Synthesis of new pyridazinone derivatives as platelet aggregation inhibitors

Article abstract of DOI:10.1007/s00044-009-9232-6

This paper describes the synthesis and the antiplatelet activity of a series of 6-(4-(substituted-amino)phenyl)-4,5-dihydro-3(2H)-pyridazinones. Antiplatelet activity was determined by using the tail transaction bleeding test. All of the newly synthesized

Full text of DOI:10.1007/s00044-009-9232-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2010) 19:808–816
DOI 10.1007/s00044-009-9232-6
ORIGINAL RESEARCH
Synthesis of new pyridazinone derivatives as platelet
aggregation inhibitors
Sridhar Thota Æ Ranju Bansal
Received: 16 April 2009 / Accepted: 2 July 2009 / Published online: 24 July 2009
¨
Ó Birkhauser Boston 2009
Abstract This paper describes the synthesis and the antiplatelet activity of a series
of 6-(4-(substituted-amino)phenyl)-4,5-dihydro-3(2H)-pyridazinones. Antiplatelet
activity was determined by using the tail transaction bleeding test. All of the newly
synthesized pyridazinone derivatives exhibited significant platelet aggregation
inhibitory activity. The compounds IIIc and IIIh displayed two times more platelet
aggregation inhibitory effect compared with standard drug aspirin.
Keywords Pyridazinone derivatives Á Platelet aggregation inhibitors Á
3(2H)-pyridazinones
Introduction
Increasing evidence clearly indicates that enhanced platelet activation plays a
critical role in the initiation and development of atherothrombotic diseases (Marcus
and Safier, 1993; Ruggeri, 2002). Accordingly, to prevent and treat thrombosis and
vascular diseases, antiplatelet therapy may be a potential strategy (Ruggeri, 2002;
Cherng et al., 2006). Aspirin, the primary antiplatelet therapy in use today, has been
shown to reduce the risk of arterial thrombosis in placebo-controlled clinical trials.
Despite the proven efficacy of aspirin, there are reasons to believe that substantial
improvements in antiplatelet therapy can be made. Among these is the fact that
aspirin and the other currently available orally administered antiplatelet agents, such
as ticlopidine and clopidogrel, are selective platelet inhibitors and thus inhibit some
but not all agonist-induced pathways of platelet activation and recruitment
(Grotemeyer et al., 1993). However, some drawbacks of these drugs, such as
S. Thota Á R. Bansal (&)
University Institute of Pharmaceutical Sciences, Panjab University,
Chandigarh 160014, India
e-mail: ranju29in@yahoo.co.in

Med Chem Res (2010) 19:808–816
809
MeO
H3C
H
N
F2HCO
O
O
MeO
N
H
N
N
H
N
N
Zardaverine
Pimobendan
Fig. 1 Structures of pyridazinone type platelet aggregation inhibitors
aspirin resistance and the risk of neutropenia, bleeding, and thrombocytopenia, were
occasionally observed. Therefore, to develop safer and effective antiplatelet agents
with a broad mechanism of action may be a promising approach for the prevention
and treatment of atherothrombosis (Sotelo et al., 2002).
6-Aryl-3(2H)-pyridazinones have attracted particular attention because of their
diversified biological activities, most of them related to the cardiovascular system.
Several compounds, such as imazodan, zardaverine, and pimobendan (Fig. 1), have
been developed as potent antiplatelet and cardiotonic agents through phosphodi-
esterase III inhibition (Curran and Ross, 1974). In recent years the potent platelet
inhibitory activity of several other 6-phenyl-4,5-disubstituted-3(2H)-pyridazinones
also has been reported (Dal et al., 1991). Because of easy functionalization of
various ring positions, 6-aryl-3(2H)-pyridazinone has emerged as an attractive
synthetic building block for the preparation of compounds of diverse biological
interest (Sotelo et al., 2000). The search for more potent and safer pyridazinones as
platelet aggregation inhibitors continues, and in the process a new series of
pyridazinone derivatives possessing substituted amino phenyl group has been
synthesized in our laboratory, which we report herein. The structures of these
compounds were established by using various spectral and elemental analyses. The
newly synthesized compounds were evaluated for antiplatelet activity using tail
transaction bleeding test.
Materials and methods
Chemistry
Melting points were determined via an MP1-Veego instrument (Veego Instruments,
Mumbai, India), uncorrected. All instrumental analysis was performed in the central
instrumental laboratory of Panjab University. Infrared (IR) spectra were recorded on
a Perkin-Elmer spectrum RX 1, FT-IR spectrophotometer (Huenenberg, Switzer-
1
land): KBr pellets; tmax in cm-1. H-nuclear magnetic resonance (1H-NMR) was
¨
measured with a Bruker AC-300F (300 MHz) instrument (Bruker AG, Fallanden,
Switzerland). All chemical shifts were reported as d (ppm) values. Me4Si as the
internal standard: J in Hz. Elemental analyses were performed on a Perkin-Elmer-
2400 apparatus. The purity of the compounds was established by TLC and
elemental analyses (TLC: plates; E. Merck, Darmstadt, Germany) were prepared

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Med Chem Res (2010) 19:808–816
according to Stahl (activated at 110°C for 30 min; AcOEt as a solvent; visualization
by I2 vapors). Materials obtained from the commercial suppliers were used without
further purification. Anhydrous Na2SO4 was used as a drying agent.
The starting compound 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)-one (I)
was prepared according to literature method (Burpitt et al., 1988).
Synthesis of 6-(4-(substituted-amino)phenyl)-4,5-dihydro-3(2H)-pyridazi-
nones IIIa–h Appropriate aldehyde IIa–h (1.58 mmol) was added to stirred
solution of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)-one (I) (1.58 mmol) in
methanol (15 ml) with constant stirring. The reaction mixture was further stirred
at room temperature overnight. The suspension obtained was cooled in ice and
sodium borohydride (0.39 g) added in small amounts with constant stirring for a
period of 30 min and the solution obtained was further stirred for 2 hr. Ice cold
water was added to it and the precipitated material was filtered off, washed with
ice cold water, dried, and recrystallization from a mixture of methanol and
chloroform resulted into the formation of desired pyridazinones IIIa–h. The
structures of these compounds were elucidated by using various spectral and
elemental analyses.
6-(4-(3,4-Dimethoxybenzylamino)phenyl)-4,5-dihydropyridazin-3(2H)-one
(IIIa). Yield: 44.91%; m.p. 137–138°C. Spectroscopic analysis: IR (KBr) tmax
/
cm-1: 3370 (NH), 3085 (CH, aromatic), 2929 (CH, aliphatic), 1661 (CO), 1600
(C=C, aromatic); 1H-NMR (CDCl3, 400 MHz, d, ppm): 2.58 (t, 2H, 4-CH2,
J = 7.42 Hz), 2.94 (t, 2H, 5-CH2, J = 7.4 Hz), 3.87 (s, 6H, 2x-OCH3), 4.30 (s,
3H, NH–CH2), 6.62 (d, 2H, Ar–H, Jo = 8.84 Hz), 6.91 (m, 3H, Ar–H), 7.58 (d,
2H, Ar–H, Jo = 8.80 Hz) and 8.36 (s, 1H, –NH). Anal. calcd. for C19H21N3O3: C:
67.24, H: 6.24, N: 12.38%; found; C: 67.08, H: 6.13; N: 12.13%.
6-(4-(3,4,5-Trimethoxybenzylamino)phenyl)-4,5-dihydropyridazin-3(2H)-one
(IIIb). Yield: 62.09%; m.p. 134–135°C. Spectroscopic analysis: IR (KBr) tmax
/
cm-1: 3360 (NH), 3069 (CH, aromatic), 2928 (CH, aliphatic), 1661 (C=O), 1600
(C=C, aromatic); 1H-NMR (CDCl3, 400 MHz, d, ppm): 2.58 (t, 2H, 4-CH2,
J = 7.46 Hz), 2.95 (t, 2H, 5-CH2, J = 7.42 Hz), 3.84 (s, 9H, 3x-OCH3), 4.31 (s,
3H, NH–CH2), 6.58 (s, 2H, Ar–H), 6.65 (dd, 2H, Ar–H, Jo = 6.88 Hz,
Jm = 1.90 Hz), 7.58 (dd, 2H, Ar–H, Jo = 6.84 Hz, Jm = 1.90 Hz) and 8.36 (s,
1H, –NH, pyridazinone). Anal. calcd. for C20H23N3O4: C: 65.03, H: 6.27, N:
11.37%; found; C: 65.06, H: 6.14; N: 11.31%.
6-(4-(2-Hydroxybenzylamino)phenyl)-4,5-dihydropyridazin-3(2H)-one (IIIc).
:
Yield: 31.25%; m.p. 197–198°C. Spectroscopic analysis: IR (KBr) tmax/cm-1
3410 (OH), 3192 (NH), 3043 (CH, aromatic), 2931 (CH, aliphatic), 1656 (C=O,
pyridazinone), 1606 (C=C, aromatic); 1H NMR (DMSO-d6, 400 MHz, d, ppm): 2.50
(t, 2H, 4-CH2, J = 8.14 Hz), 2.88 (t, 2H, 5-CH2, J = 8.16 Hz), 4.34 (d, 2H, NH–
CH2, J = 5.72 Hz), 5.26 (t, 1H, NH–CH2, J = 5.78 Hz), 6.65 (d, 2H, Ar–H,
Jo = 8.8 Hz), 6.78 (t, 1H, Ar–H, Jo = 7.36 Hz), 6.87 (d, 1H, Ar–H, Jo = 7.96 Hz),
7.07 (t, 1H, Ar–H, Jo = 7.84 Hz), 7.21 (d, 1H, Ar–H, Jo = 7.42 Hz), 7.53 (d, 2H,
Ar–H, Jo = 8.7 Hz), 9.06 (s, 1H, –OH) and 9.94 ppm (s, 1H, –NH, pyridazinone).
Anal. calcd. for C17H17N3O2: C: 69.14, H: 5.8, N: 14.23%; found; C: 68.97, H: 5.53;
N: 13.89%.

Med Chem Res (2010) 19:808–816
811
6-(4-(3-Methoxy-4-hydroxybenzylamino)phenyl)-4,5-dihydropyridazin-3(2H)-
one (IIId). Yield: 56.04%; m.p. 195–197°C. Spectroscopic analysis: IR (KBr) tmax
cm-1: 3402 (OH), 3207 (NH), 3060 (CH, aromatic), 2921 (CH, aliphatic), 1646
(C=O, pyridazinone), 1599 (C=C, aromatic); 1H NMR (DMSO-d6, 400 MHz,
d, ppm): 2.53 (t, 2H, 4-CH2, J = 7.42 Hz), 2.92 (t, 2H, 5-CH2, J = 7.44 Hz), 3.86
(s, 3H, –OCH3), 4.27 (d, 2H, NH–CH2, J = 5.08 Hz), 4.75 (t, 1H, NH–CH2,
J = 5.58 Hz), 6.62 (d, 2H, Ar–H, Jo = 7.02 Hz), 6.80 (m, 3H, Ar–H), 7.31 (s, 1H,
–OH), 7.56 (dd, 2H, Ar–H, Jo = 6.96 Hz, Jm = 1.88 Hz) and 9.27 ppm (s, 1H,
–NH, pyridazinone). Anal. calcd. for C17H19N3O3: C: 65.16, H: 6.11, N: 13.41%;
found; C: 64.84, H: 5.76; N: 12.98%.
/
6-(4-(4-Fluorobenzylamino)phenyl)-4,5-dihydropyridazin-3(2H)-one (IIIe).
:
Yield: 47.36%; m.p. 198–200°C. Spectroscopic analysis: IR (KBr) tmax/cm-1
3361 (NH), 3091 (CH, aromatic), 2925 (CH, aliphatic), 1654 (C=O, pyridazinone),
1
1609 (C=C, aromatic); H NMR (CDCl3, 400 MHz, d, ppm): 2.58 (t, 2H, 4-CH2,
J = 8.12 Hz), 2.91 (t, 2H, 5-CH2, J = 8.12 Hz), 4.34 (s, 3H, NH–CH2), 6.62 (dd,
2H, Ar–H, Jo = 6.9 Hz, Jm = 1.8 Hz), 7.03 (m, 2H, Ar–H), 7.32 (m, 2H, Ar–H),
7.56 (dd, 2H, Ar–H, Jo = 6.9 Hz, Jm = 1.9 Hz) and 8.36 ppm (s, 1H, –NH,
pyridazinone). Anal. calcd. for C17H16N3OF: C: 68.67, H: 5.42, N: 14.13%; found;
C: 68.54, H: 5.37; N: 14.10%.
6-(4-(Pyridin-3-ylmethylamino)phenyl)-4,5-dihydropyridazin-3(2H)-one (IIIf).
:
Yield: 42.07%; m.p. 203–204°C. Spectroscopic analysis: IR (KBr) tmax/cm-1
3297 (NH), 3033 (CH, aromatic), 2916 (CH, aliphatic), 1658 (C=O, pyridazinone),
1
1605 (C=C, aromatic); H NMR (CDCl3, 400 MHz, d, ppm): 2.57 (t, 2H, 4-CH2,
J = 7.46 Hz), 2.92 (t, 2H, 5-CH2, J = 7.41 Hz), 4.42 (m, 3H, NH–CH2), 6.64 (dd,
2H, Ar–H, Jo = 6.8 Hz, Jm = 2.0 Hz,), 7.57 (dd, 2H, Ar–H, Jo = 6.8 Hz,
Jm = 1.9 Hz), 7.67 (d, 1H, pyridine, Jo = 7.8 Hz), 8.34 (s, 1H, pyridine), 8.55
(m, 1H, pyridine, CH–N), 8.63 ppm (d, 1H, pyridine, CH–N, Jm = 1.8 Hz). Anal.
calcd. for C16H16N4O: C: 68.55, H: 5.75, N: 19.99%; found; C: 68.24, H: 5.58; N:
19.77%.
6-(4-(Pyridin-4-ylmethylamino)phenyl)-4,5-dihydropyridazin-3(2H)-one (IIIg).
Yield: 39.6%; m.p. 205–206°C. Spectroscopic analysis: IR (KBr) tmax/cm-1: 3205
(NH), 3056 (CH, aromatic), 2917 (CH, aliphatic), 1670 (C=O, pyridazinone), 1598
(C=C, aromatic); 1H NMR (CDCl3, 400 MHz, d, ppm): 2.56 (t, 2H, 4-CH2,
J = 7.54 Hz), 2.91 (t, 2H, 5-CH2, J = 7.52 Hz), 4.43 (m, 3H, NH–CH2), 6.58 (dd,
2H, Ar–H, Jo = 6.9 Hz, Jm = 1.9 Hz), 7.28 (s, 1H, pyridine), 7.56 (dd, 2H, Ar–H,
Jo = 6.8 Hz, Jm = 2.04 Hz), 8.37 (s, 1H, pyridine) and 8.56 ppm (s, 2H, pyridine,
CH–N–CH). Anal. calcd. for C16H16N4O: C: 68.55, H: 5.75, N: 19.99%; found; C:
67.91, H: 5.60; N: 19.84%.
6-(4-(1H-Indol-3-ylmethylamino)phenyl)-4,5-dihydropyridazin-3(2H)-one (IIIh).
Yield: 61.79%; m.p. 204–205°C. Spectroscopic analysis: IR (KBr) tmax/cm-1: 3224
(NH), 3059 (CH, aromatic), 2926 (CH, aliphatic), 1665 (C=O, pyridazinone), 1609
1
(C=C, aromatic); H NMR (DMSO-d6, 400 MHz, d, ppm): d 2.49 (t, 2H, 4-CH2
J = 7.54 Hz), 2.89 (t, 2H, 5-CH2 J = 7.5 Hz), 4.48 (d, 2H, NH–CH2,
J = 4.92 Hz), 5.09 (t, 1H, NH–CH2, J = 5.01 Hz), 6.68 (d, 2H, Ar–H,
Jo = 8.8 Hz), 7.05 (t, 1H, indole, Jo = 7.92 Hz), 7.14 (t, 1H, indole, Jo = 7.16 Hz),
7.21 (s, 1H, indole, Jm = 2.28 Hz), 7.41 (d, 1H, indole, Jo = 8.08 Hz), 7.56 (d, 2H,

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Med Chem Res (2010) 19:808–816
10
9
8
7
6
5
4
3
2
1
0
ASP
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIh
Ctrl
IIIg
Dose (30 mg/kg)
Fig. 2 Effect of compounds IIIa–h (RB-341-348) (30 mg/kg., p.o.) on bleeding time in mice.
a
Ctrl = control (n = 5); ASP = aspirin 30 mg/kg (n = 5). P \ 0.05 vs. control
Ar–H, Jo = 8.76 Hz), 7.62 (d, 1H, indole, –CH–NH, Jo = 7.76 Hz), 10.03 (s, 1H,
–NH, pyridazinone), 10.32 (s, 1H, NH, indole). Anal. calcd. for C19H18N4O: C:
71.68, H: 5.70, N: 17.6%; found; C: 71.43, H: 5.47; N: 17.4%.
Biological activity
Antiplatelet activity was determined by using the tail transaction bleeding test as
reported (Wang et al., 2004; Takao et al., 1998). Bleeding time of male mice (Laca
strain) weighing 20–24 g was determined by administering compounds IIIa–h and
aspirin (standard drug) suspended in carboxy methyl cellulose orally at various
doses 7.5, 15, 30, 60 mg/kg or vehicle control. After 1 hr, 3 mm of the tails of the
mice under light diethylether anesthesia were transected and blood was dripped on
filter paper. The duration of bleeding was recorded. Bar diagrams (Fig. 2) were
prepared by using MS Excel to represent the effect of the newly synthesized 6-
aminophenylpyridazinone derivatives IIIa–h (7.5–60 mg/kg, p.o.) on bleeding time
in mice in comparison to vehicle control and standard drug.
The bleeding time, observed from the mice treated with various pyridazinones at
different doses, was compared with standard drug aspirin and with vehicle control.
The results obtained have been summarized in Table 1.
Results and discussion
The compounds IIIa–h were synthesized according to Scheme 1. Condensation of
6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)-one (I) with various substituted
aldehydes IIa–h in methanol at room temperature gave corresponding Schiff bases,
which on subsequent reduction with sodium borohydride resulted into the formation
of desired pyridazinones IIIa–h. The structures of these compounds were elucidated
using various spectral and elemental analyses.

Med Chem Res (2010) 19:808–816
813
Table 1 Platelet aggregation inhibitory activity of compounds IIIa–h
Sr. No
Compound No. (code)
Concentration
(mg/kg body weight)
Bleeding time
mean SEM
1
IIIa (RB-341)
7.5
15
30
60
7.5
15
30
60
7.5
15
30
60
7.5
15
30
60
7.5
15
30
60
7.5
15
30
60
7.5
15
30
60
7.5
15
30
60
7.5
15
30
60
–
4.2 0.314
5.6 0.184
6.5 0.542
7.1 0.221
4.4 0.342
5.2 0.326
6.1 0.227
6.5 0.156
4.4 0.512
7.4 0.413
8.5 0.341
9.2 0.616
4.1 0.318
5.2 0.282
6.1 0.303
7.3 0.347
3.8 0.262
4.9 0.323
6.2 0.113
7.0 0.532
4.1 0.286
5.5 0.321
6.2 0.427
6.6 0.338
4.3 0.411
5.3 0.306
6.2 0.317
7.0 0.328
5.5 0.265
8.3 0.412
9.2 0.315
9.7 0.614
4.2 0.324
5.3 0.511
6.1 0.674
6.6 0.210
3.2 0.218
2
3
4
5
6
7
8
IIIb (RB-342)
IIIc (RB-343)
IIId (RB-344)
IIIe (RB-347)
IIIf (RB-345)
IIIg (RB-346)
IIIh (RB-348)
Aspirin
Control
The benzylamino substituted pyridazinones IIIa–e exhibited characteristic amide
C=O stretching bands of pyridazinone ring system at *1660 cm-1. In the NMR
spectra of these compounds, pyridazinone C4 and C5 protons resonated as triplets

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Med Chem Res (2010) 19:808–816
NH2
HN
CHR
O
+
R
H
N
N
NH
NH
O
O
Methanol
NaBH4
(I)
(IIa-h)
R
CH2
H N
N
NH
O
(IIIa-h)
R
R
OMe
(a)
(e)
F
OMe
OMe
(f)
(b)
(c)
OMe
N
OMe
(g)
N
H O
OMe
(d)
(h)
OH
N
H
Scheme 1 General synthesis of pyridazinone derivatives IIIa–h

Med Chem Res (2010) 19:808–816
815
at *d 2.58 and 2.94 ppm, respectively. Protons of the NHCH2 were found as a
doublet at *d 4.3 ppm and NHCH2 gave a triplet at varied positions. 2-
Unsubstituted N–H signal was observed at *d 9.0 ppm for all the compounds.
While methoxy protons of IIIa, IIIb, and IIId were seen at *d 3.80, the hydroxy
proton of IIIc was found at d 9.06 and those of IIId at 7.31 ppm. In case of pyridyl
substituted derivatives IIIf and IIIg, the infrared bands appeared in the
region *3300 cm-1 due to N-H stretching vibrations along with the characteristic
amide C=O stretching band of pyridazinone ring system near 1660 cm-1. Pyridyl
protons attached to nitrogen appeared at downfield positions compared with the
other aromatic protons.
The 6-(4-(1H-indol-3-yl)methylamino)phenyl)-4,5-dihydropyridazin-3(2H)-one
(IIIh) exhibited the infrared band at 3224 cm-1 due to N-H stretching vibrations.
Characteristic amide C=O stretching band of pyridazinone ring system was again
observed at 1665 cm-1. Pyridazinone C4 and C5 protons resonated as triplets at d
2.51 and 2.91 ppm, respectively. Protons of the NHCH2 were found as a doublet at
4.48 ppm and NHCH2 gave a triplet at 5.09 ppm. Signals for protons of indole ring
were found in the aromatic region. Singlets for the -NH of pyridazinone and indole
appeared at d 10.03 and 10.32 ppm, respectively.
All of the newly synthesized pyridazinone derivatives exhibited significant platelet
aggregation inhibitory activity. The compounds (6-(4-(2-hydroxybenzylami-
no)phenyl)-4,5-dihydropyridazin-3(2H)-one IIIc and 6-(4-(1H-indol-3-ylmethyla-
mino)phenyl)-4,5-dihydropyridazin-3(2H)-one IIIh were found to be more than twice
as potent as standard drug aspirin as shown in Fig. 2. They produced the antiplatelet
effect better than aspirin (30 mg/kg) at only half of the dose, i.e., 15 mg/kg.
These results show that the introduction of aryl-amino substituent at para
position of 6-phenylpyridazinone results in significant platelet aggregation inhib-
itory activity. Pharmacological evaluation of these compounds allows us to describe
the antiplatelet activity of a range of 4-substituted-amino phenylpyridazinones.
Acknowledgement The authors thank the University Grants Commission, India, for financial support.
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