Synthesis of 3-[4′-(p-chlorophenyl)-thiazol-2′-yl]-2-[(substituted azetidinone/thiazolidinone)-aminomethyl]-6-bromoquinazolin-4-ones as anti-inflammatory agent

Article abstract of DOI:10.1016/j.bmc.2007.01.042

N-Chloroacetyl-5-bromoanthranilic acid (1), 3-[4′-(p-chlorophenyl)-thiazol-2′-yl]-2-chloromethyl-6-bromoquinazolin-4-one (2), 3-[4′-(p-chlorophenyl)-thiazol-2′-yl]-2-hydrazinomethyl-6-bromoquinazolin-4-one (3), 3-[4′-(p-chlorophenyl)-thiazol-2′-yl]-2-subs

Full text of DOI:10.1016/j.bmc.2007.01.042

Bioorganic & Medicinal Chemistry 15 (2007) 3089–3096
Synthesis of 3-[40-(p-chlorophenyl)-thiazol-20-yl]-2-[(substituted
azetidinone/thiazolidinone)-aminomethyl]-6-bromoquinazolin-4-
ones as anti-inflammatory agent
Ashok Kumar,* Chatrasal Singh Rajput and Sudhir Kumar Bhati
Department of Pharmacology, L L R M Medical College, Meerut (UP) 250004, India
Received 5 October 2006; revised 23 January 2007; accepted 24 January 2007
Available online 26 January 2007
Abstract—N-Chloroacetyl-5-bromoanthranilic acid (1), 3-[40-(p-chlorophenyl)-thiazol-20-yl]-2-chloromethyl-6-bromoquinazolin-4-
one (2), 3-[40-(p-chlorophenyl)-thiazol-20-yl]-2-hydrazinomethyl-6-bromoquinazolin-4-one (3), 3-[40-(p-chlorophenyl)-thiazol-20-yl]-
2-substitutedbenzylidene aminomethyl-6-bromoquinazolin-4-ones (4–11), 2-[(40-oxo-30-chloro-20-phenylazetidin-10-yl)aminometh-
yl]-3-[400-(p-chlorophenyl)thiazol-200-yl]-6-bromoquinazolin-4-ones (12–19) and 2-(40-oxo-20-phenyl-thiazolidin-30-yl-aminomethyl)-
3-[400-(p-chlorophenyl)-thiazol-200-yl]-6-bromoquinazolin-4-ones (20–27) have been synthesized. All the compounds have been
screened for their anti-inflammatory and analgesic activities at the dose of 50 mg/kg po. Compound 21 showed maximum anti-in-
flammatory (38.35%) and analgesic (37.36%) activities. Compound 21 was also tested for ulcerogenic activity and the UD50 value
was found to be 195.6 mg/kg po. The structure of all compounds has been evaluated by elemental analysis (C, H, N) and spectral
1
analysis (IR, H NMR and mass spectrometry).
ꢀ 2007 Published by Elsevier Ltd.
1. Introduction
olinone derivatives by incorporating the thiazole moiety
at 3rd position, thiazolidinone and azetidinone moieties
at 2nd position of the quinazolinone nucleus. All the
compounds have been screened for their anti-inflamma-
tory, analgesic and ulcerogenic activities.
Quinazolinone nucleus has been gaining prominence
due to the fact that its derivatives have been found to
possess wide spectrum of activities like antibacterial,1,2
antifungal,3 anticonvulsant4 and anti-inflammatory.5–8
Furthermore, Medina et al.9 have patented quinazoli-
none derivative as anti-inflammatory drug. However,
we have also reported substituted quinazolinone10,11
derivatives as potent anti-inflammatory, analgesic and
COX-II inhibitors. Substitution pattern by different aryl
or heteroaryl moieties at 2/3 position12,13 of quinazoli-
none nucleus markedly influences anti-inflammatory
activities. Moreover, thiazolidinones,14–16 azetidinon-
es17,18 and thiazoles19–21 are other important pharmaco-
dynamic heterocyclic nuclei which when incorporated in
different heterocyclic templates have been reported to
possess potent anti-inflammatory activity. Therien
et al.22 and Roy et al.23 reported thiazole derivatives
as Selective COX-II inhibitors. In the light of the above
observation we have synthesized a new series of quinaz-
2. Results
2.1. Chemistry
The starting compound 5-bromoanthranilic acid was
prepared according to reported method by Wheeler
et al.24 Compound N-chloroacetyl-5-bromoanthranilic
acid (1) was synthesized by the reaction of 5-bromoanth-
ranilic acid with chloroacetylchloride in the presence of
dry benzene. Further on reaction with 2-amino-4-chlor-
ophenylthiazole,25 compound (1) yielded 3-[40-(p-chlor-
ophenyl)-thiazol-20-yl]-2-chloromethyl-6-bromoquinaz-
olin-4-one (2). Treatment of compound (2) with 99%
hydrazine hydrate afforded 3-[40-(p-chlorophenyl)-thia-
zol-20-yl]-2-hydrazinomethyl-6- bromoquinazolin-4-one
(3). Compound (3) on reaction with substituted benzal-
dehyde in ethanol gave 3-[40-(p-chlorophenyl)-thiazol-
20-yl]-2-substituted-benzylidenehydrazinomethyl-6-
bromoquinazolin-4-ones (4–11). 3-[40-(p-chlorophenyl)-
Keywords: Quinazolin-4-ones; Anti-inflammatory; Analgesic; Ulcero-
genic; Thiazole; Azetidinone; Thiazolidinone.
*
Corresponding author. Tel.: +91 121 2764084; fax: +91 121 2760888.
Part of Ph.D. thesis work.
0968-0896/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.bmc.2007.01.042

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A. Kumar et al. / Bioorg. Med. Chem. 15 (2007) 3089–3096
thiazol-20-yl]-2-[(400-oxo-200-substitutedphenyl-300-chloro-
azetidin-100-yl)aminomethyl]-6-bromo-quinazolin-4-ones
(12–19) have been synthesized by refluxing the com-
pounds (4–11) with chloroacetylchloride and trimethyla-
mine in the presence of dry benzene. Treatment of (4–
11) with thioglycolic acid in the presence of anhydrous
ZnCl2 afforded 3-[40-(p-chlorophenyl)-thiazol-20-yl]-2-
[(400-oxo-200-substitutedphenyl-thiazolidin-300-yl)amino-
methyl]-6- bromo quinazolin-4-ones (20–27). The
structure of all these newly synthesized compounds
was confirmed by their spectral (IR, 1H NMR and mass)
and analytical data. The compounds were evaluated for
their anti-inflammatory, analgesic and ulcerogenic
activities.
2.2. Discussion
All newly synthesized quinazolinone derivatives 4–27
have been tested for their anti-inflammatory activity of
varying degree from 17.88% to 38.35% at a dose of
50 mg/kg per oral and the biological results are given
in Table 1.

A. Kumar et al. / Bioorg. Med. Chem. 15 (2007) 3089–3096
Table 1. Pharmacological evaluation of compounds 4–27
3091
Compound
R
Anti-inflammatory activity
Analgesic activity
UD50
mg/kg ip
Acute toxicity
ALD50 mg/kg po
Dose
(mg/kg po)
% Oedema inhibitor
relation
Dose
(mg/kg po)
% Protection
4
5
H
o-Cl
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
25
50
100
50
50
50
50
50
50
25
50
100
18.75
26.44
25.12
24.66
23.29
17.88
20.23
19.14
29.16
34.21
33.07
32.45
31.67
28.55
30.65
29.88
33.88
17.84
38.35
67.45
37.06
36.98
36.11
32.89
35.13
34.25
18.46
38.90
66.58
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
25
50
100
50
50
50
50
50
50
25
50
100
17.12
24.68
23.42
22.18
21.69
16.84
18.96
18.52
28.59
34.11
32.62
31.89
30.67
27.35
29.92
29.12
32.45
14.22
37.36
61.12
36.26
35.43
34.27
28.76
333.02
32.87
16.30
36.50
60.23
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
195.6
—
—
—
—
—
—
—
—
66.6
—
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
6
p-Cl
7
o-OCH3
p-OCH3
p-N(CH3)2
p-OH
p-CH3
H
8
9
10
11
12
13
14
15
16
17
18
19
20
21
o-Cl
p-Cl
o-OCH3
p-OCH3
p-N(CH3)2
p-OH
p-CH3
H
o-Cl
>1000
22
23
24
25
26
27
p-Cl
>1000
>1000
>1000
>1000
>1000
>1000
o-OCH3
p-OCH3
p-N(CH3)2
p-OH
p-CH3
Phenyl-butazone
—
—
The compounds (4–11) of this series are characterized
by the presence of azomethene linkage between 2-ami-
nomethyl-3-[40-(p-chlorophenyl)-thiazol-20-yl]-6-bromo-
quinazolinone and substituted phenyl ring. All the nine
compounds of this step have shown varying degree
from 17.88% to 26.44% of anti-inflammatory and
16.84% to 24.68% of analgesic activities. Compound
5, which was substituted with chloro group at 2-posi-
tion of phenyl ring, showed good anti-inflammatory
activity (26.44%) and was also associated with 24.68%
analgesic activity. Compound 6, which is substituted
with chloro phenyl ring, has shown a lesser degree of
anti-inflammatory and analgesic activity in comparison
to ortho-chloro isomer. The second step compounds
are divided into two groups. The first group com-
pounds (12–19) are characterized by the presence of
azetidinone ring (4-membered heterocyclic ring). These
compounds have shown better anti-inflammatory
(28.55–34.21%) and analgesic (27.35–34.11%) activities.
Out of these nine compounds, compound 13 has shown
34.21% anti-inflammatory activity and is associated
with almost the same degree of analgesic (34.11%)
activity. The second group compounds (20–27) are
characterized by the presence of thiazolidinone ring
(5-membered heterocyclic ring) and have shown much
better both types of activity at 50 mg/kg po as com-
pared to their parent compounds (4–11) and the com-
pounds (12–19). Interestingly, Compound 21 which
was substituted with chloro group at 2nd position of
phenyl ring, has shown almost equal anti-inflammatory
activity to that of phenylbutazone at 50 mg/kg po.
Compound 21 and reference drug phenylbutazone were
further tested at graded doses, that is, 25, 50 and
100 mg/kg po, and compound 21 showed almost equal
percentage of anti-inflammatory activity at 25 and
50 mg/kg po while at 100 mg/kg po this compound
showed better anti-inflammatory activity than the stan-
dard drug. On the contrary, this compound has shown
better analgesic activity at 50 and 100 mg/kg po, while
at 25 mg/kg po it has shown less activity than the stan-
dard drug.
The UD50 value of compound 21 and phenylbutazone is
195.6 and 66.6 mg/kg i.p., respectively. ALD50 value of
all the compounds is higher than 1000 mg/kg po suggest-
ing their good safety margin.
3. Experimental
3.1. Chemistry
Melting points were taken in open capillary tubes and
are uncorrected. Analytical data of C, H, N were within
0.4% of the theoretical values. IR spectra (cmꢀ1) were
recorded on Beckman-Acculab 10 spectrophotometer.
1H NMR spectra were determined in CDCl3 on Brucker
300-FT instrument.

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A. Kumar et al. / Bioorg. Med. Chem. 15 (2007) 3089–3096
3.1.1. N-Chloroacetyl-5bromoanthranilic acid (1). 5-
bromoanthranilic acid (0.01 mol) was dissolved in
100 mL of benzene with two or three drops of pyridine
and chloroacetylchloride (0.02 mol) was added in dry
benzene under cool condition and it was refluxed for
5 h, cooled and filtered. The solid thus obtained was
recrystallized from ethanol to give 1. (72%): mp
185 ꢁC. IR (KBr) mmax in cmꢀ1: 3490 (OH), 3125 (N–
H), 3020 (C–H aromatic), 1580 (C@C), 1690 (C@O),
2950 (aliphatic C–H), 570 (C–Br), 790(C–Cl); 1H
NMR (CDCl3) d in ppm: 3.90 (s, 2H, CH2–Cl), 6.80–
7.25 (m, 3H, Ar–H), 8.90 (s, 1H, NH exchangeable),
10.90 (s, 1H, COOH, exchangeable); Anal. calcd for
C9H7NO3BrCl: C, 36.92; H, 2.39; N,4.79. Found:
C,37.09; H, 2.40; N,4.83. MS: [M]+ at m/z 292.5.
C25H17N5OBrClS: C, 54.50; H, 3.09; N, 12.72. Found:
C, 54.64; H, 3.07; N, 12.69. MS: [M]+ at m/z 550.5.
The following compounds were prepared using a similar
procedure described for 4.
3.1.5. 2-[(o-Chlorobenzylidene)hydrazinomethyl]-3-[40-(p-
chlorophenyl)-thiazol-20-yl]-6-bromoquinazolin-4-one (5).
(60%) mp 208 ꢁC (ethanol) IR (KBr) mmax in cmꢀ1: 1265
(N–N), 3025 (C–H aromatic), 1595 (C@N), 1690
(C@O), 570 (C–Br), 690 (C–S–C), 3320 (N–H); 1H
NMR (CDCl3) d in ppm: 3.20 (d, 2H, CH2–NH), 5.52
(ss, 1H, –CH2–NH exchangeable), 6.80–8.06 (m, 12H,
11 proton Ar–H and 1 proton of thiazole), 8.16 (ss,
1H, N@CHAr); Anal. calcd for C25H16N5OBrCl2S: C,
51.28; H, 2.73; N, 11.97. Found: C, 51.32; H, 2.68; N,
12.05. MS: [M]+ at m/z 585.
3.1.2. 2-Chloromethyl-3-[40-(p-chlorophenyl)-thiazol-20-yl]-
6-bromoquinazolin-4-one (2). N-Chloroacetyl-5-bromo-
anthranilic acid (0.01 mol) was refluxed for 2 h with
4-chlorophenylthiazole in the presence of 13 g K2CO3
in 100 mL of benzene under anhydrous condition. The
reaction mixture was distilled and the residue was
washed with hot water and the solid thus obtained
was recrystallized from acetone to give 2 (55%): mp
210 ꢁC; IR (KBr) mmax in cmꢀ1: 1600 (C@N), 1690
(C@O), 3030 (C–H aromatic), 2955 (aliphatic C–H),
690 (C–S–C), 575 (C–Br), 795 (C–Cl); 1H NMR
(CDCl3) d in ppm: 3.93 (s, 2H, CH2–Cl), 6.86–7.85 (m,
8H, 7 proton Ar–H and 1 proton of thiazole); Anal.
calcd for C18H10N3OBrCl2S: C, 46.25; H, 2.12; N, 8.99.
Found: C, 46.41; H, 2.12; N, 9.07. MS: [M]+ at m/z 467.
3.1.6. 2-[(p-Chlorobenzylidene)hydrazinomethyl]-3-[40-(p-
chlorophenyl)-thiazol-20-yl]-6-bromoquinazolin-4-one (6).
(58%) mp 223 ꢁC (methanol) IR (KBr) mmax in cmꢀ1
:
1260 (N–N), 3025 (C–H aromatic), 1590 (C@N), 1680
(C@O), 574 (C–Br), 685 (C–S–C), 3320 (N–H), 1H
NMR (CDCl3) d in ppm: 3.25 (d, 2H, CH2–NH), 5.56
(ss, 1H, –CH2–NH exchangeable), 6.85–8.09 (m, 12H,
11 proton Ar–H and 1 proton of thiazole), 8.20 (ss,
1H, N@CHAr); Anal. calcd for C25H16N5OBrCl2S: C,
51.28; H, 2.73; N, 11.97. Found: C, 51.37; H, 2.74; N,
11.94. MS: [M]+ at m/z 585.
3.1.7. 2-[(o-Methoxybenzylidene)hydrazinomethyl]-3-[40-
(p-chlorophenyl)-thiazol-20-yl]-6-bromoquinazolin-4-one
(7). (67%) mp 225 ꢁC (benzene) IR (KBr) mmax in cmꢀ1
:
3.1.3. 2-Hydrazinomethyl-3-[40-(p-chlorophenyl)-thiazol-
20-yl]-6-bromoquinazolin-4-one (3). A mixture of com-
pound 2 (0.01 mol) and hydrazine hydrate (99%,
0.02 mol) in ethanol (50 mL) was refluxed for 10 h.
The excess solvent was distilled off. On cooling, a crys-
talline solid obtained, which was recrystallized from
methanol to yield 3 (62%): mp 193 ꢁC; IR (KBr) mmax
in cmꢀ1: 1260 (N–N), 1590 (C@N), 1690 (C@O), 3025
(C–H aromatic), 2955 (aliphatic C–H), 690 (C–S–C),
1170 (C–O–C), 1265 (N–N), 3020 (C–H aromatic), 1595
(C@N), 1690 (C@O), 570 (C–Br), 680 (C–S–C), 3320
(N–H); 1H NMR (CDCl3) d in ppm: 3.18 (d, 2H,
CH2–NH), 3.39 (s, 3H, OCH3), 5.60 (ss, 1H, CH2–NH
exchangeable), 6.82–8.06 (m, 12H, 11 proton Ar–H
and 1 proton of thiazole), 8.26 (ss, 1H, N@CHAr);
Anal. calcd for C26H19N5O2BrClS: C, 53.75; H, 3.27;
N, 12.06. Found: C, 53.91; H, 3.25; N, 12.09 MS:
[M]+ at m/z 580.5.
1
570 (C–Br), 3350 (NH); H NMR (CDCl3) d in ppm:
3.20 (d, 2H, CH2–NH), 4.35 (br s, 2H, NH–NH2
exchangeable), 6.80–7.90 (m, 8H, 7 proton Ar–H and
1 proton of thiazole), 8.15 (s, 1H, NH–NH2 exchange-
able); Anal. calcd for C18H13N5OBrClS: C, 46.70; H,
2.81; N, 15.13. Found: C, 46.89; H, 2.83; N, 15.18.
MS: [M]+ at m/z 462.5.
3.1.8. 2-[(p-Methoxybenzylidene)hydrazinomethyl]-3-[40-
(p-chlorophenyl)-thiazol-20-yl]-6-bromoquinazolin-4-one
(8). (60%) mp 231 ꢁC (methanol) IR (KBr) mmax in cmꢀ1
:
1174 (C–O–C), 1268 (N–N), 3020 (C–H aromatic), 1590
(C@N), 1690 (C@O), 576 (C–Br), 680 (C–S–C), 3325
(N–H); 1H NMR (CDCl3) d in ppm: 3.22 (d, 2H,
CH2–NH), 3.35 (s, 3H, OCH3), 5.60 (ss, 1H, –CH2–
NH exchangeable), 6.85–8.05 (m, 12H, 11 proton Ar–
H and 1 proton of thiazole), 8.23 (ss, 1H, N@CHAr);
Anal. calcd for C26H19N5O2BrClS: C, 53.75; H, 3.27;
N, 12.06. Found: C, 53.85; H, 3.29; N, 12.03. MS:
[M]+ at m/z 580.5.
3.1.4. 2-Benzylidenehydrazinomethyl-3-[40-(p-chlorophe-
nyl)-thiazol-20-yl]-6-bromoquinazolin-4-one (4). A mix-
ture of compound 3 (0.01 mol) and benzaldehyde
(0.01 mol) was dissolved in absolute ethanol (50 mL)
in the presence of few drops of glacial acetic acid. The
reaction mixture was refluxed for 8 h and poured onto
crushed ice and the resultant solid was recrystallized
from ethanol to yield 4. (65%): mp 208 ꢁC, IR (KBr)
mmax in cmꢀ1: 1265 (N–N), 3020 (C–H aromatic), 1600
(C@N), 1695 (C@O), 576 (C–Br), 695 (C–S–C), 3320
(N–H); 1H NMR (CDCl3) d in ppm: 3.18 (d, 2H,
CH2–NH), 5.48 (ss, 1H, –CH2–NH exchangeable),
6.85–8.05 (m, 13H, 12 proton Ar–H and 1 proton of
thiazole,), 8.20 (ss, 1H, N@CHAr); Anal. calcd for
3.1.9. 2-[(p-Dimethylaminobenzylidene)hydrazinomethyl]-
3-[40-(p-chlorophenyl)-thiazol-20-yl]-6-bromoquinazolin-4-
one (9). (65%) mp 216 ꢁC (DMF/water), IR (KBr) mmax
in cmꢀ1: 1270 (N–N), 3020 (C–H aromatic), 1595
(C@N), 1690 (C@O), 680 (C–S–C), 565 (C–Br), 3330
1
(N–H); H NMR (CDCl3) d in ppm: 2.92 (s, 2 · 3H,
CH3), 3.22 (d, 2H, CH2–NH), 5.60 (ss, 1H, –CH2–NH
exchangeable), 6.85–8.10 (m, 12H, 11 proton Ar–H

A. Kumar et al. / Bioorg. Med. Chem. 15 (2007) 3089–3096
3093
and 1 proton of thiazole) 8.23 (ss, 1H, N@CHAr); Anal.
calcd for C27H22N6OBrClS: C, 54.59; H, 3.71; N, 14.15.
Found: C, 54.79; H, 3.73; N, 14.14. MS: [M]+ at m/z
593.5.
Ar–H and 1 proton of thiazole); Anal. calcd for
C27H17N5O2BrCl3S: C, 48.98; H, 2.57; N, 10.58. Found:
C, 49.05; H, 2.58; N, 10.63. MS: [M]+ at m/z 661.5.
3.1.14. 2-[(40-Oxo-30-chloro-20-{p-chlorophenyl}azetidin-
10-yl)aminomethyl]-3-[400-(p-chlorophenyl)thiazol-200-yl]-6-
bromoquinazolin-4-one (14). (53%) mp 258 ꢁC (benzene),
IR (KBr) mmax in cmꢀ1: 1260 (N–N), 3025 (C–H aromat-
ic), 1595 (C@N), 1695 (C@O), 575 (C–Br), 690(C–S–C),
3.1.10. 2-[(p-Hydroxybenzylidene)hydrazinomethyl]-3-[40-
(p-chlorophenyl)thiazol-20-yl]-6-bromoquinazolin-4-one
(10). (62%) mp 214 ꢁC (acetic acid), IR (KBr) mmax in
cmꢀ1: 3425 (OH), 1275 (N–N), 3020 (C–H aromatic),
1590 (C@N), 1690 (C@O), 570 (C–Br), 688 (C–S–C),
3325 (N–H); 1H NMR (CDCl3) d in ppm: 3.20 (d,
2H, CH2–NH), 5.68 (ss, 1H, –CH2–NH exchange-
able), 6.78–8.03 (m, 12H, 11 proton Ar–H and 1 pro-
ton of thiazole), 8.20 (ss, 1H, N@CHAr), 12.40 (s, 1H,
OH); Anal. calcd for C25H17N5O2BrClS: C, 52.96; H,
3.00; N, 12.36. Found: C, 53.06; H, 2.98; N, 12.40.
MS: [M]+ at m/z 566.5.
1
3325 (N–H), 675 (C–Cl); H NMR (CDCl3) d in ppm:
3.20 (d, 2H, CH2–NH), 4.63 (d, 1H, CH–Cl), 5.56 (ss,
1H, –CH2–NH exchangeable), 5.98 (s, 1H, N–CHAr),
6.78–8.05 (m, 12H, 11 proton Ar–H and 1 proton of thi-
azole) 670 (C–Cl); Anal. calcd for C27H17N5O2BrCl3S:
C, 48.98; H, 2.57; N, 10.58. Found: C, 49.11; H, 2.55;
N, 10.57. MS: [M]+ at m/z 661.5.
3.1.15. 2-[(40-Oxo-30-chloro-20-{o-methoxyphenyl}azeti-
din-10-yl)aminomethyl]-3-[400-(p-chlorophenyl)thiazol-200-yl]-
6-bromoquinazolin-4-one (15). (56%) mp 272 ꢁC (etha-
nol), IR (KBr) mmax in cmꢀ1: 1170 (C–O–C), 1265
(N–N), 3020 (C–H aromatic), 1600 (C@N), 1690
(C@O), 570 (C–Br), 695 (C–S–C), 3320 (N–H), 1740
3.1.11. 2-[(p-Methoxybenzylidene)hydrazinomethyl]-3-[40-
(p-chlorophenyl)thiazol-20-yl]-6-bromoquinazolin-4-one
(11). (59%) mp 198 ꢁC (ethanol), IR (KBr) mmax in cmꢀ1
:
1275 (N–N), 3025 (C–H aromatic), 1590 (C@N), 1695
(C@O), 575 (C–Br), 685 (C–S–C), 3320 (N–H); 1H
NMR (CDCl3) d in ppm: 2.85 (s, 3H, CH3), 3.24 (d, 2H,
CH2–NH), 5.60 (ss, 1H, –CH2–NH, exchangeable),
6.70–80.5 (m, 12H, 11 proton Ar–H and 1 proton of thia-
zole), 8.25 (ss,1H, N@CHAr); Anal. calcd for
C26H19N5OBrClS: C, 55.27; H, 3.37; N, 12.40. Found:
C, 55.38; H, 3.41; N, 12.37. MS: [M]+ at m/z 564.5.
1
(C@O of b lactam); 675 (C–Cl); H NMR (CDCl3) d
in ppm: 3.39 (s, 3H, OCH3), 3.20 (d, 2H, CH2–NH),
4.60 (d, 1H, CH–Cl), 5.50 (ss, 1H, –CH2–NH, exchange-
able), 5.92 (s, 1H, N–CHAr), 6.60–8.03 (m, 12H, 11 pro-
ton Ar–H and 1 proton of thiazole); Anal. calcd for
C28H20N5O3BrCl2S: C, 51.14; H, 3.04; N, 10.65. Found:
C, 51.23; H, 3.06; N, 10.62. MS: [M]+ at m/z 657.
3.1.12. 2-[(40-Oxo-30-chloro-20- phenylazetidin-10-yl)-ami-
nomethyl]-3-[400-(p-chlorophenyl)-thiazol-200-yl]-6-bromo-
quinazolin-4-one (12). To a solution of compound 4
(0.01 mol) and triethylamine (5–6 drops) in dry benzene
(50 mL) was added in monochloroacetylchloride
(0.015 mol) at 50 ꢁC. The reaction mixture was stirred
for 40 min at room temperature and refluxed for 7 h.
The reaction mixture was filtered to remove triethyl-
amine hydrogen chloride and the resultant solution
was poured onto crushed ice with constant stirring.
The solid thus obtained was recrystallized from metha-
nol to yield desired compound 12 (55%), mp 224 ꢁC,
IR (KBr) mmax in cmꢀ1: 1260 (N–N), 3020 (C–H aromat-
ic), 1590 (C@N), 1695 (C@O), 572 (C–Br), 690 (C–S–C),
3.1.16. 2-[(40-Oxo-30-chloro-20-{p-methoxyphenyl}azeti-
din-10-yl)aminomethyl]-3-[400-(p-chlorophenyl)thiazol-200-yl]-
6-bromoquinazolin-4-one (16). (51%) mp 264 ꢁC (etha-
nol), IR (KBr) mmax in cmꢀ1: 1165 (C–O–C), 1265
(N–N), 3020 (C–H aromatic), 1600 (C@N), 1690
(C@O), 574 (C–Br), 698 (C–S–C), 3325 (N–H), 1745
1
(C@O of b lactam), 680 (C–Cl); H NMR (CDCl3) d
in ppm: 3.24 (d, 2H, CH2–NH), 3.35 (s, 3H, OCH3),
4.63 (d, 1H, CH–Cl), 5.48 (ss, 1H, –CH2–NH, exchange-
able), 5.98 (s, 1H, N–CHAr), 6.68-8.04 (m, 12H, 11 pro-
ton Ar–H and 1 proton of thiazole); Anal. calcd for
C28H20N5O3BrCl2S: C, 51.14; H, 3.04; N, 10.65. Found:
C, 51.26; H, 3.03; N, 10.65. MS: [M]+ at m/z 657.
1
3325 (N–H), 1740 (C@O of b lactam) 670 (C–Cl); H
NMR (CDCl3) d in ppm: 3.26 (d, 2H, CH2–NH), 4.60
(d, 1H, CH–Cl), 5.54 (ss, 1H, CH2–NH exchangeable),
5.95 (s, 1H, N–CHAr), 6.83–8.05 (m, 13H, 12 proton
Ar–H and 1 proton of thiazole); Anal. calcd for
C27H18N5O2BrCl2S: C, 51.67; H, 2.87; N, 11.16. Found:
C, 51.81; H, 2.86; N, 11.18. MS: [M]+ at m/z 627. The
following compounds were prepared using a similar pro-
cedure described for 12.
3.1.17. 2-[(40-Oxo-30-chloro-20-{p-diethylaminophenyl}azeti-
din-10-yl)aminomethyl]-3-[400-(p-chlorophenyl)thiazol-200-yl]-
6-bromoquinazolin-4-one (17). (53%) mp 257 ꢁC (metha-
nol), IR (KBr) mmax in cmꢀ1: 1265 (N–N), 3020 (C–H
aromatic), 1590 (C@N), 1700 (C@O), 570 (C–Br), 695
(C–S–C), 3325 (N–H), 1740 (C@O of b lactam), 675
1
(C–Cl); H NMR (CDCl3) d in ppm: 2.95 (s, 2 · 3H,
CH3), 3.20 (d, 2H, CH2–NH), 4.60 (d, 1H, CH–Cl),
5.40(ss, 1H, –CH2–NH exchangeable), 5.98 (s, 1H, N–
CHAr), 6.72–7.98 (m,12H, 11 proton Ar–H and 1 pro-
ton of thiazole); Anal. calcd for C29H23N6O2BrCl2S:
C, 51.94; H, 3.43; N, 12.54. Found: C, 51.32; H, 3.41;
N, 12.57. MS: [M]+ at m/z 670.
3.1.13. 2-[(40-Oxo-30-chloro-20-{o-chlorophenyl}-azetidin-
10-yl)aminomethyl]-3-[400-(p-chlorophenyl)thiazol-200-yl]-6-
bromoquinazolin-4-one (13). (50%) mp 261 ꢁC (acetone),
IR (KBr) mmax in cmꢀ1: 1260 (N–N), 3025 (C–H aromat-
ic), 1595 (C@N), 1695 (C@O), 570 (C–Br), 695 (C–S–C),
1
3320 (N–H), 1745 (C@O of b lactam) 675 (C–Cl); H
3.1.18. 2-[(40-Oxo-30-chloro-20-{p-hydroxyphenyl}azeti-
din-10-yl)aminomethyl]-3-[400-(p-chlorophenyl)thiazol-200-
yl]-6-bromoquinazolin-4-one (18). (50%), mp234 ꢁC
(DMF/water), IR (KBr) mmax in cmꢀ1: 3425 (OH),
NMR (CDCl3) d in ppm: 3.24 (d, 2H, CH2–NH), 4.60
(d, 1H, CH–Cl), 5.54 (ss, 1H, –CH2–NH exchangeable),
5.96 (s, 1H, N–CHAr), 6.75–7.98 (m, 12H, 11 proton

3094
A. Kumar et al. / Bioorg. Med. Chem. 15 (2007) 3089–3096
1265 (N–N), 3020 (C–H aromatic), 1590 (C@N), 1695
(C@O), 576 (C–Br), 695 (C–S–C), 3330 (N–H), 1735
1590 (C@N), 1690 (C@O), 570 (C–Br), 680 (C–S–C),
1
3325 (N–H), 1730 (C@O of b thialactam); H NMR
1
(C@O of b lactam), 675 (C–Cl); H NMR (CDCl3) d
(CDCl3) d in ppm: 2.80 (s, 2H, CH2–S), 3.35 (d, 2H,
CH2–NH), 5.35 (ss, 1H, –CH2–NH exchangeable),
5.98 (s, 1H, N–CHAr), 6.75–8.05 (m, 12H, 11 proton
Ar–H and 1 proton of thiazole); Anal. calcd for
C27H18N5O2BrCl2S2: C, 49.16; H, 2.73; N, 10.62.
Found: C, 49.27; H, 2.72; N, 10.64. MS: [M]+ at m/z 659.
in ppm: 3.24 (d, 2H, CH2–NH), 4.63 (d, 1H, CH–Cl),
5.38 (ss, 1H, –CH2–NH exchangeable), 5.95 (s, 1H, N–
CHAr), 6.82–8.08 (m, 12H, 11 proton Ar–H and 1 pro-
ton of thiazole), 12.45 (s, 1H, OH); Anal. calcd for
C27H18N5O3BrCl2S: C, 50.39; H, 2.80; N, 10.89. Found:
C, 50.53; H, 2.82; N, 10.91. MS: [M]+ at m/z 643.
3.1.23. 2-(40-Oxo-20(o-methoxyphenyl)-thiazolidin-30-yl-
aminomethyl)-3-[400-(p-chlorophenyl)-thiazol-200-yl]-6-bromo-
quinazolin-4-one (23). (48%) mp 249 ꢁC (ethanol), IR
(KBr) mmax in cmꢀ1: 1175 (C–O–C), 1250 (N–N), 3035
(C–H aromatic), 1590 (C@N), 1690 (C@O), 576 (C–Br),
675 (C–S–C), 3320 (N–H),1730 (C@O of b thialactam);
1H NMR (CDCl3) d in ppm: 2.84 (s, 2H, CH2–S), 3.36
(s, 3H, O–CH3), 3.44 (d, 2H, CH2–NH), 5.35 (ss, 1H,
CH2–NH exchangeable), 5.97 (s, 1H, N–CHAr), 6.83–8.02
(m, 12H, 11 proton Ar–H and 1 proton of thiazole); Anal.
calcd for C28H21N5O3BrClS2: C, 51.34; H, 3.21; N, 10.69.
Found: C, 51.53; H, 3.20; N, 10.52. MS: [M]+ at m/z 654.5.
3.1.19. 2-[(40-Oxo-30-chloro-20-{p-methylphenyl}azetidin-
10-yl)aminomethyl]-3-[400-(p-chlorophenyl)thiazol-200-yl]-6-
bromoquinazolin-4-one (19). (59%) mp 222 ꢁC (ethanol),
IR (KBr) mmax in cmꢀ1: 1260 (N–N), 3025 (C–H aromat-
ic), 1595 (C@N), 1695 (C@O), 572 (C–Br), 695(C–S–C),
1
3320 (N–H), 1740 (C@O of b lactam), 675 (C–Cl); H
NMR (CDCl3) d in ppm: 2.85 (s, 3H, CH3), 3.20 (d, 2H,
CH2–NH), 4.60 (d, 1H, CH–Cl), 5.32 (ss, 1H, –CH2–
NH, exchangeable), 5.98 (s, 1H, N–CHAr), 6.75–7.98
(m, 12H, 11 proton Ar–H and 1 proton of thiazole); Anal.
calcd for C28H20N5O2BrCl2S: C, 52.42; H, 3.12; N, 10.94.
Found: C, 52.54; H, 3.14; N, 10.96. MS: [M]+ at m/z 641.
3.1.24. 2-(40-Oxo-20(p-methoxyphenyl)-thiazolidin-30-yl-
aminomethyl)-3-[400-(p-chlorophenyl)-thiazol-200-yl]-6-bromo-
quinazolin-4-one (24). (53%) mp 252 ꢁC (ethanol), IR
(KBr) mmax in cmꢀ1: 1170 (C–O–C), 1250 (N–N),3035
(C–H aromatic), 1600 (C@N), 1690 (C@O), 570 (C–Br),
670 (C–S–C), 3322 (N–H), 1730 (C@O of b thialactam);
1H NMR (CDCl3) d in ppm: 2.86 (s, 2H, CH2–S), 3.32
(s, 3H, O–CH3), 3.46 (d, 2H, CH2–NH), 5.39 (ss, 1H,
–CH2–NH exchangeable), 5.96 (s, 1H, N–CHAr), 6.79–
8.03 (m,12H, 11 proton Ar–H and 1 proton of thiazole);
Anal. calcd for C28H21N5O3BrClS2: C, 51.34; H, 3.21;
N, 10.69. Found: C, 51.49; H, 3.23; N, 10.73. MS: [M]+
at m/z 654.5.
3.1.20. 2-(40-Oxo-20phenyl-thiazolidin-30-yl-aminometh-
yl)-3-[400-(p-chlorophenyl)-thiazol-200-yl]-6-bromoquinazo-
lin-4-one (20). A cool mixture of compound 4 (0.01 mol)
and anhydrous ZnCl2 (one pinch) in dry benzene
(50 mL), thiolactic/thioglycolic acid (0.02 mol) was
added dropwise with stirring at ambient temperature
and the reaction mixture was kept for 3 days at room
temperature and then refluxed for 14 h. The reaction
mixture was filtered. The filtrate was concentrated and
poured on crushed ice. The resultant solid was recrystal-
lized from ethanol to yield desired compound 20 (50%),
mp 231 ꢁC, IR (KBr) mmax in cmꢀ1: 1260 (N–N), 3030
(C–H aromatic), 1590 (C@N), 1700 (C@O), 572
(C–Br), 680 (C–S–C), 3330 (N–H), 1730 (C@O of b thi-
alactam); 1H NMR (CDCl3) d in ppm: 2.81 (s, 2H, CH2–
S), 3.30 (d, 2H, CH2–NH), 5.45(ss, 1H, –CH2–NH
exchangeable), 6.75–7.98 (m, 13H, 12 proton Ar–H
and 1 proton of thiazole), 5.92 (s, 1H, N–CHAr); Anal.
calcd for C27H19N5O2BrClS2: C, 51.88; H, 3.04; N,
11.21. Found: C, 51.99; H, 3.02; N, 11.24. MS: [M]+
at m/z 624.5. The following compounds were prepared
using a similar procedure described for 20.
3.1.25. 2-(40-Oxo-20(p-diethylaminophenyl)-thiazolidin-
30-yl-aminomethyl)-3-[400-(p-chlorophenyl)-thiazol-200-yl]-
6-bromoquinazolin-4-one (25). (51%) mp 228 ꢁC (DMF/
water), IR (KBr) mmax in cmꢀ1: 1255 (N–N), 3030
(C–H aromatic), 1605 (C@N), 1700 (C@O), 572 (C–
Br), 675(C–S–C), 3320 (N–H), 1725 (C@O of b thialac-
tam); 1H NMR (CDCl3) d in ppm: 2.83 (s, 2H, CH2–S),
2.95 (s, 2 · 3H, CH3), 3.34 (d, 2H, CH2–NH), 5.36 (ss,
1H, –CH2–NH exchangeable), 5.95 (s, 1H, N–CHAr),
6.85–8.05 (m,12H, 11 proton Ar–H and 1 proton of thi-
azole); Anal. calcd for C29H24N6O2BrClS2: C, 52.13; H,
3.59; N, 12.61. Found: C, 52.38; H, 3.60; N, 12.61. MS:
[M]+ at m/z 667.5.
3.1.21.
2-(40-Oxo-20(o-chlorophenyl)-thiazolidin-30-yl-
aminomethyl)-3-[400-(p-chlorophenyl)-thiazol-200-yl]-6-bromo-
quinazolin-4-one (21). (54%) mp 244 ꢁC (methanol), IR
(KBr) mmax in cmꢀ1: 1265 (N–N), 3025 (C–H aromatic),
1595 (C@N), 1690 (C@O), 570 (C–Br), 685 (C–S–C),
3.1.26. 2-(40-Oxo-20(p-hydoxyphenyl)-thiazolidin-30-yl-
aminomethyl)-3-[400-(p-chlorophenyl)-thiazol-200-yl]-6-bromo-
quinazolin-4-one (26). (45%) mp 226 ꢁC (acetic acid), IR
(KBr) mmax in cmꢀ1: 3420 (OH), 1250 (N–N), 3036 (C–H
aromatic), 1600 (C@N), 1690 (C@O), 570 (C–Br), 670
(C–S–C), 3325 (N–H), 1730 (C@O of b thialactam);
1H NMR (CDCl3) d in ppm: 2.83 (s, 2H, CH2–S), 3.36
(d, 2H, CH2–NH), 5.33 (ss, 1H, –CH2–NH exchange-
able), 5.94 (s, 1H, N–CHAr), 6.79–8.06 (m, 12H, 11 pro-
ton Ar–H and 1 proton of thiazole) 12.42 (s, 1H, OH);
Anal. calcd for C27H19N5O3BrClS2: C, 50.58; H, 2.97;
N, 10.93. Found: C, 50.82; H, 2.99; N, 10.91. MS:
[M]+ at m/z 640.5.
1
3325 (N–H), 1728 (C@O of b thialactam); H NMR
(CDCl3) d in ppm: 2.83 (s, 2H, CH2–S), 3.35 (d, 2H,
CH2–NH), 5.40 (ss, 1H, –CH2–NH exchangeable),
5.95 (s, 1H, N–CHAr), 6.65–7.98 (m, 12H, 11 proton
Ar–H and 1 proton of thiazole); Anal. calcd for
C27H18N5O2BrCl2S2: C, 49.16; H, 2.73; N, 10.62.
Found: C, 49.32; H, 2.74; N, 10.66. MS: [M]+ at m/z 659.
3.1.22.
2-(40-Oxo-20(p-chlorophenyl)-thiazolidin-30-yl-
aminomethyl)-3-[400-(p-chlorophenyl)-thiazol-200-yl]-6-bromo-
quinazolin-4-one (22). (49%) mp 239 ꢁC (benzene), IR
(KBr) mmax in cmꢀ1: 1260 (N–N), 3025 (C–H aromatic),

A. Kumar et al. / Bioorg. Med. Chem. 15 (2007) 3089–3096
3095
3.1.27. 2-(40-Oxo-20(p-methoxyphenyl)-thiazolidin-30-yl-
aminomethyl)-3-[400-(p-chlorophenyl)-thiazol-200-yl]-6-bromo-
quinazolin-4-one (27). (50%) mp 206 ꢁC (ethanol), IR
(KBr) mmax in cmꢀ1: 1255 (N–N), 3030 (C–H aromatic),
1595 (C@N), 11705 (C@O), 570 (C–Br), 670 (C–S–C),
3335 (N–H), 1740 (C@O of b thialactam); 1HNMR
(CDCl3) d in ppm: 2.76 (s, 3H, CH3), 2.88 (s, 2H,
CH2–S), 3.33 (d, 2H, CH2–NH), 5.38 (ss, 1H, –CH2–
NH exchangeable), 5.96 (s, 1H, N–CHAr), 6.72–7.98
(m, 12H, 11 proton Ar–H and 1 proton of thiazole);
Anal. calcd for C28H21N5O2BrClS2: C, 52.62; H, 3.29;
N, 10.96. Found: C, 52.84; H, 3.29; N, 11.01. MS:
[M]+ at m/z 638.5.
All animals were sacrificed 8 h after drug treatment
and then their stomachs and small intestines were micro-
scopically examined to assess the incidence of hypera-
emia, shedding of epithelium, petechial and frank
haemorrhages and erosion or discrete ulceration with
or without perforation. The presence of any one of these
criteria was considered to be an evidence of ulcerogenic
activity.
3.6. Acute toxicity study
Approximate lethal dose (ALD50) of compound was
determined in albino mice. After 24 h of drug adminis-
tration, percent mortality in each group was observed
and from the data obtained ALD50 was calculated by
the method of Smith.29
3.2. Pharmacological evaluation
The experiments were performed with albino rats of the
Charles-Foster strain of either sex, excluding pregnant
females, of 70–95 days weighing 100–150 g. Acute toxic-
ity was tested in albino mice (15–25 g). Food (chaw pal-
let) and water were given to the animals ad libitum. The
compounds were dissolved in propylene glycol. Phenyl-
butazone drug was used as reference drug.
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Percentage of inhibition of oedema
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3.4. Analgesic activity
Acetic acid writhing test was performed on mice by fol-
lowing the method of Davis at el.27 Test compounds
were given to the animals at the dose of 50 mg/kg,
30 min later the animals were injected interperitoneally
with 0.25 mL/mouse of 0.5% acetic acid. The mean num-
ber of writhes for each experimental group and percent-
age decrease compared with that of the control group
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3.5. Ulcerogenic activity
Ulcerogenic liabilities of newly synthesized compounds
were checked by the method of Verma et al.28 Albino
rats were fasted for 24 h prior to drug administration.
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