Benzoxepin derivatives: Design, synthesis, and pharmacological evaluation with sedative-hypnotic effect

Article abstract of DOI:10.1007/s00044-011-9579-3

A series of novel benzoxepin-derived compounds were synthesized and evaluated for their sedative- hypnotic effect using Phenobarbital-induced sleep test in mice. Compound 6 in which the Phenobarbital moiety was incorporated into the benzoxepin nucleus was

Full text of DOI:10.1007/s00044-011-9579-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:747–759
DOI 10.1007/s00044-011-9579-3
ORIGINAL RESEARCH
Benzoxepin derivatives: design, synthesis, and pharmacological
evaluation with sedative–hypnotic effect
•
Nagwa M. Abdel Gawad Ghaneya S. Hassan
•
•
Hanan H. Georgey Hesham Y. El-Zorba
Received: 14 November 2010 / Accepted: 18 January 2011 / Published online: 6 February 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of novel benzoxepin-derived com-
pounds were synthesized and evaluated for their sedative–
hypnotic effect using Phenobarbital-induced sleep test in
mice. Compound 6 in which the Phenobarbital moiety was
incorporated into the benzoxepin nucleus was the most
active one. Molecular modeling, including fitting to a
3D-pharmacophore model using Discovery Studio 2.1 pro-
grams into optimized benzodiazepine receptor (hypothesis)
showed high fit values. The experimental studies for the
in vivo sedative–hypnotic effect of compounds 2–6 and
11a–c were consistent with the molecular modeling.
(Nishino et al., 2008; Westra and Stewart, 2002), muscle-
relaxant (Delgado et al., 2010; Kazanietz and Elgoyhen,
1990), and anticonvulsant actions (Shah et al., 2010;
Sommer et al., 2007). Recently, BZ derivatives signifi-
cantly showed anti-neuroinflammatory effects by sup-
pressing iNOS (inducible NO synthase enzyme) activity
(Ha et al., 2010).
Benzodiazepine receptors can be subdivided into two
types: CBR (central benzodiazepine receptors) and PBR
(peripheral benzodiazepine receptors). The CBR is found
only on neurons in the central nervous system, coupled with
the GABA a (c-aminobutyric acid) receptor (Peterson,
1987). Ligands acting at the benzodiazepine binding site of
the GABA a receptor allosterically modulate the action of
GABA on neuronal chloride ion flux. They show a wide
variety of pharmacological actions ranging in a continuum
from full agonists (sedative/hypnotic, anxiolytic, and anti-
convulsant activities) to inverse agonists (anxiogenic, and
proconvulsant activities). Antagonists do not exhibit any
direct pharmacological effects but can antagonize the actions
of both agonists and inverse agonists (Bell et al., 2003;
Barnard et al., 1998; Bloom et al., 1996; McKernan and
Whiting, 1996; Sieghart and Sieghart, 1995; Smith and
Olsen, 1995; Yeh and Grigorenko, 1995, Bellantuono et al.,
1980).
Keywords Benzoxepin ꢀ Mannich reaction ꢀ
Bromination ꢀ Phenobarbital ꢀ Sedative and hypnotic
Introduction
According to the US National Institute of Mental Health,
anxiety disorders affect annually about 40 million adults
ranging in age from 18 years and older who represents
18.1% of people in this age (PHRMA, 2010) making this
an important social problem. The BZ (benzodiazepine)
classes of drugs are used clinically for their anxiolytic
´
(Mombereau et al., 2010; Jimenez-Velazquez et al., 2010;
´
Benedetti et al., 2004; Westra and Stewart, 2002), hypnotic
From another point of view, considerable interest has
been focused on the benzoxepin structures, which have been
reported to possess central nervous system depressants
(Porter and Prus, 2009; Freedman, 1975). A compound
disclosed is 6,7,8,9,10,11-hexahydro-6,6-dimethyldibenz
[b,d]oxepin-3-ol I (Freedman, 1975). However, benzoxe-
pin derivatives have documented consistent advances in
the design of novel atypical antipsychotic (Porter and
Prus, 2009). On the other hand, pharmacological evalua-
tion of a structurally related compound to benzoxepin,
N. M. Abdel Gawad ꢀ G. S. Hassan ꢀ H. H. Georgey (&)
Department of Pharmaceutical Chemistry, Faculty of Pharmacy,
Cairo University, Cairo, Egypt
e-mail: hanan-hanna@hotmail.com
H. Y. El-Zorba
Department of Pharmacology, Faculty of Veterinary Medicine,
Cairo University, Cairo, Egypt
123

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Med Chem Res (2012) 21:747–759
2-(4-chlorophenyl)-5,6-dihydrobenzothiepino[5,4-c]pyridazin-
(2H)-on-7-oxide II had revealed that, it is highly active as
an anxioselective anxiolytic agent (Yasumatsu et al., 1994);
(Nakao et al., 1992); (Nakao et al., 1991). The selectivity of
this interesting compound was attributed to its partial ago-
nist effect on BZR (benzodiazepine receptors) (Yasumatsu
et al., 1994); (Nakao et al., 1992); (Nakao et al., 1991).
BZR partial agonists were reported as candidates that could
maintain the therapeutic potential with fewer side effects
than BZR full agonists in the treatment of anxiety (Tanaka
et al., 1995). Consequently, in the light of these facts, in the
scope of a research program aimed at the development of
new isosteric analogues to compound II, we described in
this study, the synthesis and the pharmacological evaluation
of some new benzoxepine derivatives 11a–c as sedative–
hypnotic agents. In our research, new ligands acting on BZR
among benzoxepin derivatives were synthesized and
investigated for their sedative–hypnotic activity. Moreover,
in view of the biological activity of Phenobarbital that acts
as sedative–hypnotic through enhancing GABA binding
(Gillon et al., 2010), we planned to synthesize a hybridized
benzoxepin derivative 6 by incorporating the Phenobarbital
moiety at the 4-position of the benzoxepin nucleus aiming
to obtain a highly sedative–hypnotic agent. Furthermore,
other new substituted aminomethyl-benzoxepin 3, and
benzylideno-benzoxepin 4 were also synthesized and
evaluated for their sedative–hypnotic effect.
Experimental
Chemistry
Melting points are uncorrected and determined in one end
open capillary tubes using Gallen Kamp melting point
apparatus MFB-595-010 M (Gallen Kamp, London, Eng-
land). Microanalysis was carried out at Micro analytical
Unit, Faculty of Science, Cairo University. IR spectra were
determined using KBr discs (cm-1) on Shimadzu Infrared
Spectrometer IR-435 (Shimadzu, Kyoto, Japan), Perkin-
Elmer FT-IR 1650 (Perkin-Elmer, Waltham, Massachusetts
02451, USA) and Mattson Genesis II FTIRTM Spectrom-
1
eter (Mattson, Madison, WI, USA). H-NMR (DMSO-d6,
D2O) d ppm spectra were determined using Joel NMR
Varian Gemini 200 MHz Spectrometer (Joel, Tokyo,
Japan) and Varian Mercury VX-300 MHz NMR Spec-
trometer (Varian, Oxford, England). 13C-NMR spectra
were obtained on a Bruker APX400 spectrometer in the
specified solvent (Varian, Darmstadt, Germany). Mass
spectra were recorded using Hewlett Packard Varian
(Varian, Polo, USA) and Shimadzu Gas Chromatograph
Mass spectrometer-QP 1000 EX (Shimadzu, Kyoto, Japan).
TLC were carried out using Art.DC-Plastikfolien, Kiesel-
gel 60 F254 sheets (Merck, Darmstadt, Germany), the
developing solvents were benzene/methanol (4:1) and the
spots were visualized at 366, 254 nm by UV Vilber
Cl
R
C2H5
O
N
O
O
O
N
N
NH
O
N
N
Cl
Cl
O
CH3
CH3
HO
O
S
O
O
O
I
11a-c
II
6
In addition, the design was also based on the molecular
modeling simulation study using Discovery Studio 2.1
programs, which was performed in order to predict seda-
tive–hypnotic effect of the proposed compounds. A new
BDZ receptor agonist pharmacophore model (hypothesis)
was generated in order prioritize the activity of the pro-
posed new molecules. Comparing the fit studies between
such hypothesis and the planned compounds indicated that
they have promising sedative–hypnotic activity and could
be considered hit molecules.
Lourmat 77202 (Vilber, Marne La Vallee, France). Log P
were calculated using ChemDraw Ultra V 8.0.
7-Chloro-3,4-dihydrobenzo[b]oxepin-5(2H)-one 2
(Scheme 1)
To a solution of 4-(4-chlorophenoxy)butanoic acid 1
(4.29 g, 20 mmol) in dry toluene (20 mL), was added with
stirring Celite (5 g) and phosphorus pentaoxide (5.68 g,
40 mmol). The mixture was refluxed for 4 h and then
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Med Chem Res (2012) 21:747–759
749
Scheme 1 Reagents and
O
reaction conditions: a P2O5/
Celite/dry toluene, reflux. b 1
NH.R1R2.HCl/HCHO/acetic
anhydride, reflux. 2 NH4OH
a
Cl
Cl
OCH2CH2CH2COOH
O
2
1
b
O
CH2NR1R2
Cl
O
3a NR1R2
3b NR1R2
3c NR1R2 = N(CH2)4NCH3
=
=
N(CH3)2
N(CH2)5
3a-e
3d NR1R2
3e NR1R2
=
=
N(CH2)4NC6H4-o-Cl
N(CH2)4O
filtered while hot. The filtrate was washed with 1%
NaHCO3, dried over Na2SO4, and concentrated in vacuum
to give compound 2. The residue was recrystallized from
methanol gave yellowish-white crystals, m.p. 72–74°C,
aliphatic), 1762 (C=O), 760 (C–Cl). MS (m/z): 255
(M??2), 253 (M?). Anal. C13H16ClNO2 (253.72): C,
61.54; H, 6.36; N, 5.52. Found: C, 61.04; H, 6.10; N, 5.20.
7-Chloro-4-((piperdin-1-yl)methyl)-3,4-dihydrobenzo
[b]oxepin-5(2H)-one (3b) Yield 54%, m.p. 67–69°C.
1H-NMR (DMSO-d6) d: 2.09-2.20 (6H, m, (CH2)3), 2.31
(2H, m, CH2), 2.89–2.94 (6H, m, –CH2–N–(CH2)2), 4.16
(2H, t, OCH2, J = 11.4 Hz), 4.73 (1H, s, CHCO), 6.88
(1H, d, ArH, J = 8.7 Hz), 7.19 (1H, d, ArH, J =
12.6 Hz), 7.46 (1H, d, ArH, J = 2.7 Hz). IR (KBr)
cm-1: 3078, 3062 (CH aromatic), 2966, 2941 (CH ali-
phatic), 1762 (C=O), 765 (C–Cl). MS (m/z): 291 (M?- 2).
Anal. C16H20ClNO2 (293.79): C, 65.41; H, 6.86; N, 4.77.
Found: C, 65.80; H, 6.60; N, 4.90.
1
yield 85%. H-NMR (CDCl3-D2O) d: 2.29 (2H, m, CH2),
2.94 (2H, t, CH2CO, J = 7.4 Hz), 4.16 (2H, t, OCH2,
J = 11.7 Hz), 6.84 (1H, d, ArH, J = 9.0 Hz), 7.17 (1H, d,
ArH, J = 11.0 Hz), 7.45 (1H, d, ArH, J = 2.7 Hz). IR
(KBr) cm-1: 3097, 3076, 3034 (CH aromatic), 2970, 2951
(CH aliphatic), 1718 (C=O), 740 (C–Cl). MS (m/z): 196
(M?). Anal. C10H9ClO2 (196.63): C, 61.08; H, 4.61.
Found: C, 61.20; H, 4.30.
General method for preparation of compounds 3a–
e (Scheme 1)
7-Chloro-4-((4-methylpiperazin-1-yl)methyl)-3,4-
dihydrobenzo[b]oxepin-5(2H)-one (3c) Yield 50%, m.p.
81–84°C. 1H-NMR (CDCl3) d: 1.27 (3H, s, NCH3),
2.25–2.34 (6H, m, (CH2)2 and CH2), 2.89–2.94 (6H, m,
–CH2–N–(CH2)2), 4.12-4.20 (3H, m, OCH2 and CHCO),
6.85 (1H, d, ArH, J = 9.0 Hz), 7.17 (1H, d, ArH,
J = 11.4 Hz), 7.46 (1H, d, ArH, J = 2.7 Hz). 13C-NMR
(CDCl3) d: 24.3 (C-3), 25.5 (CH3), 29.7 (C-4), 30.2 (C-20,
C-30), 67.9 (CH2N), 114.3 (C-2), 123.9 (C-9), 127.6 (C–Cl),
131.9 (C-6), 133.0 (C-8), 145.6 (C-5a), 153.1 (C-9a),
170.4 (C=O). IR (KBr) cm-1: 3095, 3076 (CH aromatic),
2921, 2852 (CH aliphatic), 1764 (C=O), 759 (C–Cl). MS
(m/z): 310 (M??2), 308 (M?). Anal. C16H21ClN2O2
(308.80): C, 62.23; H, 6.85; N, 9.07. Found: C, 62.40; H,
6.50; N, 8.70.
A solution of the appropriate secondary amine hydrochlo-
ride (15 mmol) in 37% HCHO (0.6 g, 1.6 ml, 20 mmol)
was stirred at room temperature for 0.5 h. Acetic anhydride
(5 ml) was added dropwise and the mixture was stirred at
70–75°C for further 0.5 h. Compound 2 (1.96 g, 10 mmol)
was added and the mixture was stirred at 70–75°C for 3 h.
After cooling, the reaction mixture was concentrated in
vacuum. The residue was dissolved in chilled water, neu-
tralized with 28% NH4OH and extracted with CHCl3. The
extract was washed with water, dried over Na2SO4, and
evaporated below 40°C. The residue was recrystallized
from CHCl3/ether.
7-Chloro-4-(dimethyamino)methyl-3,4-dihydro-
benzo[b]oxepin-5(2H)-one (3a) Yield 45%, m.p. 79–82°C.
1H-NMR (CDCl3-D2O) d: 2.25 (2H, m, CH2), 2.34–2,57
(8H, m, CH2–N(CH3)2), 2.94 (1H, m, CHCO), 4.16 (2H, t,
OCH2, J = 11.7 Hz), 6.85 (1H, d, ArH, J = 8.7 Hz), 7.17
(1H, d, ArH, J = 11.4 Hz), 7.46 (1H, d, ArH, J = 2.4 Hz).
IR (KBr) cm-1: 3050 (CH aromatic), 2924, 2850 (CH
7-Chloro-4-((4-(2-chlorophenyl)piperazin-1-yl)methyl)-
3,4-dihydrobenzo[b]oxepin-5(2H)-one (3d) Yield 55%,
m.p. 78–80°C. 1H-NMR (CDCl3) d: 2.00–2.20 (6H, broad,
–N(CH2)2 and CH2), 2.58–2.78 (6H, broad, CH2N(CH2)2),
4.01–4.20 (3H, broad, OCH2, CHCO), 6.71–6.85 (2H,
broad, ArH), 7.10–7.40 (5H, m, ArH). IR (KBr) cm-1
:
123

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Med Chem Res (2012) 21:747–759
3095, 3078 (CH aromatic), 2972, 2889 (CH aliphatic),
1762 (C=O), 759 (C–Cl). MS (m/z): 405 (M?), 407
(M??2). Anal. C21H22Cl2N2O2 (405.32): C, 62.23; H,
5.47; N, 6.91. Found: C, 61.90; H, 5.20; N, 6.70.
cm-1: 3095, 3078, 3034 (CH aromatic), 2970, 2891 (CH
aliphatic), 1766 (C=O), 760 (C–Cl). MS (m/z): 302 (M?),
267 (M?-35). Anal. C17H12ClFO2 (302.72): C, 67.45; H,
4.00. Found: C, 67.70; H, 4.30.
7-Chloro-4-((morphlino-1-yl)methyl)-3,4-dihydrobenzo
1
4-(Chlorobenzylidene)-7-chloro-3,4-dihydrobenzo[b]
oxepin-5(2H)-one (4c) Yield 63%, m.p. 112–114°C.
1HNMR (DMSO-d6) d: 2.30 (2H, t, CH2), 4.14 (2H, t,
OCH2), 6.89 (3H, d, ArH), 7.08–7.39 (4H, m, ArH, and
=CH–Ar), 7.46 (1H, d, ArH). IR (KBr) cm-1: 3097, 3038
(CH aromatic), 2970, 2889 (CH aliphatic), 1716 (C=O),
740 (C–Cl). MS (m/z): 320 (M??2), 318 (M?). Anal.
C17H12Cl2O2 (319.18): C, 63.97; H, 3.79. Found: C,
63.70; H, 3.90.
[b]oxepin-5(2H)-one (3e) Yield 50%, m.p. 91–93°C. H-
NMR (CDCl3) d: 2.25–2.34 (6H, m, CH2 and N(CH2)2),
2.91 (2H, t, –CH2N, J = 14.1 Hz), 4.12–4.16 (7H, m,
OCH2, CHCO and O(CH2)2), 6.88 (1H, d, ArH,
J = 8.7 Hz), .20 (1H, d, ArH, J = 11.1 Hz), 7.46 (1H, d,
ArH, J = 2.4 Hz). IR (KBr) cm-1: 3095, 3075 (CH aro-
matic), 2966, 2885 (CH aliphatic), 1762 (C=O), 758 (C–
Cl). MS (m/z): 296 (M??1). Anal. C15H18ClNO3
(295.76): C, 60.91; H, 6.13; N, 4.74. Found: C, 60.70; H,
5.90; N, 4.30.
7-Chloro-4-(methoxybenzylidene)-3,4-dihydrobenzo[b]
1
oxepin-5(2H)-one (4d) Yield 54%, m.p. 128–130°C. H-
NMR (CDCl3) d: 2.27 (2H, t, CH2, J = 12.2 Hz), 3.90
(3H, s, OCH3), 4.16 (2H, t, OCH2, J = 12 Hz), 6.85 (1H,
d, ArH, J = 8.7 Hz), 7.07–7.28 (5H, m, ArH), 7.38 (1H,
s, =CH–Ar), 7.46 (1H, d, ArH, J = 2.3 Hz). 13C-NMR
(CDCl3) d: 24.3 (C-3), 59.0 (OCH3), 67.9 (C-2), 114.3 (C-
3’), 114.5 (C-9), 123.9 (C-5a), 126.0 (C-7), 127.5 (C-20),
127.9 (C-10), 130.0 (C-6), 130.1 (C-8), 131.9 (C-4), 145.6
(-CH=Ar), 153.0 (C-9a), 154.0 (C-4’), 170.4 (C=O). IR
(KBr) cm-1: 3095, 3035 (CH aromatic), 2950, 2889 (CH
aliphatic), 1764 (C=O), 760 (C–Cl). MS (m/z): 302
[(M??2)-CH3]. Anal. C18H15ClO3 (314.76): C, 68.68; H,
4.80. Found: C, 68.50; H, 4.60
General method for preparation of compounds
4a–d (Scheme 2)
A mixture of benzoxepin derivative 2 (1.96 g, 10 mmol),
the appropriate aromatic aldehyde (10 mmol) and anhy-
drous sodium acetate (1.64 g, 20 mmol) in glacial acetic
acid (10 mL) was refluxed for 6 h, cooled, and poured into
chilled water. The separated solid was filtered, washed with
water, dried and recrystallized from methanol.
4-Benzylidene-7-chloro-3,4-dihydrobenzo[b]oxepin-
5(2H)-one (4a) Yield 65%, m.p. 96–98°C. 1H-NMR
(CDCl3) d: 2.17 (2H, t, CH2, J = 13.2 Hz), 4.14 (2H, t,
OCH2, J = 12 Hz), 6.82 (1H, d, ArH, J = 8.7 Hz), 7.17
(1H, d, ArH, J = 6.6 Hz), 7.27 (1H, s, =CH–Ar),
7.36–7.40 (5H, m, ArH), 8.11 (1H, d, ArH, J = 2.5 Hz).
IR (KBr) cm-1: 3093, 3034 (CH aromatic), 2968, 2887
(CH aliphatic), 1766 (C=O), 760 (C–Cl). MS (m/z): 285
(M??1), 283 (M?-1). Anal. C17H13ClO2 (284.74): C,
71.71; H, 4.60. Found: C, 71.50; H, 4.40.
4-Bromo-7-chloro-3,4-dihydrobenzo[b]oxepin-5(2H)-one
5 (Scheme 3)
To a suspension of copper (II) bromide (4.46 g, 20 mmol)
in chloroform (20 mL) and ethyl acetate (20 mL), com-
pound 2 (1.96 g, 10 mmol) was added. The mixture was
refluxed for 30-60 min. Completion of the reaction is
indicated by disappearance of all the black copper (II)
bromide solid and appearance of white copper (I) bromide.
The mixture was filtered while hot and the residue was
washed with hot chloroform. The combined filtrate and
washing were concentrated in vacuum to give compound 5,
which were recrystallized from benzene.
4-(Fluorobenzylidene)-7-chloro-3,4-dihydro-
benzo[b]oxepin-5(2H)-one (4b) Yield 60%, m.p.
178–180°C. 1H-NMR (DMSO-d6) d: 2.19 (2H, t, CH2,
J = 13.8 Hz), 4.09 (2H, t, OCH2, J = 12 Hz), 6.85 (3H, d,
ArH, J = 8.7 Hz), 7.15 (3H, d, ArH, J = 11.1 Hz), 7.27
(1H, s, =CH–Ar), 7.36 (1H, d, ArH, J = 2.4 Hz). IR (KBr)
Scheme 2 Reagents and
reaction conditions: a ArCHO/
anh.NaOAc/glacial acetic acid,
reflux
R
O
O
Cl
a
Cl
O
O
2
4a R = H
4b R = F
4c R = Cl
4d R = OCH3
4a-d
123

Med Chem Res (2012) 21:747–759
751
20 mmol) was added to the resulting solution below 5°C in
an ice bath. The mixture was allowed to stand at room
temperature for 24 h., and filtered. The solid was washed
with acetone and recrystallized with methanol/water. Yield
55%, m.p.[300°C. 1H-NMR (CDCl3) d: 2.30 (2H, t, CH2,
J= 12.0 Hz), 2.46–2.52 (9H, m, N(CH3)3), 3.61–4.12 (5H,
m, OCH2 CHCO, and CH2N), 7.13 (1H, d, ArH, J=
8.7 Hz), 7.32 (1H, d, ArH, J= 11.1 Hz), 7.49 (1H, d, ArH,
J= 2.3 Hz). IR (KBr) cm-1: 3075 (CH aromatic), 2970,
2942 (CH aliphatic), 1736 (C=O), 736 (C–Cl). MS (m/z):
397 (M??2), 395 (M?). Anal. C14H19ClINO5 (395.66): C,
42.50; H, 4.84; N, 3.54. Found: C, 42.90; H, 4.60; N, 3.80.
O
O
Br
Cl
Cl
a
O
O
5
2
b
C2H5
O
O
O
NH
N
Cl
O
O
6
2-(7-Chloro-2,3,4,5-tetrahydro-5-oxobenzo[b]oxepin-4-yl)
acetonitrile 8 (Scheme 4)
Scheme 3 Reagents and reaction conditions: a CuBr2/chloroform/
ethyl acetate, reflux. b Phenobarbital Sodium/anh.K2CO3/DMF, reflux
1
To a solution of compound 7 (3.95 g, 10 mmol) in meth-
anol (50 mL) was added a solution of KCN (1.95 g,
30 mmol) in water (10 mL) dropwise at room temperature.
The solution was stirred at room temperature for 1 h and
poured into ice-water. The resulting mixture was extracted
with CHCl3. The extract was washed with water, dried over
MgSO4, and concentrated in vacuum. After the addition of
diethyl ether to the residue, the crystals formed were col-
lected by filtration. The solid was recrystallized with eth-
anol/water. Yield 50%, m.p. 151–153°C. 1H-NMR
(CDCl3) d: 2.50 (2H, t, CH2, J = 11.0 Hz), 3.56 (2H, d,
CH2CN, J = 1 Hz), 3.95 (2H, d, OCH2, J = 11.5 Hz),
4.55 (1H, broad, C4-H), 6.70 (1H, d, ArH, J= 8.7 Hz), 7.15
(1H, d, ArH, J = 11.1 Hz), 7.42 (1H, d, ArH, J = 2.4 Hz).
IR (KBr) cm-1: 3075 (CH aromatic), 2930 (CH aliphatic),
2261 (C:N), 1736 (C=O), 728 (C–Cl). MS (m/z): 235
(M?), 233 (M?-2). Anal. C12H10ClNO2 (235.67): C, 61.16;
H, 4.28; N, 5.94. Found: C, 61.40; H, 4.50; N, 5.80.
Yield 90%, m.p. 175–177°C. H-NMR (CDCl3) d: 2.31
(2H, m, CH2), 4.16 (2H, t, OCH2, J= 12 Hz), 6.83 (1H, d,
ArH, J = 8.7 Hz), 7.10 (1H, t, -CH-Br), 7.38 (1H, d, ArH,
J = 11.1 Hz), 7.46 (1H, d, ArH, J = 2.3 Hz). IR (KBr)
cm-1: 3097, 3078 (CH aromatic), 2970, 2951, 2889 (CH
aliphatic), 1762 (C=O), 740 (C–Cl). MS (m/z): 275 (M?),
277 (M??2). Anal. C10H8BrClO2 (275.53): C, 43.59; H,
2.93. Found: C, 43.70; H, 3.20.
1-(7-Chloro-2,3,4,5-tetrahydro-5-oxobenzo[b]oxepin-4-yl)-
5-ethyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione 6
(Scheme 3)
A mixture of compound 5 (2.75 g, 10 mmol), Phenobar-
bital mono sodium salt (2.76 g, 10 mol), anhydrous
potassium carbonate (2 g) and dimethyl formamide
(20 mL) was heated at 100°C for 8 h. The mixture was
filtered while hot and the filtrate was concentrated in vac-
uum to give compound 6. The residue was extracted with
chloroform and washed several times with water. The
organic solution was concentrated in vacuum and the solid
was recrystallized from methanol. Yield 65%, m.p.
135–137°C. 1H-NMR (CDCl3, D2O) d: 1.29 (3H, t,
CH2CH3), 2.59 (2H, m, CH2), 4.03 (2H, m, CH2CH3), 4.19
(2H, t, OCH2, J = 12 Hz), 5.01 (1H, broad, CH) 6.82–7.60
2-(7-chloro-2,3,4,5-tetrahydro-5-oxobenzo[b]oxepin-4-yl)
acetic acid 9 (Scheme 4)
To a solution of conc. HCl (10 mL) and acetic acid
(10 mL) was added compound 8 (2.35 g, 10 mmol). The
solution was refluxed for 4 h, and poured into ice-water.
The precipitate was collected by filtration, washed with
water, and recrystallized from methanol. Yield 57%, m.p.
(8H, m, ArH), 8.84 (1H, s, NH exch. D2O). IR (KBr) cm-1
:
3308 (NH), 3087 (CH aromatic), 2970, 2933 (CH ali-
phatic), 1736, 1716 (2 C=O), 728 (C–Cl).MS (m/z): 426
(M?). Anal. C22H19ClN2O5 (426.85): C, 61.90; H, 4.40; N,
6.56. Found: C, 62.00; H, 4.10; N, 6.80.
1
193–195°C. H-NMR (CDCl3-D2O) d: 2.50 (2H, t, CH2,
J = 11.0 Hz), 2.73 (2H, d, CH2COO, J = 1 Hz), 4.09 (3H,
m, OCH2 and C4-H), 6.80 (1H, d, ArH, J = 8.6 Hz), 7.16
(1H, d, ArH, J = 11.4 Hz), 7.36 (1H, d, ArH, J = 2.4 Hz),
7.95 (1H, s, COOH, exch. D2O). IR (KBr) cm-1: 3097,
3076 (CH aromatic), 2927 (CH aliphatic), 1716, 1693 (2
C=O), 742 (C–Cl). MS (m/z): 252 (M?-2). Anal.
C12H11ClO4 (254.67): C, 56.59; H, 4.35. Found: C, 56.90;
H, 4.20.
7-Chloro-4-trimethylammoniummethyl-3,4-
dihydrobenzo[b]oxepin-5(2H)-one 7 (Scheme 4)
Compound (3a) (2.53 g, 10 mmol) was dissolved in dry
acetone (50 mL), and iodomethane (2.8 g, 1.3 mL,
123

752
Med Chem Res (2012) 21:747–759
Scheme 4 Reagents and
reaction conditions: a CH3I, dry
actone, reflux. b KCN, stirr at
room temperature. c HCl, acetic
acid, reflux. d p-
CH3
+
CH3
N
CH3
CH3
O
O
CH3
I-
CH2
CH2N
Cl
Cl
a
RC6H4NHNH2ꢀHCl, sodium
acetate, ethanol, reflux. e Acetic
acid, reflux
O
O
3a
7
b
O
O
CH2COOH
CH2CN
Cl
Cl
c
O
O
9
8
R
d
R
O
HN
N
e
N
N
CH2COOH
Cl
Cl
O
O
11a R= H
11b R= Cl
11c R= OCH3
10
11a-c
OCH2 and CH), 6.81–7.40 (7H, m, ArH). 13C-NMR
(CDCl3) d: 24.1 (C-4a), 30.3 (C-5), 31.0 (C-4), 68.2 (C-
6), 114.0 (C-50), 118.0 (C-9), 123.8 (C-20), 125.8 (C–Cl),
129.0 (C-20 & C-30), 129.8 (C–Cl), 131.0 (C-60), 139.0 (C-
40), 153.0 (C-8), 179.0 (C=O). IR (KBr) cm-1: 3097, 3076
(CH aromatic), 2924, 2854 (CH aliphatic), 1716 (C=O),
740 (C–Cl). MS (m/z): 360 (M?), 362 (M??2). Anal.
C18H14Cl2N2O2 (361.22): C, 59.85; H, 3.91; N, 7.76.
Found: C, 59.80; H, 3.70; N, 7.50.
2-(4-Methoxyphenyl)-4,40,5,6-tetrahydro-10-chlorobenzo
[40,30:2,3]oxepino[4,5-c]pyrdiazin-3(2H)one (11c). Yield
70%, oil. 1H-NMR (CDCl3) d: 2.40 (2H, t, CH2,
J = 10.5 Hz), 2.85 (2H, d, CH2C=O), 3.85 (3H, s, OCH3),
4.17 (3H, m, OCH2 and CH), 6.81–7.40 (7H, m, ArH). IR
(KBr) cm-1: 3097, 3076 (CH aromatic), 2924, 2854 (CH
aliphatic), 1685 (C=O), 740 (C–Cl). MS (m/z): 356 (M?).
Anal. C19H17ClN2O3 (356.8): C, 63.96; H, 4.80; N, 7.85.
Found: C, 64.00; H, 4.50; N, 7.60.
General method for preparation of compounds
11a–c (Scheme 4)
A mixture of compound 9 (2.54 g, 10 mmol), sodium acetate
(0.82 g, 10 mmol), and the appropriate phenyl hydrazine
hydrochloride (10 mmol) in ethanol (20 mL) was refluxed
for 15 h. After the evaporation of the solvent, the residue was
dissolved in acetic acid (10 mL). The mixture was refluxed
for 3 h, cooled, poured into ice-water, and extracted with
chloroform. The extract was washed with water, dried over
Na2SO4, and concentrated in vacuum. The solid residue was
recrystallized with chloroform/ethanol.
2-Phenyl-4,40,5,6-tetrahydro-10-chlorobenzo[40,30:2,3]
oxepino[4,5-c]pyrdiazin-3(2H)one (11a). Yield 67%,
1
m.p. 120–122°C. H-NMR (CDCl3) d: 1.90 (2H, t, CH2,
J = 10.5 Hz), 2.40 (2H, d, CH2C=O), 3.40 (2H, d, OCH2,
J = 11.0 Hz), 4.20 (1H, m, CH), 6.65–7.80 (8H, m,
ArH). IR (KBr) cm-1: 3097, 3076 (CH aromatic), 2924,
2854 (CH aliphatic), 1680 (C=O), 760 (C–Cl). MS (m/z):
328 (M??2). Anal. C18H15ClN2O2 (326.78): C, 66.16; H,
4.35; N, 8.57. Found: C, 65.90; H, 4.20; N, 8.50.
Pharmacology
2-(4-Chlorophenyl)-4,40,5,6-tetrahydro-10-chlorobenzo
Animals
[40,30:2,3]oxepino[4,5-c]pyrdiazin-3(2H)one (11b). Yield
1
60%, m.p. 136–138°C. H-NMR (CDCl3) d: 2.10 (2H, t,
CH2, J = 10.5 Hz), 2.65 (2H, d, CH2C=O), 4.08 (3H, m,
Male mice (20–25 g) were randomly divided into groups of
8, housed in a breeding room with 12 h light–dark cycle at
123

Med Chem Res (2012) 21:747–759
753
Fig. 1 Effects of the new
heterocyclic compounds
according to the Phenobarbital-
induced sleep test
140
120
100
80
60
40
20
0
Compound
24 1°C and, fed with standard rodent diet and water.
Animals were allowed to adapt to the laboratory environ-
ment for 1 week before experimentation. The experimental
tests on animals have been performed in accordance with
the Institutional Ethical Committee approval, Faculty of
Pharmacy, Cairo University.
using generation common feature pharmacophore model in
Discovery studio 2.1. The lead compounds, which were
reported to have GABA agonist activity (Fig. 2), were used
to generate common feature hypotheses for the GABA
agonist (Georgey, 2007; Krogsgaard-Larsen et al., 2002;
Tanaka et al., 1995). The set of conformational models of
each structure of the lead compounds was performed and
used to generate the common feature hypotheses, where ten
hypotheses were generated (Girgis et al., 2010; Ismail
et al., 2006). The assessment of the preferred hypothesis
among the generated ones indicated that hypothesis ranked
number 2 was the most appropriate (Fig. 3). This is
because the simulated fitting values of such a hypothesis
with the training sedative–hypnotic test set compounds 2–6
and 11a–c were more consistent with the experimental
results than the other hypotheses.
Preparation of the tested chemical compounds
All the tested chemicals and Phenobarbital (as reference
drug) were dissolved in DMSO.
Phenobarbital-induced sleep test in mice (Mora et al.,
2005; Tsuji et al., 1996; Fig. 1; Table 2)
The mice were divided into seventeen groups of 8 animals
each. The first group (control) was i.p. treated with DMSO.
Another group (reference) was i.p. injected Phenobarbital
(25 mg kg-1, 0.1 mmol.). The remaining groups received
equimolar dose i.p. (19.6–42.6 mg kg-1, 0.1 mmol) of one
of the test compounds (2–11). After 30 min, each animal in
all groups was injected with 25 mg kg-1 i.p. Phenobarbi-
tal. The onset and duration of sleep were noted by
recording the difference between the time of loss and
recovery of the righting reflex.
Such hypothesis encompassed four features consisting
of two hydrophobic (A1 and A2) appeared as a spherical
mesh and two hydrogen bond acceptor receptors (H1 and
H2) appeared as vector and its complementary site on the
receptor appeared as spherical mesh. Furthermore, the
constraint distance between the different features of the
hypothesis were recorded, Figs. 3 and 4 (Table 1). Then,
the mapping of the lead compounds as well as the test set
compounds with the above hypothesis were carried out
using best fit algorithm, during the compare/fit process.
The data collected included the fit value of the best con-
former for each compound (Table 2).
Molecular modeling
Pharmacophore was produced using the Discovery Studio
2.1 (Accelrys Inc., San Diego, CA, USA).
Result and discussion
Generation of GABA agonist hypothesis
Chemistry
The pharmacophore modeling method has been widely
used in lead discovery and optimization as a key tool of
computer aided drug design. A hypothesis was formulated
The synthesis of 7-chlorobenzoxepin-derived compounds
was illustrated in Schemes 1, 2, 3, and 4. The starting
123

754
Med Chem Res (2012) 21:747–759
Fig. 2 Structures of some
ligands for the benzodiazepine
site
H3C
O
O
H
N
N
O
O
H
N
N
COOK
O
O
N
N
N
Cl
O2N
H
N
HN
NH
Cl
Clonazepam
O
Devazepide
Diazepam
Phenobarbitone
O
N
N
N
N
N
O
N
O
N
O
O
N
N
N
N
N
N3
N
Cl
O
Cl
Triazolam
Ro15-4513
Cl
Eszopiclone
Cl
N
N
N
N
O
N
N
O
N
N
O
N
O
N
O
N
H
O
CF3
CL-218, 872
S
Zolpidem
DMCM
O
I
Fig. 3 Constraint distances of
Benzodiazepine agonist
hypothesis
compound, 7-Chloro-3,4-dihydrobenzo[b]oxepin-5(2H)-
one 2 was obtained via the intramolecular cyclization of
4-chorophenoxy butyric acid 1 using phosphorous penta-
oxide in the presence of Celite and toluene. This method
gave a higher reproducible yield than the reported one that
used PPA (polyphosphoric acid) as a dehydrating agent
(Nioche and Decerprit, 1995); (Thuillier and Bessin, 1975).
Introduction of a variable substituent at position-4 of the
benzoxepin system was achieved as shown in compounds
3–6. So, compounds 3a–e was prepared from 2 by the
Mannich reaction (Scheme 1). In another pathway, aldol
condensation of the benzoxepin 2 with the appropriate aryl
aldehydes in the presence of acidic medium afforded the
corresponding 4-benzylidenbenzoxapin-5-ones 4a–d,
(Barrett et al., 2008) (Scheme 2). Moreover, selective
bromination of the a ketone with copper (II) bromide in
123

Med Chem Res (2012) 21:747–759
755
Fig. 4 Constraint angel of
Benzodiazepine agonist
hypothesis
Table 1 Constraint distances and angles between the features of Benzodiazepine agonist hypothesis
Dimensions
Features of benzodiazepine agonist hypothesis
˚
Constraint distances (A) between features
H1–H2, 7.751; H1–A1, 4.123; H1–A2, 6.455; A1–A2, 9.218; A1–H2, 8.033; A2–H2, 4.337
H1–A1–A2, 27.50; H1–H2–A1, 33.60; H2–A1–A2, 27.59; A1–H2–A2, 56.39.
˚
Constraint angles (A) between features
chloroform–ethyl acetate led to the formation of the bromo
Table 2 Effects of the new heterocyclic compounds according to the
Phenobarbital-induced sleep test
derivative 5 in which it was reacted with Phenobarbital
sodium giving the adduct 6 (Scheme 3).
Compound
Latency (min) Duration (min) Log P Fit values
(mean SE) (mean SE)
On the other hand, the benzoxazepins containing a
condensed-ring system of pyridazinone 11a–c were pre-
pared through multistep reactions. In the first step, meth-
ylation of the Mannich base (3a) with iodomethane to
afford the corresponding quaternary ammonium salt 7.
Cyanation of 7 and consequently hydrolysis of the product
gave the carboxylic acid derivative 9. This carboxylic acid
was then cyclocondensed with un/substituted phenyl
hydrazine’s hydrochloride to yield 11a–c via intermediate
hydrazones 10 (Scheme 4).
Control
44.6 0.54
40.30 2.29
Phenobarbital 46.8 0.73
100.5 1.34 1.41
59.50* 2.25 1.92
61.30* 1.94 1.94
99.30* 2.35 2.68
92.35* 2.43 1.7
45.25 2.18 4.33
75.25* 1.72 1.54
84.30* 2.76 3.86
103.15* 2.11 4.02
105.50* 2.56 4.42
79.40* 1.83 3.73
39.15 1.13 2.44
123.25* 3.12 3.12
100.15* 2.16 3.39
42.15 1.19 3.95
38.45 1.33 3.27
3.28
2.00
1.97
2.65
2.75
3.00
2.99
3.02
2.88
2.99
3.12
2.65
3.81
2.97
2.99
2.32
2
34.5 0.53
34.0 0.51
24.5 0.38
38.8 0.60
45.5 0.23
40.8 0.82
18.0 0.26
16.5 0.25
15.0 0.32
17.6 0.27
47.0 0.42
21.5 0.33
20.0 0.30
49.5 0.26
42.5 0.27
3a
3b
3c
3d
3e
4a
4b
4c
4d
5
The structures of the prepared compounds 3a–e, 4a–d,
5, 6, 7, 8, 9, and 11a–c were confirmed by spectroscopic
methods (see ‘‘Experimental’’ section) and their microan-
alytical results for C, H, and N which they were within
0.4 of the calculated values.
6
11a
11b
11c
Pharmacological evaluation
Statistical analysis
Derivatives were injected i.p. 30 min before i.p. injection of
25 mg kg-1 of Phenobarbital sodium. Data represent means of time
between loss and recovery of the righting reflex. * P \ 0.05 relative
to Phenobarbital-treated group. Log P (Partition coefficients) were
calculated using ChemDraw Ultra V 8.0. Fit value mapped with BDZ
receptor agonist pharmacophore model (hypothesis) using Discovery
Studio 2.1 programs
It was performed using SPSS 14.0 statistical software.
Differences among groups were examined using ANOVA
(parametric one-way analysis of variance). Results are
expressed as the mean SEM. The minimal level of sig-
nificance was identified at P \ 0.05.
123

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Med Chem Res (2012) 21:747–759
Phenobarbital-induced sleep test in mice
was unfruitful as it led to inactive derivatives except with
the unsubstituted derivative (11a) that increased the
sleeping time to 100.15 2.16.
The hypnotic effect of the synthesized derivatives was
initially investigated by using the Phenobarbital-induced
sleep test (Mora et al., 2005; Tsuji et al., 1996). With the
exception of 3d, 5, 11b, and 11c, all the derivatives
decreased the onset of Phenobarbital-induced sleep as well
as prolonged the duration of hypnosis in an equimolar dose
(Fig. 1; Table 1).
We confirmed that substitution in position 4 with un/
substituted benzylidene derivatives, 4a–d afforded reduc-
tion in the sleep onset and the order of activity is 4c, 4b,
4d, and 4a. On the other hand, 7-chloro-3,4-dihydro-
benzo[b]oxepin-5(2H)-one 2 showed increase in the dura-
tion of hypnosis induced by Phenobarbital. Substitution
with dimethylaminomethyl (3a) retained the activity and
they had nearly the same Log P. Substitution with piperdin-
1-yl methyl, 4-methylpiperazin-1-ylmethyl, morpholino-1-
yl methyl (3b, 3c, 3e) led to significant increase in the
activity while substitution with 2-chlorophenylpiperzin-1-
ylmethyl (3d) abolish the activity with no correlation with
Log P (Partition coefficients).
Concerning the reduction in sleep onset, compound 4c
was the most potent followed by compound 4b, then
compounds 4d, and 4a. The reduction in sleep onset was
found to be proportional with the Log P.
Considering the duration of hypnosis, 7-chloro-3,4-
dihydrobenzo[b]oxepin-5(2H)-one 2 increased the Pheno-
barbital-induced sleep from 40.30 2.29 min (DMSO) to
59.50 2.25. Addition of dimethylamino substituent with
a methylene bridge in position 4 as shown in compound 3a
retained the activity of 2 and the duration of sleeping was
61.30 1.94, while replacement of the dimethylamino by
piperdino, 4-methylpiperazino, morpholino 3b, 3c, and 3e
led to significant increase in the Phenobarbital-induced
sleep to 99.30 2.35, 92.35 2.43, and 75.25 1.72,
respectively, while substitution with 2-chlorophenylpip-
erzino (3d) gave inactive derivative.
Considering the 4-un/substituted benzylidene deriva-
tives 4a–d, it was found that they increased the activity
especially in the Presence of electronegative atom (Garg
et al., 2010) such as the 4-choro and 4-fluoro analogues and
the activity was directly proportional with the Log P.
Moreover, the hybridized analogue 6 between the ben-
zoxepin 2 and Phenobarbital increased the sleeping dura-
tion three times and gave the most active derivative.
Unfortunately, only condensed-ring system of pyridazinone
(11a) showed activity.
Furthermore, substitution in position 4 with un/substi-
tuted benzylidene derivatives (4a, 4b, 4c, 4d) afforded
increase in the activity with different comportment and the
sleeping duration were 84.30 2.76, 103.15 2.11,
105.50 2.56, and 79.40 1.83, respectively.
Molecular modeling
The hypothetical study suggested that the basic nucleus
binds with one hydrophobic center through the benzene
ring and one hydrogen bond acceptor through the carbonyl
group as shown in compound 2 (Fig. 5). Addition of a
hydrophobic group in position 4 led to extra binding with
the second hydrophobic center, and consequently the fit
value was increased as shown in compounds 4a–d (Fig. 6).
Moreover, bromo substitution in position 4 yield inac-
tive derivative while hybridization with Phenobarbital
afforded the most active derivative and it increased in the
Phenobarbital-induced sleep to 123.25 3.12.
On the other hand, incorporation of the condensed
pyridazinone ring system into the benzoxepin nucleus 2
Fig. 5 Mapping of BZR
agonist pharmacophore with
compound 2, fit value = 2
123

Med Chem Res (2012) 21:747–759
757
Fig. 6 Mapping of BZR
agonist pharmacophore with
compound 4d, fit value = 3.12
Fig. 7 Mapping of BZR
agonist pharmacophore with
compound 6, fit value = 3.81
Fig. 8 Mapping of BZR
agonist pharmacophore with
compound 11b, fit value = 2.99
123

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Med Chem Res (2012) 21:747–759
children and adolescents with cerebral palsy (an evidence-based
review): report of the Quality Standards Subcommittee of the
American Academy of Neurology and the Practice Committee of
the Child Neurology Society. Neurology 74:336–343
Freedman J (1975) US Patent 3,859,306, 7 Jan 1975
Garg N, Chandra T, Archana Jain AB, Kumar A (2010) Synthesis and
evaluation of some new substituted benzothiazepine and ben-
zoxazepine derivatives as anticonvulsant agents. Eur J Med
Chem 45:1529–1535
Moreover, addition of carbonyl group and hydrophobic
group at position 4 exemplified by compound 6 (Fig. 7) led
to the best fitted derivative with the four features in which
the two hydrophobic centers interact with the two benzene
rings and the two hydrogen bond acceptor centers interact
with the two carbonyl groups in position 5 and 4 of the
benzoxepin and Phenobarbital, respectively. Comparing
the fit value of 6 and 11a–c (Fig. 8) suggested that rigidi-
fication of the structure afforded less fit properties.
Georgey HH (2007) Design and synthesis of certain imidazo [1,5-a]
quinazoline-5(4H)-one derivatives of anticipated anticonvulsant
activity. Egypt J Chem 50:455–472
Gillon S, Johnson M, Campbell C (2010) Review of phenobarbitone
use for deep terminal sedation in a UK hospice. Palliat Med
24:100–101
Conclusion
Girgis AS, Ismail NS, Farag H, El-Eraky WI, Saleh DO, Tala SR,
Katritzky AR (2010) Regioselective synthesis and molecular
modeling study of vasorelaxant active 7,9-dioxa-1,2-diaza-
spiro[4.5]dec-2-ene-6,10-diones. Eur J Med Chem 45:4229–
4238
Ha SK, Shobha D, Moon E, Chari MA, Mukkanti K, Kim SH, Ahn
KH, Kim SY (2010) Anti-neuroinflammatory activity of 1,5-
benzodiazepine derivatives. Bioorg Med Chem Lett 20:3969–
3971
Ismail MA, Aboul-Enein MN, Abouzid KA, Serya RA (2006) Ligand
design and synthesis of new imidazo[5,1-b]quinazoline deriva-
tives as alpha1-adrenoceptor agonists and antagonists. Bioorg
Med Chem 14:898–910
In conclusion, we described the synthesis of novel ben-
zoxepin derivatives 3–11. The structure of the newly syn-
thesized compounds was established by microanalytical
and spectral (IR, 1H-NMR, mass) data. Moreover, the
hybridized analogue 6 between the benzoxepin 2 and
Phenobarbital increased the sleeping duration three times
and gave the most active derivative. From the hypothetical
study and the pharmacological screening, it can be con-
cluded that, maximum activity was achieved for non rigid
derivative bearing hydrophobic center and hydrogen bond
as compound 6.
´
´
´
´
Jimenez-Velazquez G, Lopez-Mun˜oz FJ, Fernandez-Guasti A (2010)
Parallel anxiolytic-like and antinociceptive actions of diazepam
in the anterior basolateral amygdala and dorsal periaqueductal
gray. Brain Res 1349:11–20
Acknowledgment The authors express deep thanks to Dr. Nasser
S.M. Ismail, Lecturer of Pharmaceutical Chemistry, Pharmaceutical
Chemistry Department, Faculty of Pharmacy, Ain Shams University
for his kind help during the molecular modeling.
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