Synthesis and evaluation of some new substituted benzothiazepine and benzoxazepine derivatives as anticonvulsant agents

Article abstract of DOI:10.1016/j.ejmech.2010.01.001

A new series of 4-(4′-Hydroxyphenyl)-2-(3-substitutedphenyl)-3-(4-substitutedphenylamino methylene)-2,3-dihydro-1,5-benzothiazepines (3a-3j) and 4-(4′-Hydroxyphenyl)-2-(3-substituted phenyl)-3-(4-substitutedphenylaminomethylene)-2,3-dihydro-1,5-benzoxazep

Full text of DOI:10.1016/j.ejmech.2010.01.001

European Journal of Medicinal Chemistry 45 (2010) 1529–1535
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and evaluation of some new substituted benzothiazepine and
benzoxazepine derivatives as anticonvulsant agents
1
*
Neha Garg , Trilok Chandra, Archana, Amit B Jain, Ashok Kumar
Medicinal Chemistry Division, Department of Pharmacology, L.L.R.M. Medical College, Meerut (U.P.) 250004, India
a r t i c l e i n f o
a b s t r a c t
A new series of 4-(40-Hydroxyphenyl)-2-(3-substitutedphenyl)-3-(4-substitutedphenylamino methy-
lene)-2,3-dihydro-1,5-benzothiazepines (3a–3j) and 4-(40-Hydroxyphenyl)-2-(3-substituted phenyl)-3-
(4-substitutedphenylaminomethylene)-2,3-dihydro-1,5-benzoxazepins (3a0–3j0) were synthesized and
evaluated for their anticonvulsant activity. All these compounds were screened in vivo, for their anti-
convulsant activity and acute toxicity. Compound 3g was found to be most potent compound of this
series and was compared with the reference drug phenytion sodium. The structures of these compounds
have been established by IR, 1H NMR and 13C NMR spectroscopic data.
Article history:
Received 24 February 2009
Received in revised form
29 December 2009
Accepted 5 January 2010
Available online 18 January 2010
Keywords:
Ó 2010 Elsevier Masson SAS. All rights reserved.
Benzothiazepines
Benzoxazepines
Anticonvulsant activity
Toxicity studies
1. Introduction
2. Chemistry
Epilepsy is a neurological disorder affecting about 1% of world’s
population. Currently available drugs in clinical practice produce
satisfactory seizure control in 60–70% of patients [1]. These drugs
have a number of adverse drug reactions and other disadvantages
including the fact that the convulsions of approximately 25%
epilepsies are inadequately controlled by these medications.
Therefore, the need for more effective and less toxic antiepileptic
drugs still exists.
Benzothiazepine and benzoxazepine derivatives have docu-
mented consistent advances in the design of novel anticonvulsant
agents. Benzothiazepine and benzoxazepine derivatives have been
found to posses potent wide spectrum biological activities like
anticonvulsant [2–5], antidepressant [6], CNS depressant [7], anti-
psychotic [8,9] and neuroleptic [10]. In viewof biological activities of
benzothiazepine and benzoxazepine derivatives, we report herein
the synthesis of their new derivatives namely 4-(40-Hydroxy-
phenyl)-2-(3-substitutedphenyl)-3-(4-substitutedphenylamino
methylene)-2,3-dihydro-1,5-benzothiazepines (3a–3j) and 4-(40-
Hydroxy phenyl)-2-(3-substitutedphenyl)-3-(4-substitutedphenyl-
aminomethylene)-2,3-dihydro-1,5-benzoxazepines (3a0–3j0) along
with their anticonvulsant profile.
The synthetic routes of compounds are outlined in scheme 1.
Substituted 4-hydroxy chalconylbenzene was synthesized by the
reaction of 4-hydroxyacetophenone and substituted benzaldehyde
in the presence of KOH i.e. compounds (1a–1e). Compounds 1a–1e
on cyclization with 2-thio/aminophenol in the presence of glacial
acetic acid yielded compounds (2a–2e) and (2a0–2e0) respectively.
Compounds 2a–2e and 2a0–2e0 further undergoes Mannich reac-
tion with different substituted anilines to afford compounds (3a–
3j) and (3a0–3j0).
3. Pharmacological results and discussion
All the newly synthesized compounds were studied for their
anticonvulsant activity. The pharmacological data of all the
compounds of this series have been reported in Table 1. The
compounds were screened for their anticonvulsant activity
against maximal electroshock induced seizures at a dose of
30 mg/kg i.p., and were found to exhibit substantive anticon-
vulsant activity. The characteristic feature of this series is the
substitution by the different moieties at second and third posi-
tion of benzothiazepine ring, while evaluating the anticonvulsant
activity, it was observed that compound 2a (having 3-methoxy-
phenylgroup at second position of benzothiazepine ring) showed
least activity 30%, while compound 2b (having 2-chlorophenyl
group) exhibited maximum response 80% in comparison to other
* Corresponding author. Tel.: þ91 0121 2764084; mobile: 91 9917053074.
E-mail address: rajputak@gmail.com (A. Kumar).
1
Part of the Ph.D thesis work.
0223-5234/$ – see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.01.001

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N. Garg et al. / European Journal of Medicinal Chemistry 45 (2010) 1529–1535
Scheme 1.
substituted compounds. Further the next step compounds
substituted with different arylaminomethylene substitutions 2a–
2e at the third position of benzothiazepine ring also elicited
remarkable anticonvulsant activity up to 80%. All compounds 3a–
3j of this step exhibited potent anticonvulsant activity 40–90%.
However, compound 3g (having 4-methoxyphenylamino-
methylene substitution at third position of benzothiazepine ring)
have shown most potent activity of 90% against MES test which is
more potent than standard drug phenytoin sodium. Compounds
3a, 3b, 3c, 3d, 3e, 3f, 3h, 3i and 3j, exhibited good response
against MES model i.e. 40%, 70%, 70%, 60%, 60%, 50%, 70%, 70% and
60% respectively. On the other hand compounds 2a0–2e0
possessed benzoxazepine ring substituted by different moieties
at second and third position. The compound 2a0 (having 3-
methoxyphenylgroup at second position of benzoxazepine ring)
exhibited lowest degree of anticonvulsant activity 20%, while
compound 2b0 (having 2-chlorophenylgroup) elicited maximum
response 70% in comparison to the other substituted
compounds. Further the compounds of next step i.e. 2a0–2e0
were characterized by different arylaminomethylene substitu-
tions at the third position of benzoxazepine ring. All the
compounds 3a0–3j0 of this step exhibited anticonvulsant activity
ranging from 30% to 70%. The newly synthesized compounds
were also tested for approximate lethal dose ALD50 and were
found to exhibit a higher value of ALD50 i.e. more than 1000 mg/
kg, i.p. except compound 3g which exhibited ALD50 of more than
2000 (maximum dose tested) thus indicating the safer nature of
these compounds.
4. Conclusion
While considering all the newly synthesized compounds of this
series together, we may conclude that:
1 Presence of benzothiazepine moiety has shown better anti-
convulsant activity than the compounds having benzox-
azepines moiety.
2 2-Chlorophenyl substitution at second position of benzothia-
zepines ring showed more potent activity than other
substituted benzothiazepines.
3 Presence of electronegative atom (chlorine) plays a pivotal role
to increase the anticonvulsant activity.
5. Experimental protocols
5.1. Chemistry
The melting points of compounds were determined in open
capillaries and are uncorrected. Homogeneity of the synthesized
compounds was routinely checked by thin layer chromatography
on Silica Gel-G plates. The eluent was a mixture of different polar
and non polar solvent in different proportion and spots were
located by iodine. The IR spectra were recorded on Bruker IFS-66V
FT-IR (nmax in cmꢀ1). The 1H NMR spectra were recorded by Bruker
DRX-400 FT-NMR instrument using CDCl3 as solvent and tetra
methyl silane (TMS) as internal reference standard. All

N. Garg et al. / European Journal of Medicinal Chemistry 45 (2010) 1529–1535
1531
Table 1
75.57; H, 5.55; N -,; Found C, 75.35; H, 5.35; N,- %. M.1, 145.9, 135.6,
Anticonvulsant activity of compounds 2a–2e, 2a0–2e0, 3a–3j and 3a0–3j0.
130.0, 129.9, 121.8, 120.5: [M]þ at m/z 254.28.
Compound
No.
R
R0
Dose
(mg/kg
i.p.)
Anticonvulsant activity (SMES)c
5.1.3. 2-Chlorophenyl-4-hydroxychalconylbenzene (1b)
No. of animals % Seizure ALD50
Yield 90% (methanol): m.p 132 ꢁC; IR (KBr) nmax in cmꢀ1: 3422
exhibiting
convulsions
protection (mg/kg
i.p.)
(OH), 1655 (C]O), 1622 (C]C), 730 (C–Cl); 1H NMR (CDCl3)
d
in
ppm: 11.09 (s, 1H, OH exchangeable), 8.60 (d, 1H, ]CHAr), 7.72–
6.69 (m, 8H, Ar–H), 6.64 (d, 1H, COCH]); 13CNMR (CDCl3)
ppm:
P.G.a
2 ml
30
10
2
0
Phenytoin
sodiumb
3-OCH3
2-C1
4-C1
2-OH
4-OH
3-OCH3
2-C1
4-C1
2-OH
4-OH
3-OCH3
2-C1
4-C1
2-OH
80***
d
189.2, 164.6, 145.6, 131.7, 129.2, 127.3, 121.8, 120.1; Anal. Calcd for
C15H11ClO2: C, 69.64; H, 4.29; N-,; Found C, 69.74; H,5.45; N,- %. MS:
[M]þ at m/z 258.70.
2a
2b
2c
–
–
–
–
–
–
–
–
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
7
2
3
3
4
8
3
4
4
3
6
3
3
4
4
5
8
6
1
3
3
4
7
5
4
4
3
3
4
5
4
5
30
80***
70**
70**
60*
20
70**
60*
60*
70**
40
70**
70**
60*
60*
50*
20
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
2d
2e
2a0
2b0
2c0
2d0
2e0
3a
3b
3c
5.1.4. 4-Chlorophenyl-4-hydroxychalconylbenzene (1c)
Yield 80% (ethanol): m.p 128 ꢁC; IR (KBr) nmax in cmꢀ1: 3427
(OH), 1659 (C]O), 1627 (C]C), 735 (C–Cl); 1H NMR (CDCl3)
d
in
ppm: 11.10 (s, 1H, OH exchangeable), 8.58 (d, 1H, ]CHAr), 7.68–
6.62 (m, 8H, Ar–H), 6.60 (d, 1H, COCH]); 13CNMR (CDCl3)
ppm:
–
–
d
4-C1
4-C1
4-C1
4-C1
4-C1
189.0, 164.2, 145.8, 131.3, 129.4, 127.0, 121.2, 120.6; Anal .Calcd for
C15H11ClO2: C, 69.64; H, 4.29; N-,; Found C, 69.65; H,5.48; N,- %. MS:
[M]þ at m/z 258.70.
3d
3e
3f
4-OH T
3-OCH3
4-OCH3 30
7.5
4-OCH3 15
30
4-OCH3 30
4-OCH3 30
4-OCH3 30
5.1.5. 2-Hydroxyphenyl-4-hydroxychalconylbenzene (1d)
Yield 86% (ethanol): m.p 142 ꢁC. IR (KBr) nmax in cmꢀ1: 3440
3g
2-C1
40
(OH), 1662 (C]O), 1625 (C]C); 1H NMR (CDCl3)
d
in ppm: 11.18 (s,
2H, OH exchangeable), 8.62 (d, 1H,]CH Ar), 7.75–6.71 (m, 8H, Ar–
H), 6.65 (d, 1H, COCH]); 13CNMR (CDCl3)
ppm: 189.2, 164.9,157.8,
90***
70**
70**
60*
30
>2000
3h
3i
3j
4-C1
2-OH
4-OH
3-OCH3
2-C1
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
d
130.9, 128.2, 122.9, 116.3, 14.6; Anal. Calcd for C15H12ClO3: C, 74.99;
3a0
3b0
3c0
3d0
3e0
3f0
3g0
3h0
3i0
4-C1
4-C1
4-C1
4-C1
4-C1
30
30
30
30
30
H, 5.03; N -,; Found C, 74.85; H, 5.11; N,- %. MS: [M]þ at m/z 240.25.
50*
60*
60*
70**
70**
60*
50*
60*
50*
4-C1
2-OH
4-OH
3-OCH3
2-C1
4-C1
2-OH
4-OH–
5.1.6. 4-Hydroxyphenyl-4-hydroxychalconybenzene (1e)
Yield 82% (methanol): m.p 148 ꢁC. IR (KBr) nmax in cmꢀ1: 3428
4-OCH3 30
4-OCH3 30
4-OCH3 30
4-OCH3 30
4-OCH3 30
(OH), 1660 (C]O), 1628 (C]C); 1HNMR (CDCl3)
d
in ppm: 11.20 (s,
2H, OH exchangeable), 8.65 (d, 1H,]CHAr), 7.71–6.74 (m, 8H, Ar–
H), 6.69 (d, 1H, COCH]); 13CNMR (CDCl3)
ppm: 189.6, 164.1, 157.3,
d
3j0
130.7, 128.6, 122.1, 116.0, 14.1; Anal. Calcd for C15H12ClO3: C, 74.99;
H, 5.03; N -,; Found C, 75.05; H, 5.08; N,- %. MS: [M]þ at m/z 240.25.
*P < 0.05 **P < 0.01 ***P < 0.001.
a
P.G. – Propylene glycol standard for control.
Phenytoin sodium reference standard drug for anticonvulsant activity.
Supramaximal electroshock seizure pattern test.
b
c
5.1.7. General procedure for the synthesis of 4-(40-Hydroxyphenyl)-
2-(substitutedphenyl)-2,3-dihydro-1,5-benzothiazepines (2a–2e)
The methanolic solution (50 mL) of substituted 4-hydroxy-
chalconylbenzenes (1a–1e) (0.01 mol) was added 2-amino-
thiophenol (0.01 mol) with few drops of glacial acetic acid and
refluxed for 3–5 h. After refluxing solvents were distilled off under
reduced pressure and the solid thus obtained was recrystallized
from appropriate solvent. The physical and spectral data of the
compounds are the following.
exchangeable protons were confirmed by the addition of D2O.13
C
NMR spectra were recorded on Bruker AC 200/DPX 400 MHz. All
Chemical shift values were recorded in ppm. Elemental analysis (C,
H, N) of these newly synthesized compounds were performed on
a Carlo Erba-1108 elemental analyzer.
5.1.1. General procedure for the synthesis of substituted
4-hydroxychalconylbenzenes (1a–1e)
5.1.8. 4-(40-Hydroxyphenyl)-2-(3-methoxyphenyl)-2,3-dihydro-
1,5-benzothiazepine (2a)
A mixture of 4-hydroxyacetophenone (0.01 mol), appropriate
aldehyde (0.01 mol) in ethanol (40 mL) and aqueous potassium
hydroxide (60%, 10 mL) was stirred and kept at room temperature
for 12 h. The mixtures were poured on crushed ice and acidified
with dill HCl. The precipitate obtained after acidification were
filtered and washed thoroughly with distilled water till it is free
from acid and dried. The dry residue was recrystallized from
a suitable solvent. The physical and spectral data of the compounds
are the following.
Yield 78% (ethanol): m.p 126 ꢁC. IR (KBr) nmax in cmꢀ1: 3425
(OH), 1625 (C]C), 1462 (C]N), 1225 (OCH3), 675 (C–S–C); 1H NMR
(CDCl3)
of thiazepine ring), 7.62–6.74 (m, 12H, Ar–H), 6.45 (t, 1H, C2–H of
thiazepine ring), 3.42 (s, 3H, OCH3); 13CNMR (CDCl3)
ppm: 160.2,
d in ppm: 11.54 (s, 1H, OH exchangeable), 7.65 (d, 2H, C3–H
d
155.9, 144.2, 137.3, 133.6, 129.6, 116.6, 112.1, 55.3, 50.8, 40.9; Anal.
Calcd for C22H19NO2S: C, 73.10; H, 5.30; N, 3.88; Found C, 73.18; H,
5.45; N, 3.92%. MS: [M]þ at m/z 361.11.
5.1.9. 4-(40-Hydroxyphenyl)-2-(2-chlorophenyl)-2,3-dihydro-
1,5-benzothiazepine (2b)
5.1.2. 3-Methoxyphenyl-4-hydroxychalconylbenzene (1a)
Yield 85% (ethanol): m.p 122 ꢁC; IR (KBr) nmax in cmꢀ1: 3420
Yield 76% (ethanol): m.p 128 ꢁC. IR (KBr) nmax in cmꢀ1: 3428
(OH), 1652 (C]O), 1618 (C]C), 1225 (OCH3); 1H NMR (CDCl3)
d in
(OH), 1629 (C]C), 1460 (C]N), 690 (C–Cl), 671 (C–S–C); 1H NMR
ppm: 11.15 (s,1H, OH exchangeable), 8.62 (d,1H, ]CHAr), 7.70–6.65
(CDCl3)
of thiazepine ring), 7.66–6.68 (m, 12H, Ar–H), 6.49 (t, 1H, C2–H of
thiazepine ring); 13CNMR (CDCl3)
ppm: 160.4, 155.1, 139.7, 133.0,
d in ppm: 11.45 (s, 1H, OH exchangeable), 7.69 (d, 2H, C3–H
(m, 8H, Ar–H), 6.62 (d, 1H, COCH]), 3.35 (s, 3H, OCH3); 13C NMR
(CDCl3)
d
ppm: 189.2, 164.8, 160.1; Anal. Calcd for C16H14O3: C,
d

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N. Garg et al. / European Journal of Medicinal Chemistry 45 (2010) 1529–1535
131.9, 127.6, 125.0, 116.6, 45.8; Anal. Calcd for C21H16ClNOS: C,
68.94; H,4.41; N, 3.83%; Found C, 69.10; H,4.48; N, 3.89%. MS: [M]þ
at m/z 365.88.
oxazepine ring); 13CNMR (CDCl3)
d ppm: 160.0, 149.6, 139.0, 137.7,
129.7, 115.2, 75.3, 38.8; Anal. Calcd for C21H16ClNO2: C, 72.10; H,
4.61; N, 4.00; Found C, 72.19; H, 4.74; N, 4.12%. MS: [M]þ at m/z
349.81.
5.1.10. 4-(40-Hydroxyphenyl)-2-(4-chlorophenyl)-2,3-dihydro-1,5-
benzothiazepine (2c)
5.1.16. 4-(40-Hydroxyphenyl)-2-(4-chlorophenyl)-2,3-dihydro-
1,5-benzoxazepine (2c0)
Yield 68% (methanol): m.p 124 ꢁC. IR (KBr) nmax in cmꢀ1: 3432
(OH), 1634 (C]C), 1465 (C]N), 695 (C–Cl), 674 (C–S–C); 1H NMR
Yield 75% (methanol): m.p 130 ꢁC. IR (KBr) nmax in cmꢀ1: 3438
(CDCl3)
of thiazepine ring), 7.62–6.64 (m, 12H, Ar–H), 6.45 (t, 1H, C2–H of
thiazepine ring); 13CNMR (CDCl3)
ppm: 160.0, 155.4, 139.3, 133.6,
d in ppm: 11.42 (s, 1H, OH exchangeable), 7.65 (d, 2H, C3–H
(OH), 1629 (C]C), 1468 (C]N), 662 (C–Cl), 1072 (C–O–C); 1H NMR
(CDCl3)
of oxazepine ring), 7.68 (d, 2H, C3–H of oxazepine ring), 7.65–6.74
(m, 12H, Ar–H); 13CNMR (CDCl3)
ppm: 160.6, 149.3, 139.5, 137.4,
d in ppm: 11.60 (s, 1H, OH exchangeable), 6.48 (t, 1H, C2–H
d
131.2,127.9,125.4, 116.1, 45.2; Anal. Calcd for C21H16ClNOS: C, 68.94;
H, 4.41; N, 3.83%; Found C, 69.09; H, 4.42; N, 3.81%.MS: [M]þ at m/z
365.88.
d
129.8, 115.6, 75.0, 38.2; Anal. Calcd for C21H16ClNO2: C, 72.10; H,
4.61; N, 4.00; Found C, 72.10; H, 4.64; N, 4.08%. MS: [M]þ at m/z
349.81.
5.1.11. 4-(40-Hydroxyphenyl)-2-(2-hydroxyphenyl)-2,3-dihydro-
1,5-benzothiazepine (2d)
5.1.17. 4-(40-Hydroxyphenyl)-2-(2-hydroxyphenyl)-2,3-dihydro-
1,5-benzoxazepine (2d0)
Yield 78% (ethanol): m.p 144 ꢁC. IR (KBr) nmax in cmꢀ1: 3438
(OH), 1638 (C]C), 1469 (C]N), 680 (C–S–C); 1H NMR (CDCl3)
d
in
Yield 82% (methanol): m.p 152 ꢁC. IR (KBr) nmax in cmꢀ1: 3444
ppm: 11.52 (s, 2H, OH exchangeable), 7.68 (d, 2H, C3–H of thiaze-
pine ring), 7.64–6.60 (m, 12H, Ar–H), 6.48 (t, 1H, C2–H of thiazepine
(OH), 1624 (C]C), 1474 (C]N), 685 (C–O–C); 1H NMR (CDCl3)
d in
ppm: 11.65 (s, 2H, OH exchangeable), 7.72 (d, 2H, C3–H of oxazepine
ring), 7.68–6.64 (m,12H, Ar–H), 6.50 (t,1H, C2–H of oxazepine ring);
ring); 13CNMR (CDCl3)
d ppm: 160.4,155.2, 154.2,136.6,132.4,129.6,
125.8, 122.0, 43.6, 40.9; Anal. Calcd for C21H17NO2S: C, 72.60; H,
4.93; N, 4.03%; Found C, 72.49; H,4.79; N, 4.10%. MS: [M]þ at m/z
347.43.
13CNMR (CDCl3)
d ppm: 162.4, 160.3, 154.6, 149.7, 139.1, 130.7, 129.4,
125.9, 116.5, 115.8, 39.5; Anal. Calcd for C21H17NO3: C, 76.12; H, 5.17;
N, 4.23%; Found C, 76.18; H, 5.29; N, 4.29%. MS: [M]þ at m/z 331.12.
5.1.12. 4-(40-Hydroxyphenyl)-2-(4-hydroxyphenyl)-2,3-dihydro-
1,5-benzothiazepine (2e)
5.1.18. 4-(40-Hydroxyphenyl)-2-(4-hydroxyphenyl)-2,3-dihydro-
1,5-benzoxazepine (2e0)
Yield 70% (ethanol): m.p 138 ꢁC. IR (KBr) nmax in cmꢀ1: 3431
Yield 76% (ethanol): m.p 160 ꢁC. IR (KBr) nmax in cmꢀ1: 3442
(OH), 1630 (C]C), 1455 (C]N), 674 (C–S–C). 1H NMR (CDCl3)
d
in
(OH), 1620 (C]C), 1468 (C]N), 688 (C–O–C); 1H NMR (CDCl3)
d in
ppm: 11.45 (s, 2H, OH exchangeable), 7.63 (d, 2H, C3–H of thiaze-
pine ring), 7.64–6.62 (m, 12H, Ar–H), 6.42 (t, 1H, C2–H of thiazepine
ppm: 11.60 (s, 2H, OH exchangeable), 7.70 (d, 2H, C3–H of oxazepine
ring), 7.65–6.60 (m,12H, Ar–H), 6.48 (t,1H, C2–H of oxazepine ring);
ring); 13C NMR (CDCl3)
d
ppm: 160.3, 155.7,154.4,136.1, 132.0, 129.3,
13CNMR (CDCl3)
d ppm: 162.1, 160.5, 154.2, 149.4, 139.6, 130.3, 129.2,
125.4, 122.3, 43.4, 40.6; Anal. Calcd for C21H17NO2S: C, 72.60; H,
4.93; N, 4.03% ;Found C, 72.40; H, 4.65; N, 4.01%. MS: [M]þ at m/z
347.43.
125.4, 116.0, 115.0, 39.2; Anal. Calcd for C21H17NO3: C, 76.12; H, 5.17;
N, 4.23%; Found C, 76.12; H, 5.15; N, 4.20%. MS: [M]þ at m/z 331.12.
5.1.19. General procedure for the synthesis of 4–(40-Hydroxy-
phenyl)-2-(substitutedphenyl)-3-[(substitutedaminomethylene)]-
2,3-dihydro-1,5-benzothiazepines (3a–3j)
5.1.13. General procedure for the synthesis of 4-(40-Hydroxy-
phenyl)-2-(substitutedphenyl)-2,3-dihydro-1,5-benzoxazepines
(2a0–2e0)
The methanolic solution (50 mL) of substituted 4-hydroxy-
chalconylbenzenes (1a–1e) (0.01 mol) was added 2-aminophenol
(0.01 mol) with few drops of glacial acid and refluxed for 3–5 h.
After refluxing solvents were distilled off under reduced pressure
and the solid thus obtained were recrystallized from suitable
solvent. The physical and spectral data of the compounds are the
following.
The mixture of 4-(40-Hydroxyphenyl)-2-(substitutedphenyl)-
2,3-dihydro-1,5-benzothiazepines (2a–2e) (0.001 mol), substituted
aniline (0.001 mol) and formaldehyde (0.01 mol) in methanol
(30 mL) were refluxed for 4–6 h. The resultant reaction mixtures
were concentrated, cooled and poured on to ice. The separated
semi solids were kept overnight in petroleum ether (40–60 ꢁC). The
solid thus formed were recrystallized from appropriate solvent.
The physical and spectral data of the compounds are the following.
5.1.14. 4-(40-Hydroxyphenyl)-2-(3-methoxyphenyl)-2,3-dihydro-
1,5-benzoxazepine (2a0)
5.1.20. 4-(40-Hydroxyphenyl)-2-(3-methoxyphenyl)-3-[(4-chloro-
phenylaminomethylene)]-2,3-dihydro-1,5-benzothiazepine (3a)
Yield 80% (benzene): m.p 130 ꢁC. IR (KBr) nmax in cmꢀ1: 3435
Yield 42% (ethanol): m.p 169 ꢁC. IR (KBr) nmax in cmꢀ1
:
(OH), 1628 (C]C), 1465 (C]N), 1230 (OCH3), 1070 (C–O–C); 1H
3435 (OH), 1625 (C]C), 1465 (C]N), 1229 (OCH3), 710 (C–Cl),
NMR (CDCl3)
d
in ppm: 11.62 (s, 1H, OH exchangeable), 7.68 (d, 2H,
678 (C–S–C); 1H NMR (CDCl3)
d
in ppm: 11.74 (s, 1H, OH
C3–H of oxazepine ring), 7.65–6.78 (m, 12H, Ar–H), 6.48 (t, 1H,
exchangeable), 9.24–6.64 (m, 17H, Ar–H þ 1H,C3–H of thiaze-
pine ring), 6.45 (t, 1H, C2–H of thiazepine ring), 3.45 (s, 3H,
OCH3), 3.04 (hump, 1H, CH2NH exchangeable with D2O), 1.62(t,
C2–H of oxazepine ring), 3.48 (s, 3H, OCH3); 13CNMR (CDCl3)
d
ppm: 160.4, 149.9, 139.3, 130.6, 123.0, 121.8, 116.3, 115.2, 113.8,
111.9, 81.7, 55.2, 38.3; Anal. Calcd for C22H19NO3: C, 76.50; H, 5.54;
2H, NHCH2CH]); 13CNMR (CDCl3)
d ppm: 160.4, 157.1, 146.8,
N, 4.06; Found C, 76.62; H,5.44; N, 4.12%. MS: [M]þ at m/z 345.39.
145.2, 137.4, 129.4, 126.5, 125.9, 117.5, 116.3, 57.2, 55.3, 51.5;
Anal. Calcd for C29H25ClN2O2S: C, 69.52; H, 5.03; N,5.59;
Found C, 69.68; H, 5.14; N, 5.68%. MS: [M]þ at m/z 501.04.
5.1.15. 4-(40-Hydroxyphenyl)-2-(2-chlorophenyl)-2,3-dihydro-
1,5-benzoxazepine (2b0)
Yield 85% (ethanol): m.p 138 ꢁC. IR (KBr) nmax in cmꢀ1: 3442
5.1.21. 4-(40-Hydroxyphenyl)-2-(2-chlorophenyl)-3-[(4-chloro-
phenylaminomethylene)]-2,3-dihydro-1,5-benzothiazepine (3b)
Yield 70% (ethanol): m.p 164 ꢁC. IR (KBr) nmax in cmꢀ1: 3440
(OH), 1630 (C]C), 1469 (C]N), 715 (C–Cl), 685 (C–S–C); 1H NMR
(OH), 1633 (C]C), 1470(C]N), 660 (C–Cl), 1075 (C–O–C); 1H NMR
(CDCl3)
d in ppm: 11.67 (s, 1H, OH exchangeable), 7.72 (d, 2H, C3–H
of oxazepine ring), 7.68–6.80 (m, 12H, Ar–H), 6.52 (t, 1H, C2–H of

N. Garg et al. / European Journal of Medicinal Chemistry 45 (2010) 1529–1535
1533
(CDCl3)
d
in ppm: 11.78 (s,1H, OH exchangeable), 9.28–6.70 (m,17H,
5.1.27. 4-(40-Hydroxyphenyl)-2-(4-chlorophenyl)-3-
[(4-methoxyphenylaminomethylene)]-2,3-dihydro-
1,5- benzothiazepine (3h)
Ar–H þ 1H,C3–H of thiazepine ring), 6.50 (t, 1H, C2-H of thiazepine
ring), 3.08 (hump, 1H, CH2NH exchangeable with D2O), 1.65 (t, 2H,
NHCH2CH]); 13CNMR (CDCl3)
d
ppm: 164.3, 160.2, 155.1, 145.0,
Yield 44% (ethanol): m.p 182 ꢁC. IR (KBr) nmax in cmꢀ1: 3452
137.6, 137.5, 133.2, 131.1, 129.0, 126.8, 125.9, 117.3, 116.5, 114.3, 46.3,
41.8; Anal. Calcd for C28H22Cl2N2OS: C, 66.53; H, 4.39; N,5.54;
Found C, 66.62; H, 4.44; N, 5.62%. MS: [M]þ at m/z 505.46.
(OH), 1615 (C]C), 1455 (C]N), 712 (C–Cl), 685 (C–S–C); 1H NMR
(CDCl3)
d in ppm: 11.65 (s, 1H, OH exchangeable), 9.24–6.62 (m,
17H, Ar–H þ 1H–C3–H of thiazepine ring), 6.45 (t, 1H, C2–H of
thiazepine ring), 3.32 (s, 3H, OCH3), 3.08 (hump, 1H, CH2NH
exchangeable with D2O), 1.66 (t, 2H, NHCH2CH]); 13CNMR (CDCl3)
5.1.22. 4-(40-Hydroxyphenyl)-2-(4-chlorophenyl)-3-[(4-chloro-
phenylaminomethylene)]-2,3-dihydro-1,5- benzothiazepine (3c)
Yield 68% (methanol): m.p 177 ꢁC. IR (KBr) nmax in cmꢀ1: 3458
(OH), 1624 (C]C), 1462 (C]N), 710 (C–Cl), 682 (C–S–C); 1H NMR
d
ppm: 164.5, 160.0, 155.1, 151.7, 139.4, 133.5, 131.3, 128.4, 127.2,
126.1, 116.2, 115.0, 55.5, 46.7, 41.6, 39.3; Anal. Calcd for
C29H25ClN2O2S: C, 69.52; H, 5.03; N, 7.08; Found C, 69.45; H, 5.10;
N, 7.01%. MS: [M]þ at m/z 501.04.
(CDCl3) d in ppm: 11.71 (s,1H, OH exchangeable), 9.23–6.65 (m,17H,
Ar–H þ 1H, C3–H of thiazepine ring), 6.48 (t, 1H, C2–H of thiazepine
ring), 3.02 (hump, 1H, CH2NH exchangeable with D2O), 1.62 (t, 2H,
5.1.28. 4-(40-Hydroxyphenyl)-2-(2-hydroxyphenyl)-3-
[(4-methoxyphenylaminomethylene)]-2,3-dihydro-
1,5- benzothiazepine (3i)
NHCH2CH]); 13CNMR (CDCl3)
d ppm: 164.0, 160.7, 155.4, 144.9,
137.2, 137.0, 132.9, 130.9, 129.2, 126.4, 125.1, 117.0, 116.4, 114.1, 46.0,
41.5; Anal. Calcd for C28H22Cl2N2OS: C, 66.53; H, 4.39; N, 5.54
;Found C, 66.48; H, 4.25; N, 5.43%. MS: [M]þ at m/z 505.46.
Yield 55% (ethanol): m.p 174 ꢁC. IR (KBr) nmax in cm-1: 3466 (OH),
1638 (C]C), 1470 (C]N), 718 (C-Cl), 685 (C–S–C); 1H NMR (CDCl3)
d
in ppm: 11.68 (s, 2H, 2ꢂ OH exchangeable), 9.25–6.68 (m, 17H, Ar–
5.1.23. 4-(40-Hydroxyphenyl)-2-(2-hydroxyphenyl)-3-[(4-chloro-
phenylaminomethylene)]-2,3-dihydro-1,5- benzothiazepine (3d)
Yield 54% (DMF/water): m.p 183 ꢁC. IR (KBr) nmax in cmꢀ1: 3462
(OH), 1631 (C]C), 1468 (C]N), 715 (C–Cl), 686 (C–S–C); 1HNMR
H þ 1H–C3–H of thiazepine ring), 6.58 (t, 1H, C2–H of thiazepine
ring), 3.42 (s, 3H, OCH3), 3.15 (hump, 1H, CH2NH exchangeable with
D2O), 1.68 (t, 2H, NHCH2CH]); 13CNMR (CDCl3)
d ppm: 164.3, 160.4,
155.5, 151.4, 139.5, 133.3, 129.4, 127.3, 126.5, 120.4, 116.5, 115.4, 55.7,
45.7, 42.6, 39.6; Anal. Calcd for c: C, 72.17; H, 5.43; N, 5.80; Found C,
72.25; H, 5.75; N, 5.68%. MS: [M]þ at m/z 482.59.
(CDCl3)
d
in ppm: 11.78 (s, 2H, 2ꢂ OH exchangeable), 9.28–6.70 (m,
17H, Ar–H þ 1H,C3–H of thiazepine ring), 6.52 (t, 1H, C2–H of thia-
zepine ring), 3.10 (hump,1H, CH2NH exchangeable with D2O),1.66 (t,
2H, NHCH2CH]); Anal. Calcd for C28H23ClN2O2S: C, 69.05; H, 4.76;
N, 5.75 ;Found C, 69.15 ;H,4.65; N, 5.82%. MS: [M]þ at m/z 487.01.
5.1.29. 4-(40-Hydroxyphenyl)-2-(4-hydroxyphenyl)-3-[(4-
methoxyphenylaminomethylene)]-2,3-dihydro-1,5-benzothiazepine
(3j)
5.1.24. 4-(40-Hydroxyphenyl)-2-(4-hydroxyphenyl)-3-[(4-chloro-
phenyaminomethylene)]-2,3-dihydro-1,5- benzothiazepine (3e)
Yield 52% (benzene): m.p 163 ꢁC. IR (KBr) nmax in cmꢀ1: 3457 (OH),
1628 (C]C), 1465 (C]N), 713 (C–Cl), 682 (C–S–C); 1H NMR (CDCl3)
Yield 68% (benzene): m.p 161 ꢁC. IR (KBr) nmax in cmꢀ1: 3452
(OH), 1626 (C]C), 1462 (C]N), 711 (C–Cl), 678 (C–S–C); 1H NMR
(CDCl3)
17H, Ar–H þ 1H–C3–H of thiazepine ring), 6.41 (t, 1H, C2-H of
thiazepine ring), 3.44 (s, 3H, OCH3), 3.10 (hump, 1H, CH2NH
exchangeable with D2O), 1.60 (t, 2H, NHCH2CH]); 13CNMR (CDCl3)
d
in ppm: 11.68 (s, 2H, 2ꢂ OH exchangeable), 9.22–6.64 (m,
d
in ppm: 11.72 (s, 2H, 2ꢂ OH exchangeable), 9.25–6.68 (m, 17H, Ar–
H þ 1H–C3–H of thiazepine ring), 6.48 (t,1H, C2-H of thiazepine ring),
3.12 (hump, 1H, CH2NH exchangeable with D2O), 1.62 (t, 2H,
NHCH2CH]); Anal. Calcd for C28H23ClN2O2S: C, 69.05; H, 4.76;
N,5.75 ;Found C, 69.11; H, 4.55; N, 5.62%. MS: [M]þ at m/z 487.01.
d
ppm: 164.2, 160.5, 155.4, 151.2, 139.1, 133.5, 129.1, 127.4, 126.3,
120.1, 116.0, 115.2, 55.5, 45.4, 42.2, 39.0; Anal. Calcd for
C29H26N2O3S: C, 72.17; H, 5.43; N, 5.80; Found C, 72.10; H, 5.33; N,
5.65%. MS: [M]þ at m/z 482.59.
5.1.25. 4-(40-Hydroxyphenyl)-2-(3-methoxyphenyl)-3-
[(4-methoxyphenylaminomethylene)]-2,3-dihydro-
1,5- benzothiazepine (3f)
5.1.30. General procedure for the synthesis of 4-(40-Hydroxy-
phenyl)-2-(substitutedphenyl)-[3-(substitutedaminomethylene)]-
2,3-dihydro-1,5-benzoxazepines (3a0-3j0)
Yield 67% (methanol): m.p 185 ꢁC. IR (KBr) nmax in cmꢀ1: 3432
(OH), 1618 (C]C), 1458 (C]N), 1221 (OCH3), 665 (C–S–C); 1H NMR
The mixture of 4-(40-Hydroxyphenyl)-2-(substitutedphenyl)-
2,3-dihydro-1,5-benzoxazepines (2a0–2e0) (0.001 mol), substituted
aniline (0.001 mol) and formaldehyde (0.01 mol) in methanol
(30 mL) were refluxed for 4–6 h. The resultant reaction mixtures
were concentrated, cooled and poured on to ice. The separated semi
solid were kept overnight in petroleum ether (40–60 ꢁC). The solid
thus formed were recrystallized from appropriate solvent. The
physical and spectral data of the compounds are the following.
(CDCl3) d in ppm: 11.68 (s,1H, OH exchangeable), 9.20–6.58 (m,17H,
Ar–H þ 1H–C3–H of thiazepine ring), 6.40 (t, 1H, C2-H of thiazepine
ring), 3.41 (s, 6H, 2ꢂ OCH3), 3.00 (hump, 1H, CH2NH exchangeable
with D2O), 1.59 (t, 2H, NHCH2CH]); 13CNMR (CDCl3)
d ppm: 164.3,
160.6, 155.5, 151.3, 139.5, 137.3, 133.8, 129.3, 126.4, 121.9, 117.4, 116.2,
115.3, 112.6, 56.3, 55.6, 45.8, 42.9, 39.4; Anal. Calcd for
C30H28N2O3S: C, 72.55; H, 5.68; N,5.64; Found C, 72.42; H, 5.54; N,
5.48%. MS: [M]þ at m/z 496.62.
5.1.31. 4-(40-Hydroxyphenyl)-2-(3-methoxyphenyl)-3-[(4-chloro-
phenylaminomethylene)]-2,3-dihydro-1,5-benzoxazepine (3a0)
Yield 70% (DMF/water): m.p 165 ꢁC. IR (KBr) nmax in cm-1: 3454
(OH), 1625 (C]C), 1470 (C]N), 1235 (OCH3), 715 (C–Cl), 1035 (C–
5.1.26. 4-(40-Hydroxyphenyl)-2-(2-chlorophenyl)-3-[(4-methoxy-
phenylaminomethylene)]-2,3-dihydro-1,5-benzothiazepine (3g)
Yield 53% (methanol): m.p 162 ꢁC. IR (KBr) nmax in cm-1: 3442
(OH), 1633 (C]C), 1465 (C]N), 710 (C–Cl), 688 (C–S–C); 1H NMR
O–C); 1H NMR (CDCl3)
d in ppm: 11.84 (s, 1H, OH exchangeable),
(CDCl3)
d
in ppm: 11.75 (s,1H, OH exchangeable), 9.30–6.72 (m,17H,
9.28–6.74 (m, 17H, Ar–H þ 1H, C3–H of oxazepine ring), 6.52 (t, 1H,
C2-H of oxazepine ring), 3.55 (s, 3H, OCH3), 3.09 (hump, 1H, CH2NH
exchangeable with D2O), 1.64 (t, 2H, NHCH2CH]); 13CNMR (CDCl3)
Ar–H þ 1H–C3–H of thiazepine ring), 6.55 (t, 1H, C2–H of thiazepine
ring), 3.35 (s, 3H, OCH3), 3.10 (hump, 1H, CH2NH exchangeable with
D2O),1.68 (t, 2H, NHCH2CH]); 13CNMR (CDCl3)
d
ppm: 164.6,160.3,
d ppm: 164.5, 160.7, 149.4, 145.3, 139.6, 129.2, 126.8, 123.2, 121.4,
155.4, 151.9, 139.6, 133.3, 131.8, 128.9, 127.9, 126.3, 116.4, 115.4, 55.7,
46.8, 41.9, 39.6; Anal. Calcd for C29H25ClN2O2S: C, 69.52; H, 5.03;
N,7.08; Found C, 69.62; H, 5.44; N, 7.22% .MS: [M]þ at m/z 501.04.
120.8, 116.5, 115.4, 114.8, 112.3, 111.4, 74.6, 55.6, 40.8, 36.7; Anal.
Calcd for C29H25ClN2O3: C, 71.82; H, 5.20; N, 5.20; Found C, 71.92;
H,5.32; N, 5.32%. MS: [M]þ at m/z 484.16.

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N. Garg et al. / European Journal of Medicinal Chemistry 45 (2010) 1529–1535
5.1.32. 4-(40-Hydroxyphenyl)-2-(2-chlorophenyl)-3-[(4-chloro-
phenylaminomethylene)]-2,3-dihydro-1,5-benzoxazepine (3b0)
Yield 65% (ethanol): m.p 176 ꢁC. IR (KBr) nmax in cmꢀ1: 3440
(OH), 1630 (C]C), 1469 (C]N), 1040 (C–O–C), 715 (C–Cl); 1H NMR
(CDCl3) d in ppm: 11.71 (s, 1H, OH exchangeable), 9.30–6.74 (m, 17H,
Ar–H þ 1H–C3–H of oxazepine ring), 6.59 (t, 1H, C2–H of oxazepine
ring), 3.39 (s, 3H, OCH3), 3.12 (hump, 1H, CH2NH exchangeable with
D2O), 1.62 (t, 2H, NHCH2CH]); 13CNMR (CDCl3)
d ppm: 164.4, 160.4,
(CDCl3)
d
in ppm: 11.78 (s,1H, OH exchangeable), 9.28–6.70 (m,17H,
149.6, 139.8, 129.6, 127.5, 123.8, 121.5, 116.4, 115.8, 114.6, 113.5, 68.3,
55.6, 40.3, 36.6; Anal. Calcd for C29H25ClN2O3: C, 71.82; H, 5.20; N,
5.78; Found C, 71.94; H, 5.34; N, 5.92%. MS: [M]þ at m/z 484.16.
Ar–H þ 1H,C3–H of oxazepine ring), 6.50 (t, 1H, C2–H of oxazepine
ring), 3.08 (hump, 1H, CH2NH exchangeable with D2O), 1.65 (t, 2H,
NHCH2CH]); 13CNMR (CDCl3)
d ppm: 164.2, 160.5, 149.5, 145.0,
139.8, 133.6, 129.8, 126.3, 121.8, 116.6, 115.3, 114.5, 68.7, 40.6, 36.9;
Anal. Calcd for C28H22Cl2N2O2: C, 68.72; H, 4.53; N, 5.72; Found C,
68.83; H, 4.68; N, 5.84%. MS: [M]þ at m/z 489.39.
5.1.38. 4-(40-Hydroxyphenyl)-2-(4-chlorophenyl)-3-[(4-methoxy-
phenylaminomethylene)]-2,3-dihydro-1,5-benzoxazepine (3h0)
Yield 52% (methanol): m.p 166 ꢁC. IR (KBr) nmax in cmꢀ1: 3435
(OH), 1612 (C]C), 1450 (C]N), 708 (C–Cl), 1025 (C–O–C); 1H NMR
5.1.33. 4-(40-Hydroxyphenyl)-2-(4-chlorophenyl)-3-[(4-chloro-
phenylaminomethylene)]-2,3-dihydro-1,5-benzoxazepine (3c0)
Yield 55% (methanol): m.p 170 ꢁC. IR (KBr) nmax in cm-1: 3434
(OH), 1622 (C]C), 1461 (C]N), 711 (C–Cl), 1034 (C–O–C); 1H NMR
(CDCl3) d in ppm: 11.68 (s, 1H, OH exchangeable), 9.20–6.61 (m,
17H, Ar–H þ 1H–C3–H of oxazepine ring), 6.40 (t, 1H, C2–H of
oxazepine ring), 3.45 (s, 3H, OCH3), 3.02 (hump, 1H, CH2NH
exchangeable with D2O), 1.60 (t, 2H, NHCH2CH]);13CNMR (CDCl3)
(CDCl3)
d
in ppm: 11.72 (s,1H, OH exchangeable), 9.24–6.62 (m,17H,
d ppm: 164.3, 160.2, 149.4, 139.5, 129.0, 127.3, 123.7, 121.3, 116.2,
Ar–H þ 1H–C3–H of oxazepine ring), 6.45 (t, 1H, C2–H of oxazepine
115.5, 114.4, 113.2, 68.1, 55.4, 40.2, 36.4; Anal. Calcd for
C29H25ClN2O3: C, 71.82; H, 5.20; N, 5.78; Found C, 71.70; H, 5.04; N,
5.62%. MS: [M]þ at m/z 484.16.
ring), 3.05 (hump, 1H, CH2NH exchangeable with D2O), 1.58 (t, 2H,
NHCH2CH]); 13CNMR (CDCl3)
d ppm: 164.0, 160.1, 149.3, 145.1,
139.2, 133.4, 129.6, 126.2, 121.7, 116.2, 115.0, 114.3, 68.4, 40.2, 36.5;
Anal. Calcd for C28H22Cl2N2O2: C, 68.72; H, 4.53; N, 5.72; Found C,
68.61; H, 4.41; N, 5.63%. MS: [M]þ at m/z 489.39.
5.1.39. 4-(40-Hydroxyphenyl)-2-(2-hydroxyphenyl)-3-[(4-methoxy-
phenylaminomethylene)]-2, 3-dihydro-1,5-benzoxazepine (3i0)
Yield 69% (DMF/water): m.p 182 ꢁC. IR (KBr) nmax in cmꢀ1: 3468
(OH), 1640 (C]C), 1465 (C]N), 722 (C–Cl), 1040 (C–O–C); 1H NMR
5.1.34. 4-(40-Hydroxyphenyl)-2-(2-hydroxyphenyl)-3-[(4-chloro-
phenylaminomethylene)]-2,3-dihydro-1,5-benzoxazepine (3d0)
Yield 61% (methanol): m.p 180 ꢁC. IR (KBr) nmax in cmꢀ1: 3468
(OH), 1634 (C]C), 1470 (C]N), 720 (C–Cl), 1045 (C–O–C); 1H NMR
(CDCl3)
d
in ppm: 11.71 (s, 2H, 2ꢂ OH exchangeable), 9.20–6.71 (m,
17H, Ar–H þ 1H,C3–H of oxazepine ring), 6.61 (t, 1H, C2–H of oxa-
zepine ring), 3.31 (s, 3H, OCH3), 3.12 (hump, 1H, CH2NH
exchangeable with D2O), 1.62 (t, 2H, NHCH2CH]); 13CNMR (CDCl3)
(CDCl3)
d
in ppm: 11.84 (s, 2H, 2ꢂ OH exchangeable), 9.31–6.75 (m,
17H, Ar–H þ 1H–C3–H of oxazepine ring), 6.61 (t, 1H, C2-H of oxa-
d ppm: 164.4, 160.6, 155.4, 151.6, 149.4, 139.6, 124.0, 126.4, 124.9,
zepine ring), 3.16 (hump, 1H, CH2NH exchangeable with D2O), 1.70
116.6 115.4,114.6,113.5,112.5, 68.5, 56.4, 55.6, 41.5, 36.5; Anal. Calcd
for C29H26N2O4: C, 72.66; H, 5.62; N, 6.00; Found C, 72.75; H, 5.74;
N, 6.14%. MS: [M]þ at m/z 466.53.
(t, 2H, NHCH2CH]); 13CNMR (CDCl3)
d ppm: 164.4, 160.6, 155.4,
149.5, 145.8, 139.5, 129.4, 126.5, 123.7, 116.4, 115.0, 114.5, 67.8, 41.5,
36.8; Anal. Calcd for C28H23ClN2O3: C, 71.41; H, 4.92; N, 5.95; Found
C, 71.55; H, 4.99; N, 5.82%. MS: [M]þ at m/z 470.95.
5.1.40. 4-(40-Hydroxyphenyl)-2-(4-hydroxyphenyl)-3-[(4-methoxy-
phenylaminomethylene)]-2, 3-dihydro-1, 5-benzoxazepine (3j0)
Yield 48% (ethanol) m.p 171 ꢁC. IR (KBr) nmax in cmꢀ1: 3450 (OH),
1625 (C]C),1460 (C]N), 712 (C–Cl),1035 (C–O–C); 1HNMR (CDCl3)
5.1.35. 4-(40-Hydroxyphenyl)-2-(4-hydroxyphenyl)-3-[(4-chloro-
phenylaminomethylene)]-2,3-dihydro-1,5-benzoxazepine (3e0)
Yield 40% (ethanol): m.p 168 ꢁC. IR (KBr) nmax in cmꢀ1: 3461
(OH), 1622 (C]C), 1465 (C]N), 712 (C–Cl), 1041 (C–O–C); 1H NMR
d
in ppm: 11.65 (s, 2H, 2ꢂ OH exchangeable), 9.21–6.62 (m, 17H, Ar–
H þ 1H,C3–H of oxazepine ring), 6.40 (t, 1H, C2–H of oxazepine
(CDCl3)
d
in ppm: 11.74 (s, 2H, 2ꢂ OH exchangeable), 9.25–6.65
ring), 3.46 (s, 3H, OCH3), 3.11 (hump, 1H, CH2NH exchangeable with
(m,17H, Ar–H þ 1H–C3–H of oxazepine ring), 6.55 (t, 1H, C2–H of
D2O),1.62 (t, 2H, NHCH2CH]); 13CNMR (CDCl3)
d ppm: 164.3,160.5,
oxazepine ring), 3.10 (hump, 1H, CH2NH exchangeable with D2O),
155.2, 151.4, 149.2, 139.4, 124.3, 126.0, 124.6, 116.4115.2, 114.3, 113.1,
112.2, 68.4, 56.3, 55.2, 41.0, 36.4; Anal. Calcd for C29H26N2O4: C,
72.66; H, 5.62; N, 6.00; Found C, 72.51; H, 5.44; N, 5.84%. MS: [M]þ
at m/z 466.53.
1.65 (t, 2H, NHCH2CH]); 13CNMR (CDCl3)
d ppm: 164.3, 160.0,
155.1, 149.4, 145.6, 139.2, 129.3, 126.0, 123.4, 116.2, 115.4, 114.3, 67.5,
41.2, 36.5; Anal. Calcd for C28H23ClN2O3: C, 71.41; H, 4.92; N, 5.95;
Found C, 71.28; H, 4.79; N, 5.75%. MS: [M]þ at m/z 470.95.
5.2. Pharmacological evaluation
5.1.36. 4-(40-Hydroxyphenyl)-2-(3-methoxyphenyl)-3-[(4-methoxy-
phenylaminomethylene)]-2,3-dihydro-1,5-benzoxazepine (3f0)
Yield 58% (ethanol): m.p 174 ꢁC. IR (KBr) nmax in cmꢀ1: 3432
(OH), 1618 (C]C), 1458 (C]N), 1221 (OCH3), 1030 (C–O–C); 1H
5.2.1. Anticonvulsant screening
The anticonvulsant activity was performed according the
method of Toman et al. [11] on Charles foster rats of either sex
weighing, between 90 and 150 g. Rats were divided into groups of
ten animals each. The rats were treated with different doses of test
drugs or phenytoin sodium 30 mg/kg i.p. After 1 h they were
subjected to a shock of 150 m.A by convulsiometer, through ear
electrodes for 2 s and the presence or absence of extensor
response was noted. Animals in which extensor response was
abolished were taken as protected rats. The compounds were also
investigated for their acute toxicity ALD50 in mice by following the
method of Smith [12].
NMR (CDCl3) d
in ppm: 11.68 (s, 1H, OH exchangeable), 9.20ꢀ1, 6.58
(m, 17H, Ar–H þ 1H,C3–H of oxazepine ring), 6.40 (t, 1H, C2–H of
oxazepine ring), 3.41 (s, 6H, 2ꢂ OCH3), 3.00 (hump,1H,CH2NH
exchangeable with D2O), 1.59 (t, 2H, NHCH2CH]); 13CNMR (CDCl3)
d
ppm: 164.2, 160.5, 156.5, 151.4, 149.3, 139.5, 129.5, 124.8, 116.0,
115.4, 114.5, 113.2, 112.4, 68.6, 56.6, 55.3, 41.5, 36.4; Anal. Calcd for
C30H28N2O4: C, 74.98; H, 5.87; N, 5.83; Found C,73.11; H,5.97; N,
5.98%. MS: [M]þ at m/z 480.55.
5.1.37. 4-(40-Hydroxyphenyl)-2-(2-chlorophenyl)-3-[(4-methoxy-
phenylaminomethylene)]-2, 3-dihydro-1, 5-benzoxazepine (3g0)
Yield 61% (benzene): m.p 172 ꢁC. IR (KBr) nmax in cmꢀ1: 3445
(OH), 1637 (C]C), 1469 (C]N), 715 (C–Cl), 1035 (C–O–C); 1H NMR
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