Synthesis and anti-congestive heart failure activity of novel levosimendan analogues

Article abstract of DOI:10.1007/s00044-010-9319-0

A series of levosimendan analogues were designed and synthesized, employing the Friedel-Crafts reaction, hydrolysis, and cyclization from the key intermediate compound R(-)-6-(4-aminophenyl)-5-methyl-4, 5-dihydro-3(2H)- pyridazinone, which was obtained from the starting material, acetanilide. These compounds, except 1b, exhibited potent anti-congestive heart failure activities, especially the compounds 1e and 1k, which showed more effective action than levosimendan. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9319-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:287–292
DOI 10.1007/s00044-010-9319-0
ORIGINAL RESEARCH
Synthesis and anti-congestive heart failure activity of novel
levosimendan analogues
•
Lisheng Wang Hongxiang Zhou Bin Yang
•
•
•
Zhigang Chen Hua Yang
Received: 7 May 2009 / Accepted: 12 February 2010 / Published online: 27 February 2010
Ó Springer Science+Business Media, LLC 2010
Abstract A series of levosimendan analogues were
designed and synthesized, employing the Friedel–Crafts
reaction, hydrolysis, and cyclization from the key inter-
mediate compound R(-)-6-(4-aminophenyl)-5-methyl-4,
5-dihydro-3(2H)-pyridazinone, which was obtained from
the starting material, acetanilide. These compounds, except
1b, exhibited potent anti-congestive heart failure activities,
especially the compounds 1e and 1k, which showed more
effective action than levosimendan.
et al., 1987). They selectively inhibited phosphodiesterase
III and increased cAMP levels (Nobuo et al., 1993). The
pharmacological activity of 4,5-dihydro-6-phenyl-3(2H)-
pyridazinones has been extensively studied and is known
for its cardiovascular effects (Abouzid et al., 2009; Bansal
et al., 2009; Thota and Bansal, 2009). Among these pyrid-
azinone compounds, levosimendan, R(-){[4-(1,4,5,6-tet-
rahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrozono}
propanedinitrile, has been the most effective drug in the
treatment of CHF (Hosenpud, 1999). Therefore, in this
study, levosimendan was chosen as the leading compound
for screening potential anti-CHF analogues. In addition, 11
previously unreported analogues of levosimendan were
synthesized and tested for their anti-CHF activity in blood
pressure experiments (Fig. 1).
Keywords Pyridazinone ꢀ Anti-congestive heart failure ꢀ
Levosimendan analogues ꢀ Synthesis
Introduction
Heart failure has been one of the most important causes of
morbidity and mortality in developed countries (Nieminen
et al., 2005), with an increase in the numbers of patients
hospitalized for ischemic heart disease and chronic heart
failure related to aging populations (Cherng et al., 2006;
Gottdiener et al., 2000; Krum and Liew, 2003; McCullough
et al., 2002). Therefore, more research attention has been
paid to it. In recent years, a large number of compounds
with diverse structures have been synthesized and evaluated
for potent, but less toxic, anti-congestive heart failure
(CHF) drugs. Among anti-CHF drug candidates, R(-)-6-
(4-substitutedphenyl)-5-methyl-4, 5-dihydro-3(2H)-pyrid-
azinone compounds showed good inhibition of platelet
aggregation and cardiac failure (Bristol et al., 1984; Hayes
Results and discussion
Chemistry
The syntheses of compounds 1a–1k are shown in
Scheme 1. Acetanilide was chosen as the starting material
and the intermediate (R)(-)-6-(4-aminophenyl)-5-methyl-
4,5-dihydro-3(2H)-pyridazinone was synthesized via seven
steps of the Friedel–Crafts reaction, hydrolysis, cyclization,
etc. (Ali and Yar, 2007; Austel et al., 1982). The above
intermediate reacted with appropriate aldehydes and yiel-
ded 11 target compounds (Scheme 1). In the first step, the
maximum yield was up to 60.1% when the molar ratio of
acetanilide and anhydrous aluminum trichloride was 1:2.8.
The yield did not increase when additional anhydrous
aluminum trichloride was used. The reaction was simpler
and easier when sodium hydride and the solvent THF were
replaced with sodium ethoxide and ethanol, respectively, in
L. Wang (&) ꢀ H. Zhou ꢀ B. Yang ꢀ Z. Chen ꢀ H. Yang
College of Chemistry and Chemical Engineering, Guangxi
University, Nanning 530004, China
e-mail: lswang@gxu.edu.cn; w_lsheng@163.com
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Med Chem Res (2011) 20:287–292
H3C
CHF activities of 1k at intervals of 15, 20, and 25 min were
also significantly better than that of levosimendan
(P \ 0.05; Table 1).
RCH=N
O
N
N
In comparison with the p-substituted phenyl compound
1d, the o-hydroxyl-substituted compound 1e showed higher
anti-CHF activity, whereas the m-hydroxyl-substituted
compound 1c showed lower activity. The results indicated
that the position of the hydroxyl group on the phenyl ring
greatly influenced anti-CHF activity, at an activity order of
o [ p [ m. When the R group was a furan ring, the anti-
CHF activity of compound 1k was obviously better than
that of levosimendan. For example, after treating with 1k
for 15, 20, and 25 min, the blood pressures were 25, 25,
and 24 mmHg, respectively. However, with levosimendan
at the same treatment times, the blood pressures were 34,
36, and 34 mmHg, respectively. The results indicated that
the furan ring of compound 1k played an important role in
anti-CHF activity. As a kinetophore, the furan ring may
have changed the electron density of the pyridazinone ring,
which increased the level of cAMP in cells and inhibited
ADP III as well, and finally resulted in better anti-CHF
activity.
H
1a-1k
Fig. 1 Levosimendan analogues. 1a: R = 4-nitrophenyl; 1b: R = 3-
nitrophenyl; 1c: R = 3,4-dihydroxyphenyl; 1d: R = 4-hydroxy-
phenyl; 1e: R = 2-hydroxyphenyl; 1f: R = 2-chlorophenyl; 1g:
R = 3,4,5-trimethoxyphenyl; 1h: R = 3,4-dichlorophenyl; 1i: R =
2-pyridyl; 1j: R = phenylvinyl; 1k: R = 2-furanyl
the third step. The economical sulfuric acid was used as a
decarboxylation reagent instead of biphenyl ether in the
fifth step. In the last step of the synthesis, 95% ethanol was
used instead of anhydrous ethanol for comparison.
Biological activity
The in vivo anti-CHF activities of these compounds were
tested in blood pressure experiments with levosimendan as
the positive control group. The tracheal intubation method
was utilized to measure blood pressures. The preliminary
results revealed that these levosimendan analogues, except
1b, were effective against CHF by dilating blood vessels.
The anti-CHF activities of 1a, 1c, 1d, and 1f–1j at different
time intervals were similar to those of levosimendan
(P \ 0.01). The anti-CHF activities of compound 1e at
intervals of 10 and 20 min, however, were significantly
stronger than that of levosimendan (P \ 0.05). The anti-
Conclusions
A series of levosimendan analogues were successfully
1
synthesized and characterized by IR, H NMR, MS, and
elemental analyses. The results of the tracheal intubation
Scheme 1 Synthesis route for
levosimendan analogues.
Reagents and conditions:
a CH3CH2COCl, AlCl3, CS2,
reflux for 3 h; b Br2, HOAc,
stirred at room temperature;
Br
O
CO2Et
CO2Et
O
O
NHAc
c
a
b
c CH2(CO2Et)2, EtOH,
C2H5ONa, room temperature,
8 h; d NaOH aq; e 3 mol/l HCl,
NHAc
NHAc
NHAc
25–70°C; f H2SO4 (v:v = 1:1),
4
2
5
3
reflux; g NH2NH2ꢀH2O, HOAc,
8 h; h L (?) tartaric acid,
isopropanol; i RCHO, EtOH, or
CHCl3, heated and stirred for
5 h
O
CO2H
CO2H
O
CO2H
g
d, e
f
H2N
O
N
N
H
NHAc
NHAc
8
6
7
i
h
RCH=N
O
H2N
O
N
N
H
N
N
H
1a-1k
9
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Med Chem Res (2011) 20:287–292
289
Table 1 The blood pressures of
rats at different times after
administration (50 mg/kg) of
compounds 1a–1k in
Compound
Dosage
(mmol/kg)
Average blood pressure (mmHg) at different time intervals (min)
5
10
15
20
25
30
comparison with those in the
negative control and
levosimendan control
Control group
–
97
3
95
3
86
3
81
4
79
4
88
3
Levosimendan 0.179
51 2a 39 3a
56 3a 35 3a
77 4b 71 4a
77 3b 63 3a
34 3a
31 3a
69 3a
53 3a
32 3a
36 3a
29 4a
34 3a
28 3a
31 3a
29 2a
67 2b
53 3a
30 4a
26 2a
32 3a
27 3a
25 4a
29 3a
31 3a
1a
1b
1c
1d
1e
1f
0.149
0.149
0.224
0.163
0.163
0.145
0.131
0.139
0.171
0.158
0.178
68
3
67
3
53 2a
30 2a
53 3a
29 3a
80
2
44 3a
55 2a 28 3aB 28 4a
26 3aB 26 3a
81
4
68 2a
55 2a
37 3a
25 2a
30 3a
33 2a
34 3a
28 3a
24 4a
30 2a
36 3a
34 3a
27 3a
25 3a
29 2a
36 2a
1g
1h
1i
77 3b 46 3a
52 3a 33 3a
52 2a 39 3a
59 3a 36 2a
45 3a 30 3a
Comparison with control group:
a: P \ 0.01; b: P \ 0.05
Comparison with levosimendan
group: A: P \ 0.01; B:
P \ 0.05
1j
1k
25 2aB 25 3aB 23 2aB 24 3a
tests showed that all target compounds, except 1b, signif-
icantly reduced the blood pressures of tested rats, sug-
gesting that these compounds have good anti-CHF
activities. The research results obtained in this study pro-
vided useful information for further structural modification
of these compounds and the synthesis of potent new anti-
CHF agents.
chloride (0.412 mol, 55 g). The mixture was gently heated
and stirred until a colorless solution formed. After the
mixture was stirred for another 10 min, propionyl chloride
(0.160 mol, 14 ml) was added dropwise with a dropping
funnel for more than 30 min. Then, the mixture was stirred
at 50°C for 3 h. Removal of the solvent under normal
pressure yielded a pale red oil. The oil was then transferred
to a 250-ml beaker. A 55-ml mixture of ice, water, and
hydrochloric acid (5 ml) was added to yield 3 in the form
of a yellow solid. Recrystallization with 95% ethanol
produced a pale yellow solid (17 g, 60%).
Experimental
Instrumentation
4-(2-Bromopropionyl) acetylanilide (4)
All compounds were characterized with MS, IR, 1H NMR,
1
and elemental analysis data. H NMR data were recorded
A 250-ml round-bottomed flask was charged with 3
(0.05 mol, 10 g) and chloroform (100 ml). Bromine
(0.05 mol, 2.7 ml) was added dropwise to the mixture
while stirring. Next, the solvent was evaporated with a
rotary evaporator. The residue was adjusted to a pH of 8.0
using a saturated solution of sodium carbonate. After the
mixture was stirred for over 24 h at room temperature, the
solvent was evaporated with a rotary evaporator to form a
yellowish solid 4. Recrystallization with 95% ethanol
produced a white solid (10.2 g, 72%).
on a Bruker Avance 500 (500 MHz) spectrometer with
DMSO as the solvent and tetramethylsilane as the internal
standard. MS and IR spectra were taken on a Shimadzu
GS-MS/QP5050A mass spectrometer and a Shimadzu
FTIR-8700, respectively. Elemental analysis data were
obtained with a Perkin–Elmer 2400. Melting points were
determined in open capillary tubes on a Buchi 530 melting
point apparatus without correction. Optical rotation values
were measured on a WZZ-1S automatic spectropolarime-
ter. All chemical reagents used in the experiments were of
analytical grade and were obtained from Sinopharm
Chemical Reagent Co., Ltd., China.
2-Ethoxycarbonyl-3-(4-acetylaminobenzoyl)-ethyl
butyrate (5)
General procedures
Diethyl malonate (0.016 mol, 2.4 ml) was added portion-
wise in an ice-water bath to an ethanol solution of sodium
ethoxide prepared from absolute ethyl alcohol (60 ml) and
sodium (0.013 mol, 3 g). The resulting solution was
gradually warmed to 35°C and then an ethanol solution of 4
(0.0078 mol, 2.1 g) was added dropwise for 10 min. The
mixture was stirred at 75°C for 8 h and then evaporated
Synthesis of 4-propionacetylanilide (3)
A flame-dried round-bottomed flask (100 ml) connected to
a reflux condenser was charged with carbon disulfide
(60 ml), 2 (0.148 mol, 20 g), and anhydrous aluminum
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Med Chem Res (2011) 20:287–292
under reduced pressure (65°C, 40 mmHg) to yield 5 in the
form of a brown solid, which was used directly with no
further purification.
solution was cooled to room temperature and a white crys-
talline substance formed. The white solid was collected by
filtration and dried to produce 9 (0.8 g, 8%), [a]2D0 = -380°
(c = 1,
VC H OH : VH O : Vconc:HCl ¼ 17 : 2 : 1Þ;
m.p.
2
5
2
¨
¨
2-Carboxyl-3-(4-aminobenzoyl) butyric acid (6)
205–207°C. [Literature (Backstrom et al., 1992) data:
[a]2D5 = -383° (ethanol–water-concentrated HCl 17:2:1),
m.p. 207–210°C, optical purity 99.5%].
A sodium hydroxide solution (200 ml, 15%) was added to
5. The mixture was stirred for 4 h, and then adjusted to a
pH of 1.0 using concentrated hydrochloric acid (34 ml).
Next, the mixture was stirred for 3 h at 100°C and con-
centrated with a rotary evaporator (40 mmHg, 70°C).
Then, 20 ml of methanol was added to the residue while
stirring and a white solid precipitated. The mixture was
filtered to remove the white solid by washing it with
methanol (10 ml). The combined organic phases were
concentrated with a rotary evaporator (50°C, 40 mmHg) to
form the crude product 6, which was used directly with no
further purification.
General synthesis procedures for compounds 1a–1e
and 1g–1j
A 100-ml round-bottomed flask connected to a reflux
condenser was charged with 9 (0.0296 mol, 6 g), absolute
methanol (20 ml) (instead of the absolute ethanol used for
1g–1j), and aldehyde (0.0298 mol). The mixture was stir-
red and refluxed for 5 h and then cooled to ambient tem-
perature. The solid was collected by filtration followed by
recrystallization with acetone (instead of the absolute eth-
anol used for 1g–1j) to yield products 1a–1e and 1g–1j.
3-(4-Aminobenzoyl) butyric acid (7)
General synthesis procedures for compounds 1f and 1k
An aqueous solution of sulfuric acid (40 ml, 1:1, v/v) was
added to 6. The mixture was refluxed for 3.5 h and then
adjusted to a pH of 4.0 using a sodium carbonate aqueous
solution (20%) to yield the product 7 in the form of a
yellow solid (2.1 g, 55%).
A 250-ml round-bottomed flask connected to a reflux
condenser was charged with 9 (0.0246 mol, 5 g), chloro-
form (200 ml), and the appropriate aldehyde (0.248 mol).
The mixture was refluxed for 4 h. After removal of the
solvent, the residue was recrystallized using ethanol to
yield products 1f and 1k.
6-(4-Aminophenyl)-5-methyl-4, 5-dihydro-3(2H)-
pyridazinone (8)
R(-)-6-[4-(4-nitrobenzal)amino]phenyl-5-methyl-4,5-
dihydro-3(2H)-pyridazinoe (compound 1a)
Hydrazine hydrate (85%, 0.0034 mol, 2 ml) was added to a
25-ml ethanol solution (95%) of 7 (0.0097 mol, 2 g). The
solution was stirred at 80°C for 3 h and then cooled to
room temperature to yield 8 in the form of a yellow solid.
Recrystallization with 90% aqueous ethanol produced a
white solid (1.8 g, 92%).
Yield: 86%; m.p.: 110–112°C; [a]2D0: -421° (c = 1,
MeOH); IR (KBr, cm-1): 3210, 3110, 3020, 2940, 1690,
1
1600, 1510, 1350, 1560, and 1220; H NMR (DMSO-d6, d
ppm): 1.12 (3H, d, J = 7), 2.29 (1H, d, J = 1), 2.71 (1H,
dd, J = 7), 3.44 (1H, m, J = 7.5), 7.40 (2H, d, J = 7),
7.87 (2H, d, J = 7), 8.20 (2H, d, J = 7), 8.35 (2H, d,
J = 7), 8.84 (1H, s), and 10.95 (1H, s); MS: m/z 336 (M?),
44, 321, 279, 251, 204, 151, 129, 115, 96, 77, 69, and 57;
elemental analysis (%): calculated: C, 64.28; H, 4.79; N,
16.66; found: C, 64.34; H, 4.88; N, 16.65.
R(-)-6-(4-Aminophenyl)-5-methyl-4, 5-dihydro-3(2H)-
pyridazinone (9)
A 500-ml round-bottomed flask connected to a reflux con-
denser was charged with 8 (0.049 mol, 10 g), isopropanol
(250 ml), and L-tartaric acid (0.1 mol, 15 g). The mixture
was heated and stirred for 30 min. The mixture was then
cooled to room temperature and kept for 8 h to yield a white
solid. The solid was collected using filtration followed by
recrystallization in isopropanol (125 ml). Then, it was
transferred to a 200-ml beaker containing 50 ml of distilled
water, and this mixture was adjusted to a pH of 7–8 using
potassium carbonate and filtered to yield the solid. The solid
was then washed with water (50 ml) and dried to yield 7.3 g
of a white solid. The white solid was added to 1,4-dioxane
(60 ml) and heated under reflux for over 30 min. The
R(-)-6-[4-(3-nitrobenzal)amino]phenyl-5-methyl-4,5-
dihydro-3(2H)-pyridazinone (compound 1b)
Yield: 92%; m.p.: 215–217°C; [a]2D0: -382° (c = 1,
MeOH); IR (KBr, cm-1): 3210, 3080, 2960, 1690, 1350,
1
1540, 1600, and 1200; H NMR (DMSO-d6, ppm): 1.12
(3H, d, J = 7), 2.28 (1H, d, J = 1), 2.71 (1H, dd, J = 7),
3.44 (1H, m, J = 7.5), 7.40 (2H, d, J = 7), 7.84 (2H, m,
J = 7), 7.88 (2H, d, J = 7), 8.35 (1H, d, J = 7), 8.74 (1H,
s), 8.86 (1H, s), and 10.96 (1H, s); MS: m/z 336 (M?), 321,
123

Med Chem Res (2011) 20:287–292
291
1
279, 251, 217, 204, 129, 115, 102, 77, 63, and 44; ele-
mental analysis (%): calculated: C, 64.28; H, 4.79; N,
16.66; found: C, 64.41; H, 4.84; N, 16.62.
1580, 1500, 1330, and 750; H NMR (DMSO-d6, d ppm):
1.08 (3H, d, J = 7), 2.28 (1H, d, J = 1), 2.70 (1H, dd,
J = 7), 3.43 (1H, m, J = 7.5), 7.34 (2H, d, J = 1.5, 7.7),
7.48 (1H, m, J = 2, 7.8), 7.57 (2H, m, J = 2, 7.5), 7.85
(2H, d, J = 7), 8.17 (1H, d, J = 2, 7.7), 8.89 (1H, s), and
10.93 (1H, s); MS: m/z 325 (M?), 115, 310, 268, 254, 129,
239, 102, 141, 89, and 75; elemental analysis (%): calcu-
lated: C, 66.36; H, 4.95; N, 12.90; found: C, 66.17; H, 5.00;
N, 12.88.
R(-)-6-[4-(3,4-dihydroxybenzal)amino]phenyl-5-methyl-
4,5-dihydro-3(2H)-pyridazinone (compound 1c)
Yield: 94%; m.p.: 222–224°C; [a]2D0: -412° (c = 1,
MeOH); IR (KBr, cm-1): 3350, 2980, 1650, 1600, 1580,
and 1280 1H NMR (DMSO-d6, d ppm): 1.08 (3H, d,
J = 7), 2.27 (1H, d, J = 1), 2.68 (1H, dd, J = 7), 3.41
(1H, m, J = 7.5), 7.22 (2H, m, J = 8), 7.25 (2H, d,
J = 2.5, 7), 7.42 (1H, s), 7.80 (2H, d, J = 2, 7), 8.42 (1H,
s), 9.23 (1H, s), 9.70 (1H, s), and 10.88 (1H, s); MS: m/
z 323(M?), 203, 118, 188, 130, 146, 160, 308, 91, 77, and
65; elemental analysis (%): calculated: C, 66.86; H, 5.30;
N, 13.00; found: C, 66.66; H, 5.44; N, 12.78.
R(-)-6-[4-(3,4,5-trimethoxybenzal)amino]phenyl-5-
methyl-4,5-dihydro-3(2H)-pyridazinone (compound 1g)
Yield: 83%; m.p.: 165–167°C; [a]2D0: -318° (c = 1,
MeOH); IR (KBr, cm-1): 3330, 2960, 1690, 1600, 1580,
1
1500, 1320, and 1120; H NMR (DMSO-d6, d ppm): 1.11
(3H, d, J = 7), 2.26 (1H, d, J = 16.5), 2.70 (1H, dd,
J = 7), 3.42 (1H, m, J = 6.5), 3.76 (6H, s), 3.87 (3H, s),
7.30 (2H, s), 7.48 (2H, d, J = 2, 7), 7.83 (2H, d, J = 2, 7),
8.57 (1H, s), and 10.92 (1H, s); MS: m/z 381 (M?), 115,
366, 324, 309, 102, 271, 91, and 77; elemental analysis
(%): calculated: C, 66.13; H, 6.08; N, 11.01; found: C,
66.02; H, 6.01; N, 11.04.
R(-)-6-[4-(4-hydroxybenzal)amino]phenyl-5-methyl-4,5-
dihydro-3(2H)-pyridazinone (compound 1d)
Yield: 92%, m.p.: 253–254°C; [a]2D0: -339° (c = 1,
MeOH); IR (KBr, cm-1): 3180, 1650, 2960, 1600, 1580,
1510, and 1280; 1H NMR (DMSO-d6, d ppm): 1.10 (3H, d,
J = 7), 2.26 (1H, d, J = 1), 2.68 (1H, dd, J = 7), 3.41
(1H, m, J = 7.5), 6.90 (2H, d, J = 2, 7.8), 7.26 (2H, d,
J = 2, 7), 7.78 (4H, m, J = 1.5, 7), 8.49 (1H, s), 10.07
(1H, s), and 10.878 (1H, s); MS: m/z 307 (M?), 221, 203,
115, 132, 57, 292, 236, 250, 41, 264, 102, 77, and 65;
elemental analysis (%): calculated: C, 70.34; H, 5.58; N,
13.67; found: C, 70.50; H, 5.56; N, 13.67.
R(-)-6-[4-(3,4-dichlorobenzal)amino]phenyl-5-methyl-
4,5-dihydro-3(2H)-pyridazinone (compound 1h)
Yield: 86%; m.p.: 158–160°C; [a]2D0: -348° (c = 1,
MeOH); IR (KBr, cm-1): 3210, 3100, 2960, 1680, 1600,
1
1580, 1500, and 1320; H NMR (DMSO-d6, d ppm); 1.12
(3H, d, J = 7.5), 2.29 (1H, d, J = 1), 2.70 (1H, dd, J = 7),
3.42 (1H, m, 6.5), 7.34 (2H, d, J = 4.5), 7.76 (1H, d,
J = 8.5), 7.85 (2H, d, J = 7), 7.92 (1H, dd, J = 2, 8.5),
8.14 (1H, s), 8.67 (1H, s), and 10.93 (1H, s); MS: m/
z 360(M?), 115, 245, 303, 288, 102, 248, 77, and 51;
elemental analysis (%): calculated: C, 60.01; H, 4.20; N,
11.66; found: C, 60.08; H, 4.39; N, 11.70.
R(-)-6-[4-(2-hydroxybenzal)amino]phenyl-5-methyl-4,5-
dihydro-3(2H)-pyridazinone (compound 1e)
Yield: 93%; m.p.: 187–189°C; [a]2D0: -442° (c = 1,
MeOH); IR (KBr, cm-1): 3230, 2920, 1680, 1600, 1580,
and 1260; 1H NMR (DMSO-d6, d ppm): 1.10 (3H, d,
J = 7), 2.28 (1H, d, J = 1), 2.71 (1H, dd, J = 7), 3.44
(1H, m, J = 7.5), 6.98 (2H, m, J = 7), 7.43 (1H, m,
J = 7), 7.47 (2H, d, J = 7.5), 7.67 (1H, d, J = 7), 7.87
(2H, d, J = 7.7), 9.00 (1H, s), 10.94 (1H, s), and 12.94
(1H, s); MS: m/z 307 (M?), 221, 203, 115, 132, 292, 236,
250, 264, 102, 77, 65, 57, and 41; elemental analysis (%):
calculated: C, 70.34; H, 5.58; N, 13.67; found: C, 70.38; H,
5.62; N, 13.66.
R(-)-6-[4-(2-pyridinylmethylene)amino]phenyl-5-methyl-
4,5-dihydro-3(2H)-pyridazinone (compound 1i)
Yield: 83%; m.p.: 210–211°C; [a]2D0: -422° (c = 1,
MeOH); IR (KBr, cm-1): 3200, 3100, 3060, 1680, 1300,
1
1600, 1580, and 1500; H NMR (DMSO-d6, d ppm): 1.11
(3H, d, J = 7), 2.26 (1H, d, J = 17), 2.70 (1H, dd, J = 7),
3.44 (1H, m, J = 7), 7.39 (2H, d, J = 8.5), 7.54 (1H, m,
J = 7), 7.87 (2H, d, 8.5), 7.95 (2H, m, J = 7.5), 8.18 (1H,
d, J = 8), 8.63 (1H, s), 8.82 (1H, d, J = 6.5), and 10.93
(1H, s); MS: m/z 292 (M?), 79, 180, 206, 45, 105, 115, 221,
248, 235, 276, 264, 167, and 128; elemental analysis (%):
calculated: C, 69.85; H, 5.52; N, 19.16; found: C, 69.83; H,
5.78; N, 19.22.
R(-)-6-[4-(2-chlorobenzal)amino]phenyl-5-methyl-4,5-
dihydro-3(2H)-pyridazinone (compound 1f)
Yield: 78%; m.p.: 163–164°C; [a]2D0: -415° (c = 1,
MeOH); IR (KBr, cm-1): 3200, 3080, 2960, 1680, 1600,
123

292
Med Chem Res (2011) 20:287–292
R(-)-6-[4-(phenylvinylmethylene)amino]phenyl-5-methyl-
4,5-dihydro-3(2H)-pyridazinone (compound 1j)
References
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Yield: 81%; m.p.: 217–219°C; [a]2D0: -422° (c = 1,
MeOH); IR (KBr, cm-1): 3200, 3100, 2960, 1680, 1600,
1580, and 1500; 1H NMR (DMSO-d6, d ppm): 1.10 (3H, d,
J = 7), 2.27 (1H, d, J = 16), 2.68 (1H, dd, J = 7), 3.41
(1H, m, J = 7), 6.85 (1H, m, J = 8), 7.13 (1H, m, J = 9),
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Yield: 73%; m.p.: 175–177°C; [a]2D0: -465° (c = 1,
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and 1500; 1H NMR (DMSO-d6, d ppm): 1.10 (3H, d,
J = 7), 2.27 (1H, d, J = 16), 2.69 (1H, dd, J = 7), 3.41
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Biological activity
The tracheal intubation method of measuring blood pres-
sure was used to evaluate preliminary anti-CHF activity.
The trachea were separated from anesthetized rats with
urethane (5 ml/kg) and intubated. The carotid of the rats
was separated and then connected to a biological func-
tion examination system, BL-420E. 2% solutions of levo-
simendan and the target compounds with 1% CMC were
then inserted in the rats’ duodenums (50 mg/kg). Blood
pressure values were recorded and analyzed statistically
(Table 1).
Acknowledgment This study was supported by the Scientific
Research Startup Foundation of the Chinese Ministry of Education for
Returnees (jiaowaisiliu[2007]1108).
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