Synthesis and antiinflammatory screening of some quinazoline and quinazolyl-4-oxoquinazoline derivatives.

Article abstract of DOI:10.1002/ardp.200290009

Synthesis of some new derivatives of 2-aryl-4-oxo-1-(4-quinazolyl)quinazolines is described. Methyl N-(4-quinazolyl)anthranilate was allowed to react with phenyl iso(thio)cyanate to give 3-phenyl-1-(4-quinazolyl)-1, 2, 3, 4-tetrahydro-2, 4-dioxo- and 4-oxo-2-thioxoquinazolines (3a and 3b respectively) Alternatively, anthranilic acid amide derivatives were subjected to cyclization with aromatic aldehydes to give 2-aryl-4-oxo-1-(4-quinazolyl)-1, 2, 3, 4-tetrahydroquinazolines 5. On the other hand, 2-chloro-4-(4-substituted 1-piperazinyl)quinazoline derivatives were subjected to the same type of reactions at the 2-position to afford the corresponding quinazoline derivatives 8 and 10 respectively. Furthermore, the acid amide 4b cyclized with acid chlorides to give the corresponding 2-aryl-1-(2-chloro-4-quinazolyl)-4-oxo-1, 4-dihydroquinazolines 11 from which the triazoloquinazoline derivatives 13 and 15 were synthesized through the intermediate hydrazine derivatives 12. Most of the newly synthesized compounds were tested for their antiinflammatory activities. However, some of the novel compounds were found to exhibit good antiinflammatory potencies.

Full text of DOI:10.1002/ardp.200290009

556 Gineinah et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 11, 556–562
Magdy M. Gineinaha,
Magda A. El-Sherbenyb,
Magda N. Nasra,
Synthesis and Antiinflammatory Screening of Some
Quinazoline and Quinazolyl-4-oxoquinazoline
Derivatives
Azza R. Maaroufc
Synthesis of some new derivatives of 2-aryl-4-oxo-1-(4-quinazolyl)quinazolines is
described. Methyl N-(4-quinazolyl)anthranilate was allowed to react with phenyl
iso(thio)cyanate to give 3-phenyl-1-(4-quinazolyl)-1,2,3,4-tetrahydro-2,4-dioxo-
and 4-oxo-2-thioxoquinazolines (3 a and 3 b, respectively) Alternatively, anthranilic
acid amide derivatives were subjected to cyclization with aromatic aldehydes to give
2-aryl-4-oxo-1-(4-quinazolyl)-1,2,3,4-tetrahydroquinazolines 5. On the other hand,
2-chloro-4-(4-substituted 1-piperazinyl)quinazoline derivatives were subjected to
the same type of reactions at the 2-position to afford the corresponding quinazoline
derivatives 8 and 10, respectively. Furthermore, the acid amide 4 b was cyclized
with acid chlorides to give the corresponding 2-aryl-1-(2-chloro-4-quinazolyl)-4-
oxo-1,4-dihydroquinazolines 11, from which the triazoloquinazoline derivatives 13
and 15 were synthesized through the intermediate hydrazine derivatives 12.Most of
the newly synthesized compounds were tested for their antiinflammatory activities.
However, some of the novel compounds were found to exhibit good antiinflammato-
ry potencies.
a
Pharmaceutical Organic
Chemistry and Medicinal
Chemistry Department,
College of Pharmacy,
Mansoura University,
Mansoura 35516, Egypt
Pharmaceutical Chemistry
Department, College of
Pharmacy, King Saud
University, P.O. Box 22452,
Riyadh 11495, Saudi Arabia
c
b
Keywords: 4-Oxoquinazolines; Triazolo[4,3-a]quinazolines; Antiinflammatory ac-
tivity
Received: May 22, 2002 [FP703]
lated by proinflammatory mediators [4]. This regulated
expression suggests that a selective inhibitor of COX-2
Introduction
Nonsteroidal antiinflammatory drugs (NSAIDs) are
among the most widely used of all therapeutic agents.
The fact that so many new compounds have been pro-
duced and are still being produced is a reflection of the
fact that none is ideal in controlling and modifying the
signs and symptoms of inflammation. A particular prob-
lem is that virtually all NSAIDs can have significant side
effects.Therefore, there is a great deal of research going
on into antiinflammatory and immunosuppressant
agents. A major mechanism of action of NSAIDs is low-
ering prostaglandin production through inhibition of cy-
clooxygenase (COX), which has dual functions, media-
tion of inflammation [1] and cytoprotection of the stom-
ach and intestine [2]. Thus, long-term therapy with
NSAIDs will cause gastrointestinal damage and ulcera-
tion. However, it was discovered that COX exists in two
isoforms, COX-1 and COX-2, which are encoded by two
distinct genes [3].COX-1 is expressed constitutively pro-
viding cytoprotection while COX-2 is transiently upregu-
may have antiinflammatory properties and lack the ul-
cerogenic side effects. This hypothesis has been sup-
ported by several in vivo studies with selective COX-2 in-
hibitors [5, 6]. Among the many reported classes of anti-
inflammatory agents, 4-oxoquinazolines possess good
activity [7, 8]. Moreover, 4-anilinoquinazoline derivatives
were reported to exhibit protein kinase inhibitor activity,
which is of therapeutic value in a wide range of disease
states, such as cancer and arthritis [9]. Furthermore, we
had reported some 1,2,4-triazolo[4,3-c] and [1,5-
c]quinazoline derivatives of potent and selective COX-2
inhibition properties [10]. Directed by these findings, we
here report the synthesis of 4-oxoquinazoline deriva-
tives of potential antiinflammatory activity.
Results and discussion
Chemistry
All the compounds synthesized in the current work were
derived from 4-chloro- and 2,4-dichloroquinazoline (1 a
and 1 b, respectively) as exemplified in Schemes 1–3.
The presence of a chloro group at C-4 of the quinazoline
Correspondence: Magdy M. Gineinah, Pharmaceutical
Organic Chemistry, College of Pharmacy, Mansoura
University, Mansoura 35516, Egypt. Phone: +20 50 2247496,
fax: +20 50 2247496, e-mail: maggineinah@yahoo.com
© 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0365-6233/11/0556 $ 17.50+.50/0

Arch. Pharm. Pharm. Med. Chem. 2002, 335, 556–562
Quinazolines and Quinazolyl-4 oxoquinazolines 557
Scheme 3
Scheme 1
ring provided a functionalizable handle from which vari-
ous moieties could be obtained. A facile reaction of
methyl ester of anthranilic acid takes place with 4-chloro-
quinazoline (1 a) through a nucleophilic substitution
mechanism to give compound 2. The 4-oxoquinazoline
derivatives utilized in this study were prepared by differ-
ent synthetic methods according to the type of cyclizing
agent as shown in Schemes 1–3.Thus, 1-(4-quinazolyl)-
4-oxoquinazolines 3 and 5 were prepared from com-
pound 2 using the routes depicted in Scheme 1 (Table 1).
These compounds were prepared essentially following
two procedures for cyclization of anthranilic acid deriva-
tives.The first procedure involves the reaction of a solu-
tion of methyl ester of N-substituted anthranilic acid 2
and sodium hydride in tetrahydrofuran (THF) with a solu-
tion of phenyl iso(thio)cyanate inTHF to give compounds
3.In the second cyclization procedure, the N-substituted
anthranilic acid amide 4 a was used. Compound 4 a was
previously reported [11], however, in the current work it
was prepared by ammonolysis of the ester 2, and then
allowed to react with an ethanolic solution of the appro-
priate aromatic aldehyde in basic medium to give 5.
However, similar reactions were applied with 2,4-dichlo-
roquinazoline (1 b). Under all reaction conditions, equi-
molar amounts of several nucleophiles attack exclusive-
ly at the C-4 of quinazoline ring, which is of preferential
Scheme 2

558 Gineinah et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 556–562
Table 1. Physicochemical data of the new compounds.
Ar
R(X)
Mp
[°C]
Rec.
Sol.a
Yield
[%]
Mol.
Formula
3 a
3 b
5 a
5 b
5 c
5 d
6 a
6 b
7 a
7 b
8 a
8 b
8 c
8 d
9 a
9 b
10 a
10 b
10 c
10 d
10 e
10 f
10 g
10 h
11 a
11 b
12 a
12 b
13 a
13 b
14 a
14 b
15 a
15 b
–
–
(O)
(S)
–
-
–
–
Me
Ph
Me
Ph
Me(O)
Me(S)
Ph(O)
Ph(S)
Me
Ph
Me
Me
Me
Me
Ph
Ph
Ph
Ph
–
–
–
–
–
–
>300
277–279
>300
>300
263–265
>300
185–187
191–193
214–216
232–234
>300
E/C
E/C
E/B
E/B
E
E
M
M
M/C
M/C
A
A
A
A
M
M
M
65
72
57
65
71
62
87
91
76
72
64
69
75
62
51
54
74
62
67
61
68
80
67
72
62
56
90
82
52
46
64
73
58
87
C22H14N4O2
C22H14N4OS
C22H16N4O
C22H15ClN4O
C24H20N4O3
C22H15N5O3
C13H15ClN4
Ph
4-Cl-Ph
3,4-(OMe)2-Ph
3-NO2-Ph
–
–
–
–
–
–
–
–
–
–
Ph
C18H17ClN4
C21H23N5O2
C26H25N5O2
C27H24N6O2
C27H24N6OS
C32H26N6O2
C32H26N6OS
C20H22N6O
C25H24N6O
C27H26N6O
C27H25ClN6O
C29H30N6O3
C27H25N7O3
C32H28N6O
C32H27ClN6O
C34H32N6O3
C32H27N7O3
C22H12Cl2N4O
C22H12BrClN4O
C22H15ClN6O
C22H15BrN6O
C23H13ClN6OS
C23H13BrN6OS
C29H18ClN7O3
C29H18BrN7O3
C29H16ClN7O3
C29H16BrN7O3
281–283
>300
295–297
232–234
263–265
282–284
287–289
265–267
>300
277–279
294–296
271–273
>300
>300
>300
>300
>300
291–293
>300
281–283
278–280
265–267
283–285
4-Cl-Ph
3,4-(OMe)2-Ph
3-NO2-Ph
Ph
M
M/C
M/C
E
E
E
4-Cl-Ph
3,4-(OMe)2-Ph
3-NO2-Ph
3-Cl-Ph
4-Br-Ph
3-Cl-Ph
4-Br-Ph
3-Cl-Ph
4-Br-Ph
3-Cl-Ph
4-Br-Ph
3-Cl-Ph
4-Br-Ph
E
E/C
E/C
E
E
E
M
E
E
M
3-NO2-Ph
3-NO2-Ph
3-NO2-Ph
3-NO2-Ph
M
a
Recrystallization solvent; A: acetonitrile, B: benzene, C: chloroform, E: ethanol, M: methanol.
reactivity over the C-2 position. Synthesis of 4-oxo-1-
[4-(4-substituted 1-piperazinyl)-2-quinazolyl]-2-substitut-
edquinazolines 8 and 10 is outlined in Scheme 2. The
synthesis began with selective nucleophilic substitution
of the 4-chloro group of 1 b.Incorporation of a piperazinyl
residue into the 4-position of 1 b was accomplished by
refluxing in ethanol in presence of sodium carbonate to
give 6.Now, compounds 6 have the C-2 as the only avail-
able position for nucleophilic attack.Therefore, 6 was re-
fluxed with an ethanolic solution of methyl anthranilate to
give 7.The 3-phenyl-1-substituted quinazolyl-2,4-dioxo-
and 4-oxo-2-thioxoquinazoline derivatives 8 were pre-
pared from 7 applying the same procedure used for
preparation of 3. Moreover, 2-aryl-4-oxo-1-substituted
quinazolylquinazolines 10 were prepared from
7
(Scheme 2), which was transformed into 9 using the
same procedure as was applied for the preparation of 4,
as outlined earlier (Scheme 1).However, insertion of the

Arch. Pharm. Pharm. Med. Chem. 2002, 335, 556–562
Quinazolines and Quinazolyl-4 oxoquinazolines 559
4-oxoquinazoline moiety at the 4-position of 1 b ensured
that 4 b [11] was cyclized using benzoyl chloride deriva-
tives to yield 11 (Scheme 3).Refluxing 11 with hydrazine
formed 12, which upon cyclization under standard condi-
tions provided the desired triazolo[4,3-a]quinazoline
skeleton 13 and 15. Two potential strategies were ap-
plied for construction of the fused triazole ring. The first
methodology involves the reaction of 12 with carbon di-
sulfide under basic conditions to afford a fused thioxotri-
azole structure 13.The second method relies upon con-
densation of the aromatic aldehyde with 12 to give the
corresponding arylidene derivatives of the hydrazines
14. Formation of 15 was achieved following a published
procedure [12] by treating 14 with an acetic acid solution
of bromine followed by pouring onto sodium hydroxide
solution.
Table 2. Antiinflammatory activity of the tested com-
pounds assessed in parallel with ketoprofen as a refer-
ence standard.
Comp.
Mean % increase
in paw
% Reduction of
paw edema from
control group
weight SE
Control
3 a
3 b
4 a
5 a
5 b
5 c
5 d
7 a
7 b
8 a
8 b
8 c
8 d
9 a
10 c
10 d
10 h
512 a
13 a
14 a
14 b
15 a
15 b
Ketopr.
52.73 4.54
11.84 1.21a
8.64 1.34a
40.33 3.26
20.79 3.17a
17.16 2.38a
28.57 1.76a
13.51 2.28a
43.00 4.26
37.34 2.94
8.35 1.28a
6.13 1.67a
8.85 1.17a
12.35 1.59a
33.62 2.31a
35.56 1.93a
11.16 0.97a
12.18 1.19a
19.65 2.29a
11.34 1.12a
13.89 2.45a
12.01 1.19a
20.54 2.17a
18.29 1.29a
9.14 2.45a
–
77.54
83.61
23.52
60.57
67.46
45.82
74.38
18.45
29.19
84.16
88.37
83.22
76.58
36.24
32.56
78.83
76.90
62.73
78.49
73.66
77.22
61.05
65.31
82.67
Biological screening
Most of the newly synthesized compounds were tested
for their antiinflammatory activity against carrageenin-
induced edema at dose of 100 mg/kg using ketoprofen
as a reference standard (Table 2). With the objective of
identifying compounds with selective COX-2 inhibition,
we distinguished the selective compounds of the present
study by assessing their in vivo ulcerogenic effects. Our
initial screening efforts were directed towards the evalu-
ation of the antiinflammatory activities of the quinazolyl-
4-oxoquinazoline derivatives with interchange of the po-
sition of attachment of both nuclei.Most of these analogs
exhibit good activity ranging from 60 to 88 % edema re-
duction, as shown inTable 2.The major exception proved
to be the 3,4-dimethoxyphenyl derivatives 5 c and 10 c
with 45 % and 32 % edema reduction, respectively. As a
general rule, the non-cyclized N-substituted anthranilic
acid derivatives were found to be less potent than the cy-
clized analogs. Thus, compounds 4 a, 7 a, and 7 b pos-
sess the lowest antiinflammatory activities. Regarding
compounds 3 and 8, with the exception of 8 d, the iso-
steric replacement of the oxygen atom at the 2-position
of 2,4-dioxoquinazoline analogs with a sulfur atom gave
compounds with 4-oxo-2-thioxoquinazoline structure
characterized by better antiinflammatory activities. With
the 4-oxoquinazoline moiety in compounds 5 and 10, we
investigated the effect of the 2-aryl group in detail.When
the group on the phenyl ring was changed to a number of
substituents ranging from electron-donating to electron-
withdrawing groups, it was found to correlate quite well
with the antiinflammatory activity.Thus, insertion of a 3-
nitro group as in 5 d provided a substantial improvement
in activity. Moreover, COX-2 selectivity, as indicated by
minimal ulcerogenic effect, was significantly improved.
On the other hand, the 3,4-dimethoxy substituent in 5 c
showed relatively poor activity. However, the 4-chloro
All the test compounds and ketoprofen were given orally
at a dose of 100 mg/kg.
a Significantly different from the control group using the
student “t” test
group in 5 b led to an activity intermediate between 5 d
and 5 c. As can be seen in Table 2, this trend generally
held true in the 4-oxo-1-(4-substituted piperazinyl-2-
quinazolyl)quinazoline series 10. However, a change of
substituent on the piperazine nucleus in compounds 8
and 10 did not appreciably affect the potency. On the
contrary, cyclization of 12 to give thioxotriazoloquinazo-
line derivatives resulted in a significant increase in po-
tency. Moreover, the potency of 12 was increased again
by the formation of the corresponding arylidene deriva-
tives 14. However, cyclization of compound 14 gave the
triazolo derivatives 15 characterized by a decrease in
antiinflammatory activity.

560 Gineinah et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 556–562
Table 3. Potential ulcerogenic effect of the test com-
pounds compared with ketoprofen and indomethacin.
Comp.
Dose [mg/kg]
Mean ulcer index
S.E.
Control
Ketoprofen
Indomethacin
3 b
5 a
5 d
8 a
8 b
8 c
Vehicle
50
5
50
50
50
50
50
50
50
50
50
0
3.2 0.3a
10.1 0.7
1.7 0.2b
4.3 0.4a
1.8 0.2b
2.7 0.3a
3.9 0.3a
1.5 0.1b
2.8 0.3a
2.4 0.3a
3.8 0.4a
Figure 1. The antiinflammatory activity of ketoprofen
and compound 8 c at three different dose levels (20, 50,
and 100 mg/kg) expressed as % reduction in paw edema
SE.No significant difference between 8 c- and ketopro-
fen-treated groups using student “t” test.
10 d
13 a
14 b
by 5, the 3-nitrophenyl substituent manifested better ac-
tivity in compounds 10.It is noteworthy that the displace-
ment of the 4-oxoquinazoline residue from the 4-position
to the 2-position of the quinazoline nucleus increased
the antiinflammatory activity.
a
( p < 0.05) significantly different from indomethacin-
treated group using the student “t” test.
( p < 0.05) significantly different from ketoprofen-treat-
ed group.
b
Nevertheless, compound 8 c, as a promising antiinflam-
matory agent, was subjected to antiinflammatory testing
at different dose levels in parallel with ketoprofen (Fig-
ure 1). It was found that compound 8 c has more or less
comparable efficacy with that of ketoprofen.
The ulcerogenicity testing data are compiled in Table 3.
The selected compounds, which are the most active in
edema reduction, were tested against ketoprofen and in-
domethacin.The latter was used as a potent antiinflam-
matory drug with substantial ulcerogenic effect. As
shown inTable 3, it is obvious that indomethacin produc-
es high incidence of gastric ulceration while ketoprofen
produces much less ulcerogenic effect. On the other
hand, with the exception of compounds 5 a, 8 b, and
14 b, the tested compounds revealed less ulcerogenic
effect than ketoprofen. Moreover, compound 8 c gave
minimal gastric ulceration. Meanwhile, this compound is
almost equipotent with ketoprofen.Thus, it is considered
to be a lead compound with high antiinflammatory activi-
ty and insignificant ulcerogenic effect. In other words,
compound 8 c is a potent antiinflammatory agent with
selective COX-2 inhibitory activity.
Acknowledgement
The authors would like to thank Prof. Dr. Shehta A. Said,
Dept.of Pharmacology, College of Pharmacy, University
of Mansoura, for carrying out the biological screening.
Experimental
Chemistry
Melting points were determined on a Fischer-Johns apparatus
and are uncorrected. 1H-NMR spectra were recorded on a
Varian EM-360 (90 MHz) instrument using TMS as internal
standard (chemical shifts in ppm, δ units). The results of ele-
mental analyses (C,H,N) were within 0.4 % of the theoretical
values.Thin-layer chromatography was performed on silica gel
GLF plates, 250 µm using chloroform/methanol (9/1) as a mo-
bile phase.
In conclusion, the quinazoline ring system provided a
useful scaffold for attaching different heterocyclic moie-
ties to obtain potent and selective COX-2 inhibitors.The
2-oxo and 2-thioxo groups in 3 and 8 provide enhance-
ment of the potency of the 4-oxoquinazoline series rela-
tive to 2-aryl groups as in 5 and 10. However, in accord-
ance with the conclusion of such comparisons, the 3-thi-
oxotriazolo moiety in 13 was found to be superior in ac-
tivity to the 3-aryl substituent in 15, as shown in Table 2.
Moreover, in agreement with the findings in the 2-aryl-4-
oxo-1-(4-quinazolyl)quinazoline series represented
4-(2-Methoxycarbonylphenylamino)quinazoline (2)
A mixture of 4-chloroquinazoline (1 a) (1.65 g, 10 mmol), me-
thyl anthranilate (1.5 g, 10 mmol), pyridine (0.5 mL), and abso-
lute ethanol (40 mL) was heated under reflux for 5 h. On cool-
ing, the product obtained was collected by filtration, dried, and
recrystallized from methanol to give 2 g (72 %) of 2, mp 171–
173 °C. 1H-NMR (DMSO-d6): 3.88 (s, 3 H, CH3), 7.11–8.12 (m,
8 H, Ar-H), 8.53 (s, 1 H, Ar-H), 10.14 (s, 1 H, NH; D2O ex-
changeable).

Arch. Pharm. Pharm. Med. Chem. 2002, 335, 556–562
Quinazolines and Quinazolyl-4 oxoquinazolines 561
2-Aryl-4-oxo-1-[4-(4-substituted 1-piperazinyl)-2-quin-
azolyl]-1,2,3,4-tetrahydroquinazolines (10 a–h)
2,4-Dioxo- and 4-oxo-2-thioxo-3-phenyl-1-(4-quinazolyl)-
1,2,3,4-tetrahydroquinazolines (3 a, b)
Compounds 10 were prepared from 9 applying the same pro-
cedure as used for preparation of 5. 1H-NMR (DMSO-d6), 10 a:
2.18 (t, 4 H, piperazine-H), 2.41 (s, 3 H, CH3), 3.24 (t, 4 H, piper-
azine-H), 7.32–8.19 (m, 14 H, Ar-H and H-2), 10.82 (br s, 1 H,
NH; D2O exchangeable). 10 c: 2.20 (t, 4 H, piperazine-H), 2.38
(s, 3 H, CH3), 3.25 (t, 4 H, piperazine-H), 4.35 (s, 6 H, 2 OCH3),
7.21–8.25 (m, 12 H, Ar-H and H-2), 10.76 (br s, 1 H, NH; D2O
exchangeable). 10 e: 2.24 (t, 4 H, piperazine-H), 3.31 (t, 4 H,
piperazine-H), 7.12–8.24 (m, 19 H, Ar-H), 10.83 (br s, 1 H, NH;
D2O exchangeable). 10 h: 2.19 (t, 4 H, piperazine-H), 3.25 (t,
4 H, piperazine-H), 7.33–8.25 (m, 18 H, Ar-H and H-2), 10.74
(br s, 1 H, NH; D2O exchangeable).
A mixture of 2 (0.28 g, 1 mmol), sodium hydride (60 %, 0.04 g,
1 mmol), and THF (10 mL) was stirred at room temperature for
15 min. A solution of phenyl iso(thio)cyanate (1.5 mmol) in THF
(5 mL) was added while cooling in an ice bath to the reaction
mixture, which was then stirred for 1 h at room temperature.The
product was collected by filtration, washed with cold water,
dried, and recrystallized. 1H-NMR (DMSO-d6), 3a: 7.21–8.14
(m, 13 H, Ar-H), 8.81 (s, 1 H, Ar-H).
4-(2-Aminocarbonylphenylamino)quinazoline (4 a)
A mixture of 2 (0.56 g, 2 mmol) and methanolic solution of am-
monia saturated at 0 °C (40 mL) was stirred at room tempera-
ture for 24 h. The product obtained was collected by filtration,
washed with methanol, dried, and recrystallized from DMF/
H2O to give 0.36 g (68 %) of 4 a, mp 217–219 °C as reported
[11].
2-Aryl-1-(2-chloro-4-quinazolyl)-4-oxo-1,4-dihydroquinazo-
lines (11 a, b)
A mixture of 4 b (0.6 g, 2 mmol), substituted benzoyl chloride
(5 mmol), and chloroform (20 mL) was heated under reflux for
24 h.The solvent was evaporated under reduced pressure, the
residue was neutralized with aqueous sodium carbonate, col-
lected by filtration, washed with water, dried, and recrystallized.
1H-NMR (DMSO-d6), 11 a: 7.24–8.31 (m, 12 H, Ar-H).
2-Aryl-4-oxo-1-(4-quinazolyl)-1,2,3,4-tetrahydroquinazolines
(5 a–d)
A mixture of 4 a (0.53 g, 2 mmol), the appropriate aldehyde (2
mmol), and an ethanolic solution of NaOH (5 %, 30 mL) was
heated at reflux for 8 h. After cooling, the product was collected
by filtration, dried, and recrystallized. 1H-NMR (DMSO-d6), 5 b:
7.18–8.21 (m, 13 H, Ar-H and H-2), 8.62 (s, 1 H, Ar-H), 10.68 (s,
1 H, NH;D2O exchangeable).5 d:6.94–8.33 (m, 13 H, Ar-H and
H-2), 8.73 (s, 1 H, Ar-H), 10.72 (s, 1 H, NH;D2O exchangeable).
2-Aryl-1-(2-hydrazino-4-quinazolyl)-4-oxo-1,4-dihydroquin-
azolines (12 a, b)
A mixture of 11 (2 mmol), hydrazine hydrate (99 %, 2 mL), and
absolute ethanol (20 mL) was heated under reflux for 4 h. The
product was collected by filtration, washed with ethanol, dried,
and recrystallized. 1H-NMR (DMSO-d6), 12 b: 4.81 (br s, 2 H,
NH; D2O exchangeable), 7.31–8.35 (m, 12 H, Ar-H), 10.11 (br
s, 1 H, NH; D2O exchangeable).
2-Chloro-4-(4-substituted 1-piperazinyl)quinazolines (6 a, b)
A mixture of 2,4-dichloroquinazoline (1 b) (0.2 g, 1 mmol),
1-substituted piperazine (1 mmol), anhydrous sodium carbon-
ate (0.2 g), and absolute ethanol (25 mL) was heated under re-
flux for 2–4 h.The product obtained after cooling was collected
by filtration, washed with water, dried, and recrystallized. 1H-
NMR (DMSO-d6), 6 a: 2.24 (t, 4 H, piperazine-H), 2.41 (s, 3 H,
CH3), 3.19 (t, 4 H, piperazine-H), 7.12–8.14 (m, 4 H, Ar-H). 6 b:
2.26 (t, 4 H, piperazine-H), 3.24 (t, 4 H, piperazine-H), 7.10–
8.22 (m, 9 H, Ar-H).
9-(2-Aryl-4-oxo-1,4-dihydro-1-quinazolyl)-3-thioxo-2H-1,2,4-
triazolo[4,3-a]quinazolines (13 a, b)
A mixture of 12 (2 mmol), potassium hydroxide (0.2 g), carbon
disulfide (1.5 mL), and methanol (25 mL) was heated under re-
flux for 8 h.The solvent was removed under reduced pressure,
the residue obtained was dissolved in 10 % aqueous solution of
potassium hydroxide, the solution was filtered and neutralized
with dilute solution of hydrochloric acid. The product was col-
lected by filtration, washed with water, dried, and recrystallized.
1H-NMR (DMSO-d6), 13 b: 7.41–8.53 (m, 12 H, Ar-H), 12.11 (s,
1 H, NH; D2O exchangeable).
2-(2-Methoxycarbonylphenylamino)-4-(4-substituted 1-piper-
azinyl)quinazolines (7 a, b)
These compounds were prepared from 6 following the same
1
procedure applied for preparation of 2. H-NMR (DMSO-d6),
7 a: 2.22 (t, 4 H, piperazine-H), 2.43 (s, 3 H, CH3), 3.21 (t, 4 H,
piperazine-H), 3.92 (s, 3 H, OCH3), 7.03–8.16 (m, 8 H, Ar-H),
10.2 (s, 1 H, NH; D2O exchangeable).
2-Aryl-1-(2-arylidenehydrazino-4-quinazolyl)-4-oxo-1,4-di-
hydroquinazolines (14 a, b)
2,4-Dioxo- and 4-oxo-2-thioxo-3-phenyl-1-[4-(4-substituted 1-
piperazinyl)-2-quinazolyl]-1,2,3,4-tetrahydroquinazolines
(8 a–d)
A mixture of 12 (2 mmol), the appropriate aldehyde (2.2 mmol),
and absolute ethanol (30 mL) was heated under reflux for 2 h.
The product was collected by filtration, dried, and recrystal-
lized. 1H-NMR (DMSO-d6), 14 a: 7.51–8.49 (m, 17 H, Ar-H, and
Ar-CH=N), 12.15 (s, 1 H, NH; D2O exchangeable).
These compounds were prepared from 7 applying the proce-
dure used for preparation of compounds 3. 1H-NMR (DMSO-
d6), 8 a: 2.19 (t, 4 H, piperazine-H), 2.39 (s, 3 H, CH3), 3.22 (t,
4 H, piperazine-H), 7.21–8.33 (m, 13 H, Ar-H), 8 c: 2.18 (t, 4 H,
piperazine-H), 3.24 (t, 4 H, piperazine-H), 7.19–8.25 (m, 18 H,
Ar-H).
3-Aryl-9-(2-aryl-4-oxo-1,4-dihydroquinazolyl)-1,2,4-triazolo-
[4,3-a]quinazolines (15 a, b)
2-(2-Aminocarbonylphenylamino)-4-(4-substituted 1-piperazi-
A solution of bromine (0.1 mL) in glacial acetic acid (0.5 mL)
was added to a suspension of 14 (2 mmol) and anhydrous sodi-
um acetate (1.5 g) in acetic acid (5 mL). The reaction mixture
was stirred for 30 min at room temperature and then poured on-
to ice-cooled sodium hydroxide (5 %, 100 mL).The product was
collected by filtration, washed with water, dried, and recrystal-
lized. 1H-NMR (DMSO-d6), 15 a: 7.42–8.41 (m, 16 H, Ar-H).
nyl)quinazolines (9 a, b)
These two compounds were prepared from 7 following the pro-
cedure used for preparation of compound 4 a. 1H-NMR (DM-
SO-d6), 9 b: 2.21 (t, 4 H, piperazine-H), 3.24 (t, 4 H, piperazine-
H), 7.31–8.27 (m, 13 H, Ar-H), 8.51 (br s, 2 H, NH2; D2O ex-
changeable), 10.12 (br s, 1 H, NH; D2O exchangeable).

562 Gineinah et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 556–562
Biological screening
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