Synthesis and pharmacological investigation of novel 4-(4-ethylphenyl)-1- substituted-4H-[1,2,4]triazolo[4,3-a]-quinazolin-5-ones as new class of H 1-antihistaminic agents

Article abstract of DOI:10.1002/jhet.5570450312

(Chemical Equation Presented) A series of novel 4-(4-ethylphenyl)-1- substituted-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones were synthesized by the cyclization of 2-hydrazino intermediate with various electrophile. The starting material 2-hydrazino compound was synthesized from 2-ethyl aniline by a new innovative route with improved yield. When tested for their in vivo H ₁-antihistaminic activity on conscious guinea pigs, all the test compounds significantly protected the animals from histamine induced bronchospasm. The compound II emerged as the most active compound of the series and it is more potent (73.93% protection) when compared to the reference standard, chlorpheniramine maleate (71% protection), it showed negligible sedation (10%) when compared to chlorpheniramine maleate (30%). Therefore compound II will serve as prototype molecule for further development as a new class of H₁-antihistamines.

Full text of DOI:10.1002/jhet.5570450312

May-Jun 2008
709
Synthesis and Pharmacological Investigation of Novel
4-(4-Ethyl phenyl)-1-substituted-4H-[1,2,4]triazolo[4,3-a]-
quinazolin-5-ones as New Class of H1-Antihistaminic agents
V. Alagarsamy,a,* V. Raja Solomon,b P. Parthiban,a K. Dhanabal,c S. Murugesan, c
G. Saravanan,c G. V.Anjanac
a Medicinal Chemistry Research Laboratory, MNR College of Pharmacy, Fasalwadi ,
Sangareddy-502 294 , A.P., India.
b Medicinal & Process Chemistry Division, Central Drug Research Institute, Lucknow-226 001, India.
c Medicinal Chemistry Research Laboratory, Arulmigu Kalasalingam College of Pharmacy, Anand Nagar,
Krishnankovil-626 190, India.
Email: samy_veera@yahoo.com
Received April 19, 2007
CH2CH3
O
N
N
N
N
R
I - X
A series of novel 4-(4-ethylphenyl)-1-substituted-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones were
synthesized by the cyclization of 2-hydrazino intermediate with various electrophile. The starting material
2-hydrazino compound was synthesized from 2-ethyl aniline by a new innovative route with improved
yield. When tested for their in vivo H1-antihistaminic activity on conscious guinea pigs, all the test
compounds significantly protected the animals from histamine induced bronchospasm. The compound II
emerged as the most active compound of the series and it is more potent (73.93% protection) when
compared to the reference standard, chlorpheniramine maleate (71% protection), it showed negligible
sedation (10%) when compared to chlorpheniramine maleate (30%). Therefore compound II will serve as
prototype molecule for further development as a new class of H1-antihistamines
J. Heterocyclic Chem., 45, 709 (2008).
with least sedation. The present work is an extension of
our ongoing efforts towards for the development and
identification of new molecules therefore; we aimed to
synthesize a series of 1,2,4-triazolo-4H-[4,3-a]quinazolin-
5-ones containing 4-ethyl phenyl substitution at position 4
and alkyl/alicyclic amines substitution at position 1. The
title compounds were synthesized by the cyclization of
3-(4-ethylphenyl)-2-hydrazino-3H-quinazolin-4-one (6)
INTRODUCTION
The first generation antihistamines penetrate the blood
brain barrier and also possess anticholinergic properties;
this has led to the development of a second generation of
H1-antagonists such as terfenadine, cetirizine and
astemizole [1]. A common feature of first generation
compounds includes two aryl or heteroaryl rings linked to
an aliphatic tertiary amine via the side chain [2] (e.g.
diphenhydramine and pheniramine). The second-
generation compounds (terfenadine and cetirizine) also
contain many of the structural features of first generation
compounds. The real breakthrough of non-sedative
antihistamines came in the early eighties of the twentieth
century when the discovery of modern antihistamines,
was found to exhibit potent antihistaminic activity without
sedative effect [3]. Condensed heterocycles containing
new generation of H1-antihistamines (e.g. loratadine,
azelastine and flazelastine) that does not possess the
above mentioned pharmacophore for H1-antihistamines
gave way for the discovery of many novel antihistamines
temelastine [4] and mangostin [5]. Quinazolines and
condensed quinazolines show excellent antihistaminic
activity [6,7]. In this continuation we demonstrated that
[8,9] the quinazoline derivatives as potent antihistamines
with various electrophiles. The compound
6 was
synthesized from 4-ethyl aniline by a new innovative
route (Scheme 3). Spectral data (IR, NMR and mass
spectra) confirmed the structures of the synthesized
compounds; the purity of these compounds was
ascertained by microanalysis (Table 1). The synthesized
products were tested for their in vivo H1-antihistaminic
activity on conscious guinea pigs. As sedation is one of
the major side effects associated with antihistamines, the
test triazoloquinazolinones were also evaluated for their
sedative potentials, by measuring the reduction in
locomotor activity using actophotometer.
Chemistry. The key intermediate 3-(4-ethylphenyl)-2-
thioxo-2,3-dihydro-1H-quinazolin-4-one 4 was prepared
by refluxing methyl anthranilate with 4-ethylphenyl
isothiocyanate in ethanol (Scheme 1). However, the
preparation of 4-ethyl phenyl isothiocyanate required for

710
V. Alagarsamy, V. R. Solomon, P. Parthiban, K. Dhanabal, S. Murugesan,
G. Saravanan, G. V.Anjana
Vol 45
Thus, 4-ethyl aniline (1) treated with carbon disulphide
and sodium hydroxide in DMSO to give sodium
the reaction was a tedious, time consuming process and
the yield was also low (60%) [10].
Scheme 1. Synthesis of 3-(4-ethylphenyl)-2-thioxo-2,3-dihydro-1H-quinazolin-4-one from 4-ethylphenylisothiocyanate.
O
O
CH2CH3
OCH3
EtOH
OCH3
+
NH2
NH NH
CH2CH3
S
N
C S
CH2CH3
O
N
N
S
H
4
An alternate route to synthesize 4 was attempted
(Scheme 2). In this route, 4-ethyl aniline (1) was reacted
with carbon disulphide and anhydrous K2CO3 in acetone
to give potassium dithiocarbamate, which was methylated
with dimethyl sulphate to afford dithiocarbamic acid
methyl ester (2) [11]. Compound 2 on reflux with methyl
anthranilate (3) yielded 4. This process of synthesizing 4
suffers from the following drawbacks: it is a multistep
process, it requires prolonged reaction time (37 h) and the
yield is also very low (30%).
Hence, improvisation was carried out on this method,
by using aqueous sodium hydroxide instead of anhydrous
K2CO3, and dimethyl sulphoxide for acetone (Scheme 3).
The use of DMSO as the reaction solvent enhanced the
rate of reaction and the use of alkali in higher
concentration helped in preventing the hydrolysis of the
intermediate probably, due to less solvation. These
modifications not only curtailed the reaction time from 37
h to 25 h, also increased the yield from 30% to 81%.
dithiocarbamate, which was methylated with dimethyl
sulphate to afford the dithiocarbamic acid methyl ester
(2). Compound 2 on reflux with methyl anthranilate (3) in
ethanol yielded the desired 3-(4-ethyl phenyl)-2-thioxo-
2,3-dihydro-1H-quinazolin-4-one (4) via the thiourea
intermediate in good yield (81%).
The product obtained was cyclic and not an open chain
thiourea 3a. It was confirmed by IR spectra of 4, which
showed intense peaks at 3210 cm-1 for cyclic thiourea
(NH), 1690 cm-1 for carbonyl (C=O) and 1218 cm-1 for
thioxo (C=S) stretching. 1H NMR spectra of 4 showed a
triplet at δ 1.3-1.4 ppm due to CH3 group; a quartet at δ
2.1-2.2 due to CH2 and a multiplet at δ 7.3-8.0 ppm for
aromatic (8H) protons and a singlet at δ 10.1 ppm
indicating the presence of NH. Data from the elemental
analyses were found to be in conformity with the assigned
structure. Further the molecular ion recorded in the mass
spectra is also in agreement with the molecular weight of
the compound.
Scheme 2. Synthesis of 3-(4-ethylphenyl)-2-thioxo-2,3-dihydro-1H-quinazolin-4-one from 4-ethyl aniline.
H3CH2C
SCH3
S
H3CH2C
H3CH2C
S- K+
S
DMS
Acetone
N
H
CS2 /K2CO3
N
NH2
H
2
1
O
EtOH
OCH3
NH2
3
O
CH2CH3
O
N
OCH3
NH
NH
CH2CH3
N
H
S
S
4
3a

May-Jun 2008
New Class of H1-Antihistaminic Agents
711
Scheme 3. Synthesis of 4-(4-ethyl phenyl)-1-substituted-1,2,4-triazolo-[4,3-a]quinazolin-5(4H)-ones.
H3CH2C
H3CH2C
S- Na+
S
CS2
+
NH2
+
NaOH
N
H
1
(CH3)2SO4
H3CH2C
SCH3
S
N
H
2
O
OCH3
NH2
3
O
CH2CH3
O
EtOH
OCH3
N
NH
NH
CH2CH3
N
H
S
S
3a
4
(CH3)2SO4 NaOH / EtOH
CH2CH3
EtOH / NH2NH2
CH2CH3
CH2CH3
O
O
O
N
One Carbon
Donors
N
N
N
N
SCH3
N
NHNH2
N
N
I - X
6
5
R
The 3-(4-ethylphenyl)-2-methysulfanyl-3H-quinazolin-
4-one 5 was obtained by dissolving 4 in 2% alcoholic
sodium hydroxide solution and methylating with dimethyl
sulphate with stirring at room temperature. The IR spectra
of 5 showed disappearance of NH and C=S stretching
signals of cyclic thiourea. It showed a peak for carbonyl
formation of 6 was confirmed by the presence of NH and
NH2 signals at 3362–3281 cm-1 in the IR spectra. It also
1
showed a peak for carbonyl (C=O) at 1686 cm-1. The H
NMR spectra of the compound 6 showed triplet at δ 1.6-
1.7 ppm due to CH3 group; a quartet at δ 2.2-2.3 due to
CH2; singlet at δ 5.3 ppm and 9.8 ppm due to NH2 and NH
respectively, a multiplet at δ 7.4-8.1 ppm was observed
for aromatic (8H) protons. Data from the elemental
analyses were found to be in conformity with the assigned
structure. Further the molecular ion recorded in the mass
spectra is also in agreement with the molecular weight of
the compound.
1
(C=O) stretching at 1681 cm-1. The H NMR spectra of
compound 5 showed triplet at δ 1.5-1.6 ppm due to CH3; a
quartet at δ 2.3-2.4 due to CH2; a singlet at δ 2.7 ppm
SCH3 and multiplet at δ 7.2-7.8 ppm was observed for
aromatic (8H) protons. Data from the elemental analyses
and molecular ion recorded in the mass spectra further
confirmed the assigned structure.
Nucleophilic displacement of methylthio group of 5
with hydrazine hydrate was carried out using ethanol as
solvent to afford 3-(4-ethylphenyl)-2-hydrazino-3H-
quinazolin-4-one 6 [12]. The long duration of reaction (39
h) required might be due to the presence of bulky
aromatic ring at position 3, which might have reduced the
reactivity of quinazoline ring system at C-2 position. The
The title compounds I-V were obtained in fair to good
yields through the cyclization of 6 with a variety of
electrophiles such as formic acid, acetic acid, propionic
acid, butyric acid and chloroacetyl chloride at reflux [13].
The formation of cyclic product is indicated by the
disappearance of peaks due to NH and NH2 of the starting
material at 3362–3281 cm-1 in IR spectrum of all the
compounds I-V. The 1H NMR spectra of I-V showed the

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V. Alagarsamy, V. R. Solomon, P. Parthiban, K. Dhanabal, S. Murugesan,
G. Saravanan, G. V.Anjana
Vol 45
Table 1
Characterization data of 4-(4-ethylphenyl)-1-substituted-substituted-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones.
CH2CH3
O
N
N
N
N
R
I - X
Compd. Code
R
Mol. Formula
Mp oC
(% Yield)
Elemental analysis
Calculated/Found
%C
%H
%N
I
-H
C17H14N4O
C18H16N4O
C19H18N4O
269-271
(79)
70.33 4.86 19.30
70.36 4.83 19.32
71.04 5.30 18.41
71.01 5.31 18.45
71.68 5.70 17.60
71.69 5.73 17.63
II
-CH3
228-229
(78)
III
-CH2CH3
267-268
(73)
IV
V
-(CH2) 2CH3
-CH2Cl
C20H20N4O
C18H15ClN4O
C22H23N5O
221-222
(76)
72.27 6.06 16.86
72.29 6.08 16.84
63.81 4.46 16.54
63.85 4.48 16.51
70.76 6.21 18.75
70.79 6.25 18.79
256-257
(77)
278-279
(76)
N
VI
C23H25N5O
264-265
(77)
71.29 6.50 18.07
71.33 6.51 18.04
N
VII
C22H23N5O2
C22H24N6O
C23H26N6O
219-221
(74)
67.85 5.95 17.98
67.80 5.96 17.96
N
O
VIII
IX
247-248
(73)
68.02 6.23 21.63
68.05 6.20 21.60
N
NH
231-233
(74)
68.63 6.51 20.88
68.61 6.55 20.92
N
N
CH3
X
Table 2
Antihistaminic and sedative-hypnotic activity of compounds I-X.
Percent CNS Depression
Compound
Code
Time of onset
of convulsion
( in sec)
% Protection
1 h
2 h
3 h
I
II
398 ± 6.11*
445 ± 7.32*
416 ± 9.65*
393 ± 6.39*
381 ± 7.31*
389 ± 4.74*
396 ± 9.54*
401 ± 8.21*
423 ± 5.93*
436 ± 8.63*
400 ± 29.50*
70.85 ± 1.53*
73.93 ± 1.69*
72.11 ± 1.32*
70.48 ± 1.81*
69.55 ± 1.46*
70.17 ± 1.71*
70.70 ± 1.58*
71.07 ± 1.24*
72.57 ± 1.19*
73.39 ± 1.53*
71.00 ± 1.36*
9 ± 1.36 *
8 ± 1.31*
13 ± 1.42**
14 ± 1.71**
14 ± 1.46**
16 ± 1.41**
11 ± 1.62 *
12 ± 1.33**
12 ± 1.83**
12 ± 1.60**
13 ± 1.57**
14 ± 1.62**
32.0 ± 1.73***
6 ± 1.41*
8 ± 1.73*
9 ±1.57*
III
IV
12 ± 1.62**
13 ± 1.73**
7 ± 1.41*
10 ± 1.82*
5 ± 1.64 Ns
7 ± 1.72*
8 ± 1.56*
8 ± 1.63*
9 ± 1.45*
9 ± 1.51*
22 ± 1.98***
V
VI
VII
9 ± 1.84*
11 ± 1.33*
10 ± 1.71*
11 ± 1.83*
12 ± 1.36*
37 ± 1.82***
VIII
IX
X
Chlorphe-
niramine
Each value represents the mean ± SEM (n=6). Significance levels *p<0.5, **p<0.1 and ***p<0.05; NS indicate not significant.

May-Jun 2008
New Class of H1-Antihistaminic Agents
713
absence of NH and NH2 signals. Compounds VI-X were
obtained by the displacement of chloro of compound V
with various alicyclic amines like pyrrolidine, piperidine,
morpholine, piperazine and 4-methylpiperazine. The IR
spectrum of compounds I-X showed a peak for carbonyl
of alicyclic amines with additional heteroatom
(morpholinyl compound VIII, piperazinyl compound IX
and 4-methyl piperazinyl compound X) led to further
increase in activity. As the test compounds could not be
converted to a water-soluble form, in vitro evaluation for
antihistaminic activity could not be performed. The
results of sedative-hypnotic activity indicate that all the
test compounds were found to exhibit only negligible
sedation (10-13%), whereas the reference standard
chlorpheniramine maleate showed 30% sedation.
In the present study, synthesis of new series of 4-(4-
ethylphenyl)-1-substituted-4H-[1,2,4]triazolo[4,3-a]quin-
azolin-5-ones have been described. The key intermediate
compound of 3-(4-ethylphenyl)-2-thioxo-3H-quinazolin-
4-one has been synthesized by new innovative route with
improved the yield. The title compounds have exhibited
promising antihistaminic activity against histamine-
induced bronchospasm on conscious guinea pigs in vivo
model. Among the series, 4-(4-ethylphenyl)-1-methyl-
4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (II) was found
to be the most active compound (73.93%), which is more
potent than the reference standard chlorpheniramine
maleate (71%). Interestingly compound II also showed
negligible sedation (10%) compared to chlorpheniramine
maleate (30%) and could therefore serve as a lead
molecule for further modification to obtain a clinically
useful novel class of non-sedative antihistamines.
1
(C=O) around 1680 cm-1. The H NMR spectrum of the
compounds I-X showed multiplet around δ 7.0–8.0 ppm
integrating for aromatic protons. The mass spectra of the
title compounds are in conformity with the assigned
structure. The mass spectrum of these compounds showed
molecular ion peaks corresponding to their molecular
formula. The M++2 peak was observed in the spectra of
compound V confirming the presence of chlorine atom in
the compound. The relative intensity of this M++2 peak in
comparison to M+ peak is in the ratio of 1:3. The M++2
peak observed in the spectra of compound V is not
observed in that of compounds VI-X, which confirms the
displacement. In the mass spectrum of compounds I-X the
peak due to 1,2,4-triazolo[4,3-a]quinazoline cation was
observed at m/z 168. In addition a common peak at m/z
144 corresponding to the quinazolin-4-one moiety
appeared in all mass spectra. Elemental (C, H, N) analysis
satisfactorily confirmed elemental composition and purity
of the synthesized compounds. Physical data of the title
compounds is represented in Table 1.
RESULTS AND DISCUSSION
The compounds containing the 1,4-disubstituted[1,2,4]-
triazoloquinazoline ring system (I-X) were evaluated for
their in vivo antihistaminic activity. Histamine causes
bronchospasm and the guinea pigs are the most
susceptible animals for histamine, hence protection
against histamine-induced bronchospasm on conscious
guinea pigs method was adopted to determine the
antihistaminic potential of the test compounds. The
advantage of this method is it is a non-invasive method
and the animals are recovered after the experiment.
All the test compounds were found to exhibit good
antihistaminic activity (Table 2). Percentage protection
data showed that all compounds of the series show
significant protection in the range of 69-73 %. Biological
studies indicated that different substituents over the first
position of triazoloquinazoline ring exerted varied
biological activity. The presence of methyl group
(compound II) showed better activity over the
unsubstituted compound (compound I), with increased
lipophilicity (i.e., ethyl compound III) activity retained,
further increase in lipophilicity (i.e., propyl compound
IV) leads to decrease in activity. Replacement of a proton
of the methyl group by chloro (compound V) showed
further decrease in activity. Replacement of a proton of
the methyl group by alicyclic amines (pyrrolidinyl and
piperidinyl compound VI and VII respectively) showed
increase in activity over the chloro substituent. Placement
EXPERIMENTAL
Melting points (mp) were taken in open capillaries on Thomas
Hoover melting point apparatus and are uncorrected. The IR
spectra were recorded in film or in potassium bromide disks on a
1
Perkin-Elmer 398 spectrometer. The H spectra were recorded
on a DPX-300 MHz Bruker FT-NMR spectrometer. The
chemical shifts were reported as parts per million (δ ppm)
tetramethylsilane (TMS) as an internal standard. Mass spectra
were obtained on a JEOL-SX-102 instrument using fast atom
bombardment (FAB positive). Elemental analysis was
performed on a Perkin-Elmer 2400 C, H, N analyzer and values
were within the acceptable limits of the calculated values. The
progress of the reaction was monitored on readymade silica gel
plates (Merck) using chloroform-methanol (9:1) as a solvent
system. Iodine was used as a developing agent. Spectral data
(IR, NMR and mass spectra) confirmed the structures of the
synthesized compounds and the purity of these compounds was
ascertained by microanalysis. Elemental (C, H, N) analysis
indicated that the calculated and observed values were within the
acceptable limits (± 0.4%). All chemicals and reagents were
obtained from Aldrich (USA), Lancaster (UK) or Spectrochem
Pvt. Ltd (India) and were used without further purification.
3-(4-Ethyl phenyl)-2-thioxo-2,3-dihydro-1H-quinazolin-4-
one (4). A solution compound 1 (0.02 mol) in dimethyl
sulfoxide (10 mL) was stirred vigorously. To this was added
carbon disulphide (1.6 mL) (CAUTION: Toxic and easily
flammable substance and must be handled in high performance
fume hood) and aqueous sodium hydroxide 1.2 mL (20 molar
solution) drop wise during 30 min with stirring. Dimethyl

714
V. Alagarsamy, V. R. Solomon, P. Parthiban, K. Dhanabal, S. Murugesan,
G. Saravanan, G. V.Anjana
Vol 45
sulphate (0.02 mol) (CAUTION: Highly toxic compound and
must be handled in high performance fume hood) was added
gradually keeping the reaction mixture stirring in freezing
mixture for 2 h. The reaction mixture was then poured into ice
water. The solid obtained was collected by filtration, washed
with water, dried and recrystallized from ethanol. Methyl
anthranilate (0.01 mol) and the above prepared N-(4-ethyl
phenyl)-methyl dithiocarbamic acid (0.01 mol), were dissolved
in ethanol (20 mL). To this anhydrous potassium carbonate (100
mg) was added and refluxed for 22 h. The reaction mixture was
cooled in ice and the solid that separated was collected by
filtration and purified by dissolving in 10% alcoholic sodium
hydroxide solution and re-precipitated by treating with dilute
hydrochloric acid. The solid obtained was collected by filtration,
washed with water, dried and re-crystallized from ethanol. Yield
= 81%, mp 265-266 °C; IR (KBr) cm-1: 3210 (NH), 1690 (C=O),
NMR (CDCl3): δ 1.1-1.2 (t, 3H, CH2CH3), 1.5-1.6 (t, 3H,
CH2CH3), 2.6-2.7 (q, 3H, CH2CH3), 2.8-2.9 (q, 2H, CH2CH3),
7.2-7.8 (m, 8H, ArH); MS (m/z): 318 [M+].
4-(4-Ethylphenyl)-1-propyl-4H-[1,2,4]triazolo[4,3-a]quin-
azolin-5-one (IV). IR (KBr) cm-1: 1682 (C=O), 1606 (C=N); 1H
NMR (CDCl3): δ 0.8-0.9 (t, 2H, CH2CH2CH3), 1.1-1.3 (sext, 2H,
CH2CH2CH3), 1.6-1.7 (t, 3H, CH2CH3), 2.1-2.2 (q, 3H,
CH2CH3), 2.6-2.7 (t, 3H, CH2CH2CH3), 7.3-8.0 (m, 8H, ArH);
MS (m/z): 332 [M+].
1-Chloromethyl-4-(4-ethylphenyl)-4H-[1,2,4]triazolo[4,3-a]-
quinazolin-5-one (V). IR (KBr) cm-1: 1686 (C=O), 1603 (C=N);
1H NMR (CDCl3): δ 1.3-1.4 (t, 3H, CH2CH3), 2.5.2.6 (q, 3H,
CH2CH3), 3.5 (s, 2H, CH2), 7.2-7.9 (m, 8H, ArH); MS (m/z):
338 [M+], 340 [M+ +2].
4-(4-Ethyl phenyl)-1-(pyrrolidinyl)-4H-[1,2,4]triazolo[4,3-
a]quinazolin-5-one (VI). A mixture of 1-chloromethyl-4-(4-
ethylphenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (V)
(0.01 mol), pyrrolidine (0.05 mole) and anhydrous potassium
carbonate (100 mg) in dioxan (25 mL) were taken in a round
bottomed flask and refluxed for 37 h, cooled and poured into ice
water. The solid obtained was collected by filtration, washed
with water, dried and recrystallized from ethanol-benzene
(50:50). Adopting this procedure compounds VII-X were
1
1218 (C=S); H NMR (CDCl3) δ: 1.3-1.4 (t, 3H, CH2CH3), 2.1-
2.2 (q, 3H, CH2CH3), 7.3-8.0 (m, 8H, ArH), 10.1 (br s, 1H, NH,
D2O exchangeable); MS (m/z) 282 (M+). Anal. Calcd for
C16H14N2OS: C, 68.06; H, 5.00; N, 9.92. Found: C, 68.09; H,
5.02; N, 9.86.
3-(4-Ethyl phenyl)-2-methylsulfanyl-3H-quinazolin-4-one
(5). The compound 4 (0.01 mol) was dissolved in 40 mL of 2%
alcoholic sodium hydroxide solution. To this dimethyl sulphate
(0.01 mol) was added drop wise with stirring. The stirring was
continued for 1 h, the reaction mixture was then poured into ice
water. The solid obtained was collected by filtration, washed
with water, dried and recrystallized from ethanol-chloroform
(75:25) mixture. Yield = 85%, mp 151-153 °C; IR (KBr) cm-1:
1
prepared. IR (KBr) cm-1: 1681 (C=O), 1606 (C=N); H NMR
(CDCl3): δ 1.2-1.4 (m, 4H, CH2-Pyrrolidinyl), 1.7-1.9 (m, 4H,
CH2-Pyrrolidinyl), 2.0-2.1 (t, 3H, CH2CH3), 2.3-2.4 (q, 3H,
CH2CH3), 7.1-7.7 (m, 8H, ArH); MS (m/z): 373 [M+].
4-(4-Ethylphenyl)-1-(piperidinyl)-4H-[1,2,4]triazolo[4,3-a]-
quinazolin-5-one (VII). IR (KBr) cm-1: 1687 (C=O), 1610
1
1
1681 (C=O); H NMR (CDCl3) δ: 1.5-1.6 (t, 3H, CH2CH3), 2.3-
(C=N); H NMR (CDCl3): δ 1.1-1.4 (m, 6H, CH2-Piperidyl),
2.4 (q, 3H, CH2CH3), 2.7 (s, 3H, SCH3), 7.2-7.8 (m, 8H ArH);
MS (m/z) 296 (M+). Anal. Calcd for C17H16N2OS: C, 68.89; H,
5.44; N, 9.45. Found: C, 68.86; H, 5.47; N, 9.41.
1.7-1.9 (m, 4H, CH2-Piperidyl), 2.0-2.1 (t, 3H, CH2CH3), 2.3-2.4
(q, 3H, CH2CH3), 7.4-8.0 (m, 8H, ArH); MS (m/z): 387 [M+].
4-(4-Ethylphenyl)-1-(morpholinyl)-4H-[1,2,4]triazolo[4,3-
a]quinazolin-5-one (VIII). IR (KBr) cm-1: 1678 (C=O), 1608
3-(4-Ethyl phenyl)-2-hydrazino-3H-quinazolin-4-one (6).
Compound 5 (0.01 mol) was dissolved in ethanol (25 mL). To
this hydrazine hydrate (99%) (0.1 mol) and anhydrous potassium
carbonate (100 mg) was added and refluxed for 39 h. The
reaction mixture was cooled and poured into ice water. The
solid so obtained was collected by filtration, washed with water,
dried and recrystallized from chloroform-benzene (25:75)
mixture. Yield = 85%, mp 187-189 °C; IR (KBr) cm-1: 3362,
1
(C=N); H NMR (CDCl3): δ 1.3-1.5 (m, 4H, CH2-Morpholinyl),
1.9-2.1 (m, 4H, CH2-Morpholinyl), 2.3-2.4 (t, 3H, CH2CH3), 2.6-
2.7 (q, 3H, CH2CH3), 7.2-7.8 (m, 8H, ArH); MS (m/z): 389 [M+].
4-(4-Ethylphenyl)-1-(piperazinyl)-4H-[1,2,4]triazolo[4,3-a]-
quinazolin-5-one (IX). IR (KBr) cm-1: 1688 (C=O), 1612
1
(C=N); H NMR (CDCl3): δ 1.0-1.2 (m, 4H, CH2-Piperazinyl),
1.5-1.7 (m, 4H, CH2-Piperazinyl), 1.8-1.9 (t, 3H, CH2CH3), 2.4-
2.5 (q, 3H, CH2CH3), 7.0-7.7 (m, 8H, ArH); 9.9 (s, 1H, NH, D2O
Exchangeable ); MS (m/z): 388 [M+].
4-(4-Ethylphenyl)-1-(4-methylpiperazinyl)-4H-[1,2,4]tria-
zolo[4,3-a]quinazolin-5-one (X). IR (KBr) cm-1: 1678 (C=O),
1609 (C=N); 1H NMR (CDCl3): δ 1.3-1.5 (m, 4H, CH2-
Piperazinyl), 1.6-1.8 (m, 4H, CH2-Piperazinyl), 2.0-2.1 (t, 3H,
CH2CH3), 2.5-2.6 (q, 3H, CH2CH3), 2.8 (s, 2H, CH3), 7.2-7.9 (m,
8H, ArH); MS (m/z): 402 [M+].
Pharmacology. The synthesized compounds were evaluated
for antihistaminic and sedative-hypnotic activities. The animals
were maintained in colony cages at 25±2°C, relative humidity of
45-55%, under a 12 h light and dark cycle; they were fed standard
animal feed. All the animals were acclimatized for a week before
use. The Institutional Animal Ethics committee approved the
protocol adopted for the experimentation of animals.
Antihistaminic activity. A modification of the technique of
Van Arman [14] was adopted to determine the antihistaminic
potential of the synthesized compounds. Male Dunkin Hartley
Guinea pigs (250-300 g) were fasted for 12 h. Six animals were
taken in each group. The test compounds, was administered
orally at a dose of 10 mg/kg in 1% CMC and challenged with
1
3281 (NHNH2), 1686 (C=O); H NMR (CDCl3): δ 1.6-1.7 (t,
3H, CH2CH3), 2.2-2.3 (q, 3H, CH2CH3) 5.3 (br s, 2H, NH2 D2O
exchangeable), 7.4-8.1 (m, 8H, ArH), 9.8 (br s, 1H, NH D2O
exchangeable); MS (m/z) 280 (M+). Anal. Calcd for C16H16N4O:
C, 68.55; H, 5.75; N, 19.99. Found: C, 68.59; H, 5.74; N, 19.95.
(4-Ethyl phenyl)-4H-[1,2,4] triazolo [4,3-a] quinazolin-5-
one (I). Compound 6 (0.01 mol) and formic acid (25 mL) was
taken in a round bottomed flask and refluxed for 38 h, cooled
and poured into ice water. The solid obtained was collected by
filtration, washed with water, dried and recrystallized from
1
ethanol. IR (KBr) cm-1: 1683 (C=O), 1605 (C=N); H NMR
(CDCl3): δ 1.2-1.3 (t, 3H, CH2CH3), 2.3-2.4 (q, 3H, CH2CH3),
7.2-7.5 (m, 4H, ArH), 7.6 (s, 1H, ArH), 7.8-8.1 (m, 4H, ArH);
MS (m/z): 290 [M+].
4-(4-Ethylphenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a]quin-
1
azolin-5-one (II). IR (KBr) cm-1: 1670 (C=O), 1608 (C=N); H
NMR (CDCl3): δ 1.5 (s, 3H, CH3), 1.9-2.0 (t, 3H, CH2CH3), 2.6-
2.7 (q, 3H, CH2CH3), 7.2-7.8 (m, 8H, ArH); MS (m/z): 304
[M+].
1-Ethyl-4-(4-ethylphenyl)-4H-[1,2,4]triazolo[4,3-a]quinaz-
1
olin-5-one (III). IR (KBr) cm-1: 1689 (C=O), 1612 (C=N); H

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New Class of H1-Antihistaminic Agents
715
histamine aerosol (0.2% aqueous solution of histamine acid
chloride 3 mL) in a vaponephrin pocket nebulizer sprayed into a
closed transparent cage. The respiratory status reflecting the
increasing degree of bronchoconstriction was recorded. The time
for onset of convulsions (preconvulsion) was recorded. Animals
remaining stable for more than 6 min were considered protected
against histamine-induced bronchospasm. An intraperitoneal
injection of chlorpheniramine maleate (Avil; Hoechst, Mumbai,
India) at a dose of 25 mg/kg was given for the recovery of the
test animals. The mean preconvulsion time of animals, treated
with the test compounds was compared to control and is
expressed in terms of percentage protection (Table 2).
performed by two-tailed student ‘t’ test (manually). In all cases
significance level of the means of individual groups were
performed and compared with control. A significance level of p
< 0.5 denoted significance in all cases.
REFERENCES
[1] Simons, F. E.; Simons, K. J. N. Engl. J. Med. 1994, 330,
1663
[2] Ellis, E. F.; Adkinson, N. F.; Yungingen, J. W.; Busso, W.
W. H1-receptor antagonists. In: Musby-year book Inc, New York, NY,
1985, pp. 856-891.
[3] Carr, A. A.; Meyer, D. R. Arzneimittelforschung 1982, 32,
1157.
Percent protection = [1- (T1 / T2)] × 100
[4] Hopp, R. J.; Bewtra, A.; Nair, N. M.; Townley, R. G. J.
Allergy Clin. Immunol. 1985, 76, 609.
[5] Chairungsrilerd, N.; Furukawa, K.; Ohta, T.; Nozoe, S.;
Ohizumi, Y. Eur. J. Pharmacol. 1996, 314, 351.
[6] Wade, J. J. U. S. Patent 4, 528288, 1985; Chem. Abstr. 1986,
104, 5889.
[7] West, W. R.; July, W. R. Eur. Patent No. 34529, 1981;
Chem. Abstr. 1982, 96, 20114
[8] Alagarsamy, V.; Venkatesaperumal, R.; Vijayakumar, S.;
Angayarkanni, T.; Pounammal, P.; Senthilganesh, S.; Kandeeban, S.
Pharmazie 2002, 57, 306.
[9] Alagarsamy, V. Pharmazie 2004, 59, 753.
[10] Trabelsi, H.; Jouani, M.A.; Cambon, A. J. Fluorine Chem.
1996, 79, 27.
[11] Halls, D. J. Microchimica Acta 1969, 57, 62.
[12] Adams, R. Brown, B. K. Org. Synth. Coll. Vol. 1941, 1, 309.
[13] Babichev, F. S.; Kovtunenko, V. A. Chemistry of
Heterocyclic Compounds 1977, 13, 117.
T2 - preconvulsive time of test compound; T1 - preconvulsive
time of control.
The activity of the test compounds was compared with the
standard antihistamine chlorpheniramine maleate.
Sedative-hypnotic activity. It was determined by measuring
the reduction in locomotor activity using actophotometer
[15,16]. Swiss albino mice were chosen as test animals in a
group of 6. Basal activity score was taken and then compounds
I-X and standard chlorpheniramine maleate were administered
orally at the dose of 5 mg/kg in 1% CMC. Scores were recorded
at 1, 2 and 3 h after the drug administration. Student-t-test was
performed to ascertain the significance of the exhibited activity.
The percent reduction in locomotor activity was calculated by
the following formula and shown in Table 2.
% Reduction in motor activity = [(A-B)/A] × 100
[14] Van Arman, C. G.; Miller, L. M.; O'Malley, M. P. J.
Pharmacol. Exp. Ther. 1961, 133, 90.
Where A-basal score, B-score after drug treatment.
[15] Dews, P. B. Br. J. Pharmacol. 1953, 8, 46.
[16] Kuhn, W. L.; Van Maanen, E. F. J. Pharmacol. Exp. Ther.
1961, 134, 60.
Statistical analysis. Statistical analysis of the biological
activity of the test compounds on various animals was