyper-
glycemic activity (À26.7) than the corresponding methyl
ester 6 (À9.5). The 5-(2-indolylmethylene)thiazolidine-
2,4-dione 3h and 5-(2-pyrrolylmethylene)thiazolidine-
2,4-dione 3i displayed hyperglycemic activity in contrast
to marginal hypoglycemic activity shown by 5-benzylid-
enethiazolidine-2,4-dione derivatives.
2. Chemistry
The synthetic protocol of thiazolidinedione derivatives
presented here is shown in Scheme 1. N-Alkylation of
thiazolidine-2,4-dione 1 with alkyl bromoacetate fur-
nished alkyl 2,4-dioxothiazolidin-3-ylacetate 2, which
on Knoevenagel condensation with various aromatic
aldehydes yielded 5-arylidene-2,4-thiazolidinedione
derivative 3. Catalytic hydrogenation of 3 afforded satu-
rated thiazolidinedione 4. Compound 3a is then alkyl-
ated with various alkylating agents to give 7.
Compounds 3, 5, 7, 9, and 11a were hydrogenated to
furnish 4, 6, 8, 10, and 12.
Correlation of electronic influence of the substituents on
aryl group of thiazolidine-2,4-dione with the antihyper-
glycemic activity could not be well established as substit-
uents such as methyl, methoxy, chloro, hydroxy, acetoxy
at 3- or 4-position on the phenyl ring showed higher
antihyperglycemic activity, where as trifluoromethyl,
dimethylamino, substituent on the same position in phe-
nyl ring exhibited low to moderate antihyperglycemic
activity. As indicated in Table 1, compound 4a and 10
having hydroxy and acetoxy substituent, 5-benzylthiaz-
olidine-2,4-dione-3-acetic acid ethyl ester exhibited high-
er antihyperglycemic activity (À26.7 and À26.8,
respectively). The activity of rosiglitazone and metfor-
min were found to be À11.6 and À34.1, respectively.
3. Results and discussion
The synthesized compounds were screened for anti-
hyperglycemic activity in vivo by sucrose-loaded
model (mice) and in vitro by PPARc activation. The
marketed, rosiglitazone and metformin were selected
as positive control. The activity of all compounds is
There is moderate increase of hypoglycemic activity of
thiazolidine-2,4-dione N-acetic acid (11d,e,g, and 12)
O
O
O
O
O
c
b
a
R
R
NH
NCH2CO2Et
NCH2CO2Et
NCH2CO2Et
S
S
S
S
O
1
O
2
O
3
4
R= Different aryls as shown in table 1.
O
O
d
c
NCH2CO2Me
NCH2CO2Et
NCH2CO2Me
3a
3a
S
S
S
HO
HO
6
O
5
O
O
O
e
c
NCH2CO2Et
S
R1O
R1O
O
O
O
7
8
R1= Different substitutions on compound 3a as shown in table 1.
O
f
c
3a
NCH2CO2Et
NCH2CO2Et
S
S
AcO
AcO
g
10
O
O
9
O
O
O
c
3a, 3d, 3e, 3g
R
12
NCH2CO2H
NCH2CO2H
S
S
HO
O
11
11a
Scheme 1. Reagents: (a) NaH, ethyl bromoacetate, THF; (b) different aldehyde, CH3CO2H, pipyridine, toluene; (c) H2–Pd/C, dioxane; (d) H2SO4,
MeOH; (e) XR1, K2CO3, DMF; (f) triethylamine, dichloromethane, AcCl, (g) AcOH, HCl.

B. A. Bhat et al. / Bioorg. Med. Chem. 12 (2004) 5857–5864
5859
Table 1. Antihyperglycemic activity profile of title compounds thiazolidine-2,4-dione derivatives
O
O
Z
R
N
OX
S
A
O
Entry
Compd
R
Z
X
Antihyperglycemic activity, SLM
PPARc
10nmola
1000nmol
Standard
Standard
Rosiglitazone
Metformin
À11.6
92
248
À34.1*
1
2
3a
3b
Double bond
Double bond
–CH2CH3
–CH2CH3
+2.84b
HO
À3.30c
10
11
11
11
F C
3
3
3c
Double bond
–CH2CH3
À2.69
O N
2
4
5
3d
3e
Double bond
Double bond
–CH2CH3
–CH2CH3
À22.1
À22.2
9
7
9
8
Me
MeO
6
7
3f
Double bond
Double bond
–CH2CH3
–CH2CH3
À5.71
À15.8
3g
Me N
2
8
3h
3i
3j
Double bond
Double bond
Double bond
–CH2CH3
–CH2CH3
–CH2CH3
+1.52
+9.00
À23.2
N
H
9
N
H
10
9
8
Cl
11
12
13
3k
4a
4b
Double bond
Single bond
Single bond
–CH2CH3
–CH2CH3
–CH2CH3
À6.80
F
À26.7*
10
12
HO
À12.39
À3.12
11
F C
3
14
4c
Single bond
–CH2CH3
H N
2
15
16
4d
5
Single bond
–CH2CH3
–CH3
À12.7
À2.46
8
10
12
H N
2
Double bond
10
HO
HO
17
18
6
Single bond
–CH3
À9.55
9
11
14
7b
Double bond
–CH2CH3
+3.07
11
Br(H2C)2O
19
7c
Double bond
–CH2CH3
À1.59
H3C(H2C)3O
(continued on next page)

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B. A. Bhat et al. / Bioorg. Med. Chem. 12 (2004) 5857–5864
Table 1 (continued)
Entry
20
Compd
R
Z
X
Antihyperglycemic activity, SLM
PPARc
1000nmol
10nmola
8a
Single bond
–CH2CH3
À14.1
O
21
22
8b
9
Single bond
–CH2CH3
–CH2CH3
À8.28
12
13
Br(H2C)2O
O
O
Double bond
+7.55
O
O
23
24
25
26
27
10
Single bond
Double bond
Double bond
Double bond
Single bond
–CH2CH3
À26.8*
À26.1*
À33.4*
À15.5
11d
11e
11g
12
H
H
H
H
Me
MeO
Me N
2
À18.3
HO
*Significant p < 0.05.
a Concn in nanomolar.
b + indicates further increase in blood glucose.
c
À indicates decrease blood glucose.
compared to corresponding ester, which may be ration-
alized by assumption of the acids being the active prin-
ciple rather than the respective esters.
O
O
O
NH
NH
N
N
S
S
S
PhCH2O
N
O
O
O
rosiglitazone
In contrast to antihyperglycemic activity exhibited in
vivo by the compounds 3d,e,g,i, 4a,b,d, 8a, and 10 com-
parable or higher than rosiglitazone, these ligands have
poor agonist activity at PPARc in vitro estimated at 10
and 1000nmol concentration (Table 1). The thiazolidine-
dione, netiglitezone undergoing phase-II clinical trials
was reported to have poor potency at PPARc in vitro
than rosiglitazone.12,13 NC-210014 and some of the
(D5-unsaturated) thiazolidinedione 1315 (Chart 1) are
reported to have low or no activity at PPARc but have
high antidiabetic activity in vivo. These reports corro-
borate our observation presented herein, which raise
the possibility that some thiazolidinediones mediate
their antidiabetic activity through a mechanism other
than PPARc.
NC-2100
O
N
F
N
NH
NH
S
O
O
O
O
netoglitazone
13
NH
NH
Me2N
N
NH2
H
metformin
Chart 1.
5. Experimental
5.1. Biology
4. Conclusion
Male albino rats of Charles Foster strain of average
body weight 160 20g were selected for this study.
The blood glucose of each animal was checked after
16h starvation using glucose strips (Boehringer Mann-
heim, Germany). Animals showing blood glucose be-
tween 60 and 80mg/dl (3.33 and 4.44mM) were finally
selected and divided into groups of five to six animals
in each. Rats of experimental group were administered
suspension of the desired compound orally (made in
1.0% gum acacia) at 100mg/kg-body weight. Animals
of control group were given an equal amount of 1.0%
The antihyperglycemic activity of 5-arylidenethiazolid-
ine-2,4-dione-3-acetic acid ester, 5-arylmethylthiazol-
idine-2,4-dione-3-acetic acid ester and some of the corre-
sponding acids were evaluated by SLM model. The
2,4-dioxo-5-(4-hydroxybenzyl)thiazolidin-3-ylacetic acid
ester and its O-acylated derivatives showed comparable
or higher antihyperglycemic activity than that of rosig-
litazone and metformin, though they have poor PPARc
agonist activity. In the corresponding acids there is mar-
ginal enhancement of antihyperglycemic activity.

B. A. Bhat et al. / Bioorg. Med. Chem. 12 (2004) 5857–5864
5861
gum acacia. A sucrose load (2.0g/kg) was given to each
animal orally exactly after 30min post-administration of
the test sample/vehicle. Blood glucose profile of each rat
was again determined at 30, 60, 90, and 120min post-
administration by glucose strips. Food but not water
was withheld from the cages during the course of exper-
imentation. Quantitative glucose tolerance of each ani-
mal was calculated by Area under curve method.
Comparing the AUC of experimental and control
groups determined the percentage antihyperglycemic
activity. Pairwise comparison was done by the one-tailed
StudentÕs t test. Probability values p < 0.05 were consid-
ered to be statistically significant. All results are ex-
pressed as the mean SEM (n = 6), and the sample
size, n, represents the number of individual strips of
ileum assayed.
322 (M+H)+; Anal. Calcd for C15H15NO5S: C, 56.06;
H, 4.70; N, 4.36; S, 9.98. Found: C, 56.40; H, 4.47; N,
3.92.
5.2.2. [5-(4-Hydroxy-benzylidene)-2,4-dioxo-thiazolidin-
3-yl]-acetic acid ethyl ester (3a). Yellow solid mp 160–
162ꢁC; IR (KBr) m 3452, 2996, 2367, 1727, 1669, 1578,
1
1505, 1381, 1213, 1144cmÀ1; H NMR (CDCl3) d 1.17
(t, J = 7.12Hz, 3H, CH3), 4.11 (q, J = 7.12Hz, 2H,
CH2), 4.35 (s, 2H, CH2), 6.86 (d, J = 6.6Hz, 2H,
ArH), 7.46 (d, J = 6.6Hz, 2H, ArH), 7.68 (s, 1H, CH);
MS-FAB m/z: 308 (M+H)+; Anal. Calcd for
C14H13NO5S: C, 54.71; H, 4.26; N, 4.56; S, 9.71. Found:
C, 54.76; H, 4.22; N, 4.60.
5.2.3. [2,4-Dioxo-5-(4-trifluoromethyl-benzylidene)-thiaz-
olidin-3-yl]-acetic acid ethyl ester (3b). Mp 155–157ꢁC;
5.1.1. PPARc transactivation assay. Cells are transfected
with an expression plasmid for PPARc receptors and
the ability of these to activate a luciferase gene is meas-
ured. Day one, human embryonic kidney (HEK) 293
cells grown in DMEM was inoculated in 96-well elisa
plate 20,000 cells are added in each well. Day two, cells
were infected with PPARc expression plasmid. FuGene
transfaction reagent (Boehringer Mannheim) is used for
the transfactions. Day three, after transfaction the
media is aspirated and media containing the ligand
(drug) is added to the cells the concentration of the
ligand are 10 and 1000nm. Day four, approximately
48h after transfaction the cells are harvested and
assayed for expression of relevant gene. Luciferase is
measured on luminescence counting instrument. Renilla
assay is done to count the total number of cells; rosiglit-
azone is taken as standard compound.
IR (KBr)
m
3416, 2997, 1741, 1686, 1325,
;
1163, 1112cmÀ1
1H NMR (CDCl3)
d 1.30 (t,
J = 7.2Hz, 3H, CH3), 4.25 (q, J = 7.2Hz, 2H, CH2),
4.49 (s, 2H, CH2), 7.62 (d, J = 8.4Hz, 2H, ArH), 7.74
(d, J = 8.4Hz, 2H, ArH), 7.93(s, 1H, C H); MS-FAB
m/z: 360 (M+H)+; Anal. Calcd for C15H12F3NO4S: C,
50.14; H, 3.37; F, 15.86; N, 3.90; S, 8.92.
5.2.4.
[5-(3-Nitro-benzylidene)-2,4-dioxo-thiazolidin-3-
yl]-acetic acid ethyl ester (3c). Mp 134–136ꢁC; IR
(KBr) m 3415, 2996, 1737, 1690, 1381, 1347, 1231cmÀ1
;
1H NMR (CDCl3) d 1.32 (t, J = 7.2Hz, 3H, CH3),
4.26 (q, J = 7.2Hz, 2H, CH2), 4.5 (s, 2H, CH2), 7.6 (t,
J = 8Hz, 1H, ArH), 7.84 (d, J = 8Hz, 1H, ArH), 7.96
(s, 1H, CH), 8.29 (d, J = 8Hz, 1H, ArH), 8.37 (s, 1H,
ArH); MS-FAB m/z: 337 (M+H)+; Anal Calcd for
C14H12N2O6S: C, 50.00; H, 3.60; N, 8.33; S, 9.53.
Found: C, 50.40; H, 3.23; N, 8.71.
5.2. Chemistry
5.2.5. [5-(4-Methyl-benzylidene)-2,4-dioxo-thiazolidin-3-
yl]-acetic acid ethyl ester (3d). Mp 119–121ꢁC; IR
(KBr) m 3464, 2991, 1735, 1683, 1599, 1407, 1382,
Melting points were determined on a capillary melting
point apparatus and are uncorrected. 1H NMR
and 13C NMR spectra were recorded in the indicated
solvent on Bruker WM 200MHz spectrometer with
TMS as internal standard. Infrared spectra were
recorded in KBr on Perkin–Elmer AC-1 spectrometer.
FAB mass spectra were recorded on JEOL SX 102/DA
6000 mass spectrometer. Microanalyses were performed
on Carlo Erba EA-1108 element analyzer.
1222cmÀ1 1H NMR (CDCl3) d 1.29 (t, J = 7.2Hz,
;
3H, CH3), 2.40 (s, 3H, CH3), 4.24 (q, J = 7.2Hz, 2H,
CH2), 4.47 (s, 2H, CH2), 7.28 (d, J = 8.0Hz, 2H,
ArH), 7.41 (d, J = 8.0Hz, 2H, ArH), 7.91 (s, 1H, CH);
MS-FAB m/z: 306 (M+H)+; Anal. Calcd for
C15H15NO4S: C, 59.0; H, 4.95; N, 4.59; S, 10.50. Found:
C, 58.77; H, 5.34; N, 4.85.
5.2.1. Representative procedure for (3a–k). [5-(4-Meth-
oxy-benzylidene)-2,4-dioxo-thiazolidin-3-yl]-acetic acid
ethyl ester (3e). To a solution of 4-methoxybenzaldehyde
(0.34g, 2.5mmol) and 2,4-thiazolidinedione acetic acid
ethyl ester 2 (0.507g, 2.5mmol) in toluene (5mL), three
drops of piperidine and two drops of acetic acid were
added. The mixture was refluxed for 10h, cooled to
ambient temp and evaporated at reduced pressure. The
solid residue was extracted twice with hot methanol
(10mL each) and was filtrated to furnish 3e (0.62g,
80%). Mp 129–131ꢁC; IR (KBr) m 3445, 2987, 2317,
5.2.6.
acid ethyl ester (3f). Mp 75–77ꢁC; IR (KBr) m 3435,
2991, 2367, 1742, 1685, 1606, 1405, 1219, 1152cmÀ1
(5-Benzylidene-2,4-dioxo-thiazolidin-3-yl)-acetic
;
1H NMR (CDCl3) d 1.29 (t, J = 7.2Hz, 3H, CH3),
4.23(q, J = 7.2Hz, 2H, CH2), 4.47 (s, 2H, CH2), 7.48
(m, 5H, ArH), 7.92 (s, 1H, CH); MS-FAB m/z: 292
(M+H)+; Anal. Calcd for C14H13NO4S: C, 57.72; H,
4.50; N, 4.81; S, 11.01. Found: C, 58.11; H, 4.86; N,
4.47.
5.2.7. [5-(4-Dimethylamino-benzylidene)-2,4-dioxo-thiaz-
olidin-3-yl]-acetic acid ethyl ester (3g). Mp 170–171ꢁC;
IR (KBr) m 3385, 2946, 2363, 1735, 1676, 1589, 1531,
1744, 1689, 1596, 1512, 1382, 1259, 1156cmÀ1 1H
;
NMR (CDCl3) d 1.29 (t, J = 7.2Hz, 3H, CH3), 3.86 (s,
3H, CH3), 4.24 (q, J = 7.2Hz, 2H, CH2), 4.46 (s, 2H,
CH2), 6.99 (d, J = 8.6Hz, 2H, ArH), 7.46 (d,
J = 8.6Hz, 2H, ArH), 7.88 (s, 1H, CH); MS-FAB m/z:
1377, 1220cmÀ1
; d 1.30 (t,
1H NMR (CDCl3)
J = 7.0Hz, 3H, CH3), 3.05 (s, 6H, –(CH3)2), 4.23(q,
J = 7.0Hz, 2H, CH2), 4.45 (s, 2H, CH2), 6.71 (d,

5862
B. A. Bhat et al. / Bioorg. Med. Chem. 12 (2004) 5857–5864
J = 9Hz, 2H, ArH), 7.39 (d, J = 9Hz, 2H, ArH), 7.84 (s,
1H, CH); MS-FAB m/z: 335 (M+H)+; Anal. Calcd for
C16H18N2O4S: C, 57.47; H, 5.43; N, 8.38; S, 9.59.
Found: C, 57.90; H, 4.91; N, 7.86.
310 (M+H)+; Anal. Calcd for C14H15NO5S: C, 54.36;
H, 4.48; N, 4.53; S, 10.37. Found: C, 54.0; H, 4.93; N,
4.16.
5.2.13. [2,4-Dioxo-5-(4-trifluoromethyl-benzyl)-thiazol-
idin-3-yl]-acetic acid ethyl ester (4b). Mp 99–101ꢁC; IR
(KBr) m 3414, 2999, 2371, 1740, 1685, 1598, 1411,
5.2.8. [5-(1H-Indol-2-ylmethylene)-2,4-dioxo-thiazolidin-
3-yl]-acetic acid ethyl ester (3h). Mp 201–202ꢁC; IR
(KBr) m 3309, 2986, 2364, 1720, 1664, 1595, 1381,
1328, 1164, 1113cmÀ1 1H NMR (CDCl3) d 1.27 (t,
;
1225, 1149cmÀ1
;
1H NMR (CDCl3)
d
1.29 (t,
J = 7.2Hz, 3H, CH3), 3.19 (dd, J1 = 14Hz, J2 = 9.8Hz,
1H, CH), 3.65 (dd, J1 = 14Hz, J2 = 4Hz, 1H, CH), 4.2
(q, J = 7.2Hz, 2H, CH2), 4.3(s, 2H, C H2), 4.5 (dd,
J1 = 9.8Hz, J2 = 4Hz, 1H, CH), 7.1 (d, J1 = 8Hz, 2H,
ArH), 7.37 (d, J1 = 8Hz, 2H, ArH); MS-FAB m/z: 3 62
(M+H)+; Anal. Calcd for C15H14F3NO4S: C, 49.86; H,
3.91; F, 15.77; N, 3.88; S, 8.87.
J = 7.0Hz, 3H, CH3), 4.24 (q, J = 7.0Hz, 2H, CH2),
4.46 (s, 2H, CH2), 7.26 (br s, 4H, ArH), 7.82 (s, 1H,
CH), 8.90 (s, 1H, ArH); MS-FAB m/z: 331 (M+H)+;
Anal. Calcd for C16H14N2O4S: C, 58.17; H, 4.27; N,
8.48; S, 9.71. Found: C, 58.48; H, 4.61; N, 8.96.
5.2.9.
[2,4-Dioxo-5-(1H-pyrrol-2-ylmethylene)-thiazol-
idin-3-yl]-acetic acid ethyl ester (3i). Mp 174–176ꢁC;
5.2.14. [5-(3-Amino-benzyl)-2,4-dioxo-thiazolidin-3-yl]-
acetic acid ethyl ester (4c). Thick liq; IR (neat) m 3377,
IR (KBr) m 3343, 2989, 2362, 1729, 1681, 1604, 1376,
1223, 1141cmÀ1
;
1H NMR (CDCl3)
d
1.29 (t,
2982, 2362, 1745, 1687, 1217, 762cmÀ1 1H NMR
;
J = 7.0Hz, 3H, CH3), 4.24 (q, J = 7.0Hz, 2H, CH2),
4.46 (s, 2H, CH2), 6.44 (d, J = 3.4Hz, 1H, ArH), 6.64
(s, 1H, ArH), 7.08 (s, 1H, ArH), 7.80 (s, 1H, CH),
9.20 (bs, 1H, NH); MS-FAB m/z: 381 (M+H)+; Anal.
Calcd for C12H12N2O4S: C, 51.62; H, 4.32; N, 9.9; S,
11.44. Found: C, 51.20; H, 4.89; N, 9.46.
(CDCl3) d 1.27 (t, J = 7.2Hz, 3H, CH3), 2.93(dd,
J1 = 14Hz, J2 = 10.6Hz, 1H, CH), 3.52 (dd,
J1 = 14Hz, J2 = 3.8Hz, 1H, CH), 4.2 (q, J = 7.2Hz,
2H, CH2), 4.3(s, 2H, C H2), 4.5 (dd, J1 = 10.6Hz,
J2 = 3.8Hz, 1H, CH), 6.51 (m, 3H, ArH), 6.59 (s, 1H,
ArH); MS-FAB m/z: 309 (M+H)+; Anal. Calcd for
C14H16N2O4S: C, 54.53; H, 5.23; N, 9.08; S, 10.40.
Found: C, 54.86; H, 5.51; N, 9.55.
5.2.10. [5-(4-Chloro-benzylidene)-2,4-dioxo-thiazolidin-3-
yl]-acetic acid ethyl ester (3j). Mp 120–122ꢁC; IR (KBr)
m 3461, 2992, 1736, 1691, 1586, 1401, 1225cmÀ1
;
5.2.15. [5-(4-Amino-benzyl)-2,4-dioxo-thiazolidin-3-yl]-
acetic acid ethyl ester (4d). Mp 73–75ꢁC; IR (KBr) m
1H NMR (CDCl3) d 1.31 (t, J = 7.16Hz, 3H, CH3),
4.23(q, J = 7.16Hz, 2H, CH2), 4.47 (s, 2H, CH2), 7.46
(s, 4H, ArH), 7.88 (s, 1H, CH); MS-FAB m/z: 3 26
(M+H)+; Anal. Calcd for C14H12ClNO4S: C, 51.62; H,
3.71; Cl, 10.88; N, 4.30; S, 9.84. Found: C, 51.20; H,
4.29; N, 4.96.
3432, 2933, 2367, 1725, 1680, 1519, 1407, 1219cmÀ1
;
1H NMR (CDCl3) d 1.19 (t, J = 7.2Hz, 3H, CH3),
2.86 (dd, J1 = 13.9Hz, J2 = 10.3Hz, 1H, CH), 3.4 (dd,
J1 = 13.9Hz, J2 = 3.8Hz, 1H, CH), 4.10 (q, J = 7.2Hz,
2H, CH2), 4.21 (s, 2H, CH2), 4.38 (dd, J1 = 10.3Hz,
J2 = 3.8Hz, 1H, CH), 6.53(d, J1 = 8.2Hz, 2H, ArH),
7.1 (d, J1 = 8.2Hz, 2H, ArH); MS-FAB m/z: 3 09
(M+H)+; Anal. Calcd for C14H16N2O4S: C, 54.53; H,
5.23; N, 9.08; S, 10.40. Found: C, 54.11; H, 4.85; N,
9.43.
5.2.11. [5-(4-Fluoro-benzylidene)-2,4-dioxo-thiazolidin-3-
yl]-acetic acid ethyl ester (3k). Mp 110–112ꢁC; IR (KBr)
m 3408, 2994, 1741, 1665, 1593, 1507, 1405, 1220,
1151cmÀ1 1H NMR (CDCl3) d 1.31 (t, J = 7.2Hz,
;
3H, CH3), 4.24 (q, J = 7.2Hz, 2H, CH2), 4.47 (s, 2H,
CH2), 7.2 (m, 2H, ArH), 7.51 (m, 2H, ArH), 7.89 (s,
1H, CH); MS-FAB m/z: 310 (M+H)+; Anal. Calcd for
C14H12FNO4S: C, 54.36; H, 3.91; F, 6.14; N, 4.53; S,
10.37.
5.2.16. [5-(4-Hydroxy-benzylidene)-2,4-dioxo-thiazolidin-
3-yl]-acetic acid methyl ester (5). To the solution of [5-(4-
hydroxy-benzylidene)-2,4-dioxo-thiazolidin-3-yl]-acetic
acid ethyl ester 3a (0.921g, 3mmol) in methanol
(30mL), concd H2SO4 (0.3mL) was added and refluxed
for 16h. It was evaporated under vacuo. The solid mass
obtained was washed with water and filtered. The filter-
ate was extracted in methanol (2 · 10mL) and filtered to
yield 5 (0.856g, 93%). Mp 150–152ꢁC; IR (KBr) m 3506,
2363, 1734, 1680, 1599, 1512, 1386, 1284, 1155cmÀ1; 1H
NMR (CDCl3) d 3.69 (s, 3H, CH3), 4.39 (s, 2H, CH2),
6.87 (d, J = 8.4Hz, 2H, ArH), 7.31 (d, J = 8.4Hz,
2H, ArH), 7.77 (s, 1H, CH); MS-FAB m/z: 294
(M+H)+; Anal. Calcd for C13H11NO5S: C, 53.24; H,
3.78; N, 4.78; S, 10.93. Found: C, 53.64; H, 3.36; N,
5.13.
5.2.12. Representative procedure for (4a–d, 6a, 8a,b, 10,
and 12). [5-(4-Hydroxy-benzyl)-2,4-dioxo-thiazolidin-3-
yl]-acetic acid ethyl ester (4a). To a solution of [5-(4-hydr-
oxy-benzyl)-2,4-dioxo-thiazolidin-3-yl]-acetic acid ethyl
ester 3a (0.614g, 2mmol) in dioxane (50mL) placed in
an autoclave, palladium charcoal (10%, 0.6g) was added
and the mixture was hydrogenated at 300psi at ambient
temp with stirring for 8–10h. The product mixture was fil-
tered through bed of Celite and the filtrate was concen-
trated under vacuo to yield (0.602g, 98%). Colorless
solid mp 92–94ꢁC; IR (KBr) m 3384, 2989, 2364, 1744,
1687, 1516, 1224cmÀ1 1H NMR (CDCl3) d 1.28 (t,
;
J = 7.2Hz, 3H, CH3), 3.01 (dd, J1 = 14Hz, J2 = 10.2Hz,
1H, CH), 3.53 (dd, J1 = 14Hz, J2 = 4Hz, 1H, CH), 4.22
(q, J = 7.2Hz, 2H, CH2), 4.31 (s, 2H, CH2), 4.48 (dd,
J1 = 10.2Hz, J2 = 4Hz, 1H, CH), 6.78 (d, J1 = 8.4Hz,
2H, ArH), 7.1 (d, J1 = 8.4Hz, 2H, ArH); MS-FAB m/z:
5.2.17. [5-(4-Hydroxy-benzyl)-2,4-dioxo-thiazolidin-3-yl]-
acetic acid methyl ester (6). Mp 87–89ꢁC; IR (KBr) m
3425, 2956, 2365, 1741, 1680, 1518, 1382, 1239,
1
1164cmÀ1; H NMR (CDCl3) d 3.02 (dd, J1 = 9.5Hz,
J2 = 6.7Hz, 1H, CH), 3.49 (dd, J1 = 9.5Hz,

B. A. Bhat et al. / Bioorg. Med. Chem. 12 (2004) 5857–5864
5863
J2 = 2.6Hz, 1H, CH), 3.74 (s, 3H, CH3), 4.31 (s, 2H,
CH2), 4.47 (dd, J1 = 6.7Hz, J2 = 2.6Hz, 1H, CH), 6.76
(d, J1 = 5.6Hz, 2H, ArH), 7.06 (d, J1 = 5.6Hz, 2H,
ArH) MS-FAB m/z: 296 (M+H)+; Anal. Calcd for
C13H13NO5S: C, 52.87; H, 4.44; N, 4.74; S, 10.86.
Found: C, 52.32; H, 4.09; N, 4.66.
3.53 (dd, J1 = 14.2Hz, J2 = 4Hz, 1H, CH), 3.63 (t,
J = 6.2Hz, 2H, CH2), 4.16 (t, J = 6.2Hz, 2H, CH2),
4.25 (q, J = 7.0Hz, 2H, CH2), 4.3(s, 2H, C H2), 4.5
(dd, J1 = 10Hz, J2 = 4Hz, 1H, CH), 6.87 (d,
J1 = 8.6Hz, 2H, ArH), 7.22 (d, J1 = 8.6Hz, 2H, ArH);
MS-FAB m/z: 416 (M+H)+. Anal. Calcd for
C16H18BrNO5S: C, 46.16; H, 4.36; Br, 19.19; N, 3.36;
S, 9.84. Found: C, 46.57; H, 4.71; N, 2.93.
5.2.18. Representative procedure for (7b,c). {5-[4-(2-
Bromo-ethoxy)-benzylidene]-2,4-dioxo-thiazolidin-3-yl}-
acetic acid ethyl ester (7b). To a solution of [5-(4-hydr-
oxy-benzylidene)-2,4-dioxo-thiazolidin-3-yl]-acetic acid
ethyl ester 3a (0.614g, 2mmol) in dry DMF (30mL), an-
hyd K2CO3 (0.552g, 4mmol) and 1,2-dibromoethane
(1.87g, 10mmol) were added and the mixture was stirred
at 110–120ꢁC for 12h. The reaction mixture after cool-
ing to ambient temp was diluted with ice water (100mL)
and was extracted with CHCl3 (20 · 2mL). The com-
bined organic layer after drying over anhyd Na2SO4
was concentrated under vacuo. The crude compd thus
obtained was recrystallized from methanol (6mL) to
yield 7b (0.738g, 89%). Mp 118–120ꢁC; IR (KBr) m
3449, 2989, 2363, 1732, 1677, 1592, 1512, 1383,
5.2.22. [5-(4-Acetoxy-benzylidene)-2,4-dioxo-thiazolidin-
3-yl]-acetic acid ethyl ester (9). To a solution of [5-(4-
hydroxy-benzylidene)-2,4-dioxo-thiazolidin-3-yl]-acetic
acid ethyl ester 3a (0.767g, 2.5mmol) in CH2Cl2 (15mL)
triethylamine (0.303g, 3mmol) was added and to this
mixture, acetyl chloride (5mmol) was added while stir-
ring. The reaction mixture was further stirred for 16h
and the product mixture was concentrated in vacuo.
After usual work up the crude product thus obtained
was recrystallized from methanol to yield 9 (0.761g,
87%). Mp 139–141ꢁC; IR (KBr) m 3412, 2993, 2364,
1
1740, 1689, 1411, 1195cmÀ1; H NMR (CDCl3) d 1.29
(t, J = 7.2Hz, 3H, CH3), 2.33 (s, 3H, CH3), 4.24 (q,
J = 7.2Hz, 2H, CH2), 4.48 (s, 2H, CH2), 7.25 (d,
J = 8.6Hz, 2H, ArH), 7.54 (d, J = 8.6Hz, 2H, ArH),
7.91 (s, 1H, CH); MS-FAB m/z: 350 (M+H+); Anal.
Calcd for C16H15NO6S: C, 55.01; H, 4.33; N, 4.01; S,
9.18. Found: C, 55.58; H, 3.91; N, 3.74.
1151cmÀ1 1H NMR (CDCl3) d 1.31 (t, J = 7.2Hz,
;
3H, CH3), 3.66 (t, J = 6.2Hz, 2H, CH2), 4.22 (q,
J = 7.2Hz, 2H, CH2), 4.32 (t, J = 6.2Hz, 2H, CH2),
4.47 (s, 2H, CH2), 7.00 (d, J = 8.8Hz, 2H, ArH), 7.48
(d, J = 8.8Hz, 2H, ArH), 7.88 (s, 1H, CH); MS-FAB
m/z: 414 (M+H)+; Anal. Calcd for C16H16BrNO5S: C,
46.39; H, 3.89; Br, 19.29; N, 3.38; S, 7.74. Found: C,
46.78; H, 4.21; N, 3.84.
5.2.23. [5-(4-Acetoxy-benzyl)-2,4-dioxo-thiazolidin-3-yl]-
acetic acid ethyl ester (10). Colorless solid mp 116–
118ꢁC; IR (KBr) m 3421, 2989, 2924, 1735, 1691, 1508,
1
5.2.19. [5-(4-Butoxy-benzylidene)-2,4-dioxo-thiazolidin-3-
yl]-acetic acid ethyl ester (7c). Mp 98–100ꢁC; IR (KBr) m
3415, 2942, 1740, 1690, 1599, 1382, 1249, 1179cmÀ1; 1H
NMR (CDCl3) d 0.98 (t, J = 7.3Hz, 3H, C H3), 1.30 (t,
J = 7.2Hz, 3H, CH3), 1.48 (m, J = 7.3Hz, 2H, CH2),
1.77 (m, J = 7.3Hz, 2H, CH2), 4.02 (t, J = 7.3Hz, 2H,
CH2), 4.24 (q, J = 7.2Hz, 2H, CH2), 4.46 (s, 2H,
CH2), 6.97 (d, J = 8.6Hz, 2H, ArH), 7.45 (d,
J = 8.6Hz, 2H, ArH), 7.87 (s, 1H, CH); MS-FAB m/z:
364 (M+H)+; Anal. Calcd for C18H21NO3S: C, 59.49;
H, 5.82; N, 3.85; S, 9.71. Found: C, 58.90; H, 6.40; N,
4.40.
1411, 1377, 1227, 1160cmÀ1; H NMR (CDCl3) d 1.30
(t, J = 7.2Hz, 3H, CH3), 2.29 (s, 3H, CH3), 3.08 (dd,
J1 = 14Hz, J2 = 10.2Hz, 1H, CH), 3.63 (dd,
J1 = 14Hz, J2 = 3.8Hz, 1H, CH), 4.22 (q, J = 7.2Hz,
2H, CH2), 4.31 (s, 2H, CH2), 4.51 (dd, J1 = 10.2Hz,
J2 = 3.8Hz, 1H, CH), 7.06 (d, J = 8.4Hz, 2H, ArH),
7.25 (d, J = 8.4Hz, 2H, ArH); MS-FAB m/z: 3 52
(M+H)+; Anal. Calcd for C16H17NO6S: C, 54.69;
H, 4.88; N, 3.99; S, 9.13. Found: C, 54.14; H, 4.37; N,
4.37.
5.2.24. Representative procedure for (11a, 11d, 11e, 11g).
[5-(4-Methoxy-benzylidene)-2,4-dioxo-thiazolidin-3-yl]-
acetic acid (11e). A mixture of acetate 3e (1mmol), gla-
cial AcOH (10mL), and HCl 12N (3mL) was refluxed
for 5h. After evaporation in vacuo, the solid residue
thus obtained was washed with water and dried to give
11e (0.258g, 88%). Light yellow solid mp 214–216ꢁC; IR
(KBr) m 3425, 2836, 2364, 1685, 1595, 1510, 1380, 1258,
5.2.20. [5-(4-Isopropoxy-benzyl)-2,4-dioxo-thiazolidin-3-
yl]-acetic acid ethyl ester (8a). Mp 51–53ꢁC; IR (KBr)
m 3423, 2979, 2363, 1748, 1690, 1510, 1381, 1217,
1
758cmÀ1; H NMR (CDCl3) d 1.26 (d, J = 6.4Hz, 6H,
–(CH3)2), 1.30 (t, J = 8.0Hz, 3H, CH3), 3.01 (dd,
J1 = 14Hz, J2 = 10Hz, 1H, CH), 3.50 (dd, J1 = 14Hz,
J2 = 4Hz, 1H, CH), 4.20 (q, J = 8.0Hz, 2H, CH2),
4.29 (s, 2H, CH2), 4.45 (dd, J1 = 10Hz, J2 = 4Hz, 1H,
CH), 4.55 (m, 1H, CH), 6.83(d, J1 = 8.6Hz, 2H,
ArH), 7.13(d, J1 = 8.6Hz, 2H, ArH); MS-FAB m/z:
352 (M+H)+; Anal. Calcd for C17H21NO5S: C, 58.10;
H, 6.02; N, 3.99; S, 10.37. Found: C, 58.57; H, 6.46;
N, 3.63.
1177, 1150cmÀ1 1H NMR (CD3OD) d 3.86 (s, 3H,
;
CH3), 4.46 (s, 2H, CH2), 6.99 (d, J = 8.6Hz, 2H,
ArH), 7.46 (d, J = 8.6Hz, 2H, ArH), 7.88 (s, 1H, CH);
MS-FAB m/z: 294 (M+H)+; Anal. Calcd for
C13H11NO5S: C, 53.24; H, 3.78; N, 4.78; S, 10.93.
Found: C, 52.86; H, 4.17; N, 5.37.
5.2.25. [5-(4-Methyl-benzylidene)-2,4-dioxo-thiazolidin-3-
yl]-acetic acid (11d). Dark brick solid mp 218–220ꢁC; IR
(KBr) m 3402, 2924, 2854, 1735, 1664, 1602, 1510, 1375,
5.2.21.
{5-[4-(2-Bromo-ethoxy)-benzyl]-2,4-dioxo-thi-
azolidin-3-yl}-acetic acid ethyl ester (8b). Mp 75–77ꢁC;
1
IR (KBr) m 3422, 2993, 2365, 1736, 1686, 1513, 1232,
1238, 1148, 1089cmÀ1; H NMR (CDOD3) d 2.40 (s,
1157cmÀ1
3H, CH3), 3.04 (dd, J1 = 14.2Hz, J2 = 10Hz, 1H, CH),
;
1H NMR (CDCl3) d 1.27 (t, J = 7.0Hz,
3H, CH3), 4.47 (s, 2H, CH2), 7.28 (d, J = 8.0Hz, 2H,
ArH), 7.41 (d, J = 8.0Hz, 2H, ArH), 7.91 (s, 1H, CH);

5864
B. A. Bhat et al. / Bioorg. Med. Chem. 12 (2004) 5857–5864
MS-FAB m/z: 278 (M+H)+; Anal. Calcd for
C13H11NO4S: C, 56.31; H, 4.00; N, 5.05; S, 11.56.
Found: C, 56.86; H, 4.57; N, 5.48.
References and notes
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767–770.
5.2.26. [5-(4-Dimethylamino-benzylidene)-2,4-dioxo-thi-
azolidin-3-yl]-acetic acid (11g). Red solid mp 224–
226ꢁC; IR (KBr) m 3410, 2924, 2362, 1725, 1675,
1588, 1526, 1374, 1243, 1194, 1097cmÀ1 1H NMR
;
(CD3OD) d 3.21 (s, 6H, –(CH3)2), 4.42 (s, 2H, CH2),
7.6 (m, 4H, ArH), 7.8 (s, 1H, CH); MS-FAB m/z: 3 07
(M+H+); Anal. Calcd for C14H14N2O4S: C, 54.89;
H, 4.6; N, 9.14; S, 10.47. Found: C, 54.42; H, 5.18; N,
9.57.
5.2.27. [5-(4-Hydroxy-benzyl)-2,4-dioxo-thiazolidin-3-yl]-
acetic acid (12). Colorless solid mp 159–161ꢁC; IR
(KBr) m 3454, 2363, 1673, 1596, 1516, 1381, 1352,
1248, 1158cmÀ1
;
1H NMR (CD3OD) d 3.02 (dd,
J1 = 9.5Hz, J2 = 6.7Hz, 1H, CH), 3.49 (dd,
J1 = 9.5Hz, J2 = 2.6Hz, 1H, CH), 4.31 (s, 2H, CH2),
4.47 (dd, J1 = 6.7Hz, J2 = 2.6Hz, 1H, CH), 6.76 (d,
J1 = 5.6Hz, 2H, ArH), 7.06 (d, J1 = 5.6Hz, 2H, ArH);
MS-FAB m/z: 282 (M+H)+; Anal. Calcd for
C12H11NO5S: C, 51.24; H, 3.94; N, 4.98; S, 11.40.
Found: C, 51.68; H, 3.37; N, 5.26.
Acknowledgements
14. Fukui, Y.; Masui, S. I.; Osada, S.; Umesono, K.;
Motojima, K. Diabetes 2000, 49, 759–767.
One of us Bashir A. Bhat is thankful to CSIR for finan-
cial support, S.K.P. is thankful to ICMR for his finan-
cial support and RSIC, CDRI, Lucknow for providing
spectroscopic data.
15. Lohary, B. B.; Bhushan, V.; Reddy, A. S.; Rao, P. B.;
Reddy, N. J.; Harikishore, P.; Haritha, N.; Vikramadit-
yan, R. K.; Chakrabarati, R.; Rajagopalan, R.; Katneni,
K. J. Med. Chem. 1999, 42, 2569–2581.