Design and synthesis of new 1,3-benzdiazinan-4-one derivatives as selective cyclooxygenase (COX-2) inhibitors

Article abstract of DOI:10.1002/ardp.201100138

A new group of regioisomeric 2,3-diaryl-1,3-benzdiazinan-4-ones, possessing a methyl sulfonyl pharmacophore, were synthesized and their biological activities were tested for cyclooxygenase-2 (COX-2) inhibitory activity. In vitro COX-1/COX-2 inhibition stu

Full text of DOI:10.1002/ardp.201100138

Arch. Pharm. Chem. Life Sci. 2012, 345, 257–264
257
Full Paper
Design and Synthesis of New 1,3-Benzdiazinan-4-one
Derivatives as Selective Cyclooxygenase (COX-2) Inhibitors
Afshin Zarghi1, Tannaz Zebardast1, Fatemeh Hajighasemali2, Eskandar Alipoor2, Bahram Daraie3,
and Mehdi Hedayati4
1 Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical
Sciences, Tehran, Iran
2 Department of Chemistry, Azad University, North branch Tehran, Tehran, Iran
3 Department of Toxicology, Tarbiat Modarres University, Tehran, Iran
4 Endocrine research center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
A new group of regioisomeric 2,3-diaryl-1,3-benzdiazinan-4-ones, possessing a methyl sulfonyl
pharmacophore, were synthesized and their biological activities were tested for cyclooxygenase-2
(COX-2) inhibitory activity. In vitro COX-1/COX-2 inhibition studies identified 3-(p-fluorophenyl)-2-(4-
methylsulfonylphenyl)-1,3-benzdiazinane-4-one (2b) as a potent and highly selective (IC50 ¼ 0.07 mM;
selectivity index ¼ 572.8) COX-2 inhibitor.
Keywords: 1,3-Benzdiazinan-4-ones / COX-2 inhibition / Docking studies / SAR
Received: April 11, 2011; Revised: September 27, 2011; Accepted: September 30, 2011
DOI 10.1002/ardp.201100138
Introduction
breast, lung and prostate cancers [5–8] and neurodegenera-
tive diseases such as Parkinson [9] and Alzheimer’s [10] dis-
ease. Selective COX-2 inhibitors frequently belong to a class of
tricycles that possess vicinal diaryl moieties attached to a
central ring scaffold in conjunction with a COX-2 pharma-
cophore such as a para-SO2NH2, a para-SO2Me, substituent on
one of the phenyl rings [11]. Celecoxib and rofecoxib are two
typical selective COX-2 inhibitors in this class (COXIBs).
However, the market withdrawal of some COXIBs such as
rofecoxib due to their increasing the risk of heart attack and
cardiovascular side effects [12] encourages the researchers to
explore new selective COX-2 inhibitors to evaluate their
effects and may improve the safety profiles. For this reason
novel scaffolds with high selectivity for COX-2 inhibition
need to be found and evaluated for their biological activities.
In this regard, we recently reported several investigations
describing the design, synthesis, and COX inhibitory activi-
ties of new compounds possessing a bicyclic 1,3-benzthia-
zinan (A) [13] or quinoline (B) [14, 15] structural template
(Fig. 1). Our results showed that both 1,3-benzthiazinan and
quinoline rings are very suitable scaffolds for COX-2 inhibi-
tory activity and some of these synthesized compounds
exhibited high potency and selectivity on COX-2 inhibition
even more than the reference drug celecoxib. As part of our
research program, aimed at discovering new selective COX-2
inhibitors, we focused our attention on the synthesis, COX
inhibitory acitivity and some molecular modeling studies of
The cyclooxygenase (COX) enzymes catalyze a key step in the
conversion of arachidonate to PGH2, the immediate sub-
strate for a series of cell specific prostaglandin and throm-
boxane synthases. At least two COX isoforms have been
identified thus far: the constitutively expressed COX-1 and
COX-2, which is inducible under pathologic conditions and of
which increased concentrations have been observed in
inflamed and tumorous tissues [1, 2]. In addition to COX-1
and COX-2, a third isoform of COX enzyme (COX-3) has been
also identified. It is considered to play a key role in the
biosynthesis of prostanoids known to be important
mediators in pain and fever [3]. It is known that selective
COX-2 inhibitors can provide anti-inflammatory agents
devoid of the undesirable gastro-intestinal side effects [4].
In addition to the role of COX-2 in inflammatory disorders
such as rheumatoid arthritis and osteoarthritis, it is also
implicated in cancer and angiogenesis. In this regard, several
epidemiologic studies have reported that inhibitors of COX-2
enzyme reduce the risk of several cancer types such as colon,
Correspondence: Afshin Zarghi, Department of Pharmaceutical
Chemistry, School of Pharmacy, Shahid Beheshti University of Medical
Sciences, P.O. Box: 14155-6153, Tehran, Iran.
E-mail: azarghi@yahoo.com
Fax: þ98-21-88665341
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258
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Arch. Pharm. Chem. Life Sci. 2012, 345, 257–264
Me
SO2NH2
SO2Me
N
N
O
O
F3C
Rofecoxib
Celecoxib
SO2Me
SO2Me
N
HOOC
O
N
S
A
B
R2
R1
N
O
NH
Figure 1. Some representative examples of
COXIBs (celecoxib and rofecoxib), 1,3-
benzthiazinane-4-one
(A),
quinoline-4-
caboxylic acid (B) lead compounds and our
Designed compounds
1,3-benzdiazinan-4-one scaffolds.
a new group of regioisomeric 2,3-diaryl-1,3-benzdiazinan-4-
ones. The rationale for the design of these compounds was
based on hybrid structure of 2,3-diaryl-1,3-benzthiazinan-4-
ones and 2,3-diaryl-quinolines in our previously reported
COX-2 inhibitors.
anhydride, aldehyde and primary amine in ethanol using
alum (KAl(SO4)2.12H2O) as catalyst was used to prepare 1,3-
bendiazinan-4-ones (1 or 3; yield: 14–30%) [16]. Presumably,
the reaction proceeds through condensation of isatoic anhy-
dride with primary amine followed by decarboxylation to
yield the corresponding 2-aminobenzamide. Then, conden-
sation of the aromatic aldehyde with the amino group of 2-
aminobenzamide gives the imine intermediate which under-
goes cyclization to afford the 1,3-bendiazinan-4-one product
[16]. The low yield of the product may be explained by the
possible formation of byproducts such as the reaction
between the amine and aldehye or low activity of starting
materials such as the aldehyde having electron donating
group. Oxidation of cyclic intermediate using 30% H2O2 in
Results and discussion
Chemistry
The two sets of 1,3-benzdiazinan-4-one regioisomers in
which the 4-methylsulfonylphenyl substituent is attached
to C-2 (2a–e) or to N-3 (4a–e), were synthesized via the
route outlined in Scheme 1. Accordingly, a one-pot three-
component cyclocondensation of
a mixture of isatoic
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Arch. Pharm. Chem. Life Sci. 2012, 345, 257–264
COX-2 inhibitory activity of 1,3-benzdiazinan-4-ones
259
R1
CHO
NH2
O
O
O
N
a
+
+
N
H
O
N
H
SMe
R1
SMe
1a; R1=H
1b; R1=F
1c; R1=Cl
1d; R1=Me
1e; R1=OMe
R1
O
N
b
N
H
2a; R1=H
SO2Me
2b; R1=F
2c; R1=Cl
2d; R1=Me
2e; R1=OMe
SMe
CHO
NH2
O
O
O
N
a
+
+
N
H
O
N
H
R2
SMe
R2
3a; R2=H
3b; R2=F
3c; R2=Cl
3d; R2=Me
3e; R2=OMe
SO2Me
O
N
b
N
H
4a; R2=H
R2
4b; R2=F
4c; R2=Cl
4d; R2=Me
4e; R2=OMe
Scheme 1. Reagents and conditions: (a) Alum, EtOH, reflux, 1 h; (b) H2O2 30%, WO3, 258C, 4–5 h.
hydromethanol in the presence of a trace amount of WO3
corresponding regioisomers (4a–e), were synthesized to inves-
tigate the effect of these substituents on COX-2 selectivity and
potency. The ability of the 1,3-benzdiazinan-4-ones to inhibit
the COX-1 and COX-2 isozymes was determined using chem-
iluminescent enzyme assays (see enzyme inhibition data in
Table 1) according to our previously reported method [18].
In vitro COX-1/COX-2 inhibition studies showed that all com-
pounds were selective inhibitors of the COX-2 isozyme with
gave the target products (2 or 4, yield: 22–36%) [17].
Biological evaluation
A group of 1,3-benzdiazinan-4-one derivatives having a
MeSO2 group at the para-position of the C-2 phenyl ring
containing a variety of substituents (H, F, Cl, Me, OMe)
at the para-position of the N-3 phenyl ring (2a–e), and the
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IC50 values in the highly potent 0.07 to 0.22 mM range, and
COX-2 selectivity indexes (S.I.) in the 95.0 to 572.8 range.
SAR data (IC50 mM values) acquired by determination of the
in vitro ability of the title compounds to inhibit the COX-1 and
COX-2 isozymes showed that the position of the COX-2
SO2Me pharmacophore and the nature of the para-substituents
on the C-2 or N-3 phenyl ring were either individual, or
collective, determinants of COX-2 inhibitory potency and selec-
tivity. In vitro COX-1/COX-2 inhibition studies showed that
compounds having a MeSO2 group at the para-position of
the C-2 phenyl ring (2a–e) were more selective COX-2 inhibitors
compared to their corresponding regioisomers (4a–e). These
data showed that the nature and size of substituent attached
to C-2 or N-3 of the 1,3-benzdiazinan-4-one ring influenced
both selectivity and potency for COX-2 inhibitory activity. Our
results indicated that the introduction of suitable substituents
such as F (2b) and OMe (2e) at the para-position of N-3 phenyl
ring increased both selectivity and potency for COX-2
inhibitory activity. The similar results were obtained for
their corresponding regioisomers (4b and 4e). However,
compounds having Cl substituent (2c and 4c) showed less
selectivity and potency for COX-2 isozyme. According to these
results, 3-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-1,3-benz-
diazinan-4-one 2b was the most potent (IC50 ¼ 0.07 mM),
and selective (S.I. ¼ 572.8), COX-2 inhibitor among the syn-
thesized compounds. It was more selective than celecoxib
(IC50 ¼ 0.06 mM; S.I. ¼ 405) in terms of COX-2 inhibitory
activity but showed less potency. These data suggest
that the compound 2b should inhibit the biosynthesis of
prostaglandins via the cyclooxgenase pathway at sites of
inflammation and be devoid of ulcerogenicity due to the
absence of COX-1 inhibition.
Molecular modeling studies
The orientation of the highly potent and selective COX-2
inhibitor, 3-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-1,3-
Table 1. In vitro COX-1 and COX-2 enzyme inhibition assay data 3–9.
R1
O
N
R2
NH
Compoud
R1
R2
IC50 (mM)a)
COX-2 S.I.b)
COX-1
COX-2
2a
2b
2c
2d
2e
4a
4b
4c
H
F
Cl
Me
OMe
SO2Me
SO2Me
SO2Me
SO2Me
SO2Me
SO2Me
SO2Me
SO2Me
SO2Me
SO2Me
H
F
Cl
Me
99.8
40.1
17.7
37.2
33.4
24.1
31.8
20.9
24.1
29.7
24.30
0.35
0.07
0.17
0.10
0.07
0.12
0.09
0.22
0.11
0.11
0.06
285.1
572.8
104.1
372.0
477.1
200.8
353.3
95.0
4d
4e
Celecoxib
219.1
270.0
405
OMe
a)
Values are means of two determinations acquired using an ovine COX-1/COX-2 assay kit and the deviation from the mean is <10% of
the mean value.
In vitro COX-2 selectivity.
b)
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Arch. Pharm. Chem. Life Sci. 2012, 345, 257–264
COX-2 inhibitory activity of 1,3-benzdiazinan-4-ones
261
Experimental
General
All chemicals and solvents used in this study were purchased
from Merck AG and Aldrich Chemical. Melting points were
determined with
a Thomas–Hoover capillary apparatus.
Infrared spectra were acquired using a Perkin Elmer Model
1420 spectrometer. A Bruker FT-500 MHz instrument (Bruker
Biosciences, USA) was used to acquire 1HNMR spectra with
TMS as internal standard. Chloroform-D and DMSO-D6 were
used as solvents. Coupling constant (J) values are estimated
in Hertz (Hz) and spin multiples are given as s (singlet),
d (double), t (triplet), q (quartet), m (multiplet), and br (broad).
The mass spectral measurements were performed on an
6410 Agilent LCMS triple quadrupole mass spectrometer
(LCMS) with an electrospray ionization (ESI) interface.
Microanalyses, determined for C and H, were within ꢀ 0.4% of
theoretical values.
General procedure for preparation of 2,3-diaryl-1,3-
benzdiazinan-4-one (1a–e and 3a–e)
Alum (0.2 g) was added to a mixture of isatoic anhydride
(1 mmol), aldehyde (1 mmol) and primary amine (1.1 mmol)
in ethanol. The mixture was heated at reflux for 1 h. After
completion of the reaction, the solid 1,3-bendiazinan (1 or 3)
was separated, washed with water and recrystallized from
ethanol (yields: 14–30%). The physical and spectral data for
1a–e and 3a–e are listed below.
Figure 2. Compound 2b 3-(p-fluorophenyl)-2-(4-methylsulfonyl-
phenyl)-1,3-benzdiazinan-4-one docked in the active site of murine
COX-2 isozyme..
benzdiazinan-4-one 2b in the COX-2 active site was examined
by a docking experiment (Fig. 2) [19, 20]. This molecular
modeling shows that it binds in the primary binding site
such that the C-2 para-SO2Me substituent inserts into
the secondary pocket present in the COX-2 isozyme. One
of the O-atoms of p-SO2Me forms a hydrogen bonding
2-(4-Methylthiophenyl)-3-phenyl-1,3-benzdiazinan-4-one
(1a)
Yield, 20%; white crystalline powder, mp 202–2038Cþ; IR (KBr):
1
n cmꢁ1 3307 (NH), 1660 (C O); LCMS (ESI): 347.1 (Mþ1) ; HNMR
–
–
interaction with amino group of Arg513 (distance ¼ 2.9 A)
˚
(CDCl3) d ppm 2.48 (s, 3H, SMe), 6.09 (s, 1H, CH), 6.67 (d, 1H,
benzdiazinan H8, J ¼ 7.9 Hz), 6.94 (m, 1H, benzdiazinan H6),
7.16 (d, 2H, 4-methylthiophenyl H3 and H5, J ¼ 8.3 Hz), 7.22
(m, 1H, benzdiazinan H7), 7.23 (d, 2H, 4-methylthiophenyl H2
& H6, J ¼ 8.3 Hz), 7.30–7.36 (m, 5H, phenyl), 8.06 (d, 1H,
benzdiazinan H5, J ¼ 7.7 Hz); Anal. Calcd. for C21H18N2OS:
C, 72.80; H, 5.24; N, 8.09. Found: C, 72.99; H, 5.62; N, 8.31.
whereas the other O-atom is close to NH of His90 amino acid
˚
(distance ¼ 3.4 A). Also, the NH group of benzdiazinan
central ring is very close to carbonyl group of Gly519
˚
(distance ¼ 2 A) and can form hydrogen binding. In addition,
–
the C O of benzdiazinan-4-one ring is almost close to
–
(distance ¼ 5.4 A) NH of Tyr385. It was interesting to note
˚
that the para-fluoro substituent of N-3 phenyl ring was form-
ing a hydrogen bond with hydroxyl group (OH) of Tyr355
3-(4-Fluorophenyl)-2-(4-methylthiophenyl)-1,3-
benzdiazinan-4-one (1b)
˚
Yield, 22%; white crystalline powder, mp 242–2438C; IR (KBr):
(distance ¼ 4.8 A). These observations together with exper-
þ
n cmꢁ1 3312 (NH), 1642 (C O); LCMS (ESI): 365.1 (Mþ1) ;
–
–
imental results provide a good explanation for the potent
1HNMR (CDCl3) d ppm 2.49 (s, 3H, SMe), 6.07 (s, 1H, CH), 6.69
(d, 1H, benzdiazinan H8, J ¼ 7.9 Hz), 6.96 (m, 1H, benzdiazinan H6),
7.02 (t, 2H, 4-fluorophenyl H3 & H5, J ¼ 8.3 Hz), 7.15 (d, 2H,
4-methylthiophenyl H3 & H5, J ¼ 8.3 Hz), 7.18 (d, 4-methylthio-
phenyl H2 & H6, J ¼ 8.3 Hz), 7.28 (m, 1H, benzdiazinan H7),
7.42 (d, 2H, fluorophenyl H2 & H6, J ¼ 8.7 Hz), 8.05 (d, 1H,
benzdiazinan H5, J ¼ 7.7 Hz); Anal. Calcd. for C21H17FN2OS: C,
69.21; H, 4.70; N, 7.69. Found: C, 69.39; H, 4.42; N, 7.88.
and selective inhibitory activity of 2b.
Conclusions
The results of this investigation indicate that (i) the 1,3-
benzdiazinan-4-one moiety is a suitable scaffold (template)
to design COX-2 inhibitors, (ii) in this class of compounds
COX-1/-2 inhibition is sensitive to the position of the COX-2
SO2Me pharmacophore and the nature of the C-2 or N-3
phenyl substituents, and (iii) 3-(p-fluorophenyl)-2-(4-methyl-
sulfonylphenyl)-1,3-benzdiazinane-4-one (2b) is not only a
potent, but also a highly selective, COX-2 inhibitor.
3-(4-Chlorophenyl)-2-(4-methylthiophenyl)-1,3-
benzdiazinan-4-one (1c)
Yield, 20%; white crystalline powder, mp 230–2328Cþ; IR (KBr):
1
n cmꢁ1 3314 (NH), 1640 (C O); LCMS (ESI): 381.1 (Mþ1) ; HNMR
–
–
(CDCl3) d ppm 2.34 (s, 3H, SMe), 5.96 (s, 1H, CH), 6.03 (s, 1H, NH),
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6.61 (d, 1H, benzdiazinan H8, J ¼ 8.0 Hz), 6.72 (m, 1H,
2-(4-Chlorophenyl)-3-(4-methylthiophenyl)-1,3-
benzdiazinan-4-one (3c)
benzdiazinan H6), 7.02 (d, 2H, 4-chlorophenyl H2
&
H6,
H5,
J ¼ 8.3 Hz), 7.08 (d, 2H, 4-methylthiophenyl H3
&
Yield, 15%; white crystalline powder, mp 238.5–2408C; IR (KBr):
J ¼ 8.3 Hz), 7.15 (d, 4-methyl thiophenyl H2 and H6,
J ¼ 8.3 Hz), 7.19 (d, 2H, 4-chlorophenyl H3 and H5, J ¼ 8.7 Hz),
7.21 (m, 1H, benzdiazinan H7), 7.83 (d, 1H, benzdiazinan H5,
J ¼ 7.7 Hz); Anal. Calcd. for C21H17ClN2OS: C, 66.22; H, 4.50;
N, 7.35. Found: C, 66.49; H, 4.22; N, 7.68.
n cmꢁ1 3328 (NH), 1645 (C O); LCMS (ESI): 403.6 (Mþ23) ;
þ
–
–
1HNMR (CDCl3) d ppm 2.49 (s, 3H, SMe), 6.11 (s,1H, CH), 6.69
(d, 1H, benzdiazinan H8, J ¼ 7.9 Hz), 6.97 (m, 1H, benzdiazinan
H6), 7.13 (d, 2H, methylthiophenyl H3 & H5, J ¼ 8.6Hz), 7.21
(d, 2H, methylthiophenyl H2 & H6, J ¼ 8.6 Hz), 7.29 (d, 2H,
4-chlorophenyl H2 & H6, J ¼ 8.2 Hz), 7.32 (d, 2H, 4-chlorophenyl
H3 & H5, J ¼ 8.2 Hz), 7.36 (m, 1H, benzdiazinan H7), 8.06
(d, 1H, benzdiazinan H5, J ¼ 7.8 Hz); Anal. Calcd. for
C21H17ClN2OS: C, 66.22; H, 4.50; N, 7.35. Found: C, 65.95;
H, 4.75; N, 7.61.
3-(4-Methylphenyl)-2-(4-methylthiophenyl)-1,3-
benzdiazinan-4-one (1d)
Yield, 20%; white crystalline powder, mp 217–2188Cþ; IR (KBr):
1
n cmꢁ1 3298 (NH), 1633 (C O); LCMS (ESI): 361.1 (Mþ1) ; HNMR
–
–
(CDCl3) d ppm 2.27 (s, 3H, Me), 2.41 (s, 3H, SMe), 6.19 (s, 1H, CH),
6.72 (d, 2H, 4-methylphenyl H3 & H5, J ¼ 7.8 Hz), 7.14–7.16
(m, 3H, 4-methylphenyl H2 and H6 & benzdiazinan H8), 7.18
(d, 2H, 4-methylthiophenyl H3 & H5, J ¼ 8.4 Hz), 7.25 (m, 1H,
2-(4-Methylphenyl)-3-(4-methylthiophenyl)-1,3-
benzdiazinan-4-one (3d)
Yield, 20%; white crystalline powder, mp 217–2188C; IR (KBr):
n cmꢁ1 3298 (NH), 1633 (C O); LCMS (ESI): 361.1 (Mþ1) ;
þ
benzdiazinan H6), 7.30 (d, 4-methylthiophenyl H2
& H6,
–
–
1HNMR (CDCl3) d ppm 2.27 (s, 3H, Me), 2.41 (s, 3H, SMe),
J ¼ 8.4 Hz), 7.55 (m, 1H, benzdiazinan H7), 7.70 (d, 1H,
benzdiazinan H5, J ¼ 7.7 Hz); Anal. Calcd. for C22H20N2OS: C,
73.30; H, 5.59; N, 7.77. Found: C, 72.99; H, 5.32; N, 7.90.
6.19 (s, 1H, CH), 6.72 (d, 2H, 4-methylphenyl H3
& H5,
J ¼ 7.8 Hz), 7.14–7.16 (m, 3H, 4-methylphenyl H2 and H6
&
&
benzdiazinan H8), 7.18 (d, 2H, 4-methylthiophenyl H3
H5, J ¼ 8.4 Hz), 7.25 (m, 1H, benzdiazinan H6), 7.30
3-(4-Methoxyphenyl)-2-(4-methylthiophenyl)-1,3-
benzdiazinan-4-one (1e)
(d, 4-methylthiophenyl H2 & H6, J ¼ 8.4 Hz), 7.55 (m, 1H,
benzdiazinan H7), 7.70 (d, 1H, benzdiazinan H5, J ¼ 7.7 Hz);
Anal. Calcd. for C22H20N2OS: C, 73.30; H, 5.59; N, 7.77. Found:
C, 73.59; H, 5.88; N, 7.60.
Yield, 30%; white crystalline powder, mp 248–2508Cþ; IR (KBr):
1
n cmꢁ1 3295 (NH), 1632 (C O); LCMS (ESI): 377.1 (Mþ1) ; HNMR
–
–
(CDCl3) d ppm 2.36 (s, 3H, SMe), 3.72 (s, 3H, OMe), 6.16 (s, 1H, CH),
6.74 (d, 2H, 4-methoxyphenyl H3 & H5, J ¼ 7.9 Hz), 6.88 (d, 2H,
4-methylthiophenyl H3 & H5, J ¼ 8.4 Hz), 7.17 (d, 2H, 4-methyoxy-
phenyl H2 & H6, J ¼ 7.9 Hz), 7.25 (m, 1H, benzdiazinan H8), 7.25
(m, 1H, benzdiazinan H6), 7.29 (d, 4-methylthiophenyl H2 & H6,
J ¼ 8.4 Hz), 7.50 (m, 1H, benzdiazinan H7), 7.71 (d, 1H,
benzdiazinan H5, J ¼ 7.7 Hz); Anal. Calcd. for C22H20N2O2S: C,
70.19; H, 5.35; N, 7.44. Found: C, 70.39; H, 5.21; N, 7.53.
2-(4-Methoxyphenyl)-3-(4-methylthiophenyl)-1,3-
benzdiazinan-4-one (3e)
Yield, 15%; white crystalline powder, mp 199–2018C; IR (KBr):
n cmꢁ1 3307 (NH), 1638 (C O); LCMS (ESI): 377.4 (Mþ1) , 399.3
þ
–
–
(Mþþ23)þ; 1HNMR (DMSO-d6) d ppm 2.46 (s, 3H, SMe), 3.68 (s, 3H,
OMe), 6.19 (d, 1H, CH, J ¼ 2.1 Hz), 6.58 (m, 1H, benzdiazinan H8),
6.71 (m, 1H, benzdiazinan H6), 6.74 (d, 2H, 4-methoxyphenyl H3
& H5, J ¼ 7.9 Hz), 6.85 (d, 2H, methylthiophenyl H3 & H5,
3-(4-Methylthiophenyl)-2-phenyl-1,3-benzdiazinan-4-one
(3a)
J ¼ 8.2 Hz), 7.24 (d, 2H, 4-methyloxyphenyl H2
&
H6,
J ¼ 7.9 Hz), 7.29 (d, 2H, methylthiophenyl H2 & H6, J ¼ 8.2 Hz),
7.51 (d, 1H, NH, J ¼ 2.1 Hz) 7.59 (m, 1H, benzdiazinan H7), 7.71
(d, 1H, benzdiazinan H5, J ¼ 7.7 Hz); Anal. Calcd. for C22H20N2O2S:
C, 70.19; H, 5.35; N, 7.44. Found: C, 70.41; H, 5.66; N, 7.71.
Yield, 24%; white crystalline powder, mp 193.5–194.58C;þIR (KBr):
n cmꢁ1 3299 (NH), 1638 (C O); LCMS (ESI): 347.9 (Mþ1) , 369.8
–
–
(Mþ23)þ; 1HNMR (CDCl3) d ppm 2.47 (s, 3H, SMe), 4.78 (s, 1H, NH),
6.12 (s, 1H, CH), 6.67 (d, 1H, benzdiazinan H8, J ¼ 8 Hz), 6.93
(m, 1H, benzdiazinan H6), 7.14 (d, 2H, methylthiophenyl H3 & H5,
J ¼ 8.5 Hz), 7.2 (d, 2H, methylthiophenyl H2 & H6, J ¼ 8.5 Hz),
7.31–7.40 (m, 5H, phenyl H2 & H6 & 1H, benzdiazinan H7),
8.06 (d, 1H, benzdiazinan H5, J ¼ 7.7 Hz); Anal. Calcd. for
C21H18N2OS: C, 72.80; H, 5.24; N, 8.09. Found: C, 73.03; H,
5.42; N, 8.38.
General procedure for preparation of aryl-4-
methylsulfonylphenyl-1,3-benzdiazinan-4-one (2a–e and
4a–e)
0.5 g of 1 or 3 was dissolved in 10 mL methanol and 5 mL 30%
hydrogen peroxide solution and 100 mg WO3 as catalyst were
added. The mixture was stirred at room temperature for 5–
6 hours, after evaporation of methanol, the mixture was
extracted with ethyl acetate and dried with anhydrous sodium
sulfate and then evaporated, the product was recrystallized in
ethanol (yields: 22–36%). The physical and spectral data for 2a–e
and 4a–e are listed below.
2-(4-Fluorophenyl)-3-(4-methylthiophenyl)-1,3-
benzdiazinan-4-one (3b)
Yield, 14%; white crystalline powder, mp 191–1928C; IR (KBr):
þ
n cmꢁ1 3296 (NH), 1638 (C O); LCMS (ESI): 365.8 (Mþ1) , 387.7
–
–
(Mþ23)þ; 1HNMR (CDCl3) d 2.47 (s, 3H, SMe), 6.12 (s, 1H, CH),
6.69 (d, 1H, benzdiazinan H8, J ¼ 8 Hz), 6.95 (m, 1H, benzdia-
zinan H6), 6.99 (m, 2H, 4-fluorophenyl H2 & H6), 7.1 (d, 2H,
methylthiophenyl H3 & H5, J ¼ 8.6 Hz), 7.2 (d, 2H, methylthio-
phenyl H2 & H6, J ¼ 8.6 Hz), 7.35–7.39 (m, 3H, 4-fluorophenyl H3
& H5 & 1H, benzdiazinan H5); Anal. Calcd. for C21H17FN2OS:
C, 69.21; H, 4.70; N, 7.69. Found: C, 69.43; H, 4.99; N, 7.96.
2-(4-Methylsulfonylphenyl)-3-phenyl-1,3-benzdiazinan-4-
one (2a)
Yield, 30%; yellow crystalline powder, mp 175–1768C; IR (KBr):
n cmꢁ1 3298 (NH), 1645 (C O), 1320, 1165 (SO ); LCMS (ESI):
–
–
2
379.1 (Mþ1)þ; 1HNMR (CDCl3) d ppm 3.03 (s, 3H, SO2CH3),
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Arch. Pharm. Chem. Life Sci. 2012, 345, 257–264
COX-2 inhibitory activity of 1,3-benzdiazinan-4-ones
263
6.24 (s, 1H, CH), 6.73 (d, 1H, benzdiazinan H8, J ¼ 8.4 Hz), 6.98 (t,
1H, benzdiazinan H6, J ¼ 7.5 Hz), 7.25 (d, 2H, phenyl H3 & H5
J ¼ 7.9 Hz), 7.28 (m, 1H, benzdiazinan H7), 7.35–7.40 (m, 3H,
phenyl H3-H5), 7.62 (d, 2H, 4-methylsulfonylphenyl H2 & H6,
J ¼ 8.0 Hz), 7.89 (d, 2H, 4-methylsulfonylphenyl H3 & H5,
J ¼ 8.0 Hz), 8.07 (d, 1H, benzdiazinan H5, J ¼ 8.0 Hz); Anal.
Calcd. for C21H18N2O3S: C, 66.65; H, 4.79; N, 7.40. Found: C,
66.34; H, 4.62; N, 7.29.
(d, 2H, 4-methylsulfonylphenyl H3 & H5, J ¼ 8.3 Hz), 7.89 (d, 2H,
4-methylsulfonylphenyl H2 & H6, J ¼ 8.7 Hz), 8.07 (d, 1H,
benzdiazinan H5, J ¼ 6.1 Hz); Anal. Calcd. for C22H20N2O4S:
C, 64.59; H, 4.93; N, 6.86. Found: C, 64.77; H, 4.74; N, 6.95.
3-(4-Methylsulfonylphenyl)-2-phenyl-1,3-benzdiazinan-4-
one (4a)
Yield, 34%; yellow crystalline powder, mp 208–2098C; IR (KBr):
n cmꢁ1 3327 (NH), 1647 (C O), 1326, 1162 (SO ); LCMS (ESI): 401.7
–
–
2
3-(4-Fluorophenyl)-2-(4-methylsulfonylphenyl)-1,3-
benzdiazinan-4-one (2b)
(Mþ23)þ; 1HNMR (CDCl3) d ppm 3.21 (s, 3H, SO2CH3), 6.26 (s, 1H,
CH), 6.37 (m, 1H, benzdiazinan H6), 6.80 (d, 1H, benzdiazinan H8,
J ¼ 8.1 Hz), 7.29–7.32 (m, 3H, phenyl H3–H5), 7.35 (m, 1H,
benzdiazinan H7), 7.39 (d, 2H, phenyl H2 & H6 J ¼ 7.6 Hz), 7.58
(d, 2H, 4-methylsulfonylphenyl H2 & H6, J ¼ 8.7 Hz), 7.83 (d, 1H,
benzdiazinan H5, J ¼ 7.8 Hz), 7.87 (d, 1H, NH, J ¼ 2.9 Hz), 7 .90
(d, 2H, 4-methylsulfonylphenyl H3 & H5, J ¼ 8.7 Hz); Anal. Calcd.
for C21H18N2O3S: C, 66.65; H, 4.79; N, 7.40. Found: C, 66.29;
H, 4.51; N, 7.32.
Yield, 35%; cream crystalline powder, mp 215–2178C; IR (KBr):
n cmꢁ1 3400 (NH), 1610 (C O), 1300, 1150 (SO ); LCMS (ESI): 397.1
–
–
2
(Mþ1)þ; 1HNMR (CDCl3) d ppm 3.04 (s, 3H, SO2CH3), 4.9 (s, 1H,
NH), 6.20 (s, 1H, CH), 6.72 (d, 1H, benzdiazinan H8, J ¼ 8.0 Hz),
6.98 (t, 1H, benzdiazinan H6, J ¼ 7.5 Hz), 7.04 (t, 2H, 4-fluoro-
phenyl H3 & H5, J ¼ 8.4 Hz), 7.21 (dd, 2H, 4-fluorophenyl H2 & H6),
7.40 (m, 1H, benzdiazinan H7), 7.61 (d, 2H, 4-methylsulfonyl-
phenyl H2 & H6, J ¼ 8.2 Hz), 7.89 (d, 2H, 4-methylsulfonylphenyl
H3 & H5, J ¼ 8.2 Hz), 8.07 (d, 1H, benzdiazinan H5, J ¼ 6.7 Hz);
Anal. Calcd. for C21H17FN2O3S: C, 63.62; H, 4.32; N, 7.07. Found: C,
63.48; H, 4.12; N, 7.22.
2-(4-Fluorophenyl)-3-(4-methylsulfonylphenyl)-1,3-
benzdiazinan-4-one (4b)
Yield, 27%; yellow crystalline powder, mp 170–1718C; IR (KBr):
n cmꢁ1 3369 (NH), 1666 (C O), 1298, 1140 (SO ); LCMS (ESI): 419.3
–
3-(4-Chlorophenyl)-2-(4-methylsulfonylphenyl)-1,3-
benzdiazinan-4-one (2c)
Yield, 31%; cream crystalline powder, mp 191–1938C; IR (KBr):
–
2
(Mþ23)þ; 1HNMR (CDCl3) d ppm 3.21 (s, 3H, SO2CH3), 6.48 (s, 1H,
CH), 6.73 (m, 1H, benzdiazinan H6), 6.8 (d, 1H, benzdiazinan H8,
J ¼ 8.1 Hz), 7.16 (m, 2H, 4-fluorophenyl H3 & H5), 7.31 (m, 1H,
benzdiazinan H7), 7.42 (dd, 2H, 4-fluorophenyl H2 & H6), 7.56
(d, 2H, 4-methylsulfonylphenyl H2 & H6, J ¼ 8.7Hz), 7.74 (d, 1H,
benzdiazinan H5, J ¼ 7.8 Hz), 7.84 (d, 1H, NH, J ¼ 2.9 Hz), 7.89
(d, 2H, 4-methylsulfonylphenyl H3 & H5, J ¼ 8.7 Hz); Anal. Calcd.
for C21H17FN2O3S: C, 63.62; H, 4.32; N, 7.07. Found: C, 63.29;
H, 4.22; N, 7.12.
n cmꢁ1 3315 (NH), 1648 (C O), 1322, 1159 (SO ); LCMS (ESI): 413.1
–
–
2
(Mþ1)þ; HNMR (CDCl3) d ppm 3.20 (s, 3H, SO2CH3), 6.39 (s, 1H,
1
CH), 6.72 (d, 1H, benzdiazinan H8, J ¼ 8.1 Hz), 6.78 (t, 1H,
benzdiazinan H6, J ¼ 8.3 Hz), 7.12 (d, 2H, 4-chlorophenyl H2
&
H6, J ¼ 8.1 Hz), 7.25 (d, 2H, 4-chlorophenyl H3
& H5,
J ¼ 8.1 Hz), 7.30 (m, 1H, benzdiazinan H7), 7.56 (d, 2H, 4-
methylsulfonylphenyl H2 & H6, J ¼ 8.7 Hz), 7.80 (d, 1H, benzdia-
zinan H5, J ¼ 6.7 Hz), 7.87 (d, 2H, 4-methylsulfonylphenyl H3
& H5, J ¼ 8.7 Hz); Anal. Calcd. for C21H17ClN2O3S: C, 61.09;
H, 4.15; N, 6.78. Found: C, 59.87; H, 4.36; N, 6.88.
2-(4-Chlorophenyl)-3-(4-methylsulfonylphenyl)-1,3-
benzdiazinan-4-one (4c)
Yield, 22%; yellow crystalline powder, mp 220–2218C; IR (KBr):
n cmꢁ1 3338 (NH), 1650 (C O), 1294, 1147 (SO ); LCMS (ESI):
–
3-(4-Methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-
benzdiazinan-4-one (2d)
–
2
413.1 (Mþ1)þ, 435.1 (Mþ23)þ; 1HNMR (CDCl3) d ppm 3.21
(s, 3H, SO2Me), 6.48 (d, 1H, CH, J ¼ 3.1 Hz), 6.74 (m, 1H,
benzdiazinan H6), 6.8 (d, 1H, benzdiazinan H8, J ¼ 8.3 Hz),
7.31 (m, 1H, benzdiazinan H7), 7.4 (m, 4H, 4-chlorophenyl H2–
H6), 7.57 (d, 2H, 4-methyl sulfonylphenyl H2 & H6, J ¼ 8.7 Hz),
7.74 (d, 1H, benzdiazinan H5, J ¼ 7.8 Hz), 7.88 (d, 1H, NH,
Yield, 31%; cream crystalline powder, mp 181–1828C; IR (KBr):
n cmꢁ1 3312 (NH), 1632 (C O), 1315, 1151 (SO ); LCMS (ESI): 393.1
–
–
2
(Mþ1)þ; 1HNMR (CDCl3) d ppm 2.33 (s, 3H, CH3), 3.04 (s, 3H,
SO2CH3), 6.38 (s, 1H, CH), 6.69 (d, 1H, benzdiazinan H8,
J ¼ 8.1 Hz), 6.95 (t, 1H, benzdiazinan H6, J ¼ 7.5 Hz), 7.12
(d, 2H, 4-methylphenyl H3 & H5, J ¼ 8.4 Hz), 7.16 (d, 2H, 4-methyl-
phenyl H2 & H6, J ¼ 8.4 Hz), 7.36 (m, 1H, benzdiazinan H7), 7.59
(d, 2H, 4-methylsulfonylphenyl H2 & H6, J ¼ 8.3 Hz), 7.87 (d, 2H,
4-methylsulfonylphenyl H3 & H5, J ¼ 8.7 Hz), 8.04 (d, 1H,
benzdiazinan H5, J ¼ 6.6 Hz); Anal. Calcd. for C22H20N2O3S:
C, 67.33; H, 5.14; N, 7.14. Found: C, 67.30; H, 5.26; N, 7.22.
J ¼ 3.1 Hz), 7.9 (d, 2H, 4-methylsulfonylphenyl H3
& H5,
J ¼ 8.7 Hz); Anal. Calcd. for C21H17ClN2O3S: C, 61.09; H, 4.15;
N, 6.78. Found: C, 61.29; H, 4.29; N, 6.84.
2-(4-Methylphenyl)-3-(4-methylsulfonylphenyl)-1,3-
benzdiazinan-4-one (4d)
Yield, 24%; yellow crystalline powder, mp 177–1798C; IR (KBr):
n cmꢁ1 3038 (NH), 1670 (C O), 1326, 1158 (SO ); LCMS (ESI):
3-(4-Methoxyphenyl)-2-(4-methylsulfonylphenyl)-1,3-
benzdiazinan-4-one (2e)
–
–
2
415.6 (Mþ23)þ; 1HNMR (CDCl3) d ppm 2.22 (s, 3H, Me), 3.2
(s, 3H, SO2Me), 6.39 (d, 1H, CH, J ¼ 2.9 Hz), 6.72 (m, 1H,
benzdiazinan H6), 6.78 (d, 1H, benzdiazinan H8, J ¼ 8.1 Hz),
7.12 (d, 2H, 4-methylphenyl H3 & H5, J ¼ 8.0 Hz), 7.26 (d, 2H,
4-methylphenyl H2 & H6, J ¼ 8.0 Hz), 7.99 (m, 1H, benzdiazinan
H7), 7.56 (d, 2H, 4-methylsulfonylphenyl H2 & H6, J ¼ 8.7 Hz),
7.73 (d, 1H, benzdiazinan H5, J ¼ 7.7 Hz), 7.8 (d, 1H, NH,
J ¼ 2.9 Hz), 7.88 (d, 2H, 4-methylsulfonyl phenyl H3 & H5,
Yield, 30%; cream crystalline powder, mp 218–2208C; IR (KBr):
n cmꢁ1 3298 (NH), 1628 (C O), 1320, 1152 (SO ); LCMS (ESI):
–
–
2
409.1 (Mþ1)þ; 1HNMR (CDCl3) d ppm 3.05 (s, 3H, SO2CH3), 3.66
(s, 3H, OCH3), 6.18 (s, 1H, CH), 6.86 (d, 2H, 4-methoxyphenyl H3
& H5, J ¼ 8.9 Hz), 6.99 (d, 1H, benzdiazinan H8, J ¼ 8.1 Hz),
7.15 (d, 2H, 4-methoxyphenyl H2 & H6, J ¼ 8.9 Hz), 7.36 (t, 1H,
benzdiazinan H6, J ¼ 7.3 Hz), 7.57 (m, 1H, benzdiazinan H7), 7.60
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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264
A. Zarghi et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 257–264
J ¼ 8.7 Hz); Anal. Calcd. for C22H20N2O3S: C, 67.33; H, 5.14;
We like to thank Deputy of Research, School of Pharmacy, Shahid Beheshti
University of Medical Sciences for financial support of this work as part of
Ph.D thesis of Tannaz Zebardast.
N, 7.14. Found: C, 67.19; H, 5.31; N, 7.18.
2-(4-Methoxyphenyl)-3-(4-methylsulfonylphenyl)-1,3-
benzdiazinan-4-one (4e)
The authors have declared no conflict of interest.
Yield, 29%; yellow crystalline powder, mp 175–1768C; IR (KBr):
n cmꢁ1 3313 (NH), 1632 (C O), 1323, 1152 (SO ); LCMS (ESI): 409.6
–
–
2
(Mþ1)þ, 431.5 (Mþ23)þ; 1HNMR (CDCl3) d ppm 3.2 (s, 3H, SO2Me),
3.68 (s, 3H, OMe), 6.38 (d, 1H, CH, J ¼ 2.7 Hz), 6.72 (m, 1H,
benzdiazinan H6), 6.78 (d, 1H, benzdiazinan H8, J ¼ 8.1 Hz),
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˚
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˚
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ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com