Novel euglycemic and hypolipidemic agents. 4. Pyridyl- and quinolinyl- containing thiazolidinediones

Article abstract of DOI:10.1021/jm980622j

A series of substituted pyridyl- and quinolinyl-containing 2,4- thiazolidinediones having interesting cyclic amine as a linker have been synthesized. Both unsaturated thiazolidinediones 5 and saturated thiazolidinediones 6 and their various salts were evaluated in db/db mice for euglycemic and hypolipidemic effects and compared with BRL compound 11 and BRL-49653, respectively. Some of the potent compounds were converted to various salts in order to obtain improved activities. Among all the salts evaluated, the maleate salt of unsaturated TZD 5a was found to be a very potent euglycemic and hypolipidemic compound. Some of the more interesting compounds have also been evaluated in ob/ob mice and compared with rosiglitazone (maleate salt of BRL-49653). Oral glucose tolerance tests were performed in both db/db and ob/ob mice. Pharmacokinetic studies of 5a maleate are also reported. Receptor binding studies of PPARγ by 5a/5a maleate did not show any significant transactivation of PPARα or PPARγ.

Full text of DOI:10.1021/jm980622j

J . Med. Chem. 1999, 42, 2569-2581
2569
Novel Eu glycem ic a n d Hyp olip id em ic Agen ts. 4. P yr id yl- a n d
Qu in olin yl-Con ta in in g Th ia zolid in ed ion es‡
B. B. Lohray,*,† Vidya Bhushan,† A. Sekar Reddy,† P. Bheema Rao,† N. J aipal Reddy,† P. Harikishore,†
N. Haritha,† Reeba K.Vikramadityan,§ Ranjan Chakrabarti,§ R. Rajagopalan,§ and K. Katneni∇
Departments of Medicinal Chemistry and Drug Discovery, Pharmacology, and Pharmacokinetics,
Dr. Reddy’s Research Foundation, Bollaram Road, Miyapur, Hyderabad 500 050, India
Received March 15, 1999
A series of substituted pyridyl- and quinolinyl-containing 2,4-thiazolidinediones having
interesting cyclic amine as a linker have been synthesized. Both unsaturated thiazolidinediones
5 and saturated thiazolidinediones 6 and their various salts were evaluated in db/db mice for
euglycemic and hypolipidemic effects and compared with BRL compound 11 and BRL-49653,
respectively. Some of the potent compounds were converted to various salts in order to obtain
improved activities. Among all the salts evaluated, the maleate salt of unsaturated TZD 5a
was found to be a very potent euglycemic and hypolipidemic compound. Some of the more
interesting compounds have also been evaluated in ob/ob mice and compared with rosiglitazone
(maleate salt of BRL-49653). Oral glucose tolerance tests were performed in both db/db and
ob/ob mice. Pharmacokinetic studies of 5a maleate are also reported. Receptor binding studies
of PPARγ by 5a /5a maleate did not show any significant transactivation of PPARR or PPARγ.
In tr od u ction
thiazolidinedione class of molecules,3 which in turn may
be due to their binding to peroxisome proliferator
activator receptor (PPAR) belonging to the steroid/
thyroid/retinoid receptor superfamily of ligand-activated
transcription factors. There have been a number of
reports that the thiazolidinediones (TZDs) are high-
affinity PPARγ agonists, and there is a direct correlation
between the in vitro potency at the PPARγ receptor and
the in vivo antihyperglycemic potency in C57BL/6J /ob/
ob mice for a series of TZDs.5 Mukherjee et al.6 have
recently proposed an indirect agonism of PPARγ through
another nuclear receptor called retinoid X receptor
(RXR), which forms a heterodimer with PPARγ. They
suggest that this may lead to a new pathway for treating
type 2 diabetics. Although there has been no conclusive
evidence in support or against these hypotheses, re-
search has been directed toward finding appropriate
molecules which ameliorate insulin resistance without
binding to PPARγ. Recently, Aicher et al.7 have reported
a new class of insulin sensitizers (not TZDs) which do
not act through PPAR mechanism, although they sig-
nificantly improved glucose metabolism and insulin
sensitivity in ob/ob mice. In fact, a similar observation
has been reported on a potent antidiabetic thiazo-
lidinedione, MCC-555, which shows excellent euglyce-
mic activity, comparable to BRL-49653.8 The TZD MCC-
555 exhibits binding affinity for PPARγ less than 1/10
that of BRL-49653. Reginato et al.8 explained these
observations based on the effect of MCC-555 binding on
PPARγ transcriptional activity which is highly context-
specific, such that it can function as full agonist, partial
agonist, or antagonist depending on the cell type or DNA
binding site. These transcriptional properties are par-
tially explained by unique partial agonism of coactivator
recruitment to PPARγ. The context-specific selectivity
Impaired insulin action is thought to be the cause of
hyperglycemia and type 2 diabetes (non-insulin-depend-
ent diabetes mellitus).1 The reason for such insulin
resistance still evades our present knowledge of under-
standing. The mechanism of action of drugs which
enhance the action of insulin remains by and large
elusive. Despite our poor understanding, several thia-
zolidinedione classes of compounds have been developed
for achieving tight blood glucose control in type 2
diabetes patients.2 Recently, troglitazone has been ap-
proved in several countries for the treatment of diabetes;
however, several clinicians raised their concerns regard-
ing the safety of troglitazone as well as the thiazo-
lidinedione class of compounds.3 In the United States
and J apan, several cases of liver damage and drug-
related deaths due to liver damage3 have been reported;
however, weighing the benefit against the idiosyncratic
liver toxicity in troglitazone-treated patients, the U.S.
Food and Drug Administration authority has allowed
the marketing of troglitazone with a change of labeling
instructions together with regular monitoring of liver
enzyme levels. More recently, the Public Citizen’s
Health Research group has requested the U.S. Food and
Drug Administration to initiate action to ban troglita-
zone because of 560 cases of liver toxicity related to
troglitazone which have been reported since the drug
was first marketed in March 1997.4 Hence, there is a
definite need for a safe and efficacious euglycemic agent
for the treatment of type 2 diabetic patients.
There has been speculation that the liver toxicity
observed with troglitazone may be associated with the
‡ DRF Communication No. 61.
* Address for correspondence: Zydus Research Centre, Zydus Tower,
Satellite Cross Rd, Sarkhej-Gandhinagar Highway, Ahmedabad 380
015, India. Fax: 079-6732365. E-mail: bblohray@icenet.net.
† Department of Medicinal Chemistry and Drug Discovery.
§ Department of Pharmacology.
∇ Department of Pharmacokinetics.
10.1021/jm980622j CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/22/1999

2570 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14
Lohray et al.
amines 2 such as (S)-prolinol, piperidine, or morpholine-
3-carbinol to furnish excellent yield (50-100%) of
compound 3 which was reacted with 4-fluorobenzalde-
hyde to afford aldehyde 4 (36-67%). The latter was
treated with 2,4-thiazolidinedione12 to furnish the un-
saturated compound 5 (52-100%) which can be reduced
either by hydrogenation or by Mg-CH3OH13 to afford
the saturated thiazolidinedione 6 (Scheme 1). Alterna-
tively, the saturated TZDs are also prepared via the
reaction of 4-fluoronitrobenzene with 3 to afford 7.
Compound 7 was reduced to give aniline derivative 10.
The latter was converted to saturated TZD 6 by a known
method.14 Various salts of unsaturated TZD 5 or satu-
rated TZD 6 were prepared for pharmacological evalu-
ation and to study their pharmacokinetic profiles. The
results are collected in Tables 1-3.
F igu r e 1. Approach to novel thiazolidinediones derived from
BRL-49653.
of MCC-555 may contribute to its enhanced hypoglyce-
mic potency in vivo despite reduced affinity for PPARγ.
This raises the possibility that only a subset of the
functions of activated PPARγ contributes to insulin
sensitivity and that therapeutic strategies for NIDDM
that target these functions may lead to compounds with
increased potency and decreased toxicity.
Biologica l P r oced u r es
Eu glycem ic a n d Hyp olip id em ic Activity Stu d ies.
Male C57BL/KsJ -db/db mice were obtained at 6 weeks
age from J ackson Laboratories (Bar Harbor, ME) and
maintained at 25 ( 2 °C on a 12-h light/12-h dark cycle.
The animals were given standard laboratory chow
(National Institute of Nutrition, Hyderabad, India) and
water, ad libitum. The db/db mice were used for experi-
ments 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 6 days. Rosiglitazone (30 mg/kg) was used as a
standard drug. The control animals were given vehicle
(0.5% carboxymethylcellulose, CMC; dose 10 mL/kg). On
the final day blood samples (25-50 µL) were collected
after 1 h of drug adminstration from the retro-orbital
sinus through heparinized capillary in EDTA-containing
tubes. After centrifugation, plasma was separated and
glucose and triglyceride were estimated using com-
mercial kits (Dr. Reddy’s Laboratories Diagnostic Divi-
sion, India). 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. Dose-response
studies for selected TZDs were carried out in both db/
db and ob/ob mice. Animals were treated with different
doses for 14-15 days. Plasma glucose and triglyceride
were measured on days 0, 3, 6, 9, 12, and 15. The
percentage reduction in plasma glucose level was cal-
culated.15 Oral glucose tolerance test (OGTT) was
performed after 14/15 days of treatment in both db/db
and ob/ob mice. In the case of db/db animals, mice were
fasted overnight and challenged with glucose (3 g/kg,
po). Blood samples were collected at 0, 30, 60, and 120
min for measuring plasma glucose level. The improve-
ment in glycemic control was calculated as percentage
reduction in the area under the plasma glucose content
versus time curve (AUC). The AUC was calculated using
trapezoidal rule.
We have also found recently that several TZDs which
are weak agonists of PPARγ also exhibit good euglyce-
mic activity.9 With this mechanistic point in view, we
planned to search for molecules which may show good
euglycemic activities without agonizing PPARγ and
therefore may show less toxicity, if transactivation of
PPARγ is associated with their toxicity profile. In the
recent past, we have been interested in developing novel
thiazolidinediones which show a superior safety and
efficacy profile.10,11 Rosiglitazone (maleate salt of BRL-
49653) which is an excellent PPARγ agonist has recently
been approved by the U.S. FDA and is known to be
severalfold superior in efficacy to troglitazone. Rosigli-
tazone is also superior in efficacy to pioglitazone, which
can very well be visualized as its own congener (Figure
1). This perception led us to modify rosiglitazone which
resulted in the discovery of DRF-218910 (Figure 1). The
latter is equipotent to rosiglitazone and is currently
undergoing further studies. However, our search for
thiazolidinediones having similar efficacy and potency
with low PPARγ transactivation activities and an
improved safety profile continued. In the present article
we describe our attempts to modify the structural motif
of BRL-49653 which resulted in an equally efficacious
thiazolidinedione (vide infra) without having any sig-
nificant PPARγ activity.
Earlier, we disclosed the results of our attempts of
incorporating the methyl group on the nitrogen of BRL-
49653 in a ring with or without the help of a carbon or
nitrogen atom.10 In the present article, we wish to report
our strategy of the incorporation of the same N-Me
group of BRL-49653 in the side chain of the linker with
the help of a carbon atom or other heteroatom as shown
in Figure 1 (structure A) and also the structure-activity
relationship of this class of thiazolidinediones.
Similarly, OGTT was performed in ob/ob mice after
15 days of treatment; however, the mice were challenged
with glucose (3 g/kg, po) after a 5-h fast. Blood samples
were collected at different time intervals as described
earlier.
P h a r m a cok in etic Stu d ies. Pharmacokinetic study
of 5a maleate was carried out in male Wistar rats (n )
Ch em istr y
Several pyridyl- and quinolinyl-containing thiazo-
lidinediones were prepared. A general synthetic route
is shown in Scheme 1. Substituted 2-chloropyridine or
2-chloroquinoline 1 was treated with different cyclic

Novel Euglycemic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14 2571
Sch em e 1a
a
(a) Neat, 160 °C, 50-100% yield; (b) 4-fluorobenzaldehyde, NaH, DMF, 40-76% yield; (c) (i) methanesulfonyl chloride, triethylamine,
CH2Cl2, 83-90% yield, (ii) 4-hydroxybenzaldehyde, K2CO3, DMF, 80 °C, 36-45% yield; (d) 2,4-thiazolidinedione, piperidine, C6H5COOH,
toluene, ∆, 63-100% yield; (e) 4-fluoronitrobenzene, NaH, DMF, 36-67% yield; (f) Fe, HCl, EtOH, 96-100% yield; (g) (i) ethyl acrylate,
NaNO2, HBr or HCl, Cu2O, acetone, MeOH, 44-85% yield, (ii) thiourea, NaOAc, EtOH, 80 °C or thiourea, sulfolane, 120-130 °C; 2 N
HCl, EtOH, 80 °C, 62-95%; (h) Mg-MeOH, 48-65% yield; (i) maleic acid, acetone/Et2O, 70-80% yield; (j) HCl; (g) acetone, 73-86%
yield; (k) NaOMe, MeOH, 52-91% yield.
3) obtained from the National Institute of Nutrition
(Hyderabad, India). The animals (200-225 g) were
fasted 12 h before starting the experiment, and they had
free access to water throughout the experimental period.
Animals were given feed 3 h after drug administration.
Pharmacokinetic parameters: AUC(0-∞) is the area
under the plasma concentration versus time curve
extrapolated to infinity, Cmax is the observed maximum
plasma concentration, and tmax is the time at which
maximum concentration (Cmax) is reached.
Sin gle-Dose P h ar m acokin etics. Animals were dosed
with 5a maleate at 10 mg/kg via oral gavage as 0.5%
CMC suspension, and about 0.30 mL of blood sample
was collected into heparinized microfuge tubes at dif-
ferent time points from the retro-orbital sinus. The
samples were analyzed by reverse-phase HPLC to
generate plasma concentration-time profiles (Figure 4).
Sa m p le P r ep a r a tion a n d An a lysis. To 0.1 mL of
plasma was added internal standard (another thiazo-
lidinedione), and drug was extracted from the plasma
using 2 mL of extracting solvent (ethyl acetate:dichlo-
romethane, 1:1). The organic layer (1.5 mL) was evapo-
rated to dryness and reconstituted in 200 µL of mobile
phase; 100 µL of the sample was injected onto HPLC.
The calibration, control, and recovery samples were
prepared by spiking blank plasma and were processed
similarly. The HPLC system consisted of a Waters LC
Module-1 with Millennium software and a KROMASIL
KR100-5C18-250A (5 µm, 4.6 mm × 250 mm) column
(Hichrom, U.K.). Analysis of 5a maleate was carried out
using 0.05 M NaH2PO4 buffer (pH 4.0):methanol (25:
75) as mobile phase at a flow rate of 1 mL/min, and the
eluent was monitored with UV dector at 345 nm. Under
these conditions, retention times for 5a maleate and
internal standard were 12.6 and 8.4 min, respectively.
Absolute recovery was >95%, the limit of quantification
was 0.1 µg/mL, and the response was linear up to 50
µg/mL.
Resu lts a n d Discu ssion
We prepared several thiazolidinedione analogues
containing pyridine or quinoline moieties and evaluated
their pharmacological profiles for plasma glucose- and
triglyceride-lowering activities in db/db mice. The ani-
mals were treated for 6 days at a dose of 100 mg/kg/
day (Table 1). We have used unsaturated BRL com-
pound 11 for comparison. The results are shown in
Table 1. The unsaturated TZD 5a , which was readily
prepared by the reaction of 2-chloropyridine with (S)-
prolinol as shown in Scheme 1, showed very good
euglycemic and hypolipidemic activities in db/db mice
(Table 1, entry 1). In contrast, unsaturated TZDs
resulting from the combination of 2-chloropyridine and
other cyclic amines as the linker group such as piperi-
dine or piperazine (Table 1, entries 2-4) showed much
poorer pharmacological activities. However, compound
5e containing morpholine as the cyclic linker showed
appreciably good euglycemic and hypolipidemic activi-
ties (Table 1, entry 5). It appears that 2-(S)-prolinol is
the most suitable linker for this class of compounds.
Thus, we examined the combination of quinoline with
(S)-prolinol, which afforded unsaturated TZD 5f. The

2572 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14
Lohray et al.
Ta ble 1. Euglycemic and Hypolipidemic Activities of Unsaturated TZDs
a
b
Percentage reduction in plasma glucose after 6 days of treatment in db/db mice via oral gavage. Percentage reduction in plasma
triglyceride. BRL compound 11 was prepared according to the reported procedure;12 NS, not significant.
TZD 5f showed very good euglycemic activity but barely
had any effect on the triglyceride level (Table 1, entry
6). From these initial screenings, we concluded that a
further examination of saturated TZDs resulting from
the combination of pyridine or quinoline with (S)-
prolinol and morpholine derivatives is essential.
Hence, we prepared saturated TZDs 6a and 6e by
saturating potent unsaturated TZDs 5a and 5e, respec-
tively. Surprisingly, in both the cases, even at a 30 mg/
kg/day dose (Table 2) the euglycemic activity remained
impressive, although the hypolipidemic activity of 5e
completely disappeared (Table 2, entries 1 and 2). BRL-
49653 was used as positive control (Table 2, entry 5).
In contrast, the quinolinyl-substituted TZD 6f prepared
from 5f or through an independent route as shown in
Scheme 1 showed excellent euglycemic and hypolipi-
demic activities at 30 mg/kg dose in db/db mice (Table
2, entry 3), and the plasma glucose reached the level of
lean littermates (8 ( 1 mM). We have also examined
the effect of an electron-donating CH3 group at the C4
position of quinoline (Table 2, entry 4), which resulted
in reduction in euglycemic activity; however, an im-
provement in hypolipidemic activity was observed (6g
versus 6f).
sodium salt of 5a showed improved euglycemic and
hypolipidemic activities when compared to their parent
compound 5a (Table 1, entry 1 versus Table 3, entries
1-3; although comparison cannot be done at different
doses). The hydrochloride salt of 5e (Table 3, entry 4)
showed moderate activity. Even at 30 mg/kg/day dose,
the maleate, hydrochloride, and sodium salts of 5a
showed superior euglycemic activities (Table 3, entries
1-3) compared to the parent compound 5a (Table 1,
entry 1) which was evaluated at 100 mg/kg/day dose.
The improvement in euglycemic activities of various
salts of 5a may be attributed to the improvement of the
pharmacokinetic profile.
Similar observations were made with saturated TZDs
6a , 6e, 6f, and 6g. In all cases maleate, hydrochloride,
and sodium salts were prepared (only the maleate and
sodium salts were made for 6e), and all of them were
studied in db/db mice at 30 mg/kg dose (Table 3);
rosiglitazone (maleate salt of BRL-49653) was used as
the standard drug for comparison purposes. All the salts
of TZD 6a (Table 3, enties 5-7) showed excellent
euglycemic activities at 30 mg/kg dose, and the plasma
glucose level in these animals reached the level of lean
littermates (i.e. 8 ( 1 mM). Although all the salts of 6a
(Table 3, entries 5-7) showed equal effects on glucose
level, it is not clear why they show different levels of
triglyceride lowering. It is believed that different salts
play a role in bioavailability of the drug and should not
be affected by the mechanism of action of the drug. With
the present understanding, it is difficult to speculate
the reason for varying effects on triglyceride levels due
From the above studies, it is clear that the unsatur-
ated TZDs 5a , 5e, and 5f and their saturated counter-
parts 6a , 6e, and 6f constitute a potent class of TZDs,
and they need further detailed evaluation. Thus we
prepared various salts of 5a and 5e which are the most
potent unsaturated TZDs and evaluated their biological
activities. Interestingly, the maleate, hydrochloride, or

Novel Euglycemic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14 2573
Ta ble 2. Euglycemic and Hypolipidemic Activities of Unsaturated TZDs
a
b
Percentage reduction in plasma glucose after 6 days of treatment in db/db mice via oral gavage. Percentage reduction in plasma
triglyceride. BRL-49653 was prepared according to the reported procedure;12 NS, not significant.
Ta ble 3. Euglycemic and Hypolipidemic Activities of Various
5f and saturated TZDs 6a , 6e, 6f, and 6g, it is not
Salts of TZDs 5 and 6
possible to draw any meaningful SAR in the case of their
entry no.
compd no.
dose
PGa
TGb
various salts (Table 3, entries 1-14). When we compare
the different salts of TZDs reported in Table 3 with
BRL-49653 (Table 3, entry 15), it is clear that maleate
and hydrochloride salts of TZD 5a (Table 3, entries 1
and 2) or their saturated counterparts, i.e., 6a (Table
3, entries 5 and 6) and sodium salt of TZD 6e (Table 3,
entry 8), are comparable to rosiglitazone (Table 3, entry
15) in their pharmacological activities.
1
2
5a maleate
5a HCl
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
63.6 ( 4.61
70.8 ( 4.36
56.5 ( 7.19
35.5 ( 9.5
62.5 ( 4.33
50.5 ( 6.9
65.5 ( 5.45
63.5 ( 7.41
NS
66.4 ( 9.76
31.67 ( 14.4
56.0 ( 8.76
NS
44.75 ( 14.84
50.5 ( 7.29
NS
3
5a Na
4
5e HCl
5
6
6a maleate
6a HCl
7
6a Na
8
6e Na
56.75 ( 12.93
9
6f maleate
6f HCl
6f Na
6g maleate
6g HCl
6g Na
NS
10
11
12
13
14
15
15.75 ( 16.87 NS
61.5 ( 13.33
Finally, we selected the maleate and hydrochloride
salts of 5a , maleate salt of saturated TZD 6a , and
sodium salt of 6e for dose-response studies in db/db
mice and compared them with BRL-49653. The animals
were treated with different doses for 14-15 days, and
plasma glucose and triglyceride levels were measured
in each case. The results are summarized in Table 4.
24.75 ( 7.47
NS
53.0 ( 5.15
42.0 ( 6.88
58.5 ( 6.12
41.0 ( 17.7
25.25 ( 7.5
30.25 ( 4.63
64.6 ( 5.35
rosiglitazone
a
Percentage reduction in plasma glucose after
6 days of
b
treatment in db/db mice via oral gavage. Percentage reduction
in plasma triglyceride. Rosiglitazone was prepared according to
the reported procedure;12 NS, not significant.
Rosiglitazone showed superior euglycemic activity at
3 mg/kg dose (plasma glucose, 42 ( 2%; triglyceride, 47
( 15%) than 5a maleate, 6a maleate, and 6e sodium
salt; however, at higher doses, i.e., 10 and 30 mg/kg,
all four compounds were equipotent or sometimes
superior to rosiglitazone (BRL-49653). In addition, 5a
maleate especially showed better triglyceride-lowering
activities at 10 and 30 mg/kg dose than rosiglitazone.
It is pertinent to mention that an efficient control of
triglyceride levels in type 2 diabetic patients has shown
beneficial effects in diabetes-related complications es-
pecially atherosclerosis and cardiovascular diseases.
Thus, a consensus has emerged in the recent past that
the drugs which control both PG and TG tightly would
be more suitable candidates for further development for
the treatment of type 2 diabetes.
to various salts (Table 3, entries 5-7; triglyceride 50%-
NS). In the case of the sodium salt of saturated TZD
6e, there was no improvement in euglycemic activity
but significant changes were observed in the hypolipi-
demic activity at 30 mg/kg dose (compared to parent
compound 6e Table 3, entry 8 versus Table 2, entry 2).
In contrast, the salts of 6f were inferior in their
euglycemic and hypolipidemic activities when compared
to saturated TZD 6f (Table 3, entries 9-11 versus Table
2, entry 2). Similar observations were made with various
salts of TZD 6g which showed poorer euglycemic and
hypolipidemic activities than their parent compound 6g
(Table 3, entries 12-14 versus Table 2, entry 4).
Although there seems to be a meaningful structure-
activity relationship between unsaturated TZDs 5a -

2574 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14
Lohray et al.
Ta ble 4. Dose-Response Studies of Selected TZDs in db/db
Mice
Ta ble 5. Dose-Response Studies of Selected TZDs in ob/ob
Mice
compd no.
dose (mg/kg/day)
PGa
TGb
compd no.
5a maleate
dose (mg/kg/day)
PGa
TGb
5a maleate
3
10
30
3
10
30
3
10
20
3
10
3
12.75 ( 4.55 75.00 ( 5.31
49.60 ( 6.95 78.40 ( 3.64
63.60 ( 4.61 71.25 ( 10.58
53.80 ( 2.33
61.00 ( 2.30 43.80 ( 6.17
70.80 ( 4.36 31.67 ( 14.44
8.50 ( 6.96 41.50 ( 16.14
40.33 ( 3.53 NS
41.25 ( 9.04 34.50 ( 11.59
34.67 ( 9.39 39.25 ( 12.32
66.00 ( 3.94 39.00 ( 5.85
41.60 ( 2.29 47.00 ( 15.04
47.25 ( 5.74 35.25 ( 20.40
65.00 ( 5.36 41.00 ( 17.70
1
3
10
30
1
52.40 ( 6.36
40.25 ( 13.48 59.00 ( 14.10
65.75 ( 10.48
69.25 ( 4.01
73.00 ( 1.73
18.80 ( 7.14
50.20 ( 3.80
42.40 ( 7.26
37.20 ( 5.34
30.00 ( 8.15
35.60 ( 7.84
39.80 ( 6.61
41.50 ( 6.44
68.50 ( 2.40
46.60 ( 4.03
39.33 ( 11.02
35.00 ( 13.43
53.00 ( 7.51
NS
5a HCl
5a HCl
3
6a maleate
10
30
1
3
10
6e Na
6e Na
NS
NS
rosiglitazone
a
Percentage reduction in plasma glucose after 14 days of
10
30
b
treatment in ob/ob mice. Percentage reduction in triglyceride
after 14 days of treatment in ob/ob mice via oral gavage; NS, not
significant.
a
Percentage reduction in plasma glucose after 14 days of
b
treatment in db/db mice. Percentage reduction in triglyceride
after 14 days of treatment in db/db mice via oral gavage; NS, not
significant.
F igu r e 3. Oral glucose tolerance test of 5a maleate in ob/ob
mice.
Finally, we carried out pharmacokinetic studies of 5a
maleate in order to assess its oral bioavailability and
half-life (t1/2) in animals (Figure 4). From the results it
is clear that 5a maleate showed high AUC (26.55 ( 9.27
µg h mL-1), is absorbed very rapidly (tmax 1 h), and
reached Cmax (8.42 ( 1.9 µg mL-1). The compound is
also excreted (Kel 0.37 ( 0.08 h-1) fast and has t1/2 of
ca. 2 h (1.94 ( 0.41 h).
Although 5a maleate showed a short half-life, still it
exerts its euglycemic and hypolipidemic activities quite
effectively. Further, to understand the mode of action
of 5a and 5a maleate, we carried out a receptor
transactivation assay. Thus, we carried out transacti-
vation studies (PPARγ at 0.1, 1, and 10 µM concentra-
tion and PPARR at 50 µM concentration) for 5a and 5a
maleate. We were rather gratified to find that neither
5a nor 5a maleate showed significant PPARR or PPARγ
activation.5 (PPARγ activation for 5a maleate at 0.1, 1.0,
and 10 µM showed 0.9-, 1.1-, and 1.0-fold transactiva-
tion.) We also examined the PPARγ transactivation of
corresponding saturated TZD 6a at similar concentra-
tions (i.e. 0.1, 1.0, and 10 µM). Interestingly, the
F igu r e 2. Oral glucose tolerance test of 5a maleate in db/db
mice.
From the above dose-response studies in db/db mice,
it is clear that 5a maleate and 5a hydrochloride are
suitable candidates for further studies. The ED50 values
for 5a maleate and 5a hydrochloride are in the range
of 11-7 mg/kg. An oral glucose tolerance test performed
after 14 days of treatment of 5a maleate in db/db mice
showed remarkable improvement in glucose tolerance
as shown in Figure 2.
We further performed dose-response studies of 5a
maleate, 5a hydrochloride, and 6e sodium in another
animal model (C57BL/6J /ob/ob) to examine the species
variation. In ob/ob mice also 5a maleate showed excel-
lent plasma glucose- and triglyceride-lowering activities,
when treated for 14 days (Table 5).
We also carried out oral glucose tolerance test espe-
cially with 5a maleate in ob/ob mice after 15 days of
treatment. The results are shown in Figure 3. It is clear
that 5a maleate showed impressive improvement in
glucose tolerance even at 10 mg/kg dose.

Novel Euglycemic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14 2575
2.05 (m, 3 H), 3.2-3.9 (m, 4 H), 4.25 (m, 1 H), 6.43 (d, J ) 8.4
Hz, 1 H), 6.58 (t, J ) 6.0 Hz,1 H), 7.5 (m, 1 H), 8.02 (d, J ) 4.2
Hz, 1 H); Mass m/z (relative intensity) 179 (M+ + 1, 29), 147
(100).
(S)-4-[[1-(P yr id in -2-yl)p yr r olid in -2-yl]m eth oxy]ben za l-
d eh yd e (4a ). To a stirred suspension of sodium hydride (3 g,
60% w/w dispersion) in DMF (20 mL) was added (S)-2-
(hydroxymethyl)-1-(pyridin-2-yl)pyrrolidine (9 g, 50.5 mmol)
in dry DMF (20 mL), and the mixture was stirred for 30 min.
A solution of 4-fluorobenzaldehyde (10.8 mL, 101 mmol) in dry
DMF (20 mL) was added and stirred for 12 h at room
temperature. The reaction mixture was quenched with water
(200 mL) and extracted with EtOAc (2 × 100 mL). The
combined organic extracts were washed with brine (50 mL),
dried over anhydrous Na2SO4, and concentrated. The residue
was chromatographed over silica gel using a mixture of ethyl
acetate and petroleum ether (4:96) as eluent to get 9.6 g (67%)
of title compound as a viscous liquid: IR νmax (neat) 1690, 1600
cm-1; 1H NMR (CDCl3, 200 MHz) δ 2.1 (m, 4 H), 3.3 (m, 1 H),
3.5 (m, 1 H), 3.96 (t, J ) 8.7 Hz, 1 H), 4.4 (dd, J ) 9.6 and 3.4
Hz, 1 H), 4.55 (m, 1 H), 6.41 (d, J ) 8.8 Hz, 1 H), 6.59 (m, 1
H), 7.13 (d, J ) 8.8 Hz, 2 H), 7.46 (m, 1 H), 7.82 (d, J ) 8.8
Hz, 2 H), 8.18 (d, J ) 3.8 Hz, 1 H), 9.87 (s, 1H); Mass m/z
(relative intensity) 283 (M+ + 1, 7.5), 147 (100).
5-[4-[[1-(P yr id in -2-yl)-(2S)-p yr r olid in -2-yl]m et h oxy]-
p h en ylm eth ylen e]th ia zolid in e-2,4-d ion e (5a ). A mixture
of (S)-4-[[1-(pyridin-2-yl)pyrrolidin-2-yl]methoxy]benzaldehyde
(7.93 g, 28.12 mmol), thiazolidine-2,4-dione (3.94 g, 33.74
mmol), benzoic acid (0.446 g, 3.65 mmol), and piperidine (0.359
g, 4.2 mmol) in toluene (80 mL) was refluxed for 4 h with
continuous removal of water using a Dean-Stark water
separator. The reaction mixture was cooled to room temper-
ature and filtered. The filtrate was washed with water (100
mL), dried over anhydrous Na2SO4, and evaporated under
reduced pressure. The crude product was triturated with
methanol and filtered to afford 9.9 g (90%) of the title
F igu r e 4. Drug plasma concentration (5a maleate) versus
time curve in Wistar rats.
saturated compound 6a showed 3.5-, 7.4-, and 7.2-fold
transactivation of PPARγ, although 6a is not so impres-
sive in controlling plasma glucose in db/db mice.
It is interesting to note that 5a maleate is the first
unsaturated thiazolidinedione showing such impressive
euglycemic- and triglyceride-lowering activities. It re-
mains to be seen how this compound exhibits its
pharmacological activities, and further studies in this
class of compounds may reveal new mechanisms of
action of this class of TZDs.
27
compound: mp 164 °C; [R]D ) -73.6 (c 1.0, DMSO); IR νmax
1
(KBr) 1735.5, 1699.7, 1598 cm-1; H NMR (CDCl3, 200 MHz)
δ 2.15 (m, 4 H), 3.30 (m, 1 H), 3.55 (m, 1 H), 3.79 (t, J ) 9.2
Hz, 1 H), 4.35 (dd, J ) 9.0 and 3.2 Hz, 1 H), 4.6 (m, 1 H), 6.47
(d, J ) 8.4 Hz, 1 H), 6.65 (t, J ) 6.8 Hz, 1 H), 7.01 (d, J ) 8.8
Hz, 2 H), 7.31 (d, J ) 8.8 Hz, 2 H), 7.48 (s, 1 H), 7.56 (t, J )
6.0 Hz, 1 H), 8.16 (d, J ) 3.8 Hz, 1 H); Mass m/z (relative
intensity) 382 (M+ + 1, 25), 249 (15), 147 (100). Anal. Calcd
for C20H19N3O3S (381.45): C, 62.97; H, 5.02; N, 11.01. Found:
C, 62.81; H, 4.97; N, 11.05.
Exp er im en ta l Section
Gen er a l. 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) from downfield to TMS. The infrared
spectra were recorded on a Perkin-Elmer FT-IR 1600 spec-
trometer. The mass spectra were obtained with a HP 5989A
mass spectrometer. Optical rotations were measured on a
J asco-DIP-370 digital polarimeter. (S)-(+)-Prolinol, 2-(hy-
droxymethyl)morpholine, and 4-(hydroxymethyl)piperidine were
prepared by the reported procedure.16 4-Piperidinol, 4-(hy-
droxymethyl)piperidine, piperazine, 2-chloropyridine, 2-chlo-
roquinoline, 4-hydroxybenzaldehyde, 4-fluoronitrobenzene, and
2,4-thiazolidinedione were purchased and used directly. Com-
pound 11, BRL-49653, and rosiglitazone were prepared by the
reported procedure.12 All moisture-sensitive reactions were
conducted under an argon atmosphere in oven-dried glassware.
(S)-2-(Hydr oxym eth yl)-1-(pyr idin -2-yl)pyr r olidin e (3a).
A mixture of 2-chloropyridine (33.7 g, 297 mmol) and L-prolinol
(20 g, 198 mmol) was heated under nitrogen atmosphere at
160 °C with stirring for 4 h. The mixture was cooled to room
temperature and poured into water (100 mL), and the solution
was extracted with CH2Cl2 (3 × 150 mL). The combined
organic extracts were washed with brine (100 mL), dried (Na2-
SO4), and evaporated to dryness under reduced pressure. The
crude product was chromatographed over silica gel using 2%
methanol in chloroform to afford 19.4 g (55%) of the title
compound as a syrupy liquid: IR νmax (neat) 3372, 1600, 1491,
5-[4-[[1-(P yr id in -2-yl)-(2S)-p yr r olid in -2-yl]m et h oxy]-
p h en ylm eth ylen e]th ia zolid in e-2,4-d ion e (5a ) Ma lea te. A
solution of 5-[4-[[1-(pyridin-2-yl)-(2S)-pyrrolidin-2-yl]methoxy]-
phenylmethylene]thiazolidine-2,4-dione (50 g, 13.1 mmol) and
maleic acid (16.7 g, 14.39 mmol) in dry acetone (2 L) was
stirred at room temperature for 20 h. The resulting solid was
filtered, washed with cold acetone (2 × 200 mL), and dried
under reduced pressure to obtain 52 g (80%) of the title
27
compound: mp 132 °C; [R]D ) -77.3 (c 1.0, DMSO); IR νmax
1
(KBr) 1733, 1685, 1624 cm-1; H NMR (DMSO-d6, 200 MHz)
δ 2.13 (bs, 4 H), 3.34 (m, 1 H), 3.56 (m, 1H), 4.05 (m, 1H), 4.28
(dd, J ) 9.6 and 3.8 Hz, 1H), 4.53 (bs, 1 H), 6.25 (s, 2 H), 6.76
(m, 2 H), 7.19 (d, J ) 8.8 Hz, 2 H), 7.59 (d, J ) 8.8 Hz, 2H),
7.72 (m, 1 H), 7.79 (s, 1 H), 8.13 (d, J ) 4.2 Hz, 1 H), 12.6 (bs,
exchangeable with D2O, 1 H); Mass m/z (relative intensity)
382 (free base M+ + 1, 70), 147 (100). Anal. Calcd for
C24H23N3O7S (497.52): C, 57.94; H, 4.65; N, 8.44. Found: C,
57.69; H, 4.81; N, 8.5.
5-[4-[[1-(P yr id in -2-yl)-(2S)-p yr r olid in -2-yl]m et h oxy]-
p h en ylm eth ylen e]th ia zolid in e-2,4-d ion e (5a ) Hyd r och lo-
r id e. To a solution of 5-[4-[[1-(pyridin-2-yl)-(2S)-pyrrolidin-2-
yl]methoxy]phenylmethylene]thiazolidine-2,4-dione (40 g, 10.49
mmol) in dry acetone (2 L) at 0 °C was bubbled HCl gas for 30
min, and the resulting solid was filtered, washed with cold
acetone (2 × 200 mL), and dried under reduced pressure to
get 33 g (78%) of the title compound as a white solid: mp 241-
27
243 °C; [R]D ) -131.9 (c 1.0, DMSO); IR νmax (KBr) 1739,
1
1
1442, 1377 cm-1; H NMR (CDCl3, 200 MHz) δ 1.7 (m, 1H),
1702, 1598 cm-1; H NMR (DMSO-d6, 200 MHz) δ 2.1 (m, 4

2576 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14
Lohray et al.
H), 3.5 (m, H), 3.8 (m, 1 H), 4.19 (d, J ) 5.4 Hz, 2 H), 4.8 (m,
1 H), 6.95 (t, J ) 6.4 Hz, 1 H), 7.06 (d, J ) 8.4 Hz, 2 H), 7.29
(d, J ) 9.0 Hz, 1 H), 7.54 (d, J ) 8.8 Hz, 2 H), 7.74 (s, 1 H), 8.0
(m, 2 H), 12.6 (bs, exchangeable with D2O, 1 H), 14.0 (bs,
exchangeable with D2O, 1 H); Mass m/z (relative intensity)
382 (free base M+ + 1, 4.4), 287 (4.0), 147 (100). Anal. Calcd
for C20H20ClN3O3S (417.91): C, 57.48; H, 4.82; N, 10.05.
Found: C, 57.55; H, 4.92; N, 9.97.
alkaline with concentrated NH4OH, and extracted with EtOAc
(2 × 100 mL). The combined EtOAc extract was washed with
brine (30 mL), dried (Na2SO4), and concentrated under reduced
pressure. The crude product was chromatographed on silica
gel using 6% ethyl acetate in petroleum ether to afford 2.5 g
(44.4%) of the title compound as a syrupy liquid: IR νmax (KBr)
1738, 1598, 1512, 1478, 1441 cm-1; 1H NMR (CDCl3, 200 MHz)
δ 2.05 (m, 4 H), 3.11 (m, 3 H), 3.78 (m, 1 H), 4.11 (m, 4 H),
4.36 (m,1 H), 6.4 (d, J ) 8.4 Hz, 1 H), 6.53 (m, 1 H), 6.89 (d,
J ) 8.48 Hz, 2 H), 7.09 (d, J ) 8.39 Hz, 2 H), 7.40 (m, 1 H),
8.16 (d, J ) 3.5 Hz, 1 H); Mass m/z (relative intensity) 434
(M+ + 1, 0.8), 147 (100).
5-[4-[[1-(P yr id in -2-yl)-(2S)-p yr r olid in -2-yl]m et h oxy]-
p h en ylm eth yl]th ia zolid in e-2,4-d ion e (6a ). Meth od A: A
suspension of 5-[4-[[1-(pyridin-2-yl)-(2S)-pyrrolidin-2-yl]methoxy]-
phenylmethylene]thiazolidine-2,4-dione (10 g, 26.2 mmol) and
magnesium turnings (10.06 g, 0.4 mol) in dry MeOH (250 mL)
was stirred at room temperature for 4 h. The reaction mixture
was acidified with 6 N HCl to pH 6.5 and extracted with
dichloromethane (2 × 150 mL). The combined organic layer
was washed with water (100 mL) and brine (50 mL), dried
over Na2SO4, and evaporated under reduced pressure. The
residue was chromatographed over silica gel using 0.5% MeOH
in chloroform as eluent to afford 6.5 g (65%) of the title
compound as a white-colored fluffy solid.
5-[4-[[1-(P yr id in -2-yl)-(2S)-p yr r olid in -2-yl]m et h oxy]-
ph en ylm eth ylen e]th iazolidin e-2,4-dion e (5a) Sodiu m Salt.
To a solution of 5-[4-[[1-(pyridin-2-yl)-(2S)-pyrrolidin-2-yl]-
methoxy]phenylmethylene]thiazolidine-2,4-dione (1 g, 2.6 mmol)
in dry MeOH (10 mL) at room temperature was added NaOMe
in MeOH [prepared in situ by dissolving Na (66 mg, 2.8 mmol)
in MeOH (5 mL)]. The reaction mixture was stirred for 1 h
and then diluted with Et2O (10 mL). The resulting solid was
filtered and dried over P2O5 under reduced pressure to get the
title compound as a white solid 550 mg (52%): mp 254-250
27
°C; [R]D ) -85.2 (c 1.0, DMSO); IR νmax (KBr) 1683, 1599.8,
1558.3 cm-1 1H NMR (DMSO-d6, 200 MHz) δ 2.0 (m, 4 H),
;
3.2 (m, 1 H), 3.5 (m, 1 H), 3.88 (t, J ) 8.8 Hz, 1 H), 4.21 (dd,
J ) 9.2 and 3.0 Hz, 1 H), 4.4 (bs, 1 H), 6.55 (m, 2 H), 7.06 (d,
J ) 8.8 Hz, 2 H), 7.24 (s, 1 H), 7.25 (m, 3 H), 8.11 (d, J ) 4.0
Hz, 1 H); Mass m/z (relative intensity) 320 (2.7), 161 (100).
(S)-4-[[1-(P yr id in -2-yl)p yr r olid in -2-yl]m eth oxy]n itr o-
ben zen e (7a ). A solution of (S)-2-(hydroxymethyl)-1-(pyridin-
2-yl)pyrrolidine (5 g, 28 mol) in DMF (15 mL) was added
dropwise to a suspension of sodium hydride (60% w/w disper-
sion in paraffin oil, 1.68 g, 42.1 mmol) in DMF (10 mL). The
mixture was stirred at room temperature (ca.. 25 °C) for 30
min, after which 4-fluoronitrobenzene (5.94 g, 42.1 mmol) in
DMF (10 mL) was added dropwise and stirred at the same
temperature for 1 h. Water (50 mL) was added to the reaction
mixture, extracted with ethyl acetate (2 × 100 mL), and dried
(Na2SO4), and the solvent was removed under reduced pres-
sure to give the crude product (7.0 g) which was chromato-
graphed on silica gel using 5% ethyl acetate in petroleum ether
as an eluent to afford the title compound (5.0 g, 60%) as a
Meth od B: A mixture of ethyl 2-bromo-3-[(S)-4-[[1-(pyridin-
2-yl)pyrrolidin-2-yl]methoxy]phenyl]propanoate (2 g, 4.61 mmol),
thiourea (0.703 g, 9.23 mmol), NaOAc (0.757 g, 9.23 mmol),
and EtOH (15 mL) was stirred under reflux for 5 h. The
reaction mixture was cooled, extracted with EtOAc (2 × 40
mL), dried (Na2SO4), and concentrated to afford 2-imino-5-[4-
[[1-(pyridin-2-yl)-(2S)-pyrrolidin-2-yl]methoxy]phenylmethyl]-
4-thiazolidinone which was used in the next step without
further purification.
A mixture of the above crude product, 2 N HCl (20 mL),
and EtOH (20 mL) was stirred under reflux for 12 h. The
reaction mixture was concentrated in vacuo. The residue was
diluted with H2O (20 mL), neutralized with saturated aqueous
NaHCO3, and extracted with EtOAc (2 × 30 mL). The
combined EtOAc extract was washed with brine (20 mL), dried
(Na2SO4), and concentrated under reduced pressure. The
residue was chromatographed on silica gel with 0.5% MeOH
yellow-colored semisolid: IR νmax (KBr) 1593, 1499, 1442 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 2.09 (m, 4 H), 3.26 (t, J ) 6.64
Hz, 1 H), 3.48 (t, J ) 6.14 Hz, 1 H), 3.93 (t, J ) 9.09 Hz, 1 H),
4.41 (dd, J ) 3.32 and 3.23 Hz, 1 H), 4.55 (m, 1 H), 6.4 (d, J
) 8.39 Hz, 1 H), 6.57 (q, J ) 4.98 Hz, 1 H), 7.1 (d, J ) 9.27
Hz, 2 H), 7.43 (t, J ) 6.87 Hz, 1 H), 8.17 (d, J ) 9.04 Hz, 3 H);
Mass m/z (relative intensity) 299 (M+, 2.5), 161 (50), 147 (100).
in CHCl3 as an eluent to afford 1.1 g (62%) of the title
27
compound as a white fluffy solid: mp 79-80 °C; [R]D
)
-107.9 (c 1.0 CHCl3); IR νmax (KBr) 1697, 1599 cm-1; 1H NMR
(CDCl3, 200 MHz) δ 2.1 (m, 4 H), 3.05 (m, 1 H), 3.2-3.6 (m, 3
H), 3.82 (t, J ) 8.8 Hz, 1 H), 4.15 (m, 1 H), 4.45 (m, 2 H), 6.44
(d, J ) 8.6 Hz, 1 H), 6.56 (t, J ) 6.0 Hz, 1 H), 6.9 (d, J ) 8.4
Hz, 2 H), 7.15 (d, J ) 8.4 Hz, 2 H), 7.46 (m, 1 H), 8.14 (d, J )
2.4 Hz, 1 H); Mass m/z (relative intensity) 384 (M+ + 1, 3.3),
326 (4.4), (100). Anal. Calcd for C20H21N3O3S (383.47): C,
62.64; H, 5.51; N, 10.95. Found: C, 62.75; H, 5.49, N, 11.03.
5-[4-[[1-(P yr id in -2-yl)-(2S)-p yr r olid in -2-yl]m et h oxy]-
p h en ylm eth yl]th ia zolid in e-2,4-d ion e (6a ) Ma lea te. A so-
lution of 5-[4-[[1-(pyridin-2-yl)-(2S)-pyrrolidin-2-yl]methoxy]-
phenyl methyl]thiazolidine-2,4-dione (4 g, 10.4 mmol) and
maleic acid (1.32 g, 11.38 mmol) in dry Et2O (30 mL) was
stirred at room temperature for 20 h. The resulting solid was
filtered and washed with cold Et2O (2 × 10 mL) and dried
under reduced pressure to get 4.1 g (79%) of the title
(S)-4-[[1-(P yr id in -2-yl)p yr r olid in -2-yl]m et h oxy]a n i-
lin e (10a ). To a stirred suspension of (S)-4-[[1-(pyridin-2-yl)-
pyrrolidin-2-yl]methoxy]nitrobenzene (4 g, 13.37 mmol) and
Fe (7.47 g, 133.7 mmol) in EtOH (20 mL) was added concen-
trated HCl (20 mL), and the mixture stirred for 1 h. The
reaction mixture was filtered, neutralized with saturated
sodium carbonate solution to pH 7.0, and extracted with ethyl
acetate (2 × 50 mL). The combined organic layer was washed
with brine (20 mL) and dried over Na2SO4, and the solvent
was removed under reduced pressure to afford 3.5 g (97%) of
the title compound as a brown-colored semisolid: IR νmax (KBr)
3400, 1597, 1511 cm-1; 1H NMR (CDCl3, 200 MHz) δ 2.03 (m,
4 H), 3.24 (m, 1 H), 3.50 (m, 1 H), 3.71 (t, J ) 8.8 Hz, 1 H),
4.13 (dd, J ) 3.36 and 3.4 Hz, 1 H), 4.42 (m, 1 H), 6.4 (d, J )
8.39 Hz, 1 H), 6.51 (m, 3 H), 6.77 (d, J ) 8.81 Hz, 2 H), 7.38
(m, 1 H), 8.15 (d, J ) 3.51 Hz, 1H); Mass m/z (relative
intensity) 269 (M, 4.3), 161 (100).
Eth yl 2-Br om o-3-[(S)-4-[[1-(p yr id in -2-yl)p yr r olid in -2-
yl]m eth oxy]ph en yl]pr opan oate. A solution of NaNO2 (0.942
g, 13.66 mmol) in H2O (1.73 mL) was added dropwise to a
stirred and ice-cold mixture of (S)-4-[[1-(pyridin-2-yl)pyrrolidin-
2-yl]methoxy]aniline (3.5 g, 13.01 mmol), aqueous HBr (48%,
2.82 mL), MeOH (3.5 mL), and acetone (7 mL). After the
mixture stirred for 30 min, ethyl acrylate (14.09 mL, 130
mmol) was added. The temperature was raised to 38 °C, and
powdered Cu2O (0.111 g, 0.78 mmol) was added in small
portions to the vigorously stirred mixture. After the N2 gas
evolution ceased, the reaction mixture was concentrated under
reduced pressure. The residue was diluted with water, made
27
compound: mp 58-60 °C; [R]D ) -80.5 (c 1.27, DMSO); IR
ν
max (KBr) 1698.7, 1643, 1583 cm-1; 1H NMR (CDCl3, 200 MHz)
δ 2.25 (m, 4 H), 3.05-3.4 (m, 2 H), 3.6 (m, 1 H), 3.8 (m, 1 H),
4.1 (m, 2 H), 4.5 (m, 1 H), 4.7 (m, 1 H), 6.3 (s, 2 H), 6.7-7.0
(m, 4 H), 7.12 (d, J ) 8.4 Hz, 2 H), 7.69 (t, J ) 7.4 Hz, 1 H),
8.23 (d, J ) 4.4 Hz, 1 H); Mass m/z (relative intensity) 383
(free base M+, 5.2), 147 (100). Anal. Calcd for C24H25N3O7S
(499.54): C, 57.70; H, 5.04; N, 8.41. Found: C, 57.59; H, 4.98;
N, 8.52.
5-[4-[[1-(P yr id in -2-yl)-(2S)-p yr r olid in -2-yl]m et h oxy]-
p h en ylm eth yl]th ia zolid in e-2,4-d ion e (6a ) Sod iu m Sa lt.
The title compound (0.3 g, 56%) was prepared as a white solid
from 5-[4-[[1-(pyridin-2-yl)-(2S)-pyrrolidin-2-yl]methoxy]phe-
nylmethyl]thiazolidine-2,4-dione (0.5 g, 1.3 mmol) and NaOMe
(74 mg, 1.37 mmol) in MeOH by a similar procedure to that

Novel Euglycemic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14 2577
27
described for 8a sodium salt: mp 260-262 °C; [R]D ) -63.0
(c 0.5, DMSO); IR νmax (KBr) 1661, 1598, 1583 cm-1; 1H NMR
(CDCl3, 200 MHz) δ 2.05 (m, 4 H), 2.45-2.7 (m, 2 H), 3.25 (m,
1 H), 3.5 (m, 1 H), 3.8 (t, J ) 8.8 Hz, 1 H), 4.1 (m, 2 H), 4.4
(bs, 1 H), 6.55 (m, 2 H), 6.89 (d, J ) 8.4 Hz, 2 H), 7.1 (d, J )
8.4 Hz, 2 H), 7.5 (m, 1 H), 8.12 (d, J ) 3.8 Hz, 1 H); Mass m/z
(relative intensity) 308 (6), 161 (100).
(5.2), 161 (14.6), 86 (100). Anal. Calcd for C20H19N3O3S
(381.45): C, 62.97; H, 5.02; N, 11.01. Found: C, 62.83; H, 4.95;
N, 10.96.
4-(Hyd r oxym eth yl)-1-(p yr id in -2-yl)p ip er id in e (3c). The
title compound (2.7 g, 80%) was prepared as a syrupy liquid
from 2-chloropyridine (7.8 g, 69 mmol) and 4-(hydroxymethyl)-
piperidine (2 g, 17 mmol) by a procedure similar to that
described for 3a : IR νmax (KBr) 3355, 2922, 2853, 1597, 1561,
1486 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.3 (m, 2 H), 1.8 (m,
3 H), 2.84 (t, J ) 11.7 Hz, 2 H), 3.54 (d, J ) 6.2 Hz, 2 H), 4.32
(approx d, J ) 13.0 Hz, 2 H), 6.59 (t, J ) 5.9 Hz, 1 H), 6.67 (d,
J ) 8.8 Hz,1 H), 7.46 (m, 1 H), 8.18 (d, J ) 3.6 Hz, 1 H); Mass
m/z (relative intensity) 192 (M+, 100), 151 (40), 133 (50), 107
(76).
5-[4-[[1-(P yr id in -2-yl)-(2S)-p yr r olid in -2-yl]m et h oxy]-
p h en ylm et h yl]t h ia zolid in e-2,4-d ion e (6a ) H yd r och lo-
r id e. The title compound (2 g, 73%) was prepared as a white
solid from 5-[4-[[1-(pyridin-2-yl)-(2S)-pyrrolidin-2-yl]methoxy]-
phenylmethyl]thiazolidine-2,4-dione (2.6 g, 6.79 mmol) by an
analogous procedure to that described for 8a hydrochloride:
mp 220 °C; IR νmax (KBr) 1696, 1640, 1550 cm-1 1H NMR
;
[1-(P yr id in -2-yl)p ip er id in -4-yl]m eth yl Meth a n esu lfo-
n a te. The title compound (2.1 g, 83%) was prepared as a
semisolid from 4-(hydroxymethyl)-1-(pyridin-2-yl)piperidine
(1.8 g, 9.4 mmol) and methanesulfonyl chloride (0.8 mL, 10.3
mmol) by a procedure similar to that described for the
preparation of 1-(pyridin-2-yl)piperidin-4-yl methanesulfo-
(CDCl3, 200 MHz) δ 2.17 (m, 4 H), 3.14 (t, J ) 9.37 Hz, 2 H),
3.30 (m, 1 H), 3.69 (m, 1 H), 3.98 (t, J ) 10.05 Hz, 2 H), 4.3
(bs, 1 H), 4.43 (t, J ) 3.64 Hz, 1 H), 6.75 (d, J ) 7.66 Hz, 3 H),
6.92 (t, J ) 3.16 Hz, 1 H), 7.09 (d, J ) 7.24 Hz, 2 H), 7.78 (d,
J ) 4.29 Hz, 1 H), 8.2 (s, 1 H), 8.5 (bs, exchangeable with D2O,
1 H); Mass m/z (relative intensity) 382 (free base M+ - 1, 4),
147 (100). Anal. Calcd for C20H22ClN3O3S (419.93): C, 57.2;
H, 5.28; N, 8.44. Found C, 57.31; H, 5.17; N, 8.50.
nate: IR νmax (KBr) 2975, 2937, 1599, 1483, 1441, cm-1 1H
;
NMR (CDCl3, 200 MHz) δ 1.35 (m, 2 H), 1.8-2.15 (m, 3 H),
2.85 (t, J ) 12.2 Hz, 2 H), 3.02 (s, 3 H), 4.1 (d, J ) 6.2 Hz, 2
H), 4.35 (approx, d, J ) 12.8 Hz, 2 H), 6.6 (m, 2 H), 2.48 (t, J
) 7.8 Hz, 1 H), 8.18 (d, J ) 3.8 Hz, 1 H); Mass m/z (relative
intensity) 270 (M+, 66), 191 (100), 175 (84), 161 (28), 146 (25),
133 (48), 121 (28), 107 (82), 94 (27).
1-(P yr id in -2-yl)-4-p ip er id in ol (3b). The title compound
(3.5 g, 50%) was prepared as a semisolid from 2-chloropyridine
(6.7 g, 59 mmol) and 4-piperidinol (4 g, 39.6 mmol) by an
analogous procedure to that described for 3a : IR νmax (neat)
3345, 1596, 1485, 1438 cm-1 1H NMR (CDCl3, 200 MHz) δ
;
4-[[1-(P yr id in -2-yl)p ip er id in -4-yl]m et h oxy]b en za ld e-
h yd e (4c). The title compound (1.0 g, 45%) was prepared as a
semisolid from [1-(pyridin-2-yl)piperidin-4-yl]methyl meth-
anesulfonate (2.0 g, 7.4 mmol) and 4-hydroxybenzaldehyde (1.1
g, 9.0 mmol) by a similar procedure to that described for 4b:
1.3 (m, 2 H), 1.8 (m, 3 H), 2.84 (t, J ) 11.7 Hz, 2 H), 3.54 (d,
J ) 6.2 Hz, 2 H), 4.32 (approximately d, J ) 13.0 Hz, 2 H),
6.59 (t, J ) 5.9 Hz, 1 H), 6.67 (d, J ) 8.8 Hz, 1 H), 7.46 (m, 1
H), 8.18 (d, J ) 3.6 Hz, 1 H); Mass m/z (relative intensity)
179 (M+, 100), 161 (M+ - OH, 63.2), 133 (96.5).
IR νmax (KBr) 1690, 1597, 1562, 1508, 1475, 1431 cm-1 1H
;
1-(P yr id in -2-yl)p ip er id in -4-yl Meth a n esu lfon a te. Meth-
anesulfonyl chloride (1.69 mL, 21.9 mmol) was added dropwise
to a stirred solution of 1-(pyridin-2-yl)-4-piperidinol (2.35 g,
18.3 mmol) and triethylamine (8.14 mL, 58.4 mmol) in dichlo-
romethane (20 mL) at 0 °C. The resulting mixture was stirred
at room temperature for 2 h, then washed with water (50 mL),
dried (Na2SO4), and concentrated to afford 4.2 g (90%) of the
title compound as a semisolid: IR νmax (neat) 1593, 1563, 1481,
NMR (CDCl3, 200 MHz) δ 1.45 (m, 2 H), 1.8-2.25 (m, 3 H),
2.89 (m, 2 H), 3.92 (d, J ) 6.2 Hz, 2 H), 4.36 (approximately
d, J ) 12.8 Hz, 2 H), 6.62 (m, 2 H), 6.99 (d, J ) 8.6 Hz, 2 H),
7.47 (m, 1 H), 7.83 (d, J ) 8.6 Hz, 2 H), 8.19 (d, J ) 3.6 Hz, 1
H), 9.88 (s, 1 H); Mass m/z (relative intensity) 296 (M+, 65.6),
271 (16), 191 (31), 175 (78.1), 161 (32), 149 (32), 133 (62), 121
(50), 107 (100).
5-[4-[[1-(P yr id in -2-yl)p ip er id in -4-yl]m eth oxy]p h en yl-
m eth ylen e]th ia zolid in e-2,4-d ion e (5c). The title compound
(0.46 g, 63%) was prepared as a pale-yellow solid from 4-[[1-
(pyridin-2-yl)piperidin-4-yl]methoxy]benzaldehyde (0.55 g, 1.85
mmol) and 2,4-thiazolidinedione (0.268, 2.2 mmol) by a
procedure similar to that described for 5a : IR νmax (KBr) 3438,
2944, 1734, 1688, 1583, 1509, 1435 cm-1; 1H NMR (CDCl3, 200
MHz) δ 1.45 (m, 2 H), 1.9-2.2 (m, 3 H), 2.9 (t, J ) 11.7 Hz, 2
H), 3.9 (d, J ) 6.2 Hz, 2 H), 4.38 (approximately d, J ) 13.0
Hz, 2 H), 6.61 (t, J ) 5.8 Hz, 1 H), 6.71 (d, J ) 8.6 Hz, 1 H),
6.99 (d, J ) 8.8 Hz, 2 H), 7.5 (m, 3 H), 7.75 (s, 1 H), 8.18 (d, J
) 3.8 Hz, 1 H); Mass m/z (relative intensity) 395 (M+, 35), 175
(85), 165 (22), 146 (41), 121 (59), 107 (100). Anal. Calcd for
1
1437 cm-1; H NMR (CDCl3, 200 MHz) δ 1.35 (m, 2 H), 1.8-
2.15 (m, 3 H), 2.85 (t, J ) 12.2 Hz, 2 H), 3.02 (s, 3 H), 4.1(d,
J ) 6.2 Hz, 2 H), 4.35 (approximately d, J ) 12.8 Hz, 2 H),
6.6 (m, 2 H), 7.48 (t, J ) 7.8 Hz, 1 H), 8.18 (d, J ) 3.8 Hz, 1
H); Mass m/z (relative intensity) 256 (M+, 14.5), 161 (100).
4-[1-(P yr idin -2-yl)piper idin -4-yloxy]ben zaldeh yde (4b).
To a stirred solution of 1-(pyridin-2-yl)piperidin-4-yl meth-
anesulfonate (4.5 g, 17.56 mmol) and 4-hydroxybenzaldehyde
(2.5 g, 21.13 mmol) in dry DMF was added K2CO3 (9.7 g, 70.28
mmol), and the mixture was stirred for 10 h at 80 °C. The
reaction mixture was cooled to room temperature (ca. 25 °C);
water was added (100 mL) and the mixture extracted with
ethyl acetate (2 × 40 mL). The combined organic extracts were
washed with 5% aqueous Na2CO3 solution and brine (25 mL),
dried over anhydrous Na2SO4, and concentrated under reduced
pressure to afford 1.8 g (36.3%) of the title compound as a pale-
yellow solid: mp 114-116 °C; IR νmax (KBr) 1689.7, 1597, 1570,
1478 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.9 (m, 2 H), 2.1 (m,
2 H), 3.5 (m, 2 H), 3.9 (m, 2 H), 4.7 (m, 1 H), 6.7 (m, 2 H), 7.03
(d, J ) 8.6 Hz, 2 H), 7.49 (m, 1 H), 7.85 (d, J ) 8.8 Hz, 2 H),
8.2 (d, J ) 3.4 Hz, 1 H), 9.89 (s, 1 H); Mass m/z (relative
intensity) 283 (M+ + 1, 62.9), 282 (M+, 36), 161 (100).
C
21H21N3O3S (395.48): C, 63.78; H, 5.35; N, 10.62. Found: C,
63.82; H, 5.28; N, 10.69.
1-(P yr id in -2-yl)p ip er a zin e. A mixture of 2-chloropyridine
(15 g, 13.2 mol) and piperazine (114 g, 1.32 mol) was heated
under nitrogen atmosphere at 120 °C with stirring for 8 h.
The mixture was cooled to room temperature, poured into
water (250 mL), and extracted with EtOAc (2 × 100 mL). The
combined organic extracts were washed with brine (50 mL),
dried (Na2SO4), and evaporated under reduced pressure; the
crude product was chromatographed over silica gel using 0.5%
MeOH in chloroform to afford 15 g (70%) of the title compound
as a white solid: mp 85-87 °C; IR νmax (neat) 3293, 1594, 1562,
5-[4-[1-(P yr id in -2-yl)p ip er id in -4-yloxy]p h en ylm eth yl-
en e]th ia zolid in e-2,4-d ion e (5b). The title compound (1.5 g,
74%) was prepared as a yellow solid from 4-[1-(pyridin-2-yl)-
4-piperidinyloxy]benzaldehyde (1.5 g, 5.3 mmol) and thiazo-
lidinedione (0.622 g, 5.31 mmol) by an analogous procedure
to that described for 5a : mp 218-220 °C; IR νmax (KBr) 1739.9,
1
1482 cm-1; H NMR (CDCl3, 200 MHz) δ 2.9 (t, J ) 5 Hz, 4
H), 3.5 (t, J ) 5.2 Hz, 4 H), 6.6 (m, 2 H), 7.4 (t, J ) 7.0 Hz, 1
H), 8.2 (d, J ) 4.2 Hz, 1 H); Mass m/z (relative intensity) 163
(M+, 35), 133 (20), 121 (80), 95 (100).
1
1697.9, 1595.5 cm-1; H NMR (CDCl3 + DMSO-d6, 200 MHz)
2-[4-(P yr id in -2-yl)p ip er a zin -1-yl]eth a n ol (3d ). To a mix-
ture of 1-(pyridin-2-yl)piperazine (2 g, 12.2 mmol) and K2CO3
(5.0 g, 36 mmol) in anhydrous DMSO (25 mL) was added
2-bromoethanol (2.3 g, 18 mmol), and the reaction mixture was
heated at 80 oC for 8 h. The mixture was cooled, water (50
δ 1.9 (m, 2 H), 2.1 (m, 2 H), 3.5 (m, 2 H), 3.9 (m, 2 H), 4.65 (m,
1 H), 6.62 (t, J ) 5.9 Hz, 1 H), 6.72 (d, J ) 8.6 Hz, 1 H), 7.02
(d, J ) 8.4 Hz, 2 H), 7.5 (m, 3 H), 7.74 (s,1 H), 8.18 (d, J ) 4.0
Hz, 1 H); Mass m/z (relative intensity) 382 (M+ + 1, 4.3), 192

2578 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14
Lohray et al.
mL) was added, and the mixture was extracted with EtOAc
(60 mL). The organic extract was washed with brine (25 mL)
and dried over sodium sulfate. The solvent was removed by
distillation under reduced pressure to give 0.8 g (31%) of the
title compound as a thick liquid: IR νmax (KBr) 1806, 1594,
(d, J ) 8.72 Hz, 2 H), 7.55 (t, J ) 6.73 Hz, 1 H), 7.68 (s, 1 H),
8.23 (d, J ) 3.10 Hz, 1 H); Mass m/z (relative intensity) 397
(M+, 28.4), 177 (64.6), 163 (100). Anal. Calcd for C20H19N3O4S
(397.45): C, 60.43; H, 4.81; N, 10.57. Found: C, 60.35; H, 4.75;
N, 10.63.
1
1482, cm-1; H NMR (CDCl3, 200 MHz) δ 2.6 (t, J ) 5 Hz, 6
5-[4-[[4-(P yr id in -2-yl)m or p h olin -2-yl]m eth oxy]p h en yl-
m et h ylen e]t h ia zolid in e-2,4-d ion e (5e) H yd r och lor id e.
The title compound (0.17 g, 78%) was prepared as a pale-yellow
solid from 5-[4-[[(pyridin-2-yl)morpholin-2-l]methoxy]phenyl-
methyl]thiazolidine-2,4-dione (0.2 g, 0.03 mmol) by a procedure
similar to that described for the preparation of 6a hydrochlo-
ride: mp 238 °C; IR νmax (KBr) 2959, 1736, 1694, 1601, 1511,
H), 3.5 (t, J ) 5.2 Hz, 6 H), 6.6 (m, 2 H), 7.4 (t, J ) 6.8 Hz, 1
H), 8.2 (d, J ) 3.8 Hz, 1 H); Mass m/z (relative intensity) 208
(M+, 62), 189 (29), 176 (91), 147 (83), 121 (91), 107 (100).
4-[2-[4-(P yr id in -2-yl)p ip er a zin -1-yl]et h oxy]b en za ld e-
h yd e (4d ). A solution of [4-(pyridin-2-yl)piperazin-1-yl]ethanol
(2 g, 9.6 mmol) in DMF (10 mL) was added dropwise to a
suspension of sodium hydride (50% dispersion in paraffin oil,
0.278 g, 11.0 mmol) in DMF (10 mL). The mixture was stirred
at room temperature (ca. 25 °C) for 0.5 h after which 4-fluo-
robenzaldehyde (1.3 g, 16 mmol) was added dropwise and
stirring was continued for 2 h. Water (30 mL) was added to
the reaction mixture, extracted with ethyl acetate (2 × 50 mL),
and dried (Na2SO4), and the solvent was removed under
reduced pressure to give 3 g of crude product which was
chromatographed on silica gel using 10-20% (gradient elution)
of EtOAc in petroleum ether to afford 1.2 g (40%) of 4d as a
thick liquid: IR νmax (KBr) 1691, 1598, 1570, 1437, 1245, 1163,
1
1254 cm-1; H NMR (CDCl3, 200 MHz) δ 2.91-3.20 (m, 2 H),
3.61-4.22 (m, 7 H), 6.92-7.01 (m, 2 H), 7.14 (d, J ) 8.68 Hz,
2 H), 7.38 (d, J ) 8.68 Hz, 2 H), 7.58 (t, J ) 6.83 Hz, 1 H),
7.71 (s, 1 H), 7.86 (d, J ) 3.20 Hz, 1 H); Mass m/z (relative
intinsity) 397 (free base M+, 42), 177 (67), 163 (100). Anal.
Calcd for C20H22ClN3O4S: C, 55.10; H, 5.08; N, 9.63. Found:
C, 55.02; H, 5.14; N, 9.58.
5-[4-[[4-(P yr id in -2-yl)m or p h olin -2-yl]m eth oxy]p h en yl-
m eth yl]th ia zolid in e-2,4-d ion e (6e). The title compound
(13.2 g, 88%) was prepared as a white solid from 5-[4-[[4-
(pyridin-2-yl)morpholin-2-yl]methoxy]phenylmethylene]thia-
zolidine-2,4-dione (15 g, 37.7 mmol) and Mg (14.5 g, 0.6 mol)
by a procedure similar to that described for the preparation
of 6a : mp 63-65 °C; IR νmax (KBr) 2858, 1696, 1603, 1511,
1
1022, 833, 774, 597 cm-1; H NMR (CDCl3, 200 MHz) δ 2.78
(t, J ) 4.6 Hz, 4 H), 2.96 (t, J ) 5.6 Hz, 2 H), 3.64 (t, J ) 5 Hz,
4 H), 4.29 (t, J ) 5.4 Hz, 2 H), 6.66 (m, 2 H), 7.03 (d, J ) 8.6
Hz, 2 H), 7.5 (m, 1 H), 7.85 (d, J ) 8.6 Hz, 2 H), 8.2 (d, J ) 3.8
Hz, 1 H), 9.9 (s, 1 H); Mass m/z (relative intensity) 312 (M+,
33), 190 (50), 107 (100).
1
1248 cm-1; H NMR (CDCl3, 200 MHz) δ 2.82-3.18 (m, 2 H),
3.11 (dd, J ) 14.12 and 9.78 Hz, 1 H), 3.46 (dd, J ) 14.12 and
3.73 Hz, 1 H), 3.81 (td, J ) 11.53 and 2.49 Hz, 1 H), 3.90-
4.35 (m, 6 H), 4.48 (dd, J ) 9.78 and 3.73 Hz, 1 H), 6.65-6.75
(m, 2 H), 6.91 (d, J ) 8.63 Hz, 2 H), 7.16 (d, J ) 8.63 Hz, 2 H),
7.53 (t, J ) 6.87 Hz, 1 H), 8.22 (d, J ) 3.41 Hz, 1 H); Mass m/z
(relative intensity) 400 (M+ + 1, 100), 342 (23.2), 257 (79.3).
Anal. Calcd for C20H21N3O4S (399.47): C, 60.13; H, 5.29; N,
10.51. Found: C, 60.06; H, 5.33; N, 10.57.
5-[4-[2-[4-(P yr id in -2-yl)p ip er a zin -1-yl]eth oxy]p h en yl-
m eth ylen e]th ia zolid in e-2,4-d ion e (5d ). The title compound
(0.85 g, 64%) was prepared as a pale-yellow solid from 4-[2-
[4-(pyridin-2-yl)piperazin-1-yl]ethoxy]benzaldehyde (1.0 g, 3.2
mmol) and 2,4-thiazolidinedione (0.45 g, 3.8 mmol) by a
procedure similar to that described for 6a : mp 158-160 °C;
IR νmax (KBr) 3397, 1722, 1691, 1594, 1508, 1434, 1293, 1244,
1159, 1019, 958, 769, 686, 557 cm-1; 1H NMR (CDCl3 + DMSO-
d6, 200 MHz) δ 2.88 (m, 4 H), 2.98 (m, 2 H), 3.65 (m, 4 H),
4.25 (m, 2 H), 6.67 (m, 2 H), 6.92 (d, J ) 8.4 Hz, 2 H), 7.33 (d,
J ) 8.6 Hz, 2 H), 7.48 (m, 2 H), 8.2 (d, J ) 3.6 Hz, 1 H); Mass
m/z (relative intensity) 411 (M+, 8), 190 (25), 118 (100), 107
(75). Anal. Calcd for C21H22N4O3S (410.49): C, 61.44; H, 5.40;
N, 13.6. Found: C, 61.37; H, 5.45; N, 13.56.
2-(Hydr oxym eth yl)-4-(pyr idin -2-yl)m or ph olin e (3e). The
title compound (33.5 g, 72%) was prepared as a colorless thick
liquid from 2-chloropyridine (54.32 g, 0.48 mol) and 2-(hy-
droxymethyl)morpholine (28 g, 0.24 mol) by a similar proce-
dure to that described for the preparation of 3a : IR νmax (neat)
3405, 1594, 1481, 1437, 1247 cm-1; 1H NMR (CDCl3, 200 MHz)
δ 2.70-2.90 (m, 1 H), 2.9 (d, J ) 11.95 and 3.33 Hz, 1 H),
3.56-3.90 (m, 4 H), 3.90-4.20 (m, 3 H), 6.58-6.79 (m, 2 H),
7.51 (t, J ) 6.89 Hz, 1 H), 8.20 (d, J ) 3.73 Hz, 1 H); Mass m/z
(relative intensity) 194 (38), 164 (4), 163 (100), 133 (39).
5-[4-[[4-(P yr id in -2-yl)m or p h olin -2-yl]m eth oxy]p h en yl-
m eth yl]th ia zolid in e-2,4-d ion e (6e) Sod iu m Sa lt. The title
compound (2.9 g, 91%) was prepared as a white solid from 5-[4-
[[4-(pyridin-2-yl)morpholin-2-yl]methoxy]phenylmethyl]thiazo-
lidine-2,4-dione and NaOMe (1.26 g, 23.3 mmol) by a procedure
similar to that described for the preparation of 6a sodium
salt: mp 272 °C; IR νmax (KBr) 3437, 1594, 1563, 1546, 1234
cm-1; 1H NMR (CDCl3, 200 MHz) δ 2.51-2.92 (m, 2 H), 3.20-
3.40 (m, 1 H), 3.53-3.72 (m, 1 H), 3.74-4.20 (m, 7 H), 4.20-
4.40 (m, 1 H), 6.69 (t, J ) 5.81 Hz, 1 H), 6.86 (d, J ) 8.62 Hz,
2 H), 7.11 (d, J ) 5.81 Hz, 1 H), 7.21 (d, J ) 8.62 Hz, 2 H),
7.57 (t, J ) 8.3 Hz, 1 H), 8.14 (d, J ) 4.35 Hz, 1 H); Mass m/z
(relative intensity) 397 (free base, M+, 42), 177 (67), 163 (100).
5-[4-[[4-(P yr id in -2-yl)m or p h olin -2-yl]m eth oxy]p h en yl-
m eth yl]th ia zolid in e-2,4-d ion e (6e) Ma lea te. The title com-
pound (0.14 g, 72%) was prepared as a white solid from
5-[4-[[4-(pyridin-2-yl)morpholin-2-yl]methoxy]phenylmethyl]-
thiazolidine-2,4-dione (150 mg, 0.38 mmol) and maleic acid (44
mg, 0.38 mmol) by a similar procedure to that described for
the preparation of 6a maleate: mp 165 °C; IR νmax (KBr) 3055,
4-[[4-(P yr id in -2-yl)m or p h olin -2-yl]m eth oxy]ben za ld e-
h yd e (4e). The title compound (39 g, 75.7%) was prepared as
a colorless thick liquid from 2-(hydroxymethyl)-4-(pyridin-2-
yl)morpholine (33.5 g, 0.172 mol) and 4-fluorobenzaldehyde
(27.8 g, 0.19 mol) by a procedure similar to that described for
the preparation of 4a : IR νmax (neat) 2858, 1689, 1600, 1480,
1750, 1696, 1626, 1583 cm-1 1H NMR (CDCl3, 200 MHz) δ
;
8.12 (d, J ) 4.89 Hz, 1 H), 7.62 (t, J ) 7.81 Hz, 1 H), 7.16 (d,
J ) 8.0 Hz, 2 H), 6.92 (d, J ) 8.3 Hz, 2 H), 6.72 (t, J ) 6.06
Hz, 2 H), 6.24 (s, 2 H), 4.87 (dd, J ) 4.07 and 9.23 Hz, 1 H),
4.32-3.79 (m, 7 H), 3.71-3.58 (m, 1 H), 3.28 (dd, J ) 4.07
and 14.1 Hz, 1 H), 3.16-2.64 (m, 3 H); Mass m/z (relative
intensity) 400 (free base M+ + 1, 100), 342 (20.0), 257 (75.5).
Anal. Calcd for C24H25N3O8S (515.54): C, 55.91; H, 4.88; N,
8.15. Found: C, 55.98; H, 4.91; N, 8.02.
1
1251 cm-1; H NMR (CDCl3, 200 MHz) δ 2.89 (d, J ) 12.36
and 1.89 Hz, 1 H), 3.05 (td, J ) 12.36 and 3.46 Hz, 1 H), 3.70-
4.40 (m, 7 H), 6.60-6.80 (m, 2 H), 7.06 (d, J ) 8.72 Hz, 2 H),
7.54 (t, J ) 7.20 Hz, 1 H), 7.85 (d, J ) 8.72 Hz, 2 H), 2 H),
8.25 (d, J ) 3.83 Hz, 1 H), 9.90 (s, 1 H); Mass m/z (relative
intensity) 298 (M+, 23) 177 (23), 163 (100).
(S)-2-(Hydr oxym eth yl)-1-(qu in olin -2-yl)pyr r olidin e (3f).
The title compound (14 g, 100%) was prepared as a thick liquid
from 2-chloroquinoline (10 g, 60 mmol) and L-prolinol (37.2 g,
370 mmol) by a similar procedure to that described for the
preparation of 3a : IR νmax (neat) 2870, 1618, 1556, 1509, 1355,
5-[4-[[4-(P yr id in -2-yl)m or p h olin -2-yl]m eth oxy]p h en yl-
m eth ylen e]th ia zolid in e-2,4-d ion e (5e). The title compound
(20.6 g, 97%) was prepared as a yellow solid from 4-[[4-
(pyridin-2-yl)morpholin-2-yl]methoxy]benzaldehyde (16 g, 53.69
mmol) and 2,4-thiazolidinedione (6.9 g, 59.06 mmol) by a
procedure similar to that described for the preparation of 5a :
1
1160, 1051 cm-1; H NMR (CDCl3, 200 MHz) δ 1.7 (m, 1 H),
2.1 (m, 4 H), 3.4-3.9 (m, 4 H), 4.5 (m, 1 H), 6.76 (d, J ) 9 Hz,
1 H), 7.24 (m, 1 H), 7.62 (m, 3 H), 7.89 (d, J ) 9 Hz, 1 H);
Mass m/z (relative intensity) 228 (M+, 10), 209 (5), 197 (100),
182 (7.5), 170 (7.5).
mp 158 °C; IR νmax (KBr) 2866, 1693, 1595, 1508, 1256 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 2.82-3.18 (m, 2 H), 3.70-4.40
(m, 7 H), 6.61-6.80 (m, 2 H), 7.02 (d, J ) 8.72 Hz, 2 H), 7.41

Novel Euglycemic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14 2579
(S)-4-[[1-(Qu in olin -2-yl)p yr r olid in -2-yl]m et h oxy]ben -
za ld eh yd e (4f). The title compound (90 mg, 41%) was
prepared as a thick liquid from (S)-2-(hydroxymethyl)-1-
(quinolin-2-yl)pyrrolidine (0.15 g, 0.65 mmol) and 4-fluoroben-
zaldehyde (0.16 g, 1.3 mmol) by a similar procedure to that
described for the preparation of 4a : IR (neat) 1681, 1602, 1509
H), 7.15 (m, 5 H), 7.6 (m, 2 H), 7.73 (d, J ) 8.4 Hz, 1 H), 7.87
(d, J ) 8.8 Hz, 1 H); Mass m/z (relative intensity) 433 (M+,
6.6), 211 (33.3), 197 (100), 170 (6.6). Anal. Calcd for C24H23N3O3S
((433.53): C, 66.49; H, 5.36; N, 9.69. Found: C, 66.56; H, 5.29;
N, 9.76.
5-[4-[[1-(Qu in olin -2-yl)-(2S)-p yr r olid in -2-yl]m eth oxy]-
p h en ylm et h yl]t h ia zolid in e-2,4-d ion e (6f) Sod iu m Sa lt .
The title compound (0.27 g, 72%) was prepared as a pale-yellow
solid from 5-[4-[[1-(quinolin-2-yl)-(2S)-pyrrolidin-2-yl]methoxy]-
phenylmethyl]thiazolidine-2,4-dione (0.36 g, 0.83 mmol) and
NaOMe (45 mg, 0.83 mmol) by a similar procedure to that
described for the preparation of 6a sodium salt: mp 248-250
°C; [R]D27 ) +1.4 (c 1.0, DMSO); IR νmax (KBr) 1664, 1606, 1562,
1508, 1233, 809 cm-1; 1H NMR (DMSO-d6, 200 MHz) δ 2.1 (m,
4 H), 2.45-2.8 (m, 2 H), 3.4 (m, 1 H), 3.7 (m, 1 H), 3.88 (t, J
) 9.2 Hz, 1 H), 4.15 (m, 1 H), 4.34 (d, J ) 7.6 Hz, 1 H), 4.6 (s,
1 H), 6.9-7.3 (m, 6 H), 7.5-7.8 (m, 3 H), 8.05 (d, J ) 9.2 Hz,
1 H); Mass m/z (relative intensity) 226 (1.7), 211 (100), 181
(12.2), 157 (5.2).
1
cm-1; H NMR (CDCl3, 200 MHz) δ 2.2 (m, 4 H), 3.45 (m, 1
H), 3.7 (m, 1 H), 4.01 (t, J ) 9.3 Hz, 1 H), 4.65 (dd, J ) 10 and
3 Hz, 1 H), 4.8 (m, 1 H), 6.80 (d, J ) 9 Hz, 1 H), 6.9-8.0 (m,
9 H), 9.9 (s, 1 H); Mass m/z (relative intensity) 332 (M+, 95),
215 (19), 198 (23.8), 197 (100), 181 (7).
5-[4-[[1-(Qu in olin -2-yl)-(2S)-p yr r olid in -2-yl]m eth oxy]-
p h en ylm eth ylen e]th ia zolid in e-2,4-d ion e (5f). The title
compound (2 g, 100%) was prepared as a pale-yellow solid from
(S)-4-[[1-(quinolin-2-yl)pyrrolidin-2-yl]methoxy]benzalde-
hyde (1.5 g, 4.5 mmol) and 2,4-thiazolidinedione (0.53 g, 4.5
mmol) by a similar procedure to that described for the
27
preparation of 5a : mp 260-262 °C; [R]D ) +49.2 (c 1.0,
DMSO); IR (KBr) 1693, 1603, 1510, 1304, 1227, 1175 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 2.15 (m, 4 H), 3.45 (m, 1 H), 3.7
(m, 1 H), 4.0 (t, J ) 9.2 Hz, 1 H), 4.55 (dd, J ) 10 and 2.9 Hz,
1 H), 4.75 (s, 1 H), 6.80 (d, J ) 8.8 Hz, 1 H), 7.15-8.0 (m, 10
H); Mass m/z (relative intensity) 336 (18.8), 212 (33.9), 211
(100), 181 (20.7). Anal. Calcd for C24H21N3O3S (431.51): C,
66.80; H, 4.90; N, 9.74. Found: C, 66.71; H, 4.98; N, 9.66.
5-[4-[[1-(Qu in olin -2-yl)-(2S)-p yr r olid in -2-yl]m eth oxy]-
p h en ylm eth yl]th ia zolid in e-2,4-d ion e (6f) Ma lea te. The
title compound (0.85 g, 70%) was prepared as a yellow solid
from 5-[4-[[1-(quinolin-2-yl)-(2S)-pyrrolidin-2-yl]methoxy]phe-
nylmethyl]thiazolidine-2,4-dione (1 g, 2.3 mmol) and maleic
acid (0.27 g, 2.3 mmol) by a similar procedure to that described
27
(S)-4-[[1-(Qu in olin -2-yl)p yr r olid in -2-yl]m et h oxy]n i-
tr oben zen e (7f). The title compound (9 g, 36%) was prepared
as a yellow solid from (S)-2-(hydroxymethyl)-1-(quinolin-2-yl)-
pyrrolidine (16.5 g, 70 mmol) and 4-fluoronitrobenzene (12.3
g, 90 mmol) by a similar procedure to that described for the
preparation of 7a : mp 118-120 °C; IR νmax (KBr) 1605, 1507
for the preparation of 6a maleate: mp 50-52 °C; [R]D
)
-45.8 (c 1.0, DMSO); IR νmax (KBr) 2977, 1750, 1687, 1649,
1511 cm-1; 1H NMR (CDCl3, 200 MHz) δ 2.3 (m, 4 H), 3.0-3.4
(m, 2 H), 3.6-4.3 (m, 4 H), 4.41 (dd, J ) 8.0 and 4.0 Hz, 1 H),
5.0 (bs, 1 H), 6.33 (s, 2 H), 6.8 (m, 2 H), 7.1 (m, 3 H), 7.5 (m,
1 H), 7.75 (m, 2 H), 8.2 (d, J ) 9.4 Hz, 2 H); Mass m/z (relative
intensity) 433 (3.6), 223 (5.4), 211 (54.5), 197 (80), 107 (100).
Anal. Calcd for C28H27N3O7S (549.60): C, 61.19; H, 4.95; N,
7.64. Found: C, 61.23; H, 4.88; N, 7.71.
1
cm-1; H NMR (CDCl3, 200 MHz) δ 2.15 (m, 4 H), 3.45 (m, 1
H), 3.7 (m, 1 H), 4.0 (t, J ) 9.4 Hz, 1 H), 4.65 (dd, J ) 10.0
and 3.2 Hz, 1 H), 4.8 (s, 1 H), 6.75 (d, J ) 9.2 Hz, 1 H), 7.1-
8.00 (m, 7 H), 8.27 (d, J ) 9.2 Hz, 2 H); Mass m/z (relative
intensity) 349 (M+ 2.2), 320 (2.2), 211 (100), 182 (9), 169 (11.4).
5-[4-[[1-(Qu in olin -2-yl)-(2S)-p yr r olid in -2-yl]m eth oxy]-
p h en ylm eth yl]th ia zolid in e-2,4-d ion e (6f) Hyd r och lor id e.
The title compound (0.09 g, 83%) was prepared as a yellow
solid from 3-[4-[[1-(quinolin-2-yl)-(2S)-pyrrolidin-2-yl]methoxy]-
phenylmethyl]thiazolidine-2,4-dione (1 g, 2.3 mmol) by a
similar procedure to that described for the preparation of 6a
hydrochloride: mp 140-142 °C; [R]D27 ) -100.6 (c 1.0, DMSO);
(S)-4-[[1-(Qu in olin -2-yl)p yr r olid in -2-yl]m et h oxy]a n i-
lin e (10f). The title compound (5.5 g, 100%) was prepared as
a brown-colored solid from (S)-4-[[1-(quinolin-2-yl)pyrrolidin-
2-yl]methoxy]nitrobenzene (6 g, 170 mmol), iron (9.7 g, 170
mmol), and concentrated HCl (40 mL) by a similar procedure
to that described for the preparation of 10a : mp 138-140 °C;
IR νmax (KBr) 2974, 1748, 1695, 1648, 1511 cm-1 1H NMR
;
IR νmax (KBr) 1606, 1474, 1229 cm-1
;
1H NMR (CDCl3, 200
(DMSO-d6, 200 MHz) δ 2.1 (m, 4 H), 2.9-4.3 (complex, 7 H),
4.9 (m, 1 H), 6.83 (d, J ) 8.0 Hz, 2 H), 7.13 (d, J ) 8.6 Hz, 2
H), 7.52 (m, 2 H), 7.9 (m, 1 H), 7.96 (d, J ) 7.6 Hz, 1 H), 8.21
(d, J ) 8.0 Hz, 1 H), 8.44 (d, J ) 9.6 Hz, 1 H); Mass m/z
(relative intensity) 433 (3.5), 279 (3.5), 223 (5.3), 211 (29.8),
197 (80.7), 167 (8.7). Anal. Calcd for C24H24ClN3O3S (469.99):
C, 61.33; H, 5.15; N, 8.94. Found: C, 61.25; H, 5.23; N, 8.81.
MHz) δ 2.15 (m, 4 H), 3.4 (m, 1 H), 3.6-4.0 (m, 2 H), 4.4 (dd,
J ) 10.0 and 3.4 Hz, 1 H), 4.87 (s, 1 H), 6.70 (d, J ) 8.8, Hz,
1 H), 6.8 (d, J ) 9.2 Hz, 1 H), 7.0 (d, J ) 8.8 Hz, 2 H), 7.2 (m,
1 H), 7.58 (m, 2 H), 7.76 (d, J ) 8.2 Hz, 1 H), 7.89 (d, J ) 9.0
Hz, 1 H); Mass m/z (relative intensity) 320 (M+ + 1 16.6), 211
(100), 197 (70.3), 169 (7.4).
Eth yl 2-Br om o-3-[4-[[1-(qu in olin -2-yl)-(2S)-p yr r olid in -
2-yl]m eth oxy]p h en yl]p r op a n oa te. The title compound (1
g, 76%) was prepared as a thick liquid from (S)-4-[[1-(quinolin-
2-yl)pyrrolidin-2-yl]methoxy]aniline (0.9 g, 2.8 mmol) and ethyl
acrylate (1.7 g, 16 mmol) by a similar procedure to that
described for the preparation of ethyl 2-bromo-3-[4-[[1-(pyridin-
2-yl)-(2S)-pyrrolidin-2-yl]methoxy]phenyl]propanoate: IR νmax
(neat) 1738, 1608, 1509, 1478 cm-1; 1H NMR (CDCl3, 200 MHz)
δ 1.25 (t, J ) 7.4 Hz, 3 H), 2.2 (m, 4 H), 3.2 (dd, J ) 14.0 and
6.8 Hz, 1 H), 3.5 (m, 2 H), 3.7 (m, 1 H), 3.89 (t, J ) 9.4 Hz, 1
H), 4.2 (m, 2 H), 4.35 (m, 1 H), 4.45 (m, 1 H), 4.75 (s, 1 H), 6.8
(d, J ) 9.0 Hz, 1 H), 7.2 (m, 5 H), 7.6 (m, 2 H), 7.77 (d, J ) 8.2
Hz, 1 H), 7.91 (d, J ) 9 Hz, 1 H); Mass m/z (relative intensity)
483 (M+, 1), 405 (7.9), 359 (1.6), 197 (100).
(S)-2-(H yd r oxym et h yl)-1-(4-m et h ylq u in olin -2-yl)p yr -
r olid in e (3g). The title compound (22 g, 93.6%) was prepared
as a brown-colored thick liquid from 2-chloro-4-methylquino-
line (17.3 g, 100 mmol) and L-prolinol (59 g, 583 mmol) by a
procedure analogous to that described for the preparation of
3a : IR νmax (neat) 2854, 1614, 1555 cm-1 1H NMR (CDCl3,
;
200 MHz) δ 1.9-2.1 (m, 4 H), 2.60 (s, 3 H), 3.4-3.8 (m, 4 H),
4.4 (m, 1 H), 6.6 (s, 1 H), 7.2 (t, J ) 7.7 Hz, 1 H), 7.5 (t, J )
7.3 Hz, 1 H), 7.6 (d, J ) 8.0 Hz, 1 H), 7.7 (d, J ) 8.0 Hz, 1 H);
Mass m/z (relative intensity) 242 (M+, 11.6), 211 (100), 183
(15), 142 (16), 115 (21.6). Anal. Calcd for C15H18N2O (242.32):
C, 74.35; H, 7.48; N, 11.50. Found: C, 74.16; H, 7.53; N, 11.9.
(S)-4-[[1-(4-Meth ylqu in olin -2-yl)pyr r olidin -2-yl]m eth ox-
y]n itr obn zen e (7g). The title compound (10 g, 66.6%) was
prepared as a yellow solid from (S)-2-(hydroxymethyl)-1-(4-
methylquinolin-2-yl)pyrrolidine (10 g, 41.3 mmol) and 1-fluoro-
4-nitrobenzene (5.26 mL, 49.5 mmol) by a similar procedure
to that described for the preparation of 7a : mp 96-98 °C; IR
νmax (KBr) 1611, 1553, 1501, 1418 cm-1; 1H NMR (CDCl3, 200
MHz) δ 2.04-2.2 (m, 4 H), 2.61 (s, 3 H), 3.4 (t, J ) 4.2 Hz, 1
H), 3.6 (t, J ) 6.5 Hz, 1 H), 4.0 (t, J ) 9.5 Hz, 1 H), 4.6 (dd, J
) 2.8 and 3.2 Hz, 1 H), 7.2 (t, J ) 7.3 Hz, 1 H), 7.35-7.40 (d,
J ) 9.2 Hz, 2 H), 7.5 (t, J ) 7.6 Hz, 1 H), 7.7 (t, J ) 8.6 Hz, 2
H), 8.2 (d, J ) 9.2 Hz, 2H); Mass m/z (relative intensity) 363
(M+, 5.4), 211 (100),183 (9), 142 (14.5), 115 (16.3). Anal. Calcd
5-[4-[[1-(Qu in olin -2-yl)-(2S)-p yr r olid in -2-yl]m eth oxy]-
p h en ylm eth yl]th ia zolid in e-2,4-d ion e (6f). The title com-
pound (0.5 g, 63%) was prepared as a pale-yellow solid from
ethyl 2-bromo-3-[4-[[1-(quinolin-2-yl)-(2S)-pyrrolidin-2-yl]methox-
y]phenyl]propanoate (0.9 g, 1.9 mmol) and thiourea (0.21 g,
2.8 mmol) by a similar procedure to that described for the
preparation of 6a : mp 81-83 °C; [R]D27 ) -13.8 (c 1.0, DMSO);
IR νmax (KBr) 1752, 1699, 1606, 1555, 1508 cm-1 1H NMR
;
(CDCl3, 200 MHz) δ 2.1 (m, 4 H), 3.1 (dd, J ) 14.0 and 10.0
Hz, 1 H), 3.44 (m, 2 H), 3.69 (t, J ) 8.0 Hz, 1 H), 3.94 (t, J )
9.2 Hz, 1 H), 4.5 (m, 2 H), 4.75 (s, 1 H), 6.78 (d, J ) 9.2 Hz, 1

2580 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14
Lohray et al.
for C21H21N3O3 (363.41): C, 69.41; H, 5.82; N, 11.56. Found:
C, 69.35; H, 5.89; N, 11.64.
1688, 1647, 1609, 1512 cm-1
;
1H NMR (CDCl3, 200 MHz) δ
2.30 (m, 4 H), 2.7 (s, 3 H), 3.0-5.0 (complex, 8 H), 6.7-8.0
(complex, 9 H), 14.2 (bs, exchangeable with D2O, 1 H); Mass
m/z (relative intensity) 447 (free base M+, 5), 211 (100). Anal.
Calcd for C25H26ClN3O3S (484.02): C, 62.04; H, 5.41; N, 8.60.
Found: C, 61.91; H, 5.35; N, 8.68.
(S)-4-[[1-(4-Meth ylqu in olin -2-yl)p yr r olid in -2-yl]m eth -
oxy]a n ilin e (10g). The title compound (6.5 g, 95.5%) was
prepared as a thick liquid from (S)-4-[[1-(4-methylquinolin-2-
yl)pyrrolidin-2-yl]methoxy]nitrobenzene (7.5 g, 20.6 mmol) and
Fe (11.7 g 0.21 mol) by a similar procedure described for the
5-[4-[[1-(4-Met h ylq u in olin -2-yl)-(2S)-p yr r olid in -2-yl]-
m eth oxy]p h en ylm eth yl]th ia zolid in e-2,4-d ion e (6g) Ma le-
a te. The title compound (0.21 g, 78%) was prepared as a white
solid from 5-[4-[[1-(4-methylquinolin-2-yl)-(2S)-pyrrolidin-2-yl]-
methoxy]phenylmethyl]thiazolidine-2,4-dione (0.250 g, 0.48
mmol) and maleic acid (58 mg, 0.48 mmol) by a similar
procedure described for the preparation of 6a maleate: mp
1
preparation of 10a : IR νmax (neat) 2951, 1611, 1511 cm-1; H
NMR (CDCl3, 200 MHz) δ 2.1 (m, 4 H), 2.6 (s, 3 H), 3.5 (m, 1
H), 3.6-3.9 (m, 2 H), 4.35 (dd, J ) 9.8 and 3.2 Hz, 1 H), 4.7
(bs, 1 H), 6.7 (m, 3 H), 7.0 (d, J ) 8.6 Hz, 2 H), 7.24 (m, 1 H),
7.5 (m, 1 H), 7.76 (t, J ) 7.2 Hz, 2 H); Mass m/z (relative
intensity) 334 (M+, 4), 225 (100), 211 (75).
27
68-70 °C; [R]D ) -72.0 (c 1.0, DMSO); IR νmax (KBr) 1751,
E t h yl 2-Ch lor o-3-[4-[[1-(4-m et h ylq u in olin -2-yl)-(2S)-
pyr r olidin -2-yl]m eth oxy]ph en yl]pr opan oate. The title com-
pound (15 g, 85%) was prepared as a thick liquid from (S)-4-
[[1-(4-methylquinolin-2-yl)pyrrolidinyl]methoxy]aniline (13.7
g, 41.1 mmol) and ethyl acrylate (2.5 g, 23.4 mmol) by a similar
procedure to that described for the preparation of ethyl
2-bromo-3-[4-[[1-(pyridin-2-yl)-(2S)-pyrrolidin-2-yl]methoxy]-
phenyl]propanoate, except HCl was used instead of HBr: IR
1698, 1647, 1579, 1511, 1364, 1240, 1154, 1013, 864, 757, 713,
1
559 cm-1; H NMR (CDCl3, 200 MHz) δ 2.25 (m, 4 H), 2.7 (s,
3 H), 3.05-3.45 (m, 2 H), 3.8 (m, 1 H), 4.0 (m, 1 H), 4.2 (m, 2
H), 4.48 (dd, J ) 8.0 and 4.2 Hz, 1 H), 5.0 (m, 1 H), 6.35 (s, 2
H), 6.9 (m, 3 H), 7.14 (d, J ) 8.2 Hz, 2 H), 7.44 (t, J ) 7.6 Hz,
1 H), 7.7 (t, J ) 7.8 Hz, 1 H),7.84 (d, J ) 8.4 Hz, 1 H), 8.1 (d,
J ) 8.2 Hz, 1 H); Mass m/z (relative intensity) 444 (free base
M+, 6), 211 (100), 142 (11), 107 (68). Anal. Calcd for C29H29N3O7S
(563.63): C, 61.79; H, 5.19; N, 7.45. Found: C, 61.63; H, 5.08;
N, 4.56.
ν
max (neat) 1743, 1611, 1553, 1512 cm-1; 1H NMR (CDCl3, 200
MHz) δ 1.25 (t, J ) 7.2 Hz, 3 H), 2.15 (m, 4 H), 2.6 (s, 3 H),
3.12 (dd, J ) 14.0 and 7.6 Hz, 1 H), 3.32 (dd, J ) 14.2 and 7.6
Hz, 1 H), 3.5 (m, 1 H), 3.7 (m, 1 H), 3.86 (t, J ) 9.2 Hz, 1 H),
4.2 (q, J ) 7.2 Hz, 2 H), 4.4 (m, 2 H), 4.7 (bs, 1 H), 6.65 (s, 1
H), 7.2 (m, 5 H), 7.6 (m, 1 H), 7.77 (t, J ) 6.8 Hz, 2 H); Mass
m/z (relative intensity) 452 (M+, 2.5), 418 (3.5), 211 (100), 142
(10), 115 (10).
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-[[1-(4-Met h ylq u in olin -2-yl)-(2S)-p yr r olid in -2-yl]-
m eth oxy]ph en ylm eth yl]th iazolidin e-2,4-dion e (6g). A mix-
ture of ethyl 2-chloro-3-[4-[[1-(4-methylquinolin-2-yl)-(2S)-
pyrrolidin-2-yl]methoxy]phenyl]propanoate (15 g, 33 mmol)
and thiourea (5 g, 65 mmol) in sulfolane (20 mL) was stirred
at 120-130 °C for 4 h under N2 atmosphere. The reaction
mixture was cooled to room temperature, and 2-methoxyetha-
nol (192 mL), water (50 mL), and concentrated HCl (26 mL)
were added. The temperature was raised to 80 °C and stirred
for 15 h. The reaction mixture was cooled, diluted with EtOAc,
and washed with aqueous NH3 followed by water. The organic
layer was dried (Na2SO4) and concentrated. The crude product
was chromatographed on silica gel with 10-40% EtOAc in
petroleum ether (gradient elution) as an eluent to afford the
title compound (14 g, 95%) as a white solid: mp 95-97 °C;
Refer en ces
(1) (a) DeFronzo, R. A. The triumvirate: â cell, muscle, liver a
collusion responsible for NIDDM. Diabetes 1988, 37, 667. (b)
Turner, R. C.; Mathews, D. R.; Clark, A.; O’Rahilly, S.; Rudenski,
A. S.; Levy, J . Clin. Endrocrinol Metab. 1988, 2, 327. (c) Reaven,
G. M. Diabetes 1988, 37, 1595-1607.
(2) (a) Sohda, T.; Mizuno, K.; Tawada, H.; Sugiyama, Y.; Fujita, T.;
Kawanatsu, Y. Studies on Antidiabetic agents. II Synthesis of
5-[4-(1-Methylcyclohexylmethoxy)benzyl]thiazolidine-2,4-dione
and its derivatives. Chem. Pharm. Bull. 1982, 30, 3563-3573
and 3580-3600. (b) Momose, Y.; Meguro, K.; Ikeda, H.; Ha-
tanaka, C.; Oi, S.; Sohda, T. Studies on antidiabetic agents X
synthesis and biological activities of pioglitazone and related
compounds. Chem. Pharm. Bull. 1991, 39, 1440-1445. (c)
Meguro, K.; Fujita, T. EP 0155845, 1985; Chem. Abstr. 1986,
104, 186401a. (d) Sugiyama, Y.; Taketomi, S.; Shimara, Y.;
Ikeda, H.; Fujita, T. Effects of Pioglitazone on Glucose and Lipid
metabolism in Wistar fatty rats. Arzneim. Forsch. Drug Res.
1990, 40, 263-267. (e) Yoshioka, T.; Fujita, T.; Kanai, T.;
Aizawa, Y.; Kurumada, T.; Hasegawa, K.; Horikoshi, H. Studies
on Hindered Phenols and Analogous. 1. Hypolipidemic Agents
with Ability to Inhibit Lipid Peroxidation. J . Med. Chem. 1989,
32, 421-428. (f) Yoshioka, T.; Kotazata, E.; Yamazaki, M.;
Hasegawa, K. Thiazolidinedione Derivatives, Their preparation
and Compositions Containing Them. EP 0139421, 1984; Chem.
Abstr. 1985, 103, 540685. (g) Clark, D. A.; Goldstein, S. W.;
Volkmann, R. A.; Eggler, J . F.; Holland, G. F.; Hulin, B.;
Stevenson, R. W.; Kreutter, D. K.; Gibbs, E. M.; Krupp, M. N.
Merrigan, P.; Kelbaugh, P. L.; Andrews, E. G.; Tickner, D. L.;
Suleske, R. T.; Lamphere, C. H.; Rajeckas, F. J .; Kappeler, W.
H.; McDermott, R. E.; Hutson, N. J .; J ohnson, M. R. Substituted
Dihydrobenzopyran and Dihydrobenzofuran Thiazolidine-2,4-
diones and Hypoglycemic Agents. J . Med. Chem. 1991, 34, 319-
325. (h) Eggler, J . F.; Holland, G. F.; J ohnson, M. R.; Volkmann,
R. A. Hypoglycaemic Thiazolidinediones. U.S. Patent 4,738,972,
1985; Chem. Abstr. 1987, 107, 39794q. (i) Stevenson, R. W.;
Hutson, N. J .; Krapp, M. N.; Volkmann, R. A.; Holland, G. F.;
Eggler, J . F.; Clark, D. A.; McPherson, R. K.; Haell, K. L.;
Danburg, B. H.; Gibbs, E. M.; Krentler, D. K. Actions of Novel
Antidiabetic agents Englitazone in Hyperglycemic Hyperin-
sulinemic ob/ob mice. Diabetes 1990, 39, 1218-1227. (j) Cantello,
B. C. C.; Cawthorne, M. A.; Haigh, D.; Hindley, R. M.; Smith, S.
A.; Thurlby, P. L. The Synthesis of BRL-49653 - A Novel and
Potent Antihyperglycemic agent. Bioorg. Med. Chem. Lett. 1994,
4, 1181-1184.
27
[R]D ) -31.5 (c 1.0, CHCl3); IR νmax (KBr) 1699, 1610, 1553,
1
1511 cm-1; H NMR (CDCl3, 200 MHz) δ 2.1 (m, 4 H), 2.1 (s,
3 H), 3.1 (m, 1 H), 3.5 (m, 2 H), 3.7 (m, 1 H), 3.9 (t, J ) 9.0 Hz,
1 H), 4.5 (m, 2 H), 4.75 (bs, 1 H), 6.65 (s, 1 H), 7.2 (m, 5 H),
7.57 (t, J ) 7.6 Hz, 1 H), 7.78 (t, J ) 8.2 Hz, 2 H); Mass m/z
(relative intensity) 447 (M+, 6), 225 (24), 211 (100), 183 (7),
142 (12), 107 (20). Anal. Calcd for C25H25N3O3S (447.55): C,
67.09; H, 5.63; N, 9.39. Found: C, 66.95; H, 5.54; N, 9.49.
5-[4-[[1-(4-Met h ylq u in olin -2-yl)-(2S)-p yr r olid in -2-yl]-
m eth oxy]p h en ylm eth yl]th ia zolid in e-2,4-d ion e (6g) So-
d iu m Sa lt. The title compound (0.28 g, 53%) was prepared
as a pale-yellow solid from 5-[4-[[1-(4-methylquinolin-2-yl)-
(2S )-pyr r olidin -2-yl]m et h oxy]ph en ylm et h yl]t h ia zolidin e-
dione (0.5 g, 1.1 mmol) and NaOMe (62 mg, 1.3 mmol) by a
similar procedure described for the preparation of 6a sodium
27
salt: mp 229 °C; [R]D ) -5.3 (c 1.0, DMSO); IR νmax (KBr)
3425, 1665, 1612, 1561, 1511 cm-1; 1H NMR (CDCl3, 200 MHz)
δ 2.1 (m, 4 H), 2.4-2.7 (m, 5 H), 3.4 (m, 1 H), 3.65 (m, 1 H),
3.85 (m, 1 H), 4.1 (m, 1 H), 4.3 (m, 1 H), 4.6 (bs, 1 H), 6.85 (s,
1 H), 7.0-7.3 (m, 5 H), 7.6 (m, 2 H), 7.82 (d, J ) 8.4 Hz, 1 H);
Mass m/z (relative intensity) 224 (100), 211 (18), 195 (19), 107
(20).
5-[4-[[1-(4-Met h ylq u in olin -2-yl)-(2S)-p yr r olid in -2-yl]-
m eth oxy]p h en ylm eth yl]th ia zolid in e-2,4-d ion e (6g) Hy-
d r och lor id e. The title compound (0.2 g, 86%) was prepared
as a white solid from 5-[4-[[1-(4-methylquinolin-2-yl)-(2S)-
pyrrolidin-2-yl]methoxy]phenylmethyl] thiazolidine-2,4-dione
(0.215 g, 0.48 mmol) by a procedure analogous to that
described for the preparation of 6a hydrochloride: mp 170-
(3) (a) Scrips 1997, 2282, 21. (b) Scrips 1997, 2292, 20. (c) Matsu-
moto, K.; Miyake, S.; Yano, M.; Ueki, Y.; Tominaga, Y. Increase
of Lipoprotein (a) with Troglitazone. Lancet 1997, 350, 1748-
1749.
27
172 °C; [R]D ) -120.5 (c 1.0, DMSO); IR νmax (KBr) 3392,
(4) Scrips 1998, 2357, 22.

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