Synthesis and pharmacological evaluation of newer substituted benzoxazepine derivatives as potent anticonvulsant agents

Article abstract of DOI:10.1016/j.ejmech.2003.09.009

A series of 2-substitutedphenyl-3-(substitutedphenylamino)methyl-2,3- dihydro-4-diphenylamino-1,5-benzoxazepines (4a-4p) and 2-substitutedphenyl-3- substitutedphenylazo-2,3-dihydro-4-diphenylamino-1,5-benzoxazepines (5a-5p) have been synthesized from 2-substitutedphenyl-2,3-dihydro-4-diphenylamino-1,5- benzoxazepines (3a-3d) by the Mannich reaction and diazotization reaction, respectively. All these compounds were screened, in vivo, for their anticonvulsant activity and acute toxicity studies. Compounds 4p and 5p were found to be most potent compounds of this series and were compared with the reference drug phenytion sodium, lamotrigine and sodium valproate. The structures of these compounds have been established by IR, ¹H NMR and mass spectroscopic data.

Full text of DOI:10.1016/j.ejmech.2003.09.009

European Journal of Medicinal Chemistry 39 (2004) 369–376
www.elsevier.com/locate/ejmech
Short communication
Synthesis and pharmacological evaluation of newer substituted
benzoxazepine derivatives as potent anticonvulsant agents>
Kiran Bajaj,
Archana, Ashok Kumar *
Medicinal Chemistry Division, Department of Pharmacology,
Lala Lajpat Rai Memorial Medical College, Meerut, UP 250004, India
Received 22 April 2003; revised and accepted 22 September 2003
Abstract
A series of 2-substitutedphenyl-3-(substitutedphenylamino)methyl-2,3-dihydro-4-diphenylamino-1,5-benzoxazepines (4a–4p) and
2-substitutedphenyl-3-substitutedphenylazo-2,3-dihydro-4-diphenylamino-1,5-benzoxazepines (5a–5p) have been synthesized from
2-substitutedphenyl-2,3-dihydro-4-diphenylamino-1,5-benzoxazepines (3a–3d) by the Mannich reaction and diazotization reaction, respec-
tively. All these compounds were screened, in vivo, for their anticonvulsant activity and acute toxicity studies. Compounds 4p and 5p were
found to be most potent compounds of this series and were compared with the reference drug phenytion sodium, lamotrigine and sodium
valproate. The structures of these compounds have been established by IR, 1H NMR and mass spectroscopic data.
© 2003 Elsevier SAS. All rights reserved.
Keywords: Substituted benzoxazepines; Anticonvulsant activity; Acute toxicity
1. Introduction
N-acetyl-diphenylamine i.e. compound 1, which on further
reaction with different substituted aromatic aldehydes
yielded their corresponding N-substitutedphenyl-N,N-
diphenyl-propenamides i.e. compounds 2a–2d. Compounds
2a–2d on cyclization with 2-aminophenol in the presence
of glacial acetic acid gave 2-substitutedphenyl-4-
diphenylamino-2,3-dihydro-1,5-benzoxazepines i.e. com-
pounds 3a–3d. Compounds 3a–3d further undergoes Man-
nich reaction with different substituted anilines to afford
compounds 4a–4p. On the other hand, when compounds
3a–3d reacted with different aryldiazonium salts at 0–5 °C
yielded 2-substituted phenyl-3-substitutedphenylazo-4-
diphenylamino-2,3-dihydro-1,5-benzoxazepines i.e. com-
pounds 5a–5p.
Compounds containing a fused seven membered hetero-
cyclic ring i.e. benzoxazepines make up a broad class that
attracted attention in the past few years owing to its wide
range of biological activities especially anticonvulsant [1–4]
and CNS depressant activities [5,6]. In view of potential CNS
depressant and anticonvulsant activities of benzoxazepine
derivatives, we report herein the synthesis of some
new 2-substitutedphenyl-3-(substitutedphenylamino)methyl-
4-diphenylamino-2,3-dihydro-1,5-benzoxazepines and 2-
substitutedphenyl-3-substitutedphenylazo-4-diphenylamino-
2,3-dihydro-1,5-benzoxazepines along with their anticonvul-
sant profile.
The formation of compound 1 was confirmed by the
appearance of a sharp singlet at d 2.56, due to the three
protons of COCH3 group and a multiplet of 10 aromatic
protons at d 7.60–6.90 in the 1H NMR spectra.Appearance of
a band at 1640 cm–1 (C=O) and 1500 cm–1 (C–N) in the IR
spectrum of compound 1 also supported its structure. Ap-
pearance of a band between 1620 and 1625 cm–1 (CH=CH)
in the IR spectrum of compounds 2a–2d and appearance of a
doublet in between d 8.60 and d 8.65 for one proton
of =CH–Ar and an another doublet between d 6.60 and d
2. Chemistry
The synthetic routes of compounds are outlined in Fig. 1.
As shown in Fig. 1, the acetylation of diphenylamine yielded
> Part of the Ph.D. thesis.
* Corresponding author.
© 2003 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2003.09.009

370
K. Bajaj et al. / European Journal of Medicinal Chemistry 39 (2004) 369–376
triplet between d 4.25 and d 4.30 (1H, C2–H of oxazepine
NH
ring) and by the presence of a doublet between d 4.15 and d
4.25 (1H, C2–H of oxazepine) confirms the substitution at the
third position of oxazepine ring. Compounds 5a–5p exhib-
ited a band between 1410 and 1428 cm–1 (N=N) in the IR
spectrum which confirmed their synthesis.
CH3COCl
NCOCH3
3. Pharmacological results and discussion
1
R
CHO
All the newly synthesized compounds were tested in vivo in
order to evaluate their anticonvulsant activity. The pharmaco-
logical data of all the compounds of this series have been
reported in Table 3. These compounds were screened for their
anticonvulsant activity against maximal electroshock induced
seizures tested at 30 mg kg–1 i.p., exhibited substantive anti-
convulsant activity. The characteristic feature of this series is
the substitution by the different moieties at second and third
position of benzoxazepine ring. While evaluating the anticon-
vulsant activity, it was observed that compound 3a (having
phenyl group at second position of benzoxazepine ring showed
least activity (20%) while compound 3d (having 3-methoxy-
4-hydroxy phenyl ring) exhibited maximum response (40%)
in comparison to the other substituted compounds.
Further, the next step of this series was characterized by
the substitution at the third position of benzoxazepine ring by
different arylaminomethylene substitutions. All compounds
showed potent anticonvulsant activity, however, compound
4p (having 2-methoxy phenyl aminomethylene substitution
at third position of benzoxazepine ring) have shown most
potent response against MES test i.e. 90% protection which
is more potent and equipotent than standard drugs phenytoin
sodium and lamotrigine. Compounds 4d, 4h and 4l, also
having the same substitution at third position of benzoxaz-
pine ring, showed better response against MES model i.e.
50%, 50% and 70%, respectively, in comparison to the other
substituted derivatives. Moreover, compounds having chloro
substituted arylaminomethylene moieties have shown more
promising results in comparison to unsubstituted arylami-
nomethylene moiety (as shown in Table 3).
NCOCH CH
R
OH
(2a-2d)
NH2
N
N
O
(3a-3d)
R
NH2
N
NCl
R"
HCHO
R'
N
O
N
N
O
N
N
N
NHCH2
R
(5a-5p)
R"
R
(4a-4p)
R'
Fig. 1. Route for the synthesis of compounds.
6.68 for one proton of COCH= group in the 1H NMR spec-
trum, supported their formation. Cyclization of 2a–2d re-
sulted into compounds 3a–3d, was confirmed by the pres-
ence of a band between 1070 and 1120 cm–1 (C–O–C) in the
IR spectrum and appearance of a doublet of two protons of
C3–H2 of oxazepine ring in between d 3.20 and d 3.28 along
with a triplet of one proton of C2–H of oxazepine ring
between 4.25 and 4.30 in the 1H NMR spectrum. The struc-
ture of compounds 4a–4p was supported by the absence of a
On the other side, compounds 5a–5p, substituted with
different arylazo moieties at third position of benzoxazepine
ring, have shown varying degree (20–80%) of anticonvulsant
Table 1
Physical and analytical data of compounds 1, 2a–2d and 3a–3d
Compounds
R
m.p.
(°C)
Yield Recrystallization solvent Molecular
% elemental analysis
C calculated
(found)
(%)
formula
H calculated
(found)
N calculated
(found)
1
–
102
95
78
72
70
68
75
68
70
74
65
Ethanol
C
C
C
C
C
C
C
C
C
14H13NO
79.62 (79.58)
84.28 (84.24)
80.24 (80.20)
80.70 (80.74)
76.52 (76.48)
83.08 (83.12)
80.00 (80.04)
80.37 (80.33)
77.06 (77.10)
6.16 (6.20)
5.69 (5.73)
5.78 (5.82)
6.43 (6.39)
5.51 (5.47)
5.64 (5.60)
5.71 (5.75)
6.24 (6.20)
5.50 (5.54)
6.64 (6.60)
4.68 (4.72)
4.26 (4.22)
8.19 (8.15)
4.06 (4.10)
7.18 (7.14)
6.67 (6.62)
9.70 (9.74)
6.42 (6.46)
2a
2b
2c
2d
3a
3b
3c
3d
H
Methanol–water
Ethanol–water
Benzene–pet. ether
Ethanol
21H17NO
4-OCH3
4-N(CH3)2
3-OCH3, 4-OH
H
91
22H19NO2
23H22N2O
22H19NO3
27H22N2O
28H24N2O2
29H27N3O
28H24N2O3
82
80
104
100
96
Methanol
4-OCH3
4-N(CH3)2
3-OCH3, 4-OH
Acetic acid–water
Ethanol–water
Acetic acid–water
99

K. Bajaj et al. / European Journal of Medicinal Chemistry 39 (2004) 369–376
371
Table 2
Physical and analytical data of compounds 4a–4p and 5a–5p
Compounds R
R′
m.p. Yield Recrystallization
Molecular
formula
% elemental analysis
(°C) (%)
solvent
C calculated
(found)
H calculated
(found)
N calculated
(found)
4a
4b
4c
4d
4e
4f
4g
4h
4I
H
H
112
115
110
70
78
72
70
75
72
70
68
70
72
68
70
65
67
60
62
50
52
55
55
53
55
58
50
57
60
54
50
53
57
62
58
DMF–water
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
34H29N3O
82.42 (82.38)
77.05 (77.09)
77.05 (77.00)
80.00 (80.05)
80.00 (80.04)
75.07 (75.03)
75.07 (75.12)
77.84 (77.88)
80.30 (80.26)
75.46 (75.50)
75.46 (75.42)
78.17 (78.13)
77.63 (77.45)
72.98 (72.89)
72.98 (72.88)
75.66 (75.70)
80.16 (80.20)
74.93 (74.97)
74.93 (74.89)
77.86 (77.82)
77.86 (77.90)
73.05 (73.01)
73.05 (73.09)
75.81 (75.85)
78.21 (78.25)
73.49 (73.45)
73.49 (73.53)
76.19 (76.23)
75.55 (75.51)
71.02 (71.06)
71.02 (70.08)
73.68 (73.52)
5.86 (5.90)
5.29 (5.33)
5.29 (5.35)
5.90 (5.94)
5.90 (5.86)
5.36 (5.32)
5.36 (5.30)
5.95 (5.99)
6.32 (6.36)
5.76 (5.72)
5.76 (5.80)
6.34 (6.30)
5.73 (5.94)
5.21 (5.85)
5.21 (5.28)
5.78 (5.82)
5.26 (5.24)
4.73 (4.77)
4.73 (4.69)
5.34 (5.30)
5.34 (5.38)
4.83 (4.87)
4.83 (4.79)
5.42 (5.46)
5.77 (5.81)
5.25 (5.29)
5.25 (5.21)
5.82 (5.86)
5.19 (5.23)
4.70 (4.75)
4.70 (4.81)
5.26 (5.30)
8.48 (8.52)
7.93 (7.97)
7.93 (7.99)
8.00 (7.96)
8.00 (8.04)
7.51 (7.55)
7.51 (7.47)
7.57 (7.53)
10.41 (10.45)
9.78 (9.74)
9.78 (9.82)
9.86 (9.82)
7.76 (7.80)
7.30 (7.25)
7.30 (7.34)
7.36 (7.32)
11.34 (11.38)
10.60 (10.56)
10.60 (10.64)
10.69 (10.66)
10.69 (10.64)
10.03 (10.08)
10.03 (10.07)
10.11 (10.15)
13.04 (13.08)
12.25 (12.29)
12.25 (12.20)
12.34 (12.30)
10.37 (10.33)
9.75 (9.71)
9.75 (9.79)
9.82 (9.86)
H
2-Cl
3-Cl
Methanol–water
Methanol–water
Ethanol–water
Ethanol–water
Acetic acid–water
Acetic acid–water
Methanol–water
DMF–water
34H28N3ClO
34H28N3ClO
35H31N3O2
35H31N3O2
35H30N3ClO2
35H30N3ClO2
36H33N3O3
36H34N4O
H
H
2-OCH3 120
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-N(CH3)2
4-N(CH3)2
4-N(CH3)2
4-N(CH3)2
3-OCH3, 4-OH
H
113
118
114
2-Cl
3-Cl
2-OCH3 122
H
100
108
104
4j
4k
4l
2-Cl
3-Cl
Benzene–pet. ether
Methanol–water
DMF–water
36H33N4ClO
36H33H4ClO
37H36N4O2
35H31N3O3
35H30N3ClO3
35H30N3ClO3
36H33N3O4
33H26N4O
2-OCH3 107
4m
4n
4o
4p
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
H
111
114
116
Ethanol–water
Methanol–water
Ethanol–water
Benzene–pet. ether
Benzene–pet. ether
Methanol
3-OCH3, 4-OH 2-Cl
3-OCH3, 4-OH 3-Cl
3-OCH3, 4-OH 2-OCH3 126
H
H
118
125
120
H
2-Cl
3-Cl
33H25N4ClO
34H25N4ClO
34H28N4O2
34H28N4O2
34H27N4ClO2
34H27N4ClO2
35H30N4O3
35H31N5O
H
Ethanol–water
Methanol–water
Acetic acid–water
DMF–water
H
2-OCH3 123
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-N(CH3)2
4-N(CH3)2
4-N(CH3)2
4-N(CH3)2
3-OCH3, 4-OH
H
112
120
116
2-Cl
3-Cl
DMF–water
2-OCH3 119
Ethanol–water
DMF–water
H
126
122
128
2-Cl
3-Cl
DMF–water
35H30N5ClO
35H30N5ClO
36H33N5O2
34H28N4O3
34H27N4ClO3
34H27N4ClO3
35H30N4O4
Ethanol–water
Methanol–water
Acetic acid–water
Benzene–pet. ether
Ethanol
2-OCH3 132
5m
5n
5o
5p
H
125
120
124
3-OCH3, 4-OH 2-Cl
3-OCH3, 4-OH 3-Cl
3-OCH3, 4-OH 2-OCH3 130
Methanol
activity. However, the effect of different substitution was
found to be similar with that of compounds 4a–4p i.e. com-
pounds 5d, 5h, 5l and 5p (having 2-methoxyphenylazo
substitution) showed better response i.e. 40%, 40%, 60% and
80%, respectively, in comparison to the other substituted
derivatives of this step.
i.p.) (Fig. 3) whereas compound 4p showed less potent and
equipotent response than the references drug sodium val-
proate (Fig. 3).
4. Conclusion
Therefore, considering the compound of this series, it may
be concluded that 3-methoxy-4-hydroxyphenylsubstituted
benzoxazepine derivatives showed promising anticonvulsant
activity. Further, 2-methoxy substituted arylaminomethylene
and 2-methoxysubstituted arylazo derivatives have shown
more potent response i.e. compounds 4p and 5p, respec-
tively. These compounds were tested at three graded doses
i.e. 7.5, 15 and 30 mg kg–1 i.p. and showed higher protection
against MES model than the reference drug phenytoin so-
dium at all three doses and less potent than standard drug
lamtrigine at lower doses (Fig. 2). Being the most potent
compound of this series, compounds 4p and 5p were com-
pared with reference drug sodium valproate. Compound 5p
have shown more potent anticonvulsant activity than sodium
valproate at all three graded doses (20, 40 and 80 mg kg–1
While considering all the newly synthesized compounds
of this series together, we may conclude that:
1. Compounds having 3-methoxy-4-hydroxyphenyl sub-
stitution at second position of benzoxazepine ring
showed better protection against MES test.
2. 2-Methoxyarylamino as well as 2-methoxyarylazo sub-
stituted compounds showed more promising results
than the other substituted ones.
3. Compounds having arylazo substitution showed better
response towards pentylene tetrazole (PTZ) model than
arylaminomethylene substituted compounds.
4. Compound substituted with different arylaminomethyl-
ene moieties showed potent response against MES
model than compounds substituted with different ary-
lazo moieties.

372
K. Bajaj et al. / European Journal of Medicinal Chemistry 39 (2004) 369–376
Table 3
Pharmacological data of compounds 3a–3d, 4a–4p and 5a–5p
Compounds
Acute toxicity ALD50 Dose (mg kg–1 i.p.)
Anticonvulsant activity (% inhibition)
(mg kg–1 p.o.)
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
For MES model
For PTZ model
For MES model
For PTZ model
3a
3b
3c
3d
4a
4b
4c
4d
4e
4f
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
7.5
15
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
7.5
15
30
0.5 ml
7.5
15
30
7.5
15
30
–
–
20
30
30
40
40
30
40
50
40
30
40
50
50
50
60
70 *
50
60
60
30
50
90 *
20
30
30
40
30
30
30
40
40
50
50
60
40
50
60
20
40
80 *
0
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
4g
4h
4i
–
–
–
–
–
–
4j
–
–
4k
4l
–
–
–
–
4m
4n
4o
4p
–
–
–
–
–
–
20
40
80
–
20
30
80 *
–
5a
5b
5c
5d
5e
5f
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
–
–
–
–
–
–
–
–
–
–
5g
5h
5i
–
–
–
–
–
–
5j
–
–
5k
5l
–
–
–
–
5m
5n
5o
5p
–
–
–
–
–
–
20
40
80
0.5 ml
–
30
50
90 *
0
P.G. a
Phenytoin sodium b
20
50
80 *
20
50
90 *
–
–
–
–
–
–
Lamotrigine b
–
–
–
–
–
–
Sodium valproate c
20
40
80
30
50
80 *
–
–
–
–
* P < 0.001.
a Propylene glycol standard for control group.
b Standard drug for SMES pattern test.
c Standard drug for PTZ seizure pattern test.

K. Bajaj et al. / European Journal of Medicinal Chemistry 39 (2004) 369–376
373
Fig. 2. The bar diagram showing anticonvulsant activity (%age seizure protection) of compounds 4p and 5p their comparison with phenytoin sodium and
lamotrigine in supra maximal electroshock pattern test.
5. Experimental
5.1.1. N-Acetyl-diphenylamine (1)
To the solution of diphenylamine (0.01 mol) in dry chlo-
roform (50 ml), acetyl chloride (0.01 mol) was added drop-
by-drop at 0–5°. The reaction mixture was stirred for 4 h at
room temperature and then solvent was distilled off. The
residue thus obtained was crystallized with ethanol to give
compound 1. Physical, analytical and spectroscopic data are
given in Tables 1 and 4, respectively.
5.1. Chemistry
Melting points were taken in open capillaries with the help
of thermonic melting point apparatus and are uncorrected.
The purity of the compounds was checked by thin layer
chromatography on silica gel-G plates, eluent was a mixture
of methanol–benzene in 2:8 proportion and spots were lo-
cated by iodine. Elemental analysis were performed on CHN
analyzer, Carlo Erba 1108 analyzer at the Central Drug
Research Institute (Lucknow, India). The IR spectra were
recorded on Perkin Elmer 881 FTIR spectrophotometer (mmax
5.1.2. N-Substitutedphenyl-N,N-diphenylpropenamide
(2a–2d)
The equimolar mixture (0.01 mol) of N-acetyl-
diphenylamine and different aromatic aldehyde in ethanol
(50 ml) was refluxed for 10–12 h in the presence of 2%
NaOH solution (2 ml). The reaction mixture was distilled out
and poured onto ice in each case. The solution was then
1
in cm–1). The H NMR spectra were recorded in CDCl3 on
Brucker DRX-300 FTNMR instrument, mass spectra were
determined on JEOL D-300 instrument.
Fig. 3. The diagram showing anticonvulsant activity (%age seizure protection) of compounds 4p and 5p their comparison with sodium valproate in pentylene
tetrazol seizure pattern test.

374
K. Bajaj et al. / European Journal of Medicinal Chemistry 39 (2004) 369–376
Table 4
Spectral data of compounds 1, 2a–2d, 3a–3d, 4a–4p and 5a–5p
Compounds [M]+ m/z 1H NMR (CDCl3) d (ppm)
IR (KBr) (cm–1
1640 (C=O), 1575 (
)
1
2a
211
299
7.60–6.90 (m, 10H, Ar–H), 2.56 (s, 3H, COCH3)
of aromatic ring), 1500 (C–N)
8.60 (d, 1H, =CH–Ar), 7.80–6.85 (m, 15H, Ar–H), 6.65 (d, 1H, 1660 (C=O), 1620 (CH=CH), 1580 (
COCH=)
of aromatic ring)
of aromatic ring)
of aromatic ring)
2b
2c
2d
3a
3b
3c
329
342
345
390
420
433
8.65 (d, 1H, =CH–Ar), 7.80–6.90 (m, 14H, Ar–H), 6.65 (d, 1H, 1660 (C=O), 1625 (CH=CH), 1578 (
COCH=), 3.70 (s, 3H, OCH3)
8.62 (d, 1H, =CH–Ar), 7.80–6.92 (m, 14H, Ar–H), 6.68 (d, 1H, 1665 (C=O), 1622 (CH=CH), 1580 (
COCH=), 1.5 [s, 6H, N(CH3)2]
11.30 (s, 1H, OH), 8.60 (d, 1H, =CH–Ar), 7.90–6.85 (m, 13H, 3380 (O–H), 1620 (C=O), 1620 (CH=CH), 1575 (
of
of aromatic ring), 1485 (C–N),
of aromatic ring), 1480 (C–N),
of aromatic ring), 1480 (C–N),
Ar–H), 6.60 (d, 1H, COCH=), 3.50 (s, 3H, OCH3)
3.25 (d, 2H, C3–H2 of oxazepine ring), 7.00–6.35 (m, 19H, 1668 (C=N), 1565 (
Ar–H), 4.25 (t, 1H, C2–H of oxazepine ring) 1070 (C–O–C)
aromatic ring)
3.20 (d, 2H, C3–H2 of oxazepine ring), 7.00–6.38 (m, 18H, 1665 (C=N), 1562 (
Ar–H), 4.25 (t, 1H, C2–H of oxazepine ring), 3.65 (s, 3H, OCH3) 1070 (C–O–C)
3.28 (d, 2H, C3–H2 of oxazepine ring), 7.00–6.40 (m, 18H, 1665 (C=N), 1560 (
Ar–H), 4.28 (t, 1H, C2–H of oxazepine ring), 1.5 [s, 6H, 1077 (C–O–C)
N(CH3)2]
3d
4a
4b
4c
4d
436
495
530
530
525
11.20 (ss, 1H, OH), 3.20 (d, 2H, C3–H2 of oxazepine ring), 3669 (O–H), 1668 (C=N), 1560 (
7.00–6.50 (m, 17H, Ar–H), 4.30 (t, 1H, C2–H of oxazepine ring), 1489 (C–N), 1072 (C–O–C)
3.55 (s, 3H, OCH3)
of aromatic ring),
3.70 (dd, 1H, C3–H of oxazepine ring), 7.45–6.50 (m, 24H, 1600 (C=N), 1510 (
Ar–H), 4.19 (d, 1H, C2–H of oxazepine ring), 3.40 (hump, 1H, 1120 (C–O–C)
CH2NH exchangeable), 1.85 (hump, 2H, NHCH2)
of aromatic ring), 1480 (C–N),
of aromatic ring), 1485 (C–N),
of aromatic ring), 1480 (C–N),
of aromatic ring), 1485 (C–N),
3.72 (dd, 1H, C3–H of oxazepine ring), 7.45–6.52 (m, 23H, 1600 (C=N), 1500 (
Ar–H), 4.20 (d, 1H, C2–H of oxazepine ring), 3.43 (hump, 1H, 1120 (C–O–C), 680 (C–Cl)
CH2NH exchangeable), 1.85 (hump, 2H, CH2NH)
3.70 (dd, 1H, C3–H of oxazepine ring), 7.40–6.48 (m, 23H, 1610 (C=N), 1520 (
Ar–H), 4.20 (d, IH, C2–H of oxazepine ring), 3.40 (hump, 1H, 1122 (C–O–C), 685 (C–Cl)
CH2NH exchangeable), 1.83 (hump, 2H, CH2NH)
3.70 (dd, 1H, C3–H of oxazepine ring), 7.43–6.50 (m, 23H, 1605 (C=N), 1510 (
Ar–H), 4.22 (d, 1H, C2–H of oxazepine ring), 3.40 (hump, 1H, 1120 (C–O–C)
CH2NH exchangeable), 3.75 (s, 3H, OCH3), 1.80 (hump, 2H,
CH2NH)
4e
4f
525
560
560
555
538
573
573
3.70 (dd, 1H, C3–H of oxazepine ring), 7.45–6.50 (m, 23H, 1620 (C=N), 1510 (
Ar–H), 4.20 (d, 1H, C2–H of oxazepine ring), 3.70 (s, 3H, OCH3), 1120 (C–O–C)
3.45 (hump, 1H, CH2NH exchangeable), 1.82 (hump, 2H,
CH2NH)
of aromatic ring), 1490 (C–N),
of aromatic ring), 1485 (C–N),
of aromatic ring), 1482 (C–N),
of aromatic ring), 1485 (C–N),
of aromatic ring), 1510 (C–N),
of aromatic ring), 1500 (C–N),
of aromatic ring), 1500 (C–N),
3.70 (dd, 1H, C3–H of oxazepine ring), 7.45–6.55 (m, 22H, 1620 (C=N), 1510 (
Ar–H), 4.25 (d, 1H, C2–H of oxazepine ring), 3.76 (s, 3H, OCH3), 1125 (C–O–C), 685 (C–Cl)
3.40 (hump, IH, CH2NH exchangeable), 1.80 (hump, 2H,
CH2NH)
4g
4h
4i
3.73 (dd, 1H, C3–H of oxazepine ring), 7.40–6.50 (m, 22H, 1625 (C=N), 1520 (
Ar–H), 4.20 (d, 1H, C2–H of oxazepine ring), 3.70 (s, 3H, OCH3), 1125 (C–O–C), 700 (C–Cl)
3.45 (hump, 1H, CH2NH exchangeable), 1.83 (hump,
2H, CH2NH)
3.72 (dd, 1H, C3–H of oxazepine ring), 7.35–6.45 (m, 22H, 1620 (C=N), 1500 (
Ar–H), 4.25 (d, 1H, C2–H of oxazepine ring), 3.77 (s, 6H, 2 × 1120 (C–O–C)
OCH3), 3.42 (hump, 1H, CH2NH exchangeable), 1.80 (hump,
2H, CH2NH)
3.73 (dd, 1H, C3–H of oxazepine ring), 7.40–6.68 (m, 23H, 1605 (C=N), 1530 (
Ar–H), 4.18 (d, 1H, C2–H of oxazepine ring), 3.44 (hump, 1H, 1300 (C–O–C)
CH2NH exchangeable), 2.80 [s, 6H, N(CH3)2], 1.82 (hump, 2H,
NHCH2)
4j
3.70 (dd, 1H, C3–H of oxazepine ring), 7.43–6.68 (m, 22H, 1620 (C=N), 1525 (
Ar–H), 4.18 (d, 1H, C2–H of oxazepine ring), 3.43 (hump, 1H, 1300 (C–O–C), 675 (C–Cl)
CH2NH exchangeable), 2.85 [s, 6H, N(CH3)2], 1.80 (hump, 2H,
NHCH2)
4k
3.72 (dd, 1H, C3–H of oxazepine ring), 7.45–6.70 (m, 22H, 1600 (C=N), 1550 (
Ar–H), 4.15 (d, 1H, C2–H of oxazepine ring), 3.45 (hump, 1H, 1310 (C–O–C), 680 (C–Cl)
CH2 NH exchangeable), 2.82 [(s, 6H, NCH3)2] 1.85 (hump, 2H,
NHH CH2)
(continued on next page)

K. Bajaj et al. / European Journal of Medicinal Chemistry 39 (2004) 369–376
375
Table 4
(continued)
Compounds [M]+ m/z 1H NMR (CDCl3) d (ppm)
IR (KBr) (cm–1
)
4l
568
541
576
3.70 (dd, 1H, C3–H of oxazepine ring), 7.42–6.70 (m, 22H, 1600 (C=N), 1545 (
Ar–H), 4.20 (d, 1H, C2–H of oxazepine ring), 3.85 (s, 3H, OCH3), 1300 (C–O–C)
3.45 (hump, 1H, CH2NH exchangeable), 2.80 [(s, 6H, N(CH3)2],
1.82 (hump, 2H, NHCH2)
of aromatic ring), 1500 (C–N),
4m
4n
12.70 (ss, 1H, OH), 3.75 (dd, 1H, C3–H of oxazepine ring), 3660 (O–H), 1610 (C=N), 1550 (
7.40–6.70 (m, 22H, Ar–H), 4.25 (d, 1H, C2–H of oxazepine ring), 1500 (C–N), 1300 (C–O–C)
3.80 (s, 3H, OCH3), 3.43 (hump, 1H, CH2NH exchangeable),
of aromatic ring),
of aromatic ring),
1.85 (hump, 2H, NHCH2)
12.72 (ss, 1H, OH), 3.75 (dd, 1H, C3–H of oxazepine ring), 3665 (O–H), 1600 (C=N), 1555 (
7.45–6.70 (m, 21H, Ar–H), 4.24 (d, 1H, C2–H of oxazepine ring), 1510 (C–N), 1310 (C–O–C), 680 (C–Cl)
3.80 (s, 3H, OCH3), 3.40 (hump, 1H, CH2NH exchangeable),
1.85 (hump, 2H, NHCH2)
4o
4p
576
571
12.70 (ss, 1H, OH), 3.73 (dd, 1H, C3–H of oxazepine ring), 3662 (O–H), 1610 (C=N), 1550 (
7.40–6.65 (m, 2IH, Ar–H), 4.20 (d, 1H,C2–H of oxazepine ring), 1500 (C–N), 1300 (C–O–C), 685 (C–Cl)
3.83 (s, 3H, OCH3) 1.83 (hump, 2H, NHCH2)
of aromatic ring),
of aromatic ring),
12.73 (ss, 1H, OH), 3.70 (dd, IH, C3–H of oxazepine ring), 3660 (O–H), 1600 (C=N), 1560 (
7.43–6.68 (m, 21H, Ar–H), 4.22 (d, 1H, C2–H of oxazepine ring), 1500 (C–N), 1305 (C–O–C)
3.85 (s, 6H, 2 × OCH3), 3.40 (hump, 1H, CH2NH exchangeable),
1.80 (hump, 2H, NHCH2)
5a
5b
5c
5d
5e
5f
494
529
529
524
524
559
559
554
537
572
572
567
3.72 (d, 1H, C3–H of oxazepine ring), 7.25–6.67 (m, 24H, Ar–H), 1660 (C=N), 1560 (
4.23 (d, 1H, C2–H of oxazepine ring) 1425 (N=N), 1330 (C–O–C)
3.70 (d, 1H, C3–H of oxazepine ring), 7.20–6.60 (m, 23H, Ar–H), 1600 (C=N), 1555 (
of aromatic ring), 1510 (C–N),
of aromatic ring), 1500 (C–N),
of aromatic ring), 1500 (C–N),
of aromatic ring), 1510 (C–N),
of aromatic ring), 1495 (C–N),
of aromatic ring), 1510 (C–N),
of aromatic ring), 1500 (C–N),
of aromatic ring), 1505 (C–N),
of aromatic ring), 1500 (C–N),
of aromatic ring), 1500 (C–N),
of aromatic ring), 1505 (C–N),
of aromatic ring), 1510 (C–N),
4.20 (d, 1H, C2–H of oxazepine ring)
1420 (N=N), 1330 (C–O–C), 688 (C–Cl)
3.75 (d, 1H, C3–H of oxazepine ring), 7.15–6.55 (m, 23H, Ar–H), 1620 (C=N), 1560 (
4.20 (d, 1H, C2–H of oxazepine ring)
1410 (N=N), 1300 (C–O–C), 700 (C–Cl)
3.75 (d, 1H, C3–H of oxazepine ring), 7.20–6.60 (m, 23 H,Ar–H), 1600 (C=N), 1550 (
4.25 (d, 1H, C2–H of oxazepine ring), 3.79 (s, 3H, OCH3)
3.77 (d, 1H, C3–H of oxazepine ring), 7.36–6.55 (m, 23H, Ar–H), 1600 (C=N), 1550 (
4.20 (d, 1H, C2–H of oxazepine ring), 3.85 (s, 3H, OCH3) 1420 (N=N), 1300 (C–O–C)
3.70 (d, 1H, C3–H of oxazepine ring), 7.20–6.50 (m, 22H, Ar–H), 1620 (C=N), 1560 (
1425 (N=N), 1330 (C–O–C)
4.23 (d, 1H, C2–H of oxazepine ring), 3.85 (s, 3H, OCH3)
1425 (N=N), 1320 (C–O–C); 680 (C–Cl)
5g
5h
5i
3.73 (d, 1H, C3–H of oxazepine ring), 7.30–6.50 (m, 22H, Ar–H) 1610 (C=N), 1555 (
4.25 (d, 1H, C2–H of oxazepine ring), 3.80 (s, 3H, OCH3)
1428 (N=N), 1325 (C–O–C), 675 (C–Cl)
3.72 (d, 1H, C3–H of oxazepine ring), 7.32–6.50 (m, 22H, Ar–H), 1605 (C=N), 1552 (
4.20 (d, 1H, C2–H of oxazepine ring), 3.80 (s, 6H, 2 × OCH3)
3.70 (d, 1H, C3–H of oxazepine ring), 7.20–6.60 (m, 23H, Ar–H), 1595 (C=N), 1560 (
4.25 (d, 1H, C2–H of oxazepine ring), 2.80 [s, 6H, N(CH3)2] 1420 (N=N), 1330 (C–O–C)
3.72 (d, 1H, C3–H of oxazepine ring), 7.25–6.60 (m, 22H, Ar–H), 1598 (C=N), 1555 (
1420 (N=N), 1320 (C–O–C)
5j
4.22 (d, 1H, C2–H of oxazepine ring), 2.80 [s, 6H, N(CH3)2]
1422 (N=N), 1300 (C–O–C), 680 (C–Cl)
5k
5l
3.73 (d, 1H, C3–H of oxazepine ring), 7.20–6.55 (m, 22H, Ar–H), 1600 (C=N), 1550 (
4.20 (d, 1H, C2–H of oxazepine ring), 2.85 [s, 6H, N(CH3)2]
3.70 (d, 1H, C3–H of oxazepine ring), 7.25–6.60 (m, 22Hm 1620 (C=N), 1560 (
Ar–H), 4.25 (d, 1H, C2–H of oxazepine ring), 3.80 (s, 3H, OCH3), 1428 (N=N), 1300 (C–O–C)
2.82 [s, 6H, N(Ch3)2]
1420 (N=N), 1290 (C–O–C), 700 (C–Cl)
5m
5n
5o
540
575
575
570
12.70 [(s, 1H, OH), 3.73 (d, 1H, C3–H of oxazepine ring), 3660 (O–H), 1600 (C=N), 1560 (
7.23–6.60 (m, 23H, Ar–H), 4.26 (d, 1H, C2–H of oxazepine ring), 1510 (C–N), 1420 (N=N), 1330 (C–O–C)
3.78 (s, 3H, OCH3)
of aromatic ring),
of aromatic ring),
C of aromatic ring),
12.75 (s, 1H, OH), 3.70 (d, 1H, C3–H of oxazepine ring), 3660 (O–H), 1610 (C=N), 1556 (
7.20–6.53 (m, 22 H,Ar–H), 4.20 (d, 1H, C2–H of oxazepine ring), 1420 (N=N), 1333 (C–O–C), 700 (C–Cl)
3.77 (s, 3H, OCH3)
12.72 (s, 1H, OH), 3.74 (d, 1H, C3–H of oxazepine ring), 3665 (O–H), 1598 (C=N), 1550 (
7.25–6.62 (m, 22 H,Ar–H), 4.23 (d, 1H, C2–H of oxazepine ring), 1505 (C–N), 1425 (N=N), 1332 (C–O–C), 675 (C–Cl)
3.77 (s, 3H, OCH3)
5p
12.70 (s, 1H, OH), 3.70 (d, 1H, C3–H of oxazepine ring), 3660 (O–H), 1595 (C=N), 1560 (
7.20–6.60 (m, 22 H,Ar–H), 4.25 (d, 1H, C2–H of oxazepine ring), 1510 (C–N), 1420 (N=N), 1300 (C–O–C)
3.75 (s, 3H, OCH3)
of aromatic ring),
mixed with benzene and separated by separating funnel. The
benzene from an organic layer was distilled off and the
residue thus obtained was washed with water several times
and finally recrystallized from suitable solvents to afford
compounds 2a–2d. Physical, analytical and spectroscopic
data are given in Tables 1 and 4, respectively.

376
K. Bajaj et al. / European Journal of Medicinal Chemistry 39 (2004) 369–376
5.1.3. 2-Substitutedphenyl-2,3-dihydro-4-diphenylamino-
1,5-benzoxazepines (3a–3d)
5.2.2. Anticonvulsant activity
5.2.2.1. Supra maximal electroshock seizure (SMES) pat-
tern test. This activity was performed according to the
method of Tomon et al. [8] on albino rats of the Charles foster
strain of either sex, weighing, between 80 and 120 g. Rats
were divided into the groups of 10 animals and pregnancy
was excluded in female rats. The rats were treated with the
different doses of test drugs or phenytoin sodium 30 mg kg–1
i.p. or lamotrigine 30 mg kg–1 i.p. After 1 h, they were
subjected to the shock of 150 mA by convulsiometer through
ear electrodes for 0.2 s and the presence or absence of
extensor response was noted. Animals in which extensor
response was abolished were taken as protected rats.
An equimolar mixture (0.01 mol) of ethanolic solution of
compounds 2a–2d and 2-aminophenol was refluxed for
3–4 h in the presence of few drops of glacial acetic acid
(1 ml), completion of the reaction was determined by TLC.
The solvent was distilled off under reduced pressure and the
solid thus obtained was recrystallized by suitable solvents to
give compounds 3a–3d. Physical, analytical and spectro-
scopic data are given in Tables 1 and 4, respectively.
5.1.4. 2-Substitutedphenyl-3-(substitutedphenylamino)
methyl-2,3-dihydro-4-diphenylamino-1,5-benzoxazepines
(4a–4p)
Different aromatic anilines (0.001 mol) and formaldehyde
(0.001 mol) were added to the methanolic solution of com-
pounds 3a–3d (0.001 mol) and refluxed for 4–6 h. The
resultant mixture was concentrated, cooled and poured onto
ice. Separated solid was filtered and recrystallized from suit-
able solvents to yield compounds 4a–4p. Physical, analytical
and spectroscopic data are given in Tables 2 and 4, respec-
tively.
5.2.2.2. Pentylene tetrazole (PTZ) induced seizures test. It
was performed according to the method of Fisher [9]. Albino
rats, weighing 100–120, were injected with PTZ in a dose of
70 mg kg–1 subcutaneously in scruff of neck. After 2–4 min
of PTZ injection animals developed the sequence of excite-
ment, myoclonic jerks, clonic seizures, one or more maximal
tonic seizures. Animals exhibiting these seizure patterns
were selected and divided into the groups of 10 animals each.
Standard drug in this model was sodium valproate (80 mg
kg–1 i.p.) and was injected 60 min prior to PTZ challenge.
5.1.5. 2-Substitutedphenyl-3-substitutedphenylazo-2,3-
dihydro-4-diphenylamino-1,5-benzoxazepines (5a–5p)
Aryldiazonium salt solution of different anilines
(0.001 mol) was added dropwise with stirring to the ethanolic
solution of compounds 3a–3d (0.001 mol) containing so-
dium acetate (0.5 g) at 0–5°. The reaction mixture was kept at
room temperature for 2 h and poured onto ice cold water. The
solid thus obtained was washed several times with water,
filtered and then recrystallized by suitable solvents to afford
compounds 5a–5p. Physical, analytical and spectroscopic
data are given in Tables 2 and 4, respectively.
References
[1] K.M. Youssef, M.M. Said, Egypt. J. Pharm. Sci. 37 (1996) 45–46.
[2] T. Isobe, Jpn. Kokal Tokkyo Koho JP 05 59, 064 [93 59,064] (Cl.
C07D498/04) 9 March 1993, Appl. 91/215,503,27 August 1991; 6 p.
[3] K. Nagarajan, J. David, G.A. Bhat, Indian J. Chem. 24B (1985)
840–844.
[4] H. Kentari, M. Shigeru, M. Itsuo, I. Jiruyuki, Fr. Demande FR
2,480,751 (Cl. C07D267/14) 23 October 1981, JP Appl. 80/52, 185,
28 April 1980; 68 p.
[5] K.J. Kevin, C.E. Richard, J. Heterocycl. Chem. 30 (1993) 177–181.
[6] S. Hiroyuki, I. Yasuo, K. Hideo, E. Eiichi, O. Nobuo, M. Koji, Jpn.
Kokai Tokkyo Koho JP 03, 184, 963 [91,184,963] (Cl.C07D267/20)
12 August 1991, Appl. 89/321, 564, 13 December 1989; 5 p.
[7] Q.E. Smith, Medicinal Chemistry, vol. 1, Butterworth, London, 1960.
[8] J.E.P. Tomon, E.A. Swinyard, L.S. Goodman, J. Neurophysiol 9
(1946) 231–240.
5.2. Pharmacology
5.2.1. Acute toxicity
The compounds were investigated for their acute toxicity
(ALD50) in albino mice by following the method of Smith
[7].
[9] R.S. Fisher, Brain Res. Rev. 14 (1989) 245–278.