Synthesis, analgesic and anti-inflammatory activities of some novel 2,3-disubstituted quinazolin-4(3H)-ones.

Article abstract of DOI:10.1248/bpb.26.557

A series of novel 2-benzylamino-3-substituted quinazolin-4(3H)-ones have been synthesized by treating 3-amino-2-benzylamino quinazolin-4(3H)-one, with different aldehydes and ketones. The starting material 3-amino-2-benzylamino quinazolin-4(3H)-one was sy

Full text of DOI:10.1248/bpb.26.557

April 2003
Notes
Biol. Pharm. Bull. 26(4) 557—559 (2003)
557
Synthesis, Analgesic and Anti-inflammatory Activities of Some Novel
,3-Disubstituted Quinazolin-4(3H)-ones
2
Veerachamy ALAGARSAMY,* Veluchamy MUTHUKUMAR, Nagendran PAVALARANI,
Poongavanam VASANTHANATHAN, and Rajappan REVATHI
Medicinal Chemistry Laboratory, S.B.College of Pharmacy; Sivakasi-626130, India.
Received October 28, 2002; accepted January 8, 2003
A series of novel 2-benzylamino-3-substituted quinazolin-4(3H)-ones have been synthesized by treating 3-
amino-2-benzylamino quinazolin-4(3H)-one, with different aldehydes and ketones. The starting material 3-
amino-2-benzylamino quinazolin-4(3H)-one was synthesized by nucleophilic substitution of thiomethyl group of
3
-amino-2-methylthio quinazolin-4(3H)-one by benzylamine. The title compounds were investigated for analgesic
and anti-inflammatory activities. All the test compounds exhibited significant analgesic activity, whereas the
compound III is equipotent with diclofenac sodium. The compounds I, II and III showed more potent anti-in-
flammatory activity than diclofenac sodium.
Key words quinazoline; Schiff’s base; pyrimidine; analgesic; anti-inflammatory
Quinazolines and condensed quinazolines exhibit diversed has shown good analgesic and anti-inflammatory activities,
pharmacological activities. Of the various quinazolines re- in the present study we aimed to synthesize some 2-benzyl-
ported, the C-2 and N-3 disubstituted quinazolines exhibit amino-3-substituted quinazolines, for their analgesic and
1
)
interesting pharmacological activities like analgesic, anti- anti-inflammatory activities. The title compounds 2-benzyl-
2
)
3)
4)
inflammatory, antibacterial and anticonvulsant activities. amino-3-substituted quinazolin-4(3H)-ones were prepared by
Schiff bases possess potent analgesic and anti-inflammatory reacting 3 amino of 3-amino-2-benzylamino quinazolin-
5
)
activities. In the view of these facts and to develop our ear- 4(3H)-one with various aldehydes and ketones. The starting
6
)
lier reporting 2-phenyl-3-substituted quinazoline series that material 3-amino-2-benzylamino quinazolin-4(3H)-one was
synthesized by reacting benzylamine with 3-amino-2-
methylthio quinazolin-4(3H)-one, which in turn was prepared
from methylanthranilate (Chart 1). The chemical structures
of the synthesized compounds were confirmed on the basis
of their spectral data (IR, NMR and mass spectra) and the
purity was ascertained by microanalysis (Table 1). The syn-
thesized compounds were tested for their analgesic and anti-
inflammatory activities.
CHEMISTRY
Melting points were determined in open capillary tubes on
a Thomas Hoover apparatus and are uncorrected. IR spectra
were recorded in KBr on a Perkin Elmer-841 grating Spec-
Ϫ1
trophotometer (cm ), mass spectra on a Varian Atlas CH-7
mass spectrometer at 70 eV. Elemental analysis was per-
formed on Carlo erba 1108.
Synthesis of 3-Amino-2-mercapto Quinazolin-4(3H)-
one To a vigorously stirred solution of methylanthranilate
3
.02 g (0.02 mol) in dimethylsulfoxide (10 ml) at room tem-
perature, carbondisulphide (1.6 ml, 0.026 mol) and aqueous
sodium hydroxide 1.2 ml (20 mol solution) was added drop-
Table 1. Physical Data for 2-Benzylamino-3-substituted Quinazolin-4-
(
3H)-ones
a)
b)
Compd. code
Mol. formula
Mol. weight
mp (°C) Yield (%)
I
II
III
IV
C H N O
C H N O
22 18 4
320
354
380
395
183—185
196—198
179—182
213—216
80
76
79
71
1
9
20
4
C H N O
24 20 4
C H N O
2
2
3
17
5
a) Mol. weight determination by mass spectra. b) All compounds gave satisfac-
tory elemental analysis.
Chart 1
To whom correspondence should be addressed. e-mail: samy_veera@yahoo.com
*
© 2003 Pharmaceutical Society of Japan

5
58
Vol. 26, No. 4
wise simultaneously during 30 min and it was stirred for PHARMACOLOGY
0 min more. Dimethyl sulphate 2.5 g (0.02 mol) was added
dropwise under cooling with an ice bath. Stirring was contin-
3
The synthesized compounds were evaluated for analgesic
ued for 3 h, the reaction mixture was poured into ice-water and anti-inflammatory activities. Student-t-test was per-
and then it was extracted with chloroform. The solvent was formed for all the activities to ascertain the significance of
removed by distillation under reduced pressure. Thus the ob- the exhibited activities. The test compounds and the standard
tained crude methyl N-(2-methoxycarbonylphenyl) dithiocar- drugs were administered in the form of a suspension (1%
bamate was used for further reaction without purification. carboxyl methyl cellulose as vehicle) in the same route of ad-
Hydrazine hydrate 8.6 g (0.2 mol) was added dropwise to a ministration. Each group consisted of six animals.
stirred methyl N-(2-methoxycarbonylphenyl) dithiocarba-
Animals The animals were procured from “National Bi-
mate 4.82 g (0.02 mol) in cold condition. After the comple- ological Center”, Madurai, India, and were maintained in
tion of addition, stirring was continued for 1.5 h at 50 °C and colony cages at 25Ϯ2 °C, relative humidity of 45—55%,
the mixture was poured into ice-water. The solid obtained maintained under 12 h light and dark cycle and were fed with
was filtered, washed with water, dried and recrystallized from standard animal feed. All the animals were acclimatized for a
dimethylformamide and ethanol, yieldϭ90%, mp 236— week before use.
Ϫ1
7,8)
2
(
37 °C; IR (KBr) cm ; 3300, 3220 (NH ), 2560 (SH), 1680
Analgesic Activity
Test for analgesic activity was
2
1
CϭO); H-NMR (CDCl ) d: 3.21(s, 1H, SH), 5.12 (s, 2H, performed by “tail-flick technique” using Wistar albino mice
NH , D O exchangeable), 7.14 (m, 4H, ArH). Anal. Calcd (25—35 g) of either sex selected by random sampling tech-
3
2
2
for C H N OS: C, 49.74; H, 3.65; N, 21.77. Found: C, 49.26; nique “Diclofenac sodium” at a dose level of 10 mg/kg, and
8
7
3
H, 3.72; N, 21.94.
was administered as standard drug for comparison. The test
Synthesis of 3-Amino-2-methylthio Quinazolin-4(3H)- compounds at a dose level of 10 mg/kg were administered
one A solution of 3-amino-2-mercaptoquinazolin-4(3H)- orally. The reaction time was recorded at 30 min, 1, 2 and 3 h
one 1.93 g (0.01 mol) in sodium hydroxide 10 ml (20% w/v) after the treatment. The cut off time was 10 s. The percent
was obtained by warming on a water bath. It was clarified by analgesic activity (PAA) was calculated by the following for-
filteration while in warm condition, cooled and treated with mula,
dimethylsulphate 1.26 g (0.01 mol) under constant stirring.
The solution was stirred at room temperature for 12 h. The
PAAϭ(T /T )ϫ100
2
1
solid obtained was filtered, washed with cold water, dried and Where T is the reaction time(s) before treatment, T is the
1
2
recrystallized from chloroform–ethanol, yieldϭ90%, mp reaction time(s) after treatment.
Ϫ1
1
(
2
55—159 °C; IR (KBr) cm : 3400, 3320 (NH ), 1700
Anti-inflammatory Activity Anti-inflammatory activity
2
1
CϭO); H-NMR (DMSO-d ) d: 2.51 (s, 3H, SCH ), 6.6 (s, was performed by carrageenan-induced paw oedema test in
H, NH , D O exchangeable), 7.5—7.8 (m, 4H, ArH). Anal. rats. Diclofenac sodium 10 mg/kg was administered as stan-
6
3
9
)
2 2
Calcd for C H N OS: C, 52.22; H, 4.38; N, 20.3. Found: C, dard drug for comparison. The test compounds were admin-
9
9
3
5
2.46; H, 3.98; N, 20.52.
istered at a dose level of 10 mg/kg. The paw volumes were
Synthesis of 3-Amino-2-benzylamino Quinazolin-4(3H)- measured using the mercury displacement technique with the
one A mixture of benzylamine 5.35 g (0.05 mol) and 3- help of a plethysmograph immediately before and 30 min, 1,
amino-2-methylthio quinazolin-4(3H)-one 2.07 g (0.01 mol) 2 and 3 h after carrageenan injection. The percent inhibition
was heated at 80 °C for 36 h. The reaction mixture was of paw oedema was calculated by using the following for-
cooled and triturated with petroleum ether (60—80). The mula,
separated solid was recrystallized from ethanol, yieldϭ72%,
percent inhibition Iϭ100[1Ϫ(aϪx)/(bϪy)]
Ϫ1
mp 168—170 °C; IR (KBr) cm : 3400, 3350 (NH ), 1680
2
1
(
CϭO); H-NMR (CDCl ) d: 4.3 (t, 1H, NHCH C H , D O Where x is mean paw volume of rats before the administra-
exchangeable), 4.9 (s, 2H, CH ), 5.3 (s, 2H, NH ), 7.4—8.4 tion of carrageenan and test compounds or standard com-
3
2
6
5
2
2
2
(
m, 9H, ArH). Anal. Calcd for C H N OS: C, 72.83; H, pound (test group), a stands for the mean paw volume of rats
16 14 3
5
.33; N, 15.92. Found: C, 72.32; H, 4.98; N, 15.43.
after the administration of carrageenan in the test group
Synthesis of 2-Benzylamino-3-(2-butylidene) Quinazo- (drug treated), b is the mean paw volume of rats after the ad-
lin-4(3H)-one A mixture of 3-amino-2-benzylamino quin- ministration of carrageenan in the control group, y is the
azolin-4(3H)-one 2.66 g (0.01 mol) and ethyl methyl ketone mean paw volume of rats before the administration of car-
0
.72 g (0.01 mol) in acetic acid was refluxed for 30 h. The rageenan in the control group.
reaction mixture was poured into water and the solid ob-
tained was recrystallized from methanol–chloroform mix- RESULTS AND DISCUSSION
Ϫ1
ture, yieldϭ80%, mp 183—185 °C; IR (KBr) cm : 2880
(
(
Ar-CH), 1680 (CϭO), 1520 (CϭN), 1320 (ring CϭC), 660
The screening results revealed that all the test compounds
(I—IV) showed more potent analgesic activity (Table 2) than
Ϫ1
1
C–S) cm ; H-NMR (CDCl ) d: 1.2—1.5 (t, 3H, –CH
3
2
CH ), 2.2—2.4 (s, 3H, CH ), 4—4.3 (d, 2H, CH ), 4.7 (s, 1H, our earlier reported 2-phenyl-3-substituted quinazolines. The
3
3
2
NH, D O exchangeable), 7.3—8.2 (m, 9H, ArH). Anal. compound I with N -aliphatic substituent showed good activ-
2
3
Calcd for C H N O: C, 71.32; H, 6.3; N, 17.5. Found: C, ity, when it was replaced by aryl group leads to increase in
1
9
20
4
7
1.68; H, 5.96; N, 17.93.
activity (compounds II, III), placement of heteroaryl group at
Similarly the compounds II—IV were prepared.
N results in retaining activity. The compound III is the most
3
active analgesic agent, it is equipotent with standard di-
clofenac sodium and more than the earlier reported 2-phenyl-

April 2003
559
Table 2. Analgesic Activity (Tail–Flick Technique)
Percent analgesic activity
Compd. code
3
0 min
1 h
2 h
3 h
I
II
III
111.76Ϯ0.44**
133.3Ϯ0.2**
176.92Ϯ0.8**
121.4Ϯ0.7**
4.41Ϯ0.61
164.7Ϯ1.47**
160.1Ϯ0.5**
202.3Ϯ1.5**
150.3Ϯ0.8**
3.90Ϯ0.52
194.2Ϯ1.04**
199.7Ϯ0.6**
228.5Ϯ1.4**
200.3Ϯ0.4**
1.13Ϯ0.29
145.61Ϯ0.25**
151.9Ϯ0.35**
195.22Ϯ1.75**
140.31Ϯ0.62**
2.12Ϯ0.42
IV
Control
Standard
173.33Ϯ0.65**
200.00Ϯ0.29***
226.66Ϯ0.82***
120.00Ϯ0.85*
Significance levels: * pϽ0.5, ** pϽ0.01 and *** pϽ0.001.
Table 3. Anti-inflammatory Activity (Carrageenan Induced Rat Paw Oedema Method)
Percent protection
Compd. code
3
0 min
1 h
2 h
3 h
4 h
5 h
I
II
III
40.1Ϯ0.02**
45.6Ϯ0.04**
35.7Ϯ0.02**
31.5Ϯ0.04**
4.15Ϯ0.60
51.3Ϯ0.04**
49.4Ϯ0.02**
51.2Ϯ0.02**
37.4Ϯ0.06**
4.19Ϯ0.46
58.8Ϯ0.09**
50.5Ϯ0.06**
53.7Ϯ0.06**
40.71Ϯ0.04**
3.31Ϯ0.27
69.4Ϯ0.05**
56.1Ϯ0.04**
59.4Ϯ0.05**
45.34Ϯ0.06**
2.47Ϯ0.40
40.5Ϯ0.02**
40.5Ϯ0.04**
37.8Ϯ0.5**
37.8Ϯ0.06**
3.39Ϯ0.51
33.6Ϯ0.12**
31.8Ϯ0.02**
32.5Ϯ0.02**
30.2Ϯ0.03**
2.91Ϯ0.42
IV
Control
Standard
35.15Ϯ0.66**
42.44Ϯ0.28***
49.18Ϯ0.80***
36.19Ϯ0.86*
31.17Ϯ0.12*
27.92Ϯ0.13*
Significance levels: * pϽ0.5, ** pϽ0.01 and *** pϽ0.001.
3
-substituted quinazolines.
The results of anti-inflammatory activity revealed that all
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4
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diclofenac sodium, whereas the compound IV is comparably
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