6-Arylamino-5,8-quinazolinediones as potent inhibitors of endothelium-dependent vasorelaxation

Article abstract of DOI:10.1016/S0223-5234(01)01290-9

6-(Substituted-phenyl)amino-5,8-quinazolinediones (3) were synthesised by regioselective substitution of 5,8-quinazolinedione (5) with appropriate arylamines in the presence of Ce(III) ions. All synthesised 5,8-quinazolinediones 3 showed a potent and efficacious inhibitory effect on the acetylcholine (ACh)-induced vasorelaxation of rat aorta with the endothelium. The quinones 3, at a low concentration of 0.1 μM, reduced the maximal response with increase of EC₅₀ values for ACh. The results indicate that quinones 3 are potent inhibitors of endothelium-dependent vasorelaxation.

Full text of DOI:10.1016/S0223-5234(01)01290-9

Eur. J. Med. Chem. 37 (2002) 77–82
Short communication
6-Arylamino-5,8-quinazolinediones as potent inhibitors of
endothelium-dependent vasorelaxation
a,
a
a,b
a,b
Chung-Kyu Ryu *, Keun-Hwa Shin , Ji-Hui Seo , Hwa-Jung Kim
a
College of Pharmacy, Ewha Womans Uni6ersity, Sodaemun-Ku, Seoul 120-750, South Korea
Center for Cell Signaling Research, Ewha Womans Uni6ersity, Seoul 120-750, South Korea
b
Received 18 July 2001; received in revised form 29 October 2001; accepted 31 October 2001
Abstract
6
-(Substituted-phenyl)amino-5,8-quinazolinediones (3) were synthesised by regioselective substitution of 5,8-quinazolinedione
5) with appropriate arylamines in the presence of Ce(III) ions. All synthesised 5,8-quinazolinediones 3 showed a potent and
efficacious inhibitory effect on the acetylcholine (ACh)-induced vasorelaxation of rat aorta with the endothelium. The quinones
(
3
, at a low concentration of 0.1 mM, reduced the maximal response with increase of EC values for ACh. The results indicate
50
´
that quinones 3 are potent inhibitors of endothelium-dependent vasorelaxation. © 2002 Editions scientifiques et m e´ dicales Elsevier
SAS. All rights reserved.
Keywords: 6-arylamino-5,8-quinazolinedione; isosteres; inhibitors; endothelium-dependent vasorelaxation
1
. Introduction
xation, 6-arylamino-5,8-quinazolinediones 3, as bio-
isosteres of quinones 1 and 2, were newly synthesised
and evaluated on the inhibitory potential of endothe-
lium-dependent vasorelaxation (Fig. 1). A variety of
heterocyclic quinones with different substituents can
inhibit the vasorelaxation through different action [8].
The 6-arylamino-5,8-quinazolinediones 3 were incorpo-
rated with fluorine, chlorine or bromine, respectively, to
alter their pharmacological properties.
There have been a few report [10–13] on synthesis
and cytotoxicities of some 5,8-quinazolinedione deriva-
tives against cancer cell lines. However, the inhibitory
properties of 5,8-quinazolinediones 3 on vasorelaxation
have not been reported. We report, therefore, the syn-
thesis and inhibitory activities of quinazolinediones 3a–
j on the endothelium-dependent vasorelaxation (Fig. 2).
6-Phenylamino-5,8-quinolinedione (LY83583, 1), a
heterocyclic quinone, is a potent inhibitor of endothe-
lium-dependent vasorelaxation [1–4] and lowers intra-
cellular cGMP in several tissues [1] due to inhibitions of
endothelial nitric oxide synthase (eNOS) activity [5].
LY83583 (1) interacts with the reductase domain of
NOS, leading to a decrease in NO formation [4]. Addi-
tional quinones such as 1,4-naphthoquinones have also
been shown to inhibit the endothelium-dependent va-
sorelaxation [6,7] (Fig. 1). On the line, in our previous
report [8,9], 6-(substituted-phenyl)amino-5,8-quinoline-
diones 2, inhibited the acetylcholine (ACh)-induced va-
sorelaxation of phenylephrine (PE)-precontracted rat
aorta with the intact endothelium and the presence of
nitrogen on the heterocyclic quinones 2 might be an
important factor in the inhibitory activities. Based on
the heterocyclic quinones, with several pharmacological
activities, such as inhibitory effect on the vasorela-
2
. Chemistry
The method used to synthesise the quinones 3 is
shown in Fig. 2. 5,8-Quinazolinedione (5) that has been
*
Correspondence and reprints.
E-mail address: ckryu@mm.ewha.ac.kr (C.-K. Ryu).
previously described [13,14] was synthesised by oxidising
´
0
223-5234/02/$ - see front matter © 2002 Editions scientifiques et m e´ dicales Elsevier SAS. All rights reserved.
PII: S0223-5234(01)01290-9

78
C.-K. Ryu et al. / European Journal of Medicinal Chemistry 37 (2002) 77–82
within tissue preparations (Table 1). The tissue prepara-
tions that did not produce appropriate control ACh
responses were omitted, and control ACh responses in
the absence of test agent were always tested prior to test
ACh responses in the presence of test agent using an
identical tissue preparation.
Most of the 6-arylamino-5,8-quinazolinediones 3a–j
at the test concentration of 0.1 mM strongly inhibited
the ACh-induced vasorelaxation and increased the EC
5
0
value for ACh, whereas, L-NA inhibited the vasorelax-
ation at the higher concentration of 1 mM (Table 1).
Among them, the quinazolinediones 3a, 3c, 3e, and 3h
significantly reduced the Emax of ACh compared with
LY83583, and also these compounds caused an increase
in EC50 values by 11.8–12.7 times greater than the
control values (Fig. 3). LY83583 (1), however, in-
creased the EC50 value by only 3.4-fold relative to the
control value. Even, these three quinones 3a, 3e and 3h
as low as 0.1 mM, increasing the ACh concentration to
Fig. 1. Quinones as inhibitors of endothelium-dependent vasorelax-
ation.
the 5,8-quinazolinediol (4) with Fremy’s salt (potassium
nitrosodisulfonate) resulting in a 69% yield. 6-Ary-
lamino-5,8-quinazolinediones 3a–j (Table 1) were
synthesised by regioselective nucleophilic substitution
of the quinone 5 with appropriate arylamines in the
presence of Ce(III). These substitutions were similar to
the Michael-type regioselective substitution of ary-
lamines on 6,7-dichloro-5,8-quinolinedione in the
presence of Ce(III) [15], and had overall high yields of
1
0 mM did not restore the maximal relaxant response.
When potent inhibitors (e.g. 3a, 3e, 3h) and weak
inhibitor 3g are compared for their augmenting effect
of PE-elicited contraction in aortic rings with endothe-
lium, these potent inhibitors produced significant ef-
fects, whereas, the weak inhibitor did not (Table 2).
50–95%.
3. Pharmacology
4
. Results and discussion
The quinazolinediones 3 were tested for their in-
hibitory activities on the ACh-induced vasorelaxation
Most of the quinones 3 significantly reduced the EC50
of PE-precontracted rat aortas with the intact endothe-
and Emax of ACh-induced vasorelaxation and showed
lium according to the previously reported method [9].
more potent inhibition in the vasorelaxation in com-
G
LY83583 (1) and N -nitro-
L
-arginine (
L
-NA) [16], well-
parison with LY83583 (1) and
L-NA. In terms of
known inhibitors of the endothelium-dependent vasore-
laxation, were used as standard agents. Maximal effect
structural viewpoint, however, the 5,8-quinazolinedione
(5) without the arylamino group at the test concentra-
tion of 0.1 mM exhibited poor inhibitory activities on
the ACh-induced vasorelaxation.
The quinones 3 with the inhibitory effect on endothe-
lium-dependent vasorelaxation produced moderate
increases in basal tone of the aorta, although, statisti-
cally not significant, and augmented contractions
elicited by PE, but only in aortic rings with endothelium.
However, in aortic rings lacking endothelium, there was
no change in basal tonus and in the PE-induced
contractions, even at higher concentrations of these
(
Emax) values for Emax and EC50 values of Ach were
obtained from the mean concentration–response curves
to ACh (0.01–10 mM) for aortic rings treated with
vehicle and quinones 3 (0.1 mM) (Table 1). The EC50
value denotes the ACh concentration producing 50%
vasorelaxation in the presence of quinones, and the
Emax value represents percent of the maximal
vasorelaxation.
The percent inhibition of PE responses by ACh in
control tissues used in our study was quite consistent
Fig. 2. Synthesis of 5,8-quinazolinediones.

C.-K. Ryu et al. / European Journal of Medicinal Chemistry 37 (2002) 77–82
79
Table 1
The inhibitory effects of the quinones 3 on ACh-induced vasorelaxation of rat aorta
Compounds
Control
Substituent
R1
EC50 a(mM)
(N) b
Emax a (% of control)
R2
–
–
–
–
–
–
H
F
Cl
Br
I
H
F
CF3
OCF3
H
–
0.10090.018
1.10090.227*
0.34590.032*
1.18190.290**
0.84690.194*
1.03690.414*
0.53490.118*
1.11890.607**
0.43790.091*
0.18490.105
1.26990.438**
0.50490.142*
0.66490.151*
0.22090.017
(11)
(4)
(7)
(4)
(4)
(4)
(3)
(4)
(4)
(4)
(4)
(3)
(4)
(4)
10091
6993*
7795*
2896**
6994*
31910**
8095*
40912**
6999*
9392
L
-NA
1
3
3
3
3
3
3
3
3
3
3
5
a
b
c
d
e
f
g
h
I
H
H
H
H
H
F
F
H
H
I
4192**
6892*
6993*
9695
j
–
*
PB0.05 relative to the control group; **PB0.05 relative to LY83583 (1) by student’s t-test.
a
EC50 is the ACh concentration producing 50% of the vasorelaxation of PE-precontraction (0.3 mM) after preincubation of each quinone (0.1
mM) or -NA (1 mM) for 20 min and Emax is the percent of the maximal ACh-induced vasorelaxation (control).
Data are mean9S.E.M. using n numbers of aortic rings from separate animals.
L
b
compounds. In previous report [9], sodium nitroprus-
side (1 nM–0.3 mM) elicited concentration-dependent
relaxations in PE-precontracted aortic rings devoid of
endothelium. Under control conditions, sodium nitro-
prusside as a NO-donor produced almost complete
relaxation (98.7% n=8) in the aortic ring with a mean
EC50 value of 17 nM (n=8). In the presence of a
concentration (1 mM) of compounds 3, the compounds
were equally potent with LY83583 in inhibiting sodium
nitroprusside-induced relaxations. These observations
strongly suggest that the compounds 3 interfere with
the relaxant action of endogenously released NO, as
indicated for the similar actions of OQ1 and OQ21 in
our previous report [9] and LY83583 [2,3] on the PE-in-
duced contraction.
5. Conclusions
The 6-arylamino-5,8-quinazolinediones 3 were syn-
thesised by regioselective substitution of 5,8-quinazo-
linedione (5) in the presence of Ce(III) ions with
arylamines. All of the synthesised quinones 3 showed a
In terms of structure–activity relationship, observa-
tions presented in Table 1 and previously reported data
[8], the quinazolinedione skeletons 3 showed, in general,
more potent inhibitory activities than the bioisosteres
such as 5,8-quinolinedione 2, 5,8-isoquinolinedione and
Fig. 3. Concentration-dependent inhibition of ACh-induced endothe-
lium-dependent relaxation by quinazolinedione compounds. Rat aor-
tic rings were isolated with intact endothelium and preincubated with
indicated quinazolinedione compounds or vehicle at concentrations of
0.1 mM for 20 min prior to contraction with 0.3 mM PE. Cumulatively
increasing concentrations of ACh were added to organ baths. Relax-
ation responses are expressed as percentage of decrease in submaxi-
mal contraction elicited by PE. All concentrations represent final bath
concentrations. Values represent mean values9S.E.M. from 4 to 11
aortic rings from different animals.
1,4-naphthoquinone skeletons. In addition, the quina-
zolinedione (5) without an arylamino group exhibited
weak inhibitory activities. Thus, the arylamino moiety
is not essential for the inhibitory activities of these
quinones, but it improves the activities significantly.
The structure–activity relationship may not exist be-
tween positions of substituents (R , R and R ) for the
1
2
3
6-arylamino moieties of quinones 3.

80
C.-K. Ryu et al. / European Journal of Medicinal Chemistry 37 (2002) 77–82
Table 2
6
.1.1. The synthesis of 5,8-quinazolinedione (5)
Briefly, 5,8-quinazolinediol (4) was prepared accor-
Effects of the quinones 3 on phenylephrine (0.3 mM)-induced contrac-
tions of aortic rings with intact endothelium.
ding to known procedure [13]. To a solution of com-
pound 4 (1.62 g, 10 mmol) in 400 mL of acetone, a
solution of potassium nitrosodisulfonate (5 g, 18.65
mmol) in NaH PO buffer (0.3 M, 800 mL, pH 7) was
Tension (g) a
Compounds
Concentration (mM)
b
Control
–
1.3690.04 (11)
1.8490.19 (9)*
1.8890.29 (4)*
1.8390.16 (4)*
1.5990.06 (6)*
1.4190.08 (4)
2
4
3
3
3
3
3
a
e
h
k
g
0.1
0.1
0.1
0.1
0.1
added. The mixture was stirred at room temperature
r.t.) for 1 h and was extracted twice with CH Cl . The
(
2
2
extract was evaporated and then was purified by silica
gel column chromatography with CHCl . 5,8-Quinazo-
3
linedione (5) was crystallised from CH Cl (1.10 g,
2
2
*
Significantly different (PB0.05) from corresponding control by stu-
1
6
9%); m.p. 355–356 °C (dec.); H-NMR (DMSO-d ): l
6
dent’s t-test.
a
9.7 (s, 1H), 9.7 (s, 1H), 7.1 (d, 1H, J=7.1 Hz), 6.9 (d,
Responses were expressed as ‘g’.
+
b
1H, J=7.1 Hz) ppm; MS (m/z): 160 ([M] ); C H N O
Data are the mean9S.E.M. of n observations in parentheses.
8
4
2
2
(
160.13).
potent and efficacious inhibitory effect on the ACh-in-
duced vasorelaxation of PE-precontracted rat aorta
with intact endothelium. The quinones, at a low con-
centration of 0.1 mM, significantly reduced the maximal
response with an increase of EC values for ACh. The
results indicate that 6-arylamino-5,8-quinazolinediones
are potent inhibitors of endothelium-dependent vasore-
laxation. Further pharmacological investigations of
these quinones as inhibitors of endothelial and neuronal
NO syntheses are in progress.
6
6
.1.2. General procedure for the synthesis of
-arylamino-5,8-quinazolinediones (3a–j)
A solution of 5,8-quinazolinedione (5, 0.160 g, 1
mmol) and CeCl ·7H O (0.373 g, 1 mmol) in 15 mL of
3
2
50
9
(
2
5% EtOH was added to the solution of the arylamine
1.1 mmol) in 5 mL of 95% EtOH and stirred at r.t. for
h and then refluxed for 4–5 h. After the mixture was
kept overnight in the refrigerator or poured into 20 mL
of ice water, the precipitate was collected by filtration.
The filtered crude product was purified by silica gel
column chromatography with CHCl3 or crystallised
from 95% EtOH. Purity of reaction products was ver-
ified by both TLC and GC, and the results confirmed
that a single compound was contained.
6. Experimental protocols
6.1. Chemistry
6
.1.2.1. 6-[(Phenyl)amino]-5,8-quinazolinedione (3a).
The yield was 60% as dark brown powder (aqueous
aq.) EtOH); m.p.: 209–211 °C; IR (KBr): w 3400 (s,
NH), 3050 (m), 2800 (m), 1640 (s, CꢀO), 1440–1520,
All melting points (m.p.) were measured in open
capillary tubes with Buchi melting point B-545 and
were uncorrected. The TLC was performed on pre-
coated silica gel (60G 254, Merck) using chloroform for
the solvent. The compounds were detected under UV
light (254 nm) or by heating to 110 °C after spraying
with a 30% H SO –vanillin solution. Column chro-
(
−
1
1
1
380 (s) cm ; H-NMR (DMSO-d ): l 9.6 (s, 1H,
6
NH), 9.3 (s, 2H, H2, H4), 7.3–7.2 (m, 4H, PhꢁH), 6.2
+
(
s, 1H, H7) ppm; MS (m/z): 251 ([M] ), 222, 195, 144,
2
4
7
6; C H N O (251.24).
14 9 3 2
matography was performed on silica gel G60 (70–230
mesh, ASTM, Merck). The purity of 5,8-quinazoline-
diones (3a–j) was also verified by GC (Hewlett Packard
6.1.2.2. 6-[N-(4-Fluorophenyl)amino]-5,8-quinazoline-
dione (3b). The yield was 55% as dark brown powder
((aq.) EtOH); m.p.: 260–262 °C; IR (KBr): w 3400 (s,
NH), 3010 (m, aromatic ring), 1640 (s, CꢀO), 1180 (m)
5
890A, HP-5 capillary column at 260 °C, N gas, 17
2
−
1
mL min
as carrier gas, FID). The IR spectra were
taken from Perkin–Elmer 1420r IR spectrometer with
−1
1
cm ; H-NMR (DMSO-d ): l 10.0 (s, 1H, NH), 9.3
6
1
KBr pellets. H-NMR spectra were recorded on
(
s, 2H, H2, H4), 7.6–6.8 (m, 4H, PhꢁH), 6.1 (s, 1H,
Brucker DPX 250 MHz spectrometer using DMSO-d6
as solvents, and chemical shifts were given in ppm with
TMS as a standard. Mass spectra were obtained on
JMS AX 505 WA spectrometer (electronic impact at 70
eV). Elemental analyses were performed by CE instru-
ments EA1110 with sulfanilamide as standard material,
and analytical results for C, H and N were within
+
H7) ppm; MS (m/z): 269 ([M] ), 240, 213, 162, 95, 76;
C H FN O (269.23).
14
7
3
2
6.1.2.3. 6-[N-(4-Chlorophenyl)amino]-5,8-quinazoline-
dione (3c). The yield was 72% as black powder ((aq.)
EtOH); m.p.: 242–243 °C; IR (KBr): w 3400 (m, NH),
3100 (m, aromatic), 1690 (m, CꢀO), 1400–1500, 1380
(s), 1270 (m), 1180 (s) cm ; H-NMR (DMSO-d ): l
9.6 (s, 1H, H), 9.4 (s, 2H, H2, H4), 7.5–7.4 (m, 4H,
−
1 1
9
0.4% of theoretical values. Arylamines, DMSO-d6
and other reagents were obtained from Aldrich Chemi-
cal Co. -NA and reagents for biological screening were
obtained from Sigma Co.
6
+
L
PhꢁH), 6.2 (s, 1H, H7) ppm; MS (m/z): 285 ([M] ),
250, 229, 178, 111, 76; C H ClN O (285.69).
14
8
3
2

C.-K. Ryu et al. / European Journal of Medicinal Chemistry 37 (2002) 77–82
81
6
.1.2.4. 6-[N-(4-Bromophenyl)amino]-5,8-quinazoline-
dione (3d). The yield was 75% as dark brown powder
(aq.) EtOH); m.p.: 209–210 °C; IR (KBr): w 3470 (s,
NH), 3050 (m), 2900 (m), 1720 (s, CꢀO), 1380 (s), 1270
6.1.2.10. 6 - [N - (3 - Iodophenyl)amino] - 5,8 - quinazoline-
dione (3j). The yield was 61% as dark purple powder
((aq.) EtOH); m.p.: 166–168 °C; IR (KBr): w 3400 (s,
NH), 2900 (m, aromatic ring), 2300 (s), 1640 (s, CꢀO),
(
−
1
1
−1
1
(
m), 690 (m) cm ; H-NMR (DMSO-d ): l 10.9 (s,
1450–1550 (v, benzene), 1250 (m) cm
; H-NMR
6
1
4
H, NH), 9.6 (s, 1H, H4), 9.4 (s, 1H, H2), 7.6–7.2 (m,
(DMSO-d ): l 9.6 (s, 1H, NH), 9.4 (s, 2H, H2, 4),
6
H, PhꢁH), 6.3 (s, 1H, H7) ppm; MS (m/z): 329
7.0–7.8 (m, 4H, benzene), 6.3 (s, 1H, H7) ppm; MS
+
+
(
[M] ), 300, 273, 222, 155, 76; C H BrN O (330.14).
(m/z): 377 ([M] ), 368, 321, 270, 250, 203, C H IN O
1
4
8
3
2
14
8
3
2
(
377.14).
6.1.2.5. 6-[N-(4-Iodophenyl)amino]-5,8-quinazolinedione
(
(
3e). The yield was 81% as dark yellow brown powder
(aq.) EtOH); m.p.: 228–230 °C; IR (KBr): w 3290 (s,
6.2. Pharmacological studies on 6asorelaxant responses
in organ bath experiment
−
1
NH), 3050 (m), 2905 (s), 1650 (s, CꢀO), 1010 (m) cm
;
1
H-NMR (DMSO-d ): l 9.6 (s, 1H, NH), 9.4 (s, 2H,
The quinazolinediones 3 and 5 were tested for their
inhibitory activities on the ACh-induced vasorelaxation
of PE-precontracted rat aortas according to a pre-
viously reported method [9]. Briefly, male Sprague–
Dawley rats (200–300 g) were sacrificed by decapitation
and the thoracic aortas were removed. The aortic rings
placed in oxygenated (95% O –5% CO ) KR buffer
6
H2, 4), 7.8 (m, 2H, PhꢁH), 7.2 (m, 2H, PhꢁH), 6.3 (s,
1
2
+
H, H7) ppm; MS (m/z): 377 ([M] ), 348, 321, 270,
50, 203, 76; C H IN O (377.14).
1
4
8
3
2
6
.1.2.6. 6-[N-(3-Fluorophenyl)amino]-5,8-quinazoline-
2
2
dione (3f). The yield was 67% as brown powder ((aq.)
EtOH); m.p.: 245–256 °C; IR (KBr): w 3339 (s, NH),
(
pH 7.4) with the following composition (in mM):
NaCl, 118; KCl, 4.7; CaCl , 2.5; MgSO , 1.2; KH PO ,
2
4
2
4
3
1
1
6
2
065 (s, aromatic ring), 2900 (m), 1660 (s, CꢀO), 1450–
−
1
1
1.2; NaHCO , 25; glucose, 10; and EDTA, 0.01. Aortas
3
550, 1432 (m) cm ; H-NMR (DMSO-d ): l 9.6 (s,
6
were cut into rings, ca. 2–3 mm long. In some prepara-
tions, the endothelium was removed. Rings were sus-
pended in organ baths, attached to force displacement
transducers (Grass Model FT03) and connected to
Grass model 79E polygraph. They were equilibrated for
H, NH), 9.4 (s, 2H, H2, 4), 7.0–7.6 (m, 4H, benzene),
+
.4 (s, 1H, H6) ppm; MS (m/z): 269 ([M] ), 260, 240,
13, 162, 262, 95, 76; C H FN O (269.23).
14
7
3
2
6
.1.2.7. 6-[N-(3,4-Difluorophenyl)amino]- 5,8-quinazo-
1
h at 37 °C under a resting tension of 2.0 g in a KR
linedione (3g). The yield was 50% as violet powder
(aq.) EtOH); m.p.: 386–388 °C; IR (KBr): w 3329 (s,
NH), 3020 (m), 2900 (m), 1660 (s, CꢀO), 1430–1550,
buffer. Preparations were oxygenated by continuous
(
bubbling with 95% O –5% CO and incubation media
2
2
was routinely changed every 30 min. Following equili-
bration period, 60 mM KCl was added to the bathing
solution. Tissues were then washed until a steady base-
line was reached and tension adjusted to 2 g. Func-
tional integrity of the endothelium was assessed by the
relaxation of the pre-contracted rings in response to
ACh (3 mM), and the successful removal of endothe-
lium was ascertained by the lack of relaxation to ACh
given up to a concentration of 10 mM. Relaxant agents
were added as 100 mL aliquots to 10 mL bath chambers
at the peak of submaximal (70–80%) precontractions
elicited by 0.3 mM PE. Drugs were added directly to the
organ baths. In each experiment, a single concentration
of new quinone compounds was added, and left in
contact with the tissue for 20 min. Tissues were con-
tracted with 0.3 mM PE. Responses to each concentra-
tion of the relaxants were expressed as percent
reductions of PE contraction.
−
1
1
1
345 (s) cm ; H-NMR (DMSO-d ): l 9.6 (s, 1H,
6
NH), 9.4 (s, 2H, H2, 4), 7.2–7.6 (m, 4H, benzene), 6.3
(
1
+
s, 1H, H6) ppm; MS (m/z): 287 ([M] ), 231, 213, 180,
52, 113, 76; C H F N O (287.22).
14 7 2 3 2
6
.1.2.8. 6 - [N - (4 - Trifluoromethylphenyl)amino] - 5,8-
quinazolinedione (3h). The yield was 85% as dark or-
ange powder ((aq.) EtOH); m.p.: 202–204 °C; IR
(
KBr): w 3400 (s, NH), 3040 (m), 2920 (m), 1640 (s,
−
1
1
CꢀO), 1380 (s), 1010 (m), 740 (s) cm
; H-NMR
(DMSO-d ): l 10.0 (s, 1H, NH), 9.6 (s, 2H, H2, H4),
6
7
.3–6.8 (m, 4H, PhꢁH), 6.2 (s, 1H, H7) ppm; MS
+
(
m/z): 319 ([M] ), 300, 263, 250, 212, 145, 76;
C H F N O (319.24).
1
5
8
3
3
2
6
.1.2.9. 6 - [N - (4 - Trifluoromethoxyphenyl)amino] - 5,8-
quinazolinedione (3i). The yield was 87% as dark orange
powder ((aq.) EtOH); m.p.: 202–203 °C; IR (KBr): w
3
400 (s, NH), 3060 (m), 2910 (m, 1670 (s, CꢀO), 1380
−1 1
(
s), 1010 (m), 740 (s) cm ; H-NMR (DMSO-d ): l
Acknowledgements
6
1
0.0 (s, 1H, NH), 9.6 (s, 2H, H2, 4), 7.3–6.8 (m, 4H,
+
benzene), 6.2 (s, 1H, H7) ppm; MS (m/z): 335 ([M] ),
00, 263, 250, 212, 145, 76; C H F N O (335.24).
This study was supported by a grant of the Minister
of Health and Welfare (No HMP-00 B-21500-00111).
3
1
5
8
3
3
3

82
C.-K. Ryu et al. / European Journal of Medicinal Chemistry 37 (2002) 77–82
[
[
8] C.K. Ryu, S.H. Jung, J.A. Lee, H.J. Kim, S.H. Lee, J.H. Chung,
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