Molecular design, synthesis, and hypoglycemic and hypolipidemic activities of novel pyrimidine derivatives having thiazolidinedione

Article abstract of DOI:10.1016/j.ejmech.2005.03.019

We previously reported the synthesis and biological activity of novel substituted pyridines and purines having thiazolidinedione with hypoglycemic and hypolipidemic activities. We now report the synthesis and antidiabetic activity of novel substituted pyr

Full text of DOI:10.1016/j.ejmech.2005.03.019

European Journal of Medicinal Chemistry 40 (2005) 862–874
www.elsevier.com/locate/ejmech
Original article
Molecular design, synthesis, and hypoglycemic and hypolipidemic
activities of novel pyrimidine derivatives having thiazolidinedione
Hong Woo Lee a,*, BokYoung Kim a, Joong Bok Ahn a, Sung Kwon Kang a, Jung Hwa Lee a,
Jae Soo Shin a, Soon Kil Ahn a, Sang Joon Lee a, Seung SooYoon b
a New Drug Research Laboratories, Chong Kun Dang Research Institute, Cheonan P.O. Box 74, Cheonan 330-831, South Korea
b Department of Chemistry, Sung Kyun Kwan University, Natural Science Campus, Suwon 440-764, South Korea
Received 5 August 2004; received in revised form 7 March 2005; accepted 9 March 2005
Available online 23 May 2005
Abstract
We previously reported the synthesis and biological activity of novel substituted pyridines and purines having thiazolidinedione with
hypoglycemic and hypolipidemic activities. We now report the synthesis and antidiabetic activity of novel substituted pyrimidines having
thiazolidinedione moiety. These compounds (entry No. 5a–i, 10a–d and 16) were evaluated for their glucose and lipid lowering activity in
KKAy mice. From the results, novel compounds, 5c and 5g, exhibited considerably more potent biological activity than that of the reference
compounds, pioglitazone and rosiglitazone, respectively.
© 2005 Elsevier SAS. All rights reserved.
Keywords: Type 2 diabetes; PPARs; TZD compounds; Glucose and lipid lowering activity; Substituted pyrimidine derivatives
1. Introduction
the PPARc agonists have emerged a new class of antidiabetic
agents to treat type 2 diabetes. These agents share a common
partial chemical structure: thiazolidine-2,4-dione (TZD). The
TZD are a group of pharmacological agents that enhance insu-
lin action (insulin sensitizes) and promote glucose utilization
in peripheral tissues. Between 1997 and 1999, a new class of
drugs (Avandia and Actos) called glitazones [5,6] was
approved by FDA for the treatment of type 2 diabetes (Fig. 1)
[7,8]. Although their exact mechanism of action has not been
completely elucidated, it has been demonstrated that TZD
elicit their pharmacological actions by binding and activat-
ing nuclear receptor PPARc [9,10]. It is hypothesized that
their activation by TZDs affect the expression of a number of
genes involved in lipid and glucose metabolism and preadi-
pocyte differentiation [11,12]. Recently, several compounds
have been reported to have both PPARa/c dual agonistic acti-
vation. Among these compounds, KRP-297 (Kyorin/Merck)
C [13,14], Netoglitazone (Mitsubishi/J & J) D [15] and
AZ-242 (AstraZeneca) E [16] were comprised (Fig. 1).
Type 2 diabetes is growing epidemic, affecting an esti-
mated 16 million people in the United States [1,2]. An addi-
tional 16 million people in the United States have the predia-
betic condition of impaired glucose tolerance (IGT) [2]. Type
2 diabetes is a metabolic disorder characterized by hypergly-
cemia as well as insulin resistance and/or impaired insulin
secretion. This increased risk of macrovascular disease in both
type 2 diabetes and IGT is intricately associated with the pres-
ence of insulin resistance, which refers to an impaired ability
for the body to respond appropriately to insulin and utilize
glucose [3]. Insulin resistance and hyperinsulinemia are
closely associated with a cluster of metabolic abnormalities
termed the insulin resistance syndrome [3]. These metabolic
disease not only include hyperglycemia and glucose intoler-
ance, but also other cardiovascular risk factors, including dys-
lipidemia, hypertension, abnormal fibrinolysis, atheroscle-
rotic disease [4]. Following the initial report of a novel
antidiabetic agent ciglitazone [5] from Takeda laboratories,
Herein we describe our efforts to identify novel potent glu-
cose and lipid lowering compounds. The design of a novel
pyrimidine TZD derivatives structure came from the pyrroli-
dine series that had been studied earlier in our laboratories
* Corresponding author. Tel.: +82 41 529 3330; fax: +82 41 558 3004.
E-mail address: hwlee@ckdpharm.com (H.W. Lee).
0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.03.019

H.W. Lee et al. / European Journal of Medicinal Chemistry 40 (2005) 862–874
863
Table 1
Effect on triglyceride accumulation in 3T3-L1 cells, cytotoxicity and safety
index for the substituted pyrimidine derivatives
Compound
Effect on TG
accumulation in
3T3-L1 cells (EC50
µM)a
Cytotoxicity
(TC25, µM)b
Safety
index
(toxicity/
activity)
35,045
1760
,
5a
5b
0.0012
0.01
77
18
5c
5d
0.0012
0.1
59.4
94
49,500
1085
5e
0.008
21
2625
5f
0.009
50
5555
5g
5h
5i
10a
10b
10c
0.00041
0.0012
0.0045
0.0003
0.002
35
85,122
62,833
8822
75
40
25
83,333
45,000
2100
90
0.01
21
Fig. 1
.
10d
0.4
98
245
16
1.6
>200
130
200
121
[17,18]. Some of the partial structure of substituted moiety
were derived from recently reported a novel pyridine and
purine TZD derivatives [19]. Considering their biological
activity and structure of our previously reported compounds,
we could infer that substituted pyrrolidines and pyridines con-
taining TZD were more efficacious than reference com-
pound, rosiglitazone. Therefore, in order to enhance glucose
and lipid lowering activities, we focused our attention on the
modification of pyrimidine moiety having TZD. As a result,
we describe the design, synthesis and biological activities of
novel substituted pyrimidine derivatives containing TZD, con-
ceptually issued from modification of rosiglitazone.
The novel substituted pyrimidine analogues having TZD
moiety (entry No. 5a–i, 10a–d, 16) were synthesized and
evaluated their effect on triglyceride accumulation in 3T3-
L1 cells. Also, their hypoglycemic and triglyceride lowering
effects examined in KKAy mice (Tables 1 and 2). Among
synthesized analogues, 5-[4-{2-(6-[4-methoxyphenoxy]-
pyrimidin-4-yl)methylaminoethoxy}benzyl]thiazolidine-2,4-
dione (5g) showed the most excellent biological activity and
is presently under further pharmacological studies.
Rosiglitazone
Pioglitazone
0.047
2766
0.015
13,333
a Effective concentration for 50% enhancement of insulin-induced trigly-
ceride accumulation in 3T3-L1 cells.
b Toxic concentration (tc25) means increase 25% of neutral red uptake in
cultured rat hepatocytes.
Table 2
Glucose and triglyceride lowering effect in KKAY mice
Compound
ED25a (mg kg –1 day–1
)
ED25a (mg kg –1 day–1
)
plasma glucose
triglyceride
7.4
5c
5g
2.0
1.7
5.6
4.1
6.0
3.4
10a
Rosiglitazone
Pioglitazone
>30
>30
6.0
a Effective doses for 25% decrease in plasma and triglyceride levels were
estimated from the dose–response curves obtained with three doses.
DMF to furnish benzaldehyde compounds 3a–i in good yield.
Knoevenagel4s condensation [20] of benzaldehyde com-
pounds 3a–i with 2,4-thiazolidinedione in the presence of pip-
eridine in EtOH gave unsaturated thiazolidinedione ana-
logues 4a–i. The desired compounds 5a–i were prepared by
reduction with 20 wt.% Pd(OH)2 on carbon (Pearlman4s cata-
lyst) under hydrogen atmosphere.
2. Chemistry
Secondly, 5-position substituted pyrimidine derivatives
containing thiazolidinedione 10a–d were synthesized as
shown in Fig. 3. Amination of 5-bromo-2-chloropyrimidine
with 2-methylaminoethanol gave the compound 6. 5-Position
substituted pyrimidine compounds 7a–d were obtained
through Stille coupling with the appropriately substituted
(2-furanyl, phenyl, 2-pyridinyl and 2-thiophenyl) tri-n-butyl
stannanes agent in the presence of Pd(pph3)4 [tetrakis(triph-
enylphosphine)palladium] catalyst [21,22]. Compounds 7a–d
were reacted with 4-fluorobenzaldehyde in the presence of
NaH in DMF to furnish benzaldehyde compounds 8a–d.
Preparation of the desired 5-position substituted pyrimidine
derivatives having TZD 10a–d were obtained via catalytic
hydrogenation with 20 wt.% Pd(OH)2 under hydrogen atmo-
Several novel substituted pyrimidines with TZD were
designed and prepared as follows. General strategies to syn-
thesize novel thiazolidinediones are shown in Figs. 2–4. First
of all, 4-position substituted pyrimidine derivatives having
TZD moiety 5a–i were synthesized as depicted in Fig. 2.
Treatment of 4,6-dichloropyrimidine and methanol, isopro-
panol, phenol, substituted phenol, or aniline in the presence
of NaH in DMF generated the several 4-position substituted
pyrimidine compounds 1a–i, which were converted to sub-
stituted N-methylaminoalcohol compounds 2a–i by amina-
tion with 2-methylaminoethanol. Compounds 2a–i were then
reacted with 4-fluorobenzaldehyde in the presence of NaH in

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H.W. Lee et al. / European Journal of Medicinal Chemistry 40 (2005) 862–874
Fig. 2. (a) RH, NaH, DMF, RT, 5–10 h; (b) 2-methylaminoethanol, EtOH,
Fig. 4. (a) Isoamyl nitrite, Cu2O, benzene, reflux, 3 h; (b) 2-methyl-
reflux, 24 h; (c) 4-fluorobenzaldehyde, NaH, DMF, RT, 5 h; (d) 2,4-
thiazolidinedione (TZD), piperidine, EtOH, reflux, 24 h; (e) 20% Pd(OH)2,
H2, DMF, RT, 24–36 h.
aminoethanol, dichloromethane, reflux, 24 h; (c) 10% Pd/C, H2, Et3N, EtOH–
EtOAc (1:1 v/v), 15 h; (d) 4-fluorobenzaldehyde, NaH, DMF, RT, 4 h; (e)
2,4-thiazolidinedione (TZD), piperidine, EtOH, reflux, 24 h; (f) 20%
Pd(OH)2, H2, DMF/MeOH (1:2 v/v), RT, 4 days.
from compound 12. The desired compound 16 was prepared
by O-arylation, Knoevenagel4s reaction and reduction,
respectively, using the described procedure in Figs. 2 and 3.
3. Biology
The glucose and lipid lowering activities of the com-
pounds were tested using genetically diabetic KKAy mice [25]
and the effect on insulin-regulated differentiation was moni-
tored from the rate of triglyceride accumulation in 3T3-
L1 cells [26]. In vitro cytotoxicity of the compounds was
evaluated in cultured rat liver hepatocytes and neutral red
uptake was used as a cytotoxicity end point [27,28].
3.1. Materials
Fig. 3. (a) 2-Methylaminoethanol, RT, 1 h; (b) n-Bu3Sn R, Pd (pph3)4, toluene,
reflux, 9 h; (c) 4-fluorobenzaldehyde, NaH, DMF, RT, 6 h; (d) piperidine,
acetic acid, 2,4-thiazolidinedione, toluene, reflux, 5 h; (e) 20% Pd(OH)2,
H2, DMF, RT, 36 h.
The reference standard compounds, rosiglitazone and
pioglitazone, were synthesized in house by the published pro-
cedure and were found to be 99% pure.
sphere from compounds 9a–d, which were obtained under
Knoevenagel4s condition by reacting compounds 8a–d with
2,4-thiazolidinedione as shown in Fig. 4.
3.2. In vitro enhancement of triglyceride accumulation in
3T3-L1 cells
Finally, 2-position substituted pyrimidine compound hav-
ing thiazolidinedione 16 was synthesized as shown in Fig. 4.
Treatment of 2-amino-4,6-dichloropyrimidine and benzene
in the presence of isoamyl nitrite and copper (I) oxide (Cu2O)
generated the compound 11, which was converted to
N-methylaminoalcohol compound 12 by amination with
2-methylaminoethanol [20]. Compound 13 was obtained via
catalytic palladium hydrogenolysis [23,24] of aryl chloride
in the presence of Et3N in EtOH under hydrogen atmosphere
The effect of each compound on insulin-regulated differ-
entiation 3T3-L1 cells was monitored by the rate of triglyc-
eride accumulation. Confluent 3T3-L1 cells were incubated
in 10% heat-inactivated fetal bovine serum with isobutylm-
ethylxanthine (0.5 mM) and dexamethasone (0.25 µM) for
48 h. Cultures were then incubated in Dulbecco4s modified
Eagle4s medium/2% fetal bovine serum for 4 days with insu-

H.W. Lee et al. / European Journal of Medicinal Chemistry 40 (2005) 862–874
865
lin (10 µg ml–1) and the test compounds (3 × 10–5–3 ×
10–11 M). Cellular triglycerides were extracted with isopro-
panol and assayed by the enzymatic method using a commer-
cially available kit (TG kit, Young Dong Diagnostics, Seoul,
South Korea).
3.3. In vivo hypoglycemic activity
The hypoglycemic activity of each compound was evalu-
ated using genetically diabetic KKAy mice (male, 8 weeks
old) purchased from Clea Japan Inc., Tokyo, Japan. All ani-
mals were maintained at 25 2 °C on a 12-h light/12-h dark
cycle. The animals were given standard laboratory chow (Jeil
Saryo Inc., South Korea) and water ad libitum. The KKAy
mice were used for experiments at 9 weeks of age. The mice
were divided into experimental groups of four or five ani-
mals each according to their blood glucose levels. The test
compounds (1, 6, 30 mg kg–1) were orally administrated to
fed animals for 5 days. Animals in control groups received
vehicle (0.5% Sodium CMC, 10 ml kg–1). Blood samples were
collected from fed animals under mild ether anesthesia from
retro-orbital sinus 4 h after test compounds administration.
The plasma glucose and triglyceride levels were determined
by enzyme methods using the Glucose-E and TG kits (Young
Dong Diagnostics, Seoul, South Korea). The effective dose
to reduce plasma glucose and triglyceride levels by 25%
(ED25) was determined using results of an experiment in
which three different doses were tested.
Fig. 5
.
for antidiabetic agents to treat type 2 diabetes, we prepared
several novel thiazolidinedione analogues containing substi-
tuted pyrimidine moiety as designed in Fig. 5 and evaluated
their biological profiles for hypoglycemic and triglyceride
lowering activities in KKAy mice. Basically, these com-
pounds are issued from rosiglitazone, itself derived from
pioglitazone by modification of ethyl ether linkage contain-
ing nitrogen atom between the pyridine group and thiazo-
lidinedione moiety. This modification has dramatically
improved hypoglycemic activity compared to pioglitazone in
KKAy mice [29,30]. Thus, the pyrimidine analogues with
three differently oriented substituents 5a–i, 10a–i and 16 were
designed in order to examine the effect of pharmacophore
sites by introduction of hydrophobic functional groups to
rosiglitazone via routes I–III, respectively, synthesized and
evaluated their biological activities. As a result, almost 4- or
5-position substituted pyrimidine derivatives showed a better
triglyceride accumulation activity in 3T3-L1 cells than that
of reference compounds (rosiglitazone and pioglitazone),
except for compounds 5d and 10d as shown in Table 1. Espe-
cially, compounds 5a, 5c, 5g, and 5h not only showed an
excellent hypoglycemic activity but also had better safety
index than reference compounds. However, compounds 5b
and 10c exhibited moderate triglyceride accumulation activ-
ity in 3T3-L1 cells (Table 1). Idiosyncratically, compounds
5d and 10d, introduced phenylamino and 2-thiophenyl group,
respectively, showed relatively less triglyceride accumula-
tion activity. Although the exact reason for relatively high
triglyceride accumulation activity was not clear, these results
indicate that hydrophobicity and orientation of substituent of
the pyrimidine moiety affect the triglyceride accumulation
activity in 3T3-L1 cells. But, 2-position substituted pyrimi-
dine compound 16 dramatically reduced the activity com-
3.4. Cytotoxicity in cultured rat liver hepatocytes
Primary cultures of hepatocytes isolated by collagenase
perfusion of adult rat were used as an in vitro system for
assessing cytotoxicity of the compounds. Liver hepatocytes
were isolated from male Sprague–Dawley rats weighing about
200 g by the collagenase perfusion method of Seglen [32].
Cells with > 85% viability (confirmed by trypan blue exclu-
sion) were distributed onto collagen type I-coated 24 well
plates at a subconfluent density (105 cells per cm2), and cul-
tured in DMEM containing 5 mM glucose, 10% heat-
inactivated FBS, 10–7 M human insulin, and 10–6 M dexam-
ethasone.After incubation for 24 h, the medium was collected
and the cells were washed twice with phosphate-buffered
saline. Then, hepatocytes were cultured in serum-free DMEM
as described above. This medium was supplemented with
either 12.5, 25, 50, 100 or 200 µM compounds or with the
solvent (1% DMSO) only. Cells were exposed to the com-
pounds and/or solvent for 24 h. All cultures were performed
at 37 °C in an atmosphere of 5% CO2 and 95% air with a
relative humidity of 100%. Cytotoxicity of the compounds
tested was determined by means of the Neutral Red uptake
assay [31].
4. Results and discussion
In the course of our extensive and consecutive research
program for searching more efficient and potent compounds

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H.W. Lee et al. / European Journal of Medicinal Chemistry 40 (2005) 862–874
pared to 4- or 5-position substituted pyrimidine derivatives.
Considering the biological activities, 4- or 5-position substi-
tuted pyrimidine derivatives 5c, 5g and 10a, were selected as
primary candidates in order to examine the hypoglycemic and
hypolipidemic activities in KKAy mice [31] in vivo. The sub-
stituted pyrimidine derivatives 5c, 5g and 10a caused a 25%
decrease of plasma glucose (ED25%) at an oral dose of 2.0,
1.7 and 5.6 mg kg–1 day–1, respectively, while reference com-
pounds, rosiglitazone and pioglitazone, caused a 25% de-
crease of plasma glucose (ED25%) at 4.1 and 6.0 mg
kg–1 day–1, respectively, as shown in Table 2. Particularly,
compound 5g having para-methoxyphenoxy group at the
4-position of the pyrimidine moiety, 5g exhibited an approxi-
mately 2.4-fold and 3.5-fold increase in glucose lowering
activity than rosiglitazone and pioglitazone, respectively
(Table 2).Also, in KKAy mice, the oral lipid lowering ED25%
values of 5c, 5g and 10a also were 7.4, 3.4 and > 30 mg
kg–1 day–1, respectively, while ED25% values of rosiglita-
zone and pioglitazone were > 30 and 6.0 mg kg–1 day–1,
respectively. The data reviewed herein indicate that the glu-
cose and lipid lowering activities of the compound 5g was
more potent than reference compounds (rosiglitazone and
pioglitazone).
drous methanol (0.27 ml, 6.71 mmol) and 4,6-dichloro-
pyrimidine (1 g, 6.71 mmol) under N2 atmosphere at room
temperature for 1 h. After stirring at room temperature for
3 h, the reaction mixture was poured into ice-water solution
and extracted with EtOAc (100 ml). The organic layer was
washed with water and brine, dried over Na2SO4, and con-
centrated in vacuo to leave a colorless oil residue which was
purified by column chromatography on SiO2 with
n-hexane/EtOAc (10:1, v/v) to give the title compound 1a
(464 mg, 45% yield). IR (CHCl3) mmax cm–1: 3445, 2917,
1652. 1H-NMR (400 MHz, CDCl3) d: 4.02 (s, 3H), 6.79 (s,
1H), 8.60 (s, 1H). MS (ESI) m/z (M + 1) 145.
The following compounds 1b–i were obtained by a simi-
lar procedure to that described for the preparation of 1a.
6.1.2. Preparation of 4-chloro-6-isopropoxypyrimidine
(1b)
Yield: 86%. IR (CHCl3) mmax cm–1: 2933, 1590, 1464.
1H-NMR (400 MHz, CDCl3) d: 1.37, 5.29 (m, 1H), 6.71 (s,
1H), 8.56 (s, 1H). MS (ESI) m/z (M + 1) 173.
6.1.3. Preparation of 4-chloro-6-phenoxypyrimidine (1c)
Yield: 87%. IR (CHCl3) mmax cm–1: 2923, 2852, 1557,
1457. 1H-NMR (400 MHz, CDCl3) d: 6.93 (s, 1H), 7.16 (m,
2H), 7.33 (m, 1H), 7.48 (m, 2H), 8.61 (s, 1H). MS (ESI) m/z
(M + 1) 207.
5. Conclusion
We designed, synthesized and evaluated novel substituted
pyrimidine derivatives having TZD moiety as glucose and
lipid lowering agents. We obtained more potent compounds
5c and 5g in comparison with known reference compounds
(pioglitazone and rosiglitazone). Among these compounds,
5g was selected for further investigation because of its bio-
logical activity and synthetic feasibility.
6.1.4. Preparation of (6-chloropyrimidin-4-yl)phenylamine
(1d)
Yield: 36%. IR (CHCl3) mmax cm–1: 2955, 1745, 1689.
1H-NMR (400 MHz, CDCl3) d: 6.72 (s, 1H), 7.32 (m, 3H),
7.43 (m, 2H), 7.65 (bs, NH), 8.46 (s, 1H). MS (ESI) m/z (M +
1) 206.
6. Experimental
6.1.5. Preparation of 4-chloro-6-(4-fluorophenoxy)pyrimi-
dine (1e)
6.1. Synthesis
Yield: 73%. IR (CHCl3) mmax cm–1: 1562, 1546, 1505,
1444. 1H-NMR (400 MHz, CDCl3) d: 6.93 (s, 1H), 7.12 (m,
4H), 8.58 (s, 1H). MS (ESI) m/z (M + 1) 225.
All reactions were conducted under anhydrous condition
in solvents dried over molecular sieves type 4 Å under nitro-
gen atmosphere and performed using oven dried glassware.
Melting points were determined on a Buchi 510 capillary
apparatus and are uncorrected. IR spectra were recorded on a
Bruker Vector 22 FT-IR spectrometer. NMR spectra were
recorded on a Bruker DPX 400 MHz instrument operating at
400 MHz for proton and 100 MHz for carbon NMR and were
performed in DMSO-d6 solutions using tetramethylsilane as
an internal reference except where indicated otherwise. The
coupling constants (J) are reported in Hz. Mass spectra were
recorded on a HP 5989B instrument. Flash chromatography
was performed using Merck silica gel 60 (230–400 mesh)
according to the published procedure.
6.1.6. Preparation of 4-chloro-6-(4-chlorophenoxy)pyrimi-
dine (1f)
Yield: 90%. IR (CHCl3) mmax cm–1: 1557, 1485, 1444.
1H-NMR (400 MHz, CDCl3) d: 6.95 (s, 1H), 7.10 (m, 2H),
7.42 (m, 2H), 8.58 (s, 1H). MS (ESI) m/z (M + 1) 241.
6.1.7. Preparation of 4-chloro-6-(4-methoxyphenoxy)pyri-
midine (1g)
Yield: 81%. IR (CHCl3) mmax cm–1: 3355, 2935, 1592,
1548. 1H-NMR (400 MHz, CDCl3) d: 6.89 (s, 1H), 6.98 (m,
2H), 7.07 (m, 2H), 8.60 (s, 1H). MS (ESI) m/z (M + 1) 237.
6.1.8. Preparation of 4-chloro-6-(3,4-dimethoxyphenoxy)-
pyrimidine (1h)
6.1.1. Preparation of 4-chloro-6-methoxypyrimidine (1a).
General procedure
To a suspension of sodium hydride (60% dispersion in min-
eral oil, 537 mg, 13.4 mmol) in DMF (30 ml) was added anhy-
Yield: 82%. IR (CHCl3) mmax cm–1: 2936, 1559, 1508,
1442. 1H-NMR (400 MHz, CDCl3) d: 3.88 (s, 3H), 3.92 (s,

H.W. Lee et al. / European Journal of Medicinal Chemistry 40 (2005) 862–874
867
3H), 6.71 (m, 2H), 6.89 (m, 2H), 8.61 (s, 1H). MS (ESI) m/z
(m, 2H), 3.87 (m, 2H), 5.88 (s, 1H), 7.11 (m, 4H), 8.25 (s,
(M + 1) 267.
1H). MS (ESI) m/z (M + 1) 264.
6.1.9. Preparation of 4-(biphenyl-4-yloxy)-6-chloropyrimi-
dine (1i)
6.1.15. Preparation of 2-[6-(4-chlorophenoxy)pyrimidin-4-
yl]methylaminoethanol (2f)
Yield: 70%. IR (CHCl3) mmax cm–1: 3064, 1565, 1485,
1448. 1H-NMR (400 MHz, CDCl3) d: 6.99 (s, 1H), 7.24 (m,
2H), 7.41 (m, 1H), 7.48 (m, 2H), 7.61 (m, 2H), 7.69 (m, 2H),
8.64 (s, 1H). MS (ESI) m/z (M + 1) 283.
Yield: 95%. IR (CHCl3) mmax cm–1: 3367, 2934, 1605,
1584, 1486. 1H-NMR (400 MHz, CDCl3) d: 3.17 (s, 3H), 4.07
(m, 2H), 4.30 (m, 2H), 5.93 (s, 1H), 7.09 (m, 2H), 7.37 (m,
2H), 8.31 (s, 1H). MS (ESI) m/z (M + 1) 280.
6.1.10. Preparation of 2-[(6-methoxypyrimidin-4-yl)methy-
lamino]ethanol (2a). General procedure
6.1.16. Preparation of 2-[6-(4-methoxyphenoxy)pyrimidin-
4-yl]methylaminoethanol (2g)
To the stirred solution of 1a (460 mg, 3.18 mmol) in anhy-
drous ethanol (30 ml) was added 2-methylaminoethanol
(0.76 ml, 9.54 mmol), and the mixture was refluxed for 24 h
under N2 atmosphere. The reaction mixture was cooled to
room temperature, quenched with NH4Cl solution (50 ml),
and extracted with EtOAc (120 ml). The extracted organic
layers were washed with water and brine (50 ml), respec-
tively, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by column chromatogra-
phy over SiO2 using a mixture of n-hexane/EtOAc (2:3 v/v)
as eluent to get the title compound 2a as a foam (580 mg,
99% yield). IR (CHCl3) mmax cm–1: 2917, 16647, 1595, 1550.
1H-NMR (400 MHz, CDCl3) d: 3.07 (s, 3H), 3.80 (m, 2H),
3.87 (m, 2H), 5.79 (s, 1H), 8.32 (s, 1H). MS (ESI) m/z (M +
1) 184.
Yield: quantitative. IR (CHCl3) mmax cm–1: 3355, 2935,
1592, 1546, 1504, 1441. 1H-NMR (400 MHz, CDCl3) d: 3.05
(s, 3H), 3.65 (bs, OH), 3.78 (m, 2H), 3.85 (m, 5H), 5.84 (s,
1H), 6.93 (m, 2H), 7.06 (m, 2H), 8.27 (s, 1H). MS (ESI) m/z
(M + 1) 276.
6.1.17. Preparation of 2-[6-(3,4-dimethoxyphenoxy)pyri-
midin-4-yl]methylamino-ethanol (2h)
Yield: quantitative. IR (CHCl3) mmax cm–1: 2935, 1590,
1
1578, 1507, 1438. H-NMR (400 MHz, CDCl3) d: 3.05 (s,
3H), 3.65 (bs, OH), 3.78 (m, 2H), 3.85 (m, 5H), 5.84 (s, 1H),
6.93 (m, 2H), 7.06 (m, 2H), 8.27 (s, 1H). MS (ESI) m/z (M +
1) 306.
6.1.18. Preparation of 2-[6-(biphenyl-4-yloxy)pyrimidin-4-
yl]methylaminoethanol (2i)
The following compounds 2b–i were obtained by a simi-
lar procedure to that described for the preparation of 2a.
Yield: 100%. IR (CHCl3) mmax cm–1: 1591, 1545, 1485,
1441. 1H-NMR (400 MHz, CDCl3) d: 3.09 (s, 3H), 3.65 (bs,
OH), 3.81 (m, 2H), 3.89 (m, 2H), 5.95 (s, 1H), 7.21 (m, 2H),
7.36 (m, 1H), 7.48 (m, 2H), 7.63 (m, 4H), 8.30 (s, 1H). MS
(ESI) m/z (M + 1) 322.
6.1.11. Preparation of 2-[(6-isopropoxypyrimidin-4-yl)m-
ethylamino]ethanol (2b)
Yield: 73%. IR (CHCl3) mmax cm–1: 2978, 2933, 1594,
1504. 1H-NMR (400 MHz, CDCl3) d: 1.34 (d, J = 6.22 Hz,
6H), 3.03 (s, 3H), 3.74 (m, 2H), 3.84 (m, 2H), 4.10 (bs, OH),
5.31 (m, 1H), 5.71 (s, 1H), 8.24 (s, 1H). MS (ESI) m/z (M +
1) 212.
6.1.19. Preparation of 4-{2-[(6-methoxypyrimidin-4-
yl)methylamino]ethoxy}benzaldehyde (3a). General proce-
dure
To a suspension of sodium hydride (60% in mineral oil,
253 mg, 6.33 mmol) in anhydrous DMF (30 ml) was added
compound 2a (580 mg, 3.16 mmol) and the mixture was
stirred for 30 min. And then 4-fluorobenzaldehyde (0.68 ml,
6.33 mmol) was added slowly in the reaction mixture under
N2 atmosphere at room temperature.After stirring at the same
temperature for 3 h, the reaction mixture was quenched with
aqueous NH4Cl solution (10 ml), poured into ice-water solu-
tion (25 ml), and extracted with EtOAc (80 ml). The extract
was washed with water and brine (50 ml), dried over Na2SO4,
and concentrated by evaporation under reduced pressure. The
concentrate thus obtained was purified by column chroma-
tography on SiO2 using a mixture of n-hexane/EtOAc (1:1,
v/v) as eluent to give a title compound 3a. (370 mg, 41%
yield). IR (CHCl3) mmax cm–1: 2945, 2796, 1696, 1593, 1543,
1507. 1H-NMR (400 MHz, CDCl3) d: 3.13 (s, 3H), 3.93 (s,
3H), 4.03 (m, 2H), 4.27 (m, 2H), 5.76 (s, 1H), 7.01 (m, 2H),
7.84 (m, 2H), 8.33 (s, 1H), 9.89 (s, 1H). MS (ESI) m/z (M +
1) 288.
6.1.12. Preparation of 2-[methyl-(4-phenoxypyridin-2-
yl)amino]ethanol (2c)
Yield: 85%. IR (CHCl3) mmax cm–1: 2955, 1725, 1571,
1505. 1H-NMR (400 MHz, CDCl3) d: 3.05 (s, 3H), 3.78 (m,
2H), 3.85 (m, 2H), 5.87 (s, 1H), 7.13 (m, 2H), 7.26 (m, 1H),
7.42 (m, 2H), 8.27 (s, 1H). MS (ESI) m/z (M + 1) 246.
6.1.13. Preparation of 2-[methyl-(6-phenylaminopyrimi-
din-4-yl)amino]ethanol (2d)
Yield: 98%. IR (CHCl3) mmax cm–1: 3240, 2985, 1659,
1585. 1H-NMR (400 MHz, CDCl3) d: 2.99 (s, 3H), 3.74 (m,
2H), 3.84 (m, 2H), 5.84 (s, 1H), 6.83 (bs, NH), 7.18 (m, 1H),
7.32 (m, 2H), 7.41 (m, 2H), 8.20 (s, 1H). MS (ESI) m/z (M +
1) 245.
6.1.14. Preparation of 2-[6-(4-fluorophenoxy)pyrimidin-4-
yl]methylaminoethanol (2e)
Yield: quantitative. IR (CHCl3) mmax cm–1: 2919, 1594,
1501, 1417. 1H-NMR (400 MHz, CDCl3) d: 3.07 (s, 3H), 3.78

868
H.W. Lee et al. / European Journal of Medicinal Chemistry 40 (2005) 862–874
The following compounds 3b–i were obtained by a simi-
1H), 6.69 (m, 2H), 6.89 (m, 1H), 7.00 (m, 2H), 7.84 (m, 2H),
lar procedure to that described for the preparation of 3a.
8.34 (s, 1H), 9.90 (s, 1H). MS (ESI) m/z (M + 1) 410.
6.1.20. Preparation of 4-{2-[(6-isopropoxypyrimidin-4-yl)-
methylamino]ethoxy}benzaldehyde (3b)
6.1.27. Preparation of 4-(2-{[6-(biphenyl-4-yl-oxy)pyrimi-
din-4-yl]methylamino} ethoxy)benzaldehyde (3i)
Yield: 84%. IR (CHCl3) mmax cm–1: 2935, 1693, 1586,
1544, 1507, 1485, 1440. 1H-NMR (400 MHz, CDCl3) d: 3.17
(s, 3H), 4.08 (m, 2H), 4.31 (m, 2H), 5.97 (s, 1H), 7.01 (d, J =
1.77 Hz, 2H), 7.21 (m, 2H), 7.36 (m, 1H), 7.45 (m, 2H), 7.63
(m, 4H), 7.86 (m, 2H), 8.36 (s, 1H), 9.90 (s, 1H). MS (ESI)
m/z (M + 1) 426.
Yield: 24%. IR (CHCl3) mmax cm–1: 2940, 1691, 1601,
1
1584, 1507. H-NMR (400 MHz, CDCl3) d: 1.36 (d, J =
6.16 Hz, 6H), 3.16 (s, 3H), 4.07 (m, 2H), 4.29 (m, 2H), 5.34
(m, 1H), 6.97 (m, 2H), 7.84 (m, 2H), 8.35 (s, 1H), 9.89 (s,
1H). MS (ESI) m/z (M + 1) 316.
6.1.21. Preparation of 4-{2-[(6-phenoxypyrimidin-4-yl)-
methylamino]ethoxy}benzaldehyde (3c)
6.1.28. Preparation of 5-(4-2-[(6-methoxypyrimidin-4-
yl)methylamino]ethoxybenzyl idene)thiazolidine-2,4-dione
(4a). General procedure
Yield: 85%. IR (CHCl3) mmax cm–1: 2932, 1691, 1599,
1501. 1H-NMR (400 MHz, CDCl3) d: 3.15 (s, 3H), 4.06 (m,
2H), 4.29 (m, 2H), 5.90 (s, 1H), 7.01 (m, 2H), 7.14 (m, 2H),
7.26 (m, 1H), 7.42 (m, 2H), 7.86 (m, 2H), 8.33 (s, 1H), 9.91
(s, 1H). MS (ESI) m/z (M + 1) 350.
A mixture of an aldehyde compound 3a (370 mg,
1.29 mmol), 2,4-thiazolidinedione (196 mg, 1.68 mmol), and
piperidine (0.17 ml, 1.68 mmol) in anhydrous ethanol (80 ml)
was refluxed for 24 h. The reaction mixture was cooled to
room temperature, and diluted with EtOAc. The diluted mix-
ture was washed with water (90 ml) and brine (200 ml), and
dried over MgSO4, and concentrated by evaporation under
reduced pressure. The obtained residue was purified by col-
umn chromatography on SiO2 with n-hexane/EtOAc (3:1, v/v)
as eluent to give the title compound 4a as an off-white solid
(356 mg, 73% yield). M.p.: 151–153 °C. IR (CHCl3) mmax
cm–1: 2964, 1727, 1697, 1611, 1592, 1513. 1H-NMR
(400 MHz, DMSO-d6) d: 3.07 (s, 3H), 3.82 (s, 3H), 3.94 (m,
2H), 4.22 (m, 2H), 5.93 (s, 1H), 7.10 (m, 2H), 7.55 (m, 2H),
7.73 (s, 1H), 8.24 (s, 1H). 13C-NMR (100 MHz, DMSO-d6)
d: 41.4, 56.0, 58.8, 71.3, 99.2, 114.1, 120, 126.5, 126.8, 142,
154.9, 158.0, 166.3, 167.1, 169.8, 174.0. MS (ESI) m/z (M +
1) 387.
6.1.22. Preparation of 4-{2-[methyl(6-phenylaminopyrimi-
din-4-yl)amino]ethoxy}benzaldehyde (3d)
Yield: 33%. IR (CHCl3) mmax cm–1: 2932, 1691, 1599,
1501. 1H-NMR (400 MHz, CDCl3) d: 3.08 (s, 3H), 4.02 (m,
2H), 4.27 (m, 2H), 5.87 (s, 1H), 6.76 (bs, NH), 7.01 (m, 2H),
7.17 (m, 1H), 7.29 (m, 2H), 7.37 (m, 2H), 7.84 (m, 2H), 8.27
(s, 1H), 9.89 (s, 1H). MS (ESI) m/z (M + 1) 349.
6.1.23. Preparation of 4-{2-[6-(4-fluorophenoxy)pyrimi-
din-4-yl]methylaminoethoxy} benzaldehyde (3e)
Yield: 79%. IR (CHCl3) mmax cm–1: 2917, 1684, 1589,
1506. 1H-NMR (400 MHz, CDCl3) d: 3.16 (s, 3H), 4.07 (m,
2H), 4.30 (m, 2H), 5.91 (s, 1H), 7.02 (m, 2H), 7.09 (m, 4H),
7.85 (m, 2H), 8.31 (s, 1H), 9.91 (s, 1H). MS (ESI) m/z (M +
1) 368.
The following compounds 4b–i were obtained by a simi-
lar procedure to that described for the preparation of 4a.
6.1.24. Preparation of 4-{2-[6-(4-chlorophenoxy)pyrimi-
din-4-yl]methylaminoethoxy} benzaldehyde (3f)
Yield: 79%. IR (CHCl3) mmax cm–1: 2939, 1691, 1599,
1583, 1485. 1H-NMR (400 MHz, CDCl3) d: 3.17 (s, 3H), 4.08
(m, 2H), 4.30 (m, 2H), 5.93 (s, 1H), 7.01 (m, 2H), 7.10 (m,
2H), 7.36 (m, 2H), 7.84 (m, 2H), 8.31 (s, 1H), 9.90 (s, 1H).
MS (ESI) m/z (M + 1) 384.
6.1.29. Preparation of 5-(4-2-[(6-isopropoxypyrimidin-4-
yl)methylamino]ethoxybenzyl idene)thiazolidine-2,4-dione
(4b)
Yield: 48%. M.p.: 170–172 °C. IR (CHCl3) mmax cm–1:
1
2977, 1735, 1699, 1593, 1508, 1456. H-NMR (400 MHz,
DMSO-d6) d: 1.31 (d, J = 6.12 Hz, 6H), 3.13 (s, 3H), 3.99
(m, 2H), 4.25 (m, 2H), 5.13 (m, 1H), 5.78 (s, 1H), 7.01 (m,
2H), 7.45 (m, 2H), 7.62 (s, 1H), 8.11 (s, 1H). 13C-NMR
(100 MHz, DMSO-d6) d: 22.6, 41.7, 58.3, 70.6, 71.7, 99.4,
114.1, 121, 125.5, 126.9, 142.5, 154.3, 158.2, 167.5, 169.3,
174.3. MS (ESI) m/z (M + 1) 415.
6.1.25. Preparation of 4-(2-{[6-(4-methoxyphenoxy)pyri-
midin-4-yl]methylamino} ethoxy)benzaldehyde (3g)
Yield: 68%. IR (CHCl3) mmax cm–1: 2947, 2834, 1692,
1
1590, 1506, 1440. H-NMR (400 MHz, CDCl3) d: 3.14 (s,
3H), 3.83 (s, 3H), 4.30 (m, 2H), 4.67 (m, 2H), 5.86 (s, 1H),
6.94 (m, 2H), 7.02 (m, 2H), 7.08 (m, 2H), 7.84 (m, 2H), 8.32
(s, 1H), 9.90 (s, 1H). MS (ESI) m/z (M + 1) 380.
6.1.30. Preparation of 5-(4-2-[methyl-(6-phenoxypyrimi-
din-4-yl)amino]ethoxybenzyl idene)thiazolidine-2,4-dione
(4c)
6.1.26. Preparation of 4-(2-{[6-(3,4-dimethoxyphenoxy)py-
rimidin-4-yl]methylamino} ethoxy)benzaldehyde (3h)
Yield: 76%. IR (CHCl3) mmax cm–1: 2935, 1689, 1588,
1508, 1438. 1H-NMR (400 MHz, CDCl3) d: 3.14 (s, 3H), 3.86
(s, 3H), 3.88 (s, 3H), 4.07 (m, 2H), 4.29 (m, 2H), 5.86 (s,
Yield: 54%. M.p.: 180–182 °C. IR (CHCl3) mmax cm–1:
3052, 2931, 1738, 1698, 1584, 1509, 1489, 1443. 1H-NMR
(400 MHz, DMSO-d6) d: 3.15 (s, 3H), 4.05 (m, 2H), 4.27 (m,
2H), 5.90 (s, 1H), 6.99 (m, 2H), 7.14 (m, 2H), 7.26 (m, 2H),
7.44 (m, 4H), 7.81 (s, 1H), 8.33 (s, 1H). 13C-NMR (100 MHz,

H.W. Lee et al. / European Journal of Medicinal Chemistry 40 (2005) 862–874
869
DMSO-d6) d: 42.1, 58.3, 71.5, 94.5, 113.9, 120.5, 121.3,
124.4, 126.4, 126.9, 129.4, 141.9, 154.3, 154.7, 158.3, 166.1,
167.3, 171.9, 172.6. MS (ESI) m/z (M + 1) 449.
DMSO-d6) d: 3.14 (s, 3H), 3.87 (s, 3H), 3.91 (s, 3H), 4.05
(m, 2H), 4.27 (m, 2H), 5.87 (s, 1H), 6.69 (m, 2H), 6.89 (m,
1H), 7.00 (d, J = 8.76 Hz, 2H), 7.47 (d, J = 8.76 Hz, 2H), 7.80
(s, 1H), 8.34 (s, 1H). 13C-NMR (100 MHz, DMSO-d6) d: 39.3,
56.2, 66.5, 86.4, 94.5, 107.7, 115.4, 116.2, 121.3, 123.3, 126.5,
132.5, 132.9, 146.9, 157.2, 158.1, 160.8, 164.5, 167.4, 169.8,
171.6. MS (ESI) m/z (M + 1) 509.
6.1.31. Preparation of 5-(4-{2-[methyl-(6-phenylaminopy-
rimidin-4-yl)amino] ethoxy}benzylidene)thiazolidine-2,4-
dione (4d)
Yield: 68%. M.p.: 198–199 °C. IR (CHCl3) mmax cm–1:
1
2935, 1736, 1692, 1581, 1502, 1480. H-NMR (400 MHz,
6.1.36. Preparation of 5-[4-(2-{[6-(biphenyl-4-yl-oxy)pyri-
midin-4-yl]methyl amino}ethoxy)benzylidene]thiazolidine-
2,4-dione (4i)
DMSO-d6) d: 3.04 (s, 3H), 3.92 (m, 2H), 4.23 (m, 2H), 5.88
(s, 1H), 6.92 (m, 1H), 7.12 (m, 2H), 7.26 (m, 2H), 7.56 (m,
4H), 7.74 (s, 1H), 8.18 (s, 1H) 9.04 (s, NH), 12.51 (bs, 1H).
13C-NMR (100 MHz, DMSO-d6) d: 40.6, 57.9, 72.1, 92.1,
113.9, 115.1, 118.5, 119.9, 126.3, 126.9, 129.5, 141.9, 146.7,
156.2, 157.9, 166.5, 167.4, 171.1. MS (ESI) m/z (M + 1) 448.
Yield: 77%. M.p.: 185–187 °C. IR (CHCl3) mmax cm–1:
1741, 1704, 1591, 1509. 1H-NMR (400 MHz, DMSO-d6) d:
3.10 (s, 3H), 3.99 (m, 2H), 4.23 (m, 2H), 5.87 (s, 1H), 6.95
(d, J = 8.76 Hz, 2H), 7.16 (m, 2H), 7.31 (m, 1H), 7.41 (m,
4H), 7.72 (s, 1H), 8.26 (s, 1H). 13C-NMR (100 MHz, DMSO-
d6) d: 40.3, 56.2, 69.5, 86.4, 107.7, 115.4, 116.2, 127.3, 128.3,
129.5, 132.5, 136.9, 142.9, 157.2, 158.1, 160.8, 164.5, 167.4,
170.8, 171.6. MS (ESI) m/z (M + 1) 525.
6.1.32. Preparation of 5-[4-(2-{[6-(4-fluorophenoxy)pyri-
midin-4-yl]methylamino} ethoxy)benzylidene]thiazolidine-
2,4-dione (4e)
Yield: 69%. M.p.: 190–192 °C. IR (CHCl3) mmax cm–1:
1
1740, 1701, 1591, 1508, 1460, 1412. H-NMR (400 MHz,
6.1.37. Preparation of 5-(4-{2-[(6-methoxypyrimidin-4-
yl)methylamino]ethoxy} benzyl)thiazolidine-2,4-dione (5a).
General procedure
DMSO-d6) d: 3.10 (s, 3H), 3.96 (m, 2H), 4.25 (m, 2H), 6.15
(s, 1H), 7.10 (d, J = 8.82 Hz, 2H), 7.16 (m, 2H), 7.23 (m,
2H), 7.56 (d, J = 8.82 Hz, 2H), 7.73 (s, 1H), 8.18 (s, 1H).
13C-NMR (100 MHz, DMSO-d6) d: 41.2, 58.3, 71.7, 94.5,
114.7, 116.5, 120.3, 122.7, 126.1, 126.9, 141.9, 149.9, 154.9,
157.8, 166.1, 167.1, 171.3, 172.6. MS (ESI) m/z (M + 1) 467.
To a stirred solution of 4a (365 mg, 0.944 mmol) in anhy-
drous DMF (100 ml) was added Pd(OH)2 on carbon (360 mg)
under hydrogen atmosphere at room temperature for 36 h.
The mixture was filtered using celite and washed with MeOH.
The filtrate was condensed by evaporation under reduced pres-
sure. The concentrate thus obtained was purified by column
chromatography on SiO2 with dichloromethane/methanol
(30:1, v/v) as eluent to give the title compound 5a as a yel-
lowish solid. (100 mg, 27% yield). M.p.: 148–150 °C. IR
6.1.33. Preparation of 5-[4-(2-{[6-(4-chlorophenoxy)pyri-
midin-4-yl]methyl amino}ethoxy)benzylidene]thiazolidine-
2,4-dione (4f)
Yield: 61%. M.p.: 188–192 °C. IR (CHCl3) mmax cm–1:
1
2949, 1740, 1702, 1597, 1509, 1486. H-NMR (400 MHz,
(KBr) mmax cm–1: 2952, 1755, 1709, 1601, 1512. H-NMR
DMSO-d6) d: 3.11 (s, 3H), 3.96 (m, 2H), 4.26 (m, 2H), 6.19
(s, 1H), 7.10 (d, J = 8.82 Hz, 2H), 7.16 (m, 2H), 7.45 (m,
2H), 7.53 (d, J = 8.82 Hz, 2H), 7.73 (s, 1H), 8.19 (s, 1H).
13C-NMR (100 MHz, DMSO-d6) d: 41.1, 58.1, 71.3, 94.3,
114.3, 119.8, 122.5, 126.5, 126.8, 129.7, 129.9, 141.7, 152.4,
154.9, 157.9, 166.5, 166.9, 171.1, 172.6. MS (ESI) m/z (M +
1) 483.
1
(400 MHz, DMSO-d6) d: 2.97 (m, 2H), 3.06 (s, 3H), 3.81 (s,
3H), 3.89 (m, 2H), 4.10 (m, 2H), 4.71 (m, 1H), 5.91 (s, 1H),
6.86 (d, J = 8.49 Hz, 2H), 7.14 (d, J = 8.45 Hz, 2H), 8.23 (s,
1H). 13C-NMR (100 MHz, DMSO-d6) d: 35.9, 39.1, 49.4,
54.8, 55.9, 70.6, 95.9, 115.0, 128.8, 131.8, 156.7, 170.8, 174.1,
175.3. MS (ESI) m/z (M + 1) 389.
The following compounds 5b–i were obtained by a simi-
lar procedure to that described for the preparation of 5a.
6.1.34. Preparation of 5-[4-(2-{[6-(4-methoxyphenoxy)py-
rimidin-4-yl]methylamino}
ethoxy)benzylidene]thiazolidine-2,4-dione (4g)
Yield: 68%. M.p.: 194–195 °C. IR (KBr) mmax cm–1: 3428,
2948, 2748, 1741, 1704, 1591, 1508, 1292, 1257. 1H-NMR
(400 MHz, DMSO-d6) d: 3.07 (s, 3H), 3.75 (s, 3H), 3.94 (m,
2H), 4.23 (m, 2H), 6.05 (s, 1H), 6.95 (d, J = 8.84 Hz, 2H),
7.00 (m, 4H), 7.54 (d, J = 8.86 Hz, 2H), 7.73 (s, 1H), 8.16 (s,
1H). 13C-NMR (100 MHz, DMSO-d6) d: 37.3, 48.9, 56.2,
66.5, 86.4, 115.4, 116.2, 121.3, 123.3, 126.5, 132.5, 132.9,
146.9, 157.2, 158.1, 160.8, 164.5, 168.4, 168.8, 170.6. MS
(ESI) m/z (M + 1) 479.
6.1.38. Preparation of 5-(4-{2-[(6-isopropoxypyrimidin-4-
yl)methylamino]ethoxy} benzyl)thiazolidine-2,4-dione (5b)
Yield: 30.8%. M.p.: 150–152 °C. IR (CHCl3) mmax cm–1:
2978, 1750, 1698, 1594, 1510, 1449, 1417. 1H-NMR
(400 MHz, CDCl3) d: 1.34 (m, 6H), 3.13 (s, 4H), 3.41 (m,
1H), 3.96 (m, 2H), 4.16 (m, 2H), 4.52 (m, 1H), 5.31 (m, 1H),
5.71 (s, 1H), 6.83 (m, 2H), 7.12 (m, 2H), 8.30 (s, 1H). 13C-
NMR (100 MHz, CDCl3) d: 23.6, 35.2, 40.1, 54.8, 55.9, 70.6,
71.3, 99.3, 115.0, 128.8, 131.8, 154.7, 156.8, 167.1, 169.8,
174.1, 175.3. MS (ESI) m/z (M + 1) 417.
6.1.35. Preparation of 5-[4-(2-{[6-(3,4-dimethoxyphenoxy-
)pyrimidin-4-yl]methyl
6.1.39. Preparation of 5-(4-{2-[methyl-(6-phenoxypyrimi-
din-4-yl)amino]ethoxy} benzyl)thiazolidine-2,4-dione (5c)
Yield: 65%. M.p.: 160–163 °C. IR (CHCl3) mmax cm–1:
amino}ethoxy)benzylidene]thiazolidine-2,4-dione (4h)
Yield: 57%. M.p.: 190–193 °C. IR (KBr) mmax cm–1: 3446,
1
1
2983, 1744, 1694, 1591, 1511, 1438. H-NMR (400 MHz,
1753, 1698, 1604, 1584, 1510, 1489. H-NMR (400 MHz,

870
H.W. Lee et al. / European Journal of Medicinal Chemistry 40 (2005) 862–874
CDCl3) d: 3.13 (m, 4H), 3.45 (dd, J = 3.98, 3.98 Hz, 1H),
4.02 (m, 2H), 4.18 (m, 2H), 4.51 (m, 1H), 5.88 (s, 1H), 6.85
(m, 2H), 7.16 (m, 4H), 7.22 (m, 1H), 7.40 (m, 2H), 8.31 (s,
1H), 8.33 (bs, NH). 13C-NMR (100 MHz, CDCl3) d: 37.0,
38.1, 54.8, 55.6, 66.2, 85.7, 115.8, 122.1, 128.4, 130.5, 146.6,
157.0, 157.3, 158.1, 164.2, 170.5, 171.2, 172.3, 175.1. MS
(ESI) m/z (M + 1) 451.
146.7, 157.3, 157.9, 158.4, 164.2, 170.8, 171.1, 174.9. MS
(ESI) m/z (M + 1) 481.
6.1.44. Preparation of 5-(4-{2-[6-(3,4-dimethoxyphenoxy-
)pyrimidin-4-yl]methylamino ethoxy}benzyl)thiazolidine-
2,4-dione (5h)
Yield: 63%. M.p.: 160–163 °C. IR (CHCl3) mmax cm–1:
1
2933, 1750, 1699, 1590, 1509, 1483. H-NMR (400 MHz,
6.1.40. Preparation of 5-(4-{2-[methyl-(6-phenylaminopy-
rimidin-4-yl)amino]ethoxy} benzyl)thiazolidine-2,4-dione
(5d)
CDCl3) d: 3.13 (s, 3H), 3.16 (m, 1H), 3.46 (dd, J = 3.96,
4.00 Hz, 1H), 3.86 (s, 3H), 3.90 (s, 3H), 4.00 (m, 2H), 4.19
(m, 2H), 4.51 (m, 1H), 5.86 (s, 1H), 6.71 (m, 2H), 6.85 (m,
3H), 7.14 (m, 2H), 8.33 (s, 1H), 8.41 (bs, 1H). 13C-NMR
(100 MHz, CDCl3) d: 36.9, 38.8, 48.7, 54.5, 55.9, 56.3 68.6,
86.8, 115.5, 127.4, 128.9, 131.7, 148.7, 156.3, 157.4, 159.4,
164.2, 170.8, 171.1, 174.3. MS (ESI) m/z (M + 1) 511.
Yield: 42%. M.p.: 178–181 °C. IR (CHCl3) mmax cm–1:
1750, 1699, 1610, 1584, 1499. 1H-NMR (400 MHz, DMSO-
d6) d: 3.04 (s, 3H), 3.28 (m, 1H), 3.87 (m, 2H), 4.09 (m, 2H),
4.86 (m, 1H), 5.87 (s, 1H), 6.89 (m, 2H), 7.15 (d, J = 8.67 Hz,
2H), 7.26 (m, 2H), 7.58 (m, 2H), 8.17 (s, 1H), 9.03 (bs, NH).
13C-NMR (100 MHz, DMSO-d6) d: 37.0, 38.1, 56.8, 58.6,
66.2, 91.7, 115.8, 119.1, 128.8, 130.7, 146.4, 156.0, 156.3,
158.9, 163.2, 170.5, 171.2, 172.6, 175.1. MS (ESI) m/z (M +
1) 450.
6.1.45. Preparation of 5-(4{-2-[(6-biphenyl-4-yl-oxypyri-
midin-4-yl)methylamino]ethoxy} benzyl)thiazolidine-2,4-
dione (5i)
Yield: 27%. M.p.: 180–183 °C. IR (CHCl3) mmax cm–1:
1752, 1700, 1592, 1511, 1440. 1H-NMR (400 MHz, CDCl3)
d: 3.08 (m, 1H), 3.16 (s, 3H), 3.45 (m, 1H), 4.02 (bs, 2H),
4.19 (m, 2H), 4.50 (m, 1H), 5.95 (s, 1H), 6.86 (d, J = 8.72 Hz,
2H), 7.13 (m, 2H), 7.23 (m, 2H), 7.36 (m, 1H), 7.45 (m, 2H),
7.64 (m, 4H), 8.03 (s, 1H), 8.65(bs, NH). 13C-NMR
(100 MHz, CDCl3) d: 36.9, 39.1, 56.6, 58.8, 69.7, 94.0, 114.9,
121.6, 127.4, 128.5, 129.8, 131.8, 132.7, 136.7, 153.3, 157.9,
158.4, 167.2, 170.8, 172.1, 175.2. MS (ESI) m/z (M + 1) 527.
6.1.41. Preparation of 5-(4-{2-[6-(4-fluorophenoxy)pyrimi-
din-4-yl]methylaminoethoxy} benzyl)thiazolidine-2,4-dione
(5e)
Yield: 72%. M.p.: 172–173 °C. IR (CHCl3) mmax cm–1:
1751, 1700, 1591, 1500, 1441. 1H-NMR (400 MHz, CDCl3)
d: 3.15 (m, 4H), 3.45 (dd, J = 3.98, 3.96 Hz, 1H), 4.02 (m,
2H), 4.18 (m, 2H), 4.52 (m, 1H), 5.89 (s, 1H), 6.85 (m, 2H),
7.09 (m, 4H), 7.16 (m, 2H), 7.96 (bs, NH), 8.31 (s, 1H). 13C-
NMR (100 MHz, CDCl3) d: 36.4, 40.1, 56.5, 58.7, 66.7, 91.3,
114.8, 120.1, 127.4, 129.9, 148.7, 155.8, 156.1, 159.8, 163.2,
170.5, 171.2, 172.6, 175.3. MS (ESI) m/z (M + 1) 469.
6.1.46. Preparation of 2-[(5-bromopyrimidin-2-yl)methy-
lamino]ethanol (6)
A suspension of 2-chloro-5-bromopyrimidine (1 g,
5.1 mmol) in 2-methylamino-ethanol (5 ml) was stirred for
1 h at room temperature. The reaction mixture was diluted
with EtOAc (30 ml), washed with brine (100 ml), dried with
MgSO4, and evaporated under reduced pressure. The residue
was dried in vacuo, and obtained the title compound 6 as col-
orless oil (1.2 g, quantitative yield). IR (CHCl3) mmax cm–1:
2936, 1582, 1524, 1408. 1H-NMR (400 MHz, CDCl3) d: 3.17
(s, 3H), 3.34 (t, OH), 3.72 (m, 2H), 3.84 (m, 2H), 8.25 (s,
2H), 4.50 (m, 1H), 5.95 (s, 1H), 6.86 (d, J = 8.72 Hz, 2H),
7.13 (m, 2H), 7.23 (m, 2H), 7.36 (m, 1H), 7.45 (m, 2H), 7.64
(m, 4H), 8.03 (s, 1H), 8.65 (bs, NH). 13C-NMR (100 MHz,
CDCl3) d: 36.85, 52.70, 61.80, 105.58, 157.80, 160.68.
6.1.42. Preparation of 5-(4-{2-[6-(4-chlorophenoxy)pyri-
midin-4-yl]methylamino ethoxy}benzyl)thiazolidine-2,4-
dione (5f)
Yield: 75%. M.p.: 167–169 °C. IR (CHCl3) mmax cm–1:
1
1751, 1699, 1605, 1584, 1509, 1485. H-NMR (400 MHz,
CDCl3) d: 2.98 (m, 1H), 3.16 (s, 3H), 3.45 (dd, J = 3.93,
3.97 Hz, 1H), 4.02 (m, 2H), 4.18 (m, 2H), 4.52 (m, 1H), 5.92
(s, 1H), 6.83 (m, 2H), 7.09 (m, 2H), 7.16 (m, 2H), 7.38 (m,
2H), 8.04 (bs, NH), 8.30 (s, 1H). 13C-NMR (100 MHz,
CDCl3) d: 35.4, 39.1, 54.5, 58.8, 71.7, 94.3, 115.8, 121.1,
129.7, 130.9, 147.7, 154.6, 156.7, 158.8, 163.2, 170.4, 171.2,
172.3, 175.5. MS (ESI) m/z (M + 1) 485.
6.1.47. Preparation of 2-[(5-furan-2-yl-pyrimidin-2-yl)m-
ethylamino]ethanol (7a). General procedure
6.1.43. Preparation of 5-(4-{2-[6-(4-methoxyphenoxy)pyri-
midin-4-yl]methylamino ethoxy}benzyl)thiazolidine-2,4-
dione (5g)
To a solution of 6 (1.1 g, 7.1 mmol) in anhydrous tetrahy-
drofuran (30 ml) was added tri-n-butyl tin 2-furan (2.24 ml,
7.1 mmol) and palladium tetrakis triphenylphosphine Pd
(pph3)4 (approximately 3 mol% catalytic amount), and the
mixture was refluxed for 9 h under argon atmosphere. The
reaction mixture was diluted with EtOAc (50 ml), washed
with H2O (50 ml) and brine (50 ml), dried over MgSO4, and
evaporated under reduced pressure. The residue was purified
by column chromatography on SiO2 with EtOAc/n-hexane
Yield: 89%. M.p.: 165–167 °C. IR (KBr) mmax cm–1: 3427,
3112, 2924, 2835, 2752, 1749, 1693, 1590, 1545, 1506, 1444,
1363. 1H-NMR (400 MHz, CDCl3) d: 3.12 (m, 4H), 3.45 (m,
1H), 3.83 (s, 3H), 4.00 (m, 2H), 4.16 (m, 2H), 4.50 (m, 1H),
5.84 (bs, 1H), 6.83 (m, 2H), 7.06 (m, 2H), 7.15 (m, 2H), 8.31
(s, 1H), 8.89(bs, NH). 13C-NMR (100 MHz, CDCl3) d: 37.9,
38.1, 49.7, 54.0, 55.9, 66.6, 85.9, 115.0, 122.8, 128.8, 130.7,

H.W. Lee et al. / European Journal of Medicinal Chemistry 40 (2005) 862–874
871
(1:3, v/v) to give the title compound 7a (980 mg, 95%) as a
white solid. M.p.: 180–183 °C. IR (CHCl3) mmax cm–1: 3345,
2943, 1600, 1549, 1406. 1H-NMR (400 MHz, CDCl3) d: 3.28
(s, 3H), 3.83 (m, 2H), 3.91 (m, 2H), 6.47 (m, 2H), 7.46 (s,
1H), 8.59 (s, 2H).). 13C-NMR (100 MHz, CDCl3) d: 37.9,
53.5, 62.7, 122.2, 125.6, 127.4, 129.8, 135.4, 155.3, 161.9.
The following compounds 7b–d were obtained by a simi-
lar procedure to that described for the preparation of 7a.
The following compounds 8b–d were obtained by a simi-
lar procedure to that described for the preparation of 8a.
6.1.52. Preparation of 4-{2-[methyl-(5-phenylpyrimidin-2-
yl)amino]ethoxy}benzaldehyde (8b)
Yield: 60%. IR (CHCl3) mmax cm–1: 2939, 1693, 1600,
1527, 1408. 1H-NMR (400 MHz, CDCl3) d: 3.34 (s, 3H), 4.07
(m, 2H), 4.31 (m, 2H), 7.01 (m, 2H), 7.08 (m, 1H), 7.14 (m,
1H), 7.26 (m, 1H), 7.83 (m, 2H), 8.55 (s, 2H), 9.87 (s, 1H).
13C-NMR (100 MHz, CDCl3) d: 37.2, 49.0, 66.4, 114.8, 117.4,
122.2, 124.3, 128.1, 130.0, 132.0, 132.3, 138.4, 155.0, 160.7,
163.8, 190.8.
6.1.48. Preparation of 2-[methyl-(5-phenyl-pyrimidin-2-
yl)amino]ethanol (7b)
Yield: 59%. IR (CHCl3) mmax cm–1: 3355, 2933, 1605,
1
1529, 1407. H-NMR (400 MHz, CDCl3) d: 3.26 (s, 3H),
6.1.53. Preparation of 4-{2-[methyl-(5-pyridin-2-yl-pyrimi-
din-2-yl)amino]ethoxy}benzaldehyde (8c)
3.81 (m, 2H), 3.90 (m, 2H), 7.07 (m, 1H), 7.13 (m, 1H), 7.26
(m, 1H), 8.50 (s, 2H). 13C-NMR (100 MHz, CDCl3) d: 36.89,
5, 62.5, 117.5, 122.3, 124.3, 128.1, 138.1, 154.9, 161.6.
Yield: 57%. IR (CHCl3) mmax cm–1: 2932, 1691, 1600,
1531, 1406. 1H-NMR (400 MHz, CDCl3) d: 3.36 (s, 3H), 4.11
(m, 2H), 4.31 (m, 2H), 7.01 (m, 2H), 7.19 (m, 1H), 7.55 (m,
1H), 7.69 (m, 1H), 7.82 (m, 2H), 8.62 (m, 1H), 8.94 (s, 2H),
9.94 (s, 1H). 13C-NMR (100 MHz, CDCl3) d: 37.3, 49.0,
114.8, 118.6, 121.2, 121.7, 129.3, 130.0, 132.0, 136.8, 149.9,
153.6, 156.3, 161.5, 163.8, 190.8.
6.1.49. Preparation of 2-[methyl-(5-pyridin-2-yl-pyrimi-
din-2-yl)amino]ethanol (7c)
Yield: 67%. IR (CHCl3) mmax cm–1: 3331, 2932, 1603,
1534, 1402. 1H-NMR (400 MHz, CDCl3) d: 3.28 (s, 3H), 3.83
(m, 2H), 3.91 (m, 2H), 4.03 (t, OH), 7.17 (m, 1H), 7.53 (d, J
= 7.92 Hz, 1H), 7.70 (m, 1H), 8.62 (m, 1H), 8.89 (s, 2H).
13C-NMR (100 MHz, CDCl3) d: 36.9, 53.0, 62.4, 118.6, 121.2,
121.8, 136.9, 149.9, 153.3, 156.2, 162.4.
6.1.54. Preparation of 4-{2-[methyl-(5-thiophen-2-yl-pyri-
midin-2-yl)amino]ethoxy} benzaldehyde (8d)
Yield: 66%. IR (CHCl3) mmax cm–1: 3420, 3230, 2852,
1
1604, 1538, 1408. H-NMR (400 MHz, CDCl3) d: 3.35 (s,
3H), 4.09 (m, 2H), 4.32 (m, 2H), 7.03 (m, 2H), 7.35 (m, 1H),
7.48 (m, 4H), 7.83 (m, 2H), 8.57 (s, 2H), 9.87 (s, 1H). 13C-
NMR (100 MHz, CDCl3) d: 37.2, 49.0, 66.4, 114.8, 117.4,
122.2, 124.3, 128.1, 130.0, 132.0, 138.4, 155.0, 160.7, 163.8,
190.8.
6.1.50. Preparation of 2-[methyl-(5-thiophen-2-yl-pyrimi-
din-2-yl)amino]ethanol (7d)
Yield: 49%. IR (CHCl3) mmax cm–1: 3320, 3239, 2959,
1604, 1538, 1517, 1408. 1H-NMR (400 MHz, CDCl3) d: 3.28
(s, 3H), 3.83 (m, 2H), 3.92 (m, 2H), 4.02 (bs, OH), 7.34 (m,
1H), 7.45 (m, 1H), 8.53 (s, 2H). 13C-NMR (100 MHz, CDCl3)
d: 36.8, 53.0, 62.7, 122.9, 125.8, 127.3, 129.1, 135.4, 155.8,
161.9.
6.1.55. Preparation of 5-(4-{2-[(5-furan-2-yl-pyrimidin-2-
yl)methylamino]ethoxy} benzylidene)thiazolidine-2,4-dione
(9a). General procedure
A mixture of benzaldehyde compound 8a (750 mg,
2.32 mmol), piperidine (0.07 ml, 0.69 mmol), acetic acid
(0.04 ml, 0.69 mmol) and 2,4-thiazolidinedione (300 mg,
2.55 mmol) in toluene (25 ml) was refluxed for 5 h with con-
tinuous removal of water through Dean-Stark apparatus. The
reaction mixture then was cooled to room temperature, and
the resultant crystalline compound was filtered, washed with
methanol and dried to afford the title compound 9a (860 mg,
88% yield). M.p.: 197–198 °C. IR (CHCl3) mmax cm–1: 3320,
6.1.51. Preparation of 4-2-[(5-furan-2-yl-pyrimidin-2-
yl)methylamino]ethoxybenzaldehyde (8a). General proce-
dure
To a solution of aminoalcohol compound 7a (980 mg,
4.47 mmol) in anhydrous DMF (20 ml) was added NaH (60%
dispersion in mineral oil, 358 mg, 8.94 mmol), and the reac-
tion mixture was stirred for 1 h at ice-bath temperature under
N2 atmosphere. And 4-fluorobenzaldehyde (0.72 ml,
0.7 mmol) was added dropwise over 15 min. The reaction
mixture was stirred at room temperature for 5 h, added care-
fully to saturated ammonium chloride solution (100 ml), and
extracted with ethyl acetate (2 × 50 ml). The combined
organic layer was washed with brine (3 × 40 ml), dried
(MgSO4), filtered, and evaporated. The residue was purified
by column chromatography on SiO2 with EtOAc/n-hexane
(1:4, v/v) to give the title compound 8a (752 mg, 52% yield)
IR (CHCl3) mmax cm–1: 3355, 2933, 1605, 1529, 1407.
1H-NMR (400 MHz, CDCl3) d: 3.36 (s, 3H), 4.10 (m, 2H),
4.33 (m, 2H), 6.48 (m, 2H), 7.03 (m, 2H), 7.47 (s, 1H), 7.84
(m, 2H), 8.64 (s, 2H), 9.90 (s, 1H). 13C-NMR (100 MHz,
CDCl3) d: 36.5, 48.9, 65.6, 114.8, 117.4, 122.2, 124.3, 128.1,
130.0, 132.0, 138.4, 155.0, 160.7, 163.8, 190.8.
1
3239, 2959, 2852, 1604, 1538, 1408. H-NMR (400 MHz,
DMSO-d6) d: 3.24 (s, 3H), 4.02 (m, 2H), 4.28 (m, 2H), 6.57
(m, 1H), 6.81 (m, 1H), 7.13 (d, J = 8.85 Hz, 2H), 7.55 (d, J
= 8.8 Hz, 2H), 7.73 (m, 2H), 8.70 (s, 2H). 13C-NMR (CDCl3)
d: 35.6, 47.9, 66.2, 116.5, 122.2, 125.7, 127.4, 132.1, 132.7,
134.9, 156.2, 160.2, 161.9, 168.8. MS (ESI) m/z (M + 1) 423.
The following compounds 9b–d were obtained by a simi-
lar procedure to that described for the preparation of 9a.
6.1.56. Preparation of 5-(4-{2-[methyl-(5-phenylpyrimidin-
2-yl)amino]ethoxy} benzylidene)thiazolidine-2,4-dione
(9b)
Yield: 78%. M.p.: 195–196 °C. IR (CHCl3) mmax cm–1:
3030, 2954, 1735, 1694, 1537. 1H-NMR (400 MHz, DMSO-

872
H.W. Lee et al. / European Journal of Medicinal Chemistry 40 (2005) 862–874
d6) d: 3.23 (s, 3H), 4.02 (m, 2H), 4.28 (m, 2H), 7.12 (m, 3H),
7.40 (m, 1H), 7.49 (m, 3H), 7.73 (s, 1H), 8.66 (s, 2H). 13C-
NMR (100 MHz, DMSO-d6) d: 37.2, 49.0, 53.4, 66.4, 114.8,
122.8, 125.8, 127.2, 129.1, 129.3, 129.6, 130.0, 132.0, 132.3,
135.6, 155.9, 160.9, 162.2, 163.8, 190.8. MS (ESI) m/z (M +
1) 433.
d6) d: 3.03 (m, 1H), 3.23 (s, 3H), 3.28 (m, 1H), 3.98 (m, 2H),
4.17 (m, 2H), 4.84 (m, 1H), 6.90 (m, 2H), 7.15 (m, 3H), 7.39
(m, 1H), 7.50 (m, 1H), 8.65 (s, 2H), 11.98 (bs, NH). 13C-
NMR (100 MHz, DMSO-d6) d: 36.6, 48.5, 53.4, 65.6, 114.7,
121.9, 125.8, 127.4, 129.1, 129.4, 130.8, 135.4, 156.1, 157.8,
161.1, 172.1, 176.1. MS (ESI) m/z (M + 1) 435.
6.1.57. Preparation of 5-(4-{2-[methyl-(5-pyridin-2-yl-
pyrimidin-2-yl)amino]ethoxy} benzylidene)thiazolidine-
2,4-dione (9c)
6.1.61. Preparation of 5-(4-{2-[methyl-(5-pyridin-2-yl-
pyrimidin-2-yl)amino]ethoxy} benzyl)thiazolidine-2,4-
dione (10c)
Yield: 70%. M.p.: 180–181 °C. IR (KBr) mmax cm–1: 3010,
2805, 1730, 1696, 1579. 1H-NMR (400 MHz, DMSO-d6) d:
3.20 (s, 3H), 3.98 (m, 2H), 4.23 (m, 2H), 7.06 (d, J = 8.84 Hz,
2H), 7.24 (m, 1H), 7.48 (d, J = 8.86 Hz, 2H), 7.74 (m, 2H),
8.52 (m, 1H), 8.97 (s, 2H). 13C-NMR (100 MHz, DMSO-d6)
d: 36.8, 48.4, 66.0, 115.8, 119.1, 120.8, 120.8, 122.4, 126.0,
132.1, 132.5, 137.6, 150.0, 153.1, 156.5, 160.5, 161.6, 167.9,
168.4. MS (ESI) m/z (M + 1) 434.
Yield: 40%. M.p.: 168–170 °C. IR (CHCl3) mmax cm–1:
1
2937, 2709, 1742, 1699, 1607, 1533. H-NMR (400 MHz,
DMSO-d6) d: 2.98 (m, 1H), 3.19 (s, 3H), 3.24 (m, 1H), 3.95
(m, 2H), 4.11 (m, 2H), 4.79 (m, 1H), 6.83 (m, 2H), 7.08 (m,
2H), 7.21 (m, 1H), 7.77 (m, 2H), 8.53 (m, 1H). 13C-NMR
(100 MHz, DMSO-d6) d: 36.6, 48.5, 53.4, 65.5, 114.7, 119.0,
120.7, 122.4, 129.1, 130.8, 137.6, 149.9, 153.1, 156.5, 157.8,
161.6, 172.1, 176.1. MS (ESI) m/z (M + 1) 436.
6.1.58. Preparation of 5-(4-{2-[methyl-(5-thiophen-2-yl-
pyrimidin-2-yl)amino] ethoxy}benzylidene)thiazolidine-
2,4-dione (9d)
6.1.62. Preparation of 5-(4-{2-[methyl-(5-thiophen-2-yl-
pyrimidin-2-yl)amino]ethoxy} benzyl)thiazolidine-2,4-
dione (10d)
Yield: 70%. M.p.: 160–162 °C. IR (CHCl3) mmax cm–1:
3108, 2975, 1735, 1684, 1580, 1505, 1402. 1H-NMR
(400 MHz, DMSO-d6) d: 3.18 (s, 3H), 3.96 (m, 2H), 4.21 (m,
2H), 7.03 (m, 2H), 7.27 (m, 1H), 7.37 (m, 2H), 7.44 (m, 2H),
7.54 (m, 2H), 7.57 (m, 2H), 7.61 (s, 1H), 8.63 (s, 2H). 13C-
NMR (100 MHz, DMSO-d6) d: 36.7, 48.4, 65.9, 115.8, 117.2,
120.9, 123.1, 125.1, 126.1, 128.7, 132.1, 132.5, 138.0, 155.1,
160.5, 160.8, 168.0, 168.4. MS (ESI) m/z (M + 1) 439.
Yield: 68%. M.p.: 160–162 °C. IR (CHCl3) mmax cm–1:
2973, 1740, 1705, 1606, 1538. 1H-NMR (400 MHz, DMSO-
d6) d: 2.97 (m, 1H), 3.18 (s, 3H), 3.24 (m, 1H), 3.93 (m, 2H),
4.10 (m, 2H), 4.78 (m, 1H), 6.84 (d, J = 8.6 Hz, 2H), 7.08 (d,
J = 8.6 Hz, 2H), 7.25(m, 1H), 7.35 (m, 2H), 7.57 (m, 2H),
8.63 (s, 2H). 13C-NMR (100 MHz, DMSO-d6) d: 36.7, 48.5,
53.4, 65.5, 114.7, 117.1, 123.1, 125.0, 128.7, 129.1, 130.8,
138.1, 155.1, 157.8, 160.8, 172.1, 176.1. MS (ESI) m/z (M +
1) 441.
6.1.59. Preparation of 5-(4-{2-[(5-furan-2-yl-pyrimidin-2-
yl)methylamino]ethoxy} benzyl)thiazolidine-2,4-dione
(10a). General procedure
6.1.63. Preparation of 4,6-dichloro-2-phenylpyrimidine
(11)
To a stirred solution of 9a (200 mg, 0.473 mmol) in anhy-
drous DMF (100 ml) was added Pd(OH)2 on carbon (200 mg)
under hydrogen atmosphere at room temperature for 36 h.
The mixture was filtered through celite and washed with
MeOH. The filtrate was condensed by evaporation under
reduced pressure. The concentrate thus obtained was purified
by column chromatography over SiO2 using dichloromethane/
methanol (100:1, v/v) as eluent to give the title compound
10a as a yellowish solid. (136 mg, 68% yield). M.p.: 193–
194 °C. IR (CHCl3) mmax cm–1: 2920, 1750, 1690, 1600.
1H-NMR (400 MHz, DMSO-d6) d: 3.04 (m, 1H), 3.23 (s, 3H),
3.34 (m, 1H), 3.97 (m, 2H), 4.13 (m, 2H), 4.87 (m, 1H), 6.58
(m, 1H), 6.81 (m, 1H), 6.88 (m, 2H), 7.13 (m, 2H), 7.71 (s,
1H), 8.70 (s, 2H). 13C-NMR (100 MHz, DMSO-d6) d: 35.8,
37.8, 48.3, 53.6, 65.0, 114.5, 121.5, 125.3, 127.7, 129.6, 129.9,
130.3, 135.9, 156.3, 157.6, 161.0, 172.5, 176.8. MS (ESI)
m/z (M + 1) 425.
To a solution of 2-amino-4,6-dichloropyrimidine (1 g,
6.1 mmol) in anhydrous benzene (50 ml) was added isoamyl
nitrite (3 ml, 22.57 mmol) and copper (I) oxide (872 mg,
6.1 mmol). The reaction mixture was refluxed for 3 h through
monitoring using TLC. Insoluble materials were removed by
filtration and the filtrate was evaporated to dryness under
reduced pressure. The residue was purified by column chro-
matography over silica gel using n-hexane/EtOAc (10:1, v/v)
as eluent to give the title compound 11 (953 mg, 69% yield).
M.p.: 150–152 °C. IR (CHCl3) mmax cm–1: 2935, 1740, 1698,
1610, 1536. 1H-NMR (400 MHz, DMSO-d6) d: 7.29 (s, 1H),
7.54 (m, 3H), 8.46 (m, 2H). MS (ESI) m/z (M + 1) 225.
6.1.64. Preparation of 2-[(6-chloro-2-phenylpyrimidin-4-
yl)methylamino]ethanol (12)
To the stirred solution of 11 (953 mg, 4.23 mmol) in anhy-
drous dichloromethane (30 ml) was added 2-methyl-
aminoethanol (0.4 ml, 5.08 mmol), and the mixture was
refluxed for 24 h under nitrogen atmosphere. The reaction
mixture was cooled to room temperature and quenched with
saturated NH4Cl solution (50 ml), and extracted with EtOAc
(120 ml). The extracted organic layers were washed with water
The following compounds 10b–d were obtained by a simi-
lar procedure to that described for the preparation of 10a.
6.1.60. Preparation of 5-(4-{2-[methyl-(5-phenylpyrimidin-
2-yl)amino]ethoxy}benzyl) thiazolidine-2,4-dione (10b)
Yield: 70%. M.p.: 183–185 °C. IR (CHCl3) mmax cm–1:
2935, 1740, 1698, 1610, 1536. 1H-NMR (400 MHz, DMSO-

H.W. Lee et al. / European Journal of Medicinal Chemistry 40 (2005) 862–874
873
and brine (50 ml), dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chro-
matography over SiO2 using a mixture of dichloro-
methane/methanol (50:1, v/v) as eluent to get the title com-
pound 12 as yellowish oil (747 mg, 67% yield). IR (CHCl3)
pressure. The obtained residue was purified by column chro-
matography over SiO2 with n-hexane/EtOAc (1:1, v/v) as elu-
ent to give the title compound 15 as a yellowish solid (250 mg,
96% yield). M.p.: 191–193 °C. IR (CHCl3) mmax cm–1:2925,
1
1753, 1693, 1604. H-NMR (400 MHz, DMSO-d6) d: 3.17
1
mmax cm–1: 2936, 1605, 1560. H-NMR (400 MHz, CDCl3)
(bs, 3H), 4.09 (m, 2H), 4.33 (m, 2H), 6.70 (bs, 1H), 7.11 (d,
J = 8.8 Hz, 2H), 7.45 (m, 3H), 7.52 (d, J = 8.8 Hz, 2H), 7.71
(s, 1H), 8.30 (m, 3H), 12.5 (bs, 1H). 13C-NMR (100 MHz,
DMSO-d6) d: 36.8, 44.1, 48.3, 65.4, 103.6, 114.5, 122.2,
125.4, 126.4, 127.4, 129.8, 135.4, 156.2, 158.0, 164.7, 166.3,
167.1, 169.2. MS (ESI) m/z (M + 1) 433.
d: 3.09 (s, 3H), 3.81 (m, 2H), 3.88 (m, 2H), 6.34 (s, 1H), 7.46
(m, 3H), 8.32 (m, 2H). MS (ESI) m/z (M + 1) 264.
6.1.65. Preparation of 2-[methyl-(2-phenylpyrimidin-4-
yl)amino]ethanol (13)
A solution of aminoalcohol compound 12 (747 mg,
2.83 mmol) in a mixture of anhydrous ethanol (20 ml) and
ethyl acetate (20 ml) containing triethylamine (1.2 ml,
8.49 mmol) was added 10% palladium on carbon (50 mg)
under hydrogen atmosphere (50–55 psi) at room temperature
for 15 h. The suspension was filtered using celite and the fil-
trate was condensed in vacuo. The residue was purified by
column chromatography over SiO2 using a mixture of
dichloromethane/methanol (20:1, v/v) as eluent to give the
title compound 12 (377 mg, 59% yield). IR (CHCl3) mmax
6.1.68. Preparation of 5-(4-{2-[methyl-(2-phenylpyrimidin-
4-yl)amino]ethoxy} benzyl)thiazolidine-2,4-dione (16)
To a stirred solution of 15 (260 mg, 0.6 mmol) in anhy-
drous DMF (25 ml) and dried methanol (25 ml) was added
Pd(OH)2 on carbon (100 mg) under hydrogen atmosphere at
room temperature for 36 h. The mixture was filtered using
celite and washed with cooled MeOH. The filtrate was con-
densed by evaporation under reduced pressure. The concen-
trate thus obtained was purified by column chromatography
on SiO2 with dichloromethane/methanol (50:1, v/v) as eluent
to give the title compound 16 as a yellowish solid (100 mg,
74% yield). M.p.: 178–180 °C. IR (CHCl3) mmax cm–1: 2920,
1
cm–1: 3355, 2933, 1605, 1529, 1407. H-NMR (400 MHz,
CDCl3) d: 3.09 (s, 3H), 3.84 (m, 2H), 3.90 (m, 2H), 6.32 (d, J
= 6.0 Hz, 1H), 7.46 (m, 3H), 8.26 (d, J = 6.1 Hz, 1H), 8.34
(m, 2H). MS (ESI) m/z (M + 1) 230.
1
1750, 1690, 1600. H-NMR (400 MHz, DMSO-d6) d: 3.12
(dd, J = 14.4 Hz, 9.2 Hz, 1H), 3.25 (s, 3H), 3.44 (dd, J = 14 Hz,
3.6 Hz, 1H), 4.12 (m, 2H), 4.27 (m, 2H), 4.50 (dd, J = 9.6 Hz,
4.0 Hz, 1H), 6.41 (d, J = 6.0 Hz, 1H), 6.8 (d, J = 6.4 Hz, 2H),
6.86 (d, J = 6.4 Hz, 2H), 7.47 (m, 3H), 8.40 (m, 3H). 13C-
NMR (100 MHz, DMSO-d6) d: 36.6, 48.5, 53.4, 65.6, 114.5,
115.9, 121.2, 125.8, 126.4, 127.4, 129.1, 136.5, 156.2, 158.9,
164.7, 166.3, 172.1, 176.1. MS (ESI) m/z (M + 1) 435.
6.1.66. Preparation of 4-{2-[methyl-(2-phenylpyrimidin-4-
yl)amino]ethoxy}benzaldehyde (14)
To a solution of aminoalcohol 13 (380 mg, 1.67 mmol) in
anhydrous DMF (20 ml) was added NaH (60% dispersion in
mineral oil, 134 mg, 3.34 mmol), and the mixture was stirred
for 1 h at 0 °C under N2 atmosphere. And 4-fluorobenzal-
dehyde (0.27 ml, 2.5 mmol) was added dropwise over 15 min.
The reaction mixture was stirred at room temperature for 3 h,
added carefully to saturated ammonium chloride solution
(100 ml), and extracted with ethyl acetate (2 × 50 ml). The
combined organic phase was washed with brine (3 × 40 ml),
dried (MgSO4), filtered, and evaporated. The residue was puri-
fied by column chromatography on SiO2 using EtOAc/n-
hexane (1:1, v/v) as eluent to give the title compound 14
(381 mg, 68% yield). IR (CHCl3) mmax cm–1: 3355, 2933,
Acknowledgements
The authors like to thank for the Research Grant (HMP-
00-B-21500-014) from Ministry of Health and Welfare, South
Korea for financial support. The authors thank Dr. S.S. Lee
for emendate and Miss K.H. Yang for typing the manuscript.
1
1605, 1529, 1407. H-NMR (400 MHz, CDCl3) d: 3.25 (s,
3H), 4.13 (m, 2H), 4.37 (m, 2H), 6.41 (d, J = 6.4 Hz, 1H),
7.02 (d, J = 9.2 Hz, 2H), 7.47 (m, 3H), 7.82 (d, J = 9.2 Hz,
2H), 8.38 (m, 3H), 9.88 (s, 1H). MS (ESI) m/z (M + 1) 334.
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