Hypoglycemic activity of a series of α-alkylthio and α-alkoxy carboxylic acids related to ciglitazone

Article abstract of DOI:10.1021/jm960230h

The thiazolidinedione moiety of ciglitazone and its analogues can be replaced by an α-alkoxy or α-thioether carboxylic acid group. The influence of the nature of the R group, the length of the connector to the aromatic backbone of the molecule, and the stereochemistry have been studied. The most potent compounds have glucose-lowering activity at doses as low as 0.01 mg/kg.

Full text of DOI:10.1021/jm960230h

J . Med. Chem. 1996, 39, 3897-3907
3897
Articles
Hyp oglycem ic Activity of a Ser ies of r-Alk ylth io a n d r-Alk oxy Ca r boxylic Acid s
Rela ted to Ciglita zon e
Bernard Hulin,* Linda S. Newton, Diana M. Lewis, Paul E. Genereux, E. Michael Gibbs, and David A. Clark
Central Research, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340
Received March 25, 1996X
The thiazolidinedione moiety of ciglitazone and its analogues can be replaced by an R-alkoxy
or R-thioether carboxylic acid group. The influence of the nature of the R group, the length of
the connector to the aromatic backbone of the molecule, and the stereochemistry have been
studied. The most potent compounds have glucose-lowering activity at doses as low as 0.01
mg/kg.
Non-insulin-dependent diabetes mellitus (NIDDM) is
a metabolic disorder leading to long-term organ com-
plications such as neuropathy, nephropathy, retinopa-
thy and premature atherosclerosis.1 NIDDM patients
are usually treated by a combination of dietary mea-
sures and pharmacological agents: sulfonylureas, bigu-
anides, and/or insulin.2 This conventional treatment
suffers from a high failure rate, and attempting to
achieve the desired tight control may result in an
increase in dangerous hypoglycemic episodes. The
recently disclosed results of the Diabetes Control and
Complications Trial showed dramatic benefits for IDDM
patients on intensive insulin therapy, but at the cost of
a 3-fold increase in the risk of severe hypoglycemia.3 If
extrapolated to NIDDM, these results indicate that tight
glucose control is desirable in order to decrease the risk
of these long-term complications. This tight control
must be balanced with the risk of hypoglycemia, par-
ticularly with insulin and sulfonylureas. New therapies
which normalize blood glucose levels without raising
insulin levels are therefore an attractive alternative,
and a variety of agents with potential advantages over
the existing ones have recently been disclosed.4,5 Among
them, analogs of ciglitazone have been the objects of
widespread interest.5 Ciglitazone, reported in 1982 by
Takeda, was shown to normalize hyperglycemia in
insulin-resistant models without affecting the glycemia
in nondiabetic animals,6 therefore lowering insulin
resistance directly without any effect on insulin secre-
tion. Since then, numerous reports have appeared
describing more potent or structurally distinct ana-
logs,5,7 and positive clinical results have been reported.5,8
at the R-position could alter the chemical environment
around the carboxylic acid function in such a way that
the whole group would mimic the thiazolidinedione ring.
Resu lts a n d Discu ssion
The choice of the appropriate backbone on which to
append the carboxylic acid function was based on work
performed in the thiazolidinedione series, where we
sought to reduce the conformational freedom of the ether
linkage, without creating a stereocenter, as in the
benzopyran series where compounds isomeric at C-2 of
the benzopyran, such as englitazone,14 had similar
activities. This was accomplished by incorporating the
oxygen into a benzofuran ring system substituted at the
2-position. The resulting series of compounds exempli-
fied by 3, a direct analog of 1, displayed exceptional
potency in the ob/ob mouse. A similar modification in
the oxazolidinedione series also led to very potent
compounds.11a
Compounds containing a (2-phenyloxazol-4-yl)ethyl
chain display particularly potent activity, whether in
the ether series as in 19 or in the ketone series as in
darglitazone.10 At the other end of the molecule, the
thiazolidinedione ring has been replaced mainly by
closely related groups such as the oxazolidine-2,4-
dione11 and 1-oxa-2,4-diazolidine-3,5-dione12 rings and
the carbonylated hydroxyurea moiety.12,13 Our goal in
this study was to find derivatives such as 2 where the
acidic role is now played by a carboxylic acid function.
It was envisioned that an appropriate substituent placed
As the results in Table 1 show, all these compounds
display excellent activity at 0.1 mg/kg, and two com-
pounds, 3 and 7, are fully active at 0.01 mg/kg, i.e. they
are at least 50 times more potent than darglitazone, our
compound previously selected for clinical studies.10
X Abstract published in Advance ACS Abstracts, September 1, 1996.
S0022-2623(96)00230-0 CCC: $12.00 © 1996 American Chemical Society

3898 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Hulin et al.
Ta ble 1. Hypoglycemic Activity of Benzofuran
Thiazolidinediones
Ta ble 3. Hypoglycemic Activity of R-Alkoxy Carboxylic Acids
% glucose normalization in
compound
R
db/db mouse (mg/kg)a
no.
Ar
5
1
0.1
0.05 0.01
% glucose normalization in
compound
R
ob/ob mouse (mg/kg)a
0.1
17 Me
18 Et
Ph
94* 100*
100* NT
100* 100* 100*
83*
100*
82*
97*
76*
91*
44
69*
43
Ph
Ph
Ph
no.
1
0.01
19 n-Pr
20 allyl
3
4
5
6
7
8
Ph
NT
93*
100*
88*
91*
79*
76*
0
12
11
78*
IA
92*
100*
NT
NT
NT
85*
74
NT
NT
100* 100*
85*
NT
100* 100*
27
4-ClPh
3-FPh
2-MePh
3-MePh
100*
100*
100*
100*
100*
21 propargyl Ph
22 Bn Ph
23 (CH2)3OH Ph
NT
NT
74*
NT
46
98*
63*
91
19
IA
24 Et
25 Et
26 Et
p-OMePh
2-thienyl
2-furyl
cyclohexyl
90*
NT
NT
100* 100* 100*
100* 100* NT
a
*p < 0.05; NT, not tested; IA, inactive.
a
*p < 0.05; NT, not tested; IA, inactive.
Ta ble 2. Hypoglycemic Activity of R-Thioether Carboxylic
Acids
Ta ble 4. Hypoglycemic Activity of Alkanoic Acids of Varied
Chain Length
compound
no.
% glucose normalization in db/db mouse (mg/kg)a
compound
% glucose normalization in db/db mouse (mg/kg)a
R
5
1
0.5
0.25
0.1
11 Me
12 Et
13 n-Pr
14 n-Oct
15 Bn
16 Ph
NT
86*
94*
96*
100*
70*
89*
60*
69*
75*
88*
90*
100*
80*
82*
100*
93*
100*
16
3
39
99*
72*
92*
26
NT
NT
14
IA
86
no.
n
5
1
0.5
0.25
0.1
0.01
NT
69*
NT
27
18
28
0
1
2
9
NT
NT
90*
NT
NT
75*
NT
100*
13
NT
100*
NT
100*
100*
a
*p < 0.05; NT, not tested.
a
*p < 0.05; NT, not tested; IA, inactive.
that many different sulfur substituents are tolerated.
Larger groups appear to be somewhat preferred, as
evidenced by the activity at 0.25 mg/kg of 14, 15, and
16.
Because of the potency improvement achieved with
the thioether substitution at the R-position, we set out
to vary further the R-substituent by changing the
thioether group into an ether group. This variation is
analogous to the thiazolidinedione to oxazolidinedione
translation seen earlier,11a where the activity was
retained. Therefore, a series of R-alkoxy carboxylic acids
was synthesized and tested (Table 3).
It quickly became apparent that the ether series is
more potent than the thioether series. Whether this
difference is due to intrinsic activity or to a metabolic
liability of the latter series, i.e. rapid oxidation to the
sulfoxide or sulfone followed by elimination, was not
determined. The most active compounds, 18, 25, and
26, are comparable in potency to the thiazolidinediones
3 and 7. The nature of the oxygen substituent influ-
ences the degree of activity. Among alkyl chains a
maximum of activity is observed for the ethyl group.
Functionalization of the chain (21, 23) led to a decrease
in activity, while the benzyl-substituted compound was
also very potent. Standard replacement of the phenyl
substituent on the oxazole ring with 2-thienyl or 2-furyl
(25, 26) resulted in compounds with similar potency.
The length of the connector between the aromatic ring
and the carboxylic acid function is critical for the activity
(Table 4). Shortening this chain to one carbon led to
the acetic acid 27, which was devoid of activity even at
With highly potent compounds in hand it was deemed
feasible to start a search for carboxylic acid analogs of
3, since even a substantial (100×) loss in potency upon
replacement of the thiazolidinedione ring would lead to
a series of compounds with acceptable activity and,
possibly, devoid of associated toxicity. Our first (and
obvious) target was the unsubstituted hydrocinnamic
acid 9. This compound and the corresponding cinnamic
acid 10 lacked any activity at 5 mg/kg. Although this
lack of activity was disappointing, it was possible that
it simply reflected the absolute necessity of a substituent
at the R-position of the carboxylic acid that could take
the place of the sulfur atom of the thiazolidinedione ring.
Accordingly, we set out to prepare carboxylic acids
equipped with a thioether substituent at the R-position,
starting with the methylthio moiety, a group small
enough to fill the space occupied by the thiazolidinedi-
one ring. This compound, 11, showed remarkable
activity at 1 and 0.5 mg/kg. Other compounds with
various alkylthio groups were then prepared. The
results are shown in Table 2. All the compounds
prepared were active at 1 mg/kg or below, indicating

Activity of Ciglitazone-Related Carboxylic Acids
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 3899
Ta ble 5. Hypoglycemic Activity of Individual Enantiomers of 13 and 18
% glucose normalization in
db/db mouse (mg/kg)a
compound
no.
stereochemistry
2.5
1
0.5
(+)-13
(-)-13
ND
ND
69*
75*
91*
56*
52*
45
% glucose normalization in
db/db mouse (mg/kg)a
compound
no.
stereochemistry
1
0.1
0.01
(-)-18
(+)-18
S
R
NT
74*
100*
19
78*
16
a
*p < 0.05; ND, not determined; NT, not tested.
5 mg/kg, whereas the butyric acid analog 28 showed
significant activity at 0.5 mg/kg.
other antipode is always present because of the rapid
racemization in vivo. The alkoxy carboxylic acid series
allows one to remove this “isomeric ballast”, i.e. a 50%
impurity which does not contribute to the desired
activity but may impart toxicity. The results presented
herein may also have significance with respect to the
mechanism of action of this class of compounds: the
high in vivo and in vitro potencies and the concordance
of the in vitro and in vivo enantiospecificities for (+)-
and (-)-18 are consistent with the stimulation of glucose
uptake being responsible for the hypoglycemic activity
of these compounds.
In summary, we have shown that the thiazolidinedi-
one group of potent ciglitazone-like compounds can be
adequately replaced by an appropriately substituted
carboxylic acid. The resulting series of R-thioether and
R-alkoxy carboxylic acids have been shown to lower
blood glucose levels in an animal model of NIDDM at
low doses, equivalent to the effective doses for the
corresponding thiazolidinediones. Two of these com-
pounds, (-)-13 and (-)-18, were shown to stimulate
glucose uptake at low nanomolar concentration in an
adipocyte cell line. Both the in vivo and in vitro effects
are stereospecific for the nonracemizable alkoxy car-
boxylic acid series.
The effect of the stereochemistry at the R-position to
the carboxylic acid group was examined in both series
by preparing the individual enantiomers of 13 and 18.
The two enantiomers of 13, the absolute configuration
of which was not established, were equipotent in their
ability to lower glucose in vivo (Table 5). However it is
quite possible that the the inactive antipode readily
racemizes either directly or indirectly. The two enan-
tiomers of ciglitazone have equivalent antihyperglyce-
mic potency and have been hypothesized to intercon-
vert,15 and direct in vivo proton exchange has been
shown to take place for the thiazolidinedione englita-
zone5 and is a well-known process for 2-arylpropionic
acids such as ibuprofen.16 Indirect racemization may
proceed via the corresponding sulfoxide, since most
sulfides readily undergo reversible in vivo oxidation,17
and the resultant R-sulfinyl carboxylic acid would be
readily ionized at physiological pH. The intrinsic
potency of the two enantiomers was assayed by examin-
ing their ability to stimulate glucose uptake in 3T3-L1
adipocytes after 48 h18 incubation, an effect which had
been observed with englitazone at micromolar concen-
trations19 and with the oxazolidinedione CP-92768 (EC50
) 10 nM).11b Both antipodes of 13 increased the uptake
in a dose-responsive manner with a maximum 5-fold
stimulation. This low dose increase was followed by a
second phase of stimulation at higher concentrations
(not shown). (-)-13 was clearly more potent than (+)-
13 in this assay, with EC50’s ca. 0.2 and 20 nM,
respectively (Figure 1a).20 This result is consistent with
racemization taking place in vivo. In the case of the
alkoxy carboxylic acid 18, where in vivo racemization
would not be expected, the activity was shown to reside
entirely within the (S) enantiomer in vivo, while in the
glucose uptake assay, the same (S) antipode displayed
a 2-fold stimulation with an EC50 ca. 5 nM. In contrast,
the dose-response curve for the (R) antipode was
shifted to the right about 20-fold, with an EC50 ca. 100
nM (Figure 1b).
Ch em istr y
The thiazolidinediones in Table 1 were prepared from
intermediate 2911a by a standard sequence: transmeta-
lation and reaction with DMF to form the aldehyde,
condensation with 2,4-thiazolidinedione, and sequential
reductions of the double bond and the alcohol function
(Scheme 1).
The unsubstituted cinnamic and hydrocinnamic acids
10 and 9 were prepared from the known aldehyde 3211a
by Knoevenagel condensation followed by reduction. 32
was synthesized by an improved procedure, as detailed
in Scheme 2.
The thioether carboxylic acids were prepared from
aniline 36 by Meerwein arylation6a,21 followed by dis-
placement with the appropriate mercaptan and hy-
drolysis of the ester (Scheme 3).
The series of alkoxy carboxylic acids was obtained
from the aldehyde 32 by Wittig reaction to form the
homologated vinyl ether followed by acetal formation,
This result is the first example of nonracemizable
ciglitazone-like compounds where the stereochemistry
R to the acidic moiety has been shown to be critical for
the activity. In the case of thiazolidinediones, even if
the activity resides in only one of the enantiomers, the

3900 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Hulin et al.
Sch em e 1a
a
b
a
(a) nBuLi, DMF, THF; (b) 2,4-thiazolidinedione, piperidine,
ethanol; (c) 3% sodium amalgam, methanol, THF; (d) Et3SiH, TFA.
sized by aldol reaction of 32 with 48, a derivative of
ethoxyacetic acid fitted with an Evans’ chiral auxiliary,23
followed by removal of the hydroxyl group and hydroly-
sis of the auxiliary (Scheme 7).
Exp er im en ta l Section
Biologica l P r oced u r e. Mea su r e of in Vivo Hypoglyce-
m ic Activity. The method used has been described previ-
ously10,14 and is herein repeated for convenience, the only
difference being the use of db/db mice instead of ob/ob mice.
Six- to eight-week-old db/db mice (obtained from J ackson
Laboratories, Bar Harbor, ME) were housed five per cage
under standard animal care practices. After a 1 week ac-
climation period, the animals were weighed and 25 µL of blood
were collected via the retro-orbital sinus prior to any treat-
ment. The blood sample was immediately diluted 1:5 with
saline containing 2% sodium heparin and held on ice for
glucose analysis. Animals were then dosed daily for 4 days
with drug or vehicle. All drugs were administered by oral
gavage, once daily, in a vehicle consisting of 0.25% (w/v)
methylcellulose in water with no pH adjustment (0.1 mL of
solution per 20 g of animal weight). Animals were bled 24 h
after the fourth administration of drug or vehicle (via the retro-
orbital sinus) for blood glucose levels. The weight of each
animal was recorded on days 1 and 5 of the treatment. The
freshly collected samples (125 µL in 330 µL tubes) were
centrifuged for 2 min at 10000g at room temperature. A 50
µL sample was analyzed for glucose by the Abbott VP Super
System Analyzer,24 using the A-gent glucose UV reagent
system25 (hexokinase method using 100, 300, and 500 mg/dL
standards). Englitazone was dosed at 100 mg/kg as a positive
control, and results are reported in all tables as the percentage
of glucose normalization compared to the standard englitazone-
treated group (100% at 100 mg/kg) and the vehicle treated
group (0%).
F igu r e 1. Glucose uptake dose-response curves for indi-
vidual enantiomers of 13 (a) and 18 (b).
reaction with trimethylsilyl cyanide, and hydrolysis.
This versatile sequence allowed the variation of the
alkoxy group at a late stage in the synthesis by using
the appropriate alcohol to form the acetal (Scheme 4).
The acetic and butyric acid analogs 27 and 28 were
obtained following a variation of this sequence (Scheme
5).
Resolution of 13 was accomplished using the method
of Helmchen.22 The amides 47m (more polar by TLC
analysis) and 47l (less polar) were easily separated by
chromatography and recrystallization. Hydrolysis of the
amides under acidic conditions proceeded with ca. 10%
racemization as determined by conversion back to the
Helmchen amide under neutral conditions. The acid
could be purified by recrystallization to yield material
enantiomerically pure (by NMR analysis of the Helm-
chen amide) (Scheme 6). (+)- and (-)-18 were synthe-
Glu cose Upta ke Assa y. 3T3-L1 cells were grown as
described previously19 and treated by adding drug dissolved
in DMSO. After 48 h the cells were incubated with [1-14C]-
2-deoxyglucose (0.05 mM) for 10 min. Uptake was terminated
by aspirating the media and washing the cells three times with
saline. The cells were dissolved in 0.5 mL of 1% Triton X-100,
and radioactivity was quantitated by liquid-scintillation count-
ing.

Activity of Ciglitazone-Related Carboxylic Acids
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 3901
Sch em e 2a
a
(a) Ac2O, pyridine, ∆; (b) TFA, TFAA; (c) 4-hydroxy-3-iodobenzaldehyde, Cu2O, (PPh3)2PdCl2, pyridine, ∆; (d) malonic acid, pyridine,
∆; (e) H2, PtO2, MeOH.
Sch em e 3a
a
i
(a) 5-Nitrosalicylaldehyde, Pr2NEt, DMF, ∆; (b) NaBH4, MeOH, THF, 0 °C; (c) Et3SiH, TFA; (d) H2, PtO2, EtOAc; (e) NaNO2, HBr,
H2O, acetone, methanol; ethyl acrylate, Cu2O; (f) RSH, K2CO3, DMF; (g) NaOH, H2O, MeOH.
Sch em e 4a
a
(a) Ph3P+CH2OMeCl-, LDA, THF; (b) ROH, pTsOH, ∆; (c) TMSCN, BF3‚Et2O, CH2Cl2; (d) NaOH, H2O, EtOH, ∆.
Ch em istr y. Melting points were taken using a Thomas
Hoover apparatus and are uncorrected. Elemental analyses
were carried out by the Analytical Department of Pfizer
Central Research or Schwartzkopf Analytical Laboratory and
results obtained for specified elements are within (0.4% of
the theoretical values unless otherwise denoted. 1H and 13C
NMR spectra of deuteriochloroform or DMSO-d6 solutions were
recorded on Bruker AM-300 or Varian XL-300 spectrometers.
Low- and high-resolution mass spectra were obtained on a
Finnigan 4510 and AEI MS-30 instruments, respectively.
Infrared spectra were recorded on a Perkin-Elmer 283 spec-
trophotometer.
Syn t h esis of 5-{[2-[(5-Met h yl-2-p h en yloxa zol-4-yl)-
m eth yl]-5-ben zofu r an yl]m eth yl}-2,4-th iazolidin edion e (3):
2-[Hyd r oxy(5-m eth yl-2-p h en yloxa zol-4-yl)m eth yl]ben zo-
fu r a n -5-ca r ba ld eh yd e (30). To a solution of 5-bromo-R-(5-
methyl-2-phenyloxazol-4-yl)-2-benzofuranmethanol (29)11a (10
g, 26 mmol) in dry THF (425 mL) was added at -78 °C a 1.6
M solution of n-butyllithium in hexane (65 mL, 0.10 mol) over
30 min. The red-purple solution was stirred for 30 min at -78
°C, and then a solution of DMF (10 mL, 0.13 mol) in THF (25
mL) was added. The mixture was warmed to room tempera-
ture, diluted with saturated aqueous ammonium chloride (500
mL), and extracted with ethyl acetate (2 × 200 mL). The
combined extracts were washed with water (150 mL) and brine
(200 mL), dried over sodium sulfate, and concentrated. The
residue was recrystallized from ethyl acetate (240 mL) to give
an off-white solid (4.2 g, 48%, mp 175-176 °C): 1H NMR (300
MHz, DMSO-d6) ∂ 2.46 (s, 3 H), 5.97 (d, J ) 4.9 Hz, 1 H), 6.40
(d, J ) 5.3 Hz, 1 H), 7.05 (s, 1 H), 7.46-7.51 (m, 3 H), 7.74 (d,
J ) 8.5 Hz, 1 H), 7.84 (dd, J ) 8.5 Hz, 1.6 Hz, 1 H), 7.89-7.92
(m, 2 H), 8.23 (d, J ) 1.3 Hz, 1 H), 10.06 (s, 1 H); 13C NMR (75
MHz, DMSO-d6) ∂ 10.45, 62.51, 62.59, 104.16, 111.98, 124.28,
125.42, 125.62, 126.94, 128.65, 129.10, 130.30, 132.12, 136.75,
146.07, 157.59, 158.56, 160.84, 192.47; IR (KBR) ν 1045, 1260,
1695 (s). Anal. (C20H15NO4) C, H, N.
5-{[2-[Hyd r oxy(5-m eth yl-2-p h en yloxa zol-4-yl)m eth yl]-
ben zofu r a n -5-yl]m eth ylen e}th ia zolid in e-2,4-d ion e (31).
A solution 2-[hydroxy(5-methyl-2-phenyloxazol-4-yl)methyl]-
benzofuran-5-carbaldehyde 30 (1.0 g, 3.0 mmol), 2,4-thiazo-
lidinedione (0.53 g, 4.5 mmol), and piperidine (5 drops) in
ethanol (25 mL) was heated to reflux overnight. The solution
was cooled, and the precipitated solid was filtered (0.75 g, 58%,
mp > 250 °C): 1H NMR (300 MHz, DMSO-d6) ∂ 2.35 (s, 3 H),
5.90 (d, J ) 4 Hz, 1 H), 6.3 (d, J ) 4 Hz, 1 H), 7.0 (s, 1 H),
7.4-7.6 (m, 4 H), 7.7 (d, J ) 8 Hz, 1 H), 7.9-7.95 (m, 4 H),
12.5 (s, 1 H); MS (CI, NH3) m/e 433 (M+ + 1), 194, 178, 153;
IR (KBr) ν (cm-1) 1275, 1589, 1654, 1690 (s), 1747. Anal.
(C23H16N2O5S) C, H, N.
5-{[2-[(5-Meth yl-2-p h en yloxa zol-4-yl)m eth yl]-5-ben zo-
fu r a n yl]m eth yl}-2,4-th ia zolid in ed ion e (3). To a slurry of
5-{[2-[hydroxy(5-methyl-2-phenyloxazol-4-yl)methyl]benzofu-
ran-5-yl]methylene}thiazolidine-2,4-dione (31) (0.75 g, 1.7
mmol) in methanol (15 mL) and THF (15 mL) was added 3%
sodium amalgam (5 g). The mixture was stirred for 1 h and
then decanted. The residue was rinsed with methanol, and

3902 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Hulin et al.
Sch em e 5a
a
(a) Ph3PdCHCHO, toluene, ∆; (b) H2, Pd-C, EtOAc; (c) EtOH, Amberlyst-15, ∆; (d) TMSCN, BF3‚Et2O, CH2Cl2; (e) NaOH, H2O,
EtOH, ∆.
Sch em e 6a
a
i
(a) (COCl)2, (R)-(-)-D-phenylglycinol, benzene; (b) separation; (c) pTsOH, PrOH, H2O.
Sch em e 7a
a
(a) nBuLi, EtOCH2COCl, THF, -78 °C; (b) Bu2BOTf, Et3N, 32, CH2Cl2, 0 °C; (c) Et3SiH, TFA; (d) LiOH, THF, H2O.
the combined solutions were concentrated. The residue was
slurried in 0.1 N hydrochloric acid (60 mL) and extracted with
chloroform (2 × 70 mL). The combined extracts were washed
with water (30 mL) and brine (30 mL), dried over sodium
sulfate, and concentrated. The product was purified by flash
chromatography (hexane/ethyl acetate, 1:1) and obtained as
a white solid (0.46 g): mp 182 °C dec. To a solution of this
product (0.23 g, 0.53 mmol) in trifluoroacetic acid (3 mL) was
added triethylsilane (0.21 mL, 1.3 mmol). The solution was
heated to reflux for 1 h, then diluted with ethyl acetate (50
mL), washed with water (2 × 30 mL) and carefully with
saturated sodium bicarbonate (2 × 30 mL), water (30 mL), and
brine (30 mL), dried over sodium sulfate, and concentrated.
The tacky solid was recrystallized from ethanol (8-10 mL) and
water (a few drops) to give white crystals (110 mg, 15%, mp
160-161 °C): 1H NMR (300 MHz, DMSO-d6) ∂ 2.39 (s, 3 H),
3.17 (dd, J ) 14.2 Hz, 9.2 Hz, 1 H), 3.44 (dd, J ) 14.0 Hz, 4.5
Hz, 1 H), 4.06 (s, 2 H), 4.92 (dd, J ) 9.2 Hz, 4.3 Hz, 1 H), 6.62
(s, 1 H), 7.10 (dd, J ) 8.1 Hz, 1.7 Hz, 1 H), 7.39-7.50 (m, 5
H), 7.88-7.92 (m, 2 H); 13C NMR (75 MHz, DMSO-d6) ∂ 9.9,
25.1, 37.1, 53.3, 103.3, 110.7, 121.2. 124.9, 125.5, 127.0, 128.6,
129.1, 130.2, 131.3, 131.8, 145.3, 153.4, 156.7, 158.6, 171.7,
175.7; HRMS calcd 418.0987, found 418.0925; IR (KBr) ν 707,
1708, 1751. Anal. (C23H18N2O4S‚1/2H2O) C, H, N.
Syn th esis of (E)-3-[2-[(5-Meth yl-2-p h en yloxa zol-4-yl)-
m eth yl]ben zofu r a n -5-yl]a cr ylic Acid (10) a n d 3-[2-[(5-
Meth yl-2-p h en yloxa zol-4-yl)m eth yl]ben zofu r a n -5-yl]p r o-
p ion ic Acid (9): N-(1-Acetylbu t-3-yn yl)ben za m id e 34.
Acetic anhydride (150 mL) was added to a solution of 2-(ben-
zoylamino)-4-pentynoic acid26 (33) (73 g, 0.34 mol) in pyridine
(200 mL), and the solution was heated to 90 °C for 1 h and
then allowed to cool to 60 °C, and water (150 mL) was added.
The mixture was heated to 85-90 °C for 20 min, then cooled,
diluted with water (300 mL), and extracted with chloroform
(2 × 400 mL). The combined extracts were washed with water,
1 N hydrochloric acid (3 × 500 mL), sodium bicarbonate, and
brine and dried over magnesium sulfate. The chloroform
solution was decolorized with charcoal, filtered, and concen-
trated. The residue was recrystallized from butyl chloride to
yield a tan solid (51 g, 70%, mp 101-103 °C): 1H NMR (300

Activity of Ciglitazone-Related Carboxylic Acids
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 3903
MHz, DMSO-d6) ∂ 2.16 (s, 3 H), 2.61 (ddd, J ) 17.0 Hz, 8.9
Hz, 2.6 Hz, 1 H), 2.74 (ddd, J ) 17.0 Hz, 5.4 Hz, 2.7 Hz, 1 H),
2.86 (t, J ) 2.6 Hz, 1 H), 4.55 (m, 1 H), 7.47-7.58 (m, 3 H),
7.90 (dd, J ) 7.7 Hz, 1,6 Hz, 2 H), 8.95 (d, J ) 7.6 Hz, 1 H);
13C NMR (75 MHz, DMSO-d6) ∂ 19.23, 26.81, 57.78, 72.77,
81.08, 127.44, 128.42, 131.65, 133.68, 133.72, 166.54, 205.39;
MS (EI) m/e 172, 105, 77; IR (KBr) ν (cm-1) 720, 1486, 1517,
1645, 1725, 3215, 3400. Anal. (C13H13NO2) C, H, N.
was cooled and diluted with ethyl acetate (300 mL), and the
solid was collected, washed with chloroform (2 × 100 mL), and
dried (56 g, 85%, mp 233-234 °C): 1H NMR (300 MHz, DMSO-
d6) ∂ 2.75 (s, 3 H), 7.5-7.6 (m, 3 H), 7.96 (d, J ) 9.3 Hz, 1 H),
8.1 (m, 2 H), 8.35 (dd, J ) 8.7 Hz, 1.5 Hz, 1 H), 8.85 (s, 1 H),
8.89 (d, J ) 1.1 Hz, 1 H); HRMS calcd 348.0747, found
348.0767; IR (KBr) ν (cm-1) 710, 960, 1350, 1520, 1650. Anal.
(C19H12N2O5) C, H, N.
5-Meth yl-2-p h en yl-4-p r op -2-yn yloxa zole (35). A solu-
tion of N-(1-acetylbut-3-ynyl)benzamide (34) (30 g, 0.14 mol)
in trifluoroacetic anhydride (100 mL) and trifluoroacetic acid
(200 mL) was heated to 35-40 °C for 6 h. The solution was
concentrated and the residue taken up in ethyl acetate (400
mL). To this solution was added saturated sodium bicarbonate
solution (400 mL) followed by solid sodium bicarbonate until
the water layer became neutral. The layers were separated,
the organic layer was washed with brine, dried over magne-
sium sulfate, and concentrated to give a brown oil (28 g, 100%)
which was used as such: 1H NMR (300 MHz, CDCl3) ∂ 2.12
(t, J ) 2.8 Hz, 1 H), 2.41 (d, J ) 0.6 Hz, 3 H), 3.50 (dd, J ) 2.8
Hz, 0.7 Hz, 2 H), 7.39-7.43 (m, 3 H), 7.96-7.99 (m, 2 H).
2-[(5-Meth yl-2-ph en yloxazol-4-yl)m eth yl]-5-ben zofu r an -
ca r boxa ld eh yd e (32). To a slurry of cuprous oxide (12 g, 84
mmol) in pyridine (150 mL) was added a solution of 5-methyl-
2-phenyl-4-prop-2-ynyloxazole (35) in pyridine (150 mL) fol-
lowed by a solution of 4-hydroxy-3-iodobenzaldehyde (35 g, 0.14
mol) in pyridine (100 mL). Bis(triphenylphosphine)palladium-
(II) chloride (0.50 g, 0.7 mmol) was then added as a solid, and
the mixture was heated to reflux overnight. The mixture was
cooled and concentrated. The residue was taken up in ethyl
acetate (250 mL + 3 × 50 mL). The ethyl acetate solution
was concentrated, and the residue was extracted with hot
cyclohexane. The hot solution was filtered and cooled, and the
solid was collected (29 g, 65%). Physical and spectroscopic
properties were identical to those reported previously.11a
(E)-3-[2-[(5-Meth yl-2-p h en yloxa zol-4-yl)m eth yl]ben zo-
fu r a n -5-yl]a cr ylic Acid (10). A solution of 2-[(5-methyl-2-
phenyloxazol-4-yl)methyl]-5-benzofurancarboxaldehyde (32)
(1.0 g, 3.2 mmol), malonic acid (0.36 g, 3.5 mmol), and pyridine
(0.5 mL, 6.4 mmol) in ethanol (5 mL) was heated to reflux for
24 h, then diluted with water, and acidified with 6 N HCl.
The yellow precipitate was collected, washed with water, and
dried (0.94 g, 82%, mp 233-234 °C (acetic acid)): 1H NMR
(300 MHz, DMSO-d6) ∂ 2.39 (s, 3 H), 4.09 (s, 2 H), 6.47 (d, J )
16.2 Hz, 1 H), 6.68 (s, 1 H), 7.46-7.60 (m, 6 H), 7.66 (d, J )
16.2 Hz, 1 H), 7.86-7.91 (m, 2 H), 12.3 (s, 1 H); 13C NMR (75
MHz, DMSO-d6) ∂ 9.83, 25.03, 103.61, 111.34, 121.07, 123.99,
125.53, 127.02, 129.07, 129.34, 130.19, 131.66, 144.63, 145.34,
155.29, 157.41, 158.63; MS (CI, NH3) m/e 388 (M+ + 18), 360
(M+ + 1), 319, 318, 316, 194, 153; IR (KBr) ν (cm-1) 1294, 1311,
1319, 1632 (s), 1675 (s). Anal. (C22H17NO4) C, H, N.
3-[2-[(5-Meth yl-2-ph en yloxazol-4-yl)m eth yl]ben zofu r an -
5-yl]p r op ion ic Acid (9). A solution of (E)-3-[2-[(5-methyl-
2-phenyloxazol-4-yl)methyl]benzofuran-5-yl]acrylic acid (10)
(115 mg, 0.32 mmol) in methanol (10 mL) containing platinum
oxide (23 mg) was placed in a Parr apparatus, and the mixture
was hydrogenated at 50 psi for 3 h. The catalyst was filtered
over diatomaceous earth, and the solution was concentrated
to a yellow oil. The product was purified by flash chromatog-
raphy (hexane/ethyl acetate, 1:1, 1% acetic acid) and obtained
as a yellow solid (106 mg, 92%, mp 122-124 °C): 1H NMR
(300 MHz, CDCl3) ∂ 2.33 (s, 3 H), 2.66 (t, J ) 7.7 Hz, 2 H),
2.99 (t, J ) 7.7 Hz, 2 H), 4.01 (s, 2 H), 6.40 (s, 1 H), 7.03 (dd,
J ) 8.4, 1.6 Hz, 1 H), 7.29 (s, 1 H), 7.30 (d, J ) 9.2 Hz, 1 H),
7.39-7.44 (m, 3 H), 7.96-7.99 (m, 2 H); 13C NMR (75 MHz,
CDCl3) ∂ 10.2, 25.8, 30.6, 36.3, 103.3, 110.8, 119.9, 123.9, 126.1,
127.4, 128.7, 129.0, 130.0, 131.7, 134.6, 145.1, 153.7, 156.0,
159.7, 178.1; MS (CI, NH3) m/e 390 (M+ + 18), 362 (M+ + 1),
320, 318, 181, 164; IR (KBr) ν (cm-1) 1193, 1254, 1441, 1641,
1695 (s), 1720 (s). Anal. (C22H19NO4‚1/2H2O) C, H, N.
(5-Met h yl-2-p h en yloxa zol-4-yl)(5-n it r ob en zofu r a n -2-
yl)m eth a n ol (38). (5-Methyl-2-phenyloxazol-4-yl)(5-nitroben-
zofuran-2-yl)methanone (37) (56 g, 0.16 mol) was placed in
THF (600 mL), and methanol (300 mL) and the slurry was
cooled to 0 °C. Sodium borohydride (9.1 g, 0.24 mol) was added
portionwise over 1 h, and the cloudy solution was stirred at 0
°C for 2 h. The bulk of the solvent was removed in vacuo,
and water (700 mL) was added. The mixture was acidified
with 6 N hydrochloric acid and stirred for 30 min. The yellow-
tan solid was collected, washed with water, and dried (57 g,
100%, mp 196-197 °C): 1H NMR (300 MHz, DMSO-d6) ∂ 2.45
(s, 3 H), 5.96 (d, J ) 4.3 Hz, 1 H), 6.42 (d, J ) 5.2 Hz, 1 H),
7.08 (s, 1 H), 7.47-7.50 (m, 3 H), 7.78 (d, J ) 9.2 Hz, 1 H),
7.88-7.91, (m, 2 H), 8.16 (dd, J ) 8.8 Hz, 2.8 Hz, 1 H), 8.60
(d, J ) 2.2 Hz, 1 H); 13C NMR (75 MHz, DMSO-d6) ∂ 10.2,
62.5, 104.6, 112.0, 117.7, 119.9, 125.6, 126.9, 128.7, 129.1,
130.3, 135.6, 143.7, 146.2, 157.2, 158.6, 162.2; HRMS calcd
350.0902, found 350.1106; IR (KBr) ν (cm-1) 1263, 1346, 1449,
3202.
5-Meth yl-4-[(5-n itr oben zofu r a n -2-yl)m eth yl]-2-p h en y-
loxa zole (39). (5-Methyl-2-phenyloxazol-4-yl)(5-nitrobenzo-
furan-2-yl)methanol (38) (57 g, 0.16 mol) was dissolved in
trifluoroacetic acid (350 mL), while cooling to 0 °C. Triethyl-
silane (64 mL, 0.40 mol) was added. The solution was stirred
1.5 h at 0 °C and overnight at room temperature. The solution
was concentrated to near dryness and the residue dissolved
in ethyl acetate (750 mL). This solution was washed with
water. The precipitate formed during the wash was collected.
The organic solution was washed with saturated sodium
bicarbonate, during which more precipitate formed and was
collected. The ethyl acetate phase of the filtrate was washed
again with saturated sodium bicarbonate and then with brine,
dried over sodium sulfate, and concentrated. The residue was
triturated with isopropyl ether, and the collected solids were
combined (51 g, 95%, mp 132-133 °C): 1H NMR (300 MHz,
DMSO-d6) ∂ 2.41 (s, 3 H), 4.16 (s, 2 H), 6.90 (s, 1 H), 7.47-
7.51 (m, 3 H), 7.76 (d, J ) 8.9 Hz, 1 H), 7.88-7.91 (m, 2 H),
8.14 (dd, J ) 9.1 Hz, 2.5 Hz, 1 H), 8.52 (d, J ) 2.2 Hz, 1 H);
13C NMR (75 MHz, DMSO-d6) ∂ 9.8, 25.0, 104.5, 111.7, 117.1,
119.5, 126.5, 127.0, 129.1, 130.3, 131.2, 143.7, 145.6, 157.2,
158.7, 159.9; HRMS calcd 334.0953, found 334.0890; IR (KBr)
ν (cm-1) 705, 1347, 1451, 1514.
2-[(5-Meth yl-2-p h en yloxa zol-4-yl)m eth yl]ben zofu r a n -
5-yla m in e (36). 5-Methyl-4-[(5-nitrobenzofuran-2-yl)methyl]-
2-phenyloxazole (39) (51 g, 0.15 mol) was placed in a Parr
bottle together with platinum oxide (3 g) and ethyl acetate (1.5
L), and the mixture was hydrogenated at 40 psi for 1.25 h.
The catalyst was filtered through diatomaceous earth, and
after washing the filtering pad with more ethyl acetate, the
solvent was removed in vacuo to give a yellow residue which
was triturated with isopropyl ether (200 mL). The pale yellow
solid was collected (37.1 g, 80%, mp 161.5-162.5 °C): 1H NMR
(300 MHz, DMSO-d6) ∂ 2.36 (s, 3 H), 3.97 (s, 2 H), 4.75 (s, 2
H), 6.38 (s, 1 H), 6.48 (dd, J ) 8.5 Hz, 2.4 Hz, 1 H), 6.63 (d, J
) 1.9 Hz, 1 H), 7.13 (d, J ) 8.3 Hz, 1 H), 7.47-7.49 (m, 3 H),
7.88-7.91 (m, 2 H); 13C NMR (75 MHz, DMSO-d6) ∂ 9.84, 25.2,
103.0, 103.9, 110.6, 111.8, 125.5, 127.1, 129.1, 130.2, 132.1,
144.4, 145.1, 147.6, 155.6, 158.5; HRMS calcd 304.1211, found
304.1232; IR (KBr) ν (cm-1) 707, 784, 1208, 1481, 3310, 3436.
Anal. (C19H16N2O2) C, H, N.
2-Br om o-3-[2-[(5-m eth yl-2-p h en yloxa zol-4-yl)m eth yl]-
ben zofu r a n -5-yl]p r op ion ic Acid Eth yl Ester (40). To a
slurry of 2-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzofuran-
5-ylamine (36) (4.0 g, 13 mmol) in methanol (30 mL) and
acetone (30 mL), cooled to -10 °C, was added 48% aqueous
HBr (5.95 mL, 53 mmol). The mixture was stirred at 0 °C for
5 min, and a solution of sodium nitrite (0.985 g, 14 mmol) in
water (3 mL) was added dropwise so as to keep the reaction
temperature below 5 °C. The mixture was stirred at 0-5 °C
Syn th esis of 3-[2-[(5-Meth yl-2-p h en yloxa zol-4-yl)m eth -
yl]ben zofu r an -5-yl]-2-(pr opylsu lfan yl)pr opion ic Acid (13).
(5-Meth yl-2-p h en yloxa zol-4-yl)(5-n itr oben zofu r a n -2-yl)-
m eth a n on e 37. A solution of 4-(bromoacetyl)-5-methyl-2-
phenyloxazole27 (53 g, 0.19 mol), 5-nitrosalicylaldehyde (32 g,
0.19 mol), and diisopropylethylamine (66 mL, 0.38 mol) in
DMF (250 mL) was heated to 91-94 °C for 3 h. The mixture

3904 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Hulin et al.
for 15 min, and then ethyl acrylate (8.3 mL, 77 mmol) was
added dropwise. The mixture was warmed to 38 °C, powdered
copper(I) oxide (0.405 g, 2.8 mmol) was added, and the mixture
was stirred for 1 h, then made basic with concentrated aqueous
ammonia, and extracted with ethyl acetate (2×). The com-
bined extracts were washed with water (2X) and brine, dried
over magnesium sulfate, and concentrated. The product was
isolated by flash chromatography (hexane/ethyl acetate, 7:1)
as a yellow solid (1.78 g, 29%, mp 129-130 °C): 1H NMR (300
MHz, DMSO-d6) ∂ 1.10 (t, J ) 7.1 Hz), 2.38 (s, 3 H), 3.23 (dd,
J ) 13.8 Hz, 7.2 Hz, 1 H), 3.42 (dd, J ) 14.0 Hz, 8.1 Hz, 1 H),
4.06 (s, 2 H), 4.08 (m, 2 H), 6.61 (s, 1 H), 7.14 (dd, J ) 8.6 Hz,
1.6 Hz, 1 H), 7.41-7.50 (m, 5 H), 7.88-7.91, (m, 2 H); 13C NMR
(75 MHz, DMSO-d6) ∂ 9.9, 13.7, 25.1, 46.7, 61.5, 103.3, 110.6,
121.2, 124.9, 125.5, 127.0, 128.6, 129.1, 130.2, 131.3, 131.8,
145.3, 153.4, 156.6, 158.6, 169.0; HRMS calcd 469.0699, found
ane/ethyl acetate, 4:1) as a solid (14 g, 41%, mp 86-90 °C):
1H NMR (300 MHz, CDCl3) ∂ 2.32 (s, 3/2 H), 2.34 (s, 3/2 H), 3.67
3
3
1
(s, /2 H), 3.76 (s, /2 H), 4.01 (s, 2 H), 5.27 (d, J ) 7.1 Hz, /2
H), 5.88 (d, J ) 12.9 Hz, 1/2 H), 6.09 (d, J ) 7.0 Hz, 1/2 H), 6.42
1
(d, J ) 6.6 Hz, 1 H), 6.98 (d, J ) 12.9 Hz, /2 H), 7.09 (dd, J )
8.6 Hz, 1.7 Hz, 1/2 H), 7.28-7.32 (m, 2 H), 7.39-7.44 (m, 3 H),
1
7.73 (d, J ) 1.7 Hz, /2 H), 7.96-8.00 (m, 2 H); 13C NMR (75
MHz, CDCl3) ∂ 10.26, 26.01, 26.04, 56.49, 60.53, 103.34, 103.59,
105.41, 105.96, 110.39, 110.88, 116.80, 120.04, 121.16, 124.39,
126.01, 127.70, 128.66, 128.86, 129.26, 129.86, 129.89, 130.67,
131.01, 131.80, 13.87, 145.00, 146.62, 147.97, 153.33, 153.63,
155.79, 156.12, 159.55, 159.59; MS (CI, NH3) m/e 347, 346 (M+
+ 1); IR (KBr) ν (cm-1) 1087, 1149, 1643 (s).
4-[5-[(2,2-Dim eth oxyeth yl)ben zofu r a n -2-yl]m eth yl]-5-
m eth yl-2-p h en yloxa zole (42, R ) Me). A solution of 4-[[5-
(2-methoxyvinyl)benzofuran-2-yl]methyl]-5-methyl-2-pheny-
loxazole (41) (0.69 g, 2.0 mmol) and p-toluenesulfonic acid
monohydrate (40 mg, 0.21 mmol) in methanol (30 mL) was
heated to reflux overnight. The solvent was removed, the
residue was taken up in ethyl acetate, and the solution was
washed with 5% sodium bicarbonate and brine, dried over
magnesium sulfate, and concentrated to an oil which slowly
solidified on standing (0.75 g, 100%): 1H NMR (CDCl3, 300
MHz) ∂ 2.35 (s, 3 H), 2.96 (d, J ) 5.6 Hz, 2 H), 3.32 (s, 6 H),
4.01 (s, 2 H), 4.53 (t, J ) 5.6 Hz, 1 H), 6.43 (d, J ) 0.8 Hz, 1
H), 7.08 (dd, J ) 8.5 Hz, 1.7 Hz, 1 H), 7.31-7.34 (m, 2 H),
7.40-7.44 (m, 3 H), 7.97-8.00 (m, 2 H).
2-Meth oxy-3-[2-[(5-m eth yl-2-ph en yloxazol-4-yl)m eth yl]-
ben zofu r a n -5-yl]p r op ion itr ile (43, R ) Me). To a solution
of 4-[[5-(2,2-dimethoxyethyl)benzofuran-2-yl]methyl]-5-methyl-
2-phenyloxazole (42, R ) Me) (0.75 g, 2.0 mmol) in dichlo-
romethane (15 mL) were added trimethylsilyl cyanide (0.80
mL, 6.0 mmol) and boron trifluoride etherate (50 µL, 0.5
mmol). After 1 h the solution was diluted with dichlo-
romethane, washed with 5% sodium bicarbonate, water, and
brine, dried over magnesium sulfate, and concentrated. The
product was purified by flash chromatography (hexane/ethyl
acetate, 2:1) and isolated as a solid (0.64 g, 86%, mp 107-109
°C): 1H NMR (300 MHz, CDCl3) ∂ 2.35 (s, 3 H), 3.16 (d, J )
6.9 Hz, 1 H), 3.16 (d, J ) 6.7 Hz, 1 H), 3.46 (s, 3 H), 4.02 (s, 2
H), 4.19 (t, J ) 6.8 Hz, 1 H), 6.45 (d, J ) 0.7 Hz, 1 H), 7.10
(dd, J ) 8.4 Hz, 1.8 Hz, 1 H), 7.34-7.44 (m, 5 H), 7.97-8.00
(m, 2 H); MS (EI) m/z 372 (M+), 302, 104, 43.
2-Meth oxy-3-[2-[(5-m eth yl-2-ph en yloxazol-4-yl)m eth yl]-
ben zofu r a n -5-yl]p r op ion ic Acid (17). A mixture of 2-meth-
oxy-3-[2-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzofuran-5-
yl]propionitrile (43, R ) Me) (0.64 g, 1.7 mmol), ethanol (30
mL), and 6 N sodium hydroxide (10 mL) was heated to reflux
for 3 h. Water (30 mL) was added, and the solution was
acidified with concentrated hydrochloric acid (6 mL) and then
extracted with ethyl acetate (2×). The combined organic layers
were washed with brine, dried over magnesium sulfate, and
concentrated. The product was recrystallized from ethyl
acetate/hexane and obtained as a white solid (0.47 g, 71%, mp
159-160.5 °C): 1H NMR (300 MHz, DMSO-d6) ∂ 2.40 (s, 3 H),
2.93 (dd, J ) 14.0 Hz, 7.8 Hz, 1 H), 3.03 (dd, J ) 14.0 Hz, 4.9
Hz, 1 H), 3.22 (s, 3 H), 3.93 (dd, J ) 7.8 Hz, 5.0 Hz, 1 H), 4.07
(s, 2 H), 6.61 (s, 1 H), 7.09 (dd, J ) 8.4 Hz, 1.7 Hz, 1 H), 7.38
(s, 1 H),7.39 (d, J ) 8.7 Hz, 1 H), 7.48-7.52 (m, 3 H), 7.90-
7.93 (m, 2 H); 13C NMR (75 MHz, DMSO-d6) ∂ 9.9, 25.1, 38.2,
57.3, 81.1, 103.3, 110.3, 121.0, 125.0, 127.0, 128.4, 129.1, 130.2,
131.8, 131.9, 145.3, 153.2, 156.3, 158.6, 172.9; MS (EI) m/e 391
(M+), 302, 172, 128, 105, 104; IR (KBr) ν (cm-1) 690, 715, 1060,
1200, 1735 (s). Anal. (C23H21NO5‚1/2H2O) C, H, N.
Syn th esis of 2-Eth oxy-4-[2-[(5-m eth yl-2-p h en yloxa zol-
4-yl)m eth yl]ben zofu r a n -5-yl]bu tyr ic Acid (28): 3-[2-[(5-
Meth yl-2-p h en yloxa zol-4-yl)m eth yl]ben zofu r a n -5-yl]p r o-
pion aldeh yde (44). A solution of 2-[(5-methyl-2-phenyloxazol-
4-yl)methyl]-5-benzofurancarbaldehyde (32) (3.2 g, 10 mmol)
and (formylmethylene)triphenylphosphorane (4.6 g, 15 mmol)
in toluene (70 mL) was heated to reflux for 48 h. The solvent
was removed, and the product was purified by flash chroma-
tography (hexane/ethyl acetate, 2:1). The product (1.2 g) was
placed in a Parr shaker together with 10% palladium on carbon
(0.12 g) and ethyl acetate (100 mL) and hydrogenated at 40
psi. After 2 h, the catalyst was filtered over Diatomaceous
earth, the filtrate was concentrated, and the products were
469.0618; IR (KBr) ν 704, 1023, 1261, 1719. Anal. (C24H22
BrNO4) C, H, N.
-
3-[2-[(5-Meth yl-2-ph en yloxazol-4-yl)m eth yl]ben zofu r an -
5-yl]-2-(p r op ylsu lfa n yl)p r op ion ic Acid Eth yl Ester . To
a
solution of 2-bromo-3-[2-[(5-methyl-2-phenyloxazol-4-yl)-
methyl]benzofuran-5-yl]propionic acid ethyl ester (40) (5 g, 12
mmol) in DMF (100 mL) was added propyl mercaptan (3.0 mL,
33 mmol), followed by potassium carbonate (4.6 g, 33 mmol).
The slurry was stirred at room temperature overnight, then
poured into water (400 mL), acidified with 6 N hydrochloric
acid, and extracted with ethyl acetate (2 × 300 mL). The
combined extracts were washed with water (3 × 200 mL) and
brine, dried over sodium sulfate, and concentrated, leaving a
yellow oil (4.3 g, 87%): 1H NMR (300 MHz, CDCl3) ∂ 0.93 (t,
J ) 7.5 Hz, 3 H), 1.15 (t, J ) 7.0 Hz, 3 H), 1.56 (m, 2 H), 2.32
(s, 3 H), 2.57 (m, 2 H), 2.99 (dd, J ) 6.4 Hz, 13.9 Hz, 1 H),
3.22 (dd, J ) 9.4 Hz, 13.6 Hz, 1 H), 3.48 (dd, J ) 6.4 Hz, 9.1
Hz, 1 H), 3.99 (s, 2 H), 4.08 (m, 2 H), 6.40 (d, J ) 1.1 Hz, 1 H),
7.03 (dd, J ) 1.6 Hz, 8.6 Hz, 1 H), 7.29 (s, 1 H), 7.29 (d, J )
7.8 Hz, 1 H), 7.37-7.42 (m, 3 H), 7.96-7.99 (m, 2 H).
3-[2-[(5-Meth yl-2-ph en yloxazol-4-yl)m eth yl]ben zofu r an -
5-yl]-2-(p r op ylsu lfa n yl)p r op ion ic Acid (13). To a solution
of 3-[2-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzofuran-5-yl]-
2-(propylsulfanyl)propionic acid ethyl ester (3.8 g, 8.2 mmol)
in methanol (100 mL) was added 1 N sodium hydroxide (100
mL). The mixture was heated to reflux for 2 h, cooled, poured
onto ice (300 mL), acidified with 6 N hydrochloric acid, and
then extracted with ethyl acetate (500 mL), during which some
precipitated solid was collected. The aqueous phase was
extracted again with ethyl acetate (200 mL), and the combined
extracts were washed with water (300 mL) and brine (300 mL),
dried over sodium sulfate, and concentrated, leaving a yellow-
orange solid. The solids were combined and recrystallized
from ethyl acetate (150 mL) to give the title compound as an
off-white solid (2.5 g, 70%, mp 169-170 °C): 1H NMR (300
MHz, DMSO-d6) ∂ 0.87 (t, J ) 7.5 Hz, 3 H), 1.50 (m, 2 H), 2.38
(s, 3 H), 2.57 (t, J ) 7.3 Hz, 2 H), 2.91 (dd, J ) 14 Hz, 6.2 Hz,
1 H), 3.11 (dd, J ) 14 Hz, 9.2 Hz, 1 H), 3.48 (dd, J ) 9.3 Hz,
6.2 Hz, 1 H), 4.05 (s, 2 H), 6.59 (s, 1 H), 7.10 (dd, J ) 8.6 Hz,
1.7 Hz, 1 H), 7.37-7.40 (m, 2 H), 7.46-7.49 (m, 3 H), 7.88-
7.92 (m, 2 H); 13C NMR (75 MHz, DMSO-d6) ∂ 9.9, 13.2, 22.3,
25.1, 32.9, 37.4, 48.0, 103.3, 110.4, 120.8, 124.7, 125.5, 127.1,
128.4, 129.1, 130.2, 131.9, 132.9, 145.2, 153.2, 156.4, 158.6,
173.1; MS (EI) m/e 435 (M+), 302, 260, 259, 186, 172, 104; IR
(KBr) ν 1160, 1225, 1470, 1550, 1710 (s). Anal. (C25H25NO4S)
C, H, N.
Syn th esis of 2-Meth oxy-3-[2-[(5-m eth yl-2-ph en yloxazol-
4-yl)m eth yl]ben zofu r a n -5-yl]p r op ion ic Acid (17): 4-[5-[(2-
Meth oxyvin yl)ben zofu r a n -2-yl)m eth yl]-5-m eth yl-2-p h e-
n yloxa zole (41). To
a slurry of (methoxymethyl)tri-
phenylphosphonium chloride (34 g, 0.10 mol) and diisopropy-
lamine (9.9 mL, 75 mmol) in THF (500 mL) was added a 2.5
M n-butyllithium solution in hexane (30 mL, 75 mmol), at -10
°C. After 1 h at -10 °C a solution of 2-[(5-methyl-2-pheny-
loxazol-4-yl)methyl]-5-benzofurancarbaldehyde (32) (16 g, 50
mmol) in THF (200 mL) was added. The mixture was allowed
to warm to room temperature over 2 h, then poured into water
(600 mL), and extracted with ether (3×). The combined
extracts were washed with brine, dried over magnesium
sulfate, and concentrated. The product (1:1 mixture of geo-
metrical isomers) was isolated by flash chromatography (hex-

Activity of Ciglitazone-Related Carboxylic Acids
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 3905
separated by flash chromatography (hexane/ethyl acetate, 3:1).
The expected product was obtained as a solid (0.28 g, 8%): 1H
NMR (300 MHz, CDCl3) ∂ 2.35 (s, 3 H), 2.78 (td J ) 8 Hz, 1
Hz, 2 H), 3.05 (t, J ) 8 Hz, 2 H), 4.05 (s, 2 H), 6.42 (s, 1 H),
7.00 (dd, J ) 8 Hz, 2 Hz, 1 H), 7.28 (d, J ) 2 Hz, 1 H), 7.32 (d,
J ) 8 Hz, 1 H), 7.38-7.44 (m, 3 H), 7.95-8.01 (m, 2 H), 9.70
(t, J ) 1 Hz, 1 H); MS (EI) m/e 345 (M+), 302, 172, 151, 115,
105, 104, 77.
4-[[5-(3,3-Dieth oxyp r op yl)ben zofu r a n -2-yl]m eth yl]-5-
m eth yl-2-p h en yloxa zole (46). A solution 3-[2-[(5-methyl-
2-phenyloxazol-4-yl)methyl]benzofuran-5-yl]propionaldehyde
(44) (0.27 g, 0.78 mmol) in ethanol (20 mL) containing
Amberlyst-15 resin beads (20 mg) was heated to reflux for 2.5
h and then stirred at room temperature overnight. The
solution was filtered and concentrated to an oil (0.29 g, 89%):
1H NMR (300 MHz, CDCl3) ∂ 1.21 (t, J ) 9 Hz, 3 H), 1.95 (m,
2 H), 2.35 (s, 3 H), 2.74 (t, J ) 8 Hz, 2 H), 3.45 (m, 2 H), 3.62
(m, 2 H), 4.02 (s, 2 H), 4.48 (t, J ) 5 Hz, 1 H), 6.42 (s, 1 H),
7.00 (dd, J ) 8 Hz, 2 Hz, 1 H), 7.28-7.35 (m, 2 H), 7.38-7.44
(m, 3 H), 7.95-8.01 (m, 2 H).
2-Eth oxy-4-[2-[(5-m eth yl-2-p h en yloxa zol-4-yl)m eth yl]-
ben zofu r a n -5-yl]bu tyr on itr ile. This intermediate was pre-
pared from 4-[5-[(3,3-diethoxypropyl)benzofuran-2-yl]methyl]-
5-methyl-2-phenyloxazole (46) with TMSCN in an analogous
manner to that of 43: 1H NMR (300 MHz, CDCl3) ∂ 1.25 (t, J
) 7.0 Hz, 3 H), 2.13 (m, 2 H), 2.36 (s, 3 H), 2.87 (t, J ) 7.0 Hz,
2 H), 3.44 (m, 2 H), 3.79 (m, 2 H), 3.99 (t, J ) 7.2 Hz, 1 H),
4.02 (s, 2 H), 6.43 (d, J ) 0.9 Hz, 1 H), 7.02 (dd, J ) 8.4 Hz,
1.8 Hz, 1 H), 7.27 (d, J ) 1.5 Hz, 1 H), 7.33 (d, J ) 8.3 Hz, 1
H), 7.40-7.44 (m, 3 H), 7.97-8.00 (m, 2 H).
2-Eth oxy-4-[2-[(5-m eth yl-2-p h en yloxa zol-4-yl)m eth yl]-
ben zofu r a n -5-yl]bu tyr ic Acid (28). A solution of 2-ethoxy-
4-[2-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzofuran-5-yl]-
butyronitrile (0.22 g, 0.55 mmol) in ethanol (5 mL) and sodium
hydroxide (15 mL) was heated to reflux for 7 h, then cooled,
diluted with water, acidified with concentrated hydrochloric
acid, and extracted with ethyl acetate (2×). The combined
extracts were washed with brine, dried over magnesium
sulfate, and concentrated. The solid was recrystallized in ethyl
acetate/hexane (87 mg, 38%, mp 137-138 °C): 1H NMR
(DMSO-d6, 300 MHz) ∂ 1.13 (t, J ) 6.9 Hz, 3 H), 1.90 (m, 2
H), 2.39 (s, 3 H), 2.71 (t, J ) 7.2 Hz, 2 H), 3.33 (m, 2 H), 3.55
(m, 2 H), 3.68 (dd, J ) 7.8 Hz, 4.6 Hz, 1 H), 4.06 (s, 2 H), 6.59
(s, 1 H), 7.05 (d, J ) 8.4 Hz, 1 H), 7.34 (s, 1 H), 7.40 (d, J )
8.4 Hz, 1 H), 7.48-7.50 (m, 3 H), 7.90-7.92 (m, 2 H), 12.65 (s,
1 H); 13C NMR (75 MHz, DMSO-d6) ∂ 9.9, 15.2, 25.1, 64.9, 77.0,
103.3, 110.5, 120.0, 124.2, 125.5, 127.0, 128.6, 129.1, 130.2,
131.9, 135.6, 145.3, 152.9, 156.3, 174.0; MS (EI) m/e 419 (M+),
303, 172, 151, 105, 104; IR (KBr) ν 715, 795, 1120, 1130, 1725
(s). Anal. (C25H25NO5‚0.5H2O) C, H, N.
Syn th esis of Eth oxy[2-[(5-m eth yl-2-p h en yloxa zol-4-yl)-
m et h yl]b en zofu r a n -5-yl]a cet ic Acid (27): 4-[[5-(Di-
eth oxym eth yl)ben zofu r a n -2-yl]m eth yl]-5-m eth yl-2-p h e-
n yloxa zole (45). To a solution of 2-[(5-methyl-2-phenyloxazol-
4-yl)methyl]-5-benzofurancarbaldehyde (32) (0.63 g, 2.0 mmol)
and ethyl orthoformate (1.7 mL, 10 mmol) in methylene
chloride (5 mL) was added Amberlyst 15 resin (55 mg). The
mixture was heated to reflux for 2 h, filtered, and concentrated
to give a yellow oil. The product was purified by flash
chromatography (hexane/ethyl acetate, 4:1) and obtained as
a low-melting solid (0.54 g, 69%): 1H NMR (CDCl3, 300 MHz)
∂ 1.22 (t, J ) 7.0 Hz, 3 H), 2.34 (s, 3 H), 3.46-3.59 (m, 4 H),
4.02 (s, 2 H), 5.55 (s, 1 H), 6.47 (d, J ) 0.8 Hz, 1 H), 7.32 (dd,
J ) 8.5 Hz, 1.6 Hz, 1 H), 7.37-7.44 (m, 4 H), 7.59 (d, J ) 1.6
Hz, 1 H), 7.97-8.00 (m, 2 H).
Eth oxy[2-[(5-m eth yl-2-p h en yloxa zol-4-yl)m eth yl]ben -
zofu r a n -5-yl]a ceton itr ile. To a mixture of 4-[(5-(diethoxym-
ethyl)benzofuran-2-yl)methyl]-5-methyl-2-phenyloxazole (45)
(0.54 g, 1.4 mmol) and trimethylsilyl cyanide (3 mL, 22.5
mmol) was added boron trifluoride etherate (20 µL, 0.16 mmol).
After 15 min the reaction was quenched with saturated
NaHCO3, and ethyl acetate was added. The organic layer was
separated, washed with brine, dried over magnesium sulfate,
and concentrated. The product was purified by flash chroma-
tography (hexane/ethyl acetate, 4:1) and obtained as an oil
(0.38 g, 74%): 1H NMR (300 MHz, CDCl3) ∂ 1.28 (t, J ) 7.0
Hz, 3 H), 2.35 (s, 3 H), 3.64 (m, 2 H), 3.81 (m, 2 H), 4.04 (s, 2
H), 5.30 (s, 1 H), 6.51 (d, J ) 0.9 Hz, 1 H), 7.33 (dd, J ) 8.5
Hz, 1.9 Hz, 1 H), 7.40-7.46 (m, 4 H), 7.62 (d, J ) 1.8 Hz, 1
H), 7.97-8.00 (m, 2 H).
Eth oxy[2-[(5-m eth yl-2-p h en yloxa zol-4-yl)m eth yl]ben -
zofu r a n -5-yl]a cetic Acid (27). A solution of ethoxy[2-[(5-
methyl-2-phenyloxazol-4-yl)methyl]benzofuran-5-yl]acetoni-
trile (0.38 g, 1.0 mmol) in ethanol (15 mL) and 6 N NaOH (5
mL) was heated to reflux for 3 h, diluted with ethyl acetate
(50 mL) and water (30 mL), and acidified with concentrated
HCl (3 mL). The layers were separated, the aqueous layer
was extracted with ethyl acetate, and the combined organic
phases were washed with brine, dried over magnesium sulfate,
and concentrated. The product was recrystallized from ethyl
acetate/hexane and obtained as a white solid (0.28 g, 69%, mp
167-169 °C): 1H NMR (300 MHz, DMSO-d6) ∂ 1.15 (t, J )
7.0 Hz, 3 H), 2.40 (s, 3 H), 3.42 (m, 2 H), 3.56 (m, 2 H), 4.02 (s,
2 H), 4.91 (s, 1 H), 6.69 (s, 1 H), 7.27 (dd, J ) 8.5 Hz, 1.6 Hz,
1 H), 7.48-7.50 (m, 4 H), 7.59 (s, 1 H), 7.90-7.93 (m, 2 H),
12.75 (s, 1 H); 13C NMR (75 MHz, DMSO-d6) ∂ 9.9, 15.1, 25.1,
64.2, 80.1, 103.5, 110.6, 119.5, 122.9, 125.5, 127.0, 128.5, 129.1,
130.2, 131.8, 132.2, 145.3, 154.0, 156.8, 158.6, 172.3; MS (EI)
m/e 391 (M+), 346, 172, 159, 104; IR (KBr) ν 720, 795, 1120,
1185, 1730 (s). Anal. (C23H21NO5‚0.5H2O) Calcd: C, 68.98;
H, 5.54; N, 3.50. Found: C, 69.80; H, 5.45; N, 3.54.
Op tica l Resolu tion of 3-[2-[(5-Meth yl-2-p h en yloxa zol-
4-yl)m et h yl]b en zofu r a n -5-yl]-2-(p r op ylsu lfa n yl)p r op i-
on ic Acid (13). To a slurry of 3-[2-[(5-methyl-2-phenyloxazol-
4-yl)methyl]benzofuran-5-yl]-2-(propylsulfanyl)propionic acid
(13) (1.6 g, 3.8 mmol) in benzene (35 mL) was added oxalyl
chloride (1.8 mL, 21 mmol). Gas was evolved and the slurry
turned into a clear yellow solution within 10 min. After 2 h
the solvent was removed, and the residue was dissolved in
dioxane (25 mL) and added dropwise to a solution of (S)-(+)-
2-phenylglycinol (0.52 g, 3.8 mmol) and triethylamine (0.53
mL) in dioxane (10 mL). After 2 h, the solvent was removed,
water was added to the residue, and the mixture was acidified
with 6 N hydrochloric acid. The solid was collected, dried, and
recrystallized from ethyl acetate/hexane then from ethyl
acetate to give the less polar isomer 47l (on silica gel thin-
layer chromatography, hexane/ethyl acetate, 1:2) as a pale
yellow solid (0.41 g). The combined mother liquors were
concentrated and the products separated by flash chromatog-
raphy (hexane/ethyl acetate, 1:1). More of 47l was thus
obtained (total yield 0.55 g, 26%) as well as the more polar
isomer 47m (0.39 g, 19%).
The less polar amide 47l (0.54 g, 0.97 mmol) and p-
toluenesulfonic acid (2.8 g, 15 mmol) were placed in water (20
mL) and 2-propanol (20 mL) and heated to reflux for 3 days.
The solution was cooled, diluted with water (75 mL), and
extracted with ethyl acetate (2 × 75 mL). The combined
extracts were washed with water (2 × 75 mL) and brine (75
mL), dried over sodium sulfate, and concentrated. The product
was purified by flash chromatography (hexane/ethyl acetate/
acetic acid, 16:4:1), then recrystallized from ethyl acetate (15
mL)/hexane (5 mL). The mother liquor was concentrated to
give a white solid (+)-13 (83 mg, [R]D ) +8.8° (c 1.08, CDCl3)).
This material was subsequently found to be >95% optically
pure by conversion back to the amide under neutral conditions
(EEDQ), and its NMR spectrum was identical to the one of
the racemic material.
In the same manner the more polar amide 47m (0.39 g, 0.71
mmol) was converted into the levorotatory acid (-)-13 (81 mg,
[R]D ) -9.4° (c 1.06, CDCl3)).
Syn th esis of (S)-2-Eth oxy-3-[2-[(5-m eth yl-2-p h en ylox-
a zol-4-yl)m eth yl]ben zofu r a n -5-yl]p r op ion ic Acid [(-)-
18]: (S)-4-Ben zyl-3-(eth oxya cetyl)oxa zolid in -2-on e (48).
To a solution of (S)-4-benzyloxazolidin-2-one (4.4 g, 25 mmol)
in dry THF (20 mL), cooled to -78 °C, was added n-butyl-
lithium (2.5 M solution in hexane, 10 mL, 25 mmol) dropwise.
Another 20 mL of THF was added to facilitate stirring.
A
solution of ethoxyacetyl chloride (3.0 g, 25 mmol) in THF (5
mL) was added, and the mixture was stirred at -78 °C for 30
min, then warmed to room temperature, poured into water,
and extracted with ethyl acetate (3×). The combined extracts
were washed with water and brine, dried over sodium sulfate,
and concentrated to a yellow oil (4.3 g, 65%, [R]D ) +56.7° (c
0.095, CHCl3)): 1H NMR (300 MHz, CDCl3) ∂ 1.28 (t, J ) 6.9

3906 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Hulin et al.
Hz, 1 H), 2.79 (dd, J ) 13.3 Hz, 9.3 Hz, 1 H), 3.31 (dd, J )
13.3 Hz, 3.1 Hz, 1 H), 3.63 (q, J ) 7.1 Hz, 1 H), 3.64 (q, J )
7.2 Hz, 1 H), 4.19-4.30 (m, 2 H), 4.63-4.67 (m, 3 H), 7.17-
7.34 (m, 5 H); 13C NMR (75 MHz, CDCl3) ∂ 15.1, 37.8, 54.8,
67.3, 67.3, 70.4, 127.4, 129.0, 129.4, 135.0, 153.4, 170.4; MS
(EI) m/e 263 (M+), 218, 134, 117, 91, 85, 65, 58; IR (KBr) ν
(cm-1) 1072, 1203, 1352, 1388, 1716, 1784 (s).
raphy (hexane/ethyl acetate/acetic acid, 10:10:1) and then
recrystallized from hexane/ethyl acetate and obtained as a
white solid (48 mg, 46%, mp 129-129.5 °C, [R]D ) -12.5° (c
0.99, CDCl3)): 1H NMR (300 MHz, CDCl3) ∂ 1.13 (t, J ) 7.1
Hz, 1 H), 2.33 (s, 3 H), 3.05 (dd, J ) 14.2 Hz, 7.6 Hz, 1 H),
3.18 (dd, J ) 14.2 Hz, 4.3 Hz, 1 H), 3.40 (m, 1 H), 3.54 (m, 1
H), 3.99 (s, 2 H), 4.07 (dd, J ) 7.6 Hz, 4.3 Hz, 1 H), 6.40 (d, J
) 1.3 Hz, 1 H), 7.07 (dd, J ) 8.4 Hz, 1.9 Hz, 1 H), 7.31 (d, J )
8.5 Hz, 1 H), 7.32 (s, 1 H), 7.39-7.43 (m, 3 H), 7.96-7.99 (m,
2 H); 13C NMR (75 MHz, CDCl3) ∂ 9.87, 20.52, 33.61, 48.72,
61.47, 74.97, 98.21, 105.38, 116.08, 119.89, 120.94, 122.17,
123.53, 123.74, 123.81, 124.90, 125.95, 126.45, 139.95, 148.81,
150.70, 154.55, 170.05; MS (CI, NH3) m/e 407, 406 (M+ + 1),
362, 195; IR (KBr) ν (cm-1) 709, 1110, 1124, 1197, 1723 (s).
Anal. (C24H23NO5) C, H, N.
4(S)-Ben zyl-3-{(2S,3R)-2-eth oxy-3-h ydr oxy-3-[2-[(5-m eth -
y l -2 -p h e n y l o x a z o l -4 -y l )m e t h y l ]b e n z o fu r a n -5 -y l ]-
p r op ion yl}oxa zolid in -2-on e (49). To a solution of (S)-4-
benzyl-3-(ethoxyacetyl)oxazolidin-2-one (48) (1.0 g, 3.8 mmol)
in dichloromethane (10 mL), cooled to 0 °C, was added freshly
distilled dibutylboron triflate (1.1 mL, 4.6 mmol) dropwise,
followed by triethylamine (0.69 mL, 4.9 mmol). After 5 min
the solution was cooled to -78 °C, and a precooled solution of
2-[(5-methyl-2-phenyloxazol-4-yl)methyl]-5-benzofurancarbox-
aldehyde (32) (1.33 g, 4.2 mmol) in dichloromethane (5 mL)
was added. After 20 min the mixture was warmed to 0 °C,
stirred at that temperature for 1 h, then quenched with a
solution of pH 7 buffer (10 mL) in methanol (30 mL), followed
by a solution of 30% hydrogen peroxide (10 mL) in methanol
(30 mL), and stirred at 0 °C for 1 h. The mixture was then
diluted with water and extracted with ethyl acetate (3). The
combined extracts were washed with brine, dried over sodium
sulfate, and concentrated. The product was purified by flash
chromatography (hexane/ethyl acetate, 1:1) and obtained as
a yellow solid (1.16 g, 53%, mp 66-70 °C, [R]D ) +70° (c 0.093,
CHCl3)): 1H NMR (300 MHz, CDCl3) ∂ 1.19 (t, J ) 7.0 Hz, 1
H), 2.32 (s, 3 H), 2.73 (dd, J ) 13.3 Hz, 9.6 Hz, 1 H), 3.22 (dd,
J ) 13.3 Hz, 3.2 Hz, 1 H), 3.46-3.70 (m, 3 H), 3.95 (dd, J )
9.1 Hz, 1.8 Hz, 1 H), 3.99 (s, 2 H), 4.37 (m, 1 H), 4.97 (d, J )
5.2 Hz, 1 H), 5.39 (d, J ) 5.2 Hz, 1 H), 6.46 (s, 1 H), 7.13 (dd,
J ) 6.0 Hz, 1.8 Hz, 2 H), 7.25-7.34 (m, 5 H), 7.36-7.43 (m, 3
H), 7.52 (s, 1 H), 7.93-7.98 (m, 2 H); 13C NMR (75 MHz, CDCl3)
∂ 10.2, 15.1, 25.9, 37.8, 55.8, 66.6, 66.9, 75.5, 81.7, 103.5, 110.5,
118.8, 122.3, 126.0, 127.4, 127.6, 128.7, 1128.9, 129.4, 129.9,
131.6, 133.3, 135.0, 145.0, 153.0, 154.7, 156.5, 159.6, 171.3;
MS (EI) m/e 263, 172, 117, 105, 92, 91, 86, 85, 83; IR (KBr) ν
(cm-1) 715, 1120, 1705, 1780 (s). Anal. (C34H32N2O7‚1/2H2O)
C, H, N.
Ack n ow led gm en t. We are deeply indebted to the
following for their expert assistance in providing the in
vivo biological data: K. A. Earle, R. K. McPherson, N.
A. Nardone, and A. J . Torchia.
Refer en ces
(1) (a) Rushforth, N. B.; Miller, N.; Bennett, P. H. Fasting and Two-
hour Post-Load Glucose Levels for the Diagnosis of Diabetes.
The Relationship between Glucose Levels and Complications of
Diabetes in the Pima Indians. Diabetologia 1979, 16, 373-379.
(b) Knuiman, M. W.; Welborn, T. A.; Mc Cann, V. J .; Stanton,
K. G.; Constable, I. J . Prevalence of Diabetic Complications in
Relation to Risk Factors. Diabetes 1986, 35, 1332-1339. (c)
Feldt-Rasmussen, B.; Mathiesen, E.; Deckert, T. Effect of Two
Years of Strict Metabolic Control on Progression of Incipient
Nephropathy in Insulin-Dependent Diabetes. Lancet 1986, No.
2, 1300-1304. (d) Dahl-J orgensen, K.; Brinchmann-Hansen, O.;
Hanssen, K. F.; Ganes, T.; Kierulf, P.; Smeland, E.; Sandvik,
L.; Aagenaes, O. Effect of Near-Normoglycemia for Two Years
on Progression of Early Diabetic Retinopathy, Nephropathy, and
Neuropathy: the Oslo Study. Br. Med. J . 1986, 293, 1195-1199.
(e) Pirart, J . Diabetes Mellitus and its Degenerative Complica-
tions. A Prospective Study of 4,400 Patients Observed between
1947 and 1973. Diabetes Care 1978, 1, 168-188. (f) Pirart, J .
Diabetes Mellitus and its Degenerative Complications. A Pro-
spective Study of 4,400 Patients Observed between 1947 and
1973. Diabetes Care 1978, 1, 252-263.
4(S)-Ben zyl-3-{2(R)-eth oxy-3-[2-[(5-m eth yl-2-p h en ylox-
a zol-4-yl)m eth yl]ben zofu r a n -5-yl]p r op ion yl}oxa zolid in -
2-on e (50). To a solution of 4(S)-benzyl-3-{(2S,3R)-2-ethoxy-
3-h ydr oxy-3-[2-[(5-m et h yl-2-ph en yloxa zol-4-yl)m et h yl]-
benzofuran-5-yl]propionyl}oxazolidin-2-one (49) (1.0 g, 1.72
mmol) in trifluoroacetic acid (20 mL) was added triethylsilane
(3.0 mL, 19 mmol). The solution was stirred for 4 days at room
temperature, then diluted with ethyl acetate, washed with
water and saturated sodium bicarbonate solution (3×), dried
over sodium sulfate, and concentrated. The product was
isolated by flash chromatography (hexane/ethyl acetate, 5:1)
(2) Williams, G. Management of Non-Insulin-Dependent Diabetes
Mellitus. Lancet 1994, 95-100.
(3) (a) The Diabetes Control and Complications Trial Research
Group. The Effect of Intensive treatment on the Development
and Progression of Long-Term Complications in Insulin-Depend-
ent Diabetes Mellitus. N. Engl. J . Med. 1993, 329, 977-986. (b)
Eastman, R. C.; Siebert, C. W.; Harris, M.; Gorden, P. Implica-
tions of the Diabetes Control and Complications Trial. J . Clin.
Endoc. Metab. 1993, 77, 1105-1107. (c) American Diabetes
Association. Implications of the Diabetes Control and Complica-
tions Trial. Diabetes 1993, 42, 1555-1558.
(4) (a) Steiner, K. E.; Lien, E. L. Hypoglycaemic Agents Which Do
Not Release Insulin. Progr. Med. Chem. 1987, 24, 209-248. (b)
New Antidiabetic Drugs; Bailey, C. J ., Flatt, P. R., Eds.; Smith,
Gordon & Co.: London, 1990. (c) Hulin, B. New Hypoglycaemic
Agents. Progr. Med. Chem. 1994, 31, 1-58.
as a pale yellow solid (0.44 g, 45%, mp 116-117 °C, [R]D
)
+53.8° (c 0.12, CHCl3)): 1H NMR (300 MHz, CDCl3) ∂ 1.14 (t,
J ) 6.9 Hz, 1 H), 2.32 (s, 3 H), 2.78 (dd, J ) 13.3 Hz, 9.4 Hz,
1 H), 3.02-3.05 (m, 2 H), 3.23 (dd, J ) 13.5 Hz, 3.3 Hz, 1 H),
3.37 (m, 1 H), 3.55 (m, 1 H), 3.88 (t, J ) 8.4 Hz, 1 H), 3.98 (s,
2 H), 4.06 (dd, J ) 8.7 Hz, 2.4 Hz, 1 H), 4.48 (m, 1 H), 5.29
(dd, J ) 7.5 Hz, 5.6 Hz, 1 H), 6.41 (s, 1 H), 7.13-7.18 (m, 4
H), 7.26-7.32 (m, 4 H), 7.38-7.42 (m, 3 H), 7.95-7.98 (m, 2
H); 13C NMR (75 MHz, CDCl3) ∂ 10.3, 15.2, 26.0, 37.8, 39.5,
55.5, 66.3, 66.5, 79.0, 103.3, 110.4, 121.4, 125.2, 126.0, 127.4,
127.6, 128.7, 128.8, 128.9, 129.4, 129.9, 131.1, 131.8, 135.1,
145.0, 153.1, 154.0, 156.0, 159.6, 173.1; MS (EI) m/e 564 (M+),
518, 360, 342, 302, 172, 166; IR (KBr) ν (cm-1) 700, 710, 720,
750, 780, 810, 1125, 1200, 1240, 1260, 1295, 1355, 1380, 1480,
1705, 1790. Anal. (C34H32N2O6) C, H, N.
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