Identification of potent and selective inhibitors of PDGF receptor autophosphorylation

Article abstract of DOI:10.1021/jm0506423

We report the structure-activity relationship of quinoline and quinazoline derivatives, which include urea, thiourea, urethane, and acylthiourea groups, as inhibitors of the platelet-derived growth factor (PDGF) receptor autophosphorylation. Our previous studies showed that the quinoline and quinazoline derivatives including urea, thiourea, and carbamate groups were highly potent compounds as the PDGF receptor autophosphorylation inhibitor, but these compounds did not exhibit receptor selectivity between the PDGF receptor and the c-kit receptor. As a result of further synthesis and biological evaluation, we have found that the quinoline and quinazoline-acylthiourea derivatives showed not only good inhibitory activity for the PDGF receptor but also receptor selectivity between the PDGF receptor and the c-kit receptor. Furthermore N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N′-(2- methylbenzoyl)thiourea exhibited potent oral efficacy in in vivo assay using the rat carotid balloon injury model. Therefore, the quinoline and quinazoline-acylthiourea derivatives may be expected to have potential as therapeutic agents for the treatment of restenosis.

Full text of DOI:10.1021/jm0506423

2186
J. Med. Chem. 2006, 49, 2186-2192
Identification of Potent and Selective Inhibitors of PDGF Receptor Autophosphorylation
Takayuki Furuta,* Teruyuki Sakai, Terufumi Senga, Tatsushi Osawa, Kazuo Kubo, Toshiyuki Shimizu, Rika Suzuki,
Tetsuya Yoshino, Megumi Endo, and Atsushi Miwa
Pharmaceutical Research Laboratories, Kirin Brewery Co., Ltd., 3 Miyahara, Takasaki, Gunma 370-1295, Japan
ReceiVed July 6, 2005
We report the structure-activity relationship of quinoline and quinazoline derivatives, which include urea,
thiourea, urethane, and acylthiourea groups, as inhibitors of the platelet-derived growth factor (PDGF) receptor
autophosphorylation. Our previous studies showed that the quinoline and quinazoline derivatives including
urea, thiourea, and carbamate groups were highly potent compounds as the PDGF receptor autophospho-
rylation inhibitor, but these compounds did not exhibit receptor selectivity between the PDGF receptor and
the c-kit receptor. As a result of further synthesis and biological evaluation, we have found that the quinoline
and quinazoline-acylthiourea derivatives showed not only good inhibitory activity for the PDGF receptor
but also receptor selectivity between the PDGF receptor and the c-kit receptor. Furthermore N-{4-[(6,7-
dimethoxy-4-quinolyl)oxy]phenyl}-N′-(2-methylbenzoyl)thiourea exhibited potent oral efficacy in in vivo
assay using the rat carotid balloon injury model. Therefore, the quinoline and quinazoline-acylthiourea
derivatives may be expected to have potential as therapeutic agents for the treatment of restenosis.
Introduction
Platelet-derived growth factor (PDGF) is known as a potent
mitogen and chemotactic factor for various mesenchymal cells
such as fibroblasts and vascular smooth muscle cells. PDGF
stimulates the tyrosine kinase activity of its receptor, the PDGF
receptor, and induces the autophosphorylation of the PDGF
receptor that is followed by the stimulation of various intracel-
lular signalings. Because the PDGF/PDGF receptor is proposed
to be correlated with various cell-proliferative diseases such as
Figure 1. Structure of 1 and novel quinoline-urea derivative 2.
vascular restenosis, liver cirrhosis, and cancer,1-3 a selective
Scheme 1a
inhibitor of the autophosphorylation of the PDGF receptor may
have a therapeutic potential. Furthermore, recent success in the
clinical evaluation of tyrosine kinase inhibitors, for example 1
(STI571),4-5 strongly suggests that these targets represent drug
intervention opportunities. Several adenosine 5′-triphosphate
(ATP) competitive inhibitors of the PDGF receptor autophos-
phorylation have been reported. Recently, several series of
compounds, 3-substituted quinolines,6,7 3-substituted quinoxa-
lines,8,9 2-phenylaminopyrimidines,10-12 3-substituted indoli-
nones,13 and piperazinyl quinazolines,14 were reported as small
molecule PDGF receptor inhibitors. Even though several
compounds15,16 are known as potent inhibitors of the PDGF
receptor autophosphorylation, receptor selectivity, especially
against the c-kit receptor17 that belongs to the PDGF receptor
family, is still low. In our previous screening of in-house
compounds,18-20 we have found a novel series of N-substituted-
N′-{4-(4-quinolyloxy)phenyl}urea derivatives as potent inhibi-
tors for the PDGF receptor autophosphorylation. Especially 2,
shown in Figure 1, strongly inhibited the PDGF receptor
autophosphorylation with an IC50 value of 12 nM. Therefore,
we designed and synthesized 6,7-dimethoxyquinoline and 6,7-
dimethoxyquinazoline derivatives to increase receptor selectiv-
ity. In this paper, we present our effort to improve the inhibitory
activities for the PDGF receptor autophosphorylation and
receptor selectivity, in particular, against the c-kit receptor by
a SAR study focusing on the urea, thiourea, carbamate, and
a Reagents and conditions: (a) diethyl ethoxymethylenemalonate, 120
°C; (b) diphenyl ether, 280 °C (66% for 2 steps); (c) 10% aqueous NaOH/
MeOH, reflux; (d) diphenyl ether, 280 °C (99% for 2 steps); (e) POCl3,
reflux (85%); (f) NaH, DMSO, 100 °C (92%).
acylthiourea moieties. The result of a biological evaluation
including an in vivo study is also described.
Results and Discussion
The general synthetic route of the 4-phenoxyquinoline
derivatives is summarized in Scheme 1. 3,4-Dimethoxyaniline
3 was reacted with diethyl ethoxymethylmalonate, and then
cyclization to form the quinolone structure was carried out in
diphenyl ether at 280 °C. After hydrolysis of the ethyl ester,
removal of carbon dioxide and chlorination provided the
intermediate 4-chloro-6,7-dimethoxyquinoline 6 in good yield.
4-Aminophenol was then reacted with the quinoline derivative
6 to provide the key intermediate 7.
* Corresponding author. Mailing address: 3 Miyahara, Takasaki, Gunma,
370-1295, Japan. Phone: +81-27-346-9954. Fax: +81-27-346-1841.
E-mail: t-furuta@kirin.co.jp.
10.1021/jm0506423 CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/03/2006

Inhibitors of PDGF Receptor Autophosphorylation
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7 2187
Scheme 4a
Scheme 2a
a Reagents and conditions: (a) NCSK, CH3CN, 50 °C 1 h; (b) 7 (X )
CH) or 11 (X ) N), toluene:EtOH ) 5:1, rt 2-10 h.
Table 1. Inhibitory Activity of PDGF Receptor and c-kit Receptor
Phosphorylation
a Reagents and conditions: (a) H2NCOH, NaOMe, 150 °C 10 h (90%);
(b) POCl3, reflux, 1 h (70%); (c) nBu4NBr, 2-butanone, 20% NaOH, reflux,
10 min (80%).
Scheme 3a
a Reagents and conditions: (a) RNH2, triphosgene, Et3N, CHCl3, rt, 1
h; (b) RNH2, thiophosgene, Et3N, CHCl3, rt, 1 h; (c) ROH, triphosgene,
Et3N, toluene-CHCl3, reflux 1 h.
The synthesis of the quinazoline scaffold substituted by the
4-aminophenoxy groups at the C-4 position is illustrated in
Scheme 2. Cyclization of methyl 2-amino-4,5-dimethoxyben-
zoate 8 using formamide as a solvent provided the quinazolone
derivative 9 in high yield. The chlorination of the quinazolone
derivative with phosphoryl chloride provided 10 in good yield.
The chloroquinazoline derivative 10 was coupled with 4-ami-
nophenol in the presence of the phase-transfer catalyst n-Bu4-
NBr in 20% NaOH aqueous and 2-butanone to give the
aminophenoxyquinazoline derivative 11 in good yield. The total
yield of this synthetic route was over 50%, and the compounds
were purified by filtration without column chromatography in
each step.
The syntheses of several quinoline and quinazoline derivatives
were carried out using quinoline and quinazoline scaffold 7 and
11. The treatment of 7 and 11 with triphosgene and several
primary amines in chloroform afforded the urea derivatives 12
in high yields (>80%). In the case of using thiophosgene instead
of triphosgene, the thiourea derivatives 13 were obtained in
moderate yields. The treatment of 7 and 11 with triphosgene
and several primary or secondary alcohols in toluene-
chloroform under reflux conditions provided the carbamate
derivative 14 in high yields. The amino groups of 7 and 11
were modified into functionalized bonds using commercially
available amines or alcohols (Scheme 3).
The synthesis of quinoline and quinazoline acylthiourea
derivatives substituted by aliphatic or aromatic groups is
illustrated in Scheme 4. Several commercially available acyl
chlorides 15 were reacted with potassium thiocyanate in CH3-
CN to give the thioisocyanate derivative 16. The desired
products 17 were obtained in moderate yield from quinoline
and quinazoline key intermediates 7 and 11.
The inhibitory activities to the autophosphorylation of the
PDGF receptor and the c-kit receptor by quinoline and quinazo-
line derivatives substituted by 4′-urea, thiourea, and carbamates
a IC50 values were measured in intact cell, G292 cell for PDGF receptor
and M07e cell for c-kit receptor, using an ELISA kit. IC50 values were
determined by two separate tests and reported as mean values.
on the phenoxy ring are summarized in Table 1. The inhibitory
activities to the kinase phosphorylation were measured in intact
cells, G292 cells, and M07e cells using an ELISA kit. The urea
derivatives attached to the cyclohexyl group and the 2-cyclo-

2188 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7
Furuta et al.
Table 2. Inhibitory Activity in PDGF Receptor and c-kit Receptor
Phosphorylation Assay of Acylthiourea Derivatives
Figure 2. Inhibitory activities of 17e on PDGF-RR and c-kit (trans-
activation enzyme assays): (b) PDGF-RR; (0) c-kit.
Figure 3. Effects of 17e on the tyrosine phosphorylation of PDGF-
RR (G292 cells) and c-kit (M07e cells).
a See Table 1.
hexylethyl group exhibited comparable inhibitory activities
compared to 2. However, the selectivity between PDGF receptor
and c-kit receptor were still very low in these compounds. There
were no significant differences of in vitro activity between the
quinoline and the quinazoline derivatives. The replacement of
the urea group by a thiourea group decreased inhibitory activity
for the PDGF receptor autophosphorylation. The selectivity of
thiourea derivatives was still low. As for the carbamate
derivatives, results very similar to those for the urea derivatives
were obtained. Compounds substituted by phenyl or 2-cyclo-
hexylethyl groups showed good inhibitory activity for the PDGF
receptor, but the selectivity was still low. Even though these
compounds had a good in vitro activity, the receptor selectivity
was not satisfactory. On the other hand, using synthetic methods
for the acylthiourea bond shown in Scheme 4, compounds 17a
and 17b were synthesized and assayed. It is noted that these
compounds exhibited good inhibitory activity for the PDGF
receptor autophosphorylation; furthermore, the receptor selectiv-
ity was also increased. These results indicated that the acylth-
iourea bond was particularly effective in the receptor selectivity
between the PDGF receptor and the c-kit receptor.
As shown in Table 2, the acylthiourea derivatives exhibited
good inhibitory activity for the PDGF receptor, and the
selectivity was increased compared to that of urea, thiourea,
and carbamate derivatives. There was no significant difference
in in vitro activity between the quinoline and the quinazoline
derivatives. Furthermore replacement of the cyclohexyl or
benzyl group by an aromatic ring produced more favorable
results. It indicated that the aromatic ring attached to the
acylthiourea moiety was important for the inhibitory activity
Figure 4. Cutaway of the rat carotid artery: (left) control; (right) oral
administration of 17e for 2 weeks.
Figure 5. Inhibition of neointima formation, determined from intima/
media ratio, of the rat carotid artery by oral administration of 17e (30
mg/kg) twice daily for 2 weeks.
and high selectivity in these two receptors. Compounds 17c-f
showed good inhibitory activity and excellent receptor selectiv-
ity. Recently structural analysis of c-kit receptor was reported.21
Computational analysis on the relationship between the con-
formational difference of these receptors and the high selectivity
of 17c-f will be discussed separately.
In enzyme assays, 17e showed potent and selective inhibition
on PDGF-RR kinase compared to that on c-kit kinase (Figure
2). IC50 values were 7.6 nM for PDGF-RR and 234 nM for
c-kit. Figure 3 shows the inhibitory activities of 17e on the
tyrosine phosphorylation of PDGF-RR in G292 cells and of c-kit
in M07e cells. In these immunoprecipitation assays, 17e showed

Inhibitors of PDGF Receptor Autophosphorylation
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7 2189
an anti-c-kit antibody (c-19, Santa Cruz Biotechnology Inc.) was
added to plates as a primary antibody, incubated for 1 h, followed
by incubating with an anti-rabbit IgG conjugated with HRP
(NA9340V, Amersham Biosciences) for 1 h. Color development
was carried out using a color development kit for peroxidase
(SUMIRON, Sumitomo Bakelite Co., Ltd.), and the absorbance was
measured at 450 nm. The phosphorylation levels of kinase proteins
were measured by presuming a phosphorylation degree of the
receptor in the presence of a ligand to be 100% and in the absence
of a ligand to be 0%, and IC50 values were then determined.
Enzyme Assays. PDGF-RR (14-467, Upstate Biotechnology) or
c-kit (P3081, Invitrogen) and the serial concentrations of test
compound were incubated with ATP (10 µM) at rt for 30 min for
PDGF-RR and at 37 °C for 60 min for c-kit in the 96-well plates
precoated with poly-Glu,Tyr (4:1). Reactions in plates were stopped
by washing with PBS containing 0.05% Tween 20, and then an
anti-phosphotyrosine antibody PY-20 (610000, BD Biosciences
Pharmingen) was added and incubated for 1 h, followed by the
incubation with an anti-mouse IgG conjugated with HRP (NA9310V,
Amersham Biosciences) for 1 h. Color development was carried
out using a color development kit for peroxidase (SUMIRON,
Sumitomo Bakelite Co., Ltd.), and the absorbance was measured
at 450 nm. The phosphorylation level of poly-Glu, Tyr (4:1) was
measured by presuming the phosphorylation degree in the presence
of ATP to be 100% and in the absence of ATP to be 0%, and IC50
values of test compound were then determined.
Immunoprecipitation Assay. The serial concentrations of test
compound were added to G292 cells or M07e cells cultured in
6-well plates and incubated at 37 °C for 90 min. PDGF-RR in G292
cells and c-kit in M07e cells were activated by the 50 ng/mL of
PDGF-AA (01-309, Upstate Biotechnology) or SCF (Kirin CMC
R&D Laboratories). Cells were solubilized by adding the lysis
buffer, and equivalent amounts of proteins from each well were
immunoprecipitated overnight at 4 °C with anti-PDGF-RR antibody
(c-20, Santa Cruz Biotechnology Inc.) or anti-c-kit antibody (c-19,
Santa Cruz Biotechnology Inc.). SDS-PAGE was carried out, and
proteins were transferred to nitrocellulose membranes. Tyrosine
phosphorylation of PDGF-RR proteins or c-kit proteins were blotted
with an anti-phosphotyrosine antibody PY-20 (610000, BD Bio-
sciences Pharmingen) for 1 h and then with an anti-mouse IgG
conjugated with HRP (NA9310V, Amersham Biosciences) for 1
h, followed by development by using ECL Western blotting
detection reagents (RPN2106, Amersham Biosciences).
comparable results in the activities and the kinase selectivity
with the data in ELISA assays.
The in vivo efficacy of 17e was tested in the rat carotid
balloon injury model. The compound was suspended in meth-
ylcellulose and was orally administrated (30 mg/kg) to Sprague
Dawley rats (n ) 6) twice daily for a period of 14 days starting
on the day after the balloon injury. As shown in Figures 4 and
5, the oral administration of 17e potently inhibited the formation
of neointima in the injured carotid compared to vehicle treated
controls. The reduction of the intima/media (I/M) ratio was 92%,
with no abnormalities in the body weights of the treated animals.
These results suggest that the acylthiourea derivative 17e is a
promising compound as an inhibitor for certain types of cell-
proliferative disorders.
Conclusions
We prepared quinoline and quinazoline scaffolds to synthesize
modified compounds including urea, thiourea, carbamate, and
acylthiourea bonds, and evaluated their inhibitory activity for
the PDGF receptor and the c-kit receptor phosphorylation in
intact cells. These studies showed that the quinoline and
quinazoline derivatives including urea, thiourea, and carbamate
bonds were highly potent inhibitors of the PDGF receptor
autophosphorylation, but these compounds did not exhibit
receptor selectivity between the PDGF receptor and the c-kit
receptor. On the other hand, the quinoline and quinazoline-
acylthiourea derivatives showed not only good inhibitory activity
for the PDGF receptor but also receptor selectivity. Especially
17c-f, which have the aromatic ring directly to the acylthiourea
moiety, exhibited an excellent selectivity between the PDGF
receptor and the c-kit receptor. Additionally, 17e exhibited
potent oral efficacy in the rat balloon injury model. These results
suggest that the quinoline and quinazoline-acylthiourea deriva-
tives are promising therapeutic compounds for certain types of
cell-proliferative diseases.
Experimental Section
1
General Methods. H NMR spectra were recorded on a JEOL
JNM-LA400 (400 MHz) or JEOL JNM-A500 (500 MHz). Chemical
shifts (δ) are given in ppm downfield from tetramethylsilane as
the internal standard. MS spectra were collected with a PLATFORM-
LC (micromass). High-resolution mass spectra were performed by
TORAY Research Center, Inc. Column chromatography was carried
out on silica gel 60 (70-230 mesh, KANTO Chemical) or
preparative thin-layer chromatography (PLC plates; Merck). The
purity of compounds was checked using a Shimazu CLASS-VP
V5.032 HPLC equipped with XTerra RP18 (150 × 4.6 mm, s-3.5
µm) for methods A-D or INERTSIL ODS-3 (150 × 4.6 mm, s-5
µm) for methods E-I. The solvent system of CH3CN/H2O (100
mM NH4OAc) was 45/55 (method A), 50/50 (method B), 55/45
(method C), 60/40 (method D), 55/45 (method E), 60/40 (method
F), 65/35 (method G), 70/30 (method H), and 75/25 (method I) in
20 min; flow rate of 1 mL/min. The purity of all compounds used
by biological assay was >95%. Compound 1 was purified from
Gleevec (Novartis).
Measurement of Kinase Inhibitory Activities. Cell-Based
ELISA Assays. G292 cells for PDGF-RR assays and M07e cells
for c-kit assays were cultured in 96-well microtiter plates and
quiesced in the medium containing 0.1% FBS. The serial concen-
trations of test compounds were added and incubated at 37 °C for
1 h, followed by activating the receptors by adding the 50 ng/mL
of PDGF-AA (01-309, Upstate Biotechnology) or SCF (Kirin
CMC R&D Laboratories). Cells were solubilized by adding lysis
buffer, and the solutions were transferred to the 96-well plates
coated with an anti-phosphotyrosine antibody PY-20 (610000, BD
Biosciences Pharmingen), and incubated the overnight at 4 °C. An
anti-PDGF-RR antibody (c-20, Santa Cruz Biotechnology Inc.) or
Rat Carotid Balloon Injury Model. Wistar male rats (330 to
370 g) were anesthetized, a Fogaty 2F catheter was inserted through
the right femoral artery to the left carotid artery, and abrasion was
made three times with an expansion diameter of 2.5 mm. The test
compound suspended in 1% cremophore EL (C-5135, SOGMA)
was orally administered at 0.4 mL/100 g body weight twice a day
for 2 weeks from the day before surgery. Fourteen days after the
surgery, rats were euthanized and the left carotid artery was removed
and fixed in buffered formalin. Sliced preparations embedded in
paraffin were stained with HE and were subjected to image analysis
for the measurement of the neointima area (I) and medial area (M)
in the section of injured arteries. The I/M area ratio was calculated
as an index for the evaluation of drug efficacy.
Ethyl 6,7-Dimethoxy-4-oxo-1,4-dihydro-3-quinolinecarboxy-
late (4). A mixture of 3,4-dimethoxyaniline (3.00 g, 19.6 mmol)
and diethyl ethoxymethylenemalonate (5.08 g, 23.50 mmol) was
stirred at 120 °C for 1 h. Diphenyl ether (30 mL) was then added
and stirred at 280 °C for 1 h. The reaction mixture was purified by
column chromatography eluting with CHCl3/MeOH (100/1 to 10/
1
1) to obtain 3.58 g of 4 (66%). H NMR (DMSO-d6, 400 MHz):
δ 1.28 (t, J ) 7.1 Hz, 3H), 3.85 (s, 3H), 3.88 (s, 3H), 4.20 (q, J )
7.1 Hz, 2H), 7.05 (s, 1H), 7.52 (s, 1H), 8.43 (d, J ) 6.6 Hz, 1H),
12.06 (d, J ) 6.6 Hz, 1H). MS (ESI): m/z 278 (M+ + 1).
6,7-Dimethoxy-4-quinolone (5). To a solution of 4 (3.28 g, 11.84
mmol) in MeOH (30 mL) was added 10% aqueous NaOH (45 mL),
and the mixture was heated under reflux for 1 h. The reaction
mixture was acidified with 10% aqueous HCl. The resulting solid
was collected by filtration and washed with CHCl3/MeOH (200

2190 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7
Furuta et al.
mL/40 mL) to obtain 2.85 g of crude 6,7-dimethoxy-4-oxo-1,4-
dihydro-3-quinolinecarboxylic acid. Then, a mixture of the acid
(2.85 g) and diphenyl ether (90 mL) was stirred at 280 °C for 1 h.
The reaction mixture was purified by column chromatography
eluting with CHCl3/MeOH (100/1 to 10/1) to obtain 2.3 g of 5
concentration. The residue was purified on a column using
chloroform/methanol to give 2 (121 mg, yield 87%). 1H NMR
(CDCl3, 400 MHz): δ.1.10-1.41 (m, 5H), 1.58-1.71 (m, 3H),
1.95-1.98 (m, 2H), 3.68-3.74 (m, 1H), 4.03 (s, 6H), 5.24 (d, J )
8.05 Hz, 1H), 6.42 (d, J ) 5.37 Hz, 1H), 7.08 (d, J ) 9.03 Hz,
2H), 7.27-7.45 (m, 4H), 7.55 (s, 1H), 8.44 (d, J ) 5.37 Hz, 1H).
MS (ESI): m/z 422 (M+ + 1). Purity: 99% (method A; tR ) 10.58
min), 100% (method E; tR ) 9.94 min).
1
(99%). H NMR (DMSO-d6, 400 MHz): δ 3.82 (s, 3H), 3.86 (s,
3H), 5.95 (d, J ) 4.6 Hz, 1H), 6.69 (s, 1H), 7.43 (s, 1H), 7.78 (d,
J ) 4.6 Hz, 1H), 8.13 (s, 1H). MS (ESI): m/z 206 (M+ + 1).
4-Chloro-6,7-Dimethoxyquinoline (6). A mixture of 5 (2.13 g,
10.39 mmol) and POCl3 (1.45 mL, 15.59 mmol) was heated under
reflux for 0.5 h. The reaction mixture was concentrated and
extracted with CHCl3/MeOH (40 mL/10 mL). The organic layer
was washed with 5% aqueous NaOH and brine. The solution was
dried over Na2SO4 and concentrated. The resulting residue was
purified by column chromatography eluting with CHCl3/MeOH (50/
N-Cyclohexyl-N′-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-
phenyl}urea (12a). 11 (100 mg) was dissolved in chloroform (10
mL) and triethylamine (1 mL) to prepare a solution. A solution of
triphosgene (151 mg) in chloroform (2 mL) was then added to the
solution, and the mixture was stirred at room temperature for 10
min. Next, the solution of cyclohexylamine (49 mg) in chloroform
(2 mL) was added thereto, and the mixture was further stirred at
room temperature for 1 h. Water was added to stop the reaction,
and the reaction solution was then extracted with chloroform,
followed by concentration. The residue was purified on a column
1
1) to obtain 1.98 g of 6 (85%). H NMR (CDCl3, 400 MHz): δ
4.05 (s, 3H), 4.07 (s, 3H), 7.36 (d, J ) 4.9 Hz, 1H), 7.42 (s, 1H),
7.43 (s, 1H), 8.59 (d, J ) 4.6 Hz, 1H). MS (ESI): m/z 224 (M+
1).
+
1
using chloroform/methanol to give 12a (116 mg, yield 83%). H
NMR (CDCl3, 400 MHz): δ.1.10-1.20 (m, 2H), 1.26-1.43 (m,
2H), 1.59-1.77 (m, 4H), 1.96-1.99 (m, 2H), 3.64-3.71 (m, 1H),
4.06 (s, 6H), 4.99 (d, J ) 7.81 Hz, 1H), 6.90 (s, 1H), 7.18 (d, J )
8.78 Hz, 2H), 7.31 (s, 1H), 7.41 (d, J ) 8.78 Hz, 2H), 7.54 (s,
1H), 8.61 (s, 1H). MS (ESI): m/z 423 (M+ + 1). Purity: 99%
(method A; tR ) 7.78 min), 99% (method E; tR ) 8.10 min).
N-(2-Cyclohexyl)ethyl-N′-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-
phenyl}urea (12b). 7 (100 mg) was dissolved in chloroform (10
mL) and triethylamine (1 mL) to prepare a solution. A solution of
triphosgene (151 mg) in chloroform (2 mL) was then added to the
solution, and the mixture was stirred at room temperature for 10
min. Next, the solution of 2-cyclohexylethylamine (65 mg) in
chloroform (2 mL) was added thereto, and the mixture was further
stirred at room temperature for 1 h. Water was added to stop the
reaction, and the reaction solution was then extracted with
chloroform, followed by concentration. The residue was purified
on a column using chloroform/methanol to give 12b (63 mg, yield
41%). 1H NMR (CDCl3, 400 MHz): δ.0.88-0.93 (m, 2H), 1.13-
1.29 (m, 4H), 1.38-1.44 (m, 2H), 1.61-1.69 (m, 5H), 3.26-3.31
(m, 2H), 4.03 (s, 6H), 5.36-5.38 (m, 1H), 6.42 (d, J ) 5.37 Hz,
1H), 7.08 (d, J ) 8.79 Hz, 2H), 7.40 (s, 1H), 7.45 (d, J ) 9.03 Hz,
2H), 7.55 (s, 1H), 7.57 (s, 1H), 8.44 (d, J ) 5.12 Hz, 1H). MS
(ESI): m/z 450 (M+ + 1). Purity: 98% (method C; tR ) 8.65 min),
98% (method G; tR ) 9.76 min).
N-(2-Cyclohexyl)ethyl-N′-{4-[(6,7-dimethoxy-4-quinazolinyl)-
oxy]phenyl}urea (12c). 11 (100 mg) was dissolved in chloroform
(10 mL), and triethylamine (1 mL) to prepare a solution. A solution
of triphosgene (151 mg) in chloroform (2 mL) was then added to
the solution, and the mixture was stirred at room temperature for
10 min. Next, the solution of 2-cyclohexylethylamine (65 mg) in
chloroform (2 mL) was added thereto, and the mixture was further
stirred at room temperature for 1 h. Water was added to stop the
reaction, and the reaction solution was then extracted with
chloroform, followed by concentration. The residue was purified
on a column using chloroform/methanol to give 12c (109 mg, yield
71%). 1H NMR (CDCl3, 400 MHz): δ.0.84-0.93 (m, 2H), 1.10-
1.42 (m, 6H), 1.60-1.70 (m, 5H), 3.24-3.29 (m, 2H), 4.046 (s,
3H), 4.049 (s, 3H), 5.45-5.46 (m, 1H), 7.15 (d, J ) 9.03 Hz, 2H),
7.29 (d, J ) 0.73 Hz, 1H), 7.42 (d, J ) 9.03 Hz, 2H), 7.52 (s, 1H),
8.58 (d, J ) 0.73 Hz, 1H). MS (ESI): m/z 451 (M+ + 1). Purity:
98% (method B; tR ) 10.02 min), 98% (method G; tR ) 8.20 min).
N-Cyclohexyl-N′-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-
thiourea (13a). 7 (50 mg) was dissolved in toluene (4 mL) and
ethanol (6 mL) to prepare a solution. Cyclohexyl isothiocyanate
(42 mg) was added to the solution, and the mixture was stirred at
80 °C for 6 h. The reaction solution was concentrated, and ether
and hexane were added to the residue. The resultant crystals were
collected by filtration to give the title compound (52 mg, yield 70%).
1H NMR (CDCl3, 400 MHz): δ.1.20-1.28 (m, 3H), 1.39-1.48
(m, 2H), 1.64-1.76 (m, 3H), 2.07-2.10 (m, 2H), 3.35-3.36 (m,
1H), 4.05 (s, 3H), 4.06 (s, 3H), 6.58-6.60 (m, 1H), 7.20-7.23
(m, 2H), 7.37-7.38 (m, 1H), 7.46-7.51 (m, 2H), 7.57-7.58 (m,
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (7). Sodium hydride
(60 wt %, 3.2 g) was added to dimethyl sulfoxide (50 mL), and
the mixture was stirred at room temperature for 20 min. 4-Ami-
nophenol (8.7 g) was added thereto, and the mixture was stirred at
room temperature for 10 min. Next, 6 (18.2 g) was added thereto,
and the mixture was stirred at 100 °C for 3 h. Water was added to
the reaction solution, and the mixture was extracted with chloro-
form. The chloroform layer was then washed with a saturated
aqueous sodium hydrogen carbonate solution and was dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under reduced pressure. Methanol was added to the residue, and
the precipitated crystal was collected by suction filtration to give 7
(21.8 g, yield 92%). 1H NMR (CDCl3, 400 MHz): δ.3.82 (s, 2H),
4.09 (s, 3H), 4.13 (s, 3H), 6.64 (d, J ) 6.3 Hz, 1H), 6.64 (d, J )
8.8 Hz, 2H), 7.00 (d, J ) 8.8 Hz, 2H), 7.62 (s, 1H), 7.95 (s, 1H),
8.45 (d, J ) 6.3 Hz, 1H). MS (ESI): m/z 297 (M+ + 1).
6,7-Dimethoxy-4-quinazolone (9). To a solution of 8 (200 g)
in DMF (1.6 L) and methanol (400 mL), formamide (180 g) and
sodium methoxide (146 g) were added. The reaction mixture was
stirred for 10 h under reflux conditions. After quench by cold water,
the mixture was neutralized by 1 N hydrochloride solution.
Precipitated solid was collected by filtration and washed with water,
ethyl acetate, and hexane to give 9 (190 g, yield 97%).
4-Chloro-6,7-dimethoxyquinazoline (10). A mixture of 9 (100
g) and phosphoryl chloride (120 mL) was refluxed for 1 h. After
concentration, CHCl3 (400 mL) and cold water (200 mL) were
added carefully. The mixture was basified by 20% sodium
hydroxide solution and extracted with chloroform. The extract was
washed with saturated NaHCO3 aq., water, and brine and then dried
over sodium sulfate. The residue was concentrated to give 10 (94
g, yield 86%).
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (11). A solution
of 10 (30.3 g), aminophenol (17.7 g), and tetra-n-butylammonium
bromide (18.7 g) in methyl ethyl ketone (300 mL) and 20% sodium
hydroxide solution (150 mL) was refluxed for 30 min. After dilution
by chloroform (500 mL) and water (200 mL), the mixture was
extracted with chloroform. The extract was washed with water and
brine and then dried over sodium sulfate. The residue was
concentrated, and then precipitated solid was collected by filtration
and washed with methanol to give 11 (36.5 g, yield 91%). 1H NMR
(CDCl3, 400 MHz): δ.4.06 (s, 3H), 4.07 (s, 3H), 6.77 (d, J ) 8.78
Hz, 2H), 7.04 (d, J ) 8.78 Hz, 2H), 7.31 (s, 1H), 7.56 (s, 1H),
8.63 (s, 1H). MS (ESI): m/z 298 (M+ + 1).
N-Cyclohexyl-N′-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-
urea (2). 7 (100 mg) was dissolved in chloroform (10 mL) and
triethylamine (1 mL) to prepare a solution. A solution of triphosgene
(151 mg) in chloroform (2 mL) was then added to the solution,
and the mixture was stirred at room temperature for 10 min. Next,
a solution of cyclohexylamine (49 mg) in chloroform (2 mL) was
added thereto, and the mixture was further stirred at room
temperature for 1 h. Water was added to stop the reaction, and the
reaction solution was then extracted with chloroform, followed by

Inhibitors of PDGF Receptor Autophosphorylation
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7 2191
1H), 8.42-8.44 (m, 1H). MS (ESI): m/z 438 (M+ + 1). Purity:
98% (method B; tR ) 7.95 min), 99% (method F; tR ) 9.59 min).
N-Benzyl-N′-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-
thiourea (13b). 11 (50 mg) was dissolved in toluene (4 mL) and
ethanol (6 mL) to prepare a solution. Benzyl isothiocyanate (44
mg) was added to the solution, and the mixture was stirred at 80
°C for 6 h. The reaction solution was concentrated, and ether and
hexane were added to the residue. The resultant crystals were
collected by filtration to give the title compound (74 mg, yield 98%).
1H NMR (DMSO-d6, 400 MHz): δ.3.97 (s, 3H), 3.99 (s, 3H), 4.73-
4.79 (bs, 2H), 7.24-7.56 (m, 11H), 8.18-8.25 (bs, 1H), 8.55 (s,
1H), 9.63-9.67 (bs, 1H). MS (ESI): m/z 447 (M+ + 1). Purity:
97% (method A; tR ) 8.25 min), 98% (method E; tR ) 8.70 min).
N-Cyclohexylmethyl-N′-{4-[(6,7-dimethoxy-4-quinazolinyl)-
oxy]phenyl}thiourea (13c). 11 (50 mg) was dissolved in toluene
(4 mL) and ethanol (6 mL) to prepare a solution. Cyclohexylmethyl
isothiocyanate (53 mg) was added to the solution, and the mixture
was stirred at 80 °C for 6 h. The reaction solution was concentrated,
and ether and hexane were added to the residue. The resultant
crystals were collected by filtration to give the title compound (52
7.39 (s, 1H), 7.49 (s, 1H), 7.76 (d, J ) 8.78 Hz, 1H), 8.50 (d, J )
5.12 Hz, 1H), 11.41 (bs, 1H), 12.56 (bs, 1H). MS (ESI): m/z 466
(M+ + 1). Purity: 98% (method D; tR ) 7.62 min), 100% (method
I; tR ) 8.22 min).
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-N′-(2-pheny-
lacetyl)thiourea (17b). Compound 17b was prepared in 80% yield
from 7 and 2-phenylethanoyl isothiocyanate by a method similar
to that described for 17a. 1H NMR (DMSO-d6, 400 MHz): δ.3.82
(s, 2H), 3.96 (s, 3H), 3.98 (s, 3H), 6.51 (d, J ) 6.01 Hz, 1H),
7.25-7.35 (m, 7H), 7.44 (s, 1H), 7.48 (d, J ) 8.78 Hz, 1H), 7.51
(s, 1H), 7.69 (m, 1H), 8.14-8.16 (m, 1H), 8.57 (bs, 1H), 11.81 (s,
1H). MS (ESI): m/z 474 (M+ + 1). Purity: 98% (method C; tR )
7.32 min), 98% (method G; tR ) 8.91 min).
N-Benzoyl-N′-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-
thiourea (17c). Compound 17c was prepared in 94% yield from 7
and 1-benzenecarbonyl isothiocyanate by a method similar to that
1
described for 17a. H NMR (CDCl3, 400 MHz): δ.4.02 (s, 6H),
6.54 (d, J ) 5.12 Hz, 1H), 7.22 (d, J ) 8.78 Hz, 2H), 7.33-7.77
(m, 5H), 7.81 (t, J ) 3.42 Hz, 1H), 7.83-7.95 (m, 3H), 8.02 (d, J
) 8.76 Hz, 1H), 8.49 (d, J ) 5.12 Hz, 1H), 9.42 (bs, 1H). MS
(ESI): m/z 460 (M+ + 1). Purity: 100% (method B; tR ) 10.92
min), 99% (method G; tR ) 9.76 min).
1
mg, yield 68%). H NMR (CDCl3, 400 MHz): δ.0.92-1.00 (m,
2H), 1.11-1.30 (m, 3H), 1.65-1.74 (m, 5H), 3.50-3.53 (m, 2H),
4.07 (s, 3H), 4.08 (s, 3H), 6.21 (s, 1H), 7.27 (s, 1H), 7.35-7.36
(m, 4H), 7.53 (s, 1H), 7.87 (s, 1H), 8.63 (s, 1H). MS (ESI): m/z
453 (M+ + 1). Purity: 95% (method B; tR ) 8.53 min), 96%
(method G; tR ) 7.97 min).
N-(2-Chlorobenzoyl)-N′-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-
phenyl}thiourea (17d). Compound 17d was prepared in 100%
yield from 7 and 2-chloro-1-benzenecarbonyl isothiocyanate by a
1
method similar to that described for 17a. H NMR (CDCl3, 400
Phenyl N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}carbamate
(14a). 7 (100 mg) was added to toluene (10 mL) and triethylamine
(1 mL), and the mixture was heated under reflux to prepare a
solution. The solution of triphosgene (151 mg) in methylene
chloride (2 mL) was then added thereto, and the mixture was heated
under reflux for 10 min. Next, phenol (46 mg) was added thereto,
and the mixture was further stirred with heating under reflux for 3
h. A saturated aqueous sodium bicarbonate solution was added to
stop the reaction, and the reaction solution was then extracted with
chloroform, followed by washing with water and brine in that order.
The extract was dried over sodium sulfate and was then concen-
trated. The residue was purified on a column using chloroform/
MHz): δ.4.07 (s, 6H), 6.57 (d, J ) 5.37 Hz, 1H), 7.23-7.29 (m,
3H), 7.44-7.47 (m, 2H), 7.53-7.54 (m, 3H), 7.79-7.86 (m, 3H),
8.53 (d, J ) 5.37 Hz, 1H), 9.23 (s, 1H). MS (ESI): m/z 494 (M+
+ 1). Purity: 98% (method C; tR ) 8.02 min), 99% (method H; tR
) 8.26 min).
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-N′-(2-methyl-
benzoyl)thiourea (17e). Compound 17e was prepared in 97% yield
from 7 and 2-methyl-1-benzenecarbonyl isothiocyanate by a method
1
similar to that described for 17a. H NMR (CDCl3, 400 MHz):
δ.2.17 (s, 3H), 4.09 (s, 3H), 4.13 (s, 3H), 6.69 (d, J ) 5.86 Hz,
1H), 7.26-7.36 (m, 5H), 7.47-7.49 (m, 1H), 7.58 (d, J ) 8.05
Hz, 1H), 7.61 (s, 1H), 7.88 (bs, 1H), 7.94 (d, J ) 9.03 Hz, 2H),
8.52 (d, J ) 5.86 Hz, 1H), 8.89 (s, 1H): HRMS, (ESI): calcd for
C26H22N3O4S [M-H]- 472.1331; found: 472.1357. Purity: 97%
(method C; tR ) 7.70 min), 97% (method G; tR ) 9.95 min).
N-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]phenyl}-N′-(2-me-
thylbenzoyl)thiourea (17f). Compound 17f was prepared in 90%
yield from 11 and 2-methyl-1-benzenecarbonyl isothiocyanate by
1
methanol to give 14a (100 mg, yield 63%). H NMR (DMSO-d6,
400 MHz): δ.4.03 (s, 3H), 4.04 (s, 3H), 6.83 (d, J ) 6.3 Hz, 1H),
7.24-7.30 (m, 3H), 7.38-7.47 (m, 3H), 7.57 (s, 1H), 7.72-7.74
(m, 3H), 8.79 (d, J ) 6.6 Hz, 1H), 10.50 (s, 1H). MS (ESI): m/z
417 (M+ + 1). Purity: 95% (method B; tR ) 8.08 min), 95%
(method F; tR ) 9.15 min).
1
2-Cyclohexylethyl
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-
a method similar to that described for 17a. H NMR (DMSO-d6,
phenyl}carbamate (14b). Compound 14b was prepared in 76%
yield from 7 and 2-cyclohexyl-1-ethanol by a method similar to
that described for 14a. 1H NMR (CDCl3, 400 MHz): δ.0.95-1.01
(m, 2H), 1.15-1.27 (m, 3H), 1.40-1.43 (m, 1H), 1.57-1.77 (m,
7H), 4.10 (s, 3H), 4.17 (s, 3H), 4.24 (t, J ) 6.8 Hz, 2H), 6.70 (d,
J ) 6.3 Hz, 1H), 6.82 (s, 1H), 7.18 (d, J ) 8.8 Hz, 2H), 7.61 (d,
J ) 8.8 Hz, 2H), 7.64 (s, 1H), 8.15 (s, 1H), 8.48 (t, J ) 6.6 Hz,
1H). MS (ESI): m/z 452 (M+ + 1). Purity: 97% (method D; tR )
10.73 min), 97% (method I; tR ) 11.16 min).
N-Cyclohexylcarbonyl-N′-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-
phenyl}thiourea (17a). 1-Cyclohexanecarbonyl isothiocyanate 16
was prepared from 1-cyclohexanecarbonyl chloride as a starting
compound 15 and potassium thiocyanate. 1-Cyclohexanecarbonyl
chloride (80 mg) and potassium thiocyanate (53 mg) were dissolved
in acetonitrile (3 mL). After stirring at 50 °C for 1 h, the reaction
mixture was concentrated. The residue was diluted with AcOEt
and saturated NaHCO3 aq. and then extracted with AcOEt. The
extract was concentrated to give crude 1-cyclohexanecarbonyl
isothiocyanate. This crude compound was dissolved in ethanol (1
mL). 7 (50 mg) in toluene (5 mL) and ethanol (1 mL) were added
to the solution, and the mixture was stirred at room temperature
for 2 h. The reaction mixture was concentrated, and the residue
was purified by chromatography on silica gel using chloroform/
acetone to give 17a (60 mg, yield 76%). 1H NMR (DMSO-d6, 400
MHz): δ.1.21-1.38 (m, 6H), 1.66-1.85 (m, 5H), 3.92 (s, 3H),
3.95 (s, 3H), 6.54 (d, J ) 5.12 Hz, 1H), 7.28 (d, J ) 9.03 Hz, 3H),
400 MHz): δ.2.50 (s, 3H), 3.98 (s, 3H), 3.99 (s, 3H), 7.29-7.38
(m, 7H), 7.42-7.46 (m, 1H), 7.52 (d, J ) 7.81 Hz, 1H), 7.57 (s,
1H), 7.80-7.82 (m, 2H), 8.56 (s, 1H). MS (ESI): m/z 475 (M+
+
1). Purity: 98% (method B; tR ) 10.45 min), 99% (method G; tR
) 9.11 min).
Acknowledgment. We acknowledge the contributions of
Yasunari Fujiwara, Hideko Murooka, Akemi Iwai, Kayoko
Fukushima, and Midori Arai for their technical assistance in
the chemical syntheses, Atsuko Kobayashi for the HPLC
analysis, and Noriko Tawara for the biological assay. We thank
Dr. Yuzuru Kanakura (Osaka University Medical School) for
kindly providing the M07e cell line.
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