Novel euglycemic and hypolipidemic agents

Article abstract of DOI:10.1021/jm970444e

A series of [[(heterocyclyl)ethoxy]benzyl]-2,4-thiazolidinediones have been synthesized by the condensation of corresponding aldehyde 1 and 2,4- thiazolidinedione followed by hydrogenation. Both unsaturated thiazolidinedione 2 and its saturated counterpar

Full text of DOI:10.1021/jm970444e

J . Med. Chem. 1998, 41, 1619-1630
1619
Novel Eu glycem ic a n d Hyp olip id em ic Agen ts. 1†
Braj B. Lohray,*,‡ Vidya Bhushan,‡ Bheema P. Rao,‡ Gurram R. Madhavan,‡ Nagabelli Murali,‡
Krovvidi N. Rao,‡ Ananth K. Reddy,‡ Bagepalli M. Rajesh,‡ Pamulapati G. Reddy,‡ Ranjan Chakrabarti,§
Reeba K. Vikramadithyan,§ Ramanujam Rajagopalan,§ Rao N. V. S. Mamidi,∇ Hemant K. J ajoo,∇ and
Swaminathan Subramaniam∇
Medicinal and Organic Chemistry, Pharmacology, and Clinical Research, Dr. Reddy’s Research Foundation, Bollaram Road,
Miyapur Hyderabad 500 050, India
Received J uly 8, 1997
A series of [[(heterocyclyl)ethoxy]benzyl]-2,4-thiazolidinediones have been synthesized by the
condensation of corresponding aldehyde 1 and 2,4-thiazolidinedione followed by hydrogenation.
Both unsaturated thiazolidinedione 2 and its saturated counterpart 3 have shown antihyper-
glycemic activity. Many of these compounds have shown superior euglycemic and hypolipidemic
activity compared to troglitazone (CS 045). The indole analogue DRF-2189 (3g) was found to
be a very potent insulin sensitizer, comparable to BRL-49653 in genetically obese C57BL/6J -
ob/ob and 57BL/KsJ -db/db mice. Pharmacokinetic and tissue distribution studies conducted
on BRL-49653 and DRF-2189 (3g) indicate that these drugs are well-distributed in target
tissues. On the basis of euglycemic activity as well as enhanced selectivity against reduction
of triglycerides in plasma, DRF-2189 (3g) has been selected for further evaluation.
In tr od u ction
glitazone,13 BRL-49653,14 and many others are in vari-
ous stages of clinical development (Chart 1).
Diabetes is the root cause of several chronic and
progressive diseases which adversely affect a number
of organs including the nervous and vascular systems.
More than 90% of diabetic patients suffer from type 2
diabetes, i.e., non-insulin-dependent diabetes mellitus
(NIDDM), which is characterized by insulin resistance
and hyperglycemia.1 It has been estimated that a large
number of type 2 diabetics remain undiagnosed. Sev-
eral epidemiological and clinical studies2 indicate a
direct relationship between hyperglycemia and long-
term complications such as neuropathy, nephropathy,
retinopathy, atherosclerosis, and coronary artery dis-
ease. Therefore, it is essential to control blood glucose
levels during the early stages of the disease.3 The
treatment generally prescribed for NIDDM has been a
combination of diet, exercise, and a hypoglycemic agent,4
commonly sulfonylureas and biguanides. Sulfonylureas,
which are insulin secretagogues, stimulate insulin
secretion from pancreatic â-cells and are often known
to induce severe hypoglycemia5 and weight gain.6 In
addition, both primary and secondary treatment failure
rates with sulfonylureas are high, leading to complica-
tions.7 Therefore, drugs that reverse the insulin resis-
tance without stimulating insulin release from â-cells8,9
fulfill a major medical need in the treatment of NIDDM
and hence the potentials to reduce long-term complica-
tions of NIDDM. Since the pioneering discovery of
ciglitazone by a group of scientists at Takeda,10 which
effectively reduces insulin resistance by potentiating
insulin action in genetically diabetic and/or obese
animals, several new thiazolidine-2,4-diones have been
developed. Pioglitazone,11 troglitazone (CS 045),12 en-
In rodent models of obesity, insulin resistance, and
hyperglycemia, thiazolidinediones ameliorate insulin
resistance and normalize plasma glucose and insulin
without causing hypoglycemia even at very high doses.15
However, due to the unsatisfactory efficacy and safety
profile of these agents,16 there has been concern about
thiazolidinediones as antidiabetic drugs. Recently, tro-
glitazone has been marketed in the United States as
Rezulin and in J apan as Noscal.17 The encouraging
reports from clinicians on troglitazone as well as set
back due to its liver toxicity have rekindled the interest
among pharmaceutical companies. Therefore, there has
been a resurgence of interest in the development of
novel antihyperglycemic agents that can control hyper-
glycemia without causing hypoglcemia.18-21 Recent
symposia at San Francisco,22a Washington,22b and
Boston22c have attracted a large number of pharmaceu-
tical companies which are involved in this effort.
Recently, some of the indole derivatives have been
implicated in lowering blood glucose with a single dose
in KKAy mice (50 mg/kg).23 Certain imidazoline-
containing compounds have been found to decrease
plasma glucose in a dose-dependent manner following
an oral glucose load in healthy human subjects.24,25
More recently, BRL-49653 has advanced to phase III
in clinical trials. Our strategy for the discovery of
potent euglycemics involved the search for novel thia-
zolidinediones which are superior to or at least as active
as BRL-49653.
We believed that the methyl group on N of BRL-
49653, if incorporated in a ring with or without the help
of a carbon or heteroatom as shown in structure A,
might change the pharmacological profile of the com-
pound in the desired direction and perhaps improve the
potency of the compound, as has been observed in other
cases.20,21d Recently, we have reported our preliminary
† DRF Publication No. 27. Dedicated to our nation on the occasion
of the 50th anniversary of independence.
‡ Medicinal and Organic Chemistry.
§ Pharmacology.
∇ Clinical Research.
S0022-2623(97)00444-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/15/1998

1620 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
Lohray et al.
Ch a r t 1
Sch em e 1a
(1)
finding on a few selected indole and benzimidazole
derivatives having good euglycemic activities.26 We now
report the synthesis, structure-activity relationship
(SAR), and biological studies of several [[(heterocyclic)-
ethoxy]benzyl]-2,4-thiazolidinediones.
a
(a) 2,4-Thiazolidinedione, piperidine, C6H5COOH, toluene, ∆,
57-95% yield; (b) H2/10% Pd-C, 70-96% yield.
Sch em e 2a
Ch em istr y
A general strategy to synthesize thiazolidinediones
2 and 3 is shown in Scheme 1. The aldehydes 1 undergo
Kno¨evenagal condensation with 2,4-thiazolidinedione in
the presence of piperidinium benzoate in refluxing
toluene with azeotropic removal of water to give good
to excellent yield (57-95%) of benzylidenes 2 which
crystallize on cooling. The benzylidene-2,4-thiazo-
lidinedione derivatives 2 could be reduced by either
catalytic hydrogenation or magnesium/methanol.
In all the cases, the olefinic bond was reduced with
hydrogen in 1,4-dioxane using 10% palladium on carbon
as catalyst to give 5-benzyl-2,4-thiazolidinediones 3. In
most of the cases, more than a stoichiometric amount
of Pd-C (10%) was required for complete hydrogenation
of the olefinic bond due to poisoning of the catalyst. In
order to overcome the problem of using stoichiometric
amounts of 10% Pd-C, we attempted to employ mag-
nesium/methanol for reduction of the olefinic bond using
the electron-transfer technique of Watt et al.27 How-
ever, in many cases, reduction of CdC bond in hetero-
cyclic moieties was also observed as a side product or
sometimes as the major product.
a
(a) KOH-DMSO, 38% yield; (b) 4-fluorobenzaldehyde, NaH,
DMF, 42% yield; (c) 4-hydroxybenzaldehyde, DEAD, Ph3P, 39%
yield.
Sch em e 3a
a
(a) KOH-DMSO, NaH-DMSO, NaH-DMF, or K2CO3-DMF,
33-89% yield.
The aldehydes 1 in turn were prepared by two
different routes shown in Schemes 2 and 3. The
reaction of heterocyclic amines 4 with 2-bromoethanol
(5) gave N-ethanol compounds 6 (38%) which were
reacted with 4-fluorobenzaldehyde to give the aldehydes
1 (Scheme 2). Alternatively, Mitsunobu-type coupling
of 6 with 4-hydroxybenzaldehyde in the presence of
Ph3P-DEAD gave only moderate yield of 1 (39%).
However, in both cases, the reaction led to formation
of some unidentified side products. Thus, an alternate
route was examined (Scheme 3). Dibromoethane was

Novel Euglycemic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1621
treated with 4-hydroxybenzaldehyde in acetone in the
presence of K2CO3 as base to give 4-(2-bromoethoxy)-
benzaldehyde (7)28 in good yield (60-70%). The alde-
hyde 7 was then treated with various heterocycles 4 to
give the aldehydes 1 in 30-89% yield.
With a view to achieving this goal, ring closure of BRL
compound 8 with the help of a methylene bridge, as
shown in eq 1 (where X ) N; Y ) Z ) CH), resulted in
the azaindole analogue 2a , which showed fair glycemic
control (Table 1, entry 1) but far superior reduction
(79%) in plasma triglyceride (TG). On saturating, this
thiazolidinedione 2a gave compound 3a which is com-
parable to BRL compound 9 (Table 1, entries 14 vs 18).
However, the saturated compound 3a did not show a
significant difference in plasma glucose reduction or
triglyceride reduction in db/db mice as compared to its
unsaturated counterpart 2a (Table 1, entries 1 vs 14;
2a vs 3a ). Similarly, on comparison of 3a (Table 1,
entry 14) with compound 9 (Table 1, entry 18), com-
pound 3a is inferior in euglycemic but superior in
hypolipidemic activity. Further, the benzimidazole
derivative 2b was synthesized and evaluated. There
was no significant change in the percent reduction of
plasma glucose or TG (Table 1, entries 1 vs 2). We then
examined imidazole derivative 2c (Table 1, entry 3)
which is a smaller heterocycle that does not have an
aromatic benzene ring like 2a or 2b. Although hypo-
lipidemic activity of 2c was comparable to that of 2a ,b,
their euglycemic activity was very poor. Hence, a
systematic alteration in the structure was considered,
and the 2,3-dihydroindole derivative 2d and its satu-
rated analogue 3d were evaluated for euglycemic and
hypolipidemic activities. Surprisingly, the unsaturated
thiazolidinedione 2d showed far superior euglycemic
activity (Table 1, entry 4, 61% reduction in plasma
glucose) as compared to its saturated analogue 3d
(Table 1, entry 15, 33% reduction in plasma glucose).
In contrast, reduction in triglyceride for both the
compounds 2d (83% reduction in TG) and 3d (79%
reduction in TG) was nearly the same (Table 1, entries
4 vs 15). While this suggests that both 2d and 3d might
act via a similar mechanism for the reduction of tri-
glyceride, the reason for the difference in their eugly-
cemic activities is not clear. It is possible that different
mechanisms are responsible for euglycemic and hypo-
lipidemic activity. For example, it is known that ligands
which activate PPARγ cause a reduction in blood sugar,
whereas ligands which bind to PPARR cause a reduction
in triglyceride.31b We have not carried out studies to
prove the above in the case of the thiazolidinediones
reported in Table 1. On the other hand, Wilson et al.31b
examined binding and activation studies of a few
thiazolidinediones for PPARR, -γ, and -δ receptors and
concluded that thiazolidinediones in general do not
activate PPARR and -δ receptors even at high concen-
trations. Thus, the hypolipidemic activity of thiazoli-
dinedione may be associated with a receptor type which
is yet to be identified.
Resu lts a n d Discu ssion
We examined several 2,4-thiazolidinediones, including
troglitazone, in db/db mice. (cf. vide infra). A dose of
100, 200, 400, or 800 mg/kg troglitazone was adminis-
tered to db/db mice for 9 days, and the plasma glucose
level was examined. The reduction in plasma glucose
level at each dose was 32%, 41%, 44%, and 52%,
respectively. As observed by others,29 approximately
25% of the animals did not show any response to
troglitazone, and the maximum reduction in plasma
glucose observed with troglitazone (800 mg/kg) was only
52%, at which point the plasma glucose in db/db mice
(15 ( 1 mM) had still not reached the level of lean
littermates (8 ( 1 mM). Although the mechanism of
action of this class of compounds (glitazones) is not fully
understood, recent studies suggest that most of the
glitazone class of compounds bind to PPARγ (peroxisome
proliferator-activated receptors), a member of the steroid/
thyroid hormone receptor superfamily of transcription
factors.30,31 However, it is not clear whether binding of
these glitazones to both PPARγ1 and PPARγ2 is neces-
sary for their antihyperglycemic activity.22b,d It has also
been observed that various other classes of compounds
which bind to PPARγ receptor do not show antihyper-
glycemic activity.31a Thus, it appears that there may
be other receptors which may play a crucial role in
maintaining the antihyperglycemic activity of the gli-
tazone class of compounds.32 Moreover, since skeletal
muscle is the predominant insulin-sensitive tissue ac-
counting for >80% of insulin-regulated glucose disposal,
an increase in glucose disposal in adipocytes alone is
unlikely to account for euglycemic activity of thiazoli-
dinediones.33 Thus, we chose to follow a direct in vivo
screening procedure in db/db mice.
We prepared a series of indole and azaindole ana-
logues (Table 1) and evaluated their antihyperglycemic
activity. We first examined several unsaturated 2,4-
thiazolidinediones (2a -l) and compared their activities
against those of troglitazone or compound 8 (Table 1).
In cases where the antihyperglycemic activities were
comparable to that of compound 8, we synthesized the
corresponding saturated analogues (3a ,d ,g,l) and com-
pared their euglycemic activities with those of troglita-
zone or BRL compound 9 (cf. BRL-49653 is the maleate
salt of compound 9) (Table 1).
Pharmacokinetic studies on troglitazone have been
reported by Horikoshi et al.29 which indicate poor oral
bioavailability. Pharmacokinetic studies on BRL com-
pound 9 and BRL-49653 suggest that both compounds
are present at higher plasma concentration than tro-
glitazone. Also BRL-49653 (log P 1.32)14b is much more
hydrophilic and is one of the most potent compounds of
the glitazone class with a minimally effective dose of 3
µmol kg-1 of diet.14b On the basis of these observations
on oral bioavailability and potency, we surmised that
it might be possible to modify the structure of BRL
compounds 8 and 9 and obtain a novel glitazone with
the desired biological properties.
In order to obtain further insight into the structure-
activity relationship, we examined several indole de-
rivatives (2e-k ). Effect of various substituents on
indole ring was examined. The presence of an electron-
withdrawing group such as COOH or COOMe (2e,f) or
electron-donating group such as methyl (2i,j) has a
deleterious effect on the euglycemic as well as hypolipi-
demic activities of these thiazolidinediones. It appears
that substituents at C2 and C3 positions of the indole
ring are not tolerated. We selected thiazolidinedione
2g, having no substituent on the indole ring, for further

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Lohray et al.

Novel Euglycemic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1623
Ta ble 1 (Continued)
a
b
Percent reduction in BG (blood glucose). Percent reduction in triglyceride (TG) after 9 days of dosing in db/db mice via oral gavage.
c Compound 8, compound 9, and BRL-49653 were prepared by reported procedure.14b BRL-49653 is the maleate salt of BRL compound 9.
Troglitazone was prepared by the reported method, and log P value is quoted from ref 29. e The program used to calculate Clog P was
d
obtained from BioByte Corp. USA and is used without any correction. f The value of log P for BRL-49653 is quoted from ref 14b. DB,
double bond; dotted line, optional double bond.
study and synthesized saturated thiazolidinedione 3g
(DRF-2189) which was very effective in reducing blood
glucose (74%) and triglyceride (77%) with the blood
glucose level reaching levels close to that of the lean
littermate (8 ( 1 mM). We also examined the tryp-
tophan derivative 2k and carbazole 21. Interestingly,
tryptophan derivative 2k showed poor euglycemic and
moderate hypolipidemic activities, whereas compound
2l which has a planar heterocyclic moiety is completely
devoid of any activity (Table 1, entries 11 and 12). The
saturated thiazolidinedione analogue 3l (Table 1, entry
16) also did not show any euglycemic activity. Clearly,
despite having planar heterocycle moieties (2g vs 2l and
3g vs 3l), the enormous difference in euglycemic activity
might be due to the large size of the carbazole moiety.
Thus it appears that the size of heterocyclic moiety plays
a crucial role in binding to the receptor site responsible
for euglycemic activity. Also when one tries to rational-
ize the shape of the heterocyclic moiety (3g vs 3d ), the
planar heterocycle is preferred. Although both 3g,d
may have similar steric requirements, their potencies
differ remarkably. The compound 3g showed very good
euglycemic and hypolipidemic activity, whereas 3d is
markedly inferior. This might be associated with the
shape of the heterocycle (3g is planar, whereas 3d is
puckered). Hence, we selected DRF-2189 (3g) for
further evaluation as a potential development candi-
date.
aim to compare the efficacy of DRF-2189 with BRL-
49653, we carried out dose-response studies in db/db
and ob/ob mice examining the percent reduction of
plasma glucose and triglycerides. We examined DRF-
2189 (3g), BRL compound 9, and BRL-49653 at 100 mg/
kg/day/po in db/db mice. Interestingly, all three com-
pounds showed similar reduction in plasma glucose
(71-72%) and normalized glucose in plasma (i.e., 8 ( 1
mM). Hence we examined all three compounds at a
lower dose of 10 mg/kg/day in db/db mice for 9 days.
We observed that DRF-2189 and BRL-49653 reduced
the blood glucose by 51-55% (plasma glucose: 12.5 (
1 mM), whereas BRL compound 9 did not produce a
significant reduction. Further dose-response studies
were carried out using DRF-2189 (1, 3, and 10 mg/kg)
and BRL-49653 (1, 3, and 10 mg/kg) in db/db mice and
compared with studies of troglitazone (100, 200, and 800
mg/kg). The results are shown in Figure 1.
From these results it is clear that DRF-2189 and BRL-
49653 are approximately equipotent, whereas troglita-
zone even at 800 mg/kg dose was less effective in
reducing plasma glucose. The reductions in triglyceride
for DRF-2189 and BRL-49653 were not significantly
different in db/db mice; however, the reduction of
cholesterol was observed with the 3 and 10 mg/kg dose
of DRF-2189 (3g) (10-15% reduction in total choles-
terol), whereas BRL-49653 did not show improvement
in cholesterol. Further, oral glucose tolerance test
(OGTT) carried out after 9 days of treatment in db/db
mice with DRF-2189 (3g) (AUC, 68% reduction) and
BRL-49653 (AUC, 61% reduction) showed comparable
potency.
Both the drugs were consequently evaluated in ob/ob
mice. After similar dosage (10 mg/kg/day) for both
drugs for 14 days, the glucose and triglyceride in the
blood plasma were determined. In both cases the
percent reduction in blood glucose (51-59%) and tri-
glyceride (53-55%) was found to be similar. Having
found comparable potency of DRF-2189 (3g) with BRL-
49653, we decided to study the pharmacokinetics and
tissue distribution of both drugs. Both BRL-49653 and
Comparison of 3g with troglitazone was carried out
at 200 mg/kg dose. At this dose troglitazone reduced
plasma glucose and triglycerides by 24% and 50%,
respectively, while DRF-2189 (3g) reduced plasma
glucose and triglyceride by 74% and 77%, respectively.
Thus, it seems that DRF-2189 (3g) might have greater
efficacy at this dose compared to troglitazone. With an

1624 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
Lohray et al.
F igu r e 1. Comparison of percent reduction in random blood
sugar (RBS) in db/db mice using 1, 3, or 10 mg/kg DRF-2189
and BRL-49653 with troglitazone (100, 200, and 800 mg/kg).
F igu r e 2. Comparison of drug plasma levels of BRL-49653
(b) and DRF-2189 (9) in Wistar rats at various time intervals.
Ta ble 2. Pharmacokinetic Parameters for DRF-2189 and
BRL-49653 at 10 mg/kg/po in Wistar Rats
Ta ble 3. Tissue Levels for DRF-2189 and BRL-49653 at 10
mg/kg/po in Wistar Ratsa
parameter
DRF-2189a
BRL-49653b
tissue
DRF-2189
BRL-49653
AUC0-∞ (µg h mL-1
)
129.3 ( 46.3
14.54 ( 2.4
3.67 ( 1.2
0.25 ( 0.14
3.28 ( 1.4
59.2 ( 19.0
29.4 ( 6.0
0.5 ( 0.0
0.72 ( 0.18
1.02 ( 0.24
liver (µg g-1
)
10.01 (0.85)
1.50 (0.13)
1.23 (0.10)
0.85 (0.07)
2.45 (0.21)
7.24 (0.62)
11.76 (1.00)
10.90 (0.40)
14.32 (0.53)
2.10 (0.08)
0.87 (0.03)
1.63 (0.06)
13.76 (0.51)
27.16 (1.00)
Cmax (µg mL-1
tmax (h)
)
subcutaneous fat (µg g-1
)
brown fat (µg g-1
)
Kel (h-1
)
skeletal muscle (µg g-1
heart (µg g-1
)
half-life (h)
)
a
b
blood (µg mL-1
)
Results are mean ( SD of three animals. Results are mean
( SD of six animals.
plasma (µg mL-1
)
a
The animals were sacrificed at tmax (i.e., 3 h for DRF-2189 and
1 h for BRL-49653), and the drug concentration in various target
tissues was determined. The numbers in parentheses are tissue/
plasma ratios.
DRF-2189 were administered at a single oral dose of
10 mg/kg in Wistar rats, and blood samples were
collected and analyzed as described in the Experimental
Section. Results of these studies are presented in Table
2.
these molecules (Table 3) indicated that both drugs were
present in the plasma and liver in large amounts, but
concentrations were relatively low in skeletal muscle,
brown fat, and the heart.
The results indicate that the systemic exposure
(AUC0-∞) for DRF-2189 is more than twice that for BRL-
49653. There are considerable differences in their Cmax
,
One striking difference between the two molecules is
that BRL-49653 showed relatively high concentrations
in subcutaneous fat (tissue to plasma (t/p) ratio ) 0.53)
as compared to DRF-2189 (t/p ratio ) 0.13). In contrast,
the concentration of DRF-2189 in liver was relatively
higher (t/p ratio ) 0.85) as compared to that for BRL-
49653 (t/p ratio ) 0.4). These studies suggest that both
compounds are well-distributed in various tissues. The
high concentrations in the pharmacological target sites
such as liver and subcutaneous fat may be important
for their pharmacological action.
We have carried out preliminary toxicity studies
(LD50) for both DRF-2189 and BRL-49653, and both
compounds seem to have a similar LD50 profile. De-
tailed toxicity studies will be carried out later.
To conclude, the indole-containing thiazolidine-2,4-
dione (DRF-2189) has potential to have a better eugly-
cemic and hypolipidemic profile. The further progress
Tmax, Kel, and t1/2. DRF-2189 is absorbed slowly, reaches
a maximum plasma level in 3-4 h, and is eliminated
slowly (t1/2 3.2 h) as compared to BRL-49563 which is
absorbed rapidly (tmax 0.5 h) and is also eliminated
rapidly with a half-life of about 1 h (Figure 2).
Although Cmax for DRF-2189 is much lower (14.5 (
2.4 µg/mL-1) compared to that for BRL-49653 (29.4 (
6.0 µg/mL-1), longer plasma residence time of DRF-2189
accounts for higher systemic exposure. However, the
question of distribution of drug candidate into target
tissues needs to be addressed before selection of the
preclinical lead candidate. We carried out tissue dis-
tribution studies for both BRL-49653 and DRF-2189 in
Wistar rats. After single dosing of BRL-49653 and
DRF-2189, the animals were sacrificed at a time when
drug concentrations are maximum in the plasma (i.e.,
at tmax), and the concentration of drug in various target
tissues was determined. Tissue distribution studies for

Novel Euglycemic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1625
and the drug was extracted from the plasma using 2.0 mL of
extracting solvent. For DRF-2189, troglitazone (3 µg) was used
as internal standard and the extraction solvent was ethyl
acetate-dichloromethane (6:4, v/v), whereas for BRL-49653,
another thiazolidinedione analogue (1 µg) was used as internal
standard and a mixture of dichloromethane-methanol (2:1,
v/v) was used as extraction solvent. The organic layer (1.5
mL) was evaporated to dryness and reconstituted in 200 µL
of methanol-water (50:50); 100 µL of the sample was analyzed
by HPLC. In case of tissue homogenates, sample preparation
was carried out with 0.5 mL of homogenate and the amount
of internal standard added was 15 µg. The calibration, control,
and recovery samples were prepared by spiking blank plasma/
liver homogenate and were processed similarly.
(b) HP LC Assa y. The HPLC system consisted of a Waters
LC Module-1, Perkin Elmer LC-240 fluorescence detector,
Millennium software, and a HiChrom C18 (ODS) column (5 µm,
4.6 mm × 250 mm). Analysis of DRF-2189 was carried out
using 0.05 M NaH2PO4 buffer-acetonitrile-methanol (22.5:
37.5:40, v/v, pH 5.0) as mobile phase at a flow rate of 1.0 mL/
min, and the excitation and emission wavelengths were 280
and 320 nm, respectively. Under these conditions, the reten-
tion times for DRF-2189 and troglitazone were 10.8 and 13.9
min, respectively. For analysis of BRL-49653, mobile phase
was 0.05 M NaH2PO4 buffer (pH 5)-methanol-acetonitrile
(22:12:55, v/v) at a flow rate of 1.0 mL/min, and the excitation
and emission wavelengths were 317 and 370 nm, respectively.
Under these conditions, the retention times for BRL-49653 and
standard were 7.5 and 8.7 min, respectively. The assay
methods were validated to ensure specificity, linearity, recov-
ery, accuracy, and precision. The limits of quantitation for
DRF-2189 and BRL-49653 from plasma were 200 and 50 ng/
mL, respectively. The response was linear up to 50 µg/mL for
both methods. The absolute recoveries for both methods were
>95%.
Ch em ica l Meth od s. Thin layer chromatography was
performed on silica gel plates (60 F254; Merck). Flash
chromatography was performed on silica gel (SRL 230-400
mesh). Melting points were recorded on Veego melting point
apparatus and are uncorrected. 1H and 13C NMR spectra were
obtained with a Varian Gemini 200-MHz spectrometer and are
reported as parts per million (ppm) downfield to TMS. The
infrared spectra were recorded on a Perkin Elmer FT-IR 1600
spectrometer. The mass spectra were obtained with an HP
5989A mass spectrometer. 4-(2-Bromoethoxy)benzaldehyde28
and ethyl indole-2-carboxylate35 were prepared according to
literature procedures. Indole, 7-azaindole, 3-methylindole, 2,3-
dimethylindole, 5-chloroindole, benzimidazole, and imidazole
were purchased and used directly. Compound 8, compound
9, and BRL-49653 were prepared by a reported procedure.14b
Troglitazone was prepared by the method reported by Hori-
koshi et al.29
Gen er a l Meth od of P r ep a r a tion of 4-[2-(Heter ocyclyl)-
eth oxy]ben za ld eh yd e. To a solution of an appropriate
heterocycle 4 (10.0 mmol) in dry DMSO (15.0 mL) at 25 °C
was added an appropriate base (11.0 mmol), and the mixture
stirred for 0.25-1 h. A solution of 4-(2-bromoethoxy)benzal-
dehyde (7) (12.0 mmol) in dry DMSO (5 mL) was added and
stirred further for 0.5-6 h. To the reaction mixture was added
water (20 mL), and it was extracted with EtOAc (2 × 25 mL).
The combined organic extracts were washed with brine (25
mL), dried over anhydrous Na2SO4, and concentrated. The
residue was chromatographed over silica gel using a mixture
(3:7-8:2) of ethyl acetate and petroleum ether as eluent to
yield pure compound (30-79%).
of this compound into clinical trials depends on its safety
and efficacy.
Exp er im en ta l Section
Biological P r ocedu r e. Male C57BL/KsJ-db/db and C57BL/
6J -ob/ob mice were obtained at 6 weeks of age from J ackson
Laboratories (Bar Harbor, ME) and maintained at 25 ( 2 °C
on a 12-h light/dark cycle. Animals were given standard
laboratory chow (National Institute of Nutrition, Hyderabad,
India) and water, ad libitum.
The db/db mice were used for experiments at 8 weeks of
age. Four to six animals were used in each treatment group.
In db/db mice, the test compounds were administered at
different doses orally for 9 days. Troglitazone (200 and 800
mg/kg) and BRL-49653 (1, 3, and 10 mg/kg) were used as
standard drugs. The control animals were given vehicle (0.5%
carboxymethylcellulose, dose 10 mL/kg). The blood sample
(25-50 µL) was collected from the retro-orbital sinus through
heparinized capillary tubes in EDTA-containing tubes at
different time intervals. In db/db mice, blood samples were
collected after 1 h of drug administration on days 0, 3, 6, and
9 of treatment. Only selected compounds were tested in ob/
ob mice. The ob/ob mice were used for experiments at 10
weeks of age, and blood samples were collected on days 0 and
14 of treatment as described above. After centrifugation,
plasma was separated for glucose, cholesterol, and triglyceride
estimations using commercial kits (Dr. Reddy’s Laboratories
Diagnostic Division, India). The percent reduction in plasma
glucose level was calculated.34
Oral glucose tolerance test (OGTT) was performed after 9
days of treatment (db/db). Mice were fasted overnight (db/
db) and challenged with glucose (3 g/kg/po). Blood samples
were collected at 0, 30, 60, and 120 min for measuring plasma
glucose levels. The improvement in glycemic control was
calculated as the percent reduction in the area under the
plasma glucose content versus time curve (AUC). The AUC
was calculated using the trapezoidal rule.
Similarly, OGTT was performed in ob/ob mice after 14 days
of treatment; however, the mice were challenged with glucose
(3 g/kg/po) after a 5-h fast. Blood samples were collected and
examined as described earlier.
P h a r m a cok in etics a n d Tissu e Distr ibu tion Stu d ies.
All studies were carried out in Wistar rats obtained from
National Institute of Nutrition (Hyderabad, India). The
animals (175-200 g) were fasted 12 h before starting the
experiment and had free access to water throughout. Animals
were fed 3 h after drug administration.
(a ) Sin gle-Dose P h a r m a cok in etics. Animals were dosed
with the drug at 10 mg/kg/po as 0.5% CMC suspension, and
0.4 mL of blood sample was collected into heparinized mi-
crofuge tubes at different time points (0, 0.5, 1, 2, 3, 5, 8, 12,
and 24 h) from the orbital sinus. The samples were analyzed
by HPLC to generate drug plasma concentration versus time
profiles (Figure 2).
Pharmacokinetic parameters such as AUC0-∞, Kel, t1/2, Cmax
,
and tmax were calculated using noncompartmental model
analysis. AUC0-∞ is the area under the plasma concentration
versus time curve extrapolated to infinity, Kel is the elimina-
tion rate constant, Cmax is the observed maximum plasma
concentration, and tmax is the time at which Cmax is achieved.
The pharmacokinetic parameters for DRF-2189 and BRL-
49653 are summarized in Table 2.
(b) Tissu e Distr ibu tion Stu d ies. Tissue distribution
studies were carried out in Wistar rats. The drug was
administered to two animals (10 mg/kg/po) following which the
animals were sacrificed at tmax. Various tissues/organs were
isolated, perfused with phosphate buffer (pH 5.8) to remove
blood, and homogenized in buffer (1:4 ratio). Blood/plasma was
collected from each animal just before sacrifice. The tissue
homogenates were analyzed by HPLC for drug content, and
tissue concentrations were measured and are expressed as µg
g-1 of wet tissue (Table 3).
4-[2-(7-Aza -1-in d olyl)eth oxy]ben za ld eh yd e (1a ). The
title compound 1a was prepared by the general procedure
using azaindole (1.81 g, 10.0 mmol), aldehyde 7 (2.75 g, 12.0
mmol), and KOH (1.43 g, 25.0 mmol) in 89% yield (2.68 g):
IR νmax(KBr) 1695 cm-1; 1H NMR (CDCl3) δ 9.89 (s, 1 H), 8.32
(d, J ) 3.0 Hz, 1 H), 7.95 (d, J ) 6.0 Hz, 1 H), 7.80 (d, J )
8.72 Hz, 2 H), 7.40 (d, J ) 3.0 Hz, 1 H), 7.15-6.95 (m, 1 H),
6.98 (d, J ) 8.72 Hz, 2 H), 6.48 (d, J ) 3.0 Hz, 1 H), 4.75 (t, J
) 5.30 Hz, 2 H), 4.40 (t, J ) 5.30 Hz, 2 H).
An alysis of P lasm a/Tissu e Sam ples. (a) Sam ple P r epa-
r a tion . To 0.1 mL of plasma was added internal standard,

1626 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
Lohray et al.
4-[2-(1-Ben zim id a zolyl)eth oxy]ben za ld eh yd e (1b). The
title compound was prepared by the general procedure using
benzimidazole (1.18 g, 10.0 mmol), aldehyde 7 (2.52 g, 10.0
mmol), and NaH (290 mg, 12.0 mmol) in 51% yield (1.36 g):
IR νmax (KBr) 1690 cm-1; 1H NMR (CDCl3) δ 9.90 (s, 1 H), 8.00-
7.70 (m, 1 H), 7.85 (d, J ) 8.70 Hz, 2 H), 7.60-7.50 (m, 1 H),
7.50-7.20 (m, 3 H), 6.98 (d, J ) 8.70 Hz, 2 H), 4.64 (t, J ) 5.2
Hz, 2 H), 4.40 (t, J ) 5.2 Hz, 2 H).
The crude compound was purified by column chromatography
to afford 103 mg (39%) of 1g.
4-[2-(5-Ch lor o-1-in d olyl)et h oxy]b en za ld eh yd e (1h ).
5-Chloroindole (2.0 g, 13.2 mmol) was reacted by general
procedure with aldehyde 7 (3.4 g, 14.5 mmol) and KOH (1.48
g, 26.4 mmol) to afford the title compound, 2.75 g (69%): IR
1
νmax (KBr) 1695 cm-1; H NMR (CDCl3) δ 9.86 (s, 1 H), 7.79
(d, J ) 8.72 Hz, 2 H), 7.59 (d, J ) 1.75 Hz, 1 H), 7.40-7.15
(m, 3 H), 6.92 (d, J ) 8.72 Hz, 2 H), 6.46 (d, J ) 3.0 Hz, 1 H),
4.54 (t, J ) 5.30 Hz, 2 H), 4.34 (t, J ) 5.30 Hz, 2 H).
4-[2-(1-Im id a zolyl)eth oxy]ben za ld eh yd e (1c). The title
compound was prepared by the general procedure using
imidazole (0.34 g, 5.0 mmol), aldehyde 7 (1.26 g, 5.5 mmol),
and NaH (152 mg, 6.0 mmol, 95%) in 77% yield (0.83 g): IR
4-[2-(3-Meth yl-1-in dolyl)eth oxy]ben zaldeh yde (1i). The
title compound was prepared by the general procedure using
3-methylindole (3.0 g, 22.9 mmol), aldehyde 7 (6.3 g, 27.48
mmol), and KOH (2.57 g, 45.8 mmol) in 57% yield (3.68 g):
IR νmax (KBr) 1690 cm-1; 1H NMR (CDCl3) δ 9.88 (s, 1 H), 7.80
(d, J ) 8.72 Hz, 2 H), 7.56 (d, J ) 6.0 Hz, 1 H), 7.37 (d, J )
6.0 Hz, 1 H), 7.30-7.05 (m, 3 H), 6.91 (d, J ) 8.72 Hz, 2 H),
4.51 (t, J ) 5.30 Hz, 2 H), 4.32 (d, J ) 5.30 Hz, 2 H), 2.30 (s,
3 H).
1
νmax (KBr) 1695 cm-1; H NMR (CDCl3) δ 9.92 (s, 1 H), 7.85
(d, J ) 8.70 Hz, 2 H), 7.65 (s, 1 H), 7.10 (d, J ) 5.0 Hz, 2 H),
6.98 (d, J ) 8.70 Hz, 2 H), 4.40 (d, J ) 5.30 Hz, 2 H), 4.30 (d,
J ) 5.30 Hz, 2 H).
4-[2-(2-Car beth oxy-1-in dolyl)eth oxy]ben zaldeh yde (1e).
The title compound (2.4 g, 75%) was prepared by the general
procedure using ethyl indole-2-carboxylate (1.75 g, 10.0 mmol),
aldehyde 7 (2.29 g, 10.0 mmol), and K2CO3 (2.76 g, 20.0 mmol)
as base: IR νmax (KBr) 1695 cm-1; 1H NMR (CDCl3) δ 9.91 (s,
1 H), 7.90 (d, J ) 8.72 Hz, 2 H), 7.65 (d, J ) 6.0 Hz, 1 H), 7.85
(d, J ) 6.0 Hz, 1 H), 7.36 (t, J ) 6.0 Hz, 1 H), 7.22-7.05 (m,
2 H), 7.10 (d, J ) 8.72 Hz, 2 H), 4.92 (t, J ) 5.0 Hz, 2 H),
4.50-4.30 (m, 4 H), 1.45 (t, J ) 6.50 Hz, 3 H).
4-[2-(2,3-Dim eth yl-1-in d olyl)eth oxy]ben za ld eh yd e (1j).
The title compound was prepared by the general procedure
using 2,3-dimethylindole (2.0 g, 13.8 mmol), aldehyde 7 (4.42
g, 19.28 mmol), and KOH in 55% yield (2.22 g): IR νmax (KBr)
1
1695 cm-1; H NMR (CDCl3) δ 9.85 (s, 1 H), 7.72 (d, J ) 8.67
Hz, 2 H), 7.50 (d, J ) 7.10 Hz, 1 H), 7.30 (d, J ) 7.10 Hz, 1 H),
7.20-7.05 (m, 2 H), 6.89 (d, J ) 8.67 Hz, 2 H), 4.50 (t, J )
5.82 Hz, 2H), 4.27 (t, J ) 5.82 Hz, 2 H), 2.43 (s, 3 H), 2.25 (s,
3 H).
Syn th esis of 4-[2-(1-In d olyl)eth oxy]ben za ld eh yd e (1g).
Meth od A: The aldehyde was prepared by the general
procedure using indole (1.17 g, 10.0 mmol), sodamide (429 mg,
11.0 mmol), and aldehyde 7 (2.75 g, 12.0 mmol) to yield 2.10
4-[2-(1-Ca r ba zolyl)eth oxy]ben za ld eh yd e (1l). The title
compound (3.92 g, 52%) was prepared by the general procedure
using carbazole (4.0 g, 24 mmol), aldehyde 7 (7.12 g, 31.0
1
g (79%) of 1g: IR νmax (neat) 1690 cm-1; H NMR (CDCl3) δ
9.86 (s, 1 H), 7.79 (d, J ) 8.72 Hz, 2 H), 7.64 (d, J ) 7.89 Hz,
1 H), 7.42 (d, J ) 7.88 Hz, 1 H), 7.40-7.05 (m, 3 H), 6.94 (d,
J ) 8.72 Hz, 2 H), 6.53 (d, J ) 2.91 Hz, 1 H), 4.58 (t, J ) 5.49
Hz, 2 H), 4.38 (t, J ) 5.49 Hz, 2 H).
mmol), and KOH (2.68 g, 47.8 mmol): IR νmax (KBr) 1690 cm-1
;
1H NMR (CDCl3) δ 9.85 (s, 1 H), 8.12 (d, J ) 7.5 Hz, 2 H),
7.77 (d, J ) 8.72 Hz, 2 H), 7.52-7.46 (m, 4 H), 7.32-7.23 (m,
2 H), 6.90 (d, J ) 8.72 Hz, 2 H), 4.78 (t, J ) 5.58 Hz, 2 H),
4.45 (t, J ) 5.58 Hz, 2 H).
Meth od
B (Sch em e 2), Step A, Syn th esis of 1-(2-
Hyd r oxyeth yl)in d ole (6g): To a stirred suspension of KOH
(2.18 g, 38.4 mmol) in dry DMSO (25 mL) was added a solution
of indole (3 g, 25.6 mmol) in DMSO (5 mL) dropwise at 25 °C.
After stirring for 5 min a clear solution was observed to which
bromoethanol (1.81 mL, 3.2 g, 25.6 mmol) was added, and it
was further stirred for 30 min. The reaction mixture was
diluted with EtOAc (100 mL) and washed with water (3 × 25
mL) and brine. The EtOAc layer was dried over anhydrous
Na2SO4 and concentrated to yield 3.5 g of crude compound
which was purified by column chromatography using a mixture
of EtOAc-petroleum ether (1:9) as eluent to afford 1.56 g (38%)
of 6g: IR νmax (neat) 3376 cm-1; 1H NMR (CDCl3) δ 7.64 (d, J
) 7.67 Hz, 1 H), 7.37 (d, J ) 7.6 Hz, 1 H), 7.24 (d, J ) 6.14
Hz, 1 H), 7.22-7.02 (m, 2 H), 6.52 (d, J ) 2.9 Hz, 1 H), 4.26 (t,
Gen er a l Meth od To P r ep a r e 5-[[4-[2-(Heter ocyclyl)-
eth oxy]p h en yl]m eth ylen e]th ia zolid in e-2,4-d ion es 2a -l.
A mixture of 4-[2-(heterocyclyl)ethoxy]benzaldehyde 1 (10
mmol), thiazolidine-2,4-dione (10 mmol), benzoic acid (1.3
mmol), and piperidine (1.5 mmol) in 25 mL of toluene was
refluxed for 1 h with continuous removal of water using a
Dean-Stark water separator. The reaction mixture was
cooled to room temperature, and the resultant crystalline
compound was filtered, washed with water, and dried to afford
the pure product 2a -l (71-99%).
5-[[4-[2-(7-Aza -1-in d olyl)et h oxy]p h en yl]m et h ylen e]-
th ia zolid in e-2,4-d ion e (2a ). The title compound (3.27 g,
81%) was prepared by the general procedure using 1a (2.40 g,
8.9 mmol) and thiazolidine-2,4-dione (1.05 g, 8.9 mmol): mp
J
) 5.28 Hz, 2 H), 4.0-3.85 (m, 2 H); MS m/z (relative
intensity) 161 (M+, 19), 130 (100).
205 °C; IR νmax (KBr) 1738, 1704 cm-1 1H NMR (CDCl3
; +
Step B, P r oced u r e 1: To a stirred suspension of NaH (30
mg, 1.2 mmol, 95%) in dry DMF (3 mL) was added a solution
of 1-(2-hydroxyethyl)indole (6g) (161 mg, 1.0 mmol) in DMF
(1 mL) dropwise at 25 °C, and the mixture stirred for 30 min.
The reaction mixture was cooled to 0 °C, and 4-fluorobenzal-
dehyde (116 µL, 136 mg, 1.1 mmol) was added and stirred for
2 h at 0-25 °C. The reaction was quenched with ice and the
mixture extracted with EtOAc (3 × 15 mL). The combined
EtOAc layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated to yield 250 mg of crude reaction
mixture, which was purified by column chromatography using
EtOAc-petroleum ether (1:9) as eluent to afford 110 mg (42%)
of 1g.
DMSO-d6) δ 12.10 (bs, 1 H, D2O exchangeable), 8.35 (d, J )
3.0 Hz, 1 H), 7.9 (d, J ) 5.0 Hz, 1 H), 7.70 (s, 2 H), 7.46 (d, J
) 8.72 Hz, 2 H), 7.25-7.0 (m, 1 H), 7.01 (d, J ) 8.72 Hz, 2 H),
6.42 (d, J ) 3.0 Hz, 1 H), 4.68 (t, J ) 5.30 Hz, 2 H), 4.40 (t, J
) 5.20 Hz, 2 H); 13C NMR (CDCl3 + DMSO-d6) δ 167.73,
167.43, 159.53, 146.93, 142.11, 131.70, 131.34, 129.09, 128.24,
125.75, 120.64, 120.01, 115.45, 115.03, 99.10, 66.58, 43.07; MS
m/z (relative intensity) (M+ - 1, 15), 118 (100). Anal. Calcd
for
C19H15N3SO3 (365.41): C, 62.45; H, 4.13; N, 11.50.
Found: C, 62.00; H, 4.63; N, 11.40.
5-[[4-[2-(1-Ben zim id a zolyl)eth oxy]p h en yl]m eth ylen e]-
th ia zolid in e-2,4-d ion e (2b). The title compound (6.72 g,
92%) was prepared by the general procedure using 1b (5.32 g,
20.0 mmol) and thiazolidine-2,4-dione (2.34 g, 20.0 mmol): mp
Step B, P r oced u r e 2: To a solution of 1-(2-hydroxyethyl)-
indole (6g; 161 mg, 1.0 mmol), 4-hydroxybenzaldehyde (122
mg, 1.0 mmol), and triphenylphosphine (315 mg, 1.2 mmol)
in dry THF (3 mL) was added diethyl azodicarboxylate (189
µL, 209 mg, 1.2 mmol) at 25 °C, and the mixture stirred for 3
h at the same temperature. THF was removed under reduced
pressure, and the resultant residue was dissolved in EtOAc
(10 mL), washed with water and brine, dried over anhydrous
Na2SO4, and concentrated to yield 200 mg of crude product.
1
258-260 °C; IR νmax (KBr) 1748, 1705 cm-1; H NMR (CDCl3
+ DMSO-d6) δ 12.10 (bs, 1 H, D2O exchangeable), 8.20 (s, 1
H), 7.71 (s, 1 H), 7.75-7.60 (m, 2 H), 7.52 (d, J ) 8.30 Hz, 2
H), 7.40-7.20 (m, 2 H), 7.05 (d, J ) 8.30 Hz, 2 H), 4.68 (t, J )
4.47 Hz, 2 H), 4.43 (t, J ) 4.47 Hz, 2 H); 13C NMR (DMSO-d6)
168.15, 167.72, 161.02, 159.61, 144.50, 143.29, 133.96, 132.12,
131.61, 125.98, 122.45, 121.66, 120.83, 119.42, 115.40, 110.74,
66.71, 43.69; MS m/z (relative intensity) 365 (M+, 18), 131

Novel Euglycemic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1627
(100). Anal. Calcd for C19H15N3SO3 (365.41): C, 62.45; H,
4.13; N, 11.50. Found: C, 62.17; H, 4.20; N, 11.46.
) 7.56 Hz, 1 H), 7.06 (d, J ) 7.56 Hz, 1 H), 6.97 (d, J ) 8.72
Hz, 2 H), 6.45 (d, J ) 2.90 Hz, 1 H), 4.59 (t, J ) 4.75 Hz, 2 H),
4.37 (t, J ) 4.75 Hz, 2 H); 13C NMR (CDCl3 + DMSO-d6) δ
167.63, 167.21, 159.37, 135.61, 131.59, 131.47, 128.29, 128.02,
125.69, 121.01, 120.44, 120.29, 118.94, 114.79, 109.23, 100.91,
66.88, 44.89; MS m/z (relative intensity) 364 (M+, 30), 130
(100). Anal. Calcd for C20H16N2SO3 (364.42): C, 65.91; H,
4.42; N, 7.71. Found: C, 65.86; H, 4.31; N, 7.66.
5-[[4-[2-(1-I m id a zo ly l)e t h o x y ]p h e n y l]m e t h y le n e ]-
th ia zolid in e-2,4-d ion e (2c). The title compound (0.95 g,
78%) was prepared by the general procedure using 1c (0.83 g,
3.84 mmol) and thiazolidine-2,4-dione (0.495 g, 4.2 mmol): mp
250 °C dec; IR νmax (KBr) 1740, 1705 cm-1; 1H NMR (CDCl3 +
DMSO-d6) δ 12.05 (bs, 1 H, D2O exchangeable), 7.72 (s, 1 H),
7.62 (s, 1 H), 7.45 (d, J ) 8.20 Hz, 2 H), 7.20 (s, 1 H), 7.04 (d,
J ) 8.20 Hz, 2 H), 6.90 (bs, 1 H), 4.40 (t, J ) 4.02 Hz, 2 H),
4.25 (t, J ) 4.02 Hz, 2 H). Anal. Calcd for C15H13N3SO3
(315.35): C, 57.13; H, 4.15; N, 13.32. Found: C, 57.01; H, 4.10;
N, 13.00.
5-[[4-[2-(5-Ch lor o-1-in d olyl)eth oxy]p h en yl]m eth ylen e]-
th ia zolid in e-2,4-d ion e (2h ). The title compound (3.46 g,
91%) was prepared by the general procedure using aldehyde
1h (2.75 g, 9.20 mmol) and thiazolidine-2,4-dione (1.2 g, 10.1
1
mmol): mp 206 °C; IR νmax (KBr) 1738, 1705 cm-1; H NMR
(CDCl3 + DMSO-d6) δ 12.10 (bs, 1 H, D2O exchangeable), 7.67
(s, 1 H), 7.54 (s, 1 H), 7.49 (d, J ) 8.1 Hz, 1 H), 7.41 (d, J )
8.49 Hz, 2 H), 7.31 (d, J ) 2.90 Hz, 1 H), 7.14 (d, J ) 8.1 Hz,
1 H), 6.94 (d, J ) 8.49 Hz, 2 H), 6.44 (d, J ) 2.90 Hz, 1 H),
4.57 (t, J ) 4.90 Hz, 2 H), 4.35 (t, J ) 4.90 Hz, 2 H); MS m/z
(relative intensity) 398 (M+, 46), 164 (100). Anal. Calcd for
C20H15ClN2SO3 (398.86): C, 60.22; H, 3.79; N, 7.02. Found:
C, 59.81; H, 4.00; N, 6.96.
5-[[4-[2-(1-I n d o li n y l)e t h o x y ]p h e n y l]m e t h y le n e ]-
th ia zolid in e-2,4-d ion e (2d ). To a stirred solution of 5-[[4-
[2-(1-indolyl)ethoxy]phenyl]methylene]thiazolidine-2,4-dione (2f)
(3.64 g, 10.0 mmol) in glacial acetic acid (30 mL) at 20 °C was
added NaCNBH3 (1.86 g, 30.0 mmol) in one portion, and the
mixture was heated at 70 °C with continuous stirring for 1 h.
The precipitated compound was filtered and washed with
water to furnish 2d (3.44 g, 94%): mp 175 °C; IR νmax (KBr)
1
1742, 1689, 1592 cm-1; H NMR (CDCl3 + DMSO-d6) δ 12.08
5-[[4-[2-(3-Meth yl-1-in dolyl)eth oxy]ph en yl]m eth ylen e]-
th ia zolid in e-2,4-d ion e (2i). The title compound (4.9 g, 95%)
was prepared by the general procedure using 1i (3.84 g, 13.76
mmol) and thiazolidine-2,4-dione (1.61 g, 13.70 mmol): mp 235
°C; IR νmax (KBr) 1738, 1710 cm-1; 1H NMR (CDCl3 + DMSO-
d6) δ 12.05 (bs, 1 H, D2O exchangeable), 7.68 (s, 1 H), 7.53 (d,
J ) 7.8 Hz, 1 H), 7.41 (d, J ) 8.72 Hz, 2 H), 7.39 (d, J ) 7.80
Hz, 1 H), 7.20 (t, J ) 7.47 Hz, 1 H), 7.08 (t, J ) 7.47 Hz, 1 H),
7.01 (s, 1 H), 6.93 (d, J ) 8.72 Hz, 2 H), 4.51 (t, J ) 5.31 Hz,
2 H), 4.32 (t, J ) 5.31 Hz, 2 H), 2.31 (s, 3 H). Anal. Calcd for
(bs, 1 H, D2O exchangeable), 7.78 (s, 1 H), 7.52 (d, J ) 8.72
Hz, 2 H), 7.10-6.90 (m, 4 H), 6.78-6.52 (m, 2 H), 4.26 (t, J )
5.3 Hz, 2 H), 3.62-3.40 (m, 4 H), 3.0 (t, J ) 5.30 Hz, 2 H); 13
C
NMR (CDCl3 + DMSO-d6) δ 167.68, 167.27, 159.81, 151.52,
131.55, 129.07, 126.77, 125.50, 123.94, 120.29, 117.19, 114.78,
106.26, 65.99, 53.44, 48.00, 28.10; MS m/z (relative intensity)
(M+ + 1, 16), 132 (100). Anal. Calcd for C20H18N2SO3
(366.43): C, 65.55; H, 4.95; N, 7.64. Found: C, 65.33; H, 4.88;
N, 7.61.
C
21H18N2SO3 (378.44): C, 66.65; H, 4.79; N, 7.40. Found: C,
5-[[4-[2-(2-Ca r beth oxy-1-in d olyl)eth oxy]p h en yl]m eth -
ylen e]th ia zolid in e-2,4-d ion e (2e). The title compound (2.8
g, 82%) was prepared by the general procedure using 1e (2.62
g, 7.8 mmol) and thiazolidine-2,4-dione (0.96 g, 7.8 mmol): mp
184 °C; IR νmax (KBr) 1738, 1711, 1683 cm-1; 1H NMR (CDCl3
+ DMSO-d6) δ 12.12 (bs, 1 H, D2O exchangeable), 7.76 (s, 1
H), 7.64 (d, J ) 7.89 Hz, 1 H), 7.57 (d, J ) 8.39 Hz, 2 H), 7.49
(d, J ) 8.72 Hz, 2 H), 7.40-7.30 (m, 1 H), 7.20-7.10 (m, 1 H),
7.07 (d, J ) 8.72 Hz, 2 H), 4.86-4.79 (m, 2 H), 4.50-4.30 (m,
4 H), 1.42 (t, J ) 7.10 Hz, 3 H); 13C NMR (CDCl3 + DMSO-d6)
δ 167.72, 167.35, 159.65, 159.15, 135.66, 132.02, 131.88,
131.52, 125.91, 125.72, 122.53, 122.35, 121.28, 120.58, 115.15,
109.40, 107.17, 76.67, 65.55, 60.42, 14.00. Anal. Calcd for
66.70; H, 4.81; N, 7.33.
5-[[4-[2-(2,3-Dim et h yl-1-in d olyl)et h oxy]p h en yl]m et h -
ylen e]th ia zolid in e-2,4-d ion e (2j). The title compound (2.0
g, 94%) was prepared by the general procedure using aldehyde
1j (1.60 g, 5.46 mmol) and thiazolidine-2,4-dione (0.70 g, 6.0
1
mmol): mp 254 °C; IR νmax (KBr) 1749, 1694, 1584 cm-1; H
NMR (CDCl3 + DMSO-d6) δ 12.10 (bs, 1 H, D2O exchangeable),
7.67 (s, 1 H), 7.50-7.30 (m, 2 H), 7.42 (d, J ) 8.72 Hz, 2 H),
7.20-6.95 (m, 2 H), 6.91 (d, J ) 8.72 Hz, 2 H), 4.52 (t, J )
5.30 Hz, 2 H), 4.29 (t, J ) 5.30 Hz, 2 H), 2.44 (s, 3 H), 2.23 (s,
3 H); 13C NMR (DMSO-d6) δ 167.90, 167.40, 159.72, 135.76,
132.81, 131.98, 131.62, 128.24, 125.69, 125.09, 120.48, 120.21,
118.43, 117.48, 115.16, 109.05, 105.54, 67.15, 41.93, 9.92, 8.64;
MS m/z (relative intensity) 392 (M+, 37), 158 (100). Anal.
Calcd for C22H20N2SO3 (392.47): C, 67.32; H, 5.13; N, 7.13.
Found: C, 67.00; H, 5.00; N, 6.97.
C
23H20N2SO5 (436.47): C, 63.29; H, 4.61; N, 6.41. Found: C,
63.20; H, 4.51; N, 6.21.
5-[[4-[2-(2-Car boxyin dol-1-yl)eth oxy]ph en yl]m eth ylen e]-
th ia zolid in e-2,4-d ion e (2f). To a stirred solution of 5-[[4-
[2-(2-carbethoxyindol-1-yl)ethoxy]phenyl]methylene]thiazolidine-
2,4-dione (0.972 g, 2.23 mmol) in 1,4-dioxane (8 mL) was added
a 1 M solution of KOH (4.5 mL, 4.5 mmol) at 25 °C, and the
mixture stirred for 1 h. Dioxane was removed under reduced
pressure at 60 °C. The resultant syrup was dissolved in 6.0
mL of water and acidified to pH 2.0, with 6 N HCl. A white
solid precipitated out, which was filtered and dried over P2O5
5-[[4-[2-(Meth yltr yp top h a n -1-yl)eth oxy]p h en yl]m eth -
ylen e]th ia zolid in e-2,4-d ion e (2k ). The title compound was
prepared in three steps as follows. Step A, P r ep a r a tion of
4-[2-[Met h yl-N-(ter t-b u t oxyca r b on yl)t r yp t op h a n -1-yl]-
eth oxy]ben za ld eh yd e: The title compound was prepared by
the general procedure using N-(tert-butoxycarbonyl)tryptophan
methyl ester (2.0 g, 6.31 mmol), 4-(2-bromoethoxy)benzalde-
hyde (1.45 g, 6.31 mmol), and NaH (154 mg, 6.31 mmol) in
in a desiccator for 12 h to afford 765 mg (84%) of 2f: mp 115
1
1
°C; IR νmax (KBr) 3040, 1736, 1688 cm-1; H NMR (CDCl3
+
38% (1.1 g) yield: IR νmax (KBr) 1690 cm-1; H NMR (CDCl3)
DMSO-d6) δ 12.08 (bs, 1 H, D2O exchangeable), 7.78 (s, 1 H),
7.70-7.40 (m, 4 H), 7.38 (t, J ) 6.70 Hz, 1 H), 7.20-7.0 (m, 4
H), 4.80 (t, J ) 5.30 Hz, 2 H), 4.40 (t, J ) 5.30 Hz, 2 H); 13C
NMR (DMSO-d6) δ 167.99, 167.48, 160.83, 159.87, 135.81,
132.15, 131.75, 126.76, 125.86, 125.73, 122.52, 121.34, 120.56,
115.45, 109.53, 107.20, 76.83, 65.72. Anal. Calcd for C21H16N2-
SO5 (408.42): C, 61.70; H, 3.95; N, 6.92. Found: C, 61.88; H,
4.03; N, 7.02.
δ 9.86 (s, 1 H), 7.80 (d, J ) 8.72 Hz, 2 H), 7.55 (d, J ) 7.47 Hz,
1 H), 7.36 (d, J ) 8.21 Hz, 1 H), 7.30-7.08 (m, 2 H), 7.01 (s,
1 H), 6.94 (d, J ) 8.72 Hz, 2 H), 5.20-4.90 and 4.70-4.50 (m,
1 H), 4.51 (t, J ) 5.40 Hz, 2 H), 4.33 (t, J ) 5.40 Hz, 2 H), 3.65
(s, 3 H), 3.35-3.05 (m, 2 H), 1.42 (s, 9 H).
Step B, P r ep a r a tion of 5-[[4-[2-[Meth yl-3-N-(1-bu toxy-
ca r bon yl)tr yp top h a n -1-yl]eth oxy]p h en yl]m eth ylen e]th i-
a zolid in e-2,4-d ion e: The title compound was prepared by the
general procedure using 4-[2-[methyl-N-(tert-butoxycarbonyl)-
tryptophan-1-yl]ethoxy]benzaldehyde (2.25 g, 5.54 mmol) and
thiazolidine-2,4-dione (0.71 g, 6.09 mmol) in 71% (2.20 g)
5 -[[4 -[2 -(1 -I n d o l y l )e t h o x y ]p h e n y l ]m e t h y l e n e ]-
th ia zolid in e-2,4-d ion e (2g). The title compound (12.28 g,
78%) was prepared by the general procedure using 1g (11.4 g,
43.0 mmol), thiazolidine-2,4-dione (5.03 g, 43.0 mmol), benzoic
acid (0.68 g, 5.5 mmol), and piperidine (0.61 mL, 0.53 g, 6.4
yield: mp 140-142 °C; IR νmax (KBr) 1730, 1710, 1690 cm-1
;
1H NMR (CDCl3 + DMSO-d6) δ 12.05 (bs, 1 H, D2O exchange-
able), 9.40 (bs, 1 H, D2O exchangeable), 7.59 (d, J ) 7.80 Hz,
1 H), 7.41 (d, J ) 8.72 Hz, 2 H), 7.32-7.01 (m, 4 H), 6.92 (d,
J ) 8.72 Hz, 2 H), 5.30-5.08 and 4.28-4.10 (m, 1 H), 4.51 (t,
J ) 4.80 Hz, 2 H), 4.30 (t, J ) 4.80 Hz, 2 H), 4.20-4.00 (m, 1
1
mmol): mp 216 °C; IR νmax (KBr) 1748, 1692 cm-1; H NMR
(CDCl3 + DMSO-d6) δ 12.05 (bs, 1 H, D2O exchangeable), 7.67
(s, 1 H), 7.56 (d, J ) 7.56 Hz, 1 H), 7.53 (t, J ) 7.56 Hz, 1 H),
7.43 (d, J ) 8.72 Hz, 2 H), 7.30 (d, J ) 3.0 Hz, 1 H), 7.18 (t, J

1628 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
Lohray et al.
H), 3.70 (s, 3 H), 3.30 (d, J ) 5.30 Hz, 2 H), 1.40 (s, 9 H); 13C
NMR (CDCl3) δ 190.31, 172.89, 167.84, 167.39, 160.02, 155.32,
136.14, 133.63, 132.20, 128.31, 126.87, 125.98, 121.90, 119.38,
118.99, 118.67, 115.11, 109.31, 79.94, 66.92, 54.05, 52.26,
45.25, 27.95.
1.0 g (83%) of pure compound: mp 143-144 °C; IR νmax (KBr)
1736, 1697 cm-1 1H NMR (CDCl3) δ 8.12 (bs, 1 H, D2O
;
exchangeable), 7.20-7.00 (m, 4 H), 6.88 (d, J ) 8.72 Hz, 2 H),
6.68 (t, J ) 7.0 Hz, 1 H), 6.55 (d, J ) 7.0 Hz, 1 H), 4.50 (dd, J
) 10.0, 6.0 Hz, 1 H), 4.18 (t, J ) 5.30 Hz, 2 H), 3.60-3.40 (m,
5 H), 3.12 (dd, J ) 14.0, 10.0 Hz, 1 H), 2.98 (t, J ) 7.60 Hz, 2
H); 13C NMR (CDCl3 + DMSO-d6) δ 173.88, 169.88, 156.14,
150.55, 128.76, 127.81, 126.97, 125.57, 122.69, 115.74, 113.68,
112.88, 105.02, 82.24, 64.44, 52.13, 51.72, 46.77, 26.87; MS
m/z (relative intensity) 368 (M+, 9), 139 (100). Anal. Calcd
for C20H20N2SO3 (368.14): C, 65.15; H, 5.42; N, 7.60. Found:
C, 65.50; H, 5.20; N, 7.60.
Step C, Hyd r olysis of 5-[[4-[2-[3-m eth yl-N-(1-bu toxy-
ca r bon yl)tr yp top h a n -1-yl]eth oxy]p h en yl]m eth ylen e]th i-
a zolid in e-2,4-d ion e: To a stirred solution of 5-[[4-[2-[3-[2-
(tert-butoxycarbonylamino)-2-(carbomethoxy)ethyl]indolyl]-
ethoxy]phenyl]methylene]thiazolidine-2,4-dione (1.70 g, 3.0
mmol) in 1,4-dioxone (15 mL) was added concentrated HCl (4.0
mL) at room temperature, and stirring was continued for 3 h.
Dioxane was removed under reduced pressure, and the result-
ant residue was dissolved in water (50 mL) and neutralized
with saturated aqueous K2CO3 solution. A white solid pre-
cipitated out, which was filtered and dried under vacuum to
yield 0.89 g of 2k (64%): mp 180 °C; IR νmax (KBr) 1744, 1697
5-[[4-[2-(1-In d olyl)eth oxy]p h en yl]m eth yl]th ia zolid in e-
2,4-d ion e (3g). The title compound (0.92 g, 92%) was
prepared by the above general procedure using compound 2g
(1.0 g, 2.75 mmol) and 10% Pd-C (1.5 g): mp 103 °C; IR νmax
1
(KBr) 1754, 1695 cm-1; H NMR (CDCl3 + DMSO-d6) δ 8.18
cm-1 1H NMR (CDCl3 + DMSO-d6) δ 12.10 (bs, 1 H, D2O
;
(bs, 1 H, D2O exchangeable), 7.65 (d, J ) 7.4 Hz, 1 H), 7.39 (d,
J ) 8.30 Hz, 1 H), 7.30-7.15 (m, 2 H), 7.08 (d, J ) 8.72 Hz, 2
H), 6.76 (d, J ) 8.72 Hz, 2 H), 6.50 (d, J ) 2.92 Hz, 2 H), 4.50
(t, J ) 5.52 Hz, 2 H), 4.43 (dd, J ) 9.45, 3.75 Hz, 1 H), 4.23 (t,
J ) 5.52 Hz, 2 H), 3.39 (dd, J ) 14.11, 3.74 Hz, 1 H), 3.04 (dd,
J ) 14.11, 9.45 Hz, 1 H); 13C NMR (CDCl3) δ 174.64, 170.95,
157.64, 135.99, 130.28, 128.57, 128.32, 128.17, 121.58, 121.00,
119.48, 114.72, 109.16, 101.59, 66.77, 53.56, 45.52, 37.50; MS
m/z (relative intensity) 367 (M+ + 1, 19), 130 (100). Anal.
Calcd for C20H18N2SO3 (366.41): C, 65.50; H, 4.95; N, 7.64.
Found: C, 65.50; H, 4.49; N, 7.62.
exchangeable), 7.66 (s, 1 H), 7.54 (d, J ) 7.47 Hz, 1 H), 7.43
(d, J ) 8.72 Hz, 2 H), 7.42 (s, 1 H), 7.30-7.00 (m, 4 H), 6.96
(d, J ) 8.72 Hz, 2 H), 4.54 (t, J ) 4.88 Hz, 2 H), 4.35 (t, J )
4.88 Hz, 2 H), 3.90-3.70 (m, 1 H), 3.66 (s, 3 H), 3.30-3.10 (m,
1 H), 3.10-2.90 (m, 1 H). Anal. Calcd for C24H23N3SO5
(466.14): C, 61.84; H, 5.10; N, 9.01. Found: C, 61.77; H, 5.00;
N, 8.88.
5-[[4-[2-(1-C a r b a zo ly l)e t h o x y ]p h e n y l]m e t h y le n e ]-
th ia zolid in e-2,4-d ion e (2l). The title compound was pre-
pared by the general procedure using 1l (2.5 g, 7.9 mmol) and
thiazolidine-2,4-dione (0.93 g, 7.9 mmol) in 95% (3.1 g) yield:
5-[[4-[2-(Ca r b a zol-1-yl)et h oxy]p h en yl]m et h yl]t h ia zo-
lid in e-2,4-d ion e (3l). The title compound was prepared by
the above general procedure using 2l (1.25 g, 3.02 mmol) and
10% Pd-C (1.62 g) in 80% (1.0 g) yield: mp 214 °C; IR νmax
(KBr) 1755, 1680 cm-1; 1H NMR (CDCl3 + DMSO-d6) δ 11.89
(bs, 1 H, D2O exchangeable), 8.06 (d, J ) 7.47 Hz, 2 H), 7.57
(d, J ) 8.30 Hz, 2 H), 7.45 (t, J ) 7.47 Hz, 2 H), 7.21 (t, J )
8.20 Hz, 2 H), 7.07 (d, J ) 8.20 Hz, 2 H), 6.72 (d, J ) 8.20 Hz,
2 H), 4.75 (t, J ) 5.80 Hz, 2 H), 4.42 (dd, J ) 9.0, 6.0 Hz, 1 H),
4.35 (t, J ) 5.30 Hz, 2 H), 3.37 (dd, J ) 14.0, 6.0 Hz, 1 H),
2.99 (dd, J ) 14.0, 9.0 Hz, 2 H); 13C NMR (CDCl3 + DMSO-
d6) δ 175.76, 171.74, 157.12, 140.26, 130.34, 128.87, 125.66,
122.16, 120.16, 118.91, 114.22, 109.60, 66.25, 53.03, 42.04,
36.27; MS m/z (relative intensity) 416 (M+, 11), 180 (100). Anal.
Calcd for C24H20N2SO3 (416.48): C, 69.15; H, 4.84; N, 6.73.
Found: C, 69.50; H, 4.81; N, 6.78.
mp 277-278 °C; IR νmax (KBr) 1752, 1695 cm-1 1H NMR
;
(CDCl3 + DMSO-d6) δ 12.12 (bs, 1 H, D2O exchangeable), 8.07
(d, J ) 7.48 Hz, 2 H), 7.65 (s, 1 H), 7.60 (d, J ) 8.30 Hz, 2 H),
7.47 (t, J ) 8.30 Hz, 2 H), 7.39 (d, J ) 7.89 Hz, 2 H), 7.23 (t,
J ) 7.48 Hz, 2 H), 6.91 (d, J ) 7.89 Hz, 2 H), 4.80 (t, J ) 4.89
Hz, 2 H), 4.46 (t, J ) 4.89 Hz, 2 H); 13C NMR (DMSO-d6) δ
167.97, 167.42, 159.72, 140.23, 132.00, 131.67, 125.68, 122.18,
120.45, 120.17, 119.22, 118.96, 115.17, 109.59, 66.75, 41.91;
MS m/z (relative intensity) 414 (M+, 6), 180 (100). Anal. Calcd
for C24H18N2SO3 (414.47): C, 69.54; H, 4.37; N, 6.75. Found:
C, 69.31; H, 4.32; N, 6.70.
Gen er a l P r oced u r e of P r ep a r a tion of 5-[[4-2-(Heter o-
cyclyl)eth oxy]p h en yl]m eth yl]th ia zolid in e-2,4-d ion es 3.
A solution of the appropriate thiazolidine-2,4-dione 2 (1.0 g)
in 1,4-dioxane (35 mL) was added to 10% Pd-C (1.5 g) and
hydrogenated at 60 psi for 36-60 h. The mixture was filtered
through a bed of Celite, and the filtrate was evaporated to
dryness under reduced pressure. The residue was chromato-
graphed on silica gel using a mixture of ethyl acetate and
petroleum ether as an eluent to yield pure compound.
Ack n ow led gm en t. We are thankful to Dr. K. Anji
Reddy, Chairman, and Dr. A. Venkateswarlu, President,
of Dr. Reddy’s Research Foundation for constant en-
couragement. We wish to thank DRF for overall support.
5-[[4-[2-(7-Aza in d ol-1-yl)eth oxy]p h en yl]m eth yl]th ia zo-
lid in e-2,4-d ion e (3a ). The title compound was prepared by
the general procedure using 2a (1.0 g, 2.74 mmol) and 10%
Pd-C (1.5 g) in 70% (0.70 g) yield: mp 195 °C; IR νmax (KBr)
Refer en ces
1
1744, 1701 cm-1; H NMR (CDCl3 + DMSO-d6) δ 11.78 (bs, 1
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Turner, R. C.; Mathews, D. R.; Clark, A.; O’Rahilly, S.; Rudenski,
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H, D2O exchangeable), 8.38 (d, J ) 5.0 Hz, 2 H), 7.96 (d, J )
8.7 Hz, 1 H), 7.48 (d, J ) 5.0 Hz, 1 H), 7.20-7.12 (m, 1 H),
7.18 (d, J ) 8.70 Hz, 2 H), 6.86 (d, J ) 8.70 Hz, 2 H), 6.50 (d,
J ) 5.0 Hz, 1 H), 4.78 (t, J ) 5.30 Hz, 2 H), 4.44 (dd, J ) 9.0,
6.0 Hz, 1 H), 4.40 (t, J ) 5.30 Hz, 2 H), 3.42 (dd, J ) 14.5, 6.0
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129.09, 128.55, 128.21, 120.02, 115.40, 114.95, 99.00, 66.26,
52.95, 43.24, 36.68; MS m/z (relative intensity) 368 (M++ 1,
16), 118 (100). Anal. Calcd for C19H17N3SO3 (367.42): C,
62.11; H, 4.66; N, 11.43. Found: C, 62.50; H, 4.00; N, 11.50.
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5-[[4-[2-(1-In dolin yl)eth oxy]ph en yl]m eth yl]th iazolidin e-
2,4-d ion e (3d ). To a stirred solution of 5-[[4-[2-(1-indolyl)-
ethoxy]phenyl]methyl]thiazolidine-2,4-dione (3g) (1.2 g, 3.20
mmol) in 10 mL of glacial acetic acid was added sodium
cyanoborohydride (609 mg, 9.8 mmol) at 20 °C in portions, and
the mixture stirred for 1 h at the same temperature. The
reaction mixture was diluted with EtOAc, washed with brine,
dried over anhydrous Na2SO4, and concentrated. The result-
ant residue was crystallized from dichloromethane to furnish
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