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Synthesis and in-vitro inotropic evaluation of 2-4-substitutedbenzyl-14-diazepan-1-yl-N-45-dihydro-1-phenyl-[124]triazolo[43-a]quinolin-7-ylacetamides.

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Arch. Pharm. Chem. Life Sci. 2010, 10, 700–705
Full Paper
Synthesis and in-vitro inotropic evaluation of 2-(4substitutedbenzyl-1,4-diazepan-1-yl)-N-(4,5-dihydro-1-phenyl[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamides
Sheng-Ming Jiang1, Bai-Jun Ye1, Xue-Kun Liu1, Tian-Yi Zhang1, Xun Cui2*, and Hu-Ri Piao1
1
Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education;
Yanbian University College of Pharmacy, Yanji, P.R. China
2
Yanbian University College of Medicine, Yanji, P.R. China
We describe the synthesis and positive inotropic evaluation of a series of 2-(4-substitutedbenzyl-1,4diazepan-1-yl)-N-(4,5-dihydro-1-phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamides by measuring left
atrial stroke volume in preparations of isolated rabbit-heart. Several compounds were developed from,
and showed favorable activities compared with the standard drug milrinone. Compound 5o was the
most potent with an increased stroke volume of 9.17 0.14% (milrinone 2.47 0.08%) at 3 105 M
in our in-vitro study. The chronotropic effects of those compounds having inotropic effects were also
evaluated.
Keywords: 1,4-Diazepane / Positive inotropic activity / Stroke volume / [1,2,4]Triazolo[4,3-a]quinolines
Received: January 25, 2010; Revised: May 2, 2010; Accepted: May 7, 2010
DOI 10.1002/ardp.201000032
Introduction
Cardiac glycosides like digoxin are some of the most frequently prescribed cardiotonics used for the treatment of
congestive heart failure (CHF). Unlike other CHF drugs, they
do not increase mortality, but the high toxicity and narrow
therapeutic window still limit their clinical use as positive
inotropic agents [1]. The discovery of amrinone led to the
synthesis of a number of agents with promise for the treatment of CHF as non-sympathomimetic, non-glycoside agents
[2]. The phosphodiesterase (PDE)-inhibiting agent, milrinone,
has both vasodilator and inotropic properties and was
approved for the treatment of CHF more than a decade
ago. Nevertheless, the significant ventricular arrhythmias
and tachycardia associated with elevated cAMP levels also
limit the clinical use of milrinone [3], as well as a newer
agent, vesnarinone [4, 5]. Therefore, newer positive inotropic
agents with fewer side effects are still needed [6].
Correspondence: Hu-Ri Piao, Yanbian University College of Pharmacy,
Yanji City, Jilin Province, P.R. China.
E-mail: piaohuri@yahoo.com.cn
Fax: þ86-433-2659795
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
For many years, structural modification of compounds
derived from 3,4-dihydro-2(1H)-quinolinone has been carried
out in our research group with the aim of searching for more
potent inotropic agents with fewer side effects [7, 8]. At the
outset of our studies, a series of 2-(4-(4-substitutedbenzyloxy)3-methoxybenzyl)-1,4-diazepan-1-yl)-N-(4,5-dihydro-1-methyl
[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamides was synthesized
and tested for their biological activity. Among these compounds, 1 showed significant inotropic activity (four-times
more potent than milrinone at 1 105 M) [9]. The result
seems to indicate that incorporating triazole ring to the 1,2position of 3,4-dihydro-2(1H)-quinolinone is beneficial to
enhance the activity, and some derivatives bearing phenyl
group at 1-position of the triazole ring also showed good
activity [10]. Therefore, to further optimize compound 1 in
the present study, we keep the [1,2,4]triazolo[4,3-a]quinoline
and 1,4-diazepane moieties unchanged, replaced the methyl
group at the 1-position of the triazole ring with phenyl
group, removed the benzyloxy group, and changed the substituents on the phenyl ring of the benzyl group at the 4position of the 1,4-diazepane ring simultaneously to investi* Xun Cui contributed equally to the contribution.
E-mail: cuixun@ybu.edu.cn
Arch. Pharm. Chem. Life Sci. 2010, 10, 700–705
New synthesized inotropic agents
Table 1. Positive inotropic activity of compounds 5a–p in left atrial
stroke volume test on isolated rabbit-heart preparations.
gate the contribution of such a structural change on biological activity. The compounds were characterized by IR, 1HNMR, MS and elemental analysis. Inotropic activities were
evaluated by measuring changes in left atrial stroke volume
in preparations of isolated rabbit heart.
Compound
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
Milrinone
Results and discussion
Synthesis
Compounds 5a–p were synthesized according to the previously described methods [8] as presented in Scheme 1.
Commercially available 6-amino-3,4-dihydro-2(1H)-quinolinone (1) was sulfurized with phosphorous pentasulfide in
refluxing acetonitrile in the presence of triethylamine gave
the corresponding thione 2. Cyclization of 2 with phenylacetyl hydrazide in refluxing cyclohexanol under nitrogen
atmosphere afforded the desired triazole compound 3 in
moderate yield, followed by acylation of the amino group
with 2-chloroacetyl chloride in dichloromethane at room
temperature to provide corresponding amide 4 in excellent
yield. Nucleophilic-substitution reaction of 4 with various
monosubstituted 1,4-diazepanes in refluxing acetone in
the presence of potassium carbonate afforded desired compounds 5a–p in high yields.
1
Cl
O
R
N
1.42 0.10
1.57 0.07
1.99 0.04
–
2.15 0.08
4.67 0.05
1.28 0.06
1.01 0.06
0.85 0.09
4.62 0.06
–
1.80 0.04
2.52 0.04
–
9.17 0.14
–
2.47 0.08
5k, 5n, and 5p. Compounds 5f, 5j, and 5o exhibited more
efficacy than milrinone (2.47 0.08%, 3 105 M), in which
5o was the most potent with 9.17 0. 14% increased stroke
volume at the same concentration and exhibited similar
activity (3.7-fold more potent than milrinone) to the lead
compound 1 (4.0-fold more potent than milrinone). compound
5m showed almost the same potency (2.52 0.04%,
3 105 M) as milrinone. As for the relationship between
inotropic activity and the different substitutions (R) on the
phenyl ring of the benzyl group at the 4-position of the
diazepane ring, we did not observe a significant difference
between electron-donating and electron-withdrawing groups
for the contribution to inotropic activity. This suggested that
the electronic effect of the substituents on the phenyl ring was
not a key factor affecting such activity. The position of the
PhCONHNH 2
N
H
2
H
N
H
2-Cl
3-Cl
4-Cl
2-F
3-F
4-F
2-Br
3-Br
4-CH3
2-OCH3
3-OCH3
4-OCH3
3,4-(OCH3)2
3,4-(Cl)2
2-NO2
H2N
H 2N
O
N
H
Increased stroke
volume (%) a
The concentration for the test sample is 3 105 M. b None or
negative stroke volume increase. p < 0.05 versus milrinone.
The method of measuring left atrial stroke volume was
adopted for the biological evaluation of the compounds
5a–p in the present work. The features of congestive heart
failure are cardiac dilatation, poor contractility of cardiac
muscle, decreased ejection fraction, and depression of left
ventricular maximum pressure. Therefore, the macroscopic
measurement of the variance of left atrial stroke volume can
be used to estimate the positive inotropic effects of the compounds synthesized.
As shown in Table 1, most tested compounds showed inotropic effects on isolated rabbit heart preparations except 5d,
P2S5
R
a
Biological evaluation
H2 N
701
N
N
S
N
N
ClCH2COCl
3
NH
N
N
R
H
N
N
N
4
O
N
N
N
5a-p
Scheme 1. Synthetic scheme for the synthesis of compounds 5a–p.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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S.-M. Jiang et al.
Arch. Pharm. Chem. Life Sci. 2010, 10, 700–705
substituents on the phenyl ring significantly influenced the
inotropic activity, but no clear regularity was found for the
structure-activity relationship. For the halo substituted derivatives, fluorinated compounds showed better activity than
chlorinated and brominated compounds with an activity
order of m-F > o-F > p-F. For the methoxy substituted derivatives, para- and meta-substituted 5m and 5l displayed moderate
activity with 2.52 0.04% and 1.80 0.04% increased stroke
volume, respectively, but ortho-substituted 5k and 3,4-substituted 5n showed no potency. Since the para-methyl substituted
compound 5j exhibited more potent activity (4.62 0.06%)
than milrinone, ortho- and meta-methyl substituted derivatives
need to be prepared and to be further evaluated.
Analyzing the activities of the synthesized compounds, we
found that the extent of increasing inotropic activity for this
series of derivatives, compared with milrinone, was generally
not more significant than that of the lead compound 1, so it
seems that the substituent (phenyl or methyl group) at 1position on the triazole ring does not significantly affect the
inotropic activity. Likewise, the substituted benzyloxy moiety
of the lead compound 1 appears to have a lesser effect on the
activity (for which more derivatives need to be designed and
synthesized for further investigation).
On the other hand, we investigated the dynamics of the test
compounds in perfused beating rabbit atria and found that 5m
and 5o exhibited a similar atrial dynamic profile to milrinone
(Fig. 2A and D). Compounds 5f and 5j showed more desirable
atrial dynamic profiles with significant increased stroke volume of 4.67 0.05% and 4.62 0.06%, respectively (Fig. 2B
and C). As shown in Table 2, compounds 5f, 5j, 5m, and 5o were
also investigated for their chronotropic effects in a beating
atria and no significantly increased heart rates (p > 0.05) were
observed for 5f, 5j, and 5o at the same concentration.
Compound 5m, however, showed the changed heart rate.
Conclusion
Based on the structure of compound 1, we synthesized 2-(4substitutedbenzyl-1,4-diazepan-1-yl)-N-(4,5-dihydro-1-phenyl[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamides aimed at identifying more potent compounds for cardiac contractility without increasing heart rate. Compounds 5f, 5j, and 5o exhibited
promising cardiovascular properties and potent activities
compared with milrinone. Further modification of these
compounds is in progress.
Experimental
Chemistry
Melting points were determined in open capillary tubes and are
uncorrected. Reaction courses were monitored by TLC on silica
gel precoated F254 Merck plates and developed plates were
examined with UV lamps (254 nm). Column chromatography
was performed with Merck 200 mesh silica gel. IR spectra were
recorded (in KBr) on a FT-IR1730. 1H-NMR spectra were measured
on Bruker AV-300 spectrometer, using TMS as internal standard.
Mass spectra were measured on an HP1100LC (Agilent
Technologies, USA). Elemental analyses for C, H, and N were
within 0.4% of the theoretical values and were performed on
a 204Q CHN Rapid Analyzer (Perkin-Elmer, USA). The major
chemicals were purchased from Aldrich and Fluka Companies.
Monosubstituted 1,4-diazepanes were synthesized by the method
similar to prepare the monosubstituted piperazines [11].
2-Chloro-N-(4,5-dihydro-1-phenyl-[1,2,4]triazolo[4,3a]quinolin-7-yl)acetamide 4
To a solution of 3 in dichloromethane was added dropwise a
solution of 2-chloroacetyl chloride (0.40 g, 0.002 mol) in 20 mL
of dichloromethane (2 h). The resulting yellow solid was collected by filtration at the pump to afford 4 in 99% yield; m.p.:
197–1998C; 1H-NMR (DMSO) d: 3.15 (m, 4H, CH2CH2), 4.27 (s, 2H,
CH2), 6.69–7.78 (m, 8H, Ar-H), 10.71 (s, 1H, NH); IR (KBr) cm1:
3350 (NH), 1685 (C –
– O); ESI-MS m/z: 339 (M þ 1); Anal. calcd.
for C18H15ClN4O: C, 63.81; H, 4.46; N, 16.54. Found: C, 63.72;
H, 4.60; N, 16.55.
General procedure for compounds 5a–p
A mixture of 4 (0.35 g, 1.032 mmol), monosubstituted 1,4-diazepane (2.064 mmol), and sodium carbonate anhydrous in
refluxing methanol was stirred for 10 h. The solvent was evaporated under reduced pressure and the residue was dissolved in
dichloromethane and washed with water and brine, dried over
MgSO4, and the solvent was removed under reduced pressure.
The resulting residue was purified by silica gel column chromatography (dichloromethane/methanol 15:1). The yield, melting
point and spectra data of each compound are given below.
2-(4-Benzyl-1,4-diazepan-1-yl)-N-(4,5-dihydro-1-phenyl[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide 5a
Yield: 76%; m.p.: 71–738C; 1H-NMR (CDCl3) d: 1.83 (m, 2H, CH2),
2.71–2.85 (m, 8H, CH2), 3.06 (t, J ¼ 6.5 Hz, 2H, CH2), 3.18 (t,
J ¼ 6.5 Hz, 2H, CH2), 3.26 (s, 2H, CH2), 3.66 (s, 2H, CH2), 6.80–
O
N
CN
H3C
N
H
Milrinone
O
N
H3CO
H3CO
N
OCH3
Vesnarinone
O
N
H
O
Cl
N
N
1
H
N
O
N
H3C
N
N
Figure 1. Cardiotonic agents used for the treatment of CHF and lead compound 1.
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Arch. Pharm. Chem. Life Sci. 2010, 10, 700–705
∆ % Stroke volume
10
A)
New synthesized inotropic agents
Table 2. Changes of heart rate caused by compounds in isolated
rabbit-heart preparations.
Control
5m (30µmol/L)
Milrinone (30µmol/L)
8
***
6
4
2
0
-2
10
B)
∆ % Stroke volume
4
8
12
16
20
Fraction number
24
28
Control
5f (30µmol/L)
Milrinone (30µmol/L)
8
***
6
5f
5j
5m
5o
93.82
111.31
102.76
115.26
Control.
control.
b
Mean W SEb
0.12
0.27
0.26
0.13
91.29
108.35
97.53
113.47
Data after using the test samples.
c
0.15
0.15
0.17
0.54
P < 0.01 versus
4
2-(4-(2-Chlorobenzyl)-1,4-diazepan-1-yl)-N-(4,5-dihydro1-phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide 5b
2
-2
0
4
C)
8
12
16
20
Fraction number
24
28
Control
5j (30µmol/L)
Milrinone (30µmol/L)
10
∆ % Stroke volume
Mean W SEa
7.76 (m, 13H, Ar-H), 9.40 (s, 1H, NH); IR (KBr) cm1: 3370 (NH),
1735 (C –
– O); ESI-MS m/z: 493 (M þ 1); Anal. calcd.
for C30H32N6O: C, 73.14; H, 6.55; N, 17.06. Found: C, 73.12; H,
6.63; N, 16.95.
0
***
2
0
4
D)
23
8
12
16
20
Fraction number
24
28
Yield: 79%; m.p.: 83–858C; 1H-NMR (CDCl3) d: 1.82 (m, 2H, CH2),
2.70–2.85 (m, 8H, CH2), 3.06 (t, J ¼ 6.5 Hz, 2H, CH2), 3.16 (t,
J ¼ 6.5 Hz, 2H, CH2), 3.24 (s, 2H, CH2), 3.66 (s, 2H, CH2), 6.80–
7.73 (m, 12H, Ar-H), 9.39 (s, 1H, NH); IR (KBr) cm1: 3446 (NH),
1683 (C –
– O); ESI-MS m/z: 527 (M þ 1); Anal. calcd.
for C30H31ClN6O: C, 68.36; H, 5.93; N, 15.95. Found: C, 68.37;
H, 5.98; N, 15.88.
***
13
8
3
-2
0
4
8
12
16
20
Fraction number
Yield: 80%; m.p.: 80–828C; 1H-NMR (CDCl3) d: 1.85 (m, 2H, CH2),
2.71–2.88 (m, 8H, CH2), 3.07 (t, J ¼ 6.5 Hz, 2H, CH2), 3.16 (t,
J ¼ 6.5 Hz, 2H, CH2), 3.27 (s, 2H, CH2), 3.65 (s, 2H, CH2), 6.82–
7.77 (m, 12H, Ar-H), 9.41 (s, 1H, NH); IR (KBr) cm1: 3347 (NH),
1713 (C –
– O); ESI-MS m/z: 527 (M þ 1); Anal. calcd.
for C30H31ClN6O: C, 68.36; H, 5.93; N, 15.95. Found: C, 68.33;
H, 6.08; N, 15.93.
2-(4-(4-Chlorobenzyl)-1,4-diazepan-1-yl)-N-(4,5-dihydro1-phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide 5d
Control
5o (30µmol/L)
Milrinone (30µmol/L)
18
Yield: 81%; m.p.: 84–868C; 1H-NMR (CDCl3) d: 1.84 (m, 2H, CH2),
2.79–2.90 (m, 8H, CH2), 3.07 (t, J ¼ 6.5 Hz, 2H, CH2), 3.16 (t,
J ¼ 6.5 Hz, 2H, CH2), 3.28 (s, 2H, CH2), 3.80 (s, 2H, CH2), 6.82–
7.75 (m, 12H, Ar-H), 9.42 (s, 1H, NH); IR (KBr) cm1: 3350 (NH),
1695 (C –
– O); ESI-MS m/z: 527 (M þ 1); Anal. calcd.
for C30H31ClN6O: C, 68.36; H, 5.93; N, 15.95. Found: C, 68.32;
H, 6.13; N, 15.83.
2-(4-(3-Chlorobenzyl)-1,4-diazepan-1-yl)-N-(4,5-dihydro1-phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide 5c
6
-2
∆ % Stroke volume
Compound
a
0
703
24
28
Figure 2. Effects of milrinone and compounds 5f, 5j, 5m, and 5o on
stroke volume in beating rabbit artia (1.5 Hz). Values are
means SE. P < 0.001 versus control.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
2-(4-(2-Fluorobenzyl)-1,4-diazepan-1-yl)-N-(4,5-dihydro1-phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide 5e
Yield: 73%; m.p.: 87–898C; 1H-NMR (CDCl3) d: 1.83 (m, 2H, CH2),
2.76–2.86 (m, 8H, CH2), 3.06 (t, J ¼ 6.5 Hz, 2H, CH2), 3.17 (t,
J ¼ 6.5 Hz, 2H, CH2), 3.25 (s, 2H, CH2), 3.74 (s, 2H, CH2), 6.79–
7.75 (m, 12H, Ar-H), 9.42 (s, 1H, NH); IR (KBr) cm1: 3362 (NH),
1693 (C –
– O); ESI-MS m/z: 511 (M þ 1); Anal. calcd.
for C30H31FN6O: C, 70.57; H, 6.12; N, 16.46. Found: C, 70.39; H,
6.18; N, 16.38.
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S.-M. Jiang et al.
2-(4-(3-Fluorobenzyl)-1,4-diazepan-1-yl)-N-(4,5-dihydro1-phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide 5f
Yield: 70%; m.p.: 88–908C; 1H-NMR (CDCl3) d: 1.84 (m, 2H, CH2),
2.71–2.89 (m, 8H, CH2), 3.06 (t, J ¼ 6.5 Hz, 2H, CH2), 3.16 (t,
J ¼ 6.5 Hz, 2H, CH2), 3.27 (s, 2H, CH2), 3.65 (s, 2H, CH2), 6.81–
7.75 (m, 12H, Ar-H), 9.40 (s, 1H, NH); IR (KBr) cm1: 3458 (NH),
1688 (C –– O); ESI-MS m/z: 511 (M þ 1); Anal. calcd.
for C30H31FN6O: C, 70.57; H, 6.12; N, 16.46. Found: C, 70.28; H,
6.21; N, 16.32.
2-(4-(4-Fluorobenzyl)-1,4-diazepan-1-yl)-N-(4,5-dihydro1-phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide 5g
Yield: 78%; m.p.: 93–958C; 1H-NMR (CDCl3) d: 1.85 (m, 2H, CH2),
2.71–2.87 (m, 8H, CH2), 3.10 (t, J ¼ 6.5 Hz, 2H, CH2), 3.19 (t,
J ¼ 6.5 Hz, 2H, CH2), 3.27 (s, 2H, CH2), 3.64 (s, 2H, CH2), 6.82–
7.75 (m, 12H, Ar-H), 9.39 (s, 1H, NH); IR (KBr) cm1: 3375 (NH),
1738 (C –– O); ESI-MS m/z: 511 (M þ 1); Anal. calcd.
for C30H31FN6O: C, 70.57; H, 6.12; N, 16.46. Found: C, 70.34; H,
6.19; N, 16.40.
2-(4-(2-Bromobenzyl)-1,4-diazepan-1-yl)-N-(4,5-dihydro1-phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide 5h
Yield: 66%; m.p.: 108–1108C; 1H-NMR (CDCl3) d: 1.85 (m, 2H, CH2),
2.78–2.89 (m, 8H, CH2), 3.08 (t, J ¼ 6.5 Hz, 2H, CH2), 3.18 (t,
J ¼ 6.5 Hz, 2H, CH2), 3.27 (s, 2H, CH2), 3.75 (s, 2H, CH2), 6.81–
7.74 (m, 12H, Ar-H), 9.42 (s, 1H, NH); IR (KBr) cm1: 3430 (NH),
1679 (C –– O); ESI-MS m/z: 572 (M þ 1); Anal. calcd.
for C30H31BrN6O: C, 63.05; H, 5.47; N, 14.70. Found: C, 63.21;
H, 5.53; N, 14.46.
2-(4-(3-Bromobenzyl)-1,4-diazepan-1-yl)-N-(4,5-dihydro1-phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide 5i
Yield: 62%; m.p.: 95–978C; 1H-NMR (CDCl3) d: 1.83 (m, 2H, CH2),
2.70–2.88 (m, 8H, CH2), 3.09 (t, J ¼ 6.5 Hz, 2H, CH2), 3.19 (t,
J ¼ 6.5 Hz, 2H, CH2), 3.26 (s, 2H, CH2), 3.62 (s, 2H, CH2), 6.81–
7.76 (m, 12H, Ar-H), 9.40 (s, 1H, NH); IR (KBr) cm1: 3390 (NH),
1763 (C –– O); ESI-MS m/z: 572 (M þ 1); Anal. calcd.
for C30H31BrN6O: C, 63.05; H, 5.47; N, 14.70. Found: C, 63.17;
H, 5.67; N, 14.54.
2-(4-(4-Methylbenzyl)-1,4-diazepan-1-yl)-N-(4,5-dihydro1-phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide 5j
Yield: 73%; m.p.: 90–928C; 1H-NMR (CDCl3) d: 1.85 (m, 2H, CH2),
2.32 (s, 3H, CH3), 2.81–2.88 (m, 8H, CH2), 3.08 (t, J ¼ 6.5 Hz, 2H,
CH2), 3.18 (t, J ¼ 6.5 Hz, 2H, CH2), 3.27 (s, 2H, CH2), 3.65 (s, 2H,
CH2), 6.83–7.77 (m, 12H, Ar-H), 9.45 (s, 1H, NH); IR (KBr) cm1:
3458 (NH), 1763 (C –– O); ESI-MS m/z: 507 (M þ 1); Anal. calcd.
for C31H34N6O: C, 73.49; H, 6.76; N, 16.59. Found: C, 73.38; H,
6.91; N, 16.54.
2-(4-(2-Methoxybenzyl)-1,4-diazepan-1-yl)-N-(4,5dihydro-1-phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)
acetamide 5k
Yield: 60%; m.p.: 80–828C; 1H-NMR (CDCl3) d: 1.87 (m, 2H, CH2),
2.81–2.88 (m, 8H, CH2), 3.08 (t, J ¼ 6.5 Hz, 2H, CH2), 3.18 (t,
J ¼ 6.5 Hz, 2H, CH2), 3.27 (s, 2H, CH2), 3.65 (s, 2H, CH2), 3.79
(s, 3H, OCH3), 6.83–7.77 (m, 12H, Ar-H), 9.45 (s, 1H, NH); IR (KBr)
cm1: 3357 (NH), 1657 (C –
– O); ESI-MS m/z: 523 (M þ 1); Anal. calcd.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Chem. Life Sci. 2010, 10, 700–705
for C31H34N6O2: C, 71.24; H, 6.56; N, 16.08. Found: C, 71.38; H,
6.87; N, 15.87.
2-(4-(3-Methoxybenzyl)-1,4-diazepan-1-yl)-N-(4,5dihydro-1-phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)
acetamide 5l
Yield: 68%; m.p.: 89–918C; 1H-NMR (CDCl3) d: 1.86 (m, 2H, CH2), 2.72–
2.87 (m, 8H, CH2), 3.10 (t, J ¼ 6.5 Hz, 2H, CH2), 3.19 (t, J ¼ 6.5 Hz,
2H, CH2), 3.27 (s, 2H, CH2), 3.66 (s, 2H, CH2), 3.83 (s, 3H, OCH3), 6.77–
7.77 (m, 12H, Ar-H), 9.43 (s, 1H, NH); IR (KBr) cm1: 3475 (NH), 1725
(C –– O); ESI-MS m/z: 523 (M þ 1); Anal. calcd. for C31H34N6O2: C, 71.24;
H, 6.56; N, 16.08. Found: C, 71.19; H, 6.63; N, 15.91.
2-(4-(4-Methoxybenzyl)-1,4-diazepan-1-yl)-N-(4,5dihydro-1-phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)
acetamide 5m
Yield: 67%; m.p.: 86–888C; 1H-NMR (CDCl3) d: 1.78 (m, 2H, CH2),
2.65–2.80 (m, 8H, CH2), 3.01 (t, J ¼ 6.5 Hz, 2H, CH2), 3.11 (t,
J ¼ 6.5 Hz, 2H, CH2), 3.21 (s, 2H, CH2), 3.55 (s, 2H, CH2), 3.72
(s, 3H, OCH3), 6.76–7.72 (m, 12H, Ar-H), 9.48 (s, 1H, NH); IR (KBr)
cm1: 3445 (NH), 1685 (C –
– O); ESI-MS m/z: 523 (M þ 1); Anal. calcd.
for C30H34N6O2: C, 71.24; H, 6.56; N, 16.08. Found: C, 71.18; H,
6.79; N, 16.15.
2-(4-(3,4-Dimethoxybenzyl)-1,4-diazepan-1-yl)-N-(4,5dihydro-1-phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)
acetamide 5n
Yield: 68%; m.p.: 73–758C; 1H-NMR (CDCl3) d: 1.81 (m, 2H, CH2),
2.67–2.87 (m, 8H, CH2), 3.07 (t, J ¼ 6.5 Hz, 2H, CH2), 3.16 (t,
J ¼ 6.5 Hz, 2H, CH2), 3.25 (s, 2H, CH2), 3.58 (s, 2H, CH2), 3.84
(s, 3H, OCH3), 3.86 (s, 3H, OCH3), 6.78–7.73 (m, 11H, Ar-H), 9.40 (s,
1H, NH); IR (KBr) cm1: 3362 (NH), 1731 (C –
– O); ESI-MS m/z: 553
(M þ 1); Anal. calcd. for C32H36N6O3: C, 69.54; H, 6.57; N, 12.51.
Found: C, 69.32; H, 6.79; N, 12.76.
2-(4-(3,4-Dichlorobenzyl)-1,4-diazepan-1-yl)-N-(4,5dihydro-1-phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)
acetamide 5o
Yield: 74%; m.p.: 76–788C; 1H-NMR (CDCl3) d: 1.83 (m, 2H, CH2),
2.68–2.87 (m, 8H, CH2), 3.06 (t, J ¼ 6.5 Hz, 2H, CH2), 3.17 (t,
J ¼ 6.5 Hz, 2H, CH2), 3.26 (s, 2H, CH2), 3.60 (s, 2H, CH2), 6.81–
7.74 (m, 11H, Ar-H), 9.34 (s, 1H, NH); IR (KBr) cm1: 3362 (NH),
1731 (C –
– O); ESI-MS m/z: 562 (M þ 1); Anal. calcd.
for C30H30Cl2N6O: C, 64.17; H, 5.39; N, 14.97. Found: C, 64.32;
H, 5.53; N, 14.75.
2-(4-(2-Nitrobenzyl)-1,4-diazepan-1-yl)-N-(4,5-dihydro-1phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide 5p
Yield: 66%; m.p.: 86–888C; 1H-NMR (CDCl3) d: 1.75 (m, 2H, CH2),
2.65–2.79 (m, 8H, CH2), 3.08 (t, J ¼ 6.5 Hz, 2H, CH2), 3.16 (t,
J ¼ 6.5 Hz, 2H, CH2), 3.23 (s, 2H, CH2), 3.92 (s, 2H, CH2), 6.82–
7.76 (m, 12H, Ar-H), 9.34 (s, 1H, NH); IR (KBr) cm1: 3429 (NH),
1681 (C –
– O); ESI-MS m/z: 538 (M þ 1); Anal. calcd. for C30H31N7O3:
C, 67.02; H, 5.81; N, 18.24. Found: C, 67.32; H, 5.83; N, 18.17.
Pharmacology
The following drugs and chemicals were used in this biological
evaluation test: milrinone (Shuzhou Unite Pharmaceutical Co.,
www.archpharm.com
Arch. Pharm. Chem. Life Sci. 2010, 10, 700–705
Shuzhou), DMSO (Sigma-Aldrich Chemical Co., St. Louis, MO). All
other reagents were of analytical grade. Atria were obtained
from New Zealand white rabbits and mean atrial weight was
186.1 4.7 mg. The experiments were carried out in an isolated,
perfused atrial preparation that was prepared by using the
method described previously [12, 13]. Briefly, hearts were
removed from rabbits and the left atria were dissected free. A
calibrated transparent atrial cannula containing two small
catheters was inserted into the left atrium. The cannulated
atrium was transferred to an organ chamber and perfused
immediately with with N-2-hydroxyethylpiperazine-N’-2-ethanesulfonic acid (HEPES) buffer solution by means of a peristaltic
pump (1.25 mL/min) at 348C [14]. The composition of the buffer
was as follows (in mM): 118 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgCl2, 25
NaHCO3, 10.0 glucose, 10.0 HEPES (adjusted to pH 7.4 with 1 M
NaOH) and 0.1% bovine serum albumin (BSA). Soon after the
perfused atrium was set up, transmural electrical field stimulation with a luminal electrode was started at 1.5 Hz (duration,
0.3–0.5 ms, voltage 30 V). The changes in atrial stroke volume
were monitored by reading the lowest level of the water column
in the calibrated atrial cannula during the end diastole. The atria
were perfused for 60 min to stabilize the stroke volume. The
atrial beat rate was fixed at 1.5 Hz, the left atrial stroke volume
was recorded at 2-min intervals, and the stimulus effect of the
sample was recorded after a circulation of the control group. The
control period (12 min as an experimental cycle) was followed by
infusion of the test compounds or milrinone for 36 min.
The compounds were investigated using the single dose technique at a concentration of 1 105 M. Samples were dissolved
in DMSO and diluted with the HEPES buffer to a concentration of
0.1% of DMSO. The biological evaluation data for these compounds were expressed in means of increased stroke volume
percentage as shown in Table 1. Heart rate measurements for
those selected compounds were carried out in isolated rabbit
hearts by recording the electrocardiogram in the volume conduction model. In order to assess differences, repeated measurements were compared by means of an ANOVA test followed by
the Bonferroni’s multiple-comparison test. Statistical significance was defined as P < 0.05 and the data is presented as
means SE.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
New synthesized inotropic agents
705
This work was supported by the National Natural Science Foundation of
China (No. 30560177)
The authors have declared no conflict of interest.
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www.archpharm.com
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dihydro, synthesis, triazole, ylacetamides, substitutedbenzyl, 124, evaluation, phenyl, diazepam, quinolinic, vitro, inotropic
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