Novel antidiabetic and hypolipidemic agents. 3. Benzofuran-containing thiazolidinediones

Article abstract of DOI:10.1021/jm980549x

Several thiazolidinedione derivatives having 5-hydroxy-2,3-dihydro- 2,2,4,6,7-pentamethylbenzofuran moieties and their 5-benzyloxy derivatives and 5-hydroxy-2,4,6,7-tetramethylbenzofuran moieties were synthesized and evaluated in db/db mice. Insertion of an N-Me group into the linker between thiazolidinedione and substituted benzofuran pharmacophores showed considerable improvement in their euglycemic activity. Further improvement has been observed when a pyrrolidine moiety is introduced in the structure to give 5-[4-[N-[3(R/S)-5-benzyloxy-2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran- 3-ylmethyl]-(2S)-pyrrolidin-2-ylmethoxy]phenylene]thiazolidine-2,4-dione (21a). At a 100 mg/kg/day dose of the maleate salt, compound 21a reduced the plasma glucose and triglyceride to the level of lean littermate, i.e. 8 ± 1 mM, and is the most potent and efficacious compound reported in this series.

Full text of DOI:10.1021/jm980549x

J . Med. Chem. 1999, 42, 1927-1940
1927
Novel An tid ia betic a n d Hyp olip id em ic Agen ts. 3. Ben zofu r a n -Con ta in in g
Th ia zolid in ed ion es‡
K. Anji Reddy, B. B. Lohray,*,†,| V. Bhushan,†,| A. C. Bajji,† K. Vivekananda Reddy,† P. Rajamohan Reddy,†
T. Hari Krishna,† I. Nageswara Rao,† H. Kumar J ajoo,§ N. V. S. Mamidi Rao,§ Ranjan Chakrabarti,∇
T. Dileepkumar,∇ and R. Rajagopalan∇
Medicinal and Organic Chemistry, Drug Metabolism and Pharmacokinetics, and Pharmacology,
Dr. Reddy’s Research Foundation, Bollaram Road, Miyapur, Hyderabad 500 050, India
Received September 29, 1998
Several thiazolidinedione derivatives having 5-hydroxy-2,3-dihydro-2,2,4,6,7-pentamethylben-
zofuran moieties and their 5-benzyloxy derivatives and 5-hydroxy-2,4,6,7-tetramethylbenzofuran
moieties were synthesized and evaluated in db/db mice. Insertion of an N-Me group into the
linker between thiazolidinedione and substituted benzofuran pharmacophores showed consider-
able improvement in their euglycemic activity. Further improvement has been observed when
a pyrrolidine moiety is introduced in the structure to give 5-[4-[N-[3(R/ S)-5-benzyloxy-2,3-
dihydro-2,2,4,6,7-pentamethylbenzofuran-3-ylmethyl]-(2S)-pyrrolidin-2-ylmethoxy]phenylene]-
thiazolidine-2,4-dione (21a ). At a 100 mg/kg/day dose of the maleate salt, compound 21a reduced
the plasma glucose and triglyceride to the level of lean littermate, i.e. 8 ( 1 mM, and is the
most potent and efficacious compound reported in this series.
In tr od u ction
membered ring heterocycle along with the adjacent
carbon atom of the pyridyl group, shows very good
Since the pioneering discovery of ciglitazone,1 there
has been a surge of interest in the development of novel
antihyperglycemic agents that can reverse the insulin
resistance2 in non-insulin-dependent diabetes mellitus
(type 2) patients. In rodent models of obesity, insulin
resistance, and hyperglycemia, thiazolidinediones ame-
liorate insulin resistance3 and normalize plasma glucose
and insulin without causing hypoglycemia, even at very
high doses.4 However, due to the unsatisfactory efficacy
and safety profile of these agents,5 there has been
concern about thiazolidinediones being antidiabetic
drugs for the treatment of diabetes. The encouraging
reports from clinicians on troglitazone, which is now
marketed in J apan and North America6 (although it
still causes liver toxicity in a limited number of pa-
tients),7 have encouraged pharmaceutical companies to
continue the development of new thiazolidinedione
analogues.8-11
hypolipidemic and euglycemic activities.2e,12 (eq 1).
In our preliminary studies, we have found that the
contraction of the chroman moiety of troglitazone to
afford a benzofuran moiety (structure A) leads to a
decrease in euglycemic and hypolipidemic activities
compared to troglitazone when tested in db/db mice.13
However, insertion of a CH2N(Me)CH2 group in struc-
ture A leads to improved euglycemic and hypolipidemic
activities compared to troglitazone (structure C, eq 2).
We believe that the liver toxicity in the case of
troglitazone is idiosyncratic and may not be related to
the thiazolidinedione (TZD) pharmacophore. Therefore,
we decided to develop a new class of TZDs having a
structural motif similar to the chroman ring found in
troglitazone.
We have recently reported that DRF 2189, which is
conceptually a compound generated by cyclizing the
methyl group on nitrogen of BRL-49653 to form a five-
In the present study, we are reporting a detailed
systematic structure-activity relationship (SAR) of
several TZDs having features as shown in structures B
and C.
‡ DRF Communication No. 58. Dedicated to Prof. M. V. George on
his 70th birthday.
* Corresponding author. E-mail: drf@hdl.vsnl.net.in.
Ch em istr y
† Medicinal and Organic Chemistry.
§ Drug Metabolism and Pharmacokinetics.
∇ Pharmacology.
A general strategy to synthesize thiazolidinedione A
is shown in Scheme 1. 2,3-Dihydro-2,2,4,6,7-pentam-
ethyl-5-benzyloxybenzofuran-3-carbinol (1) was pre-
pared by a reported method14 and mesylated to furnish
Dr. Reddy’s Research Foundation.
| Present address: Zydus Research Centre, Zydus Tower, Satellite
Cross Rd, Gandhinagar-Sarkhej Hwy, Ahmedabad 380 018, India.
10.1021/jm980549x CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/15/1999

1928 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11
Reddy et al.
Sch em e 1a
a
(a) CH3SO2Cl, Et3N, DCM, 0-25 °C, 5 h, 99%; (b) 4-hydroxybenzaldehyde, K2CO3, DMF, 70-80 °C, 12 h, 51%; (c) 2,4-thiazolidinedione
(TZD), C6H5CH3, piperidinium benzoate, 130 °C, 2 h, 75%; (d) 4-fluoronitrobenzene, NaH, DMF, 25 °C, 3 h, 67%; (e) CH3COOH concd
HCl (3:1), 60 °C, 1-2 h, 54-63%; (f) Pd-C (10%), H2, 60 psi, EtOAc, 25 °C, 48 h, 75%; (g) (i) HBr, NaNO2, H2O, CH3COCH3, CH3OH,
CH2dCHCOOC2H5, Cu2O, 0-40 °C, 0.5 h, 37%, (ii) H2NCSNH2, NaOAc, EtOH, 12 h, ∆, 2 N HCl, 80 °C, 12 h, 73%; (h) Mg-CH3OH, 25
°C, 12 h, or Pd-C (10%), H2, 60 psi, EtOAc, 25 °C, 60 h.
Sch em e 2a
a
(a) MeNHCH2CH2OH, 170 °C, 20 h, 75%; (b) SOCl2, C6H6, ca. 25 °C, 1 h, 97%; (c) 4-hydroxybenzaldehyde, DMF, 50-60 °C, 24 h, 99%;
(d) 5-(4-hydroxyphenylmethyl)thiazolidine-2,4-dione, DMF, NaH, 50 °C, 12 h, 41%; (e) 2,4-thiazolidinedione (TZD), C6H5CH3, piperidinium
benzoate, 130 °C, 2 h, 63%; (f) Mg-CH3OH, 25 °C, 12 h, or Pd-C (10%), H2, 60 psi, EtOAc, 25 °C, 60 h; (g) CH3COOH, concd HCl (3:1),
60 °C, 1-2 h, 57-90%.
>95% yield of 2. The mesylate 2 was treated with
4-hydroxybenzaldehyde in the presence of K2CO3 in
DMF at 70-80 °C for 12 h to furnish the aldehyde 3
(51%) (Scheme 1).
converted to saturated thiazolidinedione 7a by a similar
method reported elsewhere.2b A similar synthetic strat-
egy (Scheme 2) was adopted for the synthesis of various
derivatives of C (eq 2).
The aldehyde 3 was reacted with 2,4-thiazolidinedione
(TZD) in the presence of piperidinium benzoate to
furnish good yield (75%) of benzylidenethiazolidinedione
analogue 4a . The benzyl protecting group was removed
by refluxing 4a in a mixture of acetic acid and concen-
trated HCl to furnish 4b (63%).
The saturated analogue 7 could not be prepared by
either hydrogenation of 4a with Pd-C or electron-
transfer method of Watt (CH3OH-Mg).15 Hence, an
alternate route was adopted as shown in Scheme 1. The
carbinol 1 was treated with 4-fluoronitrobenzene to give
the nitro derivative 5 which was subsequently reduced
to amino derivative 6. The amino compound 6 was
The mesylate 2 was heated with N-methylaminoet-
hanol to afford 75% yield of the amino alcohol 8. The
treatment of 8 with thionyl chloride in toluene furnished
good yield of chloro compound 9. The chloro compound
9 when reacted with 4-hydroxybenzaldehyde in the
presence of K2CO3 in DMF for 24 h furnished quantita-
tive yield of aldehyde 10. The latter was condensed with
2,4-thiazolidinedione under reported conditions8d to
furnish a good yield (63%) of unsaturated TZD analogue
12a . The saturated analogue 11a was prepared in 41%
yield by direct reaction of 9 with 5-(4-hydroxyphenyl-
methyl)thiazolidine-2,4-dione using NaH (60%) in DMF
at ca. 50 °C.

Novel Antidiabetic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11 1929
Sch em e 3a
a
(a) (S)-Prolinol (4 equiv), neat, ∆, 120 °C, 12 h, 73%; (b) SOCl2, C6H6, ca. 25 °C, 1 h, 73%; (c) 4-fluoronitrobenzene, NaH, DMF, 25 °C,
3 h, 67%; (d) 4-hydroxybenzaldehyde, K2CO3, DMF, 80 °C, 12 h (17:18, 13%, 65%); (e) Pd-C (10%), H2, 60 psi, EtOAc, 25 °C, 48 h, 55%;
(f) (i) HBr, NaNO2, H2O, CH3COCH3, CH3OH, CH2dCHCOOC2H5, Cu2O, 0-40 °C, 0.5 h, 38%, (ii) H2NCSNH2, NaOAc, EtOH, 12 h, ∆,
2 N HCl, 80 °C, 12 h, 83%; (g) 2,4-thiazolidinedione (TZD), C6H5CH3, piperidinium benzoate, 130 °C, 2 h, 43-84%; (h) CH3COOH, concd
HCl (3:1), 60 °C, 1-2 h, 43-63%.
Sch em e 4. Mechanism of Transformation of Pyrrolidine Derivative 13 to Piperidine Derivatives 14 and to Aldehydes
17 and 18
An analogous strategy was adopted to prepare thia-
zolidinedione derivatives B mentioned in eq 2. The
synthetic routes are outlined in Scheme 3.
The mesylate 2 was heated with (S)-prolinol (4 equiv)
at 120 °C for 12 h to furnish pyrrolidine derivative 13
in 73% yield. The reaction of 13 with thionyl chloride
in benzene at ca. 25 °C for 1 h furnished 14 in 91% yield.
The formation of 3-chloropiperidine derivative 14 may
be visualized by the reaction of SOCl2 with prolinol
derivative 13 to furnish 3-chloromethylpyrrolidine de-
rivative 13a which can undergo intramolecular dis-
placement reaction by the attack of nitrogen to give an
aziridine intermediate 14a (Scheme 4).16 The chloride
ion can attack intramolecularly to furnish a strain-free
3-chloropiperidine derivative 14. Interestingly, the reac-
tion of 14 with 4-hydroxybenzaldehyde in the presence

1930 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11
Reddy et al.
Sch em e 5. Synthesis of Benzofuran Derivative via Analogous Synthetic Transformations Reported in Scheme 2
Ta ble 1. Euglycemic and Hypolipidemic Activities of
of K2CO3 (4 equiv) in DMF at 80 °C for 12 h furnished
Thiazolidinediones in db/db Mice
a mixture of five- and six-membered ring products (17
and 18) in almost a 1:1 ratio (69%).
yielda
(%)
doseb
(mg/kg/day)
no.
compd no.
PGc
TGd
Finally, the mixture of aldehydes 17 and 18 was
condensed with 2,4-thiazolidinedione to afford a mixture
of unsaturated compounds 20a and 21a , respectively,
which were separated by flash chromatography over
silica gel. The unsaturated TZD analogue 21a was
refluxed in AcOH-HCl, to afford debenzylated product
21b. The saturated TZD analogue 19a was prepared by
an alternate route since our attempts to saturate 21a
by Pd-C (10%)/H2 or CH3OH-Mg failed to give the
desired results. Thus, the prolinol derivative 13 was
treated with 4-fluoronitrobenzene to give 67% yield of
the nitro compound 15 which was subsequently reduced
to amino derivative 16 (Scheme 3). The amino compound
16 was converted to saturated TZD 19a using a two-
step process reported earlier.8d The latter was depro-
tected to TZD 19b using CH3COOH-HCl in good yield.
We also prepared hydrochloride and maleate salts of
unsaturated TZD 21a and saturated TZD 19a .
1
2
troglitazone
4a
54
75
63
54
63
90
57
67
43
75
10
84
56
47
20
75
200
200
200
200
200
100
200
100
100
100
100
100
100
100
100
100
26
10
11
12
23
28
19
66
19
48
37
NA
50
22
NA
NA
50
NA
NA
31
3
4b
4
7b
12a
12b
11b
21a
21b
19a
19b
20a
23a
24b
25a
24a
5
NA
76
ND
52
NA
31
33
52
NA
NA
NA
NA
6
7
8
9
10
11
12
13
14
15
16
a
b
Yield in the last step of synthesis. Dose through oral gavage.
c Percent reduction of plasma glucose after 6 days of treatment.
SD ) ( 5%. This is the mean of standard deviation observed in
plasma glucose in various animals as well as in control animals
d
and is calculated according to the formula cited in ref 19. Percent
reduction in plasma triglyceride after 6 days of treatment. SD )
( 5%. This is the mean of standard deviation observed in plasma
triglyceride in various animals as well as in control animals. NA,
not active; ND, not determined.
A similar strategy was followed for the preparation
of benzofuran analogues 23a , 23b, and 24a (Scheme 5).
Biologica l P r oced u r e
percent reductions in plasma glucose and triglyceride
level were calculated.17 The results are summarized in
Table 1.
Eu glycem ic a n d Hyp olip id em ic 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 experiments at 8 weeks
of age. Four to six animals were used in each treatment
group. In db/db mice, the test compounds were admin-
istered at different doses orally for 6 days. Troglitazone
(200 mg/kg) was used as a standard drug. The control
animals were given vehicle (0.5% carboxymethylcellu-
lose; dose 10 mL/kg). The blood sample (25-50 µL) was
collected from the retro-orbital sinus through heparin-
ized capillary tubes in tubes containing EDTA at
different time intervals. In db/db mice, blood samples
were collected 1 h after drug administration. After
centrifugation, plasma was separated, and glucose and
triglyceride were estimated using commercial kits (Dr.
Reddy’s Laboratories Diagnostic Division, India). The
P h a r m a cok in etic Stu d ies
Pharmacokinetics of selected compounds and trogli-
tazone were carried out in female Wistar rats (National
Institute of Nutrition, Hyderabad, India). The animals
(200-225 g) were fasted for 12 h (overnight) before
starting the experiment and had free access to water
throughout the experimental period. The animals were
fed after 3 h of drug administration.
Sin gle-Dose P h a r m a cok in etics
The animals were dosed with the test compound at
100 mg/kg (po) as 0.5% CMC suspension, and about 0.45
mL of blood sample was collected into heparinized
microfuge tubes at different time points from the retro-
orbital sinus. The samples were analyzed by reverse-
phase HPLC to generate plasma concentration-time
profiles. Englitazone18 was used as the internal stan-
dard.

Novel Antidiabetic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11 1931
Ta ble 2. Percentage Reduction in Plasma Glucose and
Triglyceride for Selected TZDs and Their Salts
Resu lts a n d Discu ssion
All thiazolidinedione analogues including troglitazone
were examined for their glucose- and triglyceride-
lowering activities at 30-200 mg/kg dose for 6 days in
db/db mice. In a separate experiment, a dose-response
study was performed for troglitazone in db/db mice for
11 days. Dose-related reduction in the plasma glucose
level in experimental animals was observed. It is
noteworthy that animals treated even with the highest
dose (800 mg/kg) of troglitazone showed reduction in
glucose level only to an extent of 15 ( 1 mM, which is
higher than the plasma glucose level of lean littermates
(8 ( 1 mM). It is interesting to note that 25% of the
animals did not respond to troglitazone treatment.
Kobayashi has also made a similar observation in
patients.19 Thus, it appears imperative to search for a
more efficacious and potent compound than troglitazone.
Toward achieving this goal, we first prepared TZDs
containing 2,3-dihydro-5-hydroxy-2,2,4,6,7-pentameth-
ylbenzofuran in place of the chroman ring in troglita-
zone. The unsaturated thiazolidinedione analogues 4a
and 4b and saturated 7b were prepared by different
routes (Scheme 1) and evaluated in db/db mice at 200
mg/kg/day dose (po) for 6 days. For comparison, trogli-
tazone was also dosed at 200 mg/kg/day for 6 days. The
results after 6 days of treatment (Table 1, entries 1-3)
suggest that benzofuran analogues 4a and 4b do not
possess plasma glucose (PG)- and triglyceride (TG)-
lowering activities. The corresponding saturated ana-
logue 7b (Table 1, entry 4) also did not show improve-
ment of pharmacological profile. Thus, ring contraction
of chroman to benzofuran did not result in a better
compound.
19a
21a
21a
parameter 19a 19b maleate 21a maleate HCl Trog
PGa
TGa
37
22
28
29
24
64
40
38
45
42
25
57
NA
NA
a
All the db/db animals were dosed for 6 days at 30 mg/kg/po
dose with the test compounds and troglitazone. The values
reported are the percent reduction in plasma glucose and trigly-
ceride calculated according to formula cited in ref 19. SD ) ( 5%
for both plasma glucose and triglyceride.
Further, we prepared compounds with a -N(Me)-
CH2-CH2- group between 5-benzyloxy-2,3-dihydro-
2,2,4,6,7-pentamethylbenzofuran and p-hydroxyphenyl-
methylthiazolidine-2,4-dione as depicted in structure C
in eq 1. Initially, we examined unsaturated thiazo-
lidinediones 12a and 12b at 200 mg/kg dose in db/db
mice. The 5-benzyloxy TZD 12a or 5-hydroxy TZD 12b
showed only moderate euglycemic activity. In contrast,
the saturated TZD analogue 11b showed very poor
activity (Table 1, entry 7). Further, we decided to
explore the thiazolidinediones in which the N-Me group
is cyclized to form a part of the linker moiety as shown
in structure B (eq 1). Thus, we prepared a number of
compounds having pyrrolidine linkers. The unsaturated
TZD 21a showed excellent euglycemic and hypolipi-
demic activities at 100 mg/kg/day dose (Table 1, entry
8), and the plasma glucose reached the level of lean
littermates (8 ( 1 mM). This result encouraged us to
examine the related thiazolidinediones. The removal of
the benzyl protecting group gave 21b, which showed
inferior PG- and TG-lowering activities compared to 21a
(Table 1, entry 9). A similar trend was observed in their
corresponding saturated TZD analogues 19a and 19b
although less pronounced (Table 1, entries 10 and 11).
In contrast to the pyrrolidine derivatives 19a , 19b, 21a ,
and 21b, the piperidine derivative 24a (Table 1, entry
12) did not show any PG-lowering activity.
F igu r e 1. Dose-related reduction in plasma glucose in db/db
mice using 21a maleate and troglitazone.
db/db mice for 6 days. Although TZD 23a showed good
PG-lowering activity at 100 mg/kg dose, it had no effect
on triglyceride level (Table 1, entry 13). In contrast, 23b
showed very poor euglycemic activity (data not shown).
Surprisingly, saturated TZD 25a did not show any
activity at all (Table 1, entry 15). Similarly, piperidine
derivative 24a was devoid of euglycemic and hypolipi-
demic activity (Table 1, entry 16).
From these in vivo studies, we selected 19a , 19b, and
21a , for further evaluation. These test compounds were
given to db/db mice at 30 mg/kg/day dose for 6 days,
and plasma glucose and triglyceride levels were mea-
sured (Table 2). From the results we see that TZDs 19a
and 21a showed good euglycemic activity, whereas
troglitazone did not show any activity at 30 mg/kg/day
dose. Finally, we prepared the maleate salt of 19a and
21a and also the hydrochloride salt of 21a in order to
examine if the formation of salt alters its pharmacologi-
cal profile due to improvement in pharmacokinetic
parameters. From the results in Table 2, it is clear that
21a and 21a maleate are the best TZDs of this series
among the compounds studied.
We also carried out a dose-response study of trogli-
tazone at 30, 100, 200, and 800 mg/kg/day dose and 21a
maleate at 30 and 100 mg/kg/day dose for 11 days. The
result of dose-related percent reduction in plasma
glucose is depicted in Figure 1. From Figure 1 it is quite
clear that at 100 mg/kg/day dose, 21a maleate showed
We also examined benzofuran-derived unsaturated as
well as saturated thiazolidinediones. Thus, pyrrolidine
derivatives 23a and 23b were evaluated for their
plasma glucose- and triglyceride-lowering activities in

1932 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11
Reddy et al.
Ta ble 4. Pharmacokinetic Parameters of Thiazolidinedione
Analogues in Female Wistar Rats at 100 mg/kg po
21a a
21a maleatea troglitazonea
pharmacokinetic
parameters
mean SD mean
SD
mean SD
AUC(0-t) (µg‚h‚mL-1
)
)
15.50 8.17 53.79 12.63 25.94 5.97
23.60 12.10 65.04 16.01 27.40 5.75
AUC(0-∞)(µg‚h‚mL-1
Cmax (µg‚mL-1
Tmax (h)
)
1.25 0.50
3.50 2.12
0.05 0.00
4.30
5.00
0.07
1.23
0.00
0.01
1.72
5.47 0.64
2.25 0.96
0.20 0.10
4.01 1.38
Kel (h-1
T1/2 (h)
)
13.09 0.24 10.08
a
Results are mean ( SD of four animals in each group.
AUC(0-∞), Kel, half-life, Cmax, and Tmax were calculated using
noncompartmental model analysis. AUC(0-∞) is the area under the
plasma concentration versus time curve extrapolated to infinity;
K
el is the elimination rate constant; Cmax is the observed maximum
plasma concentration; and Tmax is the time at which maximum
concentration (Cmax) is reached.
better euglycemic activity than troglitazone in db/db
mice. This suggests that this class of compounds may
be exhibiting their pharmacological activities through
some other mechanism, not solely mediated through
PPARγ.20 Similar observations have been recently re-
ported by Aicher et al.21 in another class of insulin
sensitizers (not TZDs) which do not show PPARγ
transactivation, although they significantly improve
glucose metabolism and insulin sensitivity in ob/ob
mice. It is also interesting to note that the OBn-
protected analogues of TZDs 19a and 21a showed better
euglycemic and hypolipidemic activities at the same
dose than their debenzylated counterparts (19b and
21b, respectively) (Table 1, entry 8 vs 9 and entry 10
vs 11).
F igu r e 2. Comparative plasma concentration versus time
profiles of troglitazone (2), 21a (b), and 21a maleate (9) in
female Wistar rats at 100 mg/kg/po dose.
Ta ble 3. Activation of PPARR and PPARγ Receptors by
Thiazolidinedionesa
Troglitazone, which possesses a free phenolic OH, is
known to undergo extensive metabolism by formation
of glucuronide sulfate as well as oxidation at the
phenolic OH position of the tocopherol moiety.22 By
simple protection of the phenolic OH by OBn, one would
expect them to show longer half-lives as compared to
troglitazone.23 Presumably this may be one of the
reasons why TZD analogues 19a and 21a showed better
activities in db/db mice. On the basis of this conjecture,
we selected TZD 21a for pharmacokinetic studies in
Wistar rats. Interestingly, we found that the systemic
exposure of 21a is far inferior to troglitazone despite
its superior plasma glucose- and triglyceride-lowering
activities (Table 4).
fold activation
compd no.
19a
19b
21a
21b
troglitazone
PPARR (50 µM)
PPARγ (1 µM)
0.33
0.46
0.43
0.28
1.12
0.17
1.21
1.03
0.84
3.16
a
GAL4-PPAR chimeric expression constructs and the reporter
plasmids were a gift from Novo Nordisk (Denmark). GAL4 fusions
were made by fusing human PPARR-LBD (amino acids 167-468)
or human PPARγ1-LBD (amino acids 174-475) receptor to the
C-terminal end of the yeast GAL4 DBD (amino acids 1-147) of
the pM1 vector. For luciferase assays, response element (five copies
of a GAL4 DNA binding element) was cloned upstream of pGL2-
SV40-Luc reporter (Promega).
The pharmacokinetics data suggest that 21a is ab-
sorbed slowly and reached a maximum in ca. 3-5 h,
and the Cmax is only 1.2-1.5 µg‚mL-1. In contrast,
troglitazone reached Cmax (ca. 5-6 µg‚mL-1) in 2-3 h.
On the basis of this finding, we carried out the phar-
macokinetic studies of the maleate salt of 21a in Wistar
rats. Maleate salt of 21a showed slow absorption of the
drug (ca. 5 h) and reached Cmax (ca. 4.5 µg‚mL-1) in a
time frame similar to that seen with troglitazone. In
addition, the compound is eliminated slowly, and t1/2 of
the maleate salt of 21a is more than double that of
troglitazone. Thus, pharmacokinetic behavior of the
maleate salt appears to be desirable.
In conclusion, the TZDs containing the dihydroben-
zofuran moiety in structural motif have shown good
euglycemic and hypolipidemic activity. However, if the
phenolic OH at the 5 position of dihydrobenzofuran is
protected as a benzyl ether, it resulted in improved
pharmacokinetics and better euglycemic activity than
ca. 70% reduction in plasma glucose and it reached the
level of lean littermate db+/db- (8 ( 1 mM). In contrast,
even at 800 mg/kg/day dose of troglitazone, only 52%
reduction in plasma glucose was observed and still the
plasma glucose (15 ( 1 mM) was much above the
normal level. As reported earlier, 25% of the animals
did not respond to troglitazone treatment even at 800
mg/kg/dose. In contrast, all the db/db animals showed
reduction in plasma glucose when treated with 100 mg/
kg/day of 21a maleate.
On the basis of the in vivo activity in db/db mice, we
selected 19a , 19b, 21a , and 21b to evaluate their
PPARR and PPARγ transactivations to get some insight
into the mechanism of action of these TZDs.20 The
results in Table 3 indicate that none of these compounds
showed transactivation of either PPARR or PPARγ.
They exhibited much lower transactivation of PPARγ
than troglitazone, although they showed comparable or

Novel Antidiabetic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11 1933
EtOAc-petroleum ether (1.5:8.5) as eluent to give the title
compound (6.0 g, 34%) as a solid: mp 78-80 °C; IR υmax (KBr)
the corresponding 5-hydroxy analogue. However, based
on the present knowledge, it is difficult to assign the
exact reason for such a change in pharmacological
behavior. Second it may act as a prodrug and release
5-hydroxydihydrobenzofuran-containing TZD in vivo to
exhibit better pharmacodynamic activity, although we
have no evidence in favor of or against this assumption.
Third, these TZDs which do not exhibit PPARγ trans-
activation may be acting by a different mechanism.
1
3447, 1713 cm-1; H NMR (CDCl3) δ 1.4 (t, J ) 7.0 Hz, 3 H),
2.3 (s, 3 H), 2.4 (s, 3 H), 2.5 (s, 3 H), 2.6 (s, 3 H), 4.4 (q, J ) 7.0
Hz, 2 H), 4.7 (s, 1 H, D2O exchangeable); MS m/z (relative
intensity) 263 (M+, 10%), 262 (100%).
(b) Eth yl 5-Ben zyloxy-2,4,6,7-tetr a m eth yl-1-ben zofu -
r a n -3-ca r boxyla te. A mixture of ester derivative obtained
from step a (4.5 g, 17.1 mmol), benzyl bromide (4.4 g, 25.7
mmol), and potassium carbonate (9.5 g) in DMF (40 mL) was
stirred at ca. 25 °C for 18 h. Water (50 mL) was added, and
the reaction mixture was extracted with EtOAc (3 × 25 mL).
The combined organic layers were washed with water (75 mL)
and brine (75 mL) and dried (Na2SO4). The solvent was
evaporated to give the title compound (5.6 g, 92%): IR υmax
(KBr) 2926, 1714 cm-1; 1H NMR (CDCl3) δ 1.4 (t, J ) 7.0 Hz,
3 H), 2.3 (s, 3 H), 2.4 (s, 3 H), 2.6 (s, 3 H), 2.7 (s, 3 H), 4.4 (q,
J ) 7.0 Hz, 2 H), 4.8 (s, 2 H), 7.0-7.5 (m, 5 H); MS m/z (relative
intensity) 352 (M+, 10%), 91 (100%).
(c) Red u ction of Ester to Alcoh ol. To a suspension of
LiAlH4 (0.906 g, 23.8 mmol) in THF (20 mL) was added
dropwise a solution of the ester obtained in step b above (5.6
g, 15.9 mmol) in THF (30 mL) at 0 °C. Stirring was continued
at 10 °C for 1 h. The reaction was quenched with saturated
Na2SO4 solution (10 mL), the resulting mixture was filtered,
and the residue was washed with hot EtOAc (50 mL). The
combined filtrate was dried over (Na2SO4) and evaporated to
dryness to give 5-benzyloxy-2,4,6,7-tetramethyl-1-benzofuran-
3-carbinol (1c) (4.0 g, 81%): IR υmax (KBr) 3468, 2927, 1454
cm-1; 1H NMR (CDCl3) δ 2.2 (s, 3 H), 2.3 (s, 3 H), 2.5 (s, 3 H),
2.6 (s, 3 H), 4.8 (s, 2 H), 7.0-7.5 (m, 5 H); MS m/z (relative
intensity) 310 (M+, 10%), 91 (100%).
P r ep a r a tion of 5-Ben zyloxy-2,3-d ih yd r o-2,2,4,6,7-p en -
ta m eth ylben zofu r a n -3-ylm eth yl Meth a n esu lfon a te (2).
To a solution of 5-benzyloxy-2,3-dihydro-2,2,4,6,7-pentameth-
ylbenzofuran-3-carbinol (1)12c (11.4 g, 35.0 mmol) in dichlo-
romethane (100 mL) was added triethylamine (11.6 g, 115.0
mmol) under nitrogen atmosphere at ca. 25 °C. Methanesulfo-
nyl chloride (8.81 g, 77.0 mmol) was added to the above
reaction mixture at 0 °C, and stirring was continued for a
further 3 h at 25 °C. Water (50 mL) was added to the reaction
mixture, and the mixture was extracted with dichloromethane
(2 × 75 mL). The combined organic extracts were washed with
water (50 mL), dried (Na2SO4), and filtered, and the solvent
was evaporated under reduced pressure. The residue was
triturated with petroleum ether to afford 2 (14.0 g, 99%) as a
cream-colored solid: mp 88-90 °C; IR υmax (KBr) 2930, 1735
cm-1; 1H NMR (CDCl3) δ 1.35 (s, 3 H), 1.60 (s, 3 H), 2.08 (s, 3
H), 2.18 (s, 3 H), 2.25 (s, 3 H), 2.89 (s, 3 H), 3.29 (t, J ) 5.7
Hz, 1 H), 4.29 (d, J ) 5.2 Hz, 2 H), 4.70 (s, 2 H), 7.40 (m, 5 H);
MS m/z (relative intensity) 404 (M+, 10%), 313 (100%).
4-(5-Ben zyloxy-2,3-d ih yd r o-2,2,4,6,7-p en ta m eth ylben -
zofu r a n -3-ylm eth oxy)ben za ld eh yd e (3a ). A mixture of
5-benzyloxy-2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-3-yl-
methyl methanesulfonate (2) (4.2 g, 10.39 mmol), 4-hydroxy-
benzaldehyde (1.9 g, 15.57 mmol), and potassium carbonate
(5.7 g, 41.30 mmol) in dimethylformamide (75 mL) was stirred
for 12 h at 70-80 °C, and the reaction mixture was cooled to
room temperature (ca. 25 °C). Water (50 mL) was added, and
the mixture was extracted with ethyl acetate (2 × 75 mL). The
combined organic extract was washed with water (50 mL),
dried (Na2SO4), filtered, and evaporated under reduced pres-
sure. The residue was chromatographed over silica gel using
a mixture of ethyl acetate and petroleum ether (1:9) to afford
3 (2.26 g, 51%) as a white solid: mp 78-80 °C; IR υmax (KBr)
1694, 1590 cm-1; 1H NMR (CDCl3) δ 1.40 (s, 3H), 1.52 (s, 3H),
2.09 (s, 3 H), 2.09 (s, 3H), 2.20 (s, 3H), 2.25 (s, 3H), 3.40 (m,
1H), 4.06 (m, 2H), 4.70 (s, 2 H), 6.92 (d, J ) 8.6 Hz, 2 H), 7.39
(m, 5 H), 7.80 (d, J ) 8.6 Hz, 2 H), 9.85 (s, 1 H); MS m/z
(relative intensity) 430 (M+, +1, 10%), 339 (100%), 217 (58%),
91 (55%).
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. Thin-layer chromatography was
performed on precoated silica gel plates (F254, Merck). Flash
chromatography was performed on silica gel (SRL 230-400
mesh). Melting points were recorded on a 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. 2,5,6-Trimethylbenzoquinone24 and
5-bezyloxy-2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-3-
carbinol12c were prepared by the reported procedures. Proline,
N-methylaminoethanol, 2,4-thiazolidinedione, 4-hydroxyben-
zaldehyde, and 4-fluorobenzaldehyde were purchased and used
directly. Troglitazone was prepared by the reported method
of Horikoshi et al.19
P h a r m a cok in etics Exp er im en t. Sample preparation of
0.2 mL of plasma was employed for the analysis. For trogli-
tazone, englitazone (10 µg) was used as an internal standard
and extraction solvent (2 mL) was ethyl acetate:dichlo-
romethane (6:4). Extraction solvent for 21a and its maleate
salt was a mixture of methanol:ethyl acetate (1:1). For 21a
and its maleate salt, external standard method was employed
for the analysis. The organic layer was evaporated to dryness
and was reconstituted in 200 µL of respective mobile phase;
100 µL of the sample was injected on the HPLC system. The
calibration, control, and recovery samples were prepared by
spiking blank plasma and were processed similarly.
HP LC Assa y. The HPLC system consisted of a Waters LC
Module-1 with Shimadzu fluorescence detector (RF-10AXL)
with system controller (SCL10A), Millennium software, and
a HiChrom C18 (ODS) column (5 µm, 4.6 mm × 250 mm). The
analysis of troglitazone was carried out using 0.05 M NaH2-
PO4 buffer:acetonitrile:methanol:tetrahydrofuran (33:55:12:2)
as mobile phase at a flow rate of 1 mL/min, and the excitation
and emission wavelengths were 292 and 325 nm, respectively.
Under these conditions the retention times for troglitazone and
englitazone20 were 10.0 and 12.0 min, respectively. For analy-
sis of both 21a and its maleate salt, mobile phase used was
0.05 M NaH2PO4 buffer:methanol (10:90) at a flow rate of 1.0
mL/min and UV detection at 345 nm was employed. Retention
time for both 21a and its maleate salt was 12.0 min. The assay
method was validated to ensure specificity, linearity, recovery,
accuracy, and precision. The limit of quantification for trogli-
tazone was 0.05 µg/mL, whereas for 21a and its maleate salt
it was 0.10 µg/mL. The response was linear up to 50 µg/mL,
and absolute recoveries were >95%.
P r ep a r a tion of 5-Ben zyloxy-2,4,6,7-tetr a m eth yl-1-ben -
zofu r a n -3-ca r bin ol (1c). (a ) P r ep a r a tion of Eth yl 5-Hy-
d r oxy-2,4,6,7-tetr a m eth yl-1-ben zofu r a n -3-ca r boxyla te. A
suspension of ZnCl2 (13.0 g, 95.38 mmol) in ethanol (10 mL)
was heated to 80 °C until ZnCl2 dissolved and cooled to ca. 25
°C. A solution of ethyl acetoacetate (24.0 g, 184.41 mmol) in
ether (20 mL) was added. After stirring for 10 min, trimeth-
ylbenzoquinone26 (10.0 g, 66.6 mmol) in ethanol (10 mL) was
added dropwise over a period of 30 min, and the stirring was
continued at 80 °C for an additional 40 h. The reaction mixture
was cooled to room temperature, quenched with 5% aqueous
HCl solution, and extracted with EtOAc (3 × 75 mL). The
organic layer was washed with water (100 mL) and brine (100
mL) and dried (Na2SO4). The solvent was evaporated, and the
crude product was purified by column chromatography using
5-[4-(5-Ben zyloxy-2,3-d ih yd r o-2,2,4,6,7-p en t a m et h yl-
ben zofu r a n -3-ylm eth oxy)p h en ylm eth ylen e]th ia zolid in e-
2,4-d ion e (4a ). A solution of 4-(5-benzyloxy-2,3-dihydro-

1934 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11
Reddy et al.
2,2,4,6,7-pentamethylbenzofuran-5-ylmethoxy)benzaldehyde (3)
(2.4 g, 5.59 mmol) and 2,4-thiazolidinedione (0.65 g, 5.59 mmol)
with a catalytic quantity of piperidinium benzoate was refluxed
in toluene with removal of water in a Dean-Stark apparatus
for 2 h. The reaction mixture was cooled to 25 °C, and the solid
separated was collected by filtration which was crystallized
from ethanol to give the title compound (2.2 g, 75%): mp 210-
211 °C; IR υmax (KBr) δ 3111, 2974, 1747, 1690 cm-1; 1H NMR
(CDCl3) δ 1.42 (s, 3 H), 1.62 (s, 3 H), 2.21 (s, 3 H), 2.28 (s, 3
H), 2.31 (s, 3 H), 3.41 (m, 1 H), 4.10 (m, 2 H), 4.78 (s, 3 H),
7.01 (d, J ) 7.58 Hz, 2 H), 7.45 (m, 5 H), 7.82 (s, 1 H); MS m/z
(relative intensity) 529 (M+, 9%), 438 (100%), 217 (58%), 205
(52%), 91 (67%). Anal. Calcd for C31H31NO5S: C, 70.29; H, 5.89;
N, 2.64. Found C, 70.19; H, 6.00; N, 2.65.
(c) P r ep a r a tion of Eth yl 2-Br om o-3-[4-(5-ben zyl-
oxy-2,3-d ih yd r o-2,2,4,6,7-p en t a m et h ylb en zofu r a n -3-yl-
m eth oxy)p h en yl]p r op a n oa te. A solution of sodium nitrite
(0.83 g, 12 mmol) in water (2.5 mL) was slowly added to a
cold mixture of 4-(5-benzyloxy-2,3-dihydro-2,2,4,6,7-pentam-
ethylbenzofuran-3-ylmethoxy)aniline (6) (4.6 g, 11.03 mmol),
aqueous hydrobromic acid (5.3 mL), methanol (5 mL), and
acetone (35 mL) below 5 °C. The solution was stirred at ca. 5
°C for 30 min, ethyl acrylate (6.62 g, 66.2 mmol) was added,
and the temperature was raised to 38 °C. Powdered Cu2O (72
mg) was added in small portions to the vigorously stirred
reaction mixture. After N2 gas evolution had ceased, the
reaction mixture was concentrated in vacuo. The residue was
diluted with water (50 mL), made alkaline with NH4OH
solution, and extracted with ethyl acetate (2 × 75 mL). The
organic extracts were washed with water (50 mL), brine (50
mL) and dried (Na2SO4), and filtered, and the solvent was
evaporated under reduced pressure. The crude product was
chromatographed over silica gel using a mixture of ethyl
acetate and petroleum ether (1:9) to give the title compound
(2.38 g, 37%) as an oil: IR υmax (KBr) 1739, 1610 cm-1; 1H NMR
(CDCl3) δ 1.22 (t, J ) 7.0 Hz, 3 H), 1.40 (s, 3 H), 1.56 (s, 3 H),
2.10 (s, 3 H), 2.20 (s, 3 H), 2.24 (s, 3 H), 3.21 (m, 1 H), 3.38 (m,
2 H), 3.98 (m, 2 H), 4.18 (q, J ) 6.45 Hz, 2 H), 4.32 (t, J ) 7.7
Hz, 1 H), 4.75 (s, 2 H), 6.80 (d, J ) 8.38 Hz, 2 H), 7.14 (d, J )
8.38 Hz, 2 H), 7.42 (m, 5 H); MS m/z (relative intensity) 491
(9%), 411 (31%), 326 (45%), 217 (54%), 91 (100%).
(d ) P r ep a r a tion of 7a . A mixture of ethyl 2-bromo-3-[4-
(5-benzyloxy-2,3-dihydro-2,2,4,6,7-pentamethylbenzofuranyl-
methoxy)phenyl]propanoate (2.38 g, 4.0 mmol), thiourea (0.31
g, 4.09 mmol), and sodium acetate (0.33 g, 4.09 mmol) in
ethanol (25 mL) was stirred under reflux for 12 h. The solvent
was evaporated under reduced pressure, and water (50 mL)
was added to the residue and extracted with ethyl acetate (2
× 50 mL). The organic extract was washed with water (50 mL),
dried (Na2SO4), filtered, and concentrated to get 2-imino-5-[4-
(5-benzyloxy-2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-3-
ylmethoxy)phenylmethyl]-4-thiazolidinone.
The above crude compound was suspended in ethanol (25
mL), and 2 N hydrochloric acid (10 mL) was added. The
reaction mixture was stirred under reflux for 12 h and
concentrated in vacuuo. The residue was diluted with water
(25 mL), neutralized with aqueous NaHCO3, and extracted
with ethyl acetate (2 × 50 mL). The combined organic extracts
were washed with water (25 mL) and brine (25 mL), dried (Na2-
SO4), and filtered. The solvent was evaporated under reduced
pressure, and the crude product was chromatographed over
silica gel using a mixture of ethyl acetate and petroleum ether
(1:9) to afford thiazolidinedione 7a (1.58 g, 73%) as a white
solid: mp 98-100 °C; IR υmax (neat) 3205, 2926, 1754, 1700
cm-1; 1H NMR (CDCl3) δ 1.42 (s, 3 H), 1.54 (s, 3 H), 2.10 (s, 3
H), 2.14 (s, 3 H), 2.21 (s, 3 H), 2.92 (m, 1 H), 3.45 (m, 2 H),
3.98 (m, 2 H), 4.48 (m, 1 H), 6.84 (d, J ) 8.75 Hz, 2 H), 7.12
(d, J ) 8.75 Hz, 2 H), 7.42 (m, 5 H); MS m/z (relative intensity)
531 (M+, +1, 3%), 440 (38%), 217 (37%), 91 (100%). Anal. Calcd
for C31H33NO5S: C, 69.97; H, 6.20; N, 2.63. Found: C, 69.98;
H, 6.15; N, 2.60.
5-[4-(2,3-Dih yd r o-5-h yd r oxy-2,2,4,6,7-p en ta m eth ylben -
zofu r a n -3-ylm eth oxy)p h en ylm eth ylen e]th ia zolid in e-2,4-
d ion e (4b). To a solution of 4a (2.0 g, 3.78 mmol) in acetic
acid (8 mL) was added concentrated hydrochloric acid (2 mL).
The resulting mixture was heated at 90 °C for 1.5 h. The
solvent was removed under reduced pressure, neutralized with
NH4OH (25 mL), and extracted with ethyl acetate (2 × 75 mL).
The combined organic extracts were washed with water (50
mL) and brine (50 mL), dried (Na2SO4), and filtered. The
solvent was evaporated under reduced pressure. The crude
product was chromatographed over silica gel using a mixture
of methanol and chloroform (1:9) to give the title compound
4b (1.0 g, 63%) as a pale yellow solid: mp 198-200 °C; IR
υ
max (KBr) 3288, 1751, 1698 cm-1; 1H NMR (CDCl3) δ 1.35 (s,
3 H), 1.55 (s, 3 H), 2.10 (s, 3 H), 2.15 (s, 3 H), 2.21 (s, 3 H),
3.35 (m, 1 H), 4.05 (m, 2 H), 6.96 (d, J ) 7.8 Hz, 2 H), 7.43 (d,
J ) 7.85 Hz, 2 H), 7.79 (s, 1 H), 8.28 (bs, D2O exchangeable,
1 H); MS m/z (relative intensity) 439 (M+, 35%), 219 (80%),
205 (100%), 105 (60%). Anal. Calcd for C24H25NO5S: C, 65.58;
H, 5.73; N, 3.18. Found: C, 65.55; H, 5.71; N, 3.20.
P r ep a r a tion of 5-[4-(5-Ben zyloxy-2,3-d ih yd r o-2,2,4,6,7-
p en t a m et h ylb en zofu r a n -3-ylm et h oxy)p h en ylm et h yl]-
th ia zolid in e-2,4-d ion e (7a ). (a ) P r ep a r a tion of 4-(5-Ben -
zyloxy-2,3-d ih yd r o-2,2,4,6,7-p en t a m et h ylb en zofu r a n -3-
ylm eth oxy)n itr oben zen e (5). To a suspension of sodium
hydride (95%) (0.44 g, 18.0 mmol) in dry dimethylformamide
(5 mL) was added a solution of 5-benzyloxy-2,3-dihydro-
2,2,4,6,7-pentamethylbenzofuran-3-carbinol (1) (5.0 g, 15.33
mmol) in dry dimethylformamide (15 mL) at 0 °C under
nitrogen atmosphere. The reaction mixture was stirred at 25
°C for 1 h. To the above reaction mixture was added 4-fluo-
ronitrobenzene (2.16 g, 15.3 mmol) dropwise, and stirring was
continued at 25 °C for a further 3 h. Water (50 mL) was added,
and the mixture was extracted with ethyl acetate (2 × 50 mL).
The combined organic extracts were washed with water (50
mL), dried (Na2SO4), and filtered, and the solvent was evapo-
rated under reduced pressure. The crude product was crystal-
lized from ethanol to give 5 (4.6 g, 67%) as a pale yellow solid:
mp 149-150 °C; IR υmax (KBr) 1595, 1510 cm-1 1H NMR
;
(CDCl3) δ 1.41 (s, 3 H), 1.62 (s, 3 H), 2.12 (s, 3 H), 2.28 (s, 3
H), 2.31 (s, 3 H), 3.45 (m, 1 H), 4.12 (m, 2 H), 4.75 (s, 2 H),
6.94 (d, J ) 7.69 Hz, 2 H); MS m/z (relative intensity) 357
(M+ - 91, 56%), 219 (53%), 205 (100%), 91 (20%).
5-[4-(2,3-Dih yd r o-5-h yd r oxy-2,2,4,6,7-p en ta m eth ylben -
zofu r a n -3-ylm eth oxy)p h en ylm eth yl]th ia zolid in e-2,4-d i-
on e (7b). The thiazolidinedione 7a (1.58 g, 2.97 mmol) and
concentrated hydrochloric acid (1.6 mL) in acetic acid (3.2 mL)
were heated at ca. 90 °C for 1-2 h to furnish 7b (0.7 g, 54%):
(b) P r ep a r a tion of 4-(5-Ben zyloxy-2,3-d ih yd r o-2,2,4,6,7-
p en ta m eth ylben zofu r a n -3-ylm eth oxy)a n ilin e (6). To a
solution of 5 (7.0 g, 15.65 mmol) in ethyl acetate (80 mL) was
added 10% palladium on carbon (0.7 g). The reaction mixture
was stirred under 60 psi of hydrogen pressure at ambient
temperature for 48 h. The reaction mixture was filtered
through a bed of Celite, and the bed was washed with ethyl
acetate (2 × 25 mL). The combined filtrates were concentrated
under reduced pressure. The crude product was chromato-
graphed over silica gel using a mixture of ethyl acetate and
petroleum ether (2:8) to give the title compound 6 (4.85 g, 75%)
1
mp 77-79 °C; IR υmax (KBr) 3447, 3200, 1753, 1697 cm-1; H
NMR (CDCl3) δ 1.38 (s, 3 H), 1.54 (s, 3 H), 2.08 (s, 3 H), 2.15
(s, 3 H), 2.20 (s, 3 H), 3.10 (m, 1 H), 3.39 (m, 2 H), 3.95 (m, 2
H), 4.28 (s, D2O exchangeable, 1 H), 4.5 (m, 1 H), 6.82 (d, J )
8.1 Hz, 2 H), 7.11 (d, J ) 8.1 Hz, 2 H), 8.28 (s, D2O
exchangeable, 1 H); MS m/z (relative intensity) 441 (M+, 41%),
383 (17%), 205 (100%), 107 (33%), 91 (27%). Anal. Calcd for
1
as a thick oil: IR υmax (KBr) 3421, 3341, 1829 cm-1; H NMR
C
24H27NO5S: C, 65.28; H, 6.16; N, 3.17. Found: C, 65.19; H,
(CDCl3) δ 1.41 (s, 3 H), 1.60 (s, 3 H), 2.12 (s, 3 H), 2.22 (s, 3
H), 2.28 (s, 3 H), 3.35 (t, J ) 5.8 Hz, 1 H), 3.42 (bs, D2O
exchangeable, 2 H), 3.92 (d, J ) 6.45 Hz, 2 H), 4.72 (s, 2 H),
6.66 (m, 4 H), 7.45 (m, 5 H); MS m/z (relative intensity) 417
(M+, 12%), 326 (66%), 217 (39%), 122 (47%), 91 (100%).
6.05; N, 3.15.
P r ep a r a tion
of 4-[2-[N-(5-Ben zyloxy-2,3-d ih yd r o-
2 ,2 ,4 ,6 ,7 -p e n t a m e t h y l b e n z o fu r a n -3 -y l m e t h y l )-N -
m eth yla m in o]eth oxy]ben za ld eh yd e (10). To a suspension

Novel Antidiabetic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11 1935
the title compound 9 (12.95 g, 97%) as a cream-colored solid:
of sodium hydride (0.285 g, 11.87 mmol) in dry dimethylfor-
mamide (4 mL) was added 4-hydroxybenzaldehyde (1.21 g, 9.91
mmol) in dry dimethylformamide (10 mL) at ca. 0 °C under
nitrogen atmosphere. After 30 min, this mixture was added
dropwise to a solution of 2-[N-(5-benzyloxy-2,3-dihydro-2,2,4,6,7-
pentamethylbenzofuran-3-ylmethyl)-N-methylamino]ethyl chlo-
ride in dry dimethylformamide (10 mL). The reaction mixture
was stirred at 50-60 °C for 24 h. The reaction mixture was
cooled to room temperature, and water (50 mL) was added.
The reaction mixture was extracted with ethyl acetate (2 ×
40 mL). The combined organic extracts were washed with 5%
aqueous sodium hydroxide (25 mL), water (40 mL), and brine
(25 mL), dried (Na2SO4), and filtered. The solvent was evapo-
rated under reduced pressure to give the title compound 10
1
mp 80-84 °C; IR υmax (KBr) 2970, 1592, 1457 cm-1; H NMR
(CDCl3) δ 1.33 (s, 3 H), 1.59 (s, 3 H), 2.08 (s, 3 H), 2.19 (s, 3
H), 2.21 (s, 3 H), 2.34 (s, 3 H), 2.70 (m, 2 H), 2.81 (m, 2 H),
3.08 (m, 1 H), 3.53 (t, J ) 5.5 Hz, 2 H), 4.71 (s, 2 H), 7.43 (m,
5 H); MS m/z (relative intensity) 401 (M+, 3%), 106 (100%),
91 (33%).
P r ep a r a tion of 5-[4-[2-[N-(5-Ben zyloxy-2,3-d ih yd r o-
2 ,2 ,4 ,6 ,7 -p e n t a m e t h y l b e n z o fu r a n -3 -y l m e t h y l )-N -
m e t h yla m in o]e t h oxy]p h e n ylm e t h yl]t h ia zolid in e -2,4-
d ion e (11a ). The title compound 11a (1.82 g, 41%) was
prepared as a thick liquid from 2-[N-(5-benzyloxy-2,3-dihydro-
2,2,4,6,7-pentamethylbenzofuran-3-ylmethyl)-N-methylamino]-
ethyl chloride (9) (3.0 g, 7.47 mmol) and 5-(4-hydroxyphenyl-
methyl)thiazolidine-2,4-dione (1.67 g, 7.47 mmol) in DMF in
the presence of NaH (95%) while stirring at 50 °C for 12 h:
IR υmax (KBr) 2910, 1754, 1692 cm-1; 1H NMR (CDCl3) δ 1.33
(s, 3 H), 1.58 (s, 3 H), 2.08 (s, 3 H), 2.18 (s, 3 H), 2.23 (s, 3 H),
2.38 (s, 3 H), 2.72 (m, 2 H), 2.91 (m, 1 H), 3.10 (m, 3 H), 3.45
(m, 1 H), 4.00 (t, J ) 5.59 Hz, 2 H), 4.49 (dd, J ) 9.32 and
3.89 Hz, 1 H), 4.70 (s, 2 H), 6.82 (d, J ) 8.59 Hz, 2 H), 7.12 (d,
J ) 8.59 Hz, 2 H), 7.41 (m, 5 H); MS m/z (relative intensity)
497 (M+, -91, 26%), 293 (100%), 91 (21%).
5-[4-[2-[N-(2,3-Dih yd r o-5-h yd r oxy-2,2,4,6,7-p en ta m eth -
ylb en zofu r a n -3-ylm et h yl)-N-m et h yla m in o]et h oxy]p h e-
n ylm eth yl]th ia zolid in e-2,4-d ion e (11b). The title com-
pound (0.87 g, 57%) was prepared as a pale yellow solid from
11a (1.8 g, 3.06 mmol) as described in the preparation of 4b:
mp 68-70 °C; IR υmax (KBr) 3320, 1745 cm-1; 1H NMR (CDCl3)
δ 1.31 (s, 3 H), 1.57 (s, 3 H), 2.08 (s, 3 H), 2.12 (s, 3 H), 2.17
(s, 3H), 2.37 (s, 3 H), 2.71 (m, 2 H), 2.92 (m, 1 H), 3.10 (m, 3
H), 3.42 (m, 1 H), 4.01 (t, J ) 5.81 Hz, 2 H), 4.02 (dd, J ) 9.23
and 3.97 Hz, 1 H), 4.16 (s, D2O exchangeable, 1 H), 6.81 (d, J
) 8.63 Hz, 2 H), 7.13 (d, J ) 8.63 Hz, 2 H); MS m/z (relative
intensity) 499 (M+, +1, 5%), 293 (100%), 235 (96%), 107 (30%).
Anal. Calcd for C27H34N2O5S: C, 65.03; H, 6.87; N, 5.61.
Found: C, 65.0; H, 6.99; N, 5.70.
N-[(3R/S)-5-Ben zyloxy-2,3-d ih yd r o-2,2,4,6,7-p en t a m e-
t h ylb en zofu r a n -3-ylm et h yl]-(2S)-p yr r olid in e-2-m et h a -
n ol (13). A mixture of (3R/S)-5-benzyloxy-2,3-dihydro-2,2,4,6,7-
pentamethylbenzofuran-3-ylmethyl methanesulfonate (2) (15.0
g, 37.12 mmol) and L-prolinol (14.99 g, 148.4 mmol) was heated
under nitrogen atmosphere at 120 °C with stirring for 12 h.
The reaction mixture was cooled to room temperature and
poured into water, and the mixture was extracted with ethyl
acetate (2 × 100 mL). The combined organic extracts were
washed with water (50 mL) and brine (50 mL), dried (Na2-
SO4), and filtered, and the solvent was evaporated under
reduced pressure. The residue was triturated with petroleum
ether to afford 13 (11.0 g, 73%) as a cream-colored solid: mp
99-101 °C; [R]D26 ) -32.8 (c ) 1.00% in CHCl3); IR υmax (KBr)
3245, 1457 cm-1; 1H NMR (CDCl3) δ 1.30, 1.34 (2s, 3 H), 1.58,
1.62 (2s, 3 H), 1.78 (m, 4 H), 2.12 (s, 3 H), 2.20, 2.22 (2s, 3 H),
2.28, 2.30 (2s, 3 H), 2.33 (m, 2 H), 2.68 (d, J ) 6.0 Hz, 1 H),
3.09 (m, 1 H), 3.30 (m, 2 H), 3.36 (m, 1 H), 3.68 (m, 1 H), 4.76
(s, 2 H), 7.46 (s, 5 H); MS m/z (relative intensity) 410 (M+, +1,
6%), 205 (3%), 114 (100%), 91 (27%).
N-[(3R/S)-5-Ben zyloxy-2,3-d ih yd r o-2,2,4,6,7-p en t a m e-
th ylben zofu r a n -3-ylm eth yl]-(3R)-ch lor op ip er id in e (14).
To a solution of N-[(3R/S)-5-benzyloxy-2,3-dihydro-2,2,4,6,7-
pentamethylbenzofuran-3-ylmethyl]-(2S)-pyrrolidine-2-metha-
nol (13) (11.0 g, 26.89 mmol) in benzene (50 mL) was added
thionyl chloride (9.8 mL). The resulting mixture was stirred
at room temperature for 1 h, diluted with ethyl acetate (50
mL), washed with water (40 mL), brine (40 mL) and dried (Na2-
SO4), and filtered, and the solvent was evaporated in vacuo to
give the title compound (10.5 g, 91%) as a thick liquid: IR
υmax (KBr) 2945, 1592, 1455 cm-1; 1H NMR (CDCl3) δ 1.35 (s,
3 H), 1.62 (bs, 5 H), 1.80 (m, 2 H), 2.11 (s, 3 H), 2.23 (s, 6 H),
2.30 (m, 2 H), 2.53 (m, 2 H), 2.86 (m, 1 H), 3.06 (m, 1 H), 3.22
(m, 1 H), 4.0 (m, 1 H), 4.71 (s, 2 H), 7.43 (m, 5 H); MS m/z
(relative intensity) 428 (M+, +1, 3%), 132 (100%), 91 (47%).
(4.84 g, 99%) as a thick liquid: IR υmax (KBr) 1692, 1600 cm-1
;
1H NMR (CDCl3) δ 1.34 (s, 3 H), 1.61 (s, 3 H), 2.10 (s, 3 H),
2.22 (s, 3 H), 2.27 (s, 3 H), 2.40 (s, 3 H), 2.69 (m, 2 H), 2.92 (m,
1 H), 3.09 (m, 2 H), 4.10 (t, J ) 5.2 Hz, 2 H), 4.71 (s, 2 H), 6.98
(d, J ) 8.69 Hz, 2 H), 7.41 (m, 5 H), 7.81 (d, J ) 8.69 Hz, 2 H),
9.89 (s, 1 H); MS m/z (relative intensity) 487 (M+, 3%), 396
(4%), 192 (100%), 91 (26%).
P r ep a r a tion of 5-[4-[2-[N-(5-Ben zyloxy-2,3-d ih yd r o-
2 ,2 ,4 ,6 ,7 -p e n t a m e t h y l b e n z o fu r a n -3 -y l m e t h y l )-N -
m eth yla m in o]eth oxy]p h en ylm eth ylen e]th ia zolid in e-2,4-
d ion e (12a ). Using a method described for the preparation
for 4a , 12a was prepared from 10 (4.7 g, 9.6 mmol) and 2,4-
thiazolidinedione (1.13 g, 9.6 mmol) (3.54 g, 63%) as a pale
yellow solid: mp 58-60 °C; IR υmax (KBr) 3340, 1742, 1698
cm-1; 1H NMR (CDCl3) δ 1.38 (s, 3 H), 1.62 (s, 3 H), 2.12 (s, 3
H), 2.21 (s, 3 H), 2.26 (s, 3 H), 2.41 (s, 3 H), 2.76 (m, 2 H), 2.94
(m, 1 H), 3.10 (m, 2 H), 4.11 (t, J ) 5.5 Hz, 2 H), 4.72 (s, 2 H),
6.95 (d, J ) 8.2 Hz, 2 H), 7.42 (m, 7 H), 7.83 (s, 1 H); MS m/z
(relative intensity) 495 (M+, -91, 31%), 291 (86%), 205 (11%),
91 (100%). Anal. Calcd for C34H38N2O5S: C, 69.59; H, 6.51; N,
4.77. Found: C, 70.0; H, 6.90; N, 5.0.
P r ep a r a tion of 5-[4-[2-[N-(2,3-Dih yd r o-5-h yd r oxy-
2 ,2 ,4 ,6 ,7 -p e n t a m e t h y l b e n z o fu r a n -3 -y l m e t h y l )-N -
m eth yla m in o]eth oxy]p h en ylm eth ylen e]th ia zolid in e-2,4-
d ion e (12b). Following the procedure described for the
preparation of 4b, 12b (0.69 g, 90%) was prepared from 12a
(0.9 g, 1.53 mmol): mp 92-94 °C; IR υmax (KBr) 3480, 3398,
1
1740, 1704 cm-1; H NMR (CDCl3) δ 1.30 (s, 3 H), 1.56 (s, 3
H), 2.08 (s, 3 H), 2.11 (s, 3 H), 2.17 (s, 3 H), 2.38 (s, 3 H), 2.68
(m, 2 H), 3.02 (m, 3 H), 4.05 (d, J ) 5.72 Hz, 2 H), 6.59 (d, J
) 8.72 Hz, 2 H), 7.42 (d, J ) 8.72 Hz, 2 H), 7.80 (s, 1 H); MS
m/z (relative intensity) 497 (M+, +1, 4%), 291 (100%), 205
(11%). Anal. Calcd for C27H32N2O5S: C, 65.30; H, 6.49; N, 5.64.
Found: C, 65.25; H, 6.50; N, 5.62.
P r ep a r a tion of 2-[N-(5-Ben zyloxy-2,3-d ih yd r o-2,2,4,6,7-
p en t a m et h ylb en zofu r a n -3-ylm et h yl)-N-m et h yla m in o]
eth a n ol (8). A mixture of 5-benzyloxy-2,3-dihydro-2,2,4,6,7-
pentamethylbenzofuran-3-ylmethyl methanesulfonate (2) (21.7
g, 53.71 mmol) and 2-(methylamino)ethanol (40.34 g, 537.86
mmol) was heated under nitrogen atmosphere at 170 °C with
stirring for 20 h. The mixture was cooled to 25 °C, poured into
water (100 mL), and extracted with ethyl acetate (2 × 100 mL).
The combined organic extracts were washed with brine (50
mL), dried (Na2SO4), and filtered, and the solvent was evapo-
rated under reduced pressure to give 8 (15.38 g, 75%) as a
colorless solid: mp 90-93 °C; IR υmax (KBr) 3450 cm-1 1H
;
NMR (CDCl3) δ 1.33 (s, 3 H), 1.58 (s, 3 H), 2.08 (s, 3 H), 2.19
(s, 3 H), 2.22 (s, 3 H), 2.34 (s, 3 H), 2.39 (m, 2 H), 2.71 (m, 2
H), 3.08 (m, 1 H), 3.62 (m, 2 H), 4.73 (s, 2 H), 7.43 (m, 5 H);
MS m/z (relative intensity) 384 (M+, +1, 72%), 309 (100%),
292 (24%), 217 (39%), 189 (69%), 175 (44%).
P r ep a r a tion of 2-[N-(5-Ben zyloxy-2,3-d ih yd r o-2,2,4,6,7-
p en t a m et h ylb en zofu r a n -3-ylm et h yl)-N-m et h yla m in o]
eth yl Ch lor id e (9). To a solution of 8 (12.7 g, 33.15 mmol) in
dry benzene (50 mL) was added thionyl chloride (12.0 mL),
and the mixture stirred at room temperature (ca. 25 °C) for 1
h. The reaction mixture was diluted with ethyl acetate (50 mL),
washed with aqueous sodium bicarbonate solution (2 × 30 mL),
water (50 mL), and brine (50 mL), dried (Na2SO4), and filtered.
The solvent was evaporated under reduced pressure to give
Rea ction of 14 w ith 4-Hyd r oxyben za ld eh yd e. A mix-
ture of N-[(3R/S)-5-benzyloxy-2,3-dihydro-2,2,4,6,7-pentam-

1936 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11
Reddy et al.
ethylbenzofuran-3-ylmethyl]-(3R)-chloropiperidine (14) (6.4 g,
14.97 mmol), 4-hydroxybenzaldehyde (1.83 g, 14.97 mmol), and
potassium carbonate (8.26 g, 59.85 mmol) in dry dimethylfor-
mamide (60 mL) was stirred at 80 °C for 12 h. The reaction
mixture was cooled to room temperature, water (100 mL) was
added, and the mixture was extracted with ethyl acetate (2 ×
75 mL). The combined organic extracts were washed with
water (50 mL) and brine (50 mL), dried (Na2SO4), and filtered,
and the solvent was evaporated under reduced pressure. The
crude product was chromatographed over silica gel using a
mixture of ethyl acetate and petroleum ether (1:9) to give 4-[N-
[(3R/ S)-5-benzyloxy-2,3-dihydro-2,2,4,6,7-pentamethylbenzo-
furan-3-ylmethyl]-(3R)-piperidinyloxy]benzaldehyde (18) (2.66
C36H40N2O5S: C, 70.56; H, 6.57; N, 4.57. Found: C, 70.50; H,
6.80; N, 4.66.
5-[4-[N-[(3R/S)-5-Ben zyloxy-2,3-d ih yd r o-2,2,4,6,7-p en -
t a m et h ylb en zofu r a n -3-ylm et h 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 (19a ). (a )
P r epar ation of 4-[N-[(3R)-Ben zyloxy-2,3-dih ydr o-2,2,4,6,7-
p en t a m et h ylb en zofu r a n -3-ylm et h yl]-(2S)-p yr r olid in -2-
ylm eth oxy]n itr oben zen e (15). The title compound (7.25 g,
67%) was prepared as an oil from 13 (8.4 g, 20.53 mmol) and
4-fluoronitrobenzene (3.47 g, 24.64 mmol) by a similar proce-
dure reported for the preparation of 5: IR υmax (KBr) 1593
cm-1; 1H NMR (CDCl3) δ 1.29 (s, 3 H), 1.35 (s, 3 H), 1.56 (s, 3
H), 1.59 (s, 3 H), 1.85 (m, 8 H), 2.06 (s, 3 H), 2.09 (s, 3 H), 2.12
(s, 3 H), 2.20 (s, 3 H), 2.27 (s, 6 H), 2.45 (m, 3 H), 2.82 (m, 3
H), 3.00 (m, 1 H), 3.18 (m, 4 H), 3.38 (m, 1 H), 3.58 (m, 2 H),
3.86 (m, 1 H), 4.08 (m, 1 H), 4.65 (d, J ) 7.8 Hz, 2 H), 4.72 (s,
2 H), 6.74 (d, J ) 9.0 Hz, 2 H), 6.93 (d, J ) 9.00 Hz, 2 H), 7.48
(m, 10 H), 8.13 (d, J ) 9.0 Hz, 2 H), 8.19 (d, J ) 9.0 Hz, 2 H);
MS m/z (relative intensity) 530 (M+, 1%), 439 (1%), 409 (1%),
309 (2%), 235 (88%), 205 (100%), 91 (28%).
g, 35%) as a thick oil: IR υmax (neat) 1692 cm-1 1H NMR
;
(CDCl3) δ 1.35 (double s, 3 H), 1.55 (double s, 3 H), 1.83 (m, 2
H), 2.17 (double s, 3 H), 2.20 (double s, 3 H), 2.30 (double s, 3
H), 2.60 (m, 2 H), 2.90 (complex, 5 H), 3.60 (d, J ) 5.91 Hz, 2
H), 4.45 (m, 1 H), 4.65 (s, 2 H), 6.90 (double d, J ) 8.63 Hz, 2
H), 7.45 (m, 5 H), 7.80 (double d, J ) 8.67 Hz, 2 H), 9.9 (double
s, 1 H); MS m/z (relative intensity) 514 (M+, 2%), 218 (100%),
91 (46%).
(b) P r ep a r a tion of 4-[N-[(3R/S)-5-Ben zyloxy-2,3-d ih y-
d r o-2,2,4,6,7-p en t a m et h ylb en zofu r a n -3-ylm et h yl]-(2S)-
p yr r olid in -2-ylm eth oxy]a n ilin e (16). The title compound
16 (5.1 g, 55%) was prepared as a brown oil from 15 (9.8 g,
18.49 mmol) and 10% Pd-C (1.0 g) by a similar procedure
Further elution of the column gave 4-[N-[(3R/S)-5-benzyloxy-
2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-3-ylmethyl]-(2S)-
pyrrolidin-2-ylmethoxy]benzaldehyde (17; 2.58 g, 34%): IR υmax
1
(neat) 1692 cm-1; H NMR (CDCl3) δ 1.35 (s, 3 H), 1.64 (s, 3
described in the preparation of 6: IR υmax (KBr) 3480 cm-1
;
H), 1.80 (m, 4 H), 2.12 (s, 3 H), 2.21 (s, 3 H), 2.30 (s, 3 H), 2.45
(m, 2 H), 2.72 (m, 1 H), 3.15 (m, 2 H), 3.35 (m, 1 H), 3.89 (m,
1 H), 4.08 (m, 1 H), 4.75 (s, 2 H), 6.96 (d, J ) 10.4 Hz, 2 H),
7.44 (m, 5 H), 7.85 (d, J ) 10.4 Hz, 2 H), 9.94 (s, 1 H); MS m/z
(relative intensity) 514 (M+, +1, 2%), 218 (100%), 91 (26%).
1H NMR (CDCl3) δ 1.31, 1.33 (2s, 3 H), 1.56 1.61 (2s, 3 H),
1.84 (m, 4 H), 2.10 (s, 3 H), 2.22 (s, 3 H), 2.28 (s, 3 H), 2.45 (m,
2 H), 2.79 (m, 1 H), 3.12 (m, 2 H), 3.35 (m, 1 H), 3.75 (m, 1 H),
3.98 (m, 1 H), 4.75 (m, 2 H), 6.68 (m, 4 H), 7.46 (m, 5 H); MS
m/z (relative intensity) 409 (M+, -91, 1%), 378 (1%), 245 (7%),
205 (100%), 91 (14%).
5-[4-[N-[(3R/S)-5-Ben zyloxy-2,3-d ih yd r o-2,2,4,6,7-p en -
t a m et h ylb en zofu r a n -3-ylm et h 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 (21a ).
Compound 21a was prepared as a pale yellow solid from
compound 18 (1.0 g, 1.94 mmol) and 2,4-thiazolidinedione (0.23
g, 1.96 mmol) by a procedure described in the preparation for
(c) P r ep a r a tion of Eth yl 2-Br om o-3-[4-[N-[(3R/S)-5-
ben zyloxy-2,3-d ih yd r o-2,2,4,6,7-p en ta m eth ylben zofu r a n -
3-ylm e t h yl]-(2S )-p yr r olid in -2-ylm e t h oxy]p h e n yl]p r o-
p a n oa te. The title compound (2.5 g, 38%) was prepared as
an oil from 16 (5.0 g, 10.0 mmol) by a similar procedure
described in step c of the preparation of 7a : IR υmax (KBr) 1740
24
4a (0.8 g, 67% yield): mp 68-70 °C; [R]D ) -205.5 (c ) 1.00
in CHCl3); IR υmax (KBr) 3453, 1741, 1696 cm-1 1H NMR
;
1
cm-1; H NMR (CDCl3) δ 1.26 (m, 6 H), 1.58, 1.60 (2s, 3 H),
(CDCl3) δ 1.32 (s, 3 H), 1.58 (s, 3 H), 1.82 (m, 4 H), 2.08 (s, 3
H), 2.18 (s, 3 H), 2.25 (s, 3 H), 2.42 (m, 2 H), 2.76 (m, 1 H),
3.14 (m, 2 H), 3.35 (m, 1 H), 3.84 (m, 1 H), 4.02 (m, 1 H), 4.71
(s, 2 H), 6.95 (d, J ) 8.7 Hz, 2 H), 7.45 (m, 7 H), 7.80 (s, 1 H);
MS m/z (relative intensity) 317 (16%), 217 (6%), 177 (100%),
91 (16%). Anal. Calcd for C36H40N2O5S: C, 70.56; H, 6.57; N,
4.57. Found: C, 70.10; H, 6.50; N, 5.00.
1.76 (m, 4 H), 2.08 (s, 3 H), 2.22 (s, 3 H), 2.28 (s, 3 H), 2.42 (m,
2 H), 2.78 (m, 1 H), 2.99 (m, 1 H), 3.15 (m, 2 H), 3.32 (m, 1 H),
3.56 (m, 1 H), 3.72 (m, 1 H), 3.96 (m, 1 H), 4.15 (q, J ) 6.0 Hz,
2 H), 4.33 (m, 1 H), 4.71 (m, 2 H), 6.68 (d, J ) 8.0 Hz, 1 H),
6.75 (d, J ) 8.0 Hz, 1 H), 7.10 (m, 2 H), 7.45 (m, 5 H); MS m/z
(relative intensity) 586 (M+, -Br, 1%), 540 (1%), 448 (1%), 368
(7%), 290 (100%).
5-[4-[N-[(3R/S)-5-Hyd r oxy-2,3-d ih yd r o-2,2,4,6,7-p en ta -
m e t h ylb e n zofu r a n -3-ylm e t h 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 (21b).
The compound 21b (0.13 g, 43%) was prepared as a yellow
solid from 21a (0.4 g, 0.65 mmol) by a similar procedure to
(d ) P r ep a r a tion of 5-[4-[N-[(3R/S)-2,3-Dih yd r o-5-ben -
zyloxy-2,2,4,6,7-pen tam eth ylben zofu r an -3-ylm eth yl]-(2S)-
p yr r olid in -2-ylm eth oxy]p h en ylm eth yl]-2-im in o-4-th ia z-
olid in on e. The title compound (2.0 g, 87%) was prepared as
a colorless fluffy solid from the product obtained in step c (2.5
g, 76 mmol) by a similar procedure described for the prepara-
tion of 7a . The crude product was chromatographed over silica
gel using ethanol and dichloromethane (5:95) as eluent: mp
132-136 °C; IR υmax (KBr) 3425, 1641 cm-1; 1H NMR (CDCl3)
δ 1.28 and 1.33 (2s, 3 H), 1.56 and 1.59 (2s, 3 H), 1.76 (m, 4
H), 2.07 (s, 3 H), 2.18 (s, 3 H), 2.25 (s, 3 H), 2.40 (m, 2 H), 2.76
(m, 1 H), 2.92 (m, 2 H), 3.01 (brs, 1 H), 3.35 (m, 1 H)3. 503 (m,
2 H), 3.75 (m, 1 H), 3.95 (m, 1 H), 4.44 (m,1 H), 4.65 (m, 2H),
6.76 (m, 2 H), 7.08 (m, 2H), 7.43 (m, 5H); MS m/z (relative
intensity) 318 (M+, -295, 10%), 217 (16%), 91 (100%).
29
that described for 4b from 4a : mp 75-77 °C; [R]D ) -175.5
1
(c ) 1.00 in CHCl3); IR υmax (KBr) 3446, 1738, 1694 cm-1; H
NMR (CDCl3) δ 1.31 (s, 3 H), 1.58 (s, 3 H), 1.85 (m, 4 H), 2.09
(s, 3 H), 2.13 (s, 3 H), 2.22 (s, 3 H), 2.38 (m, 2 H), 2.76 (m, 1
H), 3.11 (m, 2 H), 3.36 (m, 1 H), 3.85 (dd, J ) 9.1 and 6.4 Hz,
1 H), 4.06 (dd, J ) 9.1 and 4.9 Hz), 4.16 (bs, 1 H), 6.95 (d, J )
8.7 Hz, 2 H), 7.43 (d, J ) 8.7 Hz, 2 H), 7.8 (s, 1 H); MS m/z
(relative intensity) 407 (9%), 317 (100%), 218 (9%), 205 (12%),
107 (19%). Anal. Calcd for C29H34N2O5S: C, 66.64; H, 6.55; N,
5.35. Found C, 66.60; H 6.52; N, 5.3.
5-[4-[N-[(3R/S)-5-Ben zyloxy-2,3-d ih yd r o-2,2,4,6,7-p en -
t a m et h ylb en zofu r a n -3-ylm et h yl]-(3R)-p ip er id in yloxy]-
p h en ylm eth ylen e]th ia zolid in e-2,4-d ion e (20a ). The title
compound 20a (1.5 g, 84%) was prepared from compound 17
(1.5 g, 2.92 mmol) and 2,4-thiazolidinedione (0.34 g, 2.92 mol)
in the presence of piperidinium benzoate as described in the
(e) 5-[4-[N-[(3R/S)-5-Ben zyloxy-2,3-d ih yd r o-2,2,4,6,7-
p en t a m et h ylb en zofu r a n -3-ylm et h yl]-(2S)-p yr r olid in -2-
ylm et h oxy]p h en ylm et h yl]t h ia zolid in e-2,4-d ion e (19a ).
Hydrolysis of the product obtained in step d (4.0, 6.52 mmol)
was carried out by a similar procedure described for the
preparation of 7a . The crude product was chromatographed
over silica gel using ethanol and dichloromethane (1:99) as
eluent to give 19a (3.0 g, 75%): mp 107-109 °C; [R]D29 ) -79.5
24
preparation for 4a : mp 150-152 °C; [R]D ) +87.0 (c ) 1.00
in CHCl3); IR υmax (KBr) 3173, 1741, 1699 cm-1 1H NMR
;
1
(c ) 1.00 in CHCl3); IR υmax (KBr) 3452, 1753, 1702 cm-1; H
(CDCl3) δ 1.13, 1.37 (2s, 3 H),1.43-1.69 (m, 5 H), 1.88 (m, 2
H), 2.09 (s, 3 H), 2.11 (s, 3 H), 2.19 (s, 3 H), 2.36 (m, 2 H), 2.63
(m, 2 H), 2.91 (m, 1 H), 3.09 (m, 2 H), 4.42 (m, 1 H), 4.71 (s, 2
H), 6.95 (m, 2 H), 7.45 (m, 7 H), 7.81 (s, 1 H); MS m/z (relative
intensity) 317 (28%), 217 (18%), 91 (100%). Anal. Calcd for
NMR (CDCl3) δ 1.30, 1.34 (2s, 3 H), 1.57, 1.60 (s, 3 H), 1.79
(m, 4 H), 2.09 (s, 3 H), 2.19 (s, 3 H), 2.26 (s, 3 H), 2.45 (m, 2
H), 2.78 (m, 1 H), 3.03 (m, 1 H), 3.14 (m, 2 H), 3.38 (m, 1 H),
3.55 (m, 1 H), 3.74 (m, 1 H), 3.98 (m, 1 H), 4.46 (m, 1 H), 4.70

Novel Antidiabetic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11 1937
(m, 2 H), 6.78 (m, 2 H), 7.10 (m, 2 H), 7.42 (m, 5 H); MS m/z
(relative intensity) 392 (M+, -C10H8NO3S), (37%), 309 (100%),
217 (30%). Anal. Calcd for C36H42N2O5S: C, 70.35; H, 6.84; N,
4.56. Found: C, 70.46; H, 6.74; N, 4.36.
chloride was removed under reduced pressure, and the crude
product 22b was triturated with petroleum ether, filtered, and
dried to give the title compound (20.0 g, 95%). This product
was used in the next step without further purification.
Further elution of the column using ethanol and di-
choromethane (2:98) as eluent furnished 5-[4-[N-[(3R/S)-2,3-
dihydro-5-hydroxy-2,2,4,6,7-pentamethylbenzofuran-3-ylmethyl]-
(2S)-pyrrolidin-2-ylmethoxy]phenylmethyl]thiazolidine-2,4-
dione (19b) (0.65 g, 19%) as a colorless solid: mp 72-75 °C;
The crude compound 22b obtained from the above step (9.0
g, 27.39 mmol), L-prolinol (4.15 g, 41.08 mmol), and potassium
carbonate (16 g) in dimethylformamide (75 mL) were stirred
at room temperature continuously for 10 h. The reaction was
quenched with water (100 mL), and the mixture was extracted
with EtOAc (3 × 50 mL). The combined EtOAc layers were
washed with brine (50 mL), dried (Na2SO4), and concentrated
to give the title compound (7.5 g, 69%): mp 98-100 °C; IR
29
[R]D ) -84.2 (c ) 1.00 in CHCl3); IR υmax (KBr) 3452, 1753,
1
1698 cm-1; H NMR (CDCl3) δ 1.26, 1.30 (2s, 3 H), 1.53, 1.58
(2s, 3 H), 1.78 (m, 4 H), 2.08 (s, 3 H), 2.11 (s, 3 H), 2.17, 2.20
(2s, 3 H), 2.36 (m, 2 H), 2.72 (m, 1 H), 2.98 (m, 1 H), 3.13 (m
2 H), 3.45 (m, 2 H), 3.75 (m, 1 H), 3.98 (m, 1 H), 4.19 (s, 1 H),
4.50 (dd, J ) 9.4 and 3.8 Hz, 1 H), 6.76 (m, 2 H), 7.12 (m, 2
H); MS m/z (relative intensity) 319 (M+, -205, 100%), 218 (3%),
205 (3%). Anal. Calcd for C29H36N2O5S: C, 66.41; H, 6.87; N,
5.34. Found: C, 66.44; H, 6.90; N, 5.35.
υ
max (KBr) 3352, 1451, 1232 cm-1; 1H NMR (CDCl3) δ 1.85 (m,
4 H), 2.36 (s, 3 H), 2.41 (s, 3 H), 2.48 (s, 3 H), 2.50 (m, 1 H),
2.64 (s, 3 H), 2.76 (m, 1 H), 3.04 (m, 1 H), 3.34 (dd, J ) 10.8
and 2.5 Hz, 1 H), 3.51 (dd, J ) 10.2 and 3.5 Hz, 1 H), 3.60 (d,
J ) 13.2 Hz, 1 H), 3.95 (d, J ) 13.2 Hz, 1 H), 4.78 (s, 2 H),
7.48 (m, 5 H); MS m/z (relative intensity) 393 (M+, 10%), 293
20
(100%); [R]D ) -15.5 (c ) 1.0, CHCl3).
5-[4-[N-[(3R/S)-5-Ben zyloxy-2,3-d ih yd r o-2,2,4,6,7-p en -
t a m et h ylb en zofu r a n -3-ylm et h 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, Hy-
d r och lor id e. To a stirred solution of 21a (0.1 g, 0.16 mmol)
in 2-propanol (3 mL) was added 2-propanol-HCl (5 mL, 15%
v/w), and stirring was continued for 2 h at 25 °C. The solution
was cooled in a refrigerator overnight, and the solid that
precipitated was filtered, washed with ether (5 mL), and dried
under reduced pressure vacuum to give the title compound
(90 mg, 85%): mp 217-221 °C; IR υmax (KBr) 3424, 1741, 1700
N-(5-Ben zyloxy-2,4,6,7-t et r a m et h ylb en zofu r a n -3-yl-
m eth yl)-(3R)-ch lor op ip er id in e. To a solution of pyrrolidine
derivative from the previous step (9.0 g, 22.9 mmol) in
dichloromethane (100 mL) was added thionyl chloride (3.62
g, 114.5 mmol) dropwise at 0 °C. Stirring was continued at
room temperature for 5 h. Excess SOCl2 was removed under
reduced pressure, and the reaction mixture was diluted with
EtOAc (100 mL) to give a precipitate which was basified by
adding ammonia solution (10 mL) and extracted with EtOAc
(3 × 50 mL). The combined EtOAc layers were washed with
water (100 mL) and brine (100 mL), dried (Na2SO4), and
filtered, and the filtrate was concentrated to give the title
compound as a white solid (9.0 g, 95%): mp 90-92 °C; IR υmax
1
cm-1; H NMR (CDCl3) δ 1.45 (s, 3 H), 1.60 (s, 3 H), 1.80 (m,
4 H), 2.08 (s, 3 H), 2.19 (s, 3 H), 2.26 (s, 3 H), 2.50 (m, 2 H),
2.90 (m, 1 H), 3.25 (m, 2 H), 3.40 (m, 1 H), 4.12 (m, 1 H), 4. 30
(m, 1 H), 4.71 (s, 2 H), 7.08 (d, J ) 8.6 Hz, 2 H), 7.49 (m, 7 H),
7.76 (s, 1 H); MS m/z (relative intensity) 479 (M+, -170, 1%),
1
(KBr) 3379, 1642, 1232, 1081 cm-1; H NMR (CDCl3) δ 1.68
317 (9%), 217 (10%), 91 (100%). Anal. Calcd for C36H41
-
(m, 3 H), 2.19 (m, 3 H), 2.36 (s, 3 H), 2.45 (s, 6 H), 2.62 (s, 3
H), 2.78 (m, 1 H), 3.13 (m, 1 H), 3.51 (d, J ) 6.2 Hz, 2 H), 3.92
(m, 1 H), 4.72 (s, 2 H), 7.47 (m, 5 H); MS m/z (relative intensity)
ClN2O5S: C, 66.59; H, 6.36; N, 4.31. Found: C, 66.60; H, 6.40;
N, 4.26.
412 (M+, 25%), 293 (100%); [R]D ) -49.7 (c ) 1.0, CHCl3).
20
5-[4-[N-[(3R/S)-5-Ben zyloxy-2,3-d ih yd r o-2,2,4,6,7-p en -
t a m et h ylb en zofu r a n -3-ylm et h 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, Ma le-
a te. To a stirred solution of 21a (0.1 g, 0.10 mmol) in dry ether
(5 mL) at room temperature (0 °C) was added maleic acid (0.08
g, 0.179 mmol) in absolute ethanol (2 mL). The reaction
mixture was stirred at 25 °C for 2 h. The separated solids were
filtered, washed with dry ether (2 × 10 mL), and dried under
reduced pressure over P2O5 for 6 h to get a pale yellow solid
Rea ction of N-(5-Ben zyloxy-2,4,6,7-tetr a m eth ylben zo-
fu r an -3-ylm eth yl)-(3R)-ch lor opiper idin e with 4-Hydr oxy-
b en za ld eh yd e. A mixture of N-(5-benzyloxy-2,4,6,7-tetra-
methylbenzofuran-3-ylmethyl)-(3R)-chloropiperidine (3.0 g,
7.29 mmol), 4-hydroxybenzaldehyde (0.89 g, 7.29 mmol), and
potassium carbonate (4.03 g) in dimethylformamide (30 mL)
was stirred at ca. 25 °C for 12 h. The reaction mixture was
diluted with water (100 mL) and extracted with EtOAc (3 ×
50 mL). The combined EtOAc layers were washed with water
(100 mL) and brine (75 mL) and dried (Na2SO4). The filtrate
was concentrated, and the crude product was purified by
column chromatography using EtOAc-dichloromethane (0.2:
9.8) as eluent to give 4-[N-(5-benzyloxy-2,4,6,7-tetramethyl-
benzofuran-3-ylmethyl)-(2S)-pyrrolidin-2-ylmethoxy]benzal-
dehyde (1.0 g, 27%) as an oil: IR υmax (neat) 1680, 1604, 1263,
25
(0.11 g, 92%): mp 158-161 °C; [R]D ) -107.26 (c ) 1.00 in
CHCl3); IR υmax (KBr) 3445, 1738, 1694 cm-1; 1H NMR (CDCl3)
δ 1.37 (s, 3 H), 1.63 (s, 3 H), 1.95 (m, 4 H), 2.10 (s, 3 H), 2.22
(s, 3 H), 2.27 (s, 3 H), 2.63 (m, 2 H), 3.16 (m, 1 H), 3.30 (m, 2
H), 3.52 (m, 1 H), 3.85 (m, 1 H), 4.03 (m, 1 H), 4.72 (s, 2 H),
6.28 (s, 2 H), 7.03 (d, J ) 8.4 Hz, 2 H), 7.48 (m, 7 H), 7.79 (s,
1 H); MS m/z (relative intensity) 317 (M+, -411, 11%), 217
(13%), 91 (100%). Anal. Calcd for C40H44N2O9S: C, 65.93; H,
6.04; N, 3.84. Found: C, 65.99; H, 6.00; N, 3.86.
1
1082 cm-1; H NMR (CDCl3) δ 1.80 (m, 4 H), 2.08 (m, 1 H),
2.30 (s, 3 H), 2.37 (s, 3 H), 2.42 (s, 3 H), 2.59 (s, 3 H), 3.03 (m,
2 H), 3.59 (d, J ) 12.9 Hz, 1 H), 3.79 (dd, J ) 9.6 and 6.8 Hz,
1 H), 3.93 (dd, J ) 9.6 and 5.2 Hz, 1 H), 3.79 (dd, J ) 9.6 and
6.8 Hz, 1 H), 3.93 (dd, J ) 9.6 and 5.2 Hz, 1 H), 4.05 (d, J )
12.9 Hz, 1 H), 4.70 (s, 2 H), 6.80 (d, J ) 8.6 Hz, 2 H), 7.48 (m,
5 H), 7.77 (d, J ) 8.6 Hz, 2 H), 9.86 (s, 1 H); MS m/z (relative
5-[4-[N-[(3R/S)-5-Ben zyloxy-2,3-d ih yd r o-2,2,4,6,7-p en -
t a m et h ylb en zofu r a n -3-ylm et h 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, Ma lea te.
The title compound (0.44 g, 79%) was prepared as a pale yellow
solid from 19a (0.47 g, 0.77 mmol) by a similar procedure
intensity) 497 (M+, 3%), 293 (100%); [R]D ) +51.0 (c ) 1.0,
22
25
described above: mp 179-182 °C; [R]D ) 2.400 (c ) 1.0 in
CHCl3); IR υmax (KBr) 3425, 1700 cm-1 1H NMR (CDCl3) δ
;
CH2Cl2).
1.36, 1.40 (2s, 3 H), 1.62, 1.67 (2s, 3 H), 2.06-2.45 (complex-
m, 15 H), 2.81 (m, 1 H), 3.14-3.64 (complex-m, 5 H), 4.16-
4.21 (m, complex, 2 H), 4.50 (m, 1 H), 4.64-4.72 (complex-m,
2 H), 6.27 (s, 2 H), 6.82 (m, 2 H), 7.17 (m, 2 H), 7.43 (m, 5 H);
MS m/z (relative intensity) 391 (M+, -339, 1%), 319 (80%), 91
(100%). Anal. Calcd for C40H46N2O9S: C, 65.75; H, 6.3; N, 3.83.
Found: C, 65.87; H, 6.05; N, 3.86.
N-(5-Ben zyloxy-2,4,6,7-t et r a m et h ylb en zofu r a n -3-yl-
m et h yl)-(2S)-p yr r olid in e-2-m et h a n ol. To a solution of
carbinol 22a (20.0 g, 64.5 mmol) in CH2Cl2 (150 mL) was added
thionyl chloride (38.38 g, 322 mmol) dropwise at ca. -20 °C.
The reaction mixture was allowed to warm to 0 °C, and stirring
was continued at this temperature for 5 h. Excess of thionyl
Further elution gave 4-[N-(5-Benzyloxy-2,4,6,7-tetrameth-
ylbenzofuran-3-ylmethyl)-(3R)-piperidinyloxy]benzaldehyde as
23
a white solid (0.9 g, 24%): mp 142-144 °C; [R]D ) -57.5 (c
) 0.2, CH2Cl2); IR υmax (neat) 1691, 1600, 1254, 1083 cm-1; 1H
NMR (CDCl3) δ 1.74 (m, 4 H), 2.18 (m, 2 H), 2.29 (s, 3 H), 2.32
(s, 6 H), 2.62 (s, 3 H), 2.73 (m, 1 H), 3.05 (m, 1 H), 3.45 (d, J
) 5.4 Hz, 2 H), 4.40 (m, 1 H), 4.77 (s, 2 H), 6.91 (d, J ) 8.6 Hz,
2 H), 7.49 (m, 5 H), 7.75 (d, J ) 8.7 Hz, 2 H), 9.84 (s, 1 H); MS
m/z (relative intensity) 497 (M+, 8%), 201 (100%).
P r ep a r a tion of 5-[4-[N-(5-Ben zyloxy-2,4,6,7-tetr a m eth -
ylben zofu r a n -3-ylm eth yl)-(2S)-p yr r olid in -2-ylm eth oxy]-
p h en ylm eth ylen e]th ia zolid in e-2,4-d ion e (23a ). A mixture
of 4-[N-(5-benzyloxy-2,4,6,7-tetramethylbenzofuran-3-ylmethyl)-

1938 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11
Reddy et al.
(3R)-piperidinyloxy]benzaldehyde (0.6 g, 1.2 mmol), thiazoli-
dine-2,4-dione (0.141 g, 1.2 mmol), benzoic acid (0.018 g, 0.14
mmol), and piperidine (0.015 g, 0.17 mmol) in 25 mL of toluene
was refluxed for 3 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, which was purified by column chro-
matography using EtOAc-petroleum ether (3:7) as eluent to
give the title compound 23a (0.4 g, 56%): mp 168-170 °C;
3 H), 2.59 (s, 3 H), 3.03 (m, 2 H), 3.63 (d, J ) 12.8 Hz, 1H),
3.85 (m, 2 H), 4.0 (d, J ) 12.8 Hz, 1 H), 4.72 (s, 2 H), 6.72 (d,
J ) 9 Hz, 2 H); MS m/z (relative intensity) 514 (M+, 15%),
293 (100%).
(b) 4-[N-(5-Ben zyloxy-2,4,6,7-tetr a m eth ylben zofu r a n -
3-ylm eth yl)-(2S)-p yr r olid in -2-ylm eth oxy]a n ilin e. To a so-
lution of the nitro compound from the previous step (5.0 g,
9.72 mmol) in ethyl acetate (50 mL) was added 10% Pd-C
(0.5 g), and the mixture was hydrogenated at 30 psi for 12 h.
The mixture was filtered through a bed of Celite, and the
catalyst was washed with 100 mL of ethyl acetate. The filtrate
was evaporated to dryness under reduced pressure to give the
title compound (3.3 g, 70%): IR υmax (KBr) 3385, 1510, 1238,
24
[R]D ) +107.72 (c ) 1.0, CHCl3); IR υmax (KBr) 1740, 1684
cm-1; 1H NMR (CDCl3) δ 1.75 (m, 4 H), 2.05 (m, 1 H), 2.31 (s,
3 H), 2.38 (s, 3 H), 2.42 (s, 3 H), 2.60 (s, 3 H), 3.00 (m, 2 H),
3.63 (d, J ) 12.9 Hz, 1 H), 3.78 (m, 1 H), 3.83 (m,1 H), 4.04 (d,
J ) 12.9 Hz, 1 H), 4.71 (s, 2 H), 6.78 (d, J ) 8.6 Hz, 2 H), 7.44
(m, 7 h), 7.78 (s, 1 H); MS m/z (relative intensity) 596 (M+,
5%), 376 (100%). Anal. Calcd for C35H36N2O5S: C, 70.44; H,
6.08; N, 4.69. Found: C, 70.40; H, 6.00; N, 4.70.
1
1080 cm-1; H NMR (CDCl3) δ 1.61 (m, 4 H), 2.10 (m, 1 H),
2.29 (s, 3 H), 2.34 (s, 3 H), 2.40 (s, 3 H), 2.65 (s, 3 H), 2.96 (m,
2 H), 3.41 (bs, exchangeable with D2O, 2 H), 3.48 (d, J ) 13
Hz, 1 H), 3.65 (m, 1 H), 3.85 (m, 1 H), 4.12 (d, J ) 13 Hz, 1 H),
4.75 (s, 2 H), 6.62 (s, 4 H), 7.48 (m, 5 H); MS m/z (relative
intensity) 484 (M+, 10%), 293 (100%).
P r ep a r a tion of 5-[4-[N-(5-Ben zyloxy-2,4,6,7-tetr a m eth -
ylb en zofu r a n -3-ylm et h yl)-(3R)-p ip er id in yloxy]p h en yl-
m eth ylen e]th ia zolid in e-2,4-d ion e (24a ). A mixture of 4-[N-
(5-benzyloxy-2,4,6,7-tetramethylbenzofuran-3-ylmethyl)-(3R)-
piperidinyloxy]benzaldehyde (1.0 g, 2 mmol), thiazolidine-2,4-
dione (0.235 g, 2.0 mmol), benzoic acid (0.03 g, 0.24 mmol),
and piperidine (0.025 g, 0.29 mmol) in 50 mL of toluene was
refluxed for 3 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 5% EtOAc-petroleum ether, and
dried to afford title compound 24a (0.9 g, 75%) as a solid: mp
(c) E t h yl 2-Br om o-3-[4-[N-(5-b en zyloxy-2,4,6,7-t et r a -
m e t h ylb e n zofu r a n -3-ylm e t h yl)-(2S )-p yr r olid in -2-yl-
m eth oxy]p h en yl]p r op a n oa te. To a mixture of aniline from
the previous step (3.3 g, 6.8 mmol), aqueous hydrobromic acid
(47%, 1.5 mL), and acetone (33 mL) was added an aqueous
sodium nitrite solution (0.517 g) dropwise at 0 °C, and the
mixture stirred at 0 °C for an additional 30 min. The reaction
mixture was allowed to warm to room temperature, and ethyl
acrylate (4.09 g, 40.9 mmol) was added followed by cuprous
oxide (0.058 g) in portions. The stirring was continued at ca.
25 °C for a further 1 h and at 40 °C for another 1 h. The solvent
was evaporated under vacuum, and the residue was basified
by adding ammonia solution (8 mL) and extracted with EtOAc
(3 × 50 mL). The combined EtOAc extracts were washed with
water (75 mL) and brine (75 mL), dried (Na2SO4), and filtered.
The solution was filtered, and the filtrate was concentrated.
The crude product residue was purified by column chroma-
tography using EtOAc-petroleum ether (0.5:9.5) as an eluent
to give the title compound (0.7 g, 15%) as a light brown
20
100-103 °C; [R]D ) -52.4 (c ) 1.0, CHCl3); IR υmax (KBr)
1
3174, 1738, 1694, 1507, 1253 cm-1; H NMR (CDCl3) δ 1.58
(m, 3 H), 1.78 (m, 1H), 2.16 (s, 2 H), 2.33 (s, 3 H), 2.40 (s, 6
H), 2.73 (s, 3 H), 2.78 (m, 1 H), 3.15 (m, 1 H), 3.48 (d, J ) 4.9
Hz, 2 H), 4.34 (m, 1 H), 4.77 (s, 2 H), 6.91 (d, J ) 8.7 Hz, 2 H),
7.42 (m, 7 H), 7.74 (s, 1 H); MS m/z (relative intensity) 505
(M+, -C7H7), 201 (100%). Anal. Calcd for C35H36N2O5S: C,
70.44; H, 6.08; N, 4.69. Found: C, 70.40; H, 6.00; N, 4.71.
P r ep a r a tion of 5-[4-[N-(5-Hyd r oxy-2,4,6,7-tetr a m eth -
ylben zofu r a n -3-ylm eth yl)-2(S)-p yr r olid in -2-ylm eth oxy]-
p h en ylm eth ylen e]th ia zolid in e-2,4-d ion e (23b). A mixture
of 23a (0.7 g, 1.17 mmol) and hydrochloric acid (1 mL) in glacial
AcOH (4 mL) was refluxed for 3 h. Acetic acid was removed
under reduced pressure, and the resultant solid was suspended
in EtOAc (25 mL). The pH was adjusted to pH 8.0 by adding
aqueous ammonia solution (5 mL) and extracted with EtOAc
(7 mL). The crude product was purified by column chroma-
tography using EtOAc-petroleum ether (4:6) as eluent to give
liquid: IR υmax (KBr) 1738, 1606, 1453, 1243, 1082, 1021 cm-1
;
1H NMR (CDCl3) δ 1.26 (t, J ) 7 Hz, 3 H), 1.79 (m, 4 H), 2.05
(m, 1 H), 2.31 (s, 3 H), 2.39 (s, 3 H), 2.42 (s, 3 H), 2.65 (s, 3 H),
2.98 (m, 2 H), 3.21 (m, 1 H), 3.40 (m, 1 H), 3.58 (d, J ) 12 Hz,
1 H), 3.74 (m, 1 H), 3.91 (m, 1 H), 4.21 (m, 4 H), 4.76 (s, 2 H),
6.73 (d, J ) 7.7 Hz, 2 H), 7.10 (d, J ) 7.7 Hz, 2 H), 7.48 (m, 5
H); MS m/z (relative intensity) 362 (M+, -C12H14BrO3), 293
(100%).
(d ) P r ep a r a tion of 5-[4-[N-(5-Ben zyloxy-2,4,6,7-tetr a -
m e t h ylb e n zofu r a n -3-ylm e t h 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 (25a ). A
mixture of alkoxypropionate from the above step c (2.7 g, 4.1
mmol) and sodium acetate (0.375 g) in ethanol (10 mL) was
stirred under reflux for 12 h. The solvent was evaporated
under reduced pressure, water (50 mL) was added, and the
mixture was extracted with ethyl acetate (3 × 50 mL). The
organic extract was washed with water (75 mL), dried (Na2-
SO4), filtered, and concentrated to get 5-[4-[N-(5-benzyloxy-
2,4,6,7-tetramethylbenzofuran-3-ylmethyl)pyrrolidin-(2S)-yl-
methoxy]benzyl]-2-imino-4-thiazolidinone. The above crude
compound was suspended in ethanol (10 mL), and 2 N
hydrochloric acid (10 mL) was added. The reaction mixture
was stirred under reflux for 12 h and concentrated in vacuo.
The residue was diluted with water (50 mL), neutralized with
aqueous ammonia solution (7 mL), and extracted with ethyl
acetate (3 × 50 mL). The combined organic extracts were
washed with water (75 mL) and brine (75 mL), dried (Na2-
SO4), and filtered. The solvent was evaporated under reduced
pressure, and the crude product was chromatographed on silica
gel using EtOAc-petroleum ether (3:7) as eluent, to afford the
26
23b (0.27 g, 47%): mp 157-159 °C; [R]D ) +75.1 (c ) 0.7,
EtOAc); IR υmax (KBr) 3465, 1740, 1696, 1595, 1509, 1335 cm-1
;
1H NMR (CDCl3) δ 1.78 (m, 4 H), 2.04 (m, 1 H), 2.24 (s, 3 H),
2.38 (s, 3 H), 2.40 (s, 3 H), 2.51 (s, 3 H), 3.04 (m, 2 H), 3.62 (d,
J ) 12.9 Hz, 1H), 3.79 (m, 1 H), 3.83 (m, 1 H), 4.04 (d, J )
12.9 Hz, 1 H), 6.76 (d, J ) 8.9 Hz, 2 H), 7.38 (d, J ) 8.7 Hz, 2
H); 7.78 (s, 1 H). MS m/z (relative intensity) 286 (M+, -C10H6-
NO3S), 272 (12%), 189 (100%). Anal. Calcd for C28H30N2O5S:
C, 66.37; H, 5.96; N, 5.53. Found: C, 66.30; H, 5.88; N, 5.5.
P r ep a r a tion of 5-[4-[N-(5-Ben zyloxy-2,4,6,7-tetr a m eth -
ylben zofu r a n -3-ylm eth yl)-(2S)-p yr r olid in -2-ylm eth oxy]-
p h en ylm eth yl]th ia zolid in ed ion e (25a ). (a ) 4-[N-(5-Ben -
zyloxy-2,4,6,7-t et r a m et h ylb en zofu r a n -3-ylm et h yl)-(2S)-
p yr r olid in -2-ylm eth oxy]n itr oben zen e. To a suspension of
NaH (2.93 g, 122 mmol) in dimethylformamide (50 mL) was
added a solution of N-(5-benzyloxy-2,4,6,7-tetramethylbenzo-
furan-3-ylmethyl)-(2S)-pyrrolidine-2-methanol (24.0 g, 61 mmol)
in dimethylformamide (50 mL) dropwise, and the mixture
stirred at room temperature for 3 h. The reaction mixture was
diluted with water (50 mL) and extracted with EtOAc (3 ×
100 mL). The combined EtOAc layers were washed with water
(200 mL) and brine (200 mL) and dried (Na2SO4). The solvent
was evaporated to furnish a crude product which was purified
by column chromatography using EtOAc-petroleum ether (1:
9) as eluent to give a yellow solid: mp 136-139 °C; IR υmax
25
title compound (0.48 g, 20%): mp 55-57 °C; [R]D ) +25.2 (c
) 0.5, CHCl3); IR υmax (KBr) 3191, 1754, 1700, 1512, 1237,
1
1082 cm-1; H NMR (CDCl3) δ 1.75 (m, 4 H), 2.05 (m, 1 H),
2.30 (s, 3 H), 2.37 (s, 3 H), 2.41 (s, 3 H), 2.60 (s, 3 H), 2.98 (m,
2 H), 3.10 (m, 1 H0, 3.41 (m, 1 H), 3.55 (m, 1 H), 3.72 (m, 1
H), 3.90 (m, 1 H), 4.12 (m, 1 H), 4.45 (m, 1 H), 4.74 (s, 2 H),
1
(KBr) 1593, 1506, 1443, 1263, 1110 cm-1; H NMR (CDCl3) δ
1.78 (m, 4 H), 2.06 (m, 1 H), 2.32 (s, 3 H), 2.38 (s, 3 H), 2.40 (s,

Novel Antidiabetic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11 1939
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6.70 (m, 2 H), 7.04 (d, J ) 7.0 Hz, 2 H), 7.42 (m, 5 H); MS m/z
(relative intensity) 598 (M+, 10%), 293 (100%). Anal. Calcd for
C
35H37N2O5S: C, 70.32; H, 6.24; N, 4.68. Found: C, 70.30; H,
6.20; N, 4.70.
Ack n ow led gm en t. We are thankful to Dr. A. Ven-
kateswarlu and Dr. S. Swaminathan for helpful sug-
gestions and the Analytical Department for spectral
support. We also wish to thank the reviewers of the
present article for a number of useful suggestions for
improving this manuscript.
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