Isoxazolidine-3,5-dione and noncyclic 1,3-dicarbonyl compounds as hypoglycemic agents

Article abstract of DOI:10.1021/jm970771m

Isoxazolidine-3,5-dione 2 (JTT-501), one of the cyclic malonic acid derivatives, was found to decrease blood glucose at an oral dose of 38 mg/kg/day in KKA(y) mice and is currently undergoing evaluation in phase II clinical trials. Further studies on a series of malonic acids and related compounds showed that the 1,3-dicarbonyl structure was important for insulin- sensitizing activity. Dimethyl malonate 10, which was selected as a successor for 2, was the optimum compound in a series of 1,3-dicarbonyl compounds and was more potent than the corresponding thiazolidine-2,4-dione 1.

Full text of DOI:10.1021/jm970771m

J . Med. Chem. 1998, 41, 1927-1933
1927
Isoxa zolid in e-3,5-d ion e a n d Non cyclic 1,3-Dica r bon yl Com p ou n d s a s
Hyp oglycem ic Agen ts
Hisashi Shinkai,* Syoji Onogi, Masahiro Tanaka, Tsutomu Shibata, Megumi Iwao, Korekiyo Wakitani, and
Itsuo Uchida
Central Pharmaceutical Research Institute, J T Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, J apan
Received November 12, 1997
Isoxazolidine-3,5-dione 2 (J TT-501), one of the cyclic malonic acid derivatives, was found to
decrease blood glucose at an oral dose of 38 mg/kg/day in KKAy mice and is currently undergoing
evaluation in phase II clinical trials. Further studies on a series of malonic acids and related
compounds showed that the 1,3-dicarbonyl structure was important for insulin-sensitizing
activity. Dimethyl malonate 10, which was selected as a successor for 2, was the optimum
compound in a series of 1,3-dicarbonyl compounds and was more potent than the corresponding
thiazolidine-2,4-dione 1.
In tr od u ction
Here we report on the synthesis and biological actions
of isoxazolidine-3,5-dione 2 (Chart 1) and its derivatives,
noncyclic 1,3-dicarbonyl compounds. These compounds
showed insulin-sensitizing activity in 3T3-L1 cells and
hypoglycemic activity in genetically diabetic KKAy mice.
Isoxazolidine-3,5-dione 2 (J TT-501) is currently under-
going evaluation in phase II clinical trials, because no
significant toxicity has been observed in earlier studies.
Dimethyl malonate 10 was the optimum compound in
a series of noncyclic 1,3-dicarbonyl compounds and was
selected as a successor to J TT-501.
Non-insulin-dependent diabetes (NIDDM) is a meta-
bolic disorder characterized by hyperglycemia leading
to chronic complications such as neuropathy, nephropa-
thy, retinopathy, and premature atherosclerosis.1 The
recently completed NIH-sponsored Diabetes Control and
Complications Trial demonstrated that tight blood
glucose control was associated with a reduced incidence
of diabetic complications.2 Hyperglycemia in NIDDM
is caused not only by impaired insulin secretion from
the pancreas but also by the increased insulin resistance
of peripheral tissues.3 Hence, a decrease of insulin
resistance is necessary for achieving tight blood glucose
control. Since the thiazolidinedione-based compound
ciglitazone (Chart 1) was reported as a novel oral
hypoglycemic agent that apparently potentiated the
peripheral action of insluin,4 many reports on new
analogues have appeared,5 and troglitazone has been
approved for use in J apan, the United Kingdom, and
the United States. Many studies on replacement of the
cyclohexyl portion of ciglitazone have been carried out.
Compound 1 (Chart 1), one of the optimum compounds,
possesses a (2-phenyl-4-oxazolyl)ethyl chain and is 500
times more potent than ciglitazone.6 Numerous studies
on replacement of the thiazolidine-2,4-dione ring have
also been carried out. Replacement of the thiazolidine-
2,4-dione ring has been tried with various acidic groups,7
such as oxazolidine-2,4-dione rings,8 1-oxa-2,4-diazoli-
dine-3,5-dione rings,9 carbonylated hydroxyureas,9 R-het-
eroatom-substituted carboxylic acids,10,11a and R-carbon-
substituted carboxylic acids.11b Among these compounds,
the R-alkoxy carboxylic acids have shown equipotent10
or more potent11a activity compared to the thiazolidine-
2,4-diones. Some interesting reports on the molecular
mechanism of the insulin-sensitizing action of thiazo-
lidinediones have been published. The Glaxo group
showed that a thiazolidinedione was an agonist for
peroxisome proliferator-activated receptor γ (PPARγ),
a receptor subtype selectively expressed in adipocytes
that induces adipocyte differentiation.12,13 They pro-
posed that PPARγ was a molecular target for the
adipogenic effect of thiazolidinediones.
Ch em istr y
Scheme 1 shows the preparation of 1,3-dicarbonyl
compounds containing isoxazolidine-3,5-dione 2. Kno-
evenagel condensation between the aldehyde 198 and
dimethyl malonate gave the benzylidene 16. Catalytic
hydrogenation of 16 with 5% palladium on carbon gave
dimethyl malonate 10. The 1,3-diketone 15 was pre-
pared from 10 and 2,4-pentanedione using the same
procedure. Isoxazolidine-3,5-dione 2 was synthesized
by coupling between 10 and hydroxylamine. Hydrolysis
of 10 with more than 2 equiv of sodium hydroxide gave
malonic acid 14. The diamide 9 was prepared from 10
with ammonia using strongly basic catalysis. Partial
hydrolysis of 10 with 1 equiv of sodium hydroxide gave
the half-ester 12. The Schotten-Baumann reaction
between an acid chloride of 12 and ammonia gave the
amide ester 4. The amide acid 3 was prepared by
hydrolysis of 4 or reduction of 2 with 5% palladium on
carbon as the catalyst. Methylation of 10 with io-
domethane gave the R-methylmalonate 17.
The methyl oxazolylacetate 2014 was reduced with
LiBH4 and converted to methylsulfonyl ester 21. The
ester 6 was prepared by coupling between 21 and
methyl 3-(p-hydroxyphenyl)propionate. Hydrolysis of 6
gave the carboxylic acid 5. Conversion of 6 with
ammonia gave the amide 7 (Scheme 2).
The triester 23 was prepared by coupling between 22
and ethyl bromoacetate. Reductive removal of benzyl
groups from 23 and subsequent decarboxylation gave
the monoethyl succinate 24. The amide ester 8 was
prepared by the Schotten-Baumann reaction between
the acid chloride of 24 and ammonia (Scheme 3).
* To whom correspondence should be addressed.
S0022-2623(97)00771-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/11/1998

1928 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Shinkai et al.
Ch a r t 1
Sch em e 1a
a
Reagents: (a) dimethyl malonate, piperidinium acetate, toluene, reflux; (b) 2,4-pentanedione, piperidinium acetate, toluene, reflux;
(c) H2, Pd-C; (d) NaOH; (e) KCO3, MeI; (f) 28% ammonium hydroxide; (g) hydroxylamine; (h) 1 equiv of NaOH; (i) thionyl chloride.
The dimethyl ester 18 was synthesized from 2515
using the same procedure as that used for preparing
10 (Scheme 4).
was monitored from the rate of triglyceride accumula-
tion in 3T3-L1 cells.19 Isoxazolidine-3,5-dione 2 (J TT-
501) caused a 50% increase of triglyceride accumulation
in 3T3-L1 cells at a concentration of 1.1 × 10-7 M (Table
1) and a 25% decrease of blood glucose in KKAy mice at
an oral dose of 38 mg/kg/day (Table 2). The in vivo
hypoglycemic activity of 2 was about 4 times more
potent than that of troglitazone, and 1/8 as potent as that
of pioglitazone (Table 2). Compound 2 has advanced
to clinical trials, because no significant toxicity, includ-
ing cardiac hypertrophy, has been observed in rats, dogs,
and monkeys.
Resu lts a n d Discu ssion
Because acidity of the thiazolidine-2,4-dione moiety
is considered essential for its insulin-sensitizing activ-
ity,7 we designed isoxazolidine-3,5-dione as a more acidic
heterocyclic compound than thiazolidine-2,4-dione. The
pKa of thiazolidinedione and isoxazolidinedione was
reported to be 6.8216 and 1.86,17 respectively. Insulin-
sensitizing activity was evaluated from the hypoglyce-
mic activity in genetically diabetic KKAy mice18 and by
the effect on insulin-regulated differentiation, which
The main metabolite in humans was identified as
malonic amide 3, created by reductive cleavage of 2. The

1,3-Dicarbonyl Compounds as Hypoglycemic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1929
Sch em e 2a
a
Reagents: (a) LiBH4; (b) methanesulfonyl chloride, triethylamine; (c) methyl 3-(p-hydroxyphenyl)propionate, NaH; (d) NaOH; (e)
28% ammonium hydroxide.
Sch em e 3a
a
Reagents: (a) NaH, ethyl bromoacetate; (b) H2, Pd-C; (c) 150 °C; (d) thionyl chloride; (e) 28% ammonium hydroxide.
Sch em e 4a
nonacidic compounds 4 and 9, indicating that an acidic
functionality of the 1,3-dicarbonyl moiety was not es-
sential. The diesters (10 and 11) and the half-esters
(12 and 13) were more potent than amide ester 4,
diamide 9, and dicarboxylic acid 14. The 1,3-diketone
15 showed decreased potency relative to the dicarboxyl
compounds (10-14). This may have been attributable
to the presence of keto-enol tautomerism. The keto
1
content of 15 was 37%, when measured in CDCl3 by H
NMR. Comparison between the methyl esters (10 and
12) and the ethyl esters (11 and 13) disclosed that the
minimal methyl group was more favorable than the
ethyl group. Among the 1,3-dicarbonyl compounds,
dimethyl malonate 10 and monomethyl malonate 12
showed the highest potency in vitro. This indicated that
a methyl ester combined with another methyl ester or
a carboxylic acid was the optimum structure. Since 10
can be partially hydrolyzed to 12 in vitro, and since both
10 and 12 are probably hydrolyzed to the less potent
dicarboxylic acid 14, it is difficult to decide which is the
best combination: methyl ester plus methyl ester or
methyl ester plus carboxylic acid.
a
Reagents: (a) dimethyl malonate, piperidinium acetate, tolu-
ene, reflux; (b) H2, Pd-C.
in vitro insulin-sensitizing activity of 3 was as potent
as that of 2 (Table 1). However, the nonacidic amide
ester 4 was 100 times more potent than 2 or 3.
Therefore, we questioned the necessity for acidity of
these compounds and focused on the 1,3-dicarbonyl
structure, which was common to the compounds (2-4).
The SmithKline Beecham group reported that a mal-
onate derivative, one of the R-substituted carboxylic
acids, showed hypoglycemic activity.11b However, their
compound was less potent in vivo than the parent
thiazolidine-2,4-dione, BRL 48482, and they neither
focused on the 1,3-dicarbonyl structure nor carried out
any further investigations. We first investigated whether
the 1,3-dicarbonyl structure was essential. The mono-
carbonyl compounds 5-7 and the 1,4-dicarbonyl com-
pound 8 showed decreased activity, indicating the
importance of the 1,3-dicarbonyl structure. Therefore,
we carried out further studies on 1,3-dicarbonyl com-
pounds in order to optimize the 1,3-dicarbonyl moiety
and to obtain a successor for 2.
The dimethyl malonate 10 caused a 50% increase of
triglyceride accumulation in 3T3-L1 cells at a concen-
tration of 5.9 × 10-11 M and was about 7 times more
potent than the corresponding thiazolidinedione 1. The
corresponding dimethyl malonate 18 of pioglitazone was
also about twice as potent as the parent compound with
respect to in vitro insulin-sensitizing activity. There-
fore, the dimethyl malonate structure was considered
to be superior to the thiazolidinedione structure. In
KKAy mice, the oral ED25 values of 10 and 12 were 0.011
and 0.024 mg/kg/day, respectively, while the oral ED50
values were 0.17 and 0.12 mg/kg/day, respectively. The
dispersion of the in vivo data may be attributable to the
The nonacidic diamide 9 also showed equipotent
activity with amide ester 4. The dicarboxylic acid 14,
with a pKa of less than 3, was less potent than the

1930 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Ta ble 1. Effect of Triglyceride Accumulation in 3T3-L1 Cells
Shinkai et al.
Exp er im en ta l Section
Ch em istr y. Melting points were obtained with a Yanagim-
oto micro melting point apparatus and are uncorrected.
Elemental analysis was performed on a Perkin-Elmer 2400
Series II CHNS/O analyzer, and all values are within (0.4%
of the calculated values. 1H NMR spectra were recorded on a
J eol J NM-A300W, Bruker AMX 300, or Bruker ARX 400
spectrometer in solutions of either CDCl3 or DMSO-d6 using
tetramethylsilane as the internal standard. Chemical shifts
are expressed as δ (ppm) values for protons relative to the
internal standard; all compounds gave spectra consistent with
their assigned structures.
Dim eth yl 4-[2-(5-Meth yl-2-p h en yl-4-oxa zolyl)eth oxy]-
ben zylid en em a lon a te (16). A solution of 19 (2.94 g, 10
mmol) and dimethyl malonate (1.39 g, 10 mmol) in toluene
(30 mL) containing a catalytic quantity of piperidinium acetate
was refluxed in a Dean-Stark trap for 4 h. After cooling to
room temperature, the solution was concentrated. The residue
was crystallized from methanol to give 16 as a colorless solid
(2.5 g, 60%): mp 105.9-106.7 °C; 1H NMR (300 MHz, CDCl3)
δ 2.37 (s, 3H), 2.99 (t, J ) 6.6 Hz, 2H), 3.83 (s, 3H), 3.85 (s,
3H), 4.28 (t, J ) 6.6 Hz, 2H), 6.88-6.91 (m, 2H), 7.35-7.46
(m, 5H), 7.69 (s, 1H), 7.96-7.99 (m, 2H). Anal. (C24H23NO6)
C, H, N.
Dim eth yl 4-[2-(5-Meth yl-2-p h en yl-4-oxa zolyl)eth oxy]-
ben zylm a lon a te (10). A solution of 16 (2.5 g, 60 mmol) in a
mixture of methanol (4 mL) and 1,4-dioxane (20 mL) was
stirred in the presence of 5% palladium on charcoal (150 mg)
under an atmosphere of hydrogen at room temperature until
hydrogen uptake ceased. The solution was filtered through
Celite, and the filtrate was evaporated under a vacuum. The
residue was crystallized from methanol to give 10 as a colorless
solid (2.15 g, 85%): mp 87.9-88.5 °C; 1H NMR (300 MHz,
CDCl3) δ 2.37 (s, 3H), 2.96 (t, J ) 6.6 Hz, 2H), 3.15 (d, J ) 8.1
Hz, 2H), 3.62 (t, J ) 7.5 Hz, 1H), 3.69 (s, 6H), 4.21 (t, J ) 6.6
Hz, 2H), 6.80-6.83 (m, 2H), 7.07-7.10 (m, 2H), 7.40-7.45 (m,
3H), 7.96-7.99 (m, 2H). Anal. (C24H25NO6) C, H, N.
Dieth yl 4-[2-(5-Meth yl-2-ph en yl-4-oxazolyl)eth oxy]ben -
zylm a lon a te (11). Using the above procedure, 11 was
prepared from diethyl malonate. The residue was crystallized
from ethyl acetate/hexane to give 11 as a colorless solid (5.23
g, 55%): mp 69.8-70.5 °C; 1H NMR (300 MHz, CDCl3) δ 1.27
(t, J ) 7.1 Hz, 6H), 2.43 (s, 3H), 3.02 (t, J ) 6.7 Hz, 2H), 3.20
(d, J ) 7.8 Hz, 2H), 3.64 (t, J ) 7.8 Hz, 1H), 4.20 (q, J ) 7.1
Hz, 2H), 4.21 (q, J ) 7.1 Hz, 2H), 4.27 (t, J ) 6.8 Hz, 2H),
6.87 (d, J ) 8.6 Hz, 2H), 7.16 (d, J ) 8.6 Hz, 2H), 7.47 (m,
3H), 8.04 (m, 2H). Anal. (C26H29NO6) C, H, N.
Ta ble 2. Hypoglycemic Effect in KKAy Mice
a
a
ED25
ED50
compd
(mg/kg/day)
(mg/kg/day)
2 (J TT-501)
38
10
12
14
0.011
0.024
0.44
170
0.17
0.12
2.7
4-[4-[2-(5-Meth yl-2-p h en yl-4-oxa zolyl)eth oxy]ben zyl]-
3,5-isoxa zolid in ed ion e (2). Hydroxylamine (1 mL, 17.5
mmol, 50% solution in water) and sodium carbonate (3.7 g, 35
mmol) were added to a solution of 10 (1.5 g, 3.5 mmol) in a
mixture of tetrahydrofuran (15 mL) and methanol (15 mL).
The mixture was heated at 60 °C for 3 h. After cooling and
evaporation of the solvent, 1 N hydrogen chloride (50 mL) was
added to the residue. The mixture was extracted with ethyl
acetate (2 × 50 mL), dried over sodium sulfate, and concen-
trated. The crude product was crystallized from methanol to
give 2 as a colorless solid (1.1 g, 80%): mp 154.6-155.4 °C;
1H NMR (400 MHz, CDCl3) δ 2.35 (s, 3H), 2.92 (t, J ) 6.5 Hz,
2H), 3.23-3.27 (m, 2H), 3.50 (t, J ) 4.9 Hz, 1H), 4.11 (t, J )
6.7 Hz, 2H), 6.77-7.95 (m, 9H). Anal. (C22H20N2O5) C, H, N.
2-(Meth oxyca r bon yl)-3-[4-[2-(5-m eth yl-2-p h en yl-4-ox-
a zolyl)eth oxy]p h en yl]p r op ion ic Acid (12). A 2 N aqueous
solution of sodium hydroxide (11 ml, 22 mmol) was added to a
solution of 10 (8.46 g, 20 mmol) in a mixture of methanol (80
mL) and tetrahydrofuran (40 mL) at 0 °C. The mixture was
stirred for 90 min at room temperature, and then the solvent
was removed under a vacuum. The residue was dissolved in
saturated aqueous sodium bicarbonate (50 mL) and washed
with ethyl acetate (50 mL). The aqueous solution was acidified
to pH 2-3 with dilute hydrochloric acid and extracted with
ethyl acetate (3 × 50 mL). The combined extracts were
washed with water (100 mL) and brine (100 mL), dried over
sodium sulfate, and concentrated. The residue was crystal-
troglitazone
pioglitazone
4.6
19
a
Effective doses for 25% and 50% blood glucose decreases were
estimated from the dose-response curves obtained with three
doses.
unstable ester structure, which is readily hydrolyzed in
vivo by esterases.
The benzylidene derivative 16 showed decreased
potency as well as the thiazolidinediones.6,14 This was
considered to be caused by inappropriate conformational
restriction and/or electronic influence resulting from
conjugation of the double bond on the carbonyl moiety
and the phenyl moiety. Introduction of a methyl group
at the 2-position of the malonate moiety (17) also
decreased the potency, possibly as a result of increasing
steric congestion adjacent to the methyl ester groups.
In conclusion, we have discovered the potent antihy-
perglycemic activity of a series of 1,3-dicarbonyl com-
pounds which could replace the thiazolidine-2,4-dione
structure. The initial lead compound, isoxazolidine-3,5-
dione 2 (J TT-501), has advanced to clinical development.
Dimethyl malonate 10, which was one of the optimum
compounds, has been selected as a successor for 2.

1,3-Dicarbonyl Compounds as Hypoglycemic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1931
lized from ethyl acetate/hexane (1:2) to give an off-white solid
(5.9 g, 72%): mp 126.0-127.1 °C; 1H NMR (300 MHz, CDCl3)
δ 2.36 (s, 3H), 2.96 (t, J ) 6.5 Hz, 2H), 3.18 (d, J ) 7.5 Hz,
2H), 3.65 (t, J ) 7.5 Hz, 1H), 3.71 (s, 3H), 4.15 (t, J ) 6.6 Hz,
2H), 6.79 (d, J ) 8.4 Hz, 2H), 7.11 (d, J ) 8.4 Hz, 2H), 7.38-
7.48 (m, 3H), 7.90-8.00 (m, 2H). Anal. (C23H23NO6) C, H, N.
2-(E t h oxyca r b on yl)-3-[4-[2-(5-m et h yl-2-p h en yl-4-ox-
azolyl)eth oxy]ph en yl]pr opion ic acid (13). Using the above
procedure, 13 was prepared from 11 as a colorless solid (2.91
g, 67%): mp 95.1-96.0 °C; 1H NMR (300 MHz, CDCl3) δ 1.15
(t, J ) 7.1 Hz, 6H), 2.30 (s, 3H), 2.90 (t, J ) 6.6 Hz, 2H), 3.12
(d, J ) 7.6 Hz, 2H), 3.58 (t, J ) 7.6 Hz, 1H), 4.07-4.14 (m,
4H), 6.74 (d, J ) 8.6 Hz, 2H), 7.05 (d, J ) 8.6 Hz, 2H), 7.36
(m, 3H), 7.90 (m, 2H). Anal. (C24H25NO6) C, H, N.
8.4 Hz, 2H), 7.41-7.56 (m, 3H), 7.82-7.92 (m, 2H). Anal.
(C22H21NO6) C, H, N.
2-[4-[2-(5-Meth yl-2-p h en yl-4-oxa zolyl)eth oxy]ben zyl]-
m a lon a m id e (9). A 28% ammonia solution (20 mL) and 1 N
aqueous sodium hydroxide (30 mL) were added to a solution
of 10 (3.0 g, 7.1 mmol) in a mixture of methanol (50 mL) and
tetrahydrofuran (50 mL). The mixture was stirred for 1 h at
room temperature, and the solvent was removed under a
vacuum. A mixture of tetrahydrofuran (50 mL) and ethyl
acetate (50 mL) was added to the residue. The mixture was
washed with water (50 mL) and brine (50 mL), dried over
sodium sulfate, and concentrated to give 9 as an off-white solid
(2.5 g, 90%): mp 222.5-223.4 °C; 1H NMR (300 MHz, CDCl3)
δ 2.34 (s, 3H), 2.80-2.92 (m, 4H), 3.22 (t, J ) 7.5 Hz, 1H),
4.15 (t, J ) 6.7 Hz, 2H), 6.81 (d, J ) 8.4 Hz, 2H), 6.96 (br s,
2H), 7.07 (d, J ) 8.4 Hz, 2H), 7.19 (br s, 2H), 7.40-7.52 (m,
3H), 7.82-7.95 (m, 2H). Anal. (C22H23N3O4) C, H, N.
Dim et h yl 2-Met h yl-2-[4-[2-(5-m et h yl-2-p h en yl-4-ox-
a zolyl)eth oxy]ben zyl]m a lon a te (17). 10 (4.24 g, 10 mmol)
was added to a suspension of sodium hydride (480 mg, 12
mmol, 60% dispersion) in dry dimethylformamide (40 mL) at
0 °C. When hydrogen evolution ceased, iodomethane (0.93 mL,
15 mmol) was added, and the mixture was stirred at room
temperature for 2.5 h. Then the solution was poured into iced
water (100 mL) and extracted with ethyl acetate (3 × 100 mL).
The combined extracts were washed with water (100 mL) and
brine (100 mL), dried over sodium sulfate, and concentrated
to give 17 as an off-white solid (2.71 g, 62%): mp 75.1-76.0
°C; 1H NMR (300 MHz, CDCl3) δ 1.32 (s, 3H), 2.36 (s, 3H),
2.96 (t, J ) 6.6 Hz, 2H), 3.15 (s, 2H), 3.71 (s, 6H), 4.21 (t, J )
6.3 Hz, 2H), 6.79 (d, J ) 6.6 Hz, 2H), 6.99 (d, J ) 6.6 Hz, 2H),
7.38-7.48 (m, 3H), 7.94-8.01 (m, 2H). Anal. (C25H27NO6) C,
H, N.
Meth yl 2-Ca r ba m oyl-3-[4-[2-(5-m eth yl-2-p h en yl-4-ox-
a zolyl)eth oxy]p h en yl]p r op ion a te (4). Thionyl chloride
(375 µL, 6.12 mmol) was added to a solution of 12 (2.1 g, 5.1
mmol) in benzene (20 mL) at room temperature. Then the
mixture was heated at 80 °C for 90 min. After cooling to room
temperature, the solvent was removed under a vacuum. To a
solution of the residue in acetone (2 mL) was added 28%
ammonia solution (5 mL) at room temperature. The mixture
was stirred for 30 min, and the solvent was removed under
reduced pressure. The residue was dissolved in ethyl acetate
(50 mL), washed with water (50 mL) and brine (50 mL), dried
over sodium sulfate, and concentrated. The crude product was
crystallized from ethyl acetate/hexane (1:5) to give 4 as a
1
colorless solid (700 mg, 40%): mp 154.8-155.4 °C; H NMR
(300 MHz, CDCl3) δ 2.36 (s, 3H), 2.96 (t, J ) 6.7 Hz, 2H), 3.09-
3.24 (m, 2H), 3.47 (dd, J ) 6.7 and 8.2 Hz, 1H), 3.65 (s, 3H),
4.21 (t, J ) 6.7 Hz, 2H), 5.43 (br s, 1H), 6.38 (br s, 1H), 6.81
(d, J ) 8.6 Hz, 2H), 7.07 (d, J ) 8.6 Hz, 2H), 7.35-7.46 (m,
3H), 7.91-8.00 (m, 2H). Anal. (C23H24N2O5) C, H, N.
2-Ca r b a m oyl-3-[4-[2-(5-m et h yl-2-p h en yl-4-oxa zolyl)-
eth oxy]-p h en yl]p r op ion ic Acid (3). A 2.5 N solution of
aqueous sodium hydroxide (2.5 ml, 41 mmol) was added to a
solution of 4 (1.8 g, 41 mmol) in a mixture of methanol (20
mL) and tetrahydrofuran (20 mL). The mixture was stirred
for 15 h at room temperature, and then the solvent was
removed under a vacuum. The residue was dissolved in 10%
aqueous sodium hydroxide (50 mL) and washed with ethyl
acetate (3 × 30 mL). The aqueous solution was acidified to
pH 2-3 with 3 N hydrochloric acid, and the precipitate was
collected by filtration. The crude solid was washed with water
and dried under a vacuum to give 3 as a colorless solid (1.7 g,
3-[4-[2-(5-Meth yl-2-p h en yl-4-oxa zolyl)eth oxy]ben zyl]-
p en ta n e-2,4-d ion e (15). A solution of 19 (7 g, 10 mmol) and
2,4-pentanedione (1.2 g, 12 mmol) in toluene (40 mL) contain-
ing a catalytic quantity of piperidinium acetate was refluxed
in a Dean-Stark trap for 5 h and the concentrated. Chroma-
tography of the residue on silica gel eluted with ethyl acetate/
hexane (1:1) gave 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-
benzylidene]pentane-2,4-dione as a yellow oil (2.3 g, 60%). A
solution of the oil (2 g, 5.1 mmol) in methanol (30 mL) was
stirred in the presence of 5% palladium on charcoal (400 mg)
under 3 kg/cm2 of hydrogen at room temperature until
hydrogen uptake ceased. Then the solution was filtered
through Celite, and the filtrate was evaporated under a
vacuum. The crude product was chromatographed on silica
gel eluted with ethyl acetate/hexane (2:3) to give the yellow
oil 15 (1.74 g, 87%) as a keto-enol tautomer (the keto content
at equilibrium was 37%): 1H NMR (300 MHz, CDCl3) δ 2.06
(s, 3.78H), 2.11 (s, 2.22H), 2.37 (s, 3H), 2.92-3.03 (m, 2H), 3.08
(d, J ) 7.8 Hz, 0.74H), 3.57 (s, 1.26H), 3.95 (t, J ) 7.5 Hz,
0.37H), 4.18-4.26 (m, 2H), 6.78-6.94 (m, 2H), 6.99-7.08 (m,
2H), 7.37-7.50 (m, 3H), 7.93-8.01 (m, 2H).
2-(5-Meth yl-2-ph en yl-4-oxazolyl)eth an ol Meth an esu lfo-
n yl Ester (21). Lithium borohydride (6.6 g, 0.3 mmol) was
added gradually to a solution of 20 (34.7 g, 0.15 mmol) in dry
tetrahydrofuran (120 mL) at room temperature. Then the
mixture was heated at 50 °C for 3 h. After cooling to room
temperature, the solution was poured into iced water (150 mL),
acidified with 2 N hydrochloric acid, and extracted with ethyl
acetate (2 × 200 mL). The organic extract was dried over
sodium sulfate and concentrated to give 2-(5-methyl-2-phenyl-
4-oxazolyl)ethanol as a crude solid (25.1 g, 82%). To a solution
of the product (20.3 g, 0.1 mol) in dry dichloromethane (100
mL) was added methanesulfonyl chloride (12.6 g, 0.11 mol) at
0 °C. Triethylamine (11.3 g, 0.11 mol) was added dropwise to
the mixture, and stirring was continued at room temperature
for 8 h. The solution was washed with 2 N hydrogen chloride
(2 × 100 mL), saturated aqueous sodium bicarbonate (100 mL),
and brine (100 mL), dried over sodium sulfate, and concen-
trated to give 21 as a colorless solid (28.1 g, 100%): mp 90.2-
91.0 °C; 1H NMR (300 MHz, CDCl3) δ 2.36 (s, 3H), 2.96 (s,
1
98%): mp 138.1-138.5 °C; H NMR (300 MHz, DMSO-d6) δ
1
2.35 (s, 3H), 2.83-3.00 (m, 4H), 3.40 (t, J ) 5.6 Hz, H), 4.17
1
(t, J ) 5.0 Hz, 2H), 6.82 (d, J ) 6.5 Hz, 2H), 6.96 (br s, H),
7.09 (d, J ) 6.5 Hz, 2H), 7.40 (br s, 1H), 7.41-7.52 (m, 3H),
7.82-7.95 (m, 2H), 12.39 (br s, 1H). Anal. (C22H22N2O5) C,
H, N.
3 was also synthesized using the following procedure.
A
solution of 2 (5.0 g, 12.7 mmol) in a mixture of tetrahydrofuran
(50 mL) and methanol (25 mL) was stirred in the presence of
5% palladium on charcoal (0.5 g) under 3 kg/cm2 of hydrogen
at room temperature until hydrogen uptake ceased. The
solution was filtered through Celite, and the filtrate was
evaporated under a vacuum. The residue was washed with
hexane (100 mL) and with a mixture of ethyl acetate (25 mL)
and acetone (25 mL) to give 3 as a colorless solid (4.2 g, 83%).
2-[4-[2-(5-Meth yl-2-p h en yl-4-oxa zolyl)eth oxy]ben zyl]-
m a lon ic Acid (14). A 2 N aqueous solution of sodium
hydroxide (17.7 mL, 35.5 mmol) was added to a solution of 10
(6 g, 14.2 mmol) in a mixture of methanol (60 mL) and
tetrahydrofuran (30 mL). Then the mixture was stirred for
68 h at room temperature. After evaporation of the organic
solvent, water (100 mL) was added to the residual solution,
and the mixture was acidified with 1 N hydrochloric acid. The
precipitate was collected by filtration, washed with water, and
dried under a vacuum. The crude product was crystallized
from ethyl acetate/hexane (1:5) to give 14 as a colorless solid
1
(3 g, 53%): mp 173.3-174.6 °C; H NMR (300 MHz, DMSO-
d6) δ 2.34 (s, 3H), 2.82-3.00 (m, 4H), 3.49 (t, J ) 8.0 Hz, 1H),
4.16 (t, J ) 6.8 Hz, 2H), 6.83 (d, J ) 8.4 Hz, 2H), 7.11 (d, J )

1932 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Shinkai et al.
3H), 2.96 (t, J ) 6.5 Hz, 2H), 4.53 (t, J ) 6.6 Hz, 2H), 7.38-
uptake ceased. The solution was filtered through Celite, and
the filtrate was evaporated under a vacuum. The residue was
heated at 150 °C for 30 min and chromatographed on silica
gel eluted with chloroform/methanol (20:1) to give 24 as a
yellow oil (15.0 g, 77%): 1H NMR (300 MHz, CDCl3) δ 1.21 (t,
J ) 7.1 Hz, 3H), 2.37 (s, 3H), 2.38 (dd, J ) 4.8 and 16.8 Hz,
1H), 2.55-2.78 (m, 2H), 2.90-3.17 (m, 4H), 4.09 (q, J ) 7.1
Hz, 2H), 4.20 (t, J ) 6.6 Hz, 2H), 6.82 (d, J ) 8.6 Hz, 2H),
7.07 (d, J ) 8.6 Hz, 2H), 7.44 (m, 3H), 7.97 (m, 2H).
E t h yl 3-Ca r b a m oyl-4-[4-[2-(5-m et h yl-2-p h en yl-4-ox-
a zolyl)eth oxy]p h en yl]bu tyr a te (8). A mixture of thionyl
chloride (30 mL) and 24 (4.5 g, 10.3 mmol) was stirred at 40
°C for 1 h. After evaporation of the solvent, 28% ammonia
solution (15 mL) was added to a solution of the residue in
tetrahydrofuran (25 mL) at 0 °C, and the mixture was stirred
for 10 min. The solution was acidified with 1 N sodium
hydrogensulfate, and the precipitate was collected by filtration.
The crude product was crystallized from ethyl acetate to give
8 as a colorless solid (2.9 g, 64%): mp 141.8-142.3 °C; 1H NMR
(300 MHz, CDCl3) δ 1.23 (q, J ) 7.2 Hz, 3H), 2.38 (s, 3H), 2.42
(dd, J ) 3.8 and 16.7 Hz, 1H), 2.60-2.90 (m, 4H), 2.97 (t, J )
6.5 Hz, 2H), 4.10 (q, J ) 7.2 Hz, 2H), 5.20 (br s, 1H), 5.44 (br
s, 1H), 6.83 (d, J ) 9.0 Hz, 2H), 7.09 (d, J ) 9.0 Hz, 2H), 7.43
(m, 3H), 7.97 (m, 2H). Anal. (C25H28N2O5) C, H, N.
7.50 (m, 3H), 7.90-8.02 (m, 2H). Anal. (C13H15NO4S) C, H,
N.
Meth yl 3-[4-[2-(5-Meth yl-2-p h en yl-4-oxa zolyl)eth oxy]-
p h en yl]p r op ion a te (6). Methyl 3-(p-hydroxyphenyl)propi-
onate (15.9 g, 88.1 mmol) was added to a suspension of sodium
hydride (2.11 g, 88.1 mmol, 60% dispersion) in dry dimethyl-
formamide (50 mL) at 0 °C. When hydrogen evolution ceased,
a solution of 21 (15.7 g, 56 mmol) in dry dimethylformamide
(50 mL) was added, and the mixture was stirred at room
temperature for 5 h. Then the solution was poured into iced
water (200 mL) and extracted with ethyl acetate (3 × 100 mL).
The combined extracts were washed with water (100 mL) and
brine (100 mL), dried over sodium sulfate, and concentrated.
The residue was chromatographed on silica gel eluted with
ethyl acetate/hexane (15:85) to give 6 as a colorless solid (14.0
1
g, 68%): mp 50.2-51.7 °C; H NMR (300 MHz, CDCl3) δ 2.37
(s, 3H), 2.58 (t, J ) 7.5 Hz, 2H), 2.88 (t, J ) 7.5 Hz, 2H), 2.96
(t, J ) 6.7 Hz, 2H), 3.65 (s, 3H), 4.22 (t, J ) 6.7 Hz, 2H), 6.82
(d, J ) 8.6 Hz, 2H), 7.08 (d, J ) 8.6 Hz, 2H), 7.41 (m, 3H),
7.96 (m, 2H). Anal. (C22H23NO4) C, H, N.
3-[4-[2-(5-Meth yl-2-p h en yl-4-oxa zolyl)eth oxy]p h en yl]-
p r op ion ic Acid (5). A 1 N aqueous sodium hydroxide (50
mL, 50 mmol) was added to a solution of 6 (13 g, 35.6 mmol)
in methanol (400 mL). The reaction mixture was stirred for
15 h at room temperature, and the solvent was removed under
a vacuum. Then the residue was dissolved in water (200 mL)
and washed with ethyl acetate (50 mL). The aqueous solution
was acidified with 1 N hydrochloric acid to pH 2-3. The
precipitate was collected by filtration, washed with water, and
dried under a vacuum to give 5 as a colorless solid (12 g,
96%): mp 141.8-144.0 °C; 1H NMR (300 MHz, CDCl3) δ 2.37
(s, 3H), 2.62 (t, J ) 7.5 Hz, 2H), 2.89 (t, J ) 7.5 Hz, 2H), 2.97
(t, J ) 6.7 Hz, 2H), 4.21 (t, J ) 6.7 Hz, 2H), 6.82 (d, J ) 8.6
Hz, 2H), 7.09 (d, J ) 8.6 Hz, 2H), 7.41 (m, 3H), 7.96 (m, 2H).
Anal. (C21H21NO4) C, H, N.
3-[4-[2-(5-Meth yl-2-p h en yl-4-oxa zolyl)eth oxy]p h en yl]-
p r op ion a m id e (7). 6 (0.6 g, 1.64 mmol) was dissolved in a
mixture of 28% ammonium hydroxide (20 mL) and methanol
(30 mL). The mixture was stirred at room temperature
overnight, and the solvent was removed under a vacuum.
Ethyl acetate (50 mL) was added to the residue, and the
mixture was washed with 1 N aqueous sodium hydroxide (50
mL), water (50 mL), and brine (50 mL), dried over sodium
sulfate, and concentrated to give 7 as a colorless solid (0.47 g,
80%): mp 139.2-140.0 °C; 1H NMR (300 MHz, CDCl3) δ 2.37
(s, 3H), 2.48 (t, J ) 7.5 Hz, 2H), 2.90 (t, J ) 7.5 Hz, 2H), 2.97
(t, J ) 6.7 Hz, 2H), 4.22 (t, J ) 6.7 Hz, 2H), 5.20 (br s, 2H),
6.82 (d, J ) 8.5 Hz, 2H), 7.10 (d, J ) 8.5 Hz, 2H), 7.39-7.46
(m, 3H), 7.94-7.99 (m, 2H). Anal. (C21H22N2O3) C, H, N.
Diben zyl 2-[(Eth oxyca r bon yl)m eth yl]-2-[4-[2-(5-m eth -
yl-2-p h en yl-4-oxa zolyl)eth oxy]ben zyl]m a lon a te (23). 22
(26.0 g, 45.2 mmol) was added to a suspension of sodium
hydride (2.2 g, 54.2 mmol, 60% dispersion) in dry tetrahydro-
furan (250 mL) at 0 °C. When hydrogen evolution ceased, a
solution of ethyl bromoacetate (9.0 g, 54.2 mmol) in dry
tetrahydrofuran (50 mL) was added. The mixture was stirred
at room temperature for 1 h. The solution was poured into
iced water (200 mL) and extracted with ethyl acetate (3 × 100
mL). The combined extracts were washed with water (200 mL)
and brine (200 mL), dried over sodium sulfate, and concen-
trated. The residue was chromatographed on silica gel eluted
with ethyl acetate/hexane (1:3) to give 23 as a colorless oil (30.2
g, 100%): 1H NMR (300 MHz, CDCl3) δ 1.20 (q, J ) 7.1 Hz,
3H), 2.36 (s, 3H), 2.85 (s, 2H), 2.95 (t, J ) 6.7 Hz, 2H), 3.33 (s,
2H), 4.07 (q, J ) 7.1 Hz, 2H), 4.18 (t, J ) 6.7 Hz, 2H), 5.10 (d,
J ) 13.1 Hz, 1H), 5.12 (d, J ) 13.1 Hz, 1H), 6.69 (d, J ) 8.7
Hz, 2H), 6.85 (d, J ) 8.7 Hz, 2H), 7.20-7.33 (m, 10H), 7.41
(m, 3H), 7.98 (m, 2H).
Dim eth yl 5-[4-[2-(5-Eth yl-2-p yr id yl)eth oxy]ben zyl]m a -
lon a te (18). A solution of 2515 (8.0 g, 31.4 mmol) and dimethyl
malonate (6.21 g, 47.1 mmol) in toluene (100 mL) containing
a catalytic quantity of piperidinium acetate was refluxed in a
Dean-Stark trap for 40 min, and then concentrated.
A
solution of the residue in a mixture of methanol (30 mL) and
1,4-dioxane (30 mL) was stirred in the presence of 5%
palladium on charcoal (1.0 g) under 3.5 kg/cm2 of hydrogen at
room temperature until hydrogen uptake ceased. The solution
was filtered through Celite, and the filtrate was evaporated
under a vacuum. The residue was chromatographed on silica
gel eluting with ethyl acetate/hexane (3:7) to give 18 as a
yellow oil (4.60 g, 73%): 1H NMR (300 MHz, CDCl3) δ 1.24 (t,
J ) 7.6 Hz, 3H), 2.63 (q, J ) 7.5 Hz, 2H), 3.14 (d, J ) 7.5 Hz,
2H), 3.21 (t, J ) 6.6 Hz, 2H), 3.61 (t, J ) 6.8 Hz, 1H), 3.69 (s,
6H), 4.31 (t, J ) 6.8 Hz, 2H), 6.81 (d, J ) 9.6 Hz, 2H), 7.08 (d,
J ) 8.4 Hz, 2H), 7.18 (d, J ) 8.1 Hz, 1H), 7.45 (dd, J ) 2.1
and 7.8 Hz, 1H), 8.39 (d, J ) 2.1 Hz, 1H).
Biologica l P r oced u r e. 1. In Vit r o E n h a n cem en t of
Tr iglycer id e Accu m u la tion in 3T3-L1 Cells. The effect of
each compound on insulin-regulated differentiation 3T3-L1
cells was monitored by the rate of triglyceride accumulation.
Confluent 3T3-L1 cells were incubated in 5% fetal calf serum
with isobutylmethylxanthine (0.5 mM) and dexamethasone (1
µM) for 48 h. Cultures were then incubated in Dulbecco’s
modified Eagle’s medium/2% fetal calf serum for 4 days with
insulin (10 ng/mL) and the test compounds (10-5-10-9 M).
Cellular triglycerides were extracted with 2-propanol and
assayed by the enzymatic method using a commercially
available kit (MPR2 Triglycerides GPO-PAP, Boehringer Man-
nheim).
2. In Vivo Hyp oglycem ic Activity. The hypoglycemic
activity of each compound was evaluated using genetically
diabetic KKAy mice (male, 8 weeks old) obtained from Clea
J apan Inc., Tokyo, J apan. The mice were divided into experi-
mental groups of six or seven animals each according to their
blood glucose levels. The test compounds were mixed in CRF-1
powdered diet (Oriental Yeast Co. Ltd., Tokyo, J apan) and
were given for 4 days. A control group was treated in parallel
with the CRF-1 powdered diet alone. After 4 days of this
dietary administration to the mice, blood samples were taken
from the orbital vein, and the blood glucose level was deter-
mined using the glucose oxidase method. The decrease of
blood glucose was calculated as the percent change relative
to the level in the control group.
2-[(Eth oxyca r bon yl)m eth yl]-3-[4-[2-(5-m eth yl-2-p h en -
yl-4-oxa zolyl)eth oxy]p h en yl]p r op ion ic Acid (24). A solu-
tion of 23 (29.5 g, 44.6 mmol) in methanol (150 mL) was stirred
in the presence of 5% palladium on charcoal (2.0 g) under 3
kg/cm2 of hydrogen at room temperature until hydrogen
Ack n ow led gm en t. The authors are grateful to Drs.
Masami Tsuboshima, Hisashi Iwatsuka, and Tomoyuki
Yokoyama for their significant support.

1,3-Dicarbonyl Compounds as Hypoglycemic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1933
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