Synthesis, Characterization And Biological Screening Of Some Novel
Pyridazine Derivatives
Shadab a. Siddiqui*1, anees a. Siddiqui2, k.
Nagarajan1
1
KIET School of Pharmacy, Ghaziabad, 201206
2
Department of Pharm. Chem. F/O Pharmacy, Jamia Hamdard, New Delhi.
110062
Corresponding Authors : shadabhamdard@gmail.com
ABSTRACT
A series of 2-substituted phenyl-10H-Pyridazine (6, 1-b)
quinazoline-10-one (d-i-vii) were synthesized. These
compounds were evaluated for their anticonvulsant activity. Compound d-iii, and d-v showed 100%
protection. Compound d-i, d-iv, andd-vi showed 66.67% protection and compound d-vii showed 83.33% protection. Anticonvulsant
activity of these compounds was compared with phenytoin.
Key words:
2-substituted pyridazine, anticonvulsant, pyridazines.
INTRODUCTION
The pyridazine ring system is a 1,2-diazine or o-diabenzene. The name
pyridazine was suggested by Knorr[1], however, the first substituted
pyridazines were prepared in 1886 by Fischer[2], and pyridazine itself
was prepared by Tauber[3] in 1895.During last two decades numbers of
pyridazine/pyridazinones have been synthesized due to their effect on
cardiovascular system pyridazine/pyridazinone derivatives were reported
to exhibit lots of pharmacological activities such as
anti-inflammatory[4], antibacterial[5], antithrombotic[6],
antihypertensive[7], hypotensive[8], cardiotonic[9], diuretic[10] and
anti-HIV[11] activities. A lot of work have been done on
pyridazine/pyridazinones in the last few years for their various
pharmacological activities and anticonvulsant activity[16] also. In
continuation to the work on pyridazine/pyridazinone ring system, we
have synthesized some new pyridazine derivatives and evaluated them for
anticonvulsant activity by non-invasive methods.
EXPERIMENTAL SECTION
(i) Synthesis of β-benzoyl propionic acid (a):
After suspending anhydrous aluminium chloride (15 gm.) in dry benzene
(50 ml) under anhydrous conditions, the contents were refluxed on a
water bath. Succinic anhydride (10 gm) then added in small proportion
through the condenser (care should be taken that after adding each lot,
the second lot was added only when first lot reacted completely). After
complete addition the reaction mixture was refluxed for 6 hours. A
solution of conc. Hydrochloric acid (2.5ml) in ice –cold water (7.5ml)
was then added to the reaction mixture and the contents concentrated to
a small volume by heating on a water bath. On cooling a crystalline
compound separated out which was filtered and crystallized from water
to give a colorless compound.
(ii) Synthesis of 6-phenyl 2,3,4,5-tetrahydropyridazine-3-one (b):
To a solution of β-benzoyl propionic acid in methanol (30 ml) was added
hydrazine hydrate(1ml) and sodium acetate (0.5 gm) and the contents
were refluxed for 6 hours. After completion of the reaction, methanol
was distilled off and residue poured into cold water. The solid which
separated out, was filtered and crystallized from methanol.
(iii) Synthesis of
3-chloro-6-phenylpyridazine (c):
To a solution of 6-phenyl 2,3,4,5-tetrahydropyridazine-3-one (1 gm)
phosphorous oxy chloride (10 ml) was added. Mixture was heated for 6
hours. After completion, the reaction mixture was poured into crushed
ice. The solution was neutralized with NaOH. The compound was filtered
and washed with water and re-crystallized with ethanol.
(iv) Synthesis of 2-phenyl-10H-pyridazine (6, 1-b)
quinazolin-10-one (d):
The equimolar quantity of 3-chloro-6-phenylpyridazine and anthranilic
acid were taken in methanol. The contents were heated for 1 hour
concentrate the mixture then poured into the crushed ice. Product was
filtered and washed with water, recrystallized with ethanol.
Anti convulsant activity
All the final compounds were evaluated for anticonvulsant activity on
albino mice at a dose of 25-30 mg/kg animal body weight by MES (maximal
electroshock seizure) method12. The activity was compared
with standard phenytoin. The percent protection produced by the test
compounds at equivalent to phenytoin 28-33 mg/kg animal body weight.
Standard drug showed 100% inhibition at a dose of 25 mg/kg animal body
weight.
Compounds d-iii, d-v showed 100% protection while compounds d-i, d-iv,
d-vi showed 66.67% protection and compound d-vii showed 83.33%
protection against convulsion (Table-1).
RESULT AND DISCUSSION
The series of compounds
2-substituted-10H-pyridazine(6,1-b)quinazoline-10-one was synthesized
in the following steps, illustrated with the synthesis of compound D.
the β-benzoyl propionic acid (a) was synthesized by
Friedel Craft acylation of benzene with succinic acid in the presence
of Lewis acid, aluminium chloride. The IR spectrum of acid showed band
at 3428 and 1679 cm-1 indicating the presence of carboxylic
acid group. The 1H-NMR spectrum showed triplet at δ 2.59 and
3.23 for CH2, CH2CO respectively. The aromatic
protons appear at 7.53 to 7.95 as multiplet. The carboxylic Protons
appeared at δ 12.17. The condensation of carboxylic acid with hydrazine
hydrate gave 6-phenyl-2,3,4,5-tetrahydro pyridazinone ( b). The compound was TLC pure. The IR spectrum showed
the presence of two bands at 3206 and 1676 cm-1 indicating
the presence of amide group. The 1H-NMR spectrum showed the two triplet
at δ 2.60 and 2.96 for CH2, CH2O moiety
respectively. The aromatic protons appeared in the region 7.41-7.73.
The aromatic protons appeared at δ 9.50. The
3-chloro-6-phenylpyridazine (c) was synthesized by
reaction of compound (b) with phosphorous oxy
chloride. The compound was TLC pure and different from the starting
material. The IR spectrum showed bands at 3000 and 1600 for C-H
stretching and double bond. The 1H-NMR spectrum showed aromatic protons
in the region of 7.31 (multiplet), 7.59 (multiplet) and 7.83 (singlet).
The 2-phenyl-10H-pyridazine (6,1-b)quinazoline-10-one ( d) was synthesized by condensation of compound c with
anthranilic acid. The IR spectrum showed bonds at 2997cm-1,
1672cm-1 and 1588 cm-1 for CH stretching,
carbonyl functional group and double bon. The 1H-NMR
spectrum showed aromatic protons at δ 6.47-7.66 as multiplet. The
structure was further verified by MASS spectrum. It showed the peak at
273/274-(M+/M+1) in accordance with formula C17H 11N3O. It showed the fragments i.e. peak at 261,
197. A series, 2-substituted-10H-pyridazine (6,1-b) quinazoline-10-one
was synthesized, which was illustrated with the synthesis of compound ' d'. All the synthesized compounds were TLC pure. These
synthesized compounds were characterized by IR, 1H-NMR, and Mass
Spectroscopy. The physical data of the synthesized compounds are given
in Table 2.
All the final compounds were evaluated for anticonvulsant activity on
albino mice at a dose of 25-30 mg/kg animal body weight by MES[12]
(Maximal Electroshock Seizure) method[17]. The activity was compared
with standard ' Phenytoin'. The percent protection produced by the test
compounds at Equivalent to Phenytoin (28.33 mg/kg animal body weight)
dose after 1 hour recorded in the table 1. Phenytoin was used as the
reference drug showed 100% inhibition at a dose of 25 mg/kg animal body
weight.
Compounds d-iii and d-v showed 100% protection while compound d-vii
showed 83.33% protection and compoundsd-I, d-iv and d-vi showed66.67% protection against convulsion and compound d-ii showed minimum protection towards convulsion as
compared to phenytoin.
Table 1:
Anticonvulsant Activity
S. No.
|
Compound No.
|
R
|
Anticonvulsant Activity
MES (60 min) % Protection
|
1
|
d-i
|
H
|
66.67
|
2
|
d-ii
|
CH3
|
33.33
|
3
|
d-iii
|
3,4-CH3
|
100
|
4
|
d-iv
|
C2H5
|
66.67
|
5
|
d-v
|
p-Cl
|
100
|
6
|
d-vi
|
p-OCH3
|
66.67
|
7
|
d-vii
|
C6H5
|
83.33
|
8
|
Standard
|
Phenytoin
|
100
|
Table 2:
Physical data of compound d i-vii
S.No
|
Compound
|
R
|
M.P (0C)
|
Yield (%)
|
1
|
d-i
|
H
|
140-42
|
59
|
2
|
d-ii
|
CH3
|
139-41
|
51
|
3
|
d-iii
|
3,4-CH3
|
158-61
|
63
|
4
|
d-iv
|
C2H5
|
133-32
|
53
|
5
|
d-v
|
Cl
|
119-21
|
55
|
6
|
d-vi
|
OCH3
|
126-27
|
65
|
7
|
d-vii
|
C6H5
|
138-40
|
41
|
REACTION SCHEME
(d-i-vii)
R = H, CH3, 3,4-CH3, C2H5, Cl, OCH3 & C6H5
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