New octahydroquinazoline derivatives: Synthesis and hypotensive activity

Article abstract of DOI:10.1016/j.ejmech.2010.08.064

Several novel 1-(4-chlorophenyl)-7,7-dimethyl-1,2,3,4,5,6,7,8-octahydro-5- oxo-3-(substitutedphenyl)quinazoline derivatives (2-21) structurally similar to prazosin, were prepared using Mannich reaction of 3-(4-chlorophenylamino)-5,5- dimethyl-2-cyclohexen

Full text of DOI:10.1016/j.ejmech.2010.08.064

European Journal of Medicinal Chemistry 45 (2010) 5390e5396
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
New octahydroquinazoline derivatives: Synthesis and hypotensive activity
,
b
b
c
O.I. El-Sabbagh a , Mohamed A. Shabaan , Hanan H. Kadry , Ehab Saad Al-Din
*
a Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
b Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Egypt
c Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Several novel 1-(4-chlorophenyl)-7,7-dimethyl-1,2,3,4,5,6,7,8-octahydro-5-oxo-3-(substitutedphenyl)
quinazoline derivatives (2e21) structurally similar to prazosin, were prepared using Mannich reaction of
3-(4-chlorophenylamino)-5,5-dimethyl-2-cyclohexenone (1) with different aromatic amines in the
presence of formaline. The structures of the quinazoline derivatives were established using elemental
and spectral analyses. Compounds 18, 20 and 21 were found to possess a high hypotensive effect through
their expected a1-blocking activity like the clinically used drug prazosin but with advantageous of being
did not cause reflex tachycardia and having prolonged duration of action when tested in adrenaline-
induced hypertension in anaesthetized rats.
Received 17 July 2010
Received in revised form
25 August 2010
Accepted 26 August 2010
Available online 20 September 2010
Keywords:
Synthesis
Octahydroquinazoline derivatives
Hypotensive activity
Ó 2010 Elsevier Masson SAS. All rights reserved.
1. Introduction
2. Results and discussions
Among the major risk factors for arterial diseases, hypertension
is considered the most important one for the development of
stroke, coronary heart disease, and congestive heart failure [1,2]
The estimated total number of adults with hypertension in 2000
was 972 million, and this may increase by about 60% to a total of
1.56 billion in 2025 [3].
Quinazoline derived a1-adrenergic receptor antagonist like
prazosin [4,5] terazosin and doxazosin are reputed class of anti-
hypertensive agents. Prazosin is considered the prototype of this
class which selectively blocks postsynaptic a1-adrenergic receptors
but both doxazosin and terazosin [6,7] were found to possess
longer duration and less reflex tachycardia than prazosin [8].
Moreover, it was reported that 4-amino-2-(4-cinnamoylpiper-
azino)-5,6,7,8-tetrahydroquinazoline [9] showed antihypertensive
effect when examined in spontaneously hypertensive rats. In
addition, other quinazoline derivatives [10e12] showed promising
antihypertensive activity.
2.1. Chemistry
The target 1-(4-chlorophenyl)-7,7-dimethyl-1,2,3,4,5,6,7,8-octa-
hydro-5-oxo-3-substitutedphenylquinazoline derivatives (2e21)
were synthesized as shown in Scheme 1.
Condensation of 5,5-dimethyl-1,3-cyclohexanedione with
4-chloroaniline was conducted via heating the reactants at reflux in
toluene [13,14] to afford 5,5-dimethyl-3-(4-chlorophenylamino)-2-
cyclohexenone (1). The novel 5-oxo-octahydroquinazolines (2e8)
were then obtained by heating at reflux equimolar amounts of
enaminone (1) and the primary aromatic amines with two equiv-
alents of formaline in ethanol containing catalytic amount of glacial
acetic acid.
These quinazolines (2e8) were formed through Mannich reac-
tion either at C-2 or arylamino group of the enaminone system. The
former would be kinetically favorable being irreversible followed
by ring formation using excess formaline (Scheme 1). The struc-
tures of 5-oxo-octahydroquinazolines (2e8) were characterized
using elemental and spectral analyses. IR spectral data showed the
disappearance of the NH absorption band at 3250 cmꢀ1 of the
starting enaminone. 1H NMR proved the disappearance of both
In the current study, we aimed to synthesize 1-(4-chloro-
phenyl)-7,7-dimethyl-1,2,3,4,5,6,7,8-octahydro-5-oxo-3-substitut-
edphenylquinazoline derivatives (2e21) which are structurally
similar to prazosin hoping to act as hypotensive agents with
a1-blocking activity.
singlet at
singlet at
d
¼ 7.85 ppm due to NH group and also the vinylic proton
d
¼ 5.65 ppm of the starting enaminone. Moreover, the
formation of the 5-oxo-octahydroquinazoline was confirmed
through appearance of two characteristic singlets around
and 4.87 ppm for the two methylene groups at 4- and 2-positions of
the quinazoline skeleton.
d
¼ 4.26
* Corresponding author. Tel.: þ20 109610300; fax: þ20 552303266.
E-mail addresses: osamaelsabbagh@yahoo.com, elsabbagh_59@zu.edu.eg
(O.I. El-Sabbagh).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.08.064

O.I. El-Sabbagh et al. / European Journal of Medicinal Chemistry 45 (2010) 5390e5396
5391
O
O
NH
2
H N
Cl
2
+
2CH2O
+
toluene, reflux
NH
O
R
Cl
ethanol, reflux
1
10 drops AcOH
OH
O
O
R
N
N
N
N
2: R= 4-Br
3: R= 4-Cl
4: R= 2-F
5: R= 4-F
6: R= 4-OH
7: R= 4-CH3
8: R= H
Cl
Cl
6
2-8
BrCH2COOC2H5
DMF/ K2CO3,
stir, rt, 24h
OCH CONHNH
2
2
OCH COOC H
2 5
2
O
O
N
NH
2NH2
N
N
N
ethanol, reflux 2h
Cl
10
Cl
9
CHO
ethanol
reflux 2h
O
R
1
O
N
O
N
H
R
1
11: R1 = 3-Br
12: R1 = 4-Br
13: R1 = 2-Cl
14: R1 = 4-Cl
N
N
15: R1 = 2,4-diCl
16: R1 = 3-OCH3
17: R1 = 4-OCH3
18: R1 = 4-CH3
19: R1 = 3-NO2
20: R1 = 4-NO2
21: R1 = H
Cl
11-21
Scheme 1. Synthetic pathways for preparation of the novel compounds 2e21.
The novel ester (9) was prepared by stirring equimolar
amounts of 3-(4-hydroxyphenyl)-5-oxo-octahydroquinazoline (6)
and ethyl bromoacetate in dimethylformamide (DMF) containing
K2CO3 at room temperature for 24 h.
All the target compounds were controlled using thin-layer
chromatography (TLC) and melting point techniques. Both analyt-
ical and spectral data of all compounds are in full agreement with
the proposed structures.
The ester 9 was allowed to condense with hydrazine hydrate
through refluxing the reactants in ethanol for 2 h to afford the novel
hydrazide 10 in 72% yield. The chemical structures of ester 9 and
hydrazide 10 were established using elemental and different
spectroscopic methods.
Condensation of the hydrazide key intermediate 10 with
aromatic aldehydes in equimolar amounts was conducted through
heating the reactants in ethanol containing 10 drops of glacial
acetic acid for 2 h to give the novel hydrazone derivatives 11e21.
2.2. Hypotensive activity
All novel 5-oxo-octahydroquinazolines (2e21) were screened to
study their effect on the arterial blood pressure whereas compounds
2, 4, 5, 9e17 and 19 which did not produce any effect were excluded.
On the other hand, compounds 3, 6, 7, 8,18, 20 and 21 which showed
an effect on the arterial blood pressure [15] were subjected to study
their a-blocking activity [16] using prazosin as a reference drug.

5392
O.I. El-Sabbagh et al. / European Journal of Medicinal Chemistry 45 (2010) 5390e5396
Results presented in Table 1 showed that intraperitonial (i.p.)
40
30
3
injection of prazosin (5 mg/Kg) produced significant (P < 0.05)
reduction in both systolic and diastolic arterial blood pressure
(SABP and DABP) which accompanied with rapidly occurring reflex
tachycardia (5 min after injection) declined by time denoting rapid
onset and short duration of action (Figs. 1 and 2).
20
10
0
Our results in Table 2 showed that intravenous (i.v.) injection of
6
-10
-20
-30
-40
-50
7
8
adrenaline [17] at a dose level of 3
mg/Kg produced significant
21
(P < 0.05) increase in both SABP and DABP.
20
Injection of adrenaline, 30 min after prazosin injection,
produced significant (P < 0.05) drop in arterial blood pressure due
to selective blockade of a1-receptor by prazosin (adrenaline
reversal) [18]. However, injection of adrenaline, 1 h after prazosin
injection returned the blood pressure to normal level due to short
duration of action of the drug (Figs. 3 and 4).
Compound 3 produced a time-dependent significant (P < 0.05)
increase in both SABP and DABP without causing tachycardia till
30 min (Table 1). So, this compound may be useful in treating
hypotensive cases and subsequently, it was excluded from testing
prazo
18
Systolic arterial blood pressure after 1 h
Fig. 1. Effect of i.p. injection of prazosin and compounds 3, 6e8, 18, 20, and 21 at dose
of 5 mg/Kg on the systolic blood pressure of male albino rats.
response after 30 min as shown in Table 2 which were sustained for
1 h (Figs. 3 and 4). Thus, these compounds can be considered as
rapidly acting a1-blockers like prazosin but with advantageous of
being did not cause reflex tachycardia and having prolonged
duration of action.
its a-blocking effect. Compound 6 produced non-significant change
in both arterial blood pressure and HR (Table 1). It also did not
attenuate the pressor effect of adrenaline on the blood pressure and
so it has no
a-blocking effect as shown in Table 2 and illustrated by
Figs. 3 and 4.
Compounds 7 and 8 produced a time-dependent significant
(P < 0.05) decrease in both SABP and DABP (Table 1) without
causing any change in the heart rate. In the same time, Table 2
showed that compounds 7 and 8 reversed the pressor effect of
3. Conclusion
The aim of the present study was to generate new effective
hypotensive agents with
a-blocking activity. Thus, new
adrenaline after half an hour i.e. they have
shorter duration of action like prazosin.
a-blocking effect but of
octahydroquinazoline derivatives (2e21) were prepared which
structurally related to the antihypertensive clinically used
a1-blocker prazosin. The following observations were noticed:
The results presented in Table 1 and illustrated by Figs. 1 and 2
showed that compounds 18, 20 and 21 produced significant
(P < 0.05) decrease in both SABP and DABP with rapid onset of
action (after 5 min) meanwhile such compounds caused non-
significant decrease in the HR. Compounds 18, 20 and 21 rapidly
reversed the vasopressor effect of adrenaline into depressor
1) Regarding the octahydroquinazolines
3 and 6e8, it was
observed that those having electron-withdrawing substituents
on phenyl rings at 3-position of the octahydroquinazoline
skeleton, such as compound 3 (4-Cl) was devoid of any
Table 1
Effect of prazosin and compounds 3, 6e8, 18, 20, and 21 at dose of 5mg/Kgm on the systolic (SABP), diastolic (DABP) arterial blood pressure and heart rate (HR) of anaesthetized
male adult albino rats.
Compd No.
Prazosin
Parameter
Control
Changes by time after i.p. injection
5 min
% change
15 min
% change
30 min
80c ꢁ 3
% change
60 min
% change
SABP
DABP
HR
SABP
DABP
HR
SABP
DABP
HR
SABP
DABP
HR
SABP
DABP
HR
SABP
DABP
HR
SABP
DABP
HR
SABP
DABP
HR
120a ꢁ 6
95b ꢁ 3.2
70b ꢁ 1.9
420a ꢁ 12
140c ꢁ 4
ꢀ20.8
85c ꢁ 4
ꢀ29.2
ꢀ22.22
þ26
þ23
þ25
0
0
0
0
0
ꢀ33.3
ꢀ27.7
þ16
þ32.4
þ28
þ6
80c ꢁ 2.5
55d ꢁ 1.9
280c ꢁ 13
170a ꢁ 3.1
125a ꢁ 3
255a ꢁ 11
155a ꢁ 2.1
95a ꢁ 1.9
370a ꢁ 12
170b ꢁ 2.7
130c ꢁ 6
290a ꢁ 12
150b ꢁ 5
120b ꢁ 2.1
270a ꢁ 12
85c ꢁ 3
ꢀ33.3
ꢀ38.8
ꢀ5.1
þ32.4
þ28
þ6
90a ꢁ 2.1
295c ꢁ 20
115d ꢁ 3.8
90c ꢁ 2.1
240a ꢁ 15
160a ꢁ 4.8
100a ꢁ 2.3
375a ꢁ 14
180a ꢁ 5.3
160a ꢁ 3.2
290a ꢁ 18
160a ꢁ 3.9
130a ꢁ 4.5
240b ꢁ 18
140a ꢁ 3.2
120a ꢁ 4
ꢀ22.22
70b ꢁ 3
65c ꢁ 2.4
350b ꢁ 15
170a ꢁ 2.6
125a ꢁ 2.2
255a ꢁ 15
155a ꢁ 3.4
100a ꢁ 3.5
375a ꢁ 16
170b ꢁ 3.2
150b ꢁ 4
290a ꢁ 11
160a ꢁ 5
þ30
400a ꢁ 18
150b ꢁ 4.8
120a ꢁ 4
3
þ17.8
110b ꢁ 3
240a ꢁ 12
160a ꢁ 5.1
100a ꢁ 5
þ18.2
0
0
0
0
0
0
0
0
0
240a ꢁ 14
160a ꢁ 7
6
ꢀ3
ꢀ3
100a ꢁ 4.6
375a ꢁ 13
180a ꢁ 3.9
160a ꢁ 5
0
ꢀ5
375a ꢁ 12
180a ꢁ 3.6
160a ꢁ 4
0
e
7
ꢀ6
ꢀ6
0
0
0
0
ꢀ6.25
0
ꢀ18.7
0
290a ꢁ 13
160a ꢁ 5.1
130a ꢁ 2.8
240b ꢁ 13
115b ꢁ 4
90b ꢁ 4.1
315a ꢁ 19
130b ꢁ 2.7
70b ꢁ 3
290a ꢁ 15
160a ꢁ 4.2
130a ꢁ 3.3
240b ꢁ 15
110b ꢁ 2.1
90b ꢁ 2.5
305a ꢁ 19
125b ꢁ 2.2
60c ꢁ 3
8
0
ꢀ6
120b ꢁ 3.4
255ab ꢁ 11
90c ꢁ 3
ꢀ7.7
þ6.25
ꢀ35.8
ꢀ29.16
ꢀ6.3
ꢀ26.5
ꢀ31.25
ꢀ2.1
ꢀ10
ꢀ15
0
ꢀ7.7
þ12
ꢀ39.3
ꢀ37.5
ꢀ6.3
ꢀ26.5
ꢀ31.25
ꢀ6.2
ꢀ13
ꢀ20
0
0
0
18
20
21
ꢀ17.8
ꢀ25
ꢀ2
ꢀ13
ꢀ12.5
0
ꢀ19
ꢀ10
0
ꢀ21.4
ꢀ25
ꢀ5
ꢀ17
ꢀ25
ꢀ2.1
ꢀ13
ꢀ10
ꢀ4
85b ꢁ 3
75c ꢁ 3
320a ꢁ 19
150a ꢁ 4.5
80a ꢁ 4
300a ꢁ 13
110c ꢁ 3.1
55c ꢁ 3
300a ꢁ 10
110c ꢁ 1.8
55c ꢁ 3
240a ꢁ 20
160a ꢁ 5.3
100a ꢁ 2.9
345a ꢁ 15
240a ꢁ 32
130c ꢁ 3.2
90b ꢁ 3
235a ꢁ 18
140b ꢁ 2.1
90b ꢁ 3.1
330a ꢁ 18
235a ꢁ 15
145b ꢁ 4
85bc ꢁ 3
225a ꢁ 15
140b ꢁ 3
80c ꢁ 3
345a ꢁ 13
345a ꢁ 15
345a ꢁ 12
Values were expressed as mean ꢁ S.D.; Number of experiments ¼ 6 in each parameter; Values with different superscript letters are significantly different at P < 0.05 (within
the same horizontal line).

O.I. El-Sabbagh et al. / European Journal of Medicinal Chemistry 45 (2010) 5390e5396
5393
40
30
20
6
3
15
10
5
20
10
prazo
7
8
0
-5
0
6
-10
-20
-30
-40
-50
8
20
21
-10
-15
-20
-25
7
21
20
18
prazo
18
Effect of adrenaline on SABP after 1h
Diastolic arterial blood pressure after 1 h
Fig. 2. Effect of i.p. injection of prazosin and compounds 3, 6e8, 18, 20, and 21 at dose
Fig. 3. Effect of i.v. injection of adrenaline (3 mg/Kg) 1 h after prazosin and compounds
of 5 mg/Kg on the diastolic blood pressure of male albino rats.
6e8, 18, 20, and 21 at dose of 5 mg/Kg on systolic blood pressure of anaesthetized male
albino rats.
hypotensive activity. It was noted also through analysis of
Tables 1 and 2 that the quinazolines 7 and 8 showed a-adre-
tetramethylsilane (TMS) as an internal standard (Chemical shift in
d
, ppm). 13C NMR spectra were recorded on a MacNMR5.3-AC250
noceptor blocking activity in adrenaline-induced hypertension
in anaesthetized rats but of shorter duration of action as
prazosin.
using CDCl3 as a solvent. Mass spectra were determined using Mass
spectrometer GC/MS Shimadzu QP 1000 EX (Shimadzu Corpora-
tion, Tokyo, Japan) with ionization energy 70 eV. Elemental anal-
yses were determined using Manual Elemental Analyzer Heraeus
(Germany) and Automatic Elemental Analyzer CHN Model 2400
Perkin Elmer (USA) at Microanalytical Center, Faculty of Science,
Cairo University, Egypt. All the results of elemental analyses cor-
responded to the calculated values within experimental error.
Progress of the reaction was monitored by thin-layer chromatog-
raphy (TLC) using precoated TLC sheets with ultraviolet (UV) fluo-
rescent silica gel (Merck 60F254) and spots were visualized by
iodine vapors or irradiation with UV light (254 nm). All the
chemicals were purchased from SigmaeAldrich.
2) Compound
6 showed lower hypotensive effect with no
a- blocking activity (Table 2) but its modification using the drug
extension tactic led to more active compounds 18, 20 and 21
which may be attributable to the extra binding interactions.
These compounds were found to have a1-blocking activity
(Table 2) like prazosin with advantageous of less reflex tachy-
cardia and prolonged duration of action.
4. Experimental protocols
4.1. Chemistry
4.1.1. General procedure for preparation of compounds 2e8
To a solution of enaminone 1 (1.70 mmol) in ethanol (30 ml), the
appropriate aromatic amines (1.70 mmol), 40% formalin
(3.40 mmol) and 10 drops of glacial acetic acid were added. The
reaction mixture was heated under reflux for 3 h and then left to
stand overnight at room temperature. The reaction mixture was
diluted with water, basified with NH4OH to pH 8 and then left in
refrigerator for 3 h. The separated product was filtered, washed
with water (20 ml) and crystallized from suitable solvent.
Melting points were determined with a Gallenkamp (London,
U.K.) melting point apparatus and are uncorrected. IR spectra (KBr,
cmꢀ1) were recorded on Bruker Vector, 22FT-IR (Fourier Transform
Infrared (FTIR)) (Germany) spectrometer. 1H NMR spectra were
recorded on a Varian Gemini-200 (200-MHz, Foster City, Calif.,
USA), MacNMR5.3-AC250(250 MHz) and Varian Mercury-300
(300-MHz, City: Palo Alto, State: Calif., USA) spectrometers using
dimethylsulphoxide (DMSO)-d6 or CDCl3 as
a solvent and
Table 2
Effect of adrenaline alone and after injection of compounds 6, 7, 8, 18, 20, 21 on systolic (SABP) and diastolic (DABP) arterial blood pressure in male adult albino rats.
Compd No.
Parameter
Effect of adrenaline alone
Effect of adrenaline after 1/2h. from inj.
test comp.
Effect of adrenaline after 1h. from inj. test
comp.
Control
effect
% change
30 min
effect
% change
60 min
effect
% change
Prazosin
SABP
DABP
SABP
DABP
SABP
DABP
SABP
DABP
SABP
DABP
SABP
DABP
SABP
DABP
130 ꢁ 5
150 ꢁ 2.5*
120 ꢁ 2.8*
190 ꢁ 6.1*
120 ꢁ 4.2*
190 ꢁ 5.1*
160 ꢁ 3.4*
200 ꢁ 6.1*
150 ꢁ 3.2*
190 ꢁ 3.4*
150 ꢁ 3.7*
180 ꢁ 4.2*
130 ꢁ 3.7*
190 ꢁ 5.9*
130 ꢁ 5.9*
þ15
þ20
þ27
þ20
þ27
þ23
þ25
þ25
þ27
þ25
þ38
þ18
þ36
þ24
90 ꢁ 3
80 ꢁ 1.8*
55 ꢁ 2.1*
170 ꢁ 4.6*
110 ꢁ 4.8*
125 ꢁ 2.9*
110 ꢁ 3.6*
140 ꢁ 3.1*
100 ꢁ 2.8*
85 ꢁ 1.5*
ꢀ11
ꢀ8
90 ꢁ 2.5
55 ꢁ 2.0
145 ꢁ 2.1
95 ꢁ 1.6
140 ꢁ 2.5
100 ꢁ 4.5
140 ꢁ 3.3
110 ꢁ 2.3
90 ꢁ 2.3
70 ꢁ 2.1
100 ꢁ 1.7
55 ꢁ 3.2
140 ꢁ 3.1
75 ꢁ 2.5
90 ꢁ 3n.s
55 ꢁ 1.7n.s
170 ꢁ 3.7*
110 ꢁ 3.1*
140 ꢁ 2.9ns
100 ꢁ 1.4ns
140 ꢁ 3.5ns
110 ꢁ 2.8ns
70 ꢁ 2.1*
0
0
þ17
þ16
0
0
0
0
ꢀ22
ꢀ28.5
ꢀ5
ꢀ9
ꢀ7
ꢀ7
100 ꢁ 2.2
150 ꢁ 5.0
100 ꢁ 2.6
150 ꢁ 5.3
130 ꢁ 3.3
160 ꢁ 2.9
120 ꢁ 4.1
150 ꢁ 2.2
120 ꢁ 3.5
130 ꢁ 4.1
110 ꢁ 2.5
140 ꢁ 3.0
105 ꢁ 2.9
60 ꢁ 1.1
145 ꢁ 3.2
100 ꢁ 3.1
140 ꢁ 3.4
120 ꢁ 4.2
150 ꢁ 5
6
þ17
þ10
ꢀ11
ꢀ8
7
8
ꢀ7
110 ꢁ 3.6
95 ꢁ 2.8
80 ꢁ 2.4
100 ꢁ 3.1
55 ꢁ 3.4
145 ꢁ 3.5
80 ꢁ 1.9
ꢀ9
18
20
21
ꢀ11
ꢀ19
ꢀ10
ꢀ9
65 ꢁ 2.2*
50 ꢁ 1.3*
90 ꢁ 2.5*
95 ꢁ 1.6*
50 ꢁ 2.9n.s
135 ꢁ 3.1*
75 ꢁ 2.1n.s
50 ꢁ 2.9n.s
130 ꢁ 2.7*
70 ꢁ 2.8ns
ꢀ7
ꢀ6
Values were expressed as mean ꢁ S.D. Number of experiments ¼ 6 in each parameters.
*Significantly different from respective control value at P < 0.05.
n.s. ¼ non-significantly different from respective control value at P < 0.05.

5394
O.I. El-Sabbagh et al. / European Journal of Medicinal Chemistry 45 (2010) 5390e5396
2H, CH2) 4.234 (s, 2H, CH2) 4.840 (s, 2H, CH2), 6.838e7.333 (m, 8H,
20
15
10
5
6
ArH) ppm. 13C NMR:
d
¼ 28.35(2CH3), 32.78 (C(CH3)2), 41.10 (CH2),
45.90 (CH2), 50.09(CH2),71.13 (CH2), 105.30(Csp2), 115.63e159.58
(Csp2 þ phenyl-C), 194.35 (C]O)ppm. Anal. calcd for C22H22ClFN2O:
C, 68.66; H, 5.76; N, 7.28.Found: C, 68.80; H, 5.50; N, 7.13%.
prazo
7
8
0
-5
4.1.1.5. 1-(4-Chlorophenyl)-7,7-dimethyl-3-(4-hydroxyphenyl)-5-
oxo-1,2, 3,4,5,6,7,8-octahydroquinazoline (6). Yield: 85%; mp.:
-10
-15
-20
-25
-30
-35
21
20
195e96 ꢂC; crystallized from ethanol; IR:
y
¼ 3259(OH), 3060 (CH,
aromatic), 2924 (CH, aliphatic), 1605 (CO), 1556(C]C) cmꢀ1 1H
NMR (250 MHz):
.
d
¼ 0.878 (s, 6H, 2CH3),1. 947 (s, 2H, CH2), 2.264 (s,
18
Effect of adrenaline on DABP after 1h
2H, CH2) 4.297 (s, 2H, CH2) 4.888 (s, 2H, CH2), 6.754e6.876 (m, 4H,
ArH) 7.254e7.337 (m,4H, ArH),8.20 (br s, 1H, OH) ppm. 13C NMR:
d
¼ 28.33 (2CH3), 32.87 (C(CH3)2), 41.14 (CH2),45.34(CH2), 49.58
(CH2),72.34 (CH2),104.14(Csp2), 116.14e158.87 (Csp2þphenyl-
C),195.08 (C]O) ppm. MS: m/z (rel. int.) ¼ 384 (M þ 2, 7.4), 383
(M þ 1, 8.9), 382 (Mþ, 19.40), 260 (54.30), 226 (100.00).Anal. calcd
for C22H23ClN2O2: C, 69.01; H, 6.05; N, 7.32.Found: C, 68.71; H, 5.83;
N, 7.80%.
Fig. 4. Effect of i.v. injection of adrenaline (3
6e8, 18, 20, and 21 at dose of 5 mg/kg on diastolic blood pressure of anaesthetized
male albino rats.
m
g/Kg) 1h after prazosin and compounds
4.1.1.1. 3-(4-Bromophenyl)-1-(4-chlorophenyl)-7,7-dimethyl-5-oxo-
1,2,3,4,5,6,7,8-octahydroquinazoline (2). Yield: 65%; mp.: 99e100 ꢂC;
4.1.1.6. 1-(4-Chlorophenyl)-7,7-dimethyl-3-(4-methylphenyl)-5-oxo-
crystallized from petroleum ether(60/80); IR:
aromatic), 2950 (CH, aliphatic),1608 (CO),1567 (C]C) cmꢀ1; 1H NMR
(250MHz):
¼ 0.936 (s,6H, 2CH3),1.980(s, 2H, CH2), 2.223 (s, 2H, CH2)
4.260 (s, 2H, CH2), 4.874 (s, 2H, CH2), 6.776e6.920 (2d, 4H, ArH),
y
¼
3050 (CH,
1,2,3,4,5,6,7,8-octahydroquinazoline (7). Yield: 75%; mp.: 112 ꢂC;
crystallized from petroleum ether(60/80); IR:
aromatic), 2926 (CH, aliphatic), 1613(CO), 1514(C]C) cmꢀ1
NMR (250 MHz):
y
¼ 3027 (CH,
d
;
1H
d
¼ 0.943(s, 6H, 2CH3), 1.980 (s, 2H, CH2), 2.225 (s,
7.254e7.364 (2d, 4H, ArH) ppm. 13C NMR:
d
¼ 28.35(2CH3), 32.79 (C
2H, CH2) 2.260 (s, 3H, CH3) 4.264 (s, 2H, CH2) 4.872 (s, 2H, CH2),
(CH3)2), 41.08 (CH2), 45.46(CH2), 50.06(CH2),69.98(CH2),105.36(Csp2),
113.20e156.76 (Csp2 þ phenyl-C), 194.38 (C]O) ppm. MS: m/z (rel.
int.) ¼ 445 (Mþ, 31), 444 (20.70), 260 (37.90), 226 (55.20),182 (65.50),
137 (86.20), 83 (100.00). Anal. calcd for C22H22BrClN2O: C, 59.27; H,
4.97; N, 6.28.Found: C, 59.27; H, 4.92; N, 5.95%.
6.821e6.903 (m, 4H, ArH) 7.020e7.340 (2d, 4H, ArH) ppm. 13C NMR:
d
¼ 20.56(CH3), 28.38(2CH3), 32.76 (C(CH3)2), 41.13 (CH2),45.62
(CH2), 50.09 (CH2),70.68 (CH2),105.61(Csp2), 117.88e156.77
(Csp2 þ phenyl-C), 194.35 (C]O)ppm. MS : m/z (rel. int.) ¼ 384 (M
þ2, 7.4), 383(M þ 1, 8.9), 382 (Mþ,19.40), 260(54.30), 226 (100.00).
Anal. calcd for C23H25 ClN2O: C, 72.52; H, 6.05; N, 7.32.Found: C,
72.31; H, 6.22; N, 7.74%.
4.1.1.2. 1-(4-Chlorophenyl)-3-(4-chlorophenyl)-7,7-dimethyl-5-oxo-
1,2,3,4,5,6,7,8-octahydroquinazoline (3). Yield: 70%; mp.: 109e111 ꢂC;
crystallized from petroleum ether (60/80); IR:
aromatic), 2951 (CH, aliphatic), 1608 (CO), 1568 (C]C) cmꢀ1
NMR (250 MHz):
¼ 0.936 (s, 6H, 2CH3),1.979 (s, 2H, CH2), 2.223 (s,
2H, CH2) 4.262 (s, 2H, CH2),4.875 (s, 2H, CH2),6.831e6.865(m,4H,
ArH),7.163e7.330(2d,4H, ArH) ppm; 13C NMR :
32.79 (C (CH3)2), 41.08 (CH2),45.54 (CH2), 50.06(CH2), 70.18 (CH2),
105.35(Csp2), 118.95e156.79 (Csp2 þ phenyl-C), 194.38 (C]O) ppm.
MS: m/z (rel. int.) ¼ 403 (M þ 2, 11.00), 402 (M þ 1, 18.50), 401 (Mþ,
13.70), 274(77.00), 226(100.0), 177(15.80), 138(41.60), 83(64.20).
Anal. calcd for C22H22Cl2N2O: C, 65.84; H,5.53; N, 6.98. Found: C,
65.61; H, 5.84; N, 6.94%.
y
¼ 3050 (CH,
4.1.1.7. 1-(4-Chlorophenyl)-7,7-dimethyl-5-oxo-3-phenyl-1,2,3,4,5,6,7,
;
1H
8-octahydroquinazoline (8). Yield: 73%; mp.: 105e106 ꢂC; crystal-
d
lized from petrolium ether(60/80); IR:
y
¼ 3055 (CH, aromatic), 2931
(CH, aliphatic), 1609(CO) cmꢀ1. 1H NMR (300 MHz):
d
¼ 0.967 (s, 6H,
d
¼ 28.35 (2CH3),
2CH3), 2.009 (s, 2H, CH2), 2.249 (s, 2H, CH2) 4.307 (s, 2H, CH2) 4.911
(s, 2H, CH2), 6.902e7.358 (m, 9H, ArH) ppm. MS: m/z (rel. int.) ¼ 368
(M þ 2,19.60), 366 (Mþ, 43.50), 260 (34.80), 226 (60.90),163 (15.20),
104 (100.00). Anal. calcd for C22H23 ClN2O: C, 72.02; H, 6.32; N,
7.64.Found: C, 71.99; H, 6.09; N, 7.33%.
4.1.2. 1-(4-Chlorophenyl)-7,7-dimethyl-3-[4-(ethyoxycarbonyl-
methoxy) phenyl]-5-oxo-1,2,3,4,5,6,7,8-octahydroquinazoline (9)
A mixture of compound 6 (5.24 mmol), ethyl bromoacetate
(6.28 mmol) and K2CO3 (10.48 mmol) was stirred in DMF (10 ml) at
room temperature for 24 h. The reaction mixture was filtered,
poured on ice water (20 ml) and left on the refrigerator overnight.
The formed product was filtered and crystallized from ethanol.
4.1.1.3. 1-(4-Chlorophenyl)-7,7-dimethyl-3-(2-fluorophenyl)-5-oxo-
1,2,3, 4,5,6,7,8-octahydroquinazoline(4). Yield: 78%; mp.: 116e117 ꢂC;
crystallized from petroleum ether(60/80); IR:
aromatic), 2923 (CH, aliphatic),1613(CO), 1561 (C]C) cmꢀ1; 1H NMR
(250 MHz):
¼ 0.961 (s, 6H, 2CH3), 1.998(s, 2H, CH2), 2.250 (s, 2H,
y
¼
3046 (CH,
d
CH2) 4.229 (s, 2H, CH2) 4.829 (s, 2H, CH2), 6.736e7.279 (m, 8H, ArH)
Yield: 81.3%; mp.: 80 ꢂC; IR:
y
¼ 3061 (CH, aromatic), 2941 (CH,
ppm. 13C NMR:
(CH2),50.13
d
¼ 28.40(2CH3), 32.79 (C(CH3)2), 41.13 (CH2),46.19
aliphatic),1751, 1605(CO), 1513(C]C) cmꢀ1
;
1H NMR (200 MHz):
(CH2),70.52(CH2), 116.15e157.38
105.44(Csp2),
d
¼ 0.911 (s, 6H, 2CH3),1.213e1.285 (t, 3H, J ¼ 7 Hz,CH3 of ester),1.946
(Csp2 þ phenyl-C),194.31 (C]O)ppm. MS: m/z (rel. int.) ¼ 385 (M þ 1,
12.90), 384 (Mþ, 25.80), 366 (45.20), 261 (64.50), 226 (100.00), 208
(29.00), 177 (19.40), 151 (64.50), 123 (77.40), 69 (71.00). Anal. calcd
for C22H22ClFN2O: C, 68.66; H, 5.76; N, 7.28.Found: C, 68.94; H, 5.68;
N, 7.38%.
(s, 2H, CH2), 2.196 (s, 2H, CH2) 4.191e4.273 (m, 4H, J ¼ 7 Hz, OCH2
þCH2 of ester) 4.521 (s, 2H, CH2) 4.788 (s, 2H, CH2) 6.746e7.30 3(m,
8H, ArH) ppm. MS: m/z (rel. int.) ¼ 470.84 (M þ 2, 3.70) 469.85 (M þ 1,
10.50) 468.81 (Mþ,10.20), 394.86 (2.70), 317.70 (1.50), 273.89 (19.10),
225.96 (36.50), 206.95 (100.00). Anal. calcd for C26H29ClN2O4: C,
66.59; H, 6.23; N, 5.97.Found: C, 66.26; H, 6.01; N, 5.90%.
4.1.1.4. 1-(4-Chlorophenyl)-7,7-dimethyl-3-(4-fluorophenyl)-5-oxo-
1,2,3,4,5,6,7,8-octahydroquinazoline (5). Yield: 80%; mp.: 94e95 ꢂC;
4.1.3. 1-(4-Chlorophenyl)-7,7-dimethyl-3-[4-(hydrazinocarbonylm-
ethoxy) phenyl]-5-oxo-1,2,3,4,5,6,7,8-octahydroquinazoline (10)
A mixture of ester 9 (2.14 mmol), and hydrazine hydrate
(6.42 mmol) in ethanol (10 ml) was refluxed for 2 h. The reaction
crystallized from petroleum ether(60/80); IR:
aromatic), 2950 (CH, aliphatic), 1610 (CO),1568 (C]C)cmꢀ1
NMR (250 MHz):
¼ 0.932 (s, 6H, 2CH3), 1.976 (s, 2H, CH2), 2.219 (s,
y
¼ 3050 (CH,
;
1H
d

O.I. El-Sabbagh et al. / European Journal of Medicinal Chemistry 45 (2010) 5390e5396
5395
mixture was evaporated under reduced pressure and then poured
on crushed-ice. The separated product was filtered and crystallized
from ethanol.
4.1.4.5. 1-(4-Chlorophenyl)-3-[4-(N2-2,4-dichlorophenyl-hydrazin-
ocarbonylmethoxy)phenyl]-7,7-dimethyl-5-oxo-1,2,3,4,5,6,7,8-
octahydroquinazoline (15). Yield: 70%; mp.: 135 ꢂC; IR:
y
¼ 3425
(tautomeric OH), 3210(NH),2950 (CH, aliphatic), 1697 (CO),1557
(C]C) cmꢀ1. 1H NMR (200 MHz)
Yield: 72%; mp.: 90 ꢂC; IR:
y
¼ 3420, 3340, 3240(NH, NH2), 3020
(CH, aromatic), 2930 (CH, aliphatic), 1667,1601 (CO), 1563 (C]C)
cmꢀ1; 1H NMR (200 MHz):
d
¼ 0.906 (s, 6H, 2CH3),1.946(s, 2H,
d
¼ 0.899(s, 6H, 2CH3), 1.943(s, 2H, CH2),
CH2), 2.198 (s, 2H, CH2), 4.193(s, 2H, CH2), 4.591(s, 1H, CH2CO),
4.796 (s, 2H, CH2), 5.035, 9.807(2 s, 1H, CH2CO þ tautomeric OH,
exch.),6.850e8.107(m, 12H, ArH), 8.525 (s, 1H, CH]N),9.499(s,1H,
NH, exch.) ppm. Anal. calcd for C31H29Cl3N4O3: C, 60.84; H, 4.78; N,
9.16.Found: C, 60.80; H, 4.91; N, 9.36%.
2.181 (s, 2H, CH2),3.095(br s, 2H, NH2, exch.),4.176 (s, 2H, OCH2),
4.461 (s, 2H, CH2) 4.778 (s, 2H, CH2) 6.717e7.30 4(m,8H, ArH) 7.730
(s, 1H, NH, exch.) ppm. MS: m/z (rel. int.) ¼ 456 (M þ 2, 4.50) 455
(M þ 1, 9.50) 454 (Mþ, 12.20), 383(11.3), 317 (20.7), 262 (83.0), 225
(79.5), 107 (100.00). Anal. calcd for C24H27ClN4O3:C, 63.36; H, 5.98;
N, 12.31. Found: C, 63.60; H, 5.98; N, 12.62%.
4.1.4.6. 1-(4-Chlorophenyl)-7,7-dimethyl-3-[4-(N2-3-methoxypheny-
lhydrazinocarbonylmethoxy)phenyl]-5-oxo-1,2,3,4,5,6,7,8-octahydro-
4.1.4. General procedure for preparation of compounds 11e21
A mixture of the hydrazide 10 (1.1 mmol), and aromatic alde-
hyde (1.1 mmol) was refluxed in ethanol (10 ml) containing 10
drops of glacial acetic acid for 2 h. The reaction mixture was
concentrated under reduced pressure and then poured onto ice.
The formed precipitate was filtered and crystallized from aqueous
ethanol.
quinazoline (16). Yield: 60%; mp.: 95 ꢂC; IR:
y
¼ 3430 (tautomeric
OH),3200(NH),3020 (CH, aromatic), 2955 (CH, aliphatic), 1692
(CO),1564 (C]C) cmꢀ1; 1H NMR (250 MHz)
d
¼ 0.921 (s, 6H, 2CH3),
1.966(s, 2H, CH2), 2.213 (s, 2H, CH2), 3.808(s, 3H, OCH3), 4.217 (s, 2H,
CH2), 4.594(s, 1H, CH2CO), 4.822 (s,2H, CH2), 5.088, 9.941(2 s, 1H,
CH2CO þ tautomeric OH), 6.816e7.821 (m, 12H, ArH), 8.173 (s, 1H,
CH]N), 9.590 (s, 1H, NH)ppm. Anal. calcd for C32H33ClN4O4: C,
67.07; H, 5.80; N, 9.78.Found: C, 66.87; H, 5.79; N, 10.01%.
4.1.4.1. 3-[4-(N2-Bromophenylhydrazino carbonylmethoxy)phenyl]-
1-(4-chlorophenyl)-7,7-dimethyl-5-oxo-1,2,3,4,5,6,7,8-octahydroqui-
4.1.4.7. 1-(4-Chlorophenyl)-7,7-dimethyl-3-[4-(N2-4-methoxypheny-
lhydrazinocarbonylmethoxy)phenyl]-5-oxo-1,2,3,4,5,6,7,8-octahydro-
nazoline (11). Yield: 65%; mp.: 130 ꢂC; IR:
y
¼ 3421(tautomeric OH),
3211(NH),3056 (CH, aromatic), 2954 (CH, aliphatic), 1697 (CO),1560
(C]C) cmꢀ1. 1H NMR (200 MHz)
¼ 0.698 (s, 6H, 2CH3), 1.746 (s,
quinazoline (17). Yield: 65%; mp.: 110 ꢂC; IR:
y
¼ 3431 (tautomeric
OH), 3210(NH),3049 (CH, aromatic), 2954 (CH, aliphatic), 1693,1605
(CO),1562(C]C) cmꢀ1 1H NMR (250 MHz)
¼ 0.919 (s, 6H, 2CH3),
d
2H, CH2), 1.985 (s, 2H, CH2), 3.990 (s, 2H, CH2) 4.369(s, 1H, CH2CO),
4.593 (s, 2H, CH2), 4.852, 9.709 (2 s, 1H, CH2CO þ tautomeric OH,
exch.), 6.593e7.687 (m, 12H, ArH), 7.971(s, 1H, CH]N), 9.448 (s, 1H,
NH, exch.) ppm. MS: m/z (rel. int.) ¼ 622 (M þ 1, 4.50), 621 (Mþ,
13.70), 512 (7.80), 359 (25.50), 300 (19.60), 262 (25.50), 226 (39.20),
178 (39.20), 120 (60.80), 77(100.00). Anal. calcd for
C31H30BrClN4O3: C, 59.87; H, 4.86; N, 9.01. Found: C, 60.09; H, 4.78;
N, 8.99%.
;
d
1.964 (s, 2H, CH2), 2.142(s, 2H, CH2), 3.810 (s, 3H, OCH3), 4.214 (s,2H,
CH2), 4.580(s, 1H, CH2CO), 4.819 (s,2H, CH2),5.072, 9.989 (2 s, 1H,
CH2CO þ tautomeric OH), 6.814e7.788 (m, 12H, ArH), 8.113 (s, 1H,
CH]N), 9.569 (s,1H, NH) ppm. MS: m/z (rel. int.) ¼ 575 (M þ2, 6.70),
574 (M þ 1, 11.50), 573 (Mþ, 15.00), 421 (77.00), 366 (10.30), 311
(24.10), 261 (22.40), 226 (50.00),191(34.50),139 (36.40),121 (77.60),
77(100.00). Anal. calcd for C32H33ClN4O4: C, 67.07; H, 5.80; N,
9.78.Found: C, 66.87; H, 5.79; N, 10.00%.
4.1.4.2. 3-[4-(N2-4-Bromophenyl-hydrazinocarbonylmethoxy)phenyl]-
1-(4-chlorophenyl)-7,7-dimethyl-5-oxo-1,2,3,4,5,6,7,8-octahydroquin-
azoline (12). Yield: 70%; mp.: 140e141 ꢂC; 1H NMR (250 MHz)
4.1.4.8. 1-(4-Chlorophenyl)-7,7-dimethyl-3-[4-(N2-4-methylphenylh-
ydrazinocarbonylmethoxy)phenyl]-5-oxo-1,2,3,4,5,6,7,8-octahydroq-
d
¼ 0.917 (s, 6H, 2CH3), 1.964 (s, 2H, CH2), 2.210 (s, 2H, CH2), 4.208 (s,
uinazoline (18). Yield: 72%; mp.: 106 ꢂC; IR:
y
¼ 3431 (tautomeric
OH), 3216(NH),3048 (CH, aromatic), 2954 (CH, aliphatic), 1695
(CO),1562(C]C) cmꢀ1 ;1H NMR (250 MHz)
2H, CH2), 4.585(s, 1H, CH2CO), 4.801 (s, 2H, CH2), 5.067, 10.43(2 s, 1H,
CH2CO þ tautomeric OH),6.819e7.818 (m, 12H, ArH), 8.178 (s, 1H,
CH]N), 9.790 (s, 1H, NH), ppm. Anal. calcd for C31H30BrClN4O3: C,
59.87; H, 4.86; N, 9.01. Found: C, 60.09; H, 4.78; N, 8.99%.
d
¼ 0.932 (s, 6H, 2CH3),
1.978 (s, 2H, CH2), 2.223 (s, 2H, CH2), 2.357(s, 3H, CH3), 4.229 (s, 2H,
CH2) 4.597(s, 1H, CH2CO), 4.831(s,2H, CH2),5.093,9.915(2 s, 1H,
CH2CO þ tautomeric OH),6.823e7.807 (m, 12H, ArH), 8.152 (s, 1H,
CH]N), 9.569 (s, 1H, NH) ppm. Anal. calcd for C32H33ClN4O3: C,
68.99; H, 5.97; N, 10.06.Found: C, 68.89; H, 6.24; N, 9.77%.
4.1.4.3. 3-[4-(N2-2-Chlorophenyl-hydrazinocarbonylmethoxy)phenyl]-
1-(4-chlorophenyl)-7,7-dimethyl-5-oxo-1,2,3,4,5,6,7,8-octahydroquin-
azoline (13). Yield: 58%; mp.: 125 ꢂC; IR:
y
¼ 3425 (tautomeric OH),
3210(NH),3057 (CH, aromatic), 2954 (CH, aliphatic), 1699 (CO),1560
(C]C) cmꢀ1; 1H NMR (250 MHz)
¼ 0.924 (s, 6H, 2CH3),1.969 (s, 2H,
CH2), 2.218 (s, 2H, CH2), 4.226 (s, 2H, CH2) 4.615(s, 1H, CH2CO), 4.830
(s, 2H, CH2), 5.077, 9.74(2 s, 1H, CH2CO tautomeric OH),
4.1.4.9. 1-(4-chlorophenyl)-7,7-dimethyl-3-[4-(N2-3-nitrophenylhyd-
razinocarbonylmethoxy)phenyl]-5-oxo-1,2,3,4,5,6,7,8-octahydroquin-
d
azoline (19). Yield: 65%; mp.: 117 ꢂC; IR:
y
¼ 3220(NH),3050 (CH,
aromatic), 2955 (CH, aliphatic), 1696 (CO), 1560 (C]C),1532, 1351
(NO2) cmꢀ1. 1H NMR (200 MHz)
þ
6.818e8.241 (m, 12H, ArH), 8.590 (s, 1H, CH]N), 9.879 (s, 1H, NH)
ppm. MS: m/z (rel. int.) ¼ 579 (M þ2, 7.5), 578 (M þ 1, 9.20), 577 (Mþ,
14.70), 515 (15.80), 315 (23.80), 281(26.30), 226 (39.50), 166 (34.20),
121 (86.80), 83 (100.00). Anal. calcd for C31H30Cl2N4O3:C, 64.47; H,
5.24; N, 9.70. Found: C, 64.30; H, 5.22; N, 9.56%.
d
¼ 0.847 (s, 6H, 2CH3), 1.897(s, 2H,
CH2), 2.137 (s, 2H, CH2), 4.142 (s, 2H, CH2), 4.535(s, 1H, CH2CO),
4.747 (s, 2H, CH2), 5.030, 9.966 (2 s, 1H, CH2CO þ tautomeric OH,
exch.), 6.794e8.405 (m, 13H, ArH þ CH]N), 9.770(s, 1H, NH, exch.)
ppm. Anal. calcd for C31H30ClN5O5: C, 63.32; H, 5.14; N, 11.91.Found:
C, 63.41; H, 5.29; N, 12.11%.
4.1.4.4. 3-[4-(N2-4-Chlorophenyl-hydrazinocarbonylmethoxy)phenyl]-
1-(4-chlorophenyl)-7,7-dimethyl-5-oxo-1,2,3,4,5,6,7,8-octahydroquin-
4.1.4.10. 1-(4-Chlorophenyl)-7,7-dimethyl-3-[4-(N2-4-nitrophenylh-
ydrazinocarbonylmethoxy)phenyl]-5-oxo-1,2,3,4,5,6,7,8-octahydroq-
azoline (14). Yield: 72%; mp.: 161 ꢂC; 1H NMR (200 MHz)
d
¼ 0.862 (s,
6H, 2CH3),1.907(s, 2H, CH2), 2.151 (s, 2H, CH2), 4.149 (s, 2H, CH2) 4.530
(s, 1H, CH2CO),4.757(s, 2H, CH2), 5.088, 10.05 (2 s, 1H,
CH2CO þ tautomeric OH exch.), 6.794e7.621 (m,12H, ArH), 8.151 (s,1H,
CH]N), 9.614 (s,1H, NH exch.) ppm. Anal. calcd for C31H3 ꢂCl2N4O3: C,
64.47; H, 5.24; N, 9.70. Found: C, 64.30; H, 5.22; N, 9.56%.
uinazoline (20). Yield: 75%; mp.: 194e195 ꢂC; IR:
y
¼ 3238
(NH),3080 (CH, aromatic), 2953 (CH, aliphatic),1709 (CO),1605 (C]
N) 1580 (C]C) and 1511, 1342 (NO2) cmꢀ1 1H NMR (200 MHz)
¼ 0.955 (s, 6H, 2CH3), 2.002 (s, 2H, CH2), 2.244 (s, 2H, CH2), 4.247
(s, 2H, CH2), 4.642, 5.123(2 s, 2H, CH2CO), 4.850 (s, 2H, CH2),
.
d

5396
O.I. El-Sabbagh et al. / European Journal of Medicinal Chemistry 45 (2010) 5390e5396
6.916e8.359 (m, 12H, ArH), 8.449 (s, 1H, CH]N), 9.78 (s, 1H, NH,
exch.) ppm. Anal. calcd for C31H30ClN5O5: C, 63.32; H, 5.14; N,
11.91.Found: C, 63.41; H, 5.29; N, 12.11%.
16 I.U./ml to inhibit blood clotting) [16] in the common carotid
artery. The cannula was connected to PT 400 blood pressure
transducer, which was connected to FC137 strain gauge coupler
which was fixed to one of the 4-channel oscillograph MD4
(Bioscience, U.K.). The blood pressure was recorded on chart paper.
ECG was recorded according the method of Burden et al. [15]. The
ECG limb cable was connected to FC123 coupler which switched on
lead II and connected to another channel of the 4-channel oscillo-
graph MD4.
4.1.4.11. 1-(4-Chloropheyl)-7,7-dimethyl-5-oxo-3-[4-(N2-phenylhyd-
razinocarbonylmethoxy)phenyl]-1,2,3,4,5,6,7,8-octahydroquinazoline
(21). Yield: 60%; mp.: 100 ꢂC; 1H NMR (200 MHz)
d
¼ 0.796 (s, 6H,
2CH3), 1.841 (s, 2H, CH2), 2.093 (s, 2H, CH2), 4.088 (s, 2H, CH2) 4.469
(s, 1H, CH2CO), 4.691 (s, 2H, CH2), 4.965, 9.736 (2 s, 1H,
CH2CO þ tautomeric OH, exch.), 6.755e8.085 (m, 13H, ArH), 8.210
(s, 1H, CH]N), 9.416 (s, 1H, NH, exch.) ppm. MS: m/z (rel. int.) ¼ 545
(M þ 2, 7.20), 544 (M þ 1, 15.60), 543 (Mþ, 12.70), 281 (17.30), 196
(16.40), 161 (24.50), 120 (40.90), 65 (100.00). Anal. calcd for
C31H31ClN4O3: C, 68.56; H, 5.75; N, 10.32.Found: C, 68.36; H, 5.81;
N, 10.00%.
4.2.4. Statistical analysis
The values of the systolic and diastolic arterial blood pressure as
well as the heart rate were presented as mean ꢁ S.E. and subjected
to either one-way ANOVA test or unpaired “t” test for statistical
analysis [19].
4.2. Hypotensive activity
Acknowledgements
Rats were maintained on a 12 h-light/dark cycle under regulated
temperature (25 ꢁ 2 ꢂC) and humidity (50 ꢁ 10%) as well as fed
with standard diet and water ad libitum. They were allowed to
acclimate seven days before use. This protocol was approved by the
Animal Care and Use Committee of the Pharmacology Department,
Faculty of Medicine, Zagazig University, Zagazig, Egypt.
The authors would like to express their thanks to Dr. Rasha
Husseiny Mohamed in the Central Biochemistry Laboratory at
Faculty of Medicine, Zagazig University and Dr. Gamal A. El-Sher-
biny in the Pharmacology and Toxicology Department, Faculty of
Pharmacy, Beni Suief University, Egypt for their efforts in per-
forming hypotensive activity and statistical analysis.
4.2.1. Determination of arterial blood pressure and heart rate
Fifty four male rats weighing (180e220 g) were classified into 9
groups; each of 6 rats. All the test compounds were dissolved in
tween 80 and diluted with distilled water to the final volume (1:3).
Tween 80 was used as a solvent for the test compounds because it
did not show any effect on the activity (solvent-treated group).
These groups were used to study the effect of solvent, prazosin
(Sigma Chemicals Co. USA), and the test compounds on the arterial
blood pressure and heart rate, which were recorded 5, 15, 30 and
60 min after i.p. injection of 5 mg/Kg of each compounds (Table 1).
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