Novel 5-(3-aryl-2-propynyl)-5-(arylsulfonyl)thiazolidine-2,4-diones as antihyperglycemic agents

Article abstract of DOI:10.1021/jm9706168

Novel 5-(3-aryl-2-propynyl)-5-(arylsulfonyl)thiazolidine-2,4-diones and 5-(3-aryl-2-propynyl)5-(arylsulfanyl)thiazolidine-2,4-diones were prepared and evaluated as oral antihyperglycemic agents in the obese, insulin resistant db/db mouse model at 100 mg/kg and, if the analogue had sufficient potency, 20 mg/kg. The sulfonylthiazolidinediones, 2, were more potent than the corresponding sulfanylthiazolidinedione congeners, 1. With regard to substituent effects on the 3-propynyl phenyl ring (Ar') of 2, 4-halogen substitution generally resulted in the more potent analogues. Substituent effects on the phenylsulfonyl moiety (Ar) of 2 were less clear, although para-halogen substitution on Ar generally was preferable. 2-Pyridinesulfonyl derivatives (Ar = 2-pyridine in 2) also had good potency. Several compounds from series 2 were effective at lowering glucose and insulin in the obese, insulin resistant ob/ob mouse at the 50 mg/kg oral dose. Compound 20 significantly improved the glucose tolerance of obese, insulin resistant Zucker rats at the 20 mg/kg dose level and had no effect on plasma glucose or on glucose tolerance in normal rats fasted for 18 h at the 100 mg/kg level.

Full text of DOI:10.1021/jm9706168

1084
J . Med. Chem. 1998, 41, 1084-1091
Novel 5-(3-Ar yl-2-p r op yn yl)-5-(a r ylsu lfon yl)th ia zolid in e-2,4-d ion es a s
An tih yp er glycem ic Agen ts
J ay Wrobel,* Zenan Li, Arlene Dietrich, Michael McCaleb,† Brenda Mihan, J anet Sredy,‡ and Donald Sullivan
Wyeth-Ayerst Research, Inc., CN 8000, Princeton, New J ersey 08543-8000
Received September 12, 1997
Novel 5-(3-aryl-2-propynyl)-5-(arylsulfonyl)thiazolidine-2,4-diones and 5-(3-aryl-2-propynyl)-
5-(arylsulfanyl)thiazolidine-2,4-diones were prepared and evaluated as oral antihyperglycemic
agents in the obese, insulin resistant db/db mouse model at 100 mg/kg and, if the analogue
had sufficient potency, 20 mg/kg. The sulfonylthiazolidinediones, 2, were more potent than
the corresponding sulfanylthiazolidinedione congeners, 1. With regard to substituent effects
on the 3-propynyl phenyl ring (Ar′) of 2, 4-halogen substitution generally resulted in the more
potent analogues. Substituent effects on the phenylsulfonyl moiety (Ar) of 2 were less clear,
although para-halogen substitution on Ar generally was preferable. 2-Pyridinesulfonyl
derivatives (Ar ) 2-pyridine in 2) also had good potency. Several compounds from series 2
were effective at lowering glucose and insulin in the obese, insulin resistant ob/ob mouse at
the 50 mg/kg oral dose. Compound 20 significantly improved the glucose tolerance of obese,
insulin resistant Zucker rats at the 20 mg/kg dose level and had no effect on plasma glucose
or on glucose tolerance in normal rats fasted for 18 h at the 100 mg/kg level.
In tr od u ction
name Rezulin. More recently, Boehringer Mannheim
has reported a number of R-arylsulfonyl carboxylic
acids12,13 and structurally related R-aryloxy carboxylic
acids14,15 that also normalized plasma glucose and
insulin levels in animal models of type 2 diabetes. In
addition, the R-arylsulfonylbutynoic acid BM 13.090712,13
was shown to increase glucose uptake and metabolism
in rat adipocytes and to stimulate translocation of
glucose transporters in this model. A new series of
antihyperglycaemic R-aryloxy carboxylic acids, based on
the Boehringer Mannheim work, was also recently
disclosed.16
Type 2 diabetes is a metabolic disease caused, in part,
by insulin resistance in peripheral tissues.1 In turn,
glucose metabolism is decreased in muscle and fat, and
glucose output by liver rises. The sustained, high
plasma glucose levels further result in a gradual
progression of a number of complications, including
neuropathy, nephropathy, retinopathy, and premature
atherosclerosis. Treatment of type 2 diabetes usually
consists of a regimen of diet and exercise, oral hypogly-
cemic agents, and, in severe cases, insulin. Recent
results from the Diabetes Control and Complications
Trial (DCCT) showed that intensive management to
control euglycaemia in insulin-dependent diabetes mel-
litus (type 1) correlated with a reduction in diabetic
complications.2 Proper glycaemic control is, most likely,
necessary for the control of diabetic complications in
type 2 patients, as well; however, current therapies to
reduce plasma glucose levels have inherent problems
including compliance, ineffectiveness, and occurrences
of hypoglycemic episodes with insulin and the sulfonyl-
ureas. Accordingly, there is a need for more effective,
orally administered agents,3 particularly ones that
normalize both glucose and insulin levels.
In this regard, a number of arylmethylthiazolidinedi-
one antihyperglycemic agents have been described in
the last 15 years. The prototype, ciglitazone,4,5 and
more potent congeners6-10 were active in animal models
of insulin resistance and did not induce hypoglycaemia.
Recently, troglitazone, a member of the class of aryl-
methylthiazolidinediones, has shown positive clinical
results11 and is now marketed in the US under the trade
* Please address all correspondence to this author at Wyeth-Ayerst
Research, Inc., 145 King of Prussia Road, Radnor, PA 19087.
† Present address: Amgen, Inc., 1840 DeHavilland Drive, Thousand
Oaks, CA 91320-1789.
We were intrigued by the structural similarity be-
tween BM 13.0907 and (arylsulfonyl)thiazolidinediones,
such as A,17 which also lowered plasma glucose in the
diabetic db/db mouse. Both compounds contained acidic
‡ Present address: Institute for Diabetes Discovery, 23 Business
Park Drive, Branford, Conn. 06405.
S0022-2623(97)00616-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/25/1998

Thiazolidinediones as Antihyperglycemic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1085
Sch em e 1.a Synthesis of Precursors, Methods A-H
Sch em e 2.a Synthesis of Target Compounds, Methods
I-M
a
Method I: g2 equiv of NaH/8/THF. Method J : g2 equiv of
n-BuLi/8/THF. Method K: (1) g1 equiv of NaH/8/THF. (2) TFA/
CH2Cl2. Method L: g2 equiv of NaH/8/THF. Method M: g2 equiv
of n-BuLi/8/THF.
C), oxone (method D), or MCPBA (method E). An
alternative, but generally less satisfactory, preparation
of (arylsulfonyl)thiazolidinediones 5 (method F) involved
oxidation of aryl thiols 3 with hydrogen peroxide to the
arylsulfinic acid, treatment with base to provide the
arylsulfinate, and alkylation of the sulfinate with 5-bro-
mothiazolidine-2, 4-dione. The thiazolidinedione nitro-
gen of compounds 5 could be protected with trityl
chloride to form the trityl derivatives 6 (method G).
The 3-arylprop-2-ynyl bromides 8 were prepared from
commercially available aryl iodides 7 and propargyl
alcohol using a two-step process (method H) involving
palladium/copper-catalyzed Castro-Stevens type cou-
pling followed by conversion of the 3-arylprop-2-ynyl
alcohols to the bromides 8 with PBr3.
Target compounds 1 and 2 were prepared according
to methods I-M in Scheme 2. The dianion of 4 could
be prepared using either sodium hydride (method I) or
n-butyllithium (method J ) and these dianions could be
reacted with the 3-arylprop-2-ynyl bromides 8. Alky-
lation occurred exclusively on carbon to afford the
(arylsulfanyl)thiazolidinediones 1. Similarly, the dian-
ion of 5 could be generated with either n-butyllithium
or sodium hydride (method L or M) and reacted with 8
to afford the C-alkylated product 2 exclusively. Alter-
natively, the N-protected thiazolidinediones 6 could be
alkylated with 8 using sodium hydride as base, and the
trityl protecting groups could be removed to provide the
target thiazoladinediones 2. All compounds were race-
mic, and none were resolved or synthesized enantio-
merically pure during the course of this study.
a
Method A: TMS2NLi/5-bromothiazolidine-2,4-dione/THF.
Method B: Na2CO3/5-bromothiazolidine-2,4-dione/H2O. Method
C: H2O2/HOAc/∆. Method D: oxone/MeOH. Method E: MCPBA/
CHCl3. Method F: (1) H2O2/aq NaOH/EtOH, (2) 5-bromothiazo-
lidine-2,4-dione/DMF. Method G: Ph3CCl/TEA/CH2Cl2. Method
H: (1) propargyl alcohol/(Ph3P)2Cl2Pd/CuI/Et2NH, (2) PBr3/Pyr/
Et2O.
residues adjacent to an R-arylsulfonyl moiety. However,
compound A lacked the 3-arylpropynyl chain of BM
13.0907. We envisioned that replacement of the car-
boxylic acid function of BM 13.0907 with a more
lipophilic thiazolidinedione ring would lead to com-
pounds of general structure 2 that would possibly have
enhanced bioavailability and therefore greater antidia-
betic potency. Our objective, therefore, was to find
potent analogues of 2 using an empirical structure-
activity approach. In the course of the investigation,
some of the sulfanylthiazolidinedione precursors of 2,
that is, compounds 1, were also shown to have antidia-
betic activity, and their data are also reported here.
Ch em istr y
The (arylsulfanyl)- and (arylsulfonyl)thiazolidinedi-
ones 1 and 2 were synthesized according to the methods
in Schemes 1 and 2. Precursor (arylsulfanyl)thiazo-
lidinediones 4 were best prepared from reaction of
5-bromothiazolidine-2,4-dione17 with aryl thiols 3 using
either lithium (bis)trimethylsilylamide in THF (method
A) or sodium carbonate in water (method B). Oxidation
of 4 to the (arylsulfonyl)thiazolidinediones 5 could be
accomplished using several different oxidation proce-
dures, including hydrogen peroxide/acetic acid (method
Resu lts a n d Discu ssion
The antidiabetic activity of analogues of 1 and 2 was
assessed orally in the db/db mouse,18 a model of type 2
diabetes. These mice are obese, are glucose intolerant,
and have fasting hyperglycemia sometimes accompanied

1086 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
Ta ble 1. (Arylsulfanyl)thiazolidindiones
Wrobel et al.
db/db mouse % decrease, glucoseb
synthesis
100
20
compd
Ar
Ar′
methods
formula
mp (°C)
(mg/kg/day)
(mg/kg/day)
9
4-methylphenyl
phenyl
4-fluorophenyl
2-pyridyl
2-quinolyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
A, H, I
B, H, I
B, H, I
A, H, I
A, H, I
B, H, J
A, H, J
C
C
C
C
C
C
C
19H14ClNO2S2
18H12ClNO2S2
18H11ClFNO2S2 116-117
17H11ClN2O2S2
21H13ClN2O2S2
18H11Cl2NO2S2
18H13ClN2O2S2
108-109
87-88
27
a
a
a
a
24
a
30
21
32d
nt
nt
nt
nt
nt
nt
nt
nt
nt
a
10
11
12
13
14
15
124-125
163-165
146-147
147-148
2-(6-methyl)pyridyl 4-chlorophenyl
BM 13.0907
A
ciglitazonec
a
b
Less than 15% decrease at dose tested. All values for the drug-treated groups, other than a or nt (not tested), are significant vs
vehicle-treated mice: p < 0.05. c Reference standard. Mean of 38 experiments.
d
by hyperinsulinemia.18 Traditional hypoglycemic agents,
the sulfonylureas, which exert their effect primarily
through stimulation of insulin release, are not effective
in this model, even at high doses.19 Analogues from
series 1 and 2 were evaluated for 4 days in the db/db
mouse at 100 mg/kg/day and, if sufficient potency was
seen, at 20 mg/kg/day (see Tables 1 and 2 for results).
In this assay, plasma glucose levels of the drug-treated
group were measured relative to a vehicle-treated
control group. A 50-60% decrease in the plasma
glucose levels generally is a reduction that normalizes
plasma glucose (i.e. treated animals with this decrease
have the same plasma glucose levels as nondiabetic
controls).
A quick examination of Tables 1 and 2 reveals that
the sulfonylthiazolidinediones were much more potent
as antihyperglycemic agents than the corresponding
sulfanylthiazolidinediones. Most of the compounds in
Table 1 were not effective at 100 mg/kg with the
exception of two analogues, 9 and 14, that had modest
potency. Therefore, most of our effort was directed
toward the sulfonylthiazolidinediones series in Table 2.
The reference compounds, BM 13.0907 and sulfonylthi-
azolidinedione A, were approximately equipotent to
ciglitazone in the db/db mouse (Table 1).
4-chloro compound 20. 4-Trifluoromethyl (40) and
4-trifluoromethoxy (57) also appeared to be good sub-
stituents. Disubstitution on Ar′ did not enhance po-
tency, although there were only a few examples, e.g. 3,5-
bis-CF3 49) and 3,4-difluoro (58).
Substituent effects on the phenylsulfonyl moiety (Ar)
of 2 were less clear. Generally, as previously discussed
for Ar′, 4-halogen substitution on Ar was preferable. For
example, in the Ar′ ) 4-chlorophenyl series, compounds
17 (4-F), 24 (4-Cl) and 26 (4-Br) normalized plasma
glucose at 100 mg/kg. The 4-methyl (16), 4-methoxy
(32), and 3-methyl (43) congeners were less effective,
although these analogues did have good potency at this
dose. In general, however, the substituent on Ar had
less of an impact than the same substituent on Ar′. The
substituted phenylsulfonyl compounds were also more
potent than 2-naphthylsulfonyl analogues (19 and 33).
Several 2-pyridinesulfonyl derivatives (Ar ) 2-pyri-
dine) were prepared. Two analogues in particular, 18
and 56, normalized plasma glucose at 100 mg/kg and
showed robust activity at the 20 mg/kg dose. However,
substitution of a methyl group onto the 6-position of the
pyridine ring (61) greatly diminished potency. Like-
wise, the 2-quinoline derivative 60 was not nearly as
effective as the two 2-pyridine analogues.
The compounds in Table 2 varied mostly in the
substituents attached to the phenyl rings of Ar and Ar′,
although there were several congeners where Ar was a
pyridyl group. More than 80% of the analogues in Table
2 showed a statistically significant drop in plasma
glucose at the 100 mg/kg dose, and almost one-half of
the compounds normalized glucose at this dose. Ap-
proximately one-fifth of the analogues showed a statisti-
cally significant glucose drop at the 20 mg/kg dose.
With regard to substituent effects on the 3-propynyl
phenyl ring (Ar′), 4-halogen substitution generally
resulted in the more potent analogues. For example,
examination of the phenylsulfonyl series (Ar ) phenyl),
4-halophenyl analogues, 20 (4-Cl), 27 (4-F), and 36 (4-
Br) normalized plasma glucose, while 21 (unsubsti-
tuted), 29 (4-methyl) and 45 (4-methoxy) were much less
potent. The position of the halogen on the phenyl ring
was also crucial since 2-chloro and 3-chloro analogues
(46 and 50, respectively) had less activity than the
Several of the more potent compounds from series 2
were further evaluated in another diabetic model, the
genetically obese hyperglycemic ob/ob mouse.18 This
model exhibits many of the metabolic abnormalities of
type 2 diabetes including obesity, hyperglycemia, ab-
normal insulin secretion, hyperinsulinemia, and insulin
resistance. The analogues from series 2 were admin-
istered orally for 4 days at 50 or 100 mg/kg/day (see
Table 3). In this assay, plasma glucose and insulin
levels of the drug-treated group were measured relative
to a vehicle-treated control group. A 40-60% decrease
in plasma glucose levels and a 70-90% decrease in
plasma insulin levels were equivalent to the levels of
nondiabetic animals. As in the previous model, the
(arylsulfonyl)thiazolidinediones outperformed the refer-
ence standards, ciglitazone and BM 13.907. The four
analogues tested at the 50 mg/kg dose showed a robust
response at lowering both glucose and insulin levels.
Compounds 24 (Ar ) 4-chlorophenyl, Ar′ ) 4-chlorophe-

Thiazolidinediones as Antihyperglycemic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1087
Ta ble 2. (Arylsulfonyl)thiazolidinediones
db/db mouse % decrease, glucoseb
synthesis
methods
100
20
compd
Ar
Ar′
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
phenyl
phenyl
phenyl
4-chlorophenyl
phenyl
4-chlorophenyl
4-fluorophenyl
4-fluorophenyl
4-methylphenyl
4-methylphenyl
phenyl
formula
mp (°C)
(mg/kg/day)
(mg/kg/day)
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
4-methylphenyl
4-fluorophenyl
2-pyridyl
A, C, G, H, K
A, C, H, L
A, E, H, L
A, C, H, L
B, D, H, L
B, D, H, L
A, C, H, L
B, C, H, L
B, C, H, L
B, C, H, L
B, D, H, L
B, D, H, L
A, C, H, L
A, C, H, L
A, C, H, L
B, D, H, L
B, D, H, L
A, C, H, L
B, D, H, L
A, C, H, L
B, D, H, L
A, C, H, L
A, C, H, L
B, D, H, L
B, D, H, L
B, C, H, L
B, C, H, L
B, D, H, L
A, C, H, L
B, D, H, L
B, D, H, L
A, C, H, L
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
19H14ClNO4S2
18H11ClFNO4S2
17H11ClN2O4S2
22H14ClNO4S2
18H12ClNO4S2
18H13NO4S2
172-174
176-177
140-141
190-191
92-93
35
79
55
20
52
a
43
36
70
26
69
58
65
a
28
43
45
24
21
36
53
a
51
48
59
57
54
33
30
25
a
30
54
22
a
70
68
52
37
64
67
56
33
a
nt
31
38
nt
21
nt
23
nt
18
nt
a
a
a
nt
nt
a
2-naphthyl
phenyl
phenyl
130-131
143-145
144-146
172-173
135-141
171-175
171-172
154-156
168-169
195-196
172-176
134-136
174-177
142-143
78-80
4-methylphenyl
4-chlorophenyl
4-chlorophenyl
4-fluorophenyl
4-bromophenyl
phenyl
4-methylphenyl
phenyl
4-methylphenyl
4-bromophenyl
4-methoxyphenyl 4-chlorophenyl
2-naphthyl phenyl
4-methoxyphenyl phenyl
4-methylphenyl
phenyl
4-methylphenyl
4-methylphenyl
3-methylphenyl
phenyl
4-fluorophenyl
4-chlorophenyl
3-methylphenyl
4-methylphenyl
phenyl
19H15NO4S2
18H12ClNO4S2
18H11Cl2NO4S2
18H12FNO4S2
18H11BrClNO4S2
18H12FNO4S2
19H14FNO4S2
19H15NO4S2
20H17NO4S2
18H12BrNO4S2
19H14ClNO5S2
22H15NO4S2
a
nt
nt
a
19H15NO5S2
4-(trifluoromethyl)phenyl
20H14F3NO4S2
18H12BrNO4S2
20H17NO5S2
19H14BrNO4S2
19H15NO4S2
4-bromophenyl
4-methoxyphenyl
4-bromophenyl
phenyl
4-(trifluoromethyl)phenyl
4-fluorophenyl
4-fluorophenyl
4-chlorophenyl
3-chlorophenyl
4-methoxyphenyl
2-chlorophenyl
2-chlorophenyl
81-83
a
80-82
nt
23
a
a
25
a
nt
nt
nt
nt
nt
21
nt
nt
a
a
a
nt
a
36
a
nt
nt
a
a
a
161-162
128-130
19H12F3NO4S2‚0.53H2O 80-81
18H11F2NO4S2
18H11ClFNO4S2
19H14ClNO4S2
19H14ClNO4S2
19H15NO5S2‚0.71H2O
18H12ClNO4S2
19H14ClNO4S2
20H11F6NO4S2
21H13F6NO4S2
18H12ClNO4S2
18H11BrFNO4S2
18H11BrClNO4S2
19H11F4NO4S2
19H11ClF3NO4S2
18H11BrFNO4S2
17H11FN2O4S2
19H11F4NO5S2
18H10F3NO4S2
19H14FNO4S3
177-181
171-173
136-138
70-72
161-162
162-163
160-161
226-229
207-209
107-108
155-157
160-161
143-145
144-145
186-188
92-94
133-135
130-133
74-76
191-192
104-106
150-152
phenyl
4-methylphenyl
phenyl
4-methylphenyl
phenyl
4-fluorophenyl
4-chlorophenyl
4-fluorophenyl
4-chlorophenyl
4-bromophenyl
2-pyridyl
4-fluorophenyl
4-fluorophenyl
4-fluorophenyl
2-quinolyl
3,5-bis(trifluoromethyl)phenyl B, D, H, L
3,5-bis(trifluoromethyl)phenyl A, C, H, L
3-chlorophenyl
4-bromophenyl
4-bromophenyl
4-(trifluoromethyl)phenyl
4-(trifluoromethyl)phenyl
4-fluorophenyl
B, D, H, L
B, C, H, L
B, D, H, L
B, C, H, L
B, D, H, L
B, D, H, L
A, E, H, L
B, C, H, L
B, C, H, L
B, C, H, L
F, H, L
4-fluorophenyl
4-(trifluoromethoxy)phenyl
3,4-difluorophenyl
4-(methylthio)phenyl
4-chlorophenyl
21H13ClN2O4S2
18H13ClN2O4S2
19H10F6N2O4S2
nt
a
nt
6-methyl-2-pyridyl 4-chlorophenyl
2-pyridyl
F, H, M
3,5-bis(trifluoromethyl)phenyl A, E, H, M
a
b
Less than 15% decrease at dose tested. All values from drug-treated mice, other than a or nt (not tested), are significant vs vehicle-
treated mice: p < 0.05.
Ta ble 3
resistance, the obese Zucker rat. Compound 20 signifi-
cantly improved the glucose tolerance of these animals
at the 20 mg/kg dose level (Figure 1). Furthermore, 20
at 100 mg/kg had no effect on plasma glucose nor on
glucose tolerance in normal rats fasted for 18 h (data
not shown).
4 day ob/ob mouse
dose
(mg/kg/day)
% decrease,
% decrease,
insulinb
compd
glucoseb
20
24
26
28
56
100
50
50
50
50
40
47
36
30
44
a
65
56
69
30
54
54
39
In summary, novel 5-(3-aryl-2-propynyl)-5-(arylsul-
fonyl)thiazolidine-2,4-diones and 5-(3-aryl-2-propynyl)-
5-(arylsulfanyl)thiazolidine-2,4-diones were evaluated
as antihyperglycemic agents. Three different animal
models of insulin resistance were used in this evalua-
tion. Half of the sulfonylthiazolidinediones (2) prepared
normalized plasma glucose at the 100 mg/kg dose in the
obese, insulin resistant db/db mouse model, and these
analogues were more potent than the corresponding
sulfanylthiazolidinedione congeners (1). Several com-
pounds from series 2 were also effective at lowering
glucose and insulin in the obese, insulin resistant ob/
BM 13.0907
50
100
ciglitazonec
43
a
b
Less than 15% decrease at dose tested. All values from drug
treated-mice, other than a, are significant vs vehicle-treated mice:
p < 0.05. c Reference standard.
nyl) and 56 (Ar ) 2-pyridyl, Ar′) 4-fluorophenyl) caused
a near normalization of these levels.
Compound 20 (Ar ) phenyl, Ar′) 4-chlorophenyl) was
further evaluated in a third animal model of insulin

1088 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
Wrobel et al.
After 30 min the reaction mixture was warmed to room
temperature. After an additional 3 h, 10% HCl was added to
pH ) 1. The layers were separated, and the aqueous phase
was extracted with ethyl acetate (2 × 500 mL). The combined
organic phase was washed with water (500 mL) and brine (500
mL), dried (MgSO4), and concentrated to provide the title
compound as a green solid (30.45 g, 93%): mp 118-120 °C;
NMR (DMSO-d6) δ 12.35 (s, 1H, NH), 8.39 (d, J ) 5.3 Hz, 1H,
PyrH), 7.69 (dd, J ) 7.3, 8.3 Hz, 1H, PryH), 7.42 (d, J ) 8.3
Hz, 1H, PyrH), 7.19 (dd, J ) 5.3,7.3 Hz, 1H, PyrH), 6.31 (s,
1H, CH); MS (EI) 226 (MI, 12), 155 (10), 79 (100). Anal.
(C8H6N2O2S2) C, H, N.
Meth od B. 5-(4-F lu or op h en ylsu lfa n yl)th ia zolid in e-
2,4-d ion e (4, Ar ) 4-F lu or op h en yl). 5-Bromothiazolidine-
2,4-dione17 (15.0 g, 76.5 mmol) was added to a 0 °C, mechani-
F igu r e 1. Effect of 20 on SCGTT in fasted Zucker rats.
Compounds (po, 4 days) or vehicle (2% Tween 80/saline) were
administered 1 h prior to a subcutaneous administration of
D-glucose. Blood samples were collected from the tail tip of
unanesthetized rats, and plasma glucose levels were deter-
mined by an Abbott VP analyzer. N ) 5 rats per group. *p <
0.05 vs vehicle group using Dunnett’s two-tailed t-test.
cally stirred solution of 4-fluorothiophenol [(3, Ar
)
4-fluorophenyl), 9.8 g, 76.5 mmol], sodium carbonate (27.75
g, 262 mmol) and water (120 mL). After 16 h, the reaction
mixture was diluted with water (500 mL), acidified with
concentrated HCl to pH ) 1 and filtered. The resultant solid
was washed with water and petroleum ether and dried in
vacuo to provide the title compound as a white solid (14.05 g,
75%): mp 99-100 °C; NMR (DMSO-d6) δ 12.14 (s, 1H, NH),
7.66 (t, J ) 8.0 Hz, 2H, ArH), 7.29 (t, J ) 8.5 Hz, 2H, ArH),
6.05 (s, 1H, CH); MS (EI) 243 (MI, 100), 200 (30), 128 (60),
127 (50). Anal. (C9H6FNO2S2) C, H, N.
ob mouse. One compound (20) was tested in the obese
Zucker rat and was active at 20 mg/kg. Finally, these
compounds appear to ameliorate insulin resistance and
normalize plasma glucose levels but have little or no
effect on plasma glucose in normal rodents.
Meth od C. 5-(4-F lu or op h en ylsu lfon yl)th ia zolid in e-
2,4-d ion e, (5, Ar ) 4-F lu or op h en yl). A 30% hydrogen
peroxide solution (50.4 mL, 0.489 mol) was added dropwise
over a 1 h, 20 min period to a mechanically stirred solution of
5-(4-fluorophenylsulfanyl)thiazolidine-2,4-dione [(4, Ar ) 4-flu-
orophenyl), 11.9 g, 48.9 mmol] in glacial acetic acid (457 mL)
at 60 °C. After an additional 3 h, the reaction mixture was
cooled to ambient temperatures and concentrated. The residue
was partitioned between water and ethyl acetate. The ethyl
acetate layer was dried (MgSO4) and concentrated to provide
the title compound as a white solid (10.9 g, 81%): mp 190-
196 °C; NMR (DMSO-d6) δ 12.78 (broad s, 1H, NH) 8.00 (m,
2H, ArH), 7.58 (t, J ) 8.9 Hz, 2H, ArH), 6.70 (s, 1H, CH); MS
(CI) 276 (M + H, 100). Anal. (C9H6FNO4S2) C, H, N.
Meth od D. 5-(Ben zen esu lfon yl)th ia zolid in e-2,4-d ion e,
(5, Ar ) P h en yl). A solution of 5-(benzenesulfanyl)thiazoli-
dine-2,4-dione [(4, Ar ) phenyl), 10.0 g, 41.8 mmol] in
methanol (105 mL) was added to a mechanically stirred
suspension of oxone (51.4 g, 83.6 mmol) in water (210 mL) at
0 °C. The suspension was immediately warmed to room
temperature. After 3.5 h, the reaction was diluted with water
(1.5 L) and the solid was filtered. The solid was washed with
water and dried in vacuo to provide the title compound as a
white solid (8.31 g, 73%): mp 130-133 °C; NMR (CDCl3) δ
8.07 (s, 1H, NH), 7.98 (d, J ) 7.2 Hz, 2H, ArH), 7.78 (t, J )
7.5 Hz, 1H, ArH), 7.67 (t, J ) 8.1 Hz, 2H, ArH), 5.44 (s, 1H
CH); MS (EI) 225 (MI, 24), 182 (18), 153 (12), 110 (100).
Meth od E. 5-(P yr id in e-2-su lfon yl)th ia zolid in e-2,4-d i-
on e (5, Ar ) 2-P yr id yl). m-Chloroperbenzoic acid (25.7 g,
146 mmol) was added portionwise over 30 min to a stirred
suspension of 5-(pyridine-2-sulfanyl)thiazolidine-2,4-dione [(4,
Ar ) 2-pyridyl), 15.0 g, 66.3 mmol] in chloroform (600 mL) at
room temperature. After 18 h, more m-chloroperbenzoic acid
(4.65 g, 26.4 mmol) was added, and the reaction mixture was
stirred an additional 6 h. The reaction mixture was cooled in
an ice bath, and the resultant solid (18.7 g) was filtered. A
10 g portion of the resultant solid was purified by flash
chromatography (9:1 CH2Cl2:acetonitrile) to provide the title
compound as a white solid (4.18 g, 46%): mp 129-131 °C;
NMR (DMSO-d6) δ 12.00 (broad s, 1H, NH), 8.85 (d, J ) 4.0
Hz, 1H, PyrH), 8.23 (dd, J ) 6.1, 7.9 Hz, 1H, PyrH), 8.12 (d,
J ) 7.9 Hz, 1H, PyrH), 7.85 (dd, J ) 4.0, 6.1 Hz, 1H, PyrH),
6.79 (s, 1H, CH); MS (EI) 258 (MI, 8), 215 (55), 123 (22), 78
(100).
Exp er im en ta l Section
Ch em istr y. Melting points were determined on an Elec-
trothermal capillary melting point apparatus and are not
corrected. Proton magnetic resonance (1H NMR) spectra were
recorded at 200 (Varian XL-200), 300 (VXR-300), or at 400
MHz (Bruker AM-400 or VXR-400). Infrared spectra were
obtained on either a Beckman Accu Lab 2 or a Perkin-Elmer
model 781 spectrophotometer as KBr pellets, as thin films on
sodium chloride plates, or as solutions in chloroform and are
reported as reciprocal centimeters (cm-1). Electron impact (EI,
IE ) 70 eV) and chemical ionization (CI, isobutane reagent
gas) mass spectra were recorded on a Finnigan model 8230
spectrometer. Fast atom bombardment (FAB) were recorded
on a Kratos MS50. Analyses (C, H, N) were carried out on a
modified Perkin-Elmer model 240 CHN analyzer. Analytical
results for elements were within ( 0.4% of the theoretical
values. Flash chromatography was carried out according to
the procedure of Still.20 Thin layer analyses were done on E.
Merck silica gel 60 F-254 plates of 0.25 mm thickness.
2-Methyl-6-mercaptopyridine was prepared according to the
procedure of Dunn et al.21 All commercial reagents and
solvents were used as received unless otherwise noted.
Meth od A. 5-(Tolu en e-4-su lfa n yl)th ia zolid in e-2,4-d i-
on e (4, Ar ) 4-Meth ylp h en yl). To a solution of 5-bro-
mothiazolidine-2,4-dione17 (5.0 g, 25.5 mmol) and p-thiocresol
[(3, Ar ) 4-methylphenyl), 3.17 g, 25.5 mmol] in dry THF (200
mL) at -78 °C was added lithium bis(trimethylsilyl)amide (1.0
M in hexanes, 56 mL, 56 mmol) dropwise. After 30 min the
reaction mixture was warmed to room temperature. After an
additional hour, 2 N HCl was added to pH ) 1. The layers
were separated, and the aqueous phase was extracted with
ethyl acetate (3 × 300 mL). The combined organic phase was
dried (MgSO4), concentrated, and flash chromatographed (3:2
petroleum ether:ethyl acetate) to provide the title compound
as a white solid (4.4 g, 72%): mp 124-126 °C; NMR (CDCl3)
δ 8.08 (s, 1H, NH), 7.48 (d, J ) 8.7 Hz, 2H, ArH), 7.18 (d, J )
8.7 Hz, 2H, ArH), 5.32 (s, 1H, CH); MS (EI) 239 (MI, 90), 196
(18), 123 (100).
Meth od A. 5-(P yr id in e-2-su lfa n yl)th ia zolid in e-2,4-d i-
on e (4, Ar ) 2-P yr id yl). To a solution of 5-bromothiazolidine-
2,4-dione17 (28.24 g, 0.144 mol) and 2-mercaptopyridine [(3,
Ar ) 2-pyridyl), 16.0 g, 0.144 mol] in dry THF (200 mL) at
-78 °C was added lithium bis(trimethylsilyl)amide (1.0 M in
hexanes, 317 mL, 0.317 mol) dropwise over a 40 min period.
Meth od F . 5-(Qu in olin e-2-su lfon yl)th ia zolid in e-2,4-
d ion e, (5, Ar ) 2-Qu in olyl). A 30% aqueous hydrogen
peroxide solution (10 0.7 mL, 104 mmol) was added dropwise
to a stirred solution of 2-quinolinethiol [(3, Ar ) 2-quinolyl),

Thiazolidinediones as Antihyperglycemic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1089
8.0 g, 49.6 mmol] in 2.5% aqueous NaOH (229 mL) and ethanol
(229 mL). After 1 h the reaction mixture was concentrated to
provide a white solid (8.34 g) which contained mainly sodium
2-naphthalenesulfinate. A 7.0 g portion of this compound
(e32.5 mmol) was added to a solution of 5-bromothiazolidine-
2,4-dione17 (6.38 g, 32.5 mmol) in dry DMF (53 mL), and the
resultant solution was stirred at room temperature for 4 h.
The DMF was removed in vacuo, and water (400 mL) was
added to the residue. The water phase was extracted with
ethyl acetate (2 × 400 mL), and the combined ethyl acetate
phase was dried (brine) and concentrated. The crude product
was flash chromatographed (gradient: 98:2 to 97:3 CH2Cl2:
2-propanol) to provide the title compound as a yellow solid (1.1
g, 9%): mp 168-169 °C; NMR (DMSO-d6) δ 12.9 (broad s, 1H,
NH), 8.85 (d, J ) 8.8 Hz, 1H, ArH), 8.24 (d, J ) 8.1 Hz, 1H,
ArH), 8.16 (d, J ) 8.7 Hz, 2H, ArH), 8.02 (dd, J ) 6.9, 8.3 Hz,
1H, ArH), 7.89 (dd, J ) 6.9, 8.1 Hz, 1H, ArH), 6.95 (s, 1H,
CH); MS (EI) 308 (MI, 10), 265 (8), 145 (18), 129 (100), 128
(75). Anal. (C12H8N2O4S2) C, H, N.
(1.25 g, 38%): mp 108-109 °C; NMR (DMSO-d6) δ 12.27 (s,
1H, NH), 7.46 (d, J ) 8.5 Hz, 2H, ArH, Ar′H), 7.39 (d, J ) 8.7
Hz, 1H, Ar′H), 7.27 (d, J ) 7.9 Hz, 1H, ArH), 3.48 (d, J ) 17.3
Hz, 1H, CH2), 3.32 (d, J ) 17.3 Hz, 1H, CH2), 2.34 (s, 3H, CH3);
MS (EI) 387 (MI, 5), 389 (2), 124 (85), 91 (100). Anal. Calcd
for C19H14ClNO2S2: C, H, N.
Met h od J . 5-[3-(4-Ch lor op h en yl)p r op -2-yn yl]-5-(4-
ch lor op h en ylsu lfa n yl)th ia zolid in e-2,4-d ion e (14). n-Bu-
tyllithium (2.5 M in hexanes, 12.3 mL, 30.8 mmol) was added
to a solution of 5-(4-chlorophenylsulfanyl)thiazolidine-2,4-dione
[(4, Ar ) 4-chlorophenyl), 4.0 g, 15.4 mmol] in dry THF (195
mL) at -78 °C under a dry N2 atmosphere over a 40 min
period. After an additional 30 min, a solution of [3-(4-
chlorophenyl)prop-2-ynyl] bromide [(8, Ar′ ) 4-chlorophenyl),
3.53 g, 15.4 mmol] in dry THF (65 mL) was added over a 12
min period. After 10 min, the reaction mixture was allowed
to warm to room temperature. After 2 h, the reaction mixture
was added to saturated aqueous ammonium chloride (1 L) and
extracted with ethyl acetate (800 mL). The extracts were dried
(brine), concentrated, and purified by flash chromatography
(4:1 petroleum ether:ethyl acetate) to provide the title com-
pound as a white solid (2.58 g, 41%): mp 144-146 °C: NMR
(DMSO-d6) δ 12.37 (s, 1H, NH), 7.59 (d, J ) 8.5 Hz, 2H, ArH),
7.56 (d, J ) 8.7 Hz, 2H, ArH), 7.46 (d, J ) 8.5 Hz, 2H, Ar′H),
7.40 (d, J ) 8.3 Hz, 2H, Ar′H), 3.52 (d, J ) 17.3 Hz, 1H, CH2),
3.35 (d, J ) 17.3 Hz, 1H, CH2); MS (EI) 407, 409, 411 (MI, 5),
364, 366 (8), 264 (30), 193 (40), 149 (100), 143 (20). Anal. Calcd
for C18H11Cl2NO2S2: C, H, N.
Meth od G. N-(Tr ip h en ylm eth yl)-5-(tolu en e-4-su lfo-
n yl)t h ia zolid in e-2,4-d ion e, (6, Ar ) 4-Met h ylp h en yl).
Triphenylmethyl chloride (2.67 g, 9.58 mmol) was added to a
stirred, room-temperature solution of 5-(toluene-4-sulfonyl)-
thiazolidine-2,4-dione [(5, Ar ) 4-methylphenyl), 1.30 g, 4.79
mmol], triethylamine (0.67 mL, 4.79 mmol), and dichlo-
romethane (6.5 mL). After 1 h, water (300 mL) was added
and the organic material was extracted with ethyl acetate (2
× 200 mL). The combined extracts were dried (brine, MgSO4),
concentrated, and purified by flash chromatography (4:1
petroleum ether:ethyl acetate) to provide the title compound
as a white solid (1.1 g, 45%): mp 105-110 °C; NMR (CDCl3)
δ 7.85 (d, J ) 8.3 Hz, 2H, ArH), 7.48 (d, J ) 8.1 Hz, 6H,
CPh3H), 7.38 (d, J ) 8.3 Hz, 2H, ArH),7.23 (m, 9H, CPh3H),
5.13 (s, 1H, CH), 2.46 (s, 3H, CH3).
Meth od H. [3-(4-Ch lor op h en yl)p r op -2-yn yl]Br om id e
(8, Ar ′ ) 4-Ch lor op h en yl). A suspension of p-iodochloroben-
zene [(7, Ar′ ) 4-chlorophenyl), 7.15 g, 30.0 mmol], propargyl
alcohol (1.75 mL, 30 mmol), dichlorobis(triphenylphosphine)-
palladium(II) (0.21 g, 0.3 mmol), copper(I) iodide (29 mg, 0.15
mmol), and diethylamine (50 mL) was stirred under a N2
atmosphere at room temperature, and dissolution occurred
within 20 min. After 5 h, the diethylamine was removed, and
the crude product was partitioned between water and ether.
The ether phase was dried (brine), concentrated, and flash
chromatographed (4:1 petroleum ether:ethyl acetate) to provide
3-(4-chlorophenyl)prop-2-yn-ol (4.09 g, 82%). This compound
(3.47 g, 20.83 mmol) was suspended in dry ether (12 mL), and
pyridine (0.42 mL) was added. The reaction mixture was
cooled in an ice bath, and a solution of phosphorus tribromide
(1.0 mL, 10.42 mmol) in dry ether (6 mL) was added dropwise
over a 15 min period. The reaction mixture was then stirred
at room temperature for 2.5 h and cooled in an ice bath, and
crushed ice was added. The reaction mixture was added to
water (200 mL) and extracted with ether (200 mL). The ether
phase was washed with water, saturated aqueous NaHCO3,
and brine. The extract was concentrated and purified by flash
chromatography (9:1 petroleum ether:ethyl acetate) to provide
the title compound as a white solid (3.38 g, 86%): mp 41-43
°C; NMR (CDCl3) δ 7.37 (d, J ) 8.7 Hz, 2H, ArH), 7.27 (d, J )
8.7 Hz, 2H, ArH), 4.16 (s, 2H, CH2).
Meth od K. 5-[3-(4-Ch lor op h en yl)p r op -2-yn yl]-5-(tolu -
en e-4-su lfon yl)th ia zolid in e-2,4-d ion e (16). Sodium hy-
dride (80% dispersion in mineral oil, 93 mg, 3.10 mmol) was
added to a solution of N-(triphenylmethyl)-5-(toluene-4-sulfo-
nyl)thiazolidine-2,4-dione [(6, Ar ) 4-methylphenyl), 1.06 g,
2.07 mmol] in dry DMF (9 mL) at 0 °C under a dry N2
atmosphere. After 20 min, [3-(4-chlorophenyl)prop-2-ynyl]
bromide [(8, Ar′ ) 4-chlorophenyl), 0.52 g, 2.27 mmol] was
added, and the reaction mixture was stirred an additional 20
min at 0 °C. Saturated aqueous NH4Cl (60 mL) was added,
followed by water (60 mL). After 10 min of stirring, the solid
was filtered, washed with water, and triturated with petro-
leum ether to provide N-(triphenylmethyl)-5-[3-(4-chlorophe-
nyl)prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione as
a gray solid (1.16 g, 90%): mp 221-223 °C; NMR (CDCl3) δ
7.80 (d, J ) 8.2 Hz, 2H, ArH), 7.45 (d, J ) 7.5 Hz, 6H, CPh3H),
7.35 (d, J ) 8.2 Hz, 2H, ArH), 7.14 (m, 11H, Ar′H, CPh3H),
6.98 (d, J ) 8.5 Hz, 2H, Ar′H), 3.29 (d, J ) 16.7 Hz, 1H, CH2),
3.12 (d, J ) 16.7 Hz, 1H, CH2), 2.46 (s, 3H, CH3). Trifluoro-
acetic acid (0.32 mL, 4.07 mmol) was added to a room
temperature, stirred suspension of this compound (1.29 g, 1.94
mmol) in CH2Cl2 (2 mL). Dissolution occurred immediately.
After 1 h, the reaction mixture was added to water (200 mL)
and extracted with ethyl acetate (200 mL). The ethyl acetate
phase was washed with water and brine and then concen-
trated. The crude product was purified by flash chromatog-
raphy (95:5 CH2Cl2:2-propanol) and then triturated in petro-
leum ether to provide the title compound as a off-white solid
(0.52 g, 64%): mp 172-174 °C; NMR (CDCl3) δ 8.00 (s, 1H,
NH) 7.85 (d, J ) 8.3 Hz, 2H, ArH), 7.41 (d, J ) 8.3 Hz, 2H,
ArH), 7.26 (s, 4H, Ar′H), 3.65 (d, J ) 17.1 Hz, 1H, CH2), 3.33
(d, J ) 17.1 Hz, 1H, CH2), 2.49 (s, 3H, CH3); MS (CI) 420 (M
+ H, 58), 422 (M + H, 24), 265 (40), 267 (26),157 (100). Anal.
Calcd for C19H14ClNO4S2: C, H, N.
Meth od I. 5-[3-(4-Ch lor oph en yl)pr op-2-yn yl]-5-(tolu en e-
4-su lfa n yl)th ia zolid in e-2,4-d ion e (9). Sodium hydride (80%
dispersion in mineral oil, 0.63 g, 21.1 mmol) was added to a
solution of 5-(toluene-4-sulfanyl)thiazolidine-2,4-dione [(4, Ar
) 4-methylphenyl), 1.75 g, 8.44 mmol] in dry THF (9 mL) at
0 °C under a dry N2 atmosphere. After 10 min, a solution of
[3-(4-chlorophenyl)prop-2-ynyl] bromide [(8, Ar′ ) 4-chlorophe-
nyl), 1.94 g, 8.44 mmol] in dry THF (9 mL) was added over a
30 min period. After 2.5 h, the reaction mixture was concen-
trated and dilute aqueous HCl was added (85 mL). The
organics were extracted with ethyl acetate (2 × 85 mL), and
the extracts were dried (brine), concentrated, purified by flash
chromatography (98:2 CH2Cl2:2-propanol), and triturated with
petroleum ether to provide the title compound as a white solid
Met h od L. 5-[3-(4-Ch lor op h en yl)p r op -2-yn yl]-5-(4-
flu or oben zen esu lfon yl)th ia zolid in e-2,4-d ion e (17). So-
dium hydride (80% dispersion in mineral oil, 0.55 g, 18.2 mmol)
was added to a solution of 5-(4-fluorophenylsulfonyl)thiazoli-
dine-2,4-dione [(5, Ar ) 4-fluorophenyl), 2.0 g, 7.27 mmol] in
dry THF (12 mL) at 0 °C under a dry N2 atmosphere. After
1.5 h, a solution of [3-(4-chlorophenyl)prop-2-ynyl] bromide [(8,
Ar′ ) 4-chlorophenyl), 1.67 g, 7.27 mmol] in dry THF (12 mL)
was added over a 25 min period. After 20 h, the reaction
mixture was concentrated and dilute aqueous HCl was added
(100 mL). The organics were extracted with ethyl acetate (3
× 100 mL), and the extracts were dried (brine), concentrated,

1090 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
Wrobel et al.
purified by flash chromatography (97:3 CH2Cl2:methanol), and
triturated with petroleum ether to provide the title compound
as a white solid (0.99 g, 32%). The solid was further purified
by recrystallization from ethanol: water: mp 176-177 °C;
NMR (DMSO-d6) δ 13.0 (broad s, 1H, NH), 8.02 (m, 1H, ArH),
7.59 (t, J ) 8.9 Hz, 1H, ArH), 7.45 (d, J ) 8.5 Hz, 1H, Ar′H),
7.35 (d, J ) 8.5 Hz, 1H, Ar′H), 3.66 (d, J ) 17.5 Hz, 1H, CH2),
3.50 (d, J ) 17.3 Hz, 1H, CH2); MS (-DCI) 422 (M - H, 22),
424 (M - H, 16), 263 (100), 265 (40). Anal. Calcd for
were excluded and the remaining 30 mice were randomly
assigned into seven groups of equivalent mean plasma glucose
level (vehicle control, ciglitazone, and five drug groups).
Ciglitazone was used as a reference standard in all db/db
experiments so that the responsiveness of the animals to a
known compound could be ascertained as well as to have a
comparator for the compounds of unknown activity. On the
afternoon of days l, 2, and 3 the vehicle (0.2 mL of 2% Tween
80/saline w/v) or test drugs were administered (po) to the ad
libitum fed mice. On the morning of day 4, the mice were
weighed and fasted, but water was available ad libitum. Three
hours later, a blood sample was collected, and then the mice
were given the fourth administration of drug or vehicle. Blood
samples were collected again from the unanesthetized mice
at 2 and 4 h after drug administration. The plasma was
separated, and levels of glucose in plasma were determined
by the Abbott VP analyzer.
C
18H11ClFNO4S2: C, H, N.
Meth od L. 5-[3-(4-Ch lor op h en yl)p r op -2-yn yl]-5-(p yr i-
d in e-2-su lfon yl)th ia zolid in e-2,4-d ion e (18). Sodium hy-
dride (80% dispersion in mineral oil, 0.32 g, 10.8 mmol) was
added to a solution of 5-(pyridine-2-sulfonyl)thiazolidine-2,4-
dione [(5, Ar ) 2-pyridyl), 1.1 g, 4.30 mmol] in dry THF (7.5
mL) at 0 °C under a dry N2 atmosphere. After 10 min, a
solution of [3-(4-chlorophenyl)prop-2-ynyl] bromide [(8, Ar )
4-chlorophenyl), 0.99 g, 4.30 mmol] in dry THF (7.5 mL) was
added, over a 30 min period. After 27 h at room temperature,
the reaction mixture was quenched with saturated aqueous
NH4Cl (20 mL), water (120 mL) was added and the organics
were extracted with ethyl acetate (2 × 150 mL). The extracts
were dried (brine), concentrated, and purified by flash chro-
matography (gradient: 97:3 to 88:12 CH2Cl2:methanol) to
provide the title compound as a yellow solid (0.63 g, 36%): mp
140-141 °C; NMR (DMSO-d6) δ 13.2 (broad s, 1H, NH), 8.82
(dd, J ) 0.6, 4.0 Hz, 1H, PyrH), 8.23 (td, J ) 1.6, 7.8 Hz, 1H,
PyrH), 8.15 (d, J ) 7.9 Hz, 1H, PyrH), 7.87 (ddd, J ) 1.1, 5.3,
7.7 Hz, 1H, PyrH), 7.45 (d, J ) 8.5 Hz, 1H, Ar′H), 7.35 (d, J )
8.5 Hz, 1H, Ar′H), 3.88 (d, J ) 17.2 Hz, 1H, CH2), 3.74 (d, J )
17.2 Hz, 1H, CH2); MS (+DCI) 407 (M + H, 50), 409 (M + H,
To assess drug activity, the percent change of the animal’s
plasma glucose level on day 4 (mean of the 2 and 4 h samples)
from its respective level before drug administration (day l
baseline sample) was determined as follows:
mean of 2 and 4 h samples (day 4)
× 100
baseline sample (day 1)
A 50-60% reduction of plasma glucose levels in the hyper-
glycemic db/db mice represented a normalization of glucose
levels.
Analysis of variance followed by Dunnett’s multiple com-
parison (one-sided) was used to estimate the degree of statisti-
cal significance of the difference between the vehicle control
group and the individual drug-treated groups. A drug was
considered active, at the specific dosage administered, if the
difference between the plasma glucose levels of the control and
treated groups have a p < 0.05.
The procedure using ob/ob mice was as follows: Mice (male
(C57 Bl/6J ) J ackson Laboratories, ages 2 to 3 months (40 to
50 g)) were used to assess the effects of compounds on both
glucose and insulin lowering. In each study the ob/ob mice
were from the same litter so they were age-matched and had
similar body weights and levels of glycemia. Since the degree
of glycemia does vary somewhat within the litter, the mice
from the litter were randomized into different treatment
groups by body weight (4 groups of 10 mice). (We used body
weight instead of glycemia as a parameter since we found that
body weight in this age of ob/ob mice is well correlated with
glycemic state. From earlier studies we know that randomiza-
tion by body weight yields tight plasma glucose values for each
group.) The mice were housed five per cage and were main-
tained on normal rodent chow with water ad libitum. Mice
received compound daily (morning) by gavage (suspended in
0.5 mL of 0.5% methyl cellulose) for 4 days. The dose given
(Table 3) was calculated based on the fed weekly body weight
and is expressed as active moiety. Control mice received
vehicle only.
On the morning of day 4, 4 h after drug administration,
blood was collected into sodium fluoride-containing tubes after
decapitation under anesthesia. The plasma was isolated by
centrifugation, and the concentration of glucose was measured
enzymatically on an Abbott VP analyzer; plasma insulin was
quantitated by radioimmunoassay.22
For each mouse, the percentage change in plasma glucose
on day 4 was calculated relative to the mean plasma glucose
of the vehicle treated mice. Analysis of variance followed by
Dunnett’s comparison test (one-tailed) were used to estimate
the significant difference between the plasma glucose values
from the control group and the individual compound treated
groups. A compound was considered active if the difference
in plasma glucose levels between control and treated groups
have a p < 0.05.
24), 264 (80), 266 (36), 144 (100). Anal. Calcd for C17H11
ClN2O4S2: C, H, N.
-
Meth od M. 5-[3-(4-Ch lor op h en yl)p r op -2-yn yl]-5-(6-m e-
th ylp yr id in e-2-su lfon yl)th ia zolid in e-2,4-d ion e (61). n-
Butyllithium (2.5 M in hexanes, 2.77 mL, 6.93 mmol) was
added to a solution of 5-(6-methylpyridine-2-sulfonyl)thiazo-
lidine-2,4-dione, [(5, 6-methyl-2-pyridyl), 0.92 g, 3.38 mmol]
in dry THF (30 mL) at -78 °C under a dry N2 atmosphere
over a 20 min period. A solution of [3-(4-chlorophenyl)prop-
2-ynyl] bromide [(8, Ar′ ) 4-chlorophenyl), 3.53 g, 15.4 mmol]
in dry THF (10 mL) was added over a 20 min period. The
reaction mixture was allowed to warm to room temperature.
After 16 h, the reaction mixture was added to saturated
aqueous ammonium chloride (80 mL) and extracted with ethyl
acetate (2 × 300 mL). The extracts were washed with water,
dried (brine), concentrated, and purified by flash chromatog-
raphy (gradient 97:3 to 93:7 CH2Cl2: 2-propanol) to provide a
sticky solid which was triturated with petroleum ether (90
mL): benzene (2 mL) to provide the title compound as an off-
white solid (0.55 g, 39%): mp 104-106 °C; NMR (DMSO-d6)
δ 13.1 (broad s, 1H, NH), 8.10 (t, J ) 7.8 Hz, 1H, pyH), 7.95
(d, J ) 7.7 Hz, 1H, pyH), 7.71 (d, J ) 7.7 Hz, 1H, pyH), 7.45
(d, J ) 8.8 Hz, 2H, ArH), 7.35 (d, J ) 8.7 Hz, 2H, ArH), 3.86
(d, J ) 17.4 Hz, 1H, CH2), 3.72 (d, J ) 17.4 Hz, 1H, CH2),
2.57 (s, 3H, CH3); MS (EI) 420 (MI, 3), 265 (12), 263 (38), 194
(25), 192 (70), 149 (40), 93 (100). Anal. Calcd for C18H13
ClN2O4S2: C, H, N.
-
An tih yp er glycem ic Assa ys. The procedure using db/db
mice was as follows: on the morning of day l, 35 mice [male
db/db (C57BL/KsJ ), J ackson Laboratories, 3.3 to 5.5 months
of age and body weight 35-60 g] were fasted for 4 h and
weighed, and a baseline blood sample was collected from the
tail-tip of each mouse without anesthesia, placed directly into
a fluoride-containing tube, mixed, and maintained on ice. [In
each individual experiment, ages of the mice were identical
between treatment groups (i.e. groups were always age
matched in any given experiment and the range of ages as
indicated above was actually much narrower than indicated.]
Food was then returned to the mice. The plasma was
separated, and levels of glucose in plasma were determined
by the Abbott VP analyzer. Because of the variable plasma
glucose levels of the db/db mice, the five mice having the most
extreme (i.e., highest or lowest) plasma glucose levels
The procedure for subcutaneously administered glucose
tolerance test (SCGTT) in the obese Zucker rat was as
follows: male obese Zucker (fa/fa) rats weighing between 582
and 719 g (x ) 644 ( 35 g) were studied. Animals were

Thiazolidinediones as Antihyperglycemic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1091
(6) Sohda, T.; Mizuno, K.; Momose, Y.; Ikeda, H.; Fujita, T.; Meguro,
K. Studies on Antidiabetic Agents. 11. Novel Thiazolidinedione
Derivatives as Potent Hypoglycemic and Hypolipidemic Agents.
J . Med. Chem. 1992, 35, 2617-2626.
(7) Yu, M. M.; Meguro, K.; Ikeda, H.; Hatanaka, C.; Oi, S.; Sohda,
T. Studies on Antidiabetic Agents. 10. Synthesis and Biological
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(8) Clark, D. A.; Goldstein, S. W.; Volkmann, R. A.; Eggler, J . F.;
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Agents. J . Med. Chem. 1992, 35, 1853-1864.
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randomized to three treatment groups of five animals each
based on responses to a subcutaneously administered glucose
load. Vehicle (2% Tween 80 in saline) or drugs (ciglitazone,
100 mg/kg or compound 20, 20 mg/kg) were administered, po,
once daily for 4 days. On the afternoon of day 3, food was
removed and the animals were fasted overnight. One hour
after drug administration on day 4, a 1 g/kg subcutaneous
glucose load was administered. Blood was collected from the
tail tip just prior to administration of glucose and 30, 60, 90,
and 120 min after. Blood was collected in fluoride containing
tubes and centrifuged at 10000g for 1 min to obtain plasma.
Plasma glucose was determined using an Abbott VP auto
analyzer. Treatment groups were compared to controls using
a Dunnett’s T test. Data are expressed as mean values.
Effects of compound 20 on basal plasma glucose and the
disposition of a glucose load in fasted normal rats were
determined as follows: male Sprague-Dawley rats (210-270
g) from Charles River were used in all studies. Rats were
weighed and randomly assigned to one of three treatment
groups [vehicle controls, tolbutamide (50 mg/kg)] as a reference
or 20 (100 mg/kg) and fasted for 18 h prior to treatment. All
rats had ad lib access to water.
Effects on basal plasma glucose: Following an 18 h fast, a
blood sample (approximately 50 µL) was collected from the tail
tip of each animal and placed into a fluoride-containing tube.
The tube was immediately mixed and kept on ice until the
plasma was separated by centrifugation. Vehicle or drugs
were administered by oral gavage immediately after collection
of the initial blood sample. Serial blood samples were collected
similarly at 1/2, 1, 2, and 4 h after vehicle or drug administra-
tion. Plasma glucose levels were determined using an Abbott
VP autoanalyzer. Data are expressed as mean ( SEM.
Effects on disposition of a glucose load: Following an 18 h
fast, vehicle or drugs were administered by oral gavage, and
an SCGTT was performed as desribed above for Zucker rats.
Ack n ow led gm en t. We are grateful to the Analytical
(15) Heitzmann, T.; Neidlein, R.; Freund, P.; Strein, K. Pharmaco-
kinetics of the New Oral Blood Glucose Lowering Agent (-)2-
(4-tert-Butylphenoxy)-7-(4-chlorophenyl)-heptanoic Acid Sodium
Salt in Mice, Rats and Dogs. Araneim.-Forsch./ Drug Res. 1995,
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L.; Hargrove, D. M.; Treadway, J . L.; Gibbs, E. M. Glucose
Transport-Enhancing and Hypoglycemic Activity of 2-methyl-
2-phenoxy-3-phenylpropanoic Acids. J . Med. Chem. 1996, 39,
4783-4803.
Department of Wyeth-Ayerst for elemental analyses,
1
400-MHz H NMR, and mass spectroscopy data and to
Dr. Kurt Steiner for informative discussions and valu-
able input with regard to the preparation of the manu-
script.
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