Novel pyridazine derivatives: Synthesis and antimicrobial activity evaluation

Article abstract of DOI:10.1016/j.ejmech.2008.09.047

A general method for the preparation of new hydrazones is reported. The 1-[4-(2-methoxybenzyl)-6-aryl pyridazin-3(2H)-ylidene] hydrazines or their tautomeric structures (1_a-d) were condensed with different aldehydes, dialdehydes, ketones, α-dic

Full text of DOI:10.1016/j.ejmech.2008.09.047

European Journal of Medicinal Chemistry 44 (2009) 1989–1996
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Novel pyridazine derivatives: Synthesis and antimicrobial activity evaluation
*
N.G. Kandile , M.I. Mohamed, H. Zaky, H.M. Mohamed
Chemistry Department, Faculty of Women, Ain Shams University, Heliopolis Cairo 11757, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A general method for the preparation of new hydrazones is reported. The 1-[4-(2-methoxybenzyl)-6-aryl
Received 13 June 2008
Received in revised form
19 September 2008
Accepted 30 September 2008
Available online 11 October 2008
pyridazin-3(2H)-ylidene] hydrazines or their tautomeric structures (1a–d) were condensed with different
aldehydes, dialdehydes, ketones,
a-dicarbonyl compounds and simple carbohydrates to afford the
hydrazones and dihydrazones (2a–d), (3a–d), (4a–d), (5a–d), (6d), (7c), (8a–d), (9a–d), (10a–d), (11a–d), (12a,c,d),
(13a–d), (14a–d), (15a–d), (16a–d) and (17a–d). The structures of all synthesized compounds were confirmed
from microanalytical and spectral data. Some of the products were screened for their antimicrobial
activity against Staphylococcus aureus and Streptococcus faecalis, Escherichia coli and Pseudomonas aeru-
ginosa. The hydrazone derivative 15d (1-[4-(2-methoxybenzyl)-6-methylphenyl pyridazin-3(2H)-yli-
dene]-2-(2-carboxydiphenyl methyl) hydrazine) showed the highest biological activity.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords:
Hydrazones
Pyridazine
Aldehydes
Carbohydrates
Dihydrazones
Antimicrobial activity
1. Introduction
for preparation of these hydrazones (Scheme 1). Thus, condensation
reaction of compounds 1a–d with 3-methoxy-4-hydroxy benzalde-
Pyridazines are an important class of heterocycles, which have
been the subject of extensive research, particularly in the pharma-
ceutical and agrochemical areas due to their broad-activities, such as
antihypertensive activity and anti-inflammatory [1–3]. Their
synthesis and application have been comprehensively reviewed [4,5].
Information from several previous SAR (Structure–Activity
Relationships) studies [6–18] allowed us to focus this investigation
on a well-defined set of compounds, a series of diverse variations of
the substitution at the pyridazine derivatives. In view of wide
spread resistant strains of microorganism there is an urgent need
for the development of new antimicrobial agents.
hyde in ethanol gave 2a–d. The IR spectra of 2a–d displayed bands at
3346–3325 (OH, NH) and 1598–1592 cmꢀ1 (C]N). The presence of
the OH group in compounds 2a–d was confirmed chemically by an
acetylation reaction to yield 3a–d. While the IR absorption spectra of
3a–d showed bands at 3445–3418 (NH),1767–1762 (C]O) and 1604–
1598 cmꢀ1 (C]N). While condensation reactions of compounds
1a–d with dialdehydes such as 4,40-diformyl, 2,20-dimethoxy or
2,20,6,60-tertramethoxy-1,2-diphenoxyethane [20,21] in ethanol
yielded monohydrazone derivatives (4a–d), (5a–d) and (6d), the dihy-
drazone (7c) was obtained by the solid phase reaction of the mono-
hydrazone (5c) with compound 1c. The spectral data of all structures
of the new compounds are given in Section 4.
It was reported that several base-modified nucleosides act as
antiviral and anticancer agents most likely due to their capability to
mimic natural counterparts and function [22]. The synthesis and
biological activities of sugar-modified nucleoside analogs have
been active research areas for many years [23], so we report here
2. Chemistry
The required 1-[4-(2-methoxybenzyl)-6-aryl-pyridazin-3(2H)-
ylidene] hydrazines or its tautomeric structures (1a–d
prepared following the literature method [14–17]. It was reported
that hydrazones have been demonstrated to possess, amongst
other activities, antimicrobial, anticonvulsant, analgesic, anti-
platelet, antitubercular and antitumoral activity [19].
As a route for the synthesis of hydrazones, the reaction of
compounds 1a–d with aldehydes, dialdehydes, ketones, a-dicarbonyl
compounds and simple carbohydrates seemed to be a logical method
) were
the reaction of 1a–d with simple carbohydrates such as
and -glucose in ethanol to yield the corresponding hydrazono
derivatives 8a–d and 9a–d respectively. Acetylation of these
compounds using Ac2O in the presence of pyridine as a catalyst
gave the acetyl derivatives 10a–d and 11a–d
This study was extended to report the reaction of 1a–d with
some ketones, -keto benzoic acid and -dicarbonyl compounds.
D-arabinose
D
,
.
a
a
Thus, condensation reactions of compounds 1a,c,d with acetone in
ethanol furnished compounds 12a,c,d. The IR spectra of 12a,c,d dis-
played bands at 3422–3282 cmꢀ1 (NH), 2927–2905 cmꢀ1 (CH
* Corresponding author. Tel./fax: þ20 224 157804.
E-mail address: nadiaghk@yahoo.com (N.G. Kandile).
0223-5234/$ – see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.09.047

1990
N.G. Kandile et al. / European Journal of Medicinal Chemistry 44 (2009) 1989–1996
OCH3
OCH3
OCH3
Ar'
Ar'
CHO
OCOCH3
OH
Ar
N
Ar
N
AcOH/Ac2O
AcOH/Ac2O
HO
N
N
N
H
N
N
H
N
EtOH
(3
)
(2
)
a-d
a-d
Ar'
Ar'
Ar
N
O
Ar
N
R
N
R
HC-(CHOH)n-CH2OH
N
N
H
N
R
N
N
R
H
EtOH
(CHOCOCH3)nCH2OCOCH3
(CHOH)nCH2OH
Ar'
(8
)
(10
)
a-d
n=3
n=4
n=3
n=4
a-d
Ar
(9
)
(11
)
a-d
a-d
N
N
NHNH2
R1
O
H C
Ar'
O
R3
R1
R2
Ar
N
Ar'
R2
O
R
N
Ar
C
H
O
N
N
R3
N
H
R4
N
NNH2
H
O
R
EtOH
(1
)
a-d
R4
(4
)
R1= R2= R3= R4=H, R=CHO
R1= R3= OCH3 , R2= R4=H, R=CHO`
a-d
Ar=C6H4CO-H3(o)
Ar', a=C6H5
(5
)
a-d
(p)
(6 ) R1= R2=R3= R4=OCH3, R=CHO
b=C6H4-CH3
d
Ar'
Ar
c=C6H4-Cl(p)
d=C6H4-OCH3(p)
(7 ) R1= R3= OCH3 , R2= R4=H, R=
C
N
N
N
H
N
C
H
O
C
Ar'
Ar
N
R1
R2
R1
R2
N
N
N
C
H
EtOH or
AcOH
R1
R2
(12
(13
(14
(15
(16
(17
)
CH3
CH3
ph
CH3
ph
ph
a,c,d
)
a-d
)
a-d
ph
C6H5-COOH(o)
)
a-d
CO CH3
Ar
CH3
CH3
)
Ar'
a-d
)
a-d
CH3
N
N
N
H
N
C
Scheme 1.
aliphatic) and 1637–1630 cmꢀ1 (C]N), while reaction of
compounds 1a–d with acetophenone in ethanol gave the corre-
sponding hydrazone derivatives 13a–d. The IR absorption spectra of
13a–d showed bands at 3370–3356 cmꢀ1 (NH), 2932–2916 cmꢀ1
(CH aliphatic) and 1628–1625 cmꢀ1 (C]N). Reaction of 1a–d with
benzophenone in ethanol yielded the corresponding hydrazones
14a–d. Structures of 14a–d were established from their analytical and
spectral data. The IR spectra displayed bands at 3376–3282 cmꢀ1
(NH) and 1631–1623 cmꢀ1 (C]N).
equimolar amounts of 1a–d with diacetyl in ethanol gave mono-
hydrazone derivatives 16a–d. When the reaction was carried out in
glacial acetic acid, it yielded the corresponding dihydrazone
derivative 17d,b is{1-[4-(2-methoxybenzyl)-6-arylpyridazin-3(2H)-
ylidene]-2-(butan-2,3-ylidene)} hydrazines (17a–c) which could
be obtained also from refluxing the monohydrazone compounds
(17a–c) with another mole of the pyridazine derivatives (1a–c) in
glacial acetic acid. The spectral data of all structures of the new
compounds are given in Section 4.
However, reaction of 1a–d with
a-benzoyl benzoic acid in
a
mixture of acetic anhydride:glacial acetic acid (1:1) gave
3. Antimicrobial activity
compounds 15a–d. The IR absorption spectra of 15a–c showed broad
bands at 3447–3401 cmꢀ1 (OH), 3316–3212 cmꢀ1 (NH), 1718–
1651 cmꢀ1 (C]O) and 1604–1595 cmꢀ1 (C]N).
The reaction of 1a–d with diacetyl in different solvents involved
one or both of the carbonyl groups in the reaction. Thus, refluxing
The in vitro antimicrobial activities for the synthesized
compounds against Staphylococcus aureus and Streptococcus faecalis
as (Gram þve) bacteria and Escherichia coli and Pseudomonas aer-
uginosa as (Gram ꢀve) bacteria were determined .The biological

N.G. Kandile et al. / European Journal of Medicinal Chemistry 44 (2009) 1989–1996
1991
assay was performed according to the agar diffusion method [24–
27] at a concentration 20 mg/mL using DMSO as the solvent.
The results of the in vitro antimicrobial activity of 18 compounds
and of tetracycline, recorded as average diameter of inhibition zone
in mm, are given in Table 1. The hydrazone derivative 15d showed
the highest biological activity and the hydrazone derivative 5d
showed the lowest biological activity.
69.49), IR: 3329 cmꢀ1 (OH, NH) and 1595 cmꢀ1 (C]N). Anal. Calcd
for C27H26N4O3: C, 71.35; H, 5.77; N, 12.33. Found: C, 71.33; H, 5.80;
N, 12.35.
4.1.3. 1-[4-(2-Methoxybenzyl)-6-chlorophenyl pyridazin-3(2H)-
ylidene]-2-(3-methoxy-4-hydroxybenzylidene) hydrazine (2c)
Prepared from 3-methoxy-4-hydroxybenzaldehyde, orange
crystals in 87% yield, mp 232 ꢁC (DMF); MS: m/e 475 (Mþ þ 1, 21),
474 (Mþ, 44.44) IR: 3325 cmꢀ1 (OH, NH) and 1597 cmꢀ1 (C]N).
Anal. Calcd for C26H23N4O3 Cl: C, 65.75; H, 4.88; N, 11.80; Cl, 7.46.
Found: C, 65.40; H, 5.02; N, 11.82; Cl, 7.42.
4. Experimental
Melting points are uncorrected. The IR spectra of the
compounds were recorded on a Perkin–Elmer spectrophotometer
model 1430 as potassium bromide pellets and frequencies are
reported in cmꢀ1. The 1H NMR spectra were observed on a Varian
4.1.4. 1-[4-(2-Methoxybenzyl)-6-methoxyphenyl pyridazin-3(2H)-
ylidene]-2-(3-methoxy-4-hydroxybenzylidene) hydrazine (2d)
Prepared from 3-methoxy-4-hydroxy benzaldehyde, orange
crystals in 88.89% yield, mp 226–228 ꢁC (DMF); MS: m/e 471
(Mþ þ 1, 21.86), 470 (Mþ, 81), IR: 3346 cmꢀ1 (OH, NH) and
Genini-300 MHz spectrometer and chemical shifts (d) are in ppm.
The mass spectra were recorded on a mass spectrometer HP model
MS–QPL000EX (Shimadzu) at 70 eV. Elemental analyses and Anti-
microbial activity Evaluation were carried out at the Microanalyt-
ical Center of Cairo University, Giza, Egypt.
1598 cmꢀ1 (C]N); 1H NMR (DMSO, 300 MHz)
d 9.30 (s, 1H, OH),
8.23 (s, 1H, N]CH), 7.80 (s, 1H, NH), 7.61–6.79 (m, 11H, 3Ar-H), 6.77
(s, 1H, CH hetero), 4.15 (s, 2H, CH2) and 3.80–3.17 (s, 6H, 2ꢁ CH3) .
Anal. Calcd for C27H26N4O4: C, 68.92; H, 5.57; N, 11.91. Found: C,
69.16; H, 5.66; N, 11.90.
4.1. General procedure for the preparation of hydrazones from 1-[4-(2-
methoxybenzyl)-6-aryl pyridazin-3(2H)-ylidene] hydrazines (1a–d
)
anddifferentaldehydes, dialdehydes, simplecarbohydratesandketones
4.1.5. Compound 4a
Yellow crystals in 74.6% yield, mp 184–186 ꢁC (DMF); MS: m/e
558 (Mþ, 22.40), IR: 3381 cmꢀ1 (NH), 2936 cmꢀ1 (CH aliphatic),
1686 cmꢀ1 (C]O) and 1629 (C]N). 1H NMR (DMSO, 300 MHz)
A solution of compounds 1a–d (1 mmol) in ethanol (20 ml) was
treated with the corresponding aldehydes, dialdehydes and simple
carbohydrates (1 mmol). The reaction mixture was refluxed for 5 h.
The separated solid product was filtered off and crystallized from
the appropriate solvent.
d
9.88 (s, 1H, CHO), 8.63 (s, 1H, N]CH), 8.32 (s, 1H, NH), 8.15–6.93
(m, 17H, 4Ar-H), 6.93 (s, 1H, CH hetero), 4.48–4.18 (d, 4H, 2CH2),
3.83 (s, 2H, CH2), 3.31 (s, 3H, OCH3). Anal. Calcd for C34H30N4O4: C,
73.10; H, 5.41; N, 10.03. Found: C, 72.82; H, 5.25; N, 10.10.
4.1.1. 1-[4-(2-Methoxybenzyl)-6-phenyl pyridazin-3(2H)-ylidene]-
2-(3-methoxy-4-hydroxybenzylidene) hydrazine (2a)
Prepared from 3-methoxy-4-hydroxy benzaldehyde, orange
crystals in 89.3% yield, mp 176–178 ꢁC (DMF); MS: m/e 440 (Mþ,
22.89), IR: 3328 cmꢀ1 (OH, NH) and 1592 cmꢀ1 (C]N); 1H NMR
4.1.6. Compound 4b
Yellow crystals in 69% yield, mp 202–204 ꢁC (DMF); MS: m/e 572
(Mþ, 2.76), IR: 3333 cmꢀ1 (NH), 2927 cmꢀ1 (CH aliphatic),1686 cmꢀ1
(C]O) and 1628 cmꢀ1 (C]N). Anal. Calcd for C35H32N4O4: C, 73.41;
H, 5.63; N, 9.78. Found: C, 73.57; H, 5.64; N, 9.77.
(DMSO, 300 MHz) d 9.33 (s, 1H, OH), 8.56 (s, 1H, N]CH), 8.23 (s,1H,
NH), 7.79–6.81 (m, 12H, 3Ar-H), 6.78 (s, 1H, CH hetero), 3.91 (s, 2H,
CH2) and 3.86–3.80 (s, 6H, 2ꢁ CH3). Anal. Calcd for C26H24N4O3: C,
70.89; H, 5.49; N, 12.72. Found: C, 70.60; H, 5.66; N, 12.70.
4.1.7. Compound 4c
Yellow crystals in 69% yield, mp 208–210 ꢁC (DMF); MS: m/e 594
(Mþ þ 1, 3.71), 593 (Mþ, 5.20), IR: 3376 cmꢀ1 (NH), 2927 cmꢀ1 (CH
aliphatic), 1685 cmꢀ1 (C]O) and 1627 cmꢀ1 (C]N). Anal. Calcd for
C34H29N4O4 Cl: C, 68.86; H, 4.93; N, 9.45; Cl, 5.98; Found: C, 68.62;
H, 4.26; N, 9.46; Cl, 5.80.
4.1.2. 1-[4-(2-Methoxybenzyl)-6-methyl-phenyl pyridazin-3(2H)-
ylidene]-2-(3-methoxy-4-hydroxybenzylidene) hydrazine (2b)
Prepared from 3-methoxy-4-hydroxybenzaldehyde, orange
crystals in 86.67% yield, mp 218–220 ꢁC (DMF); MS: m/e 454 (Mþ,
Table 1
Antimicrobial screening results of the tested compounds.
Compound
Inhibition zone diameter (mm/mg sample)
Staphylococcus aureus
Streptococcus faecalis
Escherichia coli
Pseudomonas aeruginosa
2d
3d
4a
5c
5d
6a
7c
8c
8d
9d
10b
11d
12a
13a
14a
15d
12
14
14
12
10
14
12
16
12
16
13
13
16
13
13
18
13
14
20
12
13
12
12
10
13
12
17
12
15
13
14
16
13
13
17
13
13
26
12
15
12
13
11
12
12
16
12
15
13
14
15
12
12
16
13
13
22
13
12
13
13
10
14
12
15
11
14
12
13
15
12
13
17
13
14
24
16d
17b
Tetracycline

1992
N.G. Kandile et al. / European Journal of Medicinal Chemistry 44 (2009) 1989–1996
4.1.8. Compound 4d
4.1.15. 1-[4-(2-Methoxybenzyl)-6-methylphenyl pyridazin-3(2H)-
ylidene]-2-(penta-1-ylidene-2,3,4,5-tetraol) hydrazine (8b)
Yellow crystals in 66% yield, mp 214–216 ꢁC (DMF); MS: m/e
589(Mþ þ 1, 1.63), 588 (Mþ, 4.02), IR: 3381 cmꢀ1 (NH), 2930 cmꢀ1
(CH aliphatic), 1683 cmꢀ1 (C]O) and 1630 cmꢀ1 (C]N). 1H NMR
Prepared from D-arabinose, yellow crystals in 80% yield, mp
196–198 ꢁC (ethanol); MS: m/e 423 (Mþ ꢀ 29, 1.29), 419 (77.23), 359
(48.64), 299 (100), 239 (18.45), 199 (14.05), 182 (29.21), 116 (18.23),
91 (19.03), IR: broad band at 3341 cmꢀ1 (OH, NH), 2923 cmꢀ1 (CH
aliphatic) and 1603 cmꢀ1 (C]N). Anal. Calcd for C24H28N4O5: C,
63.70; H, 6.24; N, 12.38. Found: C, 63.40; H, 6.30; N, 12.19.
(DMSO, 300 MHz)
d 9.88 (s, 1H, CHO), 8.30 (s, 1H, N]CH), 7.95 (s,
1H, NH), 7.95–7.02 (m, 16H, 4Ar-H), 6.91 (s, 1H, CH hetero), 4.47–
4.17 (d, 4H, 2CH2), 3.79 (s, 2H, CH2), 3.36–3.23 (s, 6H, 2ꢁ CH3). Anal.
Calcd for C35H32N4O5: C, 71.41; H, 5.48; N, 9.52. Found: C, 71.14; H,
5.54; N, 9.59.
4.1.16. 1-[4-(2-Methoxybenzyl)-6-chlorophenyl pyridazin-3(2H)-
ylidene]-2-(penta-1-ylidene-2,3,4,5-tetraol) hydrazine (8c)
4.1.9. Compound 5a
Yellow crystals in 70% yield, mp 206–208 ꢁC (DMF); MS: m/e 618
(Mþ, 6.19), IR: 3198 cmꢀ1 (NH), 2930 cmꢀ1 (CH aliphatic),
1683 cmꢀ1 (C]O) and 1597 cmꢀ1(C]N). 1H NMR (DMSO,
Prepared from D-arabinose, yellow crystals in 76% yield, mp 98–
100 ꢁC (ethanol); MS: m/e 442 (Mþ ꢀ 30, 4.65), 439 (48.28), 379
(10.29), 319 (100), 294 (21.41), 219 (23.04), 182 (55.16), 128 (19.94),
91 (42.30), IR: broad band at 3377 cmꢀ1 (OH, NH), 2926 cmꢀ1 (CH
aliphatic) and 1580 cmꢀ1 (C]N). Anal. Calcd for C23H25N4O5Cl: C,
58.41; H, 5.33; N, 11.85; Cl, 7.50. Found: C, 58.21; H, 5.44; N, 11.80;
Cl, 7.57.
300 MHz)
d 9.86 (s, 1H, CHO), 8.29 (s, 1H, N]CH), 7.68 (s,1H, NH),
7.58–6.92 (m, 15H, 4Ar-H), 6.90 (s, 1H, CH hetero), 4.48–4.37 (d, 4H,
2CH2), 3.82 (s, 2H, CH2), 3.84–3.82 (s, 6H, 2ꢁ CH3), 3.37–3.24 (s, 3H,
OCH3). Anal. Calcd for C36H34N4O6: C, 69.89; H, 5.54; N, 9.06. Found:
C, 70.34; H, 5.46; N, 9.21.
4.1.17. 1-[4-(2-Methoxybenzyl)-6-methoxyphenyl pyridazin-3(2H)-
ylidene]-2-(penta-1-ylidene-2,3,4,5-tetraol) hydrazine (8d)
4.1.10. Compound 5b
Yellow crystals in 90% yield, mp 190–192 ꢁC (DMF); MS: m/e 633
(Mþ þ 1, 0.59), 632 (Mþ, 1.47), IR: 3395 cmꢀ1 (NH), 2926 cmꢀ1 (CH
aliphatic), 1680 cmꢀ1 (C]O) and 1628 cmꢀ1 (C]N). Anal. Calcd for
C37H36N4O6:C,70.24;H, 5.74;N,8.86. Found:C,69.58;H, 5.94;N,8.56.
Prepared from D-arabinose, yellow crystals in 92% yield, mp
178–180 ꢁC (ethanol); MS: m/e 467 (Mþ ꢀ 1, 1.18), IR: broad band at
3318 cmꢀ1 (OH, NH), 2936 (CH aliphatic) and 1602 (C]N). 1H NMR
(CDCl3, 300 MHz)
d 9.09 (s, 1H, N]CH), 7.80 (s, 1H, NH), 7.76–6.93
(m, 8H, 2Ar-H), 6.91 (s, 1H, CH hetero), 4.50–4.46 (m, 3H, 3CH),
3.99–3.91 (d, 4H, 2CH2), 3.89–3.86 (s, 6H, 2ꢁ CH3) and 3.83–3.80 (s,
4H, OH). Anal. Calcd for C24H28N4O6: C, 61.53; H, 6.02; N, 11.96.
Found: C, 61.20; H, 5.62; N, 11.66.
4.1.11. Compound 5c
Yellow crystals in 80% yield, mp 196–198 ꢁC (DMF); MS: m/e
652.5 (Mþ, 1.42), IR: 3199 cmꢀ1 (NH), 2933 cmꢀ1 (CH aliphatic),
1683 cmꢀ1 (C]O) and 1596 cmꢀ1 (C]N). 1H NMR (DMSO,
300 MHz)
d
9.86 (s, 1H, CHO), 8.65 (s, 1H, N]CH), 8.30 (s, 1H, NH),
4.1.18. 1-[4-(2-Methoxybenzyl)-6-phenyl pyridazin-3(2H)-
ylidene]-2-(hexan-1-ylidene-2,3,4,5,6-pentaol) hydrazine (9a)
7.85–6.96 (m, 14H, 4Ar-H), 6.94 (s, 1H, CH hetero), 4.47–4.37 (d, 4H,
2CH2), 3.88 (s, 2H, CH2), 3.84–3.80 (s, 6H, 2ꢁ CH3), 3.37–3.30 (s, 3H,
OCH3). Anal. Calcd for C36H33N4O6Cl: C, 66.20; H, 5.09; N, 8.58; Cl,
5.43. Found: C, 66.10; H, 4.90; N, 8.59; Cl, 5.53.
Prepared from D-glucose, yellow crystals in 60% yield, mp 152–
154 ꢁC (ethanol); MS: m/e 462 (Mþ ꢀ 6, 1.11), 405 (78.65), 345
(31.26), 285 (100), 210 (10.36), 182 (20.29),115 (5.12), 77 (20.59), IR:
broad band at 3465 cmꢀ1 (OH), 3284 cmꢀ1 (NH), 2910 cmꢀ1 (CH
aliphatic) and 1600 cmꢀ1 (C]N). Anal. Calcd for C24H28N4O6: C,
61.53; H, 6.02; N, 11.96. Found: C, 61.31; H, 6.04; N, 11.67.
4.1.12. Compound 5d
Yellow crystals in 60% yield, mp 215–217 ꢁC (DMF); MS: m/e 649
(Mþ, 10.38), IR: 3388 cmꢀ1 (NH), 2936 cmꢀ1 (CH aliphatic),
1679 cmꢀ1 (C]O) and 1629 cmꢀ1 (C]N). 1H NMR (DMSO,
4.1.19. 1-[4-(2-Methoxybenzyl)-6-methyl phenyl pyridazin-3(2H)-
ylidene]-2-(hexan-1-ylidene-2,3,4,5,6-pentaol) hydrazine (9b)
300 MHz)
d 9.80 (s, 1H, CHO), 8.30 (s, 1H, N]CH), 7.87 (s, 1H, NH),
7.62–6.99 (m, 14H, 4Ar-H), 6.91 (s, 1H, CH hetero), 4.37 (d, 4H,
2CH2), 3.89 (s, 2H, CH2), 3.84–3.82 (s, 6H, 2ꢁ CH3), 3.31 (s, 6H, 2ꢁ
CH3). Anal. Calcd for C37H36N4O7: C, 68.51; H, 5.59; N, 8.64. Found:
C, 68.30; H, 5.18; N, 8.86.
Prepared from D-glucose, yellow crystals in 90% yield, mp 130–
132 ꢁC (ethanol); MS: m/e 480 (Mþ ꢀ 2, 1.06), IR: broad band at
3276 cmꢀ1 (OH, NH), 2915 cmꢀ1 (CH aliphatic) and 1602 cmꢀ1
(C]N). Anal. Calcd for C25H30N4O6: C, 62.23; H, 6.27; N, 11.61.
Found: C, 61.96; H, 5.80; N, 11.92.
4.1.13. Compound 6d
Yellow crystals in 68% yield, mp 204–206 ꢁC (DMF); MS: m/e 710
(Mþ þ 2, 0.49), 708 (Mþ, 0.59), IR: 3181 cmꢀ1 (NH), 2934 cmꢀ1 (CH
aliphatic), 1688 cmꢀ1 (C]O) and 1583 cmꢀ1 (C]N). 1H NMR
4.1.20. 1-[4-(2-Methoxybenzyl)-6-chlorophenyl pyridazin-3(2H)-
ylidene]-2-(hexan-1-ylidene-2,3,4,5,6-pentaol) hydrazine (9c)
Prepared from D-glucose, yellow crystals in 80% yield, mp 108–
(DMSO, 300 MHz)
d
9.80 (s, 1H, CHO), 8.29 (s, 1H, N]CH), 7.63 (s,
110 ꢁC (ethanol); MS: m/e 494 (Mþ ꢀ 8, 2.94), 451 (8.15), 417 (7,25),
333 (12.80), 319 (100), 244 (5.80), 182 (24.35), 115 (15.97), 75
(18.91), IR: broad band at 3391 cmꢀ1 (OH), 3323 cmꢀ1 (NH),
2924 cmꢀ1 (CH aliphatic) and 1626 cmꢀ1 (C]N). Anal. Calcd for
C24H27N4O6Cl: C, 57.31; H, 5.41; N, 11.14; Cl, 7.05. Found: C, 57.17; H,
5.30; N, 11.15; Cl, 7.13.
1H, NH), 7.60–6.95 (m, 12H, 4Ar-H), 6.92 (s, 1H, CH hetero), 4.18–
4.15 (d, 4H, 2CH2), 3.84 (s, 2H, CH2), 3.86–3.79 (s, 12H, 4ꢁ CH3),
3.78–3.30 (s, 6H, 2ꢁ CH3). Anal. Calcd for C39H40N4O9: C, 66.09; H,
5.69; N, 7.90. Found: C, 67.25; H, 5.50; N, 8.26.
4.1.14. 1-[4-(2-Methoxybenzyl)-6-phenyl pyridazin-3(2H)-
ylidene]-2-(penta-1-ylidene-2,3,4,5-tetraol) hydrazine (8a)
4.1.21. 1-[4-(2-Methoxybenzyl)-6-methoxyphenyl pyridazin-3(2H)-
ylidene]-2-(hexan-1-ylidene-2,3,4,5,6-pentaol) hydrazine (9d)
Prepared from
D
-arabinose, yelloþw crystals in 80% yield, mp
187 ꢁC (ethanol); MS: m/e 438 (M , 8.20), IR: broad band at
Prepared from D-glucose, yellow crystals in 94% yield, mp 138–
3382 cmꢀ1 (OH, NH), 2930 cmꢀ1 (CH aliphatic) and 1587 cmꢀ1
140 ꢁC (ethanol); MS: m/e 490 (Mþ ꢀ 8, 2.24), 447 (29.38), 387
(7.38), 345 (11.26), 315 (100), 240 (11.71), 182 (42.38), 135 (6.83), 97
(9.75), IR: broad band at 3386 cmꢀ1 (OH), 3298 cmꢀ1 (NH),
2930 cmꢀ1 (CH aliphatic) and 1607 cmꢀ1 (C]N). 1H NMR (CDCl3,
(C]N). 1H NMR (CDCl3, 300 MHz)
d 9.09 (s, 1H, N]CH), 7.84 (s,1H,
NH), 7.48–6.94 (m, 9H, 2Ar-H), 6.91 (s, 1H, CH hetero), 4.52–4.15 (m,
3H, 3CH), 4.05–3.91 (d, 4H, 2CH2), 3.83 (s, 3H, OCH3) and 3.82–3.73
(s, 4H, OH) . Anal. Calcd for C23H26N4O5: C, 63.00; H, 5.98; N, 12.78.
Found: C, 63.02; H, 6.17; N, 12.48.
300 MHz)
d 9.09 (s, 1H, N]CH), 7.89 (s, 1H, NH), 7.58–6.73 (m, 8H,
2Ar-H), 6.64 (s, 1H, CH hetero), 4.50–4.08 (m, 4H, 4CH), 4.00–3.88

N.G. Kandile et al. / European Journal of Medicinal Chemistry 44 (2009) 1989–1996
1993
(d, 4H, 2CH2), 3.87–3.80 (s, 6H, 2ꢁ CH3) and 3.76–3.60 (s, 4H, OH).
Anal. Calcd for C25H30N4O7: C, 60.23; H, 6.07; N, 11.24. Found: C,
60.06; H, 6.03; N, 11.14.
Anal. Calcd for C31H25N4OCl: C, 73.73; H, 4.99; N, 11.09; Cl, 7.02.
Found: C, 73.80; H, 5.93; N, 11.08; 7.25.
4.1.29. 1-[4-(2-Methoxybenzyl)-6-phenyl pyridazin-3(2H)-
ylidene]-2-(diphenylmethyl) hydrazine (14d)
4.1.22. 1-[4-(2-Methoxybenzyl)-6-phenyl pyridazin-3(2H)-
ylidene]-2-(1-phenylethylidene) hydrazine (13a)
Prepared from benzophenone, yellow crystals in 92% yield, mp
117–118 ꢁC (ethanol); MS: m/e 502 (Mþ þ 2, 1.43), 501 (Mþ þ 1,
8.52), 500 (Mþ, 22.56), IR: 3376 cmꢀ1 (NH) and 1627 cmꢀ1 (C]N);
Prepared from acetophenone, yellow crystals in 96% yield, mp
174 ꢁC (ethanol); MS: m/e 410 (Mþ þ 2, 1.14), 409 (Mþ þ 1, 6.05),
408 (Mþ, 19.07), IR: 3356 cmꢀ1 (NH), 2920 cmꢀ1 (CH aliphatic) and
1H NMR (CDCl3, 300 MHz)
d 8.25 (s,1H, NH), 7.83–6.90 (m, 18H, 4Ar-
1628 cmꢀ1 (C]N); 1H NMR (CDCl3, 300 MHz)
d
7.89 (s, 1H, NH),
H), 6.87 (s, 1H, CH hetero), 4.20 (s, 2H, CH2) and 3.87–3.76 (s, 6H, 2ꢁ
CH3). Anal. Calcd for C32H28N4O2: C, 76.78; H, 5.64; N, 11.19. Found:
C, 76.60; H, 5.89; N, 11.19.
7.87–6.93 (m, 14H, 3Ar-H), 6.87 (s, 1H, CH hetero), 4.03 (s, 2H,
CH2), 3.84 (s, 3H, OCH3) and 2.56 (s, 3H, CH3). Anal. Calcd for
C26H24N4O: C, 76.45; H, 5.92; N, 13.72. Found: C, 76.39; H, 5.81; N,
13.75.
4.2. General procedure for the preparation of hydrazones from 1-[4-
(2-methoxybenzyl)-6-aryl pyridazin-3(2H)-ylidene] hydrazines
(1a,c,d) and acetone
4.1.23. 1-[4-(2-Methoxybenzyl)-6-methylphenyl pyridazin-3(2H)-
ylidene]-2-(1-phenylethylidene) hydrazine (13b)
Prepared from acetophenone, yellow crystals in 98% yield, mp
156 ꢁC (ethanol); MS: m/e 424 (Mþ þ 2,1.18), 423 (Mþ þ 1, 6.18), 422
(Mþ,13.49), IR: 3363 cmꢀ1 (NH), 2916 cmꢀ1 (CH aliphatic) and 1625
(C]N); Anal. Calcd for C27H26N4O: C, 76.75; H, 6.20; N, 13.26.
Found: C, 76.80; H, 5.97; N, 13.21.
A solution of compounds 1a–d (1 mmol) in acetone (5 ml) was
refluxed for 5 h. The separated solid product was filtered off and
crystallized from an appropriate solvent.
4.2.1. 1-[4-(2-Methoxybenzyl)-6-phenyl pyridazin-3(2H)-ylidene]-
2-(propan-2-ylidene) hydrazine (12a)
4.1.24. 1-[4-(2-Methoxybenzyl)-6-chlorophenyl pyridazin-3(2H)-
ylidene]-2-(1-phenylethylidene) hydrazine (13c)
Prepared from acetone, yellow crystals in 40% yield, mp 96 ꢁC
(ethanol); MS: m/e 347 (Mþ þ 1, 4.59), 346 (Mþ, 18.34), IR:
3282 cmꢀ1 (NH), 2907 cmꢀ1 (CH aliphatic) and 1637 cmꢀ1 (C]N);
Prepared from acetophenone, yellow crystals in 92% yield, mp
158–159 ꢁC (ethanol); MS: m/e 445 (Mþ þ 2, 1.11), 444 (Mþ þ 1,
3.16), 443 (Mþ, 3.09), IR: 3370 cmꢀ1 (NH), 2926 cmꢀ1 (CH
aliphatic) and 1628 cmꢀ1 (C]N); Anal. Calcd for C26H23N4OCl: C,
70.50; H, 5.23; N, 12.65; Cl, 8.00. Found: C, 70.35; H, 5.35; N, 12.65;
Cl, 8.11.
1H NMR (CDCl3, 300 MHz)
d 8.30 (s, 1H, NH), 7.65–6.94 (m, 8H, 2Ar-
H), 6.92 (s, 1H, CH hetero), 3.95 (s, 2H, CH2), 3.82 (s, 3H, OCH3) and
2.17–2.08 (s, 6H, 2CH3). Anal. Calcd for C21H22N4O: C, 72.81; H, 6.40;
N, 16.17. Found: C, 73.01; H, 6.25; N, 15.96.
4.2.2. 1-[4-(2-Methoxybenzyl)-6-chlorophenyl pyridazin-3(2H)-
ylidene]-2-(propan-2-ylidene) hydrazine (12c)
4.1.25. 1-[4-(2-Methoxybenzyl)-6-methoxyphenyl pyridazin-
3(2H)-ylidene]-2-(1-phenylethylidene) hydrazine (13d)
Prepared from acetophenone, yellow crystals in 86% yield, mp
109–110 ꢁC (ethanol); MS: m/e 440 (Mþ, 1.04), IR: 3358 cmꢀ1 (NH),
2932 cmꢀ1 (CH aliphatic) and 1628 cmꢀ1 (C]N); 1H NMR (CDCl3,
Prepared from acetone, yellow crystals in 40% yield, mp 93–
94 ꢁC (ethanol); MS: m/e 383 (Mþ þ 3, 1.23), 382 (Mþ þ 2, 6.18), 381
(Mþ, 5.08), IR: 3347 cmꢀ1 (NH), 2905 cmꢀ1 (CH aliphatic) and
1631 cmꢀ1 (C]N). Anal. Calcd for C21H21N4OCl: C, 66.22; H, 5.56; N,
14.71; 9.31. Found: C, 66.01; H, 5.79; N, 14.73; 9.34.
300 MHz)
d 7.88 (s, 1H, NH), 7.85–6.93 (m, 13H, 3Ar-H), 6.93 (s, 1H,
CH hetero), 4.05 (s, 2H, CH2), 3.90–3.77 (s, 6H, 2ꢁ CH3) and 2.55 (s,
3H, CH3). Anal. Calcd for C27H26N4O2: C, 73.95; H, 5.98; N, 12.78.
Found: C, 73.71; H, 5.83; N, 12.75.
4.2.3. 1-[4-(2-Methoxybenzyl)-6-chlorophenyl pyridazin-3(2H)-
ylidene]-2-(propan-2-ylidene) hydrazine (12d)
Prepared from acetone, yellow crystals in 30% yield, mp 81–82 ꢁC
(ethanol); MS: m/e 377 (Mþ þ 1, 7.13), 376 (Mþ,18.30), IR: 3422 cmꢀ1
(NH), 2927 cmꢀ1 (CH aliphatic) and 1630 cmꢀ1 (C]N); Anal. Calcd
for C22H24N4O2: C, 70.19; H, 6.43. Found: C, 70.14; H, 6.22.
4.1.26. 1-[4-(2-Methoxybenzyl)-6-phenyl pyridazin-3(2H)-
ylidene]-2-(diphenylmethyl) hydrazine (14a)
Prepared from benzophenone, yellow crystals in 90% yield, mp
137–138 ꢁC (ethanol); MS: m/e 471 (Mþ þ 1, 28.95), 470 (Mþ,
81.58), IR: 3282 cmꢀ1 (NH) and 1631 cmꢀ1 (C]N); 1H NMR (CDCl3)
7.79–7.77 (s, 1H, NH), 7.53–6.86 (m, 19H, 4Ar-H), 6.83 (s, 1H, CH
hetero), 4.06 (s, 2H, CH2) and 3.72 (s, 3H, OCH3). Anal. Calcd for
C31H26N4O: C, 79.12; H, 5.56; N, 11.91. Found: C, 79.05; H, 5.56; N,
11.92.
4.3. General procedure for the preparation of compounds 3a–d
,
10a–d and 11a–d
Refluxing of 2a–d and/or 10a–d and/or 11a–d (1 mmol) in
a mixture of (10 ml) acetic anhydride and (0.3 ml) pyridine for 10 h.
The reaction solution was concentrated under reduced pressure
and left to cool. The separated solid product was filtered off and
crystallized from an appropriate solvent.
4.1.27. 1-[4-(2-Methoxybenzyl)-6-methylphenyl pyridazin-3(2H)-
ylidene]-2-(diphenylmethyl) hydrazine (14b)
Prepared from benzophenone, yellow crystals in 94% yield, mp
133–134 ꢁC (ethanol); MS: m/e 486 (Mþ þ 2, 1.40), 485 (Mþ þ 1,
7.23), 484 (Mþ, 16.30), IR: 3369 cmꢀ1 (NH) and 1626 cmꢀ1 (C]N).
Anal. Calcd for C32H28N4O: C, 79.31; H, 5.82; N, 11.56. Found: C,
79.01; H, 5. 61; N, 11.35.
4.3.1. 1-[4-(2-Methoxybenzyl)-6-phenyl pyridazin-3(2H)-ylidene]-
2-(3-methoxy-4-O-acetylbenzylidene) hydrazine (3a)
Dark brown crystals in 85.33% yield, mp 190 ꢁC (benzene);
MS: m/e 481 (Mþ, 0.87), IR: 3421 cmꢀ1 (NH), 2935 cmꢀ1 (CH
aliphatic), 1767 cmꢀ1 (C]O) and 1603 cmꢀ1 (C]N); 1H NMR
4.1.28. 1-[4-(2-Methoxybenzyl)-6-chlorophenyl pyridazin-3(2H)-
ylidene]-2-(diphenylmethyl) hydrazine (14c)
(CDCl3, 300 MHz)
d 8.30 (s, 1H, N]CH), 8.27 (s, 1H, NH), 7.89–
Prepared from benzophenone, yellow crystals in 94% yield, mp
134–135 ꢁC (ethanol); MS: m/e 507 (Mþ þ 2, 1.87), 506 (Mþ þ 1,
4.19), 505 (Mþ, 4.47), IR: 3369 cmꢀ1 (NH) and 1623 cmꢀ1 (C]N).
6.97 (m, 12H, 3Ar-H), 6.94 (s, 1H, CH hetero), 4.56 (s, 2H, CH2),
3.98–3.82 (s, 6H, 2ꢁ CH3) and 2.85 (s, 3H,COCH3). Anal. Calcd for
C28H26N4O4: C, 69.70; H, 5.43; N, 11.61. Found: C, 69.29; H, 5.12;
N, 11.24.

1994
N.G. Kandile et al. / European Journal of Medicinal Chemistry 44 (2009) 1989–1996
4.3.2. 1-[4-(2-Methoxybenzyl)-6-methyl phenyl pyridazin-3(2H)-
ylidene]-2-(3-methoxy-4-O-acetylbenzylidene) hydrazine (3b)
Dark brown crystals in 89.56% yield, mp 154–156 ꢁC (benzene);
MS: m/e 496 (Mþ, 0.45), IR: 3421 cmꢀ1 (NH), 2940 cmꢀ1 (CH
aliphatic), 1762 cmꢀ1 (C]O) and 1603 cmꢀ1 (C]N). Anal. Calcd for
C29H28N4O4: C, 70.15; H, 5.68; N, 11.28. Found: C, 69.89; H, 5.83; N,
11.09.
2.00 (s, 12H, 4COCH3). Anal. Calcd for C32H36N4O10: C, 60.37; H,
5.70; N, 8.80. Found: C, 60.70; H, 5.88; N, 8.49.
4.3.9. 1-[4-(2-Methoxybenzyl)-6-phenyl pyridazin-3(2H)-ylidene]-
2-(hexan-1-ylidene-2,3,4,5,6-penta-O-acetyl) hydrazine (11a)
Dark brown crystals in 36.87% yield, mp 100–102 ꢁC (benzene);
MS: m/e 679 (Mþ þ 1, 0.05), 678 (Mþ, 0.10), IR: 3422 cmꢀ1 (NH),
2928 cmꢀ1 (CH aliphatic), 1751 cmꢀ1 (C]O) and 1601 cmꢀ1 (C]N).
Anal. Calcd for C34H38N4O11: C, 60.17; H, 5.64; N, 8.26. Found: C,
60.50; H, 5.64; N, 7.89.
4.3.3. 1-[4-(2-Methoxybenzyl)-6-chlorophenyl pyridazin-3(2H)-
ylidene]-2-(3-methoxy-4-O-acetylbenzylidene) hydrazine (3c)
Dark brown crystals in 80% yield, mp 130–132 ꢁC (benzene); MS:
m/e 516.5 (Mþ, 1.01), IR: 3445 cmꢀ1 (NH), 2938 cmꢀ1 (CH aliphatic),
1762 cmꢀ1 (C]O) and 1598 cmꢀ1 (C]N). Anal. Calcd for
C28H25N4O4Cl: C, 65.05; H, 4.87; Cl, 6.86. Found: C, 64.61; H, 5.09;
Cl, 6.94.
4.3.10. 1-[4-(2-Methoxybenzyl)-6-methylphenyl pyridazin-3(2H)-
ylidene]-2-(hexan-1-ylidene-2,3,4,5,6-penta-O-acetyl)hydrazine(11b)
Dark brown crþystals in 44.73% yield, mp 76–78 ꢁC (benzene);
MS: m/e 692 (M , 0.24), IR: 3422 cmꢀ1 (NH), 2927 cmꢀ1 (CH
aliphatic), 1753 cmꢀ1 (C]O) and 1603 cmꢀ1 (C]N). Anal. Calcd for
C35H40N4O11: N, 8.09. Found: N, 7.85.
4.3.4. 1-[4-(2-Methoxybenzyl)-6-methoxyphenyl pyridazin-3(2H)-
ylidene]-2-(3-methoxy-4-O-acetylbenzylidene) hydrazine (3d)
Dark brown crystals in 55% yield, mp 82–84 ꢁC (benzene); MS:
m/e 480 (Mþ ꢀ 32,1.24), 479 (3.73), 437 (3.73), 329 (100), 313 (5.15),
254 (7.38), 196 (42.14), 153 (3.73), 77 (6.89), 63 (4.92), 52 (5.64), IR:
3418 cmꢀ1 (NH), 2933 cmꢀ1 (CH aliphatic), 1766 cmꢀ1 (C]O) and
4.3.11. 1-[4-(2-Methoxybenzyl)-6-chlorophenyl pyridazin-3(2H)-
ylidene]-2-(hexan-1-ylidene-2,3,4,5,6-penta-O-acetyl)
hydrazine (11c)
Dark brown crystals in 37.50% yield, mp 86–88 ꢁC (benzene);
MS: m/e 715 (Mþ þ 2, 0.16), 713(Mþ, 0.16), IR: 3429 cmꢀ1 (NH),
2929 cmꢀ1 (CH aliphatic), 1753 cmꢀ1 (C]O) and 1597 cmꢀ1 (C]N).
Anal. Calcd for C34H37N4O11Cl: C, 57.26; H, 5.23; N, 7.86; Cl, 4.97.
Found: C, 56.89; H, 4.90; N, 7.87; Cl, 4.85.
1604 cmꢀ1 (C]N); 1H NMR (CDCl3, 300 MHz)
d 8.29 (s, 1H, N]CH),
8.26 (s,1H, NH), 7.85–6.96 (m, 11H, 3Ar-H), 6.94 (s, 1H, CH hetero),
4.54 (s, 2H, CH2), 3.98–3.82 (s, 9H, 3ꢁ CH3) and 2.85 (s, 3H, COCH3).
Anal. Calcd for C29H28N4O5: C, 67.96; H, 5.51; N, 10.93. Found: C,
67.67; H, 5.90; N, 10.49.
4.3.12. 1-[4-(2-Methoxybenzyl)-6-methoxy phenyl pyridazin-
3(2H)-ylidene]-2-(hexan-1-ylidene-2,3,4,5,6-penta-O-acetyl)
hydrazine (11d)
Dark brown crystals in 38.60% yield, mp 90–92 ꢁC (benzene);
MS: m/e 675 (Mþ ꢀ 28, 3.00), 413 (5.16), 329 (100), 254 (6.78), 196
(37.38), 77 (8.47), IR: 3422 cmꢀ1 (NH), 2932 cmꢀ1 (CH aliphatic),
1752 cmꢀ1 (C]O) and 1605 cmꢀ1(C]N). 1H NMR (CDCl3, 300 MHz)
4.3.5. 1-[4-(2-Methoxybenzyl)-6-phenyl pyridazin-3(2H)-ylidene]-
2-(penta-1-ylidene-2,3,4,5-tetra-O-acetyl) hydrazine (10a)
Dark brown crystals in 35% yield, mp 90–92 ꢁC (benzene); MS:
m/e 576 (Mþ ꢀ 30, 6.56), 573 (100), 551 (12.28), 501 (17.34), 383
(9.46), 313 (54.36), 239 (32.37), 129 (51.29), 57 (76.51), IR:
3418 cmꢀ1 (NH), 2928 cmꢀ1 (CH aliphatic), 1750 cmꢀ1 (C]O) and
1601 cmꢀ1 (C]N). 1H NMR (CDCl3, 300 MHz)
d
9.09 (s, 1H, N]CH),
d 9.10 (s, 1H, N]CH), 7.82 (s, 1H, NH), 7.40–6.99 (m, 8H, 2Ar-H), 6.97
7.86 (s, 1H, NH), 7.84–6.93 (m, 9H, 2Ar-H), 6.82 (s, 1H, CH hetero),
5.90–5.44 (m, 3H, 3CH), 4.48–4.24 (d, 4H, 2CH2), 3.82 (s, 3H, OCH3)
and 2.19–2.00 (s, 12H, 4COCH3). Anal. Calcd for C31H34N4O9: C,
61.38; H, 5.65; N, 9.24. Found: C, 61.96; H, 5.67; N, 8.96.
(s, 1H, CH hetero), 5.25–5.14 (m, 4H, 4CH), 4.48–4.13 (d, 4H, 2CH2),
3.86–3.81(s, 6H, 2ꢁ CH3) and 2.28–1.87 (s,15H, 5COCH3). Anal. Calcd
for C35H40N4O12: N, 7.91. Found: N, 7.90.
4.4. Reaction of hydrazone derivative 5c with 1c
4.3.6. 1-[4-(2-Methoxybenzyl)-6-methyl phenyl pyridazin-3(2H)-
ylidene]-2-(penta-1-ylidene-2,3,4,5-tetra-O-acetyl) hydrazine (10b)
Dark brown crystals in 32.67% yield, mp 86–88 ꢁC (benzene);
MS: m/e 619 (Mþ ꢀ 1, 0.25), IR: 3421 cmꢀ1 (NH), 2927 cmꢀ1 (CH
aliphatic), 1751 cmꢀ1 (C]O) and 1604 cmꢀ1 (C]N). Anal. Calcd for
C32H36N4O9: C, 61.93; H, 5.85; N, 9.03. Found: C, 62.24; H, 5.44; N,
8.66.
The hydrazone derivatives (5c) (1 mmol) were heated above
their melting points with 1c (1 mmol) in a sand bath for 3 h. The
product which solidified on cooling was triturated with pet. ether
40–60 ꢁC, filtered off and crystallized from an appropriate solvent.
4.4.1. Compound 7c
Dark brown crystals in 45% yield, mp 214–216 ꢁC (DMF); IR:
3395 cmꢀ1 (NH), 2932 cmꢀ1 (CH aliphatic) and 1594 cmꢀ1 (C]N).
Anal. Calcd for C54H48N8O6Cl2: C, 66.46; H, 4.96; Cl, 7.27. Found: C,
66.70; H, 4.71; Cl, 7.03.
4.3.7. 1-[4-(2-Methoxybenzyl)-6-chlorophenyl pyridazin-3(2H)-
ylidene]-2-(penta-1-ylidene-2,3,4,5-tetra-O-acetyl) hydrazine (10c)
Dark brown crystals in 30% yield, mp 56–58 ꢁC (benzene); MS:
m/e 609 (Mþ ꢀ 32, 9.88), 333 (72.70), 320 (15.17), 196 (25.02), 129
(51.15), 73 (100), IR: 3449 cmꢀ1 (NH), 2930 cmꢀ1 (CH aliphatic),
1752 cmꢀ1 (C]O) and 1598 cmꢀ1 (C]N). Anal. Calcd for
C31H33N4O9Cl: C, 58.08; H, 5.19; N, 8.74; Cl, 5.53. Found: C, 58.30; H,
5.06; N, 8.71; Cl, 5.54.
4.5. General procedure for the preparation of hydrazones from 1-[4-
(2-methoxybenzyl)-6-aryl pyridazin-3(2H)-ylidene] hydrazines
(1a–d) and 2-benzoylbenzoic acid
A solution of compounds 1a–d (1 mmol) in glacial acetic acid
(20 ml) was treated with 2-benzoylbenzoic acid (1 mmol) and
freshly prepared anhydrous sod. acetate. The reaction mixture was
refluxed for 8 h. The separated product was filtered off and crys-
tallized from an appropriate solvent.
4.3.8. 1-[4-(2-Methoxybenzyl)-6-methoxyphenyl pyridazin-3(2H)-
ylidene]-2-(penta-1-ylidene-2,3,4,5-tetra-O-acetyl) hydrazine (10d)
Dark brown crystals in 53% yield, mp 64–66 ꢁC (benzene); MS:
m/e 605 (Mþ ꢀ 31, 5.49), 531 (6.50), 459 (4.70), 343 (16.37), 315
(100), 240 (15.36), 182 (45.48), 79 (31.52), IR: 3424 cmꢀ1 (NH),
2933 cmꢀ1 (CH aliphatic), 1751 cmꢀ1 (C]O) and 1604 cmꢀ1 (C]N).
4.5.1. 1-[4-(2-Methoxybenzyl)-6-phenyl pyridazin-3(2H)-ylidene]-
2-(2-carboxydiphenyl methyl) hydrazine (15a)
1H NMR (CDCl3, 300 MHz)
d 9.09 (s, 1H, N]CH), 7.84 (s,1H, NH),
7.81–6.93 (m, 8H, 2Ar-H), 6.82 (s, 1H, CH hetero), 5.94–5.44 (m, 3H,
3CH), 4.46–4.24 (d, 4H, 2CH2), 3.87–3.81 (s, 6H, 2ꢁ CH3) and 2.18–
Prepared from 2-benzoylbenzoic acid, pale brown crystals in 60%
yield, mp 119–120 ꢁC (benzene); MS: m/e 497 (Mþ ꢀ 17, 2.35), 405

N.G. Kandile et al. / European Journal of Medicinal Chemistry 44 (2009) 1989–1996
1995
(100), 361 (29.40), 299 (26.25), 258 (25.31), 202 (13.30), 130 (17.73),
77 (35.83), IR: 3401 cmꢀ1 (OH), 3300 cmꢀ1 (NH), 1662 cmꢀ1 (C]O)
and 1597 cmꢀ1 (C]N); 1H NMR (CDCl3, 300 MHz)
8.13 (s, 1H, OH),
8.11 (s,1H, NH), 7.85–6.95 (m, 18H, 4Ar-H), 6.93 (s, 1H, CH hetero),
4.46 (s, 2H, CH2) and 3.81 (s, 3H, OCH3). Anal. Calcd for C32H26N4O3:
C, 74.69; H, 5.09; N, 10.89. Found: C, 74.11; H, 5.18; N, 10.92.
4.6.3. 1-[4-(2-Methoxybenzyl)-6-chlorophenyl pyridazin-3(2H)-
ylidene]-2-(2-oxo-butan-3-ylidene) hydrazine (16c)
d
Prepared from diacetyl, red crystals in 50% yield, mp 237–238 ꢁC
(benzene); MS: m/e 407 (Mþ ꢀ 1, 5.83), IR: 3365 cmꢀ1 (NH),
2921 cmꢀ1 (CH aliphatic),1675 cmꢀ1 (C]O) and 1623 cmꢀ1 (C]N);
1H NMR (DMSO, 300 MHz)
d 8.01–7.98 (s,1H, NH), 7.74–6.91 (m, 8H,
2Ar-H), 6.89 (s, 1H, CH hetero), 3.89 (s, 2H, CH2), 3.80 (s, 3H, OCH3)
and 3.30 (s, 6H, 2CH3). Anal. Calcd for C22H21N4O2Cl: C, 64.62; H,
5.18; N, 13.70; Cl, 8.67. Found: C, 64.50; H, 5.00; N, 13.72; Cl, 8.67.
4.5.2. 1-[4-(2-Methoxybenzyl)-6-methylphenyl pyridazin-3(2H)-
ylidene]-2-(2-carboxydiphenyl methyl) hydrazine (15b)
Prepared from 2-benzoylbenzoic acid, pale brown crystals in
80% yield, mp 122 ꢁC (benzene); MS: m/e 511 (Mþ ꢀ 17, 1.39), 419
(27.50), 375 (100), 284 (6.06), 258 (11.19), 207 (9.88), 110 (10.94),
105 (15.84), IR: 3447 cmꢀ1 (OH), 3203 cmꢀ1(NH), 1651 cmꢀ1 (C]O)
and 1604 cmꢀ1 (C]N). Anal. Calcd for C33H28N4O3: C, 74. 98; H,
5.34; N, 10.60. Found: C, 74.67; H, 5.83; N, 10.41.
4.6.4. 1-[4-(2-Methoxybenzyl)-6-methoxyphenyl pyridazin-3(2H)-
ylidene]-2-(2-oxo-butan-3-ylidene) hydrazine (16d)
Prepared from diacetyl, red crystals in 34% yield, mp 255–256 ꢁC
(benzene); MS: m/e 410 (Mþ þ 6, 6.51), 368 (18.91), 313 (925.27), 236
(17.83), 201 (23.10), 155 (100), 127 (78.45), 57 (37.83), IR: 3379 cmꢀ1
(NH), 2928 cmꢀ1 (CH aliphatic), 1734 cmꢀ1 (C]O) and 1625 cmꢀ1
4.5.3. 1-[4-(2-Methoxybenzyl)-6-chlorophenyl pyridazin-3(2H)-
ylidene]-2-(2-carboxydiphenyl methyl) hydrazine (15c)
(C]N); 1H NMR (DMSO, 300 MHz)
d 7.82–7.66 (s, 1H, NH), 7.69–6.91
(m, 8H, 2Ar-H), 6.89 (s, 1H, CH hetero), 3.97 (s, 2H, CH2), 3.89–3.68 (s,
6H, 2ꢁ CH3) and 3.30 (s, 6H, 2CH3). Anal. Calcd for C23H24N4O3: C,
68.30; H, 5.98; N, 13.85. Found: C, 68.40; H, 5.74; N, 14.89.
Prepared from 2-benzoylbenzoic acid, pale brown crystals in
52% yield, mp 162–163 ꢁC (benzene); MS: m/e 470 (Mþ ꢀ 78.5,
0.42), 439 (100), 395 (54.57), 264 (3.62), 284 (4.29), 258 (11.53), 189
(4.67), 111 (16.13), 91(18.31), IR: 3425 cmꢀ1 (OH), 3316 cmꢀ1 (NH),
1666 (C]O), 1595 (C]N). Anal. Calcd for C32H25N4O3Cl: C, 70.01; H,
4.59; N, 10.20; Cl, 6.46. Found: C, 69.90; H, 4.40; N, 10.22; 6.64.
4.7. Preparation of bis [1-[4-(2-methoxybenzyl)-6-aryl pyridazin-
3(2H)-ylidene]-2-(butan-2,3-ylidene) hydrazines from 1a–d
and diacetyl
4.5.4. 1-[4-(2-Methoxybenzyl)-6-methoxyphenyl pyridazin-3(2H)-
ylidene]-2-(2-carboxydiphenyl methyl) hydrazine (15d)
Method A. Refluxing a mixture of 1a–c (1 mmol) and 16a–c
(1 mmol) in glacial acetic acid (20 ml) for 8 h. The solution obtained
was concentrated under reduced pressure. The solid product
obtained was crystallized from an appropriate solvent.
Method B. Refluxing a mixture of 1d (2 mmol) and diacetyl
(1 mmol) in glacial acetic acid 20 ml for 8 h. The solution obtained
was concentrated under reduced pressure. The solid product
obtained was crystallized from an appropriate solvent.
Prepared from 2-benzoylbenzoic acid, pale brown crystals in 56%
yield, mp 135–136 ꢁC (benzene); MS: m/e 544 (Mþ, 0.27), 443 (0.35),
402 (0.57), 329 (1.08), 263 (0.38),182 (51.82),149 (57.20),105 (10), 77
(92.11), IR: 3401 cmꢀ1 (OH), 3212 cmꢀ1 (NH), 1718 cmꢀ1 (C]O) and
1604 cmꢀ1 (C]N); 1H NMR (CDCl3, 300 MHz)
d 8.14 (s, 1H, OH), 8.11
(s, 1H, NH), 7.78–6.94 (m, 17H, 4Ar-H), 6.90 (s, 1H, CH hetero), 4.33 (s,
2H, CH2) and 3.84–3.78 (s, 6H, 2ꢁ CH3). Anal. Calcd for C33H28N4O4: C,
72.78; H, 5.18; N, 10.29. Found: C, 71.92; H, 4.94; N, 10.18.
4.7.1. Bis{1-[4-(2-methoxybenzyl)-6-phenyl pyridazin-3(2H)-
ylidene]-2-(butan-2,3-ylidene)} hydrazine (17a)
4.6. General procedure for the preparation of hydrazones from
1-[4-(2-methoxybenzyl)-6-aryl pyridazin-3(2H)-ylidene]
hydrazines (1a–d) (1 mmol) and diacetyl
Prepared from 7a, pale brown crystals in 48.5% yield, mp 190 ꢁC
(pet .ether 40–60 ꢁC); MS: m/e 665 (Mþ þ 3, 2.49), 664 (Mþ þ 2,
3.12), 663 (Mþ þ 1, 3.12), IR: 3445 cmꢀ1 (NH), 2941 cmꢀ1 (CH
aliphatic) and 1600 cmꢀ1 (C]N); 1H NMR (CDCl3, 300 MHz)
d 7.87–
Compounds 1a–d (1 mmol) in ethanol (20 ml) were treated with
the corresponding ketones (1 mmol). The reaction mixtures were
refluxed for 5 h. The product that separated during reflux was
filtered off and crystallized from the appropriate solvent.
7.83 (s, 2H, 2NH), 7.50–6.97 (m, 18H, 4Ar-H), 6.96–6.93 (s, 2H, 2CH
hetero), 4.52–4.50 (s, 4H, 2CH2), 3.82–3.80 (s, 6H, 2ꢁ CH3) and 2.87–
2.85 (s, 6H, 2CH3). Anal. Calcd for C40H38N8O2: C, 72.49; H, 5.78; N,
16.91. Found: C, 72.71; H, 5.60; N, 16.79.
4.6.1. 1-[4-(2-Methoxybenzyl)-6-phenyl pyridazin-3(2H)-ylidene]-
2-(2-oxo-butan-3-ylidene) hydrazine (16a)
4.7.2. Bis{1-[4-(2-methoxybenzyl)-6-phenyl pyridazin-3(2H)-
ylidene]-2-(butan-2,3-ylidene)} hydrazine (17b)
Prepared from 7b, pale brown crystals in 74.7% yield, mp 80 ꢁC
(pet. ether 40–60 ꢁC); MS: m/e 692 (Mþ þ 2, 2.55), IR: 3444 cmꢀ1
(NH), 2923 cmꢀ1 (CH aliphatic) and 1605 cmꢀ1 (C]N). Anal. Calcd
for C42H42N8O2: N, 16.22. Found: N, 16.64.
Prepared from diacetyl, red crystals in 40% yield, mp 145–146 ꢁC
(benzene); MS: m/e 375 (Mþ þ 1, 3.31), 374 (Mþ, 13.73), 331 (100),
259 (39.68), 230 (14.84), 202 (10.51), 140 (10.20), 91 (19.32), 55
(14.99), IR: 3238 cmꢀ1 (NH), 2922 cmꢀ1 (CH aliphatic), 1660 cmꢀ1
(C]O) and 1628 cmꢀ1 (C]N); 1H NMR (DMSO, 300 MHz)
d 7.97–
7.95 (s, 1H, NH), 7.72–6.90 (m, 9H, 2Ar-H), 6.88 (s, 1H, CH hetero),
3.90 (s, 2H, CH2), 3.78 (s, 3H, OCH3) and 3.33 (s, 6H, 2CH3). Anal.
Calcd for C22H22N4O2: C, 70.57; H, 5.92; N,14.96. Found: C, 69.78; H,
5.67; N, 15.02.
4.7.3. Bis{1-[4-(2-methoxybenzyl)-6-chlorophenyl pyridazin-
3(2H)-ylidene]-2-(butan-2,3-ylidene)} hydrazine (17c)
Prepared from 7c, pale brown crystals in 40% yield, mp 77–78 ꢁC
(pet. ether 40–60 ꢁC); MS: m/e 704 (Mþ ꢀ 27, 4.26), 696 (4.79), 551
(45.74), 523 (25.00), 423 (17.02), 313 (100), 264 (58.51), 207 (25.00),
95 (82.98), IR: 3389 cmꢀ1 (NH), 2933 cmꢀ1 (CH aliphatic) and
1596 cmꢀ1 (C]N). Anal. Calcd for C40H36N8O2Cl2: N, 15.31; Cl, 9.69.
Found: N, 15.98; Cl, 10.18.
4.6.2. 1-[4-(2-Methoxybenzyl)-6-methylphenyl pyridazin-3(2H)-
ylidene]-2-(2-oxo-butan-3-ylidene) hydrazine (16b)
Prepared from diacetyl, red crystals in 32% yield, mp 242 ꢁC
(benzene); MS: m/e 376 (Mþ ꢀ 12, 3.36), 339 (23.25), 313 (40.17),
274 (20.67), 213 (13.28), 199 (18.88), 129 (50.59), 97 (79.89), 93
(20.11), 77 (33.33), IR: 3369 cmꢀ1 (NH), 2920 cmꢀ1 (CH aliphatic),
1653 cmꢀ1 (C]O) and 1625 cmꢀ1 (C]N). Anal. Calcd for
C23H24N4O2: C, 71.11; H, 6.23; N, 14.42. Found: C, 71.20; H, 6.20; N,
14.13.
4.7.4. Bis{1-[4-(2-methoxybenzyl)-6-methoxyphenyl pyridazin-
3(2H)-ylidene]-(butan-2,3-ylidene)} hydrazine (17d)
Prepared from 1d, pale brown crystals in 20% yield, mp 136–
137 ꢁC (pet. ether 40–60 ꢁC); MS: m/e 724 (Mþ þ 2, 0.08), IR:
3380 cmꢀ1 (NH), 2932 cmꢀ1 (CH aliphatic) and 1604 cmꢀ1 (C]N);

1996
N.G. Kandile et al. / European Journal of Medicinal Chemistry 44 (2009) 1989–1996
[9] N.G. Kandile, Acta Chem. Hung. 126 (4) (1989) 533–538.
1H NMR (CDCl3, 300 MHz)
d
7.82–7.79 (s, 2H, 2NH), 7.41–6.97 (m,
[10] N.G. Kandile, Orient. J. Chem. 5 (1989) 139–142.
16H, 4Ar-H), 6.95–6.93 (s, 2H, 2CH hetero), 4.48–4.40 (s, 4H, 2CH2),
3.86–3.82 (s, 12H, 4ꢁ CH3) and 2.85–2.80 (s, 6H, 2CH3). Anal. Calcd
for C42H42N8O4: C, 69.79; H, 5. 86; N,15.50. Found: C, 69.78; H, 5.77;
N, 14.94.
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[16] M.I. Mohamed, H.T. Zaky, N.G. Kandile, J. Bulg. Chem. Commun. 47 (3) (2004)
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