Synthesis of different substituted pyridazinone derivatives and their anticonvulsant activity

Article abstract of DOI:10.1155/2011/873470

6-Phenyl(3'-imino-benzylidene)-2,3,4,5-tetrahydro pyridazin-3-one derivatives were synthesized from 6-(3'-aminophenyl)-2,3,4,5-tetrahydro pyridazin-3-one by reaction with different aldehydes. The respective pyridazinone was prepared by cyclization of appropriate β-(aminophenyl) propionic acid with hydrazine hydrate. The pyridazinone derivatives were tested for anticonvulsant activity by MES (maximal electro shock) method and found that few of them have shown significant anticonvulsant activity.

Full text of DOI:10.1155/2011/873470

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2011, 8(1), 245-251
http://www.e-journals.net
Synthesis of Different Substituted Pyridazinone
Derivatives and Their Anticonvulsant Activity
KARTICK CHANDRA SAMANTA#* MOHD. ASIF¶, POOJA#,
VIKAS GARG§, PRIYANKA SHARMA# and RAVINDER SINGH
#School of Pharmacy, Suresh Gyan Vihar University, Jaipur-302025, India
¶Department of Pharmacy, GRD (PG) Institute of Management & Technology
214, Rajpur Road, Dehradun, Uttarakhand, India
§Manipal College of Pharmaceutical Sciences, Manipal-576104, India
Nandha College of Pharmacy and Research Institute, Erode, Tamilnadu, India
kc_samanta2006@yahoo.com
Received 31 January 2010; Accepted March 2010
Abstract: 6-Phenyl(3’-imino-benzylidene)-2,3,4,5-tetrahydro pyridazin-3-one
derivatives were synthesized from 6-(3’-aminophenyl)-2,3,4,5-tetrahydro
pyridazin-3-one by reaction with different aldehydes. The respective
pyridazinone was prepared by cyclization of appropriate β-(aminophenyl)
propionic acid with hydrazine hydrate. The pyridazinone derivatives were
tested for anticonvulsant activity by MES (maximal electro shock) method and
found that few of them have shown significant anticonvulsant activity.
Keywords: Anticonvulsant, Cyclization, MES, Pyridazinone.
Introduction
Pyridazinone derivatives have been reported to possess wide variety of biological activities like
antidiabetic1, anticancer2,3 anti AIDS, antihypertensive1,4,5, antimicrobial6, fungicidal7, herbicidal8,
antifeedant9, antiplatelet10,11, analgesic, anti-inflammatory3,12-15 and anticonvulsant16-18 activities. In
the view of above biological importance the new substituted pyridazinone derivatives were
developed. The rationale behind the present study mainly was to prepare and identify the esteemed
new molecule effective against the deadly convulsions. The wide range of activities of
pyridazinone derivatives enacted us to proceed onto the present study. In continuation to our work
on such derivatives, we now report the synthesis of nine pyridazinone derivatives (Table 1) and
their anticonvulsant activity (Table 2). The pyridazinone derivatives were synthesized as shown in
Scheme 1 by following sequence of reactions: (i) Friedel Craft acylation of benzene with succinic
anhydride in the presence of anhydrous aluminium chloride yielded β-benzoyl propionic acid; (ii)
nitration of β-benzoyl propionic acid with conc. HNO3 and conc. H2SO4 that form
β-m-nitrobenzoyl propionic acid; (iii) reduction of β-m-nitrobenzoyl propionic acid with Sn and

246
K C. SAMANTA et al.
Conc. HCl to form β-m-aminobenzoyl propionic acid; (iv) cyclization of β-m-nitrobenzoyl
propionic acid to react with hydrazine hydrate to form 6-(3’-nitrophenyl)-2,3,4,5-tetrahydro
pyridazin-3-one (pyridazinone ring) and (iv) condensation of 6-(3’-nitrophenyl)-2,3,4,5-
tetrahydro pyridazin-3-one with different aldehydes to form different pyridazinone
derivatives.
Compound 1
O2N
Compound 2
H2N
Compound 3
H2N
Compound 4
Compound 5(a-i)
Scheme 1. Reaction scheme
Aldehydes used were:
5a:Acetaldehyde, 5b:4-OH benzaldyde, 5c:Anisaldehyde, 5d:Benzaldehyde, 5e:Vanillin
5f:Furfuradehyde, 5g:2-Methoxy benzaldehyde, 5h:p-Dimethyl amino Benzaldehyde,
5i: Salicylaldehyde
Experimental
Chemicals
Chemicals were procured from Central Drug House (P) Ltd., India. All other chemicals &
solutions used were of analytical grade.
Melting points of the pyridazinone derivatives were recorded in open capillary tube in
liquid paraffin bath as well as in precision melting point apparatus and are uncorrected.
Percentage yields were recorded accordingly (Table 1). Solvent system used throughout the
experimental work for running TLC plates was toluene, ethyl acetate and formic acid (TEF)
in the ratio of 5:4:1 and another solvent system also used were benzene and acetone in the
ratio of 4:1. IR spectra were recorded by using KBr pellet technique on Perkin Elmer 337 IR
1
spectrophotometer. H NMR spectra were recorded in deuterated chloroform using tetra
methyl silane (TMS) as an internal reference standard on BRUKER AVANCEII 400 NMR
spectrometer.

Synthesis of Different Substituted Pyridazinone Derivatives
247
Table 1. IR and 1H NMR characteristics of the compounds
Compd No. M.P, 0C Yield,% Molecular formula
I.R and 1H NMR spectra
1
2
3
4
120
108
95
70
50
52
65
C10H10O3
C10H9NO5
C10H11NO3
C10H11N3O
IR: 3250 cm-1 (OH), 1720 cm-1 (C=O),
3400 cm-1(NH2), 1617 cm-1 (C=C),
1H NMR: (CDCL3) ppm 2.82(2H,
t, CH2), 3.32(2H, t, CH2), 7.40-8.0 (m,Ar-
H ), 7.79(2H, m, H-2, 6).
90
130
140
127
139
164
158
146
157
145
48
42
55
51
62
53
42
55
62
C12 H13N3O
C17H25N3O2
C18H17N3O2
C17H15N3O
C18H17N3O3
C15H14N3O2
C18H17N3O2
C19H20N4O
C17H15N3O2
IR:1360 cm-1 (NO2), 1700 cm-1 (C=O),
1580 cm-1 (C=C) exo, 3450 cm-1 (NH).
1H NMR:(CDCl3) ppm 2.8(s, 2H, CH2),
3.1(s, 2H, CH2), 7.2(s, H =CH), 7.40-
8.0(m, H, Ar-H), 8.8-9.0.0 (s, H, NH).
5a
5b
5c
5d
5e
5f
5g
5h
5i
Synthesis of benzoylpropionic acid (1)
A mixture of benzene (30 mL) and anhydrous aluminium chloride (0.15 mole) was taken in
three neck flask and refluxed on a water bath under anhydrous condition using calcium
chloride guard tube at the top of condenser, followed by addition of succinic anhydride (0.10
mole) in small quantity with continuous stirring1,3,13. The stirring and heating were
continued for 4 h. The reaction usually starts immediately. HCl gas was evolved and mixture
becomes hot. In case of minimal and gentle reactions warmed gently. After leaving over
night at room temperature the contents were poured into ice cold hydrochloric acid (2.5% v/v)
followed by steam distillation. The aqueous solution was concentrated to small volume by
evaporating on the water bath to obtain crude compound. It was purified by dissolving the
5% w/v of sodium bicarbonate solution followed by extraction with ether and chloroform.
The aqueous layer on acidification with dilute hydrochloric acid gave 1 and was re-
crystallized from aqueous ethanol.
0
Melting point:120 C, yield 70%, Rf = 0.77, IR Spectra: 3250 cm-1 (OH),1720 cm-1
1
(C=O). NMR Spectra: H NMR(CDCL3) ppm 2.82 (2H, t, CH2), 3.32 (2H, t, CH2), 7.74
(CH2, m, H-3, 5), 7.79 (2H, m, H-2, 6).
Synthesis of β-m-nitrobenzoylpropionic acid (2)
To a mechanically stirred mixture of 12 mL concentrated nitric acid and 12 mL of concentrated
sulphuric acid, 6 g of 1 was added in portion while keeping the mixture at 0-10 0C by efficient
cooling (30-40 min.)19-21. The temperature was further allowed to rise to 15 0C in the course of 120
minutes and the solution was slowly stirred in ice-water. The precipitated material was washed
with cold water to free from acid and re-crystallized from methanol. Lightly yellow color 2 was
obtained. IR Spectra: 3091 cm-1 (CH), 1705 cm-1 (C=O), 1353 cm-1 (NO2), 1617 cm-1 (C=C).
1
NMR Spectra: H NMR (DMSO) ppm 3.0 (t, 2H, CH2), 3.36 ((t, 2H, CH2),7.30- 8.2 (m, Ar-H),
8.82 (s, H, Ar-H).
Synthesis of β-m-aminobenzoyl propionic acid (3)
0.05 mole 2 was taken in 50 mL of ethanol and was refluxed with 5.00 g of tin and 10 mL of
conc. HCl for 30-40 min20. The reaction mixture was then poured into water treated with
sodium carbonate and extracted with ether. The ethereal solution after washing with water,
dried with sodium sulphate, evaporated to get 3 and crystallized from methanol.

248
K C. SAMANTA et al.
IR Spectra: 3400 cm-1 (NH2), 1700 cm-1 (C=O), 1617 cm-1 (C=C), 3090 cm-1 (CH).NMR
Spectra: 1H NMR (CDCl3) ppm 2.8 (t, 2H, CH2), 3.20 (t, 2H, CH2), 7.40-8.0 (m, H, Ar-H),
8.8-9.0 (s, H, NH)(s, 2H,NH2)
Synthesis of 6-(3’-amino phenyl)-2,3,4,5-tetrahydro pyridazin-3-one (4)
The compound 3 (0.01 mole) was refluxed for 6 h with hydrazine hydrate (0.01 mole) in
methanol (10 mL.) containing sodium acetate (50 mg)1,3. The content was concentrated and
then poured into ice cold water to get the compound 4. It was re-crystallized from ethanol.
IR Spectra: 1685 cm-1 (C=O), 1352 cm-1 (NO2), 3100 cm-1 (CH), 3550 cm-1 (NH). 1H NMR
(CDCl3) ppm 2.8 (t, 2H, CH2), 3.2 (t, 2H, CH2), 7.40-8.0 (m, H, Ar-H), 8.8-9.0 (s, H, NH)
(s, 2H,NH2) .
Synthesis of 6-(3’-iminophenyl benzylidene)-2,3,4,5-tetrahydropyridazin-3-one
derivatives (5a-i)
A mixture of 4 (0.005 mole) and different aldehydes (0.005 mole) were taken in glacial
acetic acid (20 mL) and sodium acetate (2 g.) was added in it5,22. The content was refluxed
for 6-8 hours (monitored by TLC), cooled and then poured into ice. The solid compound
(5a-5i) was obtained and then re-crystallized with ethanol. IR Spectra:1360 cm-1 (NO2),
1
1700 cm-1 (C=O), 1580 cm-1 (NH). H NMR Spectra: (CDCl3) ppm 3.10 (s, 2H, CH2),
7.2(s,H =CH), 7.40-8.0 (m, H, Ar-H) 8.8.0 (s, H, NH).
Structure activity relationship
The maximum activity shown by the compounds were 5h (p-dimethyl amino
benzaldehyde derivative) in flexion phase, 5d (benzaldehyde derivative) in extensor
phase, 5i (salicylaldehyde derivative) in clonus phase, and 5f (furfuraldehyde
derivative) in stupor phase. The derivatives acetaldehyde, 4-OH-benzaldehyde,
anisaldehyde, vanillin and 2-methoxy benzaldehyde were not produce maximum
protection against convulsion in terms of recovery in comparison with others. The
compounds 5h, 5d, 5i and 5f which have shown the maximum inhibition in different
stages suggest that the substitution of the amino group by p-dimethyl amino
benzaldehyde, benzaldehyde, salicylaldehyde and furfuraldehyde impart maximum
efficacy i.e.100% recovery or 66.66% protection.
Animals
Swiss albino mice weighing 20-30 g of male sex were maintained under controlled
0
conditions of light (12 h) and temperature 25 1 C in the animal house of Department of
Pharmacy, GRD (PG) Institute of Management & Technology, 214, Rajpur Road, Dehradun,
Uttaranchal, India, two weeks prior to the experiment for acclimatization. Animals had
access to food and water ad libitum. All pharmacological activities were carried out as per
CPCSEA (Committee for the Purpose of Control and Supervision of Experiments on
Animals) norms (Regn No: 1145/a/07/CPCSEA), after obtaining the approval from the
Institutional Animal Ethics Committee of Department.
Results and Discussion
1
The compounds were characterized on the basis of IR and H NMR spectral data. IR
spectrum (Table 1) showed the characteristics band at 1700, 1352, 3450, and 1580 cm-1
1
authenticated the presence of C=O, NO2, NH and C=C groups. The H NMR spectrum

Synthesis of Different Substituted Pyridazinone Derivatives
249
showed the signal in the form of multiplet near δ=2.8 for CH2 protons at 5-position,
another multiplet was observed at about δ=3.0 for CH2 at 4 position of (1, 2, 3, 4 & 5)
compounds. Aromatic proton also observed in the aromatic region ranging from δ=7.0-
8.0. Presence of other substitutes also authenticated in the 1H NMR spectra at the
assigned value (Table 1).
The present study on the synthesized pyridazinone derivatives have shown significant
protection against Maximal Electro Shock (MES) Induced Seizure (Table 2) as compared to
diphenyl hydantoin sodium (Phenytoin sodium). It is well known fact that the drug which
provide protection against seizure induced by maximal electro shock method are generally
effective against toxic-clonic seizure.
Table 2. Anticonvulsant effect of different pyridazinone derivative
Flexion,
sec
Extensor,
sec
Clonus,
sec
Stupor,
sec
Treatment
Control
*3.34 0.125
1.44 0.051
2.58 0.271
2.92 0.278
3.00 0.310
2.77 0.281
3.04 0.117
2.88 0.346
2.76 0.102
a2.45 0.308
2.82 0.152
A
*15.76 01.11 *6.76 01.11 *48.90 07.65
*60
100
80
--
B Phenytoin
0.00 0.00
14.40 1.45
12.83 1.64
1.84 0.23
7.40 3.25
9.52 2.54
7.78 0.573
40.24 5.35
29.68 3.42
--
C
D
E
F
G
H
I
33.33
33.33
33.33
5a
5b
5c
5d
5e
5f
80
12.80 1.85 7.72 1.035 26.72 1.07
b12.38 0.78 10.91 1.82 20.40 4.81
13.66 0.75 8.68 0.885 32.48 5.32
13.06 1.03 9.62 0.668 d20.28 2.27
80
e100 66.66
80
e100 66.66
80 33.33
33.33
13.32 1.16
4.94 1.04
26.56 4.32
5g
5h
5i
J
12.40 1.05 5.80 0.735 25.51 4.92
13.86 1.08 c4.30 0.721 29.82 1.58
100 66.66
100 66.66
K
Standard drug: Phenytoin sodium (25mg/kg) Control: Distilled water *Value represent mean S.E.
aP< 0.05, bP< 0.05, cP< 0.02, dP< 0.01 and eP< 0.01 when compared to control (Group A)
Anticonvulsant activity
Male albino mice (25-35 g) were used to test the drugs (synthesized pyridazinone
derivatives). Maximal Electro Shock (MES) method23,24 was used for inducing seizures
(Model: Techno Electro Convulsometer). The MES induced convulsions in animal
represent grand mal type of epilepsy. In MES, electro shock was applied through the ear
pinna passing current of 60 mA for 0.2 sec. The MES convulsions were divided into
five phases: (i) flexion; (ii) extensor; (iii) clonus; (iv) stupor and (v) recovery or death.
The female mice were excluded because of the fact that oestrous cycle influence the
seizure threshold. Suspension of test compounds was prepared in 0.5% CMC and was
injected intraperitoneally at dose level 50 mg/ kg body weight, to different group of five
mice each. Reduction in the extension phase was calculated in comparison to diphenyl
hydantoin sodium (Phenytoin Sodium) which was used as a standard at 25 mg/kg body
weight dose (Table 2). The animals were observed for all the five phases as well as the
duration. The abolition of the extensor phase in drug treated group was taken as
experimental criterion for anticonvulsant activity. Thereby, the compound 5d may be
assumed to bear significant anticonvulsant activity.

250
K C. SAMANTA et al.
Statistical analysis
Significance of differences between mean values of different convulsive levels were
assessed by Student’s ‘t’ test and the data were expressed as mean
inhibition was calculated by applying the formula:
S.E. Percentage
Percentage inhibition = [(mean treatment-mean control)/(mean control)]
x100.
Conclusion
Aldehyde derivatives of pyridazinone ring have shown sufficient anticonvulsant activity as
compared to standard drug diphenyl hydantoin sodium against MES seizure on MES induced
seizure in albino mice after intraperitonially administration of 50 mg/kg body weight dose. The
potency order of the test compound on the extensor phase: 5d > 5h > 5c > 5b > 5f > 5g > 5e > 5i
>5a. The compound 5h, 5d, 5i and 5f have shown maximum recovery in practice. So, the
compound 5d may be regarded as true anticonvulsant because a substance is known to possess
anticonvulsant property if it reduces or abolishes the extensor phase of MES convulsions.
The essentiality of anticonvulsant drugs in the eradication of convulsion is evident. The
title compounds thus may have immense potential for contribution to human benefit.
Scientific exploration of further studies of more derivatives as well as on more parameters is
needed to elucidate the defined role of pyridazinones at the anticonvulsive levels.
Acknowledgment
The authors are thankful to School of Pharmacy, Suresh Gyan Vihar University, Jaipur-
302025, India; GRD (PG) Institute of Management & Technology, Dehradun, India and to
SAIF, Punjab University, Chandigarh, India for providing financial as well as technical
support and facilities to carry out this work.
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