Synthesis and biological activity of some 1,3-dihydro-2H-3-benzazepin-2- ones with a piperazine moiety as bradycardic agents

Article abstract of DOI:10.1002/ardp.200900169

A series of 1,3-dihydro-2H-3-benzazepin-2-ones with a piperazine moiety were designed and synthesized by treating the common intermediate of 1,3-dihydro-7,8-dimethoxy-3-[3-(1-piperazinyl)-propyl]-2H-3-benzazepin-2-ones with a variety of N-aryl-2-chloroacetamides and acyl chlorides. Their structures have been characterized by ¹H-NMR, MS, and elemental analysis. The title compounds were evaluated for their bradycardic activity in vitro. Most of the synthesized compounds exhibited some vasorelaxant activity and heart-rate-reducing activity with bradycardic potency.

Full text of DOI:10.1002/ardp.200900169

114
Arch. Pharm. Chem. Life Sci. 2010, 343, 114–119
Full Paper
Synthesis and Biological Activity of Some 1,3-Dihydro-2H-3-
benzazepin-2-ones with a Piperazine Moiety as Bradycardic
Agents
Hong-Yu Liang1, Deng-Qing Zhang1, Yun Yue2, Zhe Shi3, and Sheng-Yin Zhao1
1 Department of Chemistry, Donghua University, Shanghai, P.R. China
2 Department of Pharmacology, Foshan University, Foshan, P.R. China
3 Shenzhen Kangzhe Pharmaceutical Co. Ltd., Shenzhen, P.R. China
A series of 1,3-dihydro-2H-3-benzazepin-2-ones with a piperazine moiety were designed and syn-
thesized by treating the common intermediate of 1,3-dihydro-7,8-dimethoxy-3-[3-(1-piperazinyl)-
propyl]-2H-3-benzazepin-2-ones with a variety of N-aryl-2-chloroacetamides and acyl chlorides.
1
Their structures have been characterized by H-NMR, MS, and elemental analysis. The title com-
pounds were evaluated for their bradycardic activity in vitro. Most of the synthesized compounds
exhibited some vasorelaxant activity and heart-rate-reducing activity with bradycardic potency.
Keywords: Bradycardic activity / 1,3-Dihydro-2H-3-benzazepin-2-one / Heart-rate reduction / Vasorelaxant activity /
Received: July 18, 2009; Accepted: October 14, 2009
DOI 10.1002/ardp.200900169
initiated [3–5]. Hence, over the past few years, there have
Introduction
been significant research activities towards selective If
inhibitors. A series of novel benzazepin-2-ones and
related derivatives were developed for clinical trail [6–
11], such as Zatebradine [9], Cilobradine [12], and Ivabra-
dine [13].
Stable angina pectoris is very common nowadays in eld-
erly. Treatment for angina includes reducing heart rate
with agents such as b-adrenergic blockers and some cal-
cium-channel antagonists. However, these agents also
exert other unwanted activities such as negative ino-
tropic and hypotensive effects which could have serious
consequences [1, 2]. The reduction of sinus heart rate (HR)
is one of major interests in the treatment of cardiac ische-
mia. Myocardial ischemia results from an imbalance
between oxygen supply and demand. HR reduction can
correct this balance by improving myocardial perfusion
and reducing myocardial oxygen demand. Lowering the
heart rate is therefore one of the most important thera-
peutic approaches in the treatment of stable angina pec-
toris. Heart rate is determined by spontaneous electrical
pacemaker activity in the sinoatrial node controlled by
the If current. Thus, the search for novel heart-rate-reduc-
ing compounds without unwanted inotropic effects was
Ivabradine (I) (Procoralanm, Servier) is the potent brady-
cardic agent which has been approved by the European
agency for the evaluation of medicinal products for the
treatment of ischemic heart disease, congestive heart fail-
ure, and angina pectoris. It is the first representative of a
new class of selective agents for reducing heart rate
which inhibit the If current in the sinoatrial node [6, 13].
Ranolazine (II) is a selective inhibitor of the late
sodium current relative to the peak sodium channel cur-
rent; it may decrease the sodium-dependent intracellular
calcium overload during ischemia and reperfusion. This
mechanism contributes to a reduction in intracellular
sodium and intracellular calcium, and leads to reduce
ischemic injury [14, 15]. Based on the results of these tri-
als, Ranolazine was recently approved by the United
States Food and Drug Administration (FDA) for treatment
of patients with chronic stable angina (Scheme 1).
Correspondence: Sheng-Yin Zhao, Department of Chemistry, Donghua
University, Shanghai, P.O. Box 201620, P.R. China.
E-mail: syzhao8@dhu.edu.cn
In view of the outstanding pharmacological profiles of
Ivabradine and Ranolazine and taking into account the
benzazepin-2-one backbone of the Ivabradine unit and
Fax: +86 21 67792608
Abbreviation: sinus heart rate (HR)
i 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2010, 343, 114–119
1,3-Dihydro-2H-3-benzazepin-2-ones as Bradycardic Agents
115
Scheme 1. The structures of Ivabradine and Ranolazine.
the acylpiperazine of the Ranolazine unit, as well as a
tether length of a propyl group and a double bond in the
benzazepinone ring for a good antimyocardial ischemia
activity [6, 11], we have designed and synthesized a series
of new propyl-linked 1,3-dihydro-7,8-dimethoxy-2H-3-
benzazepin-2-one-Ranolazine hybrid-related derivatives
based on Ivabaradine and Ranolazine. As a continuation
of our ongoing efforts towards the development and
identification of new molecules for antimyocardial ische-
mia drugs [16, 17], we now present the synthesis and bra-
dycardic activity of a series of 1,3-dihydro-7,8-dimethoxy-
2H-3-benzazepin-2-ones with a piperazine moiety.
Results and discussion
The synthetic route depicted in Scheme 2 outlines the
chemistry part of the present work. Though a series of
synthetic procedures were developed for sythesis the ben-
zazepin-2-one derivatives, including ring-closing olefin
metathesis and Azido–Schmidt reaction [18–26], a facile
synthesis was used in the preparation of the title com-
pounds [6, 25, 26]. The key intermediate, 7,8-dimethoxy-
1,3-dihydro-2H-3-benzazepin-2-one 4, was obtained by
treating 3,4-dimethoxyphenylacetic acid 1 with thionyl
chloride in dichloromethane to give 3,4-dimethoxyphe-
nylacetyl chloride 2, which was acylated with aminoacet-
aldehyde dimethyl acetal to afford the N-(2,2-dimethoxy-
ethyl)-3,4-dimethoxyphenylacetamide 3 as a white solid.
Compound 3, in the presence of hydrochloride acid and
acetic acid, perfomed the ring-closing reaction to yield
the desired intermediate 4 with an overall yield of 55%
for three steps.
Reagents and conditions: (a) SOCl2, CH2Cl2, r.t.,
8 h; (b) NH2CH2CH(OCH3)2,
N(C2H5)3, CH2Cl2, r.t., 5 h; (c) 37% HCl, AcOH, 6 h; (d) BrCH2CH2CH2Cl, NaH, DMF,
08C, 10 h; (e) piperazine, K2CO3, EtOH, reflux, 24 h; N(C2H5)3, toluene, 808C, 12 h; (g)
acyl chloride; N(C2H5)3, r.t., 6 h.; (f) THF, N(C2H5)3, r.t., 6 h; (h) N-aryl-2-chloroacet-
amide 11e-11f.
Scheme 2. Synthetic route to compounds 7a–7f, 8a–8c, and 11e–
11f.
the weak electrophilicity of compound 5. The formation
of compound 6 was confirmed by the presence of pipera-
zine in the 1H-NMR spectrum of compound 6. Two broad
peaks at d = 2.60 ppm and 3.12 ppm were observed for the
signal of four CH2 groups on the piperazine ring. Data
from the elemental analyses and molecular ion recorded
in the mass spectrum further comfirmed the assigned
structure.
The target compounds, 1,3-dihydro-7,8-dimethoxy-3-[3-
Having compound 4 in hands, it was treated with 1-
bromo-3-chloropropane in the presence of sodium
hydride in DMF at 08C to give 1-(7,8-dimethoxy-1,3-dihy-
dro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane 5 in 66%
yield [8]. After recrystallization from ethanol, the reac-
tion of compound 5 with piperazine was carried out
using ethanol as solvent in the presence of potassium car-
bonate to provide 1,3-dihydro-7,8-dimethoxy-3-[3-(1-piper-
azinyl)propyl]-2H-3-benzazepin-2-one 6. In order to obtain
more monosubstituted piperazine derivative 6, an over-
dose of piperazine was used in this reaction. The long
duration of the reaction might have been required due to
1-(piperazinylpropyl)]-2H-3-benzazepin-2-ones
7
were
obtained by alkylation of compound 6 with the corre-
sponding N-aryl-2-chloroacetamides 11a–11f [27, 28]. Acy-
lation of compound 6 with acyl chlorides in THF provided
compounds 8. The formation of the title products is indi-
cated by the presence of peaks of N-aryl-2-chloroacet-
amides and the acyl group in IR and1H-NMR spectra of all
the target compounds. Two broad peaks around d = 2.40
and 2.65 ppm were observed for the signal of four CH2
groups on the disubstituted piperazine ring. The mass
spectra of the title compounds are in conformity with
i 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

116
H.-Y. Liang et al.
Arch. Pharm. Chem. Life Sci. 2010, 343, 114–119
Table 1. Vasorelaxant activity of tested benzezapin-2-ones.
compared to the reference standard Ivabradine. These
compounds displayed vasorelaxant activities in rat thora-
cic aorta and were lowering heart rate on guinea pig.
These dual activities revealed that these compounds can
serve as new antimyocardial ischemia agents.
With regards to the possible SAR, our preliminary
assumption was to synthesize the compounds by intro-
ducing a piperazine moiety in order to enhance the abil-
ity of the molecules to induce vascular relaxation and
keep the heart rat reduced. The phenyl group as a elec-
tron donor can favor the bradycardic activity. Further
biological evaluation and structural modification are
under way. The results will be presented in another
paper.
Compound
Vasorelaxant Compound
(% over control
Vasorelaxant
(% over control
at 10 lM)
at 10 lM)a
7a
7c
7e
8a
8c
20.9%
24.5%
18.3%
39.8%
31.2%
7b
7d
7f
8b
43.6%
28.8%
35.2%
47.6%
24.6%
Ivabradine
a
Vasorelaxant effects of benzazepin-2-ones on aortic rings
with endothelium pre-contracted with KCl (80 mM) and
CaCl2 (2 mM). The results based on three determinations are
given.
Table 2. Heart-rate reduction effect of tested benzazepin-2-
ones.
Compound
Heart rate
reduction
Compound
Heart rate
reduction
Conclusion
(% over control
(% over control
at 10 lM)
at 10 lM)a
A series of 1,3-dihydro-7,8-dimethoxy-3-[3-(1-piperazinyl)
propyl]-2H-3-benzazepin-2-one derivatives were synthe-
sized and evaluated for their vasorelaxant activity and
heart-rate-reducing activity. Most of the tested com-
pounds showed potent bradycardic activity. On the basis
of pharmacological properties and preliminary struc-
ture-activity relationships (SAR), the target compounds
represent a novel lead for the development of specific
bradycardic agents. Futher studies of compounds 7b are
in progress in order to clarify the possible mechanism of
its vasorelaxant and heart-rate-reducing activity.
7a
7c
7e
8a
8c
–18.5%
–15.5%
–12.2%
–16.6%
–10.2%
7b
7d
7f
8b
–28.3%
–8.8%
–21.2%
–24.8%
–30.5%
Ivabradine
a
The results based on three determinations are given.
the assigned structure. The mass spectra of these com-
pounds showed molecular ion peaks corresponding to
their molecular formula. Elemental analyses satisfacto-
rily confirmed the elemental composition and purity of
the synthesized compounds.
Experimental
The biological evaluation for bradycardic activity was
part of this paper. The vasorelaxant activity of synthe-
sized 2H-3-benzazepin-2-ones was evaluated in the rat
thoracic aorta rings with endothelium against a KCl- (80
mM) and CaCl2- (2 mM) induced contraction model. The
heart-rate reducion in rats was also assayed using Ivabra-
dine as positive control. The effects of the title com-
pounds on contraction of rat aortic strip are shown in
Table 1. The results indicated that some of the test com-
pounds exhibited significant vasorelexant activity. The
activities of compounds 8a–8c are stronger than those of
compounds 7a–7f, especially the inhibition of com-
pounds 7b and 8b is 43.6% and 47.6%, respectively, given
a concentration of 10 lM. The heart-rate-reducing activ-
ity data are shown in Table 2. The biological evaluation
suggested the target compounds showed different reduc-
tion on the heart rate in rats on the concentration of 10
lM. Heart rate reduction of compound 7b is –28.3%. It
exhibited equipotent heart-rate-reducing activity when
Chemistry
Melting points were taken in open capillaries on a B-shape melt-
ing point apparatus and were uncorrected. IR spectra were
recorded in potassium bromide disks on a Nicolet 3080 spec-
trometer (Nicolet, Madison, WI, USA) in the range of 4000–400
cm–1. The1H-NMR spectra were recorded on a Bruker AV 400 MHz
NMR spectrometer (Bruker Bioscience, USA). The chemical shifts
were reported as parts per million (d, ppm) tetramethylsilane
(TMS) as an internal standard. Mass spectra (EI) were obtained on
a QP-2010 instrument (Shimadzu Scientific Instruments, Japan).
The progress of the reaction was monitored on ready-made silica
gel plates using chloroform/methanol as a solvent system. Spec-
1
tral data (IR, H-NMR, and mass spectra) confirmed the struc-
tures of the synthesized compounds and the purity of these com-
pounds was ascertained by microanalysis. All chemicals and
reagents were purchased from known commercial suppliers and
were used without further purification. 7,8-Dimethoxy-1,3-dihy-
dro-2H-3-benzazepin-2-one 4 [6, 25] and N-aryl-2-chloroacet-
amides 11a–11f [27, 28] were synthesized according to the litera-
ture procedures with minor changes. The yields were not opti-
mized.
i 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2010, 343, 114–119
1,3-Dihydro-2H-3-benzazepin-2-ones as Bradycardic Agents
117
m/z (EI): 478 [M+]. Anal. calcd. for C27H34N4O4: C, 67.76; H, 7.16; N,
11.71. Found: C, 67.48; H, 7.32; N, 11.92.
3-(3-Chloropropyl)-1,3-dihydro-7,8-dimethoxy-2H-3-
benzazepin-2-one 5
1,3-Dihydro-7,8-dimethoxy-2H-3-benzazepin-2-one 4 (2.8 g, 13
mmol) was dissolved in DMF (25 mL), and then sodium hydride
(0.60 g, 15 mmol) was added in batches with stirring for 30 min.
To this solution, the mixture of 1-bromo-3-chloropropane (1.60
mL, 16 mmol) and DMF (8 mL) was added dropwise for 30 min at
room temperature. The stirring was continued for 10 h, the reac-
tion mixture was then poured into ice water. The solid obtained
was filtered, washed, dried, and recrystallized from ethanol to
give 2.56 g (66.5%) of compound 5 as yellow needle crystals. M.p.:
100–1028C (lit. [6]: m.p.: 101–1038C); 1H-NMR(CDCl3, 40 MHz) d:
1.89–1.95 (m, 2H, CH2), 3.35–3.38 (m, 4H, 2 CH2), 3.64 (t, J = 6.8
Hz, 2H, CH2), 3.81 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.16 (d, J = 9.2
Hz, 1H, Ar-CH=CH-), 6.29 (d, J = 9.2 Hz, 1H, Ar-CH=CH-), 6.66 (s, 1H,
Ar-H), 6.72 (s, 1H, Ar-H).
N-(4-Methoxyphenyl)-2-[4-[3-(7,8-dimethoxy-1,3-dihydro-
2H-3-benzazepin-2-on-3-yl)propyl] piperazinyl]acetamide
7b
Yield: 56%; m.p.: 100–1028C; IR(KBr) m cm–1: 3286, 2928, 1660,
1613, 1554, 1508, 1409, 1274, 1255; 1H-NMR (CDCl3, 400 MHz) d:
1.69–1.72 (m, 2H, CH2), 2.29–2.33 (m, 2H, CH2), 2.45 (brs, 4H, 2
CH2), 2.61 (brs, 4H, 2 CH2), 3.10 (s, 2H, CH2), 3.48 (s, 2H, CH2), 3.60
(t, J = 6.8 Hz, 2H, CH2), 3.79 (s, 3H, OCH3), 3.88 (s, 6H, 2 OCH3), 6.22
(d, J = 9.2 Hz,1H, Ar-CH=CH-), 6.34 (d, J = 9.2 Hz, 1H, Ar-CH=CH-),
6.72 (s, 1H, Ar-H), 6.79 (s, 1H, Ar-H), 6.87 (d, J = 8.2 Hz, 2H, Ar-H),
7.46 (d, J = 8.2 Hz, 2H, Ar-H), 8.96 (s, 1H, Ar-NH-C=O); MS m/z (EI):
508 [M+]. Anal. calcd. for C28H36N4O5: C, 66.12; H, 7.13; N, 11.02.
Found: C, 66.59; H, 7.41; N, 10.96.
1,3-Dihydro-7,8-dimethoxy-3-[3-(1-piperazinyl)propyl]-
2H-3-benzazepin-2-one 6
N-(2-Chloro-6-methylphenyl)-2-[4-[3-(7,8-dimethoxy-1,3-
dihydro-2H-3-benzazepin-2-on-3-yl)propyl]
piperazinyl]acetamide 7c
To a solution of compound 5 (6.0 g, 20.3 mmol) in ethanol (50
mL), a little potassium iodide was added and heated to reflux for
30 min, then cooled to the room temperature. This solution was
droped into a mixture of piperazine (9.5 g, 0.11 mol), potassium
carbonate (14.1 g, 0.10 mol), and ethanol (100 mL); the reaction
was stirred at reflux for 24 h. After the solvent was removed in
vacuum, the residue was diluted with water (100 mL), and the
product was extracted with dichloromethane (36100 mL). The
organic layer was washed with water (26100 mL), and dried
over MgSO4. The solvent was removed and purified by flash col-
umn chromatography (dichloromethane/methanol; 15:1, v/v) to
give 5.54 g (79%) of compound 6 as yellow solid. M.p.: 86–898C;
1H-NMR (CDCl3, 400 MHz) d: 1.64–1.71 (m, 2H, CH2), 2.32 (t, J = 6.8
Hz, 2H, CH2), 2.60 (brs, 4H, 2 CH2), 3.12 (brs, 4H, 2 CH2), 3.42–3.46
(m, 2H, CH2), 3.58 (t, J = 6.8 Hz, 2H, CH2), 3.88 (s, 6H, 2 OCH3), 6.18
(d, J = 9.2 Hz, 1H, Ar-CH=CH-), 6.33 (d, J = 9.2 Hz, 1H, Ar-CH=CH-),
6.72 (s, 1H, Ar-H), 6.78 (s, 1H, Ar-H); MS m/z (EI): 345 [M+]. Anal.
calcd. for C19H27N3O3: C, 66.06; H, 7.88; N, 12.16. Found: C, 66.31;
H, 7.58; N, 12.48.
Yield: 41%; m. p.: 90–928C; IR (KBr) m cm–1: 3312, 2936, 2817,
1655, 1511, 1458, 1401,1377, 1275, 1236; 1H-NMR (CDCl3, 400
MHz) d: 1.69–1.73 (m, 2H, CH2), 2.18–2.29 (m, 5H, CH2, CH3), 2.48
(brs, 4H, 2 CH2), 2.72 (brs, 4H, 2 CH2), 3.18 (s, 2H, CH2), 3.43 (s, 2H,
CH2), 3.61 (t, J = 6.8 Hz, 2H, CH2), 3.88 (s, 6H, 2 OCH3), 6.23 (d, J =
9.2 Hz, 1H, Ar-CH=CH-), 6.34 (d, J = 9.2 Hz, 1H, Ar-CH=CH-), 6.73 (s,
1H, Ar-H), 6.79 (s, 1H, Ar-H), 7.11–7.15 (m, 2H, Ar-H), 7.27 (d, J =
8.4 Hz, 1H, Ar-H), 8.90 (s, 1H, Ar-NH-C=O); MS m/z (EI): 526 [M+].
Anal. calcd. for C28H35ClN4O4: C, 63.81; H, 6.69; N, 10.63. Found:
C, 63.50; H, 6.71; N, 11.13.
N-(4-Fluorophenyl)-2-[4-[3-(7,8-dimethoxy-1,3-dihydro-
2H-3-benzazepin-2-on-3-yl)propyl] piperazinyl]acetamide
7d
Yield: 43%; m.p.: 108–1108C; IR(KBr) m cm–1: 3448, 2920, 2850,
1690, 1649, 1509, 1460, 1404, 1236; 1H-NMR (CDCl3, 400 MHz) d:
1.69–1.72 (m, 2H, CH2), 2.28–2.34 (m, 2H, CH2), 2.45 (brs, 4H, 2
CH2), 2.61 (brs, 4H, 2 CH2), 3.11 (s, 2H, CH2), 3.43 (s, 2H, CH2), 3.59
(t, J = 6.8 Hz, 2H, CH2), 3.88 (s, 6H, 2 OCH3), 6.22 (d, J = 9.2 Hz, 1H,
Ar-CH=CH-), 6.34 (d, 1H, J = 9.2 Hz, Ar-CH=CH-), 6.72 (s, 1H, Ar-H),
6.79 (s, 1H, Ar-H), 7.00 (d, J = 8.4 Hz, 2H, Ar-H), 7.52 (d, J = 8.4 Hz,
2H, Ar-H), 9.07 (s, 1H, Ar-NH-C=O); MS m/z (EI): 496 [M+]. Anal.
calcd. for C27H33FN4O4: C, 65.31; H, 6.70; N, 11.28. Found: C,
65.16; H, 6.82; N, 11.17.
General procedure for preparation of compounds 7a–7f
A mixture of compound 6 (5 mmol), triethylamine (3 mL), tol-
uene (20 mL), and N-aryl-2-chloroacetamide (6.0 mmol) was
refluxed for 12 h. The reaction mixture was washed with 10%
Na2CO3 solution (2620 mL) and water (2615 mL). The organic
layer was dried over NaSO4. The solvent was removed and puri-
fied by flash column chromatography (dichloromethane/metha-
nol; 20:1, v/v) to give compounds 7a–7f as white solid. The physi-
cal and spectral data of the compounds 7a–7f are as follows:
N-(4-Nitrophenyl)-2-[4-[3-(7,8-dimethoxy-1,3-dihydro-2H-
3-benzazepin-2-on-3-yl)propyl]piperazinyl]acetamide 7e
Yield: 57%; m.p.: 167–1688C; IR(KBr) m cm–1: 3448, 2927, 1697,
1636, 1531, 1504, 1458, 1403, 1345, 1272, 1257; 1H-NMR (CDCl3,
400 MHz) d: 1.66–1.72 (m, 2H, CH2), 2.32–2.37 (m, 2H, CH2), 2.48
(brs, 4H, 2 CH2), 2.64 (brs, 4H, 2 CH2), 3.16 (s, 2H, CH2), 3.49 (s, 2H,
CH2), 3.60 (t, J = 6.8 Hz, 2H, CH2), 3.89 (s, 6H, 2 OCH3), 6.21 (d, J =
9.2 Hz, 1H, Ar-CH=CH-), 6.34 (d, J = 9.2 Hz, 1H, Ar-CH=CH-), 6.72 (s,
1H, Ar-H), 6.79 (s, 1H, Ar-H), 7.74 (d, J = 8.2 Hz, 2H, Ar-H), 8.22 (d, J
= 8.2 Hz, 2H, Ar-H), 9.47 (s, 1H, Ar-NH-C=O); MS m/z (EI): 523 [M+].
Anal. calcd. for C27H33N5O6: C, 61.94; H, 6.35; N, 13.38. Found: C,
62.24; H, 6.01; N, 13.76.
N-Phenyl-2-[4-[3-(7,8-dimethoxy-1,3-dihydro-2H-3-
benzazepin-2-on-3-yl)propyl]piperazinyl]acetamide 7a
Yield: 48%; m.p.: 140–1428C; IR (KBr) m cm–1: 3286, 2920, 2850,
1686, 1663, 1518, 1460, 1401, 1377, 1269, 1238; 1H-NMR (CDCl3,
400 MHz) d: 1.67–1.73 (m, 2H, CH2), 2.26–2.31 (m, 2H, CH2), 2.45
(brs, 4H, 2 CH2), 2.61 (brs, 4H, 2 CH2), 3.11 (s, 2H, CH2), 3.43 (s, 2H,
CH2), 3.59 (t, J = 6.8 Hz, 2H, CH2), 3.88 (s, 6H, 2 OCH3), 6.21 (d, J =
9.2 Hz, 1H, Ar-CH=CH-), 6.33 (d, J = 9.2 Hz, 1H, Ar-CH=CH-), 6.72 (s,
1H, Ar-H), 6.78 (s, 1H, Ar-H), 7.10–7.12 (m, 1H, Ar-H), 7.26–7.35
(m, 2H, Ar-H), 7.54–7.56 (m, 2H, Ar-H), 9.08 (s, 1H, Ar-NH-C=O); MS
i 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

118
H.-Y. Liang et al.
Arch. Pharm. Chem. Life Sci. 2010, 343, 114–119
calcd. for C26H30N4O6: C, 63.15; H, 6.11; N, 11.33. Found: C, 62.85;
H, 5.91; N, 11.66.
N-(2-Thiazolyl)-2-[4-[3-(7,8-dimethoxy-1,3-dihydro-2H-3-
benzazepin-2-on-3-yl)propyl]piperazinyl] acetamide 7f
Yield: 40%; m.p.: 136–1388C; IR (KBr) m cm–1: 3448, 2927, 2361,
1
1654, 1636, 1509, 1458, 1430, 1401, 1276, 1251, 1172; H-NMR
Biological evaluation
(CDCl3, 400 MHz) d: 1.72–1.76 (m, 2H, CH2), 2.32–2.37 (m, 2H,
CH2), 2.49 (brs, 4H, 2 CH2), 2.63 (brs, 4H, 2 CH2), 3.23 (s, 2H, CH2),
3.43 (s, 2H, CH2), 3.61(t, J = 7.2 Hz, 2H, CH2), 3.89 (2s, 6H, 2 OCH3),
6.21 (d, J = 9.2 Hz, 1H, Ar-CH=CH-), 6.33(d, J = 9.2 Hz, 1H, Ar-
CH=CH-), 6.72(s, 1H, Ar-H), 6.79 (s, 1H, Ar-H), 6.99 (d, J = 3.6 Hz,1H,
thiazole-H), 7.45 (d, J = 3.6 Hz, 1H, thiazole-H), 10.28 (s, 1H, Ar-
NH-C=O); MS m/z (EI): 485 [M+]. Anal. calcd. for C24H31N5O4S: C,
59.36; H, 6.43; N, 14.42. Found: C, 59.73; H, 6.68; N, 14.26.
Effects on isolated aortic strips of the rat
Vascular rings were prepared from the aorta of male Sprague-
Dawley rats (four to six months old and weighing on average
250 g; received from the experimental animals center, Sun Yat-
Sen University, Guangzhou, experimental animals permission
number: 2008A063.) and contraction studies were performed
following the general procedure detailed in the literature [16,
29]. After an equilibration period of at least 1 h, isometric con-
tractions induced by KCl (80 mM) and CaCl2 (2 mM) were
obtained. When the contraction of the tissue in response to this
vasoconstrictor agent had stabilized (after about 20 min), cumu-
latively increasing concentrations of the test compounds were
added to the bath at 15–20 min intervals (the time was needed
to obtain a steady-state relaxation). Control tissues were simulta-
neously subjected to the same procedures, but omitting the com-
pounds and adding the vehicle. The benzazepin-2-ones induced
maximal relaxation. Emax in aortic rings was calculated as a per-
centage of the contraction in response to KCl (80 mM) and CaCl2
(2 mM). The half-maximum effective concentration (EC50) was
defined as the concentration of the title compound that induced
50% of maximum relaxation from the contraction elicited by
KCl (80 mM) and CaCl2 (2 mM) and was calculated from the con-
centration–response curve by nonlinear regression (curve fit)
using GraphPad Prism (Version 4.0).
General procedure for preparation of compounds 8a–8c
Compound 6 (5 mmol) and triethylamine (10 mmol) were mixed
thoroughly in THF (10 mL). To this solution, acyl chloride (6
mmol) in THF (5 mL) was added dropwise at room temperature.
The reaction mixture was stirred for 6 h. Water (15 mL) was
added, the mixture was extracted with ethyl acetate (2615 mL)
and washed with saturated NaHCO3 solution (2615 mL) and
water (2615 mL). The solvent was removed and the compound
purified by flash column chromatography (dichloromethane/
methanol; 20:1, v/v) to give a white solid. The physical and spec-
tral data of the compounds 8a–8c are as follows:
1-[3-(7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-
3-yl)propyl]-4-(4-chlorobenzoyl)piperazine 8a
Yield: 47%; m.p.: 70–728C; IR (KBr) m cm–1: 3297, 2945, 1700,
1639, 1533, 1518, 1461, 1405, 1283, 1270, 1238; 1H-NMR (CDCl3,
400 MHz) d: 1.70–1.74 (m, 2H, CH2), 2.30–2.34 (m, 6H, 3 CH2), 2.35
(brs, 4H, 2 CH2), 3.43 (s, 2H, CH2), 3.61 (t, 2H, CH2), 3.87 (s, 3H,
OCH3), 3.90 (s, 3H, OCH3), 6.20 (d, J = 9.2 Hz, 1H, Ar-CH=CH-), 6.34
(d, J = 9.2 Hz, 1H, Ar-CH=CH-), 6.71 (s, 1H, Ar-H), 6.78 (s, 1H, Ar-H),
7.33 (d, J = 8.2 Hz, 2H, Ar-H), 7.37 (d, J = 8.2 Hz, 2H, Ar-H); MS m/z
(EI): 483 [M+]. Anal. calcd. for C26H30ClN3O4: C, 64.52; H, 6.25; N,
8.68. Found: C, 64.81; H, 6.43; N, 8.56.
Experiments with isolated guinea pig atria
Guinea pigs of various breeds, 300–500 g of either sex, (experi-
mental animals center, Sun Yat-Sen University, Guangzhou,
experimental animals permission number: 2008A007.) were
killed by a blow on the head, the heart was removed and the
atria were dissected. The preparation was suspended in 40 mL of
modified Tyrode’s solution (136.8 mM NaCl, 2.68 mM KCl, 0.26
mM MgCl2, 0.42 mM NaH2PO4, 11.9 mM NaHCO3, 1.8 mM CaCl2,
15 mM glucose), gassed with a mixture of 98% O2 + 2% CO2. The
resulting tension on the muscle was 1 g. Mechanograms were
recorded isometrically via a strain gauge on a multichannel
recorder.
1-[3-(7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-
3-yl)propyl]-4-(4-methoxybenzoyl)piperazine 8b
Yield: 45%; m.p.: 76–788C; IR (KBr) m cm–1: 3463, 2933, 1655,
Drug effects on atrial rate were tested in spontaneously beat-
ing atria, bath temperature at 378C, after an equilibrium period
of at least 30 min, until the rate did not change by more than 5
beats/min [6, 7].
1
1636, 1513, 1460, 1431, 1277, 1238, 1101; H-NMR (CDCl3, 400
MHz) d: 1.70–1.74 (m, 2H, CH2), 2.30 (t, J = 6.8 Hz, 2H, CH2), 2.32
(brs, 4H, 2 CH2), 2.40 (brs, 4H, 2 CH2), 3.43 (s, 2H, CH2), 3.62 (t, J =
6.8 Hz, 2H, CH2), 3.83 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.90 (s, 3H,
OCH3), 6.21 (d, J = 9.2 Hz, 1H, Ar-CH=CH-), 6.34(d, J = 9.2 Hz, 1H,
Ar-CH=CH-), 6.72 (s, 1H, Ar-H), 6.78 (s, 1H, Ar-H), 6.90 (d, J = 8.8 Hz,
2H, Ar-H), 7.35 (d, J = 8.8 Hz, 2H, Ar-H); MS m/z (EI): 479 [M+]. Anal.
calcd. for C27H33N3O5: C, 67.62; H, 6.94; N, 8.76. Found: C, 67.28;
H, 6.71; N, 8.96.
We thank the Donghua University for finanacial support for funding
the outstanding young faculty.
The authors have declared no conflict of interest.
1-[3-(7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-
3-yl)propyl]-4-(4-nitrobenzoyl)piperazine 8c
References
Yield: 48%; m.p.: 78–808C; IR (KBr) m cm–1: 3448, 2925, 1636,
1
1601, 1516, 1458, 1438, 1401, 1351,1274; H-NMR (CDCl3, 400
[1] I. Ben-Dor, A. Battler, Heart 2007, 93, 868–874.
MHz) d: 1.68–1.72 (m, 2H, CH2), 2.31 (brs, 6H, 3 CH2), 2.47 (brs, 4H,
2 CH2), 3.42 (s, 2H, CH2), 3.60 (t, J = 6.8 Hz, 2H, CH2), 3.88 (2s, 6H, 2
OCH3), 6.20 (d, J = 9.2 Hz, 1H, Ar-CH=CH-), 6.35 (d, J = 9.2 Hz, 1H,
Ar-CH=CH-), 6.72(s, 1H, Ar-H), 6.78 (s, 1H, Ar-H), 7.54 (d, J = 6.8 Hz,
2H, Ar-H), 8.28 (d, J = 6.8 Hz, 2H, Ar-H); MS m/z (EI): 494 [M+]. Anal.
[2] U. Thadani, J. Cardiovasc. Pharmacol. Ther. 2004, 9 (Suppl. 1),
S11–S29.
[3] K. Fox, Expert Opin. Pharmacother. 2006, 7, 1211–1220.
[4] J. S. Borer, Pharmacol. Res. 2006, 53, 440–445.
i 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2010, 343, 114–119
1,3-Dihydro-2H-3-benzazepin-2-ones as Bradycardic Agents
119
[5] A. Bucchi, A. Barbuti, M. Baruscotti, D. DiFrancesco, Curr.
Opin. Pharmacol. 2007, 7, 208–213.
[18] S. B. Hoyt, C. London, M. Park, Tetrahedron Lett. 2009, 50,
1911–1913.
[19] L. Jean-Gerard, M. Pauvert, S. Collet, A. Guingant, M. Evain,
[6] R. Manfred, E. Wolfgang, M. Peter, P. Manfred, et al., J. Med.
Chem. 1990, 33, 1496–1504.
Tetrahedron 2007, 63, 11250–11259.
[20] J. S. Yadav, B. V. S. Reddy, U. V. S. Reddy, K. Praneeth, Tetra-
hedron Lett. 2008, 49, 4742–4745.
[7] B. Andreas, R. Manfred, H. Joachim, P. Manfred, L. Chris-
tian, J. Med. Chem. 1991, 34, 942–947.
[21] M. Katoh, H. Inoue, T. Honda, Heterocycles 2007, 72, 497–
[8] R. Budriesi, A. Rampa, A. Bisi, G. Fabbri, et al., Arzneimittel-
forschung 1995, 45, 234–239.
516.
[22] P. V. Fish, A. D. Brown, E. Evrard, L. R. Roberts, Bioorg. Med.
Chem. Lett. 2009, 19, 1871–1875.
[9] A. Bisi, A. Rampa, R. Budriesi, S. Gobbi, et al., Bioorg. Med.
Chem. 2003, 11, 1353–1361.
[23] L. Joucla, A. Putey, B. Joseph, Tetrahedron Lett. 2005, 46,
[10] H. Kubota, T. Watanabe, A. Kakefuda, N. Masuda, et al., Bio-
org. Med. Chem. Lett. 2004, 14, 3049–3052.
8177–8179.
[24] Y. Yu, G. A. Stephenson, D. Mitchell, Tetrahedron Lett. 2006,
47, 3811–3814.
[11] M. N. Romanelli, E. Cerbai, S. Dei, L. Guandalini, et al., Bio-
org. Med. Chem. 2005, 13, 1211–1220.
[25] A. Bomhard, M. Psiorz, J. Heider, N. Hauel, et al., EP 204349.
1986 [Chem. Abstr. 1987, 107, 23256].
[12] Y. P. Cheng, I. George, G. H. Yi, S. Reiken, et al., J. Pharmacol.
Exp. Ther. 2007, 321, 469–476.
[26] W. Phakhodee, P. Ploypradith, P. Sahakitpichan, S. Ruchir-
[13] R. De Silva, K. M. Fox, Nat. Rev. Cardiol. 2009, 6, 329–330.
[14] G. M. Keating, Drugs 2008, 68, 2483–2503.
awat, Tetrahedron 2009, 65, 351–356.
[27] K. H. Chikhalia, M. J. Patel, D. B. Vashi, ARKIVOC 2008, 13,
[15] D. T. Nash, S. D. Nash, Lancet 2008, 372, 1335–1341.
189–197.
[16] S. Y. Zhao, W. L. Huang, Chin. J. Org. Chem. 2008, 28, 240–
[28] P. Vicini, A. Geronikaki, K. Anastasia, M. Incerti, F. Zani,
245.
Bioorg. Med. Chem. 2006, 14, 3859–3864.
[17] S. Y. Zhao, W. L. Huang, Chin. J. Appl. Chem. 2007, 24, 698–
[29] L. Qian, H. Wang, W. Qiu, H. Huang, et al., Vascul. Pharma-
col. 2006, 45, 374–382.
702.
i 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com