New approaches for the synthesis of hydrazone derivatives and their antitumor evaluation

Article abstract of DOI:10.4067/S0717-97072012000200013

The hydrazide-hydrazone 3 reacted with benzenediazonium chloride to give the phenylhydrazone derivative 5. The latter underwent a series of hetero-cyclization reactions to give pyridazine, 1,2,3-triazole and pyrazole derivatives. The antitumor evaluation

Full text of DOI:10.4067/S0717-97072012000200013

J. Chil. Chem. Soc., 57, Nº 2 (2012)
NEW APPROACHES FOR THE SYNTHESIS OF HYDRAZONE DERIVATIVES AND THEIR ANTITUMOR
EVALUATION
WAGNAT WAHBA WARDAKHAN* AND EMAN MOHAMED SAMIR
National Organization for Drug Control & Research (NODCAR) P.O. 29, Cairo, A. R. Egypt
(Received: August 2, 2011 - Accepted: January 23, 2012)
ABSTRACT
The hydrazide-hydrazone 3 reacted with benzenediazonium chloride to give the phenylhydrazone derivative 5. The latter underwent a series of hetero-
cyclization reactions to give pyridazine, 1,2,3-triazole and pyrazole derivatives. The antitumor evaluation of the newly synthesized products against the three
cancer cells lines namely breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) showed that some of them have
higher inhibitory effects towards the three cell lines compared to the standard.
Key word: hydrazide-hydrazone, pyridazine, 1,2,3-triazole, pyrazole, anti-tumor.
group of compound 15 using sodium nitrite solution in the presence of acetic/
hydrochloric acids resulted in the formation of intermediate pyrazole-3-
diazonium salt 16. Coupling of the latter diazonium salt with malononitrile
in ethanol containing sodium acetate afforded the hydrazo derivative 17. The
analytical and spectral data of the obtained product were consistence with the
proposed structure (Scheme 2).
INTRODUCTION
Hydrazide-/hydrazones have been demonstrated to possess antibacterial,1-7
anticonvulsant8-11 and antitubercular12-16 activities. These observations
led us to synthesize novel hydrazide-hydrazones and to investigate their
possible antitumor activities. It has been reported in the literature17,18 that
hydrazide-hydrazones can give the corresponding hydrazide and aldehyde
metabolites whereas the related hydrazides are known to yield carboxylic
acids via hydrolytic route. Based on this knowledge, hydrazide-hydrazones
derivative 3 was prepared easily from the reaction of cyanoacetyl hydrazine
with benzaldehyde and subsequently used for the synthesis of pyridazine,
1,2,3-triazole and pyrazole derivatives. The newly synthesized compounds
were tested to evaluate their in vitro anti-tumor activities against three
human tumor cell lines representing different tumor types, namely, breast
adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS
cancer (SF-268). It was found that some of these compounds showed inhibitory
effects on the three cell lines, indicating their potential use in the development
of anti-cancer agents.
RESULTS AND DISCUSION
The reaction of the cyanoacetylhydrazine 1 with benzaldehyde 2 gives the
hydrazide-hydrazone 3.19 Reaction of the latter product with benzenediazonium
chloride 4 afforded the phenylhydrazone derivative 5. The structure of
compound 5 was confirmed on the basis of analytical and spectral data.
Heterocyclization of compound 5 to form different heterocyclic derivatives
with potential pharmaceutical applications was studied. Thus, compound 5
reacted with either malononitrile 6a or ethyl cyanoacetate 6b in 1,4-dioxan
containing a catalytic amount of triethylamine, gave the pyridazine derivatives
7a and 7b, respectively. The structures of compounds 7a & 7b were established
on the basis of their analytical and spectral data. Thus, the 1H NMR spectrum
of 7a showed the presence of a singlet at d 4.87 ppm corresponding to NH2
group, a singlet at d 6.69 ppm for the CH=N group, a multiplet at d 7.28-7.58
ppm for the two phenyl groups and two singlets (D2O exchangeable) at d 8.23
and 8.30 ppm for the two NH groups. On the other hand, reaction of compound
5 with hydrazine hydrate gave the triazole derivative 9. Moreover, the reaction
of compound 5 with phenylisothiocyanate 10 gave the 1,2,4-triazine derivative
12. The structures of compounds 9 and 12 were established on the basis of their
analytical and spectral data (see experimental section).
Next, the reaction of compound 3 with phenylisothiocyanate in DMF/
KOH solution was studied. This reaction led to the formation of the nonisolable
intermediate potassium sulphide salt 13 which subsequently allowed to react
with hydrazine hydrate to afford the hydrazino derivative 14 was formed. The
structure of the latter product was confirmed on the basis of its analytical and
spectral data. Thus, the 1H NMR spectrum showed the presence of a singlet at d
5.02 ppm corresponding to NH2 group, a singlet at d 6.99 for the CH=N group,
a multiplet at d 7.28-7.49 ppm corresponding to the two phenyl group and
three singlets at d 8.02, 8.90, 9.21 ppm corresponding to the three NH groups.
Compound 14 was cyclized readily in sodium ethoxide solution affording the
3-amino-5-(phenylamino)-1H-pyrazole-4-N-benzalcarbohydrazide derivative
15. The structure of the latter product was established based on its analytical
and spectral data (see experimental sections). Diazotization of the 3-amino
Sheme 1
The reaction of compound 14 with either acetylacetone 18a or ethyl
acetoacetate 18b gave the pyrazole derivatives 19a and 19b, respectively.
In a similar manner, the reaction of 14 with either malononitrile 6a or ethyl
cyanoacetate 6b gave the pyrazole derivatives 20a and 20b, respectively.
Moreover, the reaction of 14 with either a-cyanocinnamonitrile 21a or ethyl
a-cyanocinnamate 21b gave the 5-phenylpyrazole derivatives 22a and 22b,
e-mail: wagnatward@hotmail.com
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J. Chil. Chem. Soc., 57, Nº 2 (2012)
respectively (Scheme 3). The analytical and spectral data of compounds 19a,b-
22a,b were in agreement with their structures (see experimental section).
Sheme 3
Table I. Effect of compounds 5-22b on the growth of three human tumor
cell lines.
Compound
GI50 (m mol L-1)
NCI-H460
MCF-7
SF-268
5
7a
7b
9
12
14
15
17
10.2 ± 0.6
20.3 ± 0.4
60.6 ± 12.8
32.8 ± 8.2
35.4 ± 10.2
14.8 ± 3.6
60.7 ± 12.5
50.1 ± 0.7
22.0 ± 0.2
32.0 ± 4.5
22.0 ± 3.7
6.4 ± 2.6
12.3 ± 1.2
24.3 ± 0.8
31.3 ± 6.4
30.6 ± 8.6
22.1 ± 0.8
10.3 ± 0.9
33.2 ± 10.6
23.2 ± 4.8
30.6 ± 1.4
41.0 ± 2.4
20.0 ± 4.4
10.1 ± 2.8
48.6 ± 4.8
22.8 ± 2.8
0.09 ± 0.008
20.3 ±2.5
30 ± 0.8
44.2 ± 3.8
40.4 ± 4.6
6.7 ± 4.7
16.7 ± 1.6
66.0 ± 9. 1
10.4 ± 1.8
32.6 ± 2.9
22.5 ± 1.6
30.5 ± 8.0
4.2 ± 1.5
50.8 ± 0.8
56.2 ± 3.8
0.09 ± 0.007
Scheme 2
Material, methods
&
Reagents: Fetal bovine serum (FBS) and
L-glutamine, were obtained from Gibco Invitrogen Co. (Scotland, UK). RPMI-
1640 medium was from Cambrex (New Jersey, USA). Dimethyl sulfoxide
(DMSO), doxorubicin, penicillin, streptomycin and sulforhodamine B (SRB)
from Sigma Chemical Co. (Saint Louis, USA). Samples: Stock solutions of
o
compounds 5-22b were prepared in DMSO and kept at -20 C. Appropriate
19a
19b
20a
20b
22a
22b
Doxorubicin
dilutions of the compounds were freshly prepared just prior the assays. Final
concentrations of DMSO did not interfere with the cell growth.
Cell cultures: Three human tumor cell lines, MCF-7 (breast
adenocarcinoma), NCI-H460 (non-small cell lung cancer), and SF-268 (CNS
cancer) were used. MCF-7 was obtained from the European Collection of Cell
Cultures (ECACC, Salisbury, UK) and NCI-H460 and SF-268 were kindly
provided by the National Cancer Institute (NCI, Cairo, Egypt). They grow as
monolayer and routinely maintained in RPMI-1640 medium supplemented
with 5% heat inactivated FBS, 2 mM glutamine and antibiotics (penicillin
70.9 ± 0.9
30.4 ± 2.6
0.04 ± 0.008
Results are given in concentrations that were able to cause 50 % of cell
growth inhibition (GI50) after a continuous exposure of 48 h and show means ±
SEM of three-independent experiments performed in duplicate.
o
100 U/mL, streptomycin 100 mg/mL), at 37 C in a humidified atmosphere
containing 5% CO2. Exponentially growing cells were obtained by plating 1.5
X 105 cells/mL for MCF-7 and SF-268 and 0.75 X 104 cells/mL for NCI-H460,
followed by 24 h of incubation. The effect of the vehicle solvent (DMSO) on
the growth of these cell lines was evaluated in all the experiments by exposing
untreated control cells to the maximum concentration (0.5%) of DMSO used
in each assay.
Effect on the growth of human tumor cell lines
The effect of compounds 5-22b was evaluated on the in vitro growth
of three human tumor cell lines representing different tumor types, namely,
breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and
CNS cancer (SF-268), after a continuous exposure of 48 h. The results are
summarized in Table 1.
All the compounds were able to inhibit the growth of the human tumor cell
lines in a dose-dependent manner (data not shown). Compounds 5 and 20b
showed the best results, exhibiting an equivalent potency in all the three tumor
cell lines which is still much lower than the control doxorubicin, On the other
hand, compounds 7a, 14, 19a and 20a showed moderated growth inhibitory
effect. Comparing the activities of 20a and 20b it is observed that OH group
present in 20b presents a stronger growth inhibitory effect than compound 20a
1119

J. Chil. Chem. Soc., 57, Nº 2 (2012)
°
with the NH2 group. It is obvious that compounds 7b, 15, 17, 19b, 22a showed
Yellow crystals from 1,4-dioxan, yield (3.42 g, 80 %), m.p. 40 C. IR
the lowest inhibitory effect towards the three cell lines.
(KBr):
υ/cm-1 = 3438-3322 (NH2, NH), 3052 (CH aromatic), 1685 (CO),
1630 (C=C), 1628 (C=N). 1HNMR (DMS): δ = 4.68 (s, 2H, D2O exchangeable,
NH2), 6.72 (s, 1H, CH=N), 7.28-7.42 (m, 16H, 3C H5 , pyridazine CH), 8.29
(s, 1H, D2O exchangeable, NH). Calcd for C23H20N66OS (428.51): C, 64.47; H,
4.70; N, 19.61; S, 7.48 %. Found: C, 64.55; H, 4.66; N, 19.55; S, 7.71 %. MS
m/z: 428 (M+).
EXPERIMENTAL SECTION
All melting points were determined in open capillaries and are uncorrected.
IR spectra were measured using KBr discs on a Pye Unicam SP-1000
1
spectrophotometer. H-NMR spectra were measured on a Varian EM390-200
MHz instrument in CD3SOCD3 as solvent using TMS as internal standard, and
chemical shifts are expressed as δ in units of parts per million (ppm). Analytical
data were obtained from the Micro analytical data unit at Cairo University.
a-Cyano-b-phenylamino-b-hydrazinoylidino-N-benzalacrylohydrazi-
de (14)
To a stirred solution of compound 5 (1.91 g, 0.01 mol) in dimethylfor-
mamide (20 mL) containing potassium hydroxide (0.56 g, 0.01 mol) phenyli-
sothiocyanate (1.35 g, 0.01 mol) was added. The whole reaction mixture was
kept at room temperature overnight then hydrazine hydrate (0.50 g, 0.01 mol)
was added. The formed solid product was collected by filtration.
2- Cyano-2-phenylhydrazo-N-benzalacetylhydrazide (5):
To a cold solution (0-5 °C) of compound 3 (1.87 g, 0.01 mol) in ethanol (50
mL) containing sodium acetate (4.0 g), benzenediazonium chloride [prepared
by adding sodium nitrite solution (0.70 g in 10 mL water) to a cold solution
°
(0-5 C) of aniline (0.94 g, 0.01 mol) in concentrated hydrochloric acid (10
White crystals from ethanol, yield (2.81 g, 88 %), m.p. 110 °C. IR (KBr):
υ/cm-1 = 3459-3331 (NH2, 3NH), 3056 (CH aromatic), 1689 (CO), 1631 (C=C),
1623 (C=N). H1NMR (DMSO) δ = 4.77 (s, 2H, D2O exchangeable, NH ),
6.59 (s, 1H, CH=N), 7.22-7.38 (m, 10H, 2C6H5), 8.24, 8.44, 8.50 (3s, 3H, D22O
exchangeable, 3NH). Calcd for C17H16N6O (320.35): C, 63.74; H, 5.03; N,
26.23 %. Found: C, 64.01; H, 4.89; N, 26.51 %. MS m/z: 320 (M+).
mL) with continuous stirring] was added with continuous stirring. The reaction
mixture was then stirred at room temperature for additional 1 h and the formed
solid product was collected by filtration.
Orange crystals from ethanol, yield (2.03 g, 70 %), m.p. 70 °C . IR (KBr):
υ/cm-1 = 3522-3332 (2NH), 3057 (CH aromatic), 2222 (CN), 1690 (CO), 1645
1
(C=C), 1637 (C=N). H NMR (DMSO) δ = 6.56 (s, 1H, CH=N), 7.30-7.39
(m, 10H, 2C6H5), 8.30, 8.37 (2s, 2H, D O exchangeable, 2NH). Calcd for
C16H13N5O (291.31): C, 65.97; H, 4.50; N,224.04 %. Found: C, 66.01; H, 4.48;
N, 24.33 %. MS m/z: 291 (M+).
3-Amino-5-phenylamino-3-N-benzalcarbohydrazido-pyrazole (15)
A suspension of compound 14 (3.20 g, 0.01 mol) in sodium ethoxide
solution [prepared by dissolving sodium metal (0.64 g, 0.02 mol) in absolute
ethanol (40 mL) was heated in a boiling water bath for 3 h. The reaction
mixture was left to cool and the formed solid product upon pouring onto ice/
water containing few hydrochloric acid (till pH 6) was collected by filtration.
5-Amino-4-cyano-3-imino-1-phenylpyridazin-6-N-benzalcarbohydra-
zide (7a) and 5-Amino-4-cyano-3-oxo-1-phenylpyridazin-6-N-benzalcar-
bohydrazide (7b)
General procedure: To a solution of compound 5 (1.91 g, 0.01 mol) in
1,4-dioxan (40 mL) containing triethylamine (0.50 mL), either malononitrile
(0.66 g, 0.01 mol) or ethyl cyanoacetate (1.25 g, 1.18 mL, 0.01 mol) was
added. The reaction mixture was heated under reflux for 3 h then poured onto
ice/water mixture containing few drops of hydrochloric acid and the formed
solid product was collected by filtration.
°
Pale yellow crystals from ethanol, yield (2.21 g, 69 %), m.p. 60 C. IR
(KBr): υ/cm-1 = 3446-3323 (NH2, 3NH), 3051 (CH aromatic), 1686 (CO),
1
1630 (C=C), 1626 (C=N). H NMR (DMSO) δ = 4.82 (s, 2H, NH2), 6.61
(s, 1H, CH=N), 7.29-7.39 (m, 10H, 2C6H5), 8.20, 8.76, 8.82 (3s, 3H, D2O
exchangeable, 3NH). Calcd for C17H16N6O (320.35): C, 63.74; H, 5.03; N,
26.23 %. Found: C, 63.71; H, 5.24; N, 26.49 %. MS m/z: 320 (M+).
3-Hydrazodicyanoylideno-5-phenylamino-3-N-benzalcarbohydrazi-
dopyrazole (17)
Compound 7a: Yellow crystals from 1,4-dioxan, yield (2.74 g, 77 %), m.p.
°
90 C. IR (KBr): υ/cm-1 = 3480-3330 (NH2, 2NH), 3060 (CH aromatic), 2223
A solution of the 3-diazo-5-phenylamino-3-N-benzalcarbohydrazidopyr-
azole (0.01 mol) [prepared by adding sodium nitrite solution (0.70 g, 0.01 mol)
to a cold solution (0 °C) of compound 15 (3.20 g, 0.01 mol) in acetic acid (20
mL) and concentrated hydrochloric acid (10 mL) with continuous stirring] was
added to a cold solution of malononitrile (0.66 g, 0.01 mol) in ethanol (40 mL)
containing sodium acetate (4.0 g) with continuous stirring for 2 h. The formed
solid product was collected by filtration.
(CN), 1688 (CO), 1638 (C=C), 1628 (C=N). 1HNMR (DMSO) δ = 4.87 (s, 2H,
D O exchangeable, NH2), 6.69 (s, 1H, CH=N), 7.28-7.58 (m, 10H, 2C H5),
8.223, 8.30 (2s, 2H, D2O exchangeable, 2NH). Calcd for C H15N O (3576.37):
C, 63.86; H, 4.23; N, 27.44 %. Found: C, 64.08; H, 4.47; N,129 7.727%. MS m/z:
357 (M+).
Compound 7b: Pale orange crystals from 1,4-dioxan, yield (2.74 g, 77 %),
°
m.p.160 C. IR (KBr): υ/cm-1 = 3477-3328 (NH2, NH), 3055 (CH aromatic),
Orange crystals from ethanol, yield (3.02 g, 76 %), m.p. 160 °C. IR (KBr):
υ/cm-1 = 3560-3328 (4NH), 3046 (CH aromatic), 2227, 2220 (2CN), 1691
(CO), 1633 (C=C), 1626 (C=N). 1H NMR (DMSO) δ = 6.70 (s, 1H, CH=N),
7.31-7.40 (m, 10H, 2C6H ), 8.14, 8.23, 8.40, 8.66 (4s, 4H, D2O exchangeable,
4NH). Calcd for C20H15N95O(397.39): C, 60.45; H, 3.80; N, 31.72 %. Found: C,
60.53; H, 4.48; N, 32.06 %. MS m/z: 397 (M+).
1
2220 (CN), 1686 (2 CO), 1636 (C=C), 1625 (C=N). H NMR (DMSO) δ =
4.85 (s, 2H, D2O exchangeable, NH ), 6.66 (s, 1H, CH=N), 7.29-7.49 (m, 10H,
2C6H5), 8.26 (s, 1H, D2O exchange2able, NH). Calcd for C H14N6O2 (358.35):
C, 63.68; H, 3.94; N, 23.45 %. Found: C, 63.84; H, 4.02; N1,923.66 %. MS m/z:
358 (M+).
4-Amino-2-phenyl-5-N-benzalcarbohydrazido-1,2,3-triazole (9)
General procedure: To a solution of compound 5 (1.91 g, 0.01 mol) in
1,4-dioxan (40 mL), hydrazine hydrate (0.50 g, 0.01 mol) was added. The
reaction mixture was heated under reflux for 4 h then poured onto ice/water
containing few drops of hydrochloric acid. The formed solid product was
collected by filtration.
a-Cyano-b-phenylamino-b-(3,5-dimethylpyrazol-1-yl)-N-
benzalacrylo-hydrazide (19a) and a-Cyno-b-phenylamino-b-(3-hydroxy-
5-methylpyrazol-1-yl)-N-benzalacrylohydrazide (19b)
General procedure: To a solution of compound 14 (3.20 g, 0.01 mol) in
1,4-dioxan (30 mL) either acetylacetone (1.0 g, 0.01 mol) or ethyl acetoacetate
(1.30 g, 0.01 mol) was added. The reaction mixture was heated under reflux
for 2 h then the solvent was evaporated under reduced pressure. The remaining
residue was triturated with ethanol and the formed solid product was collected
by filtration.
Yellow crystals from 1,4-dioxan, yield (2.45 g, 80 %), m.p. 60 °C. IR
(KBr): υ/cm-1 = 3467-3338 (NH2, NH), 3059 (CH aromatic), 1689 (CO), 1632
1
(C=C), 1620 (C=N). H NMR (DMSO) δ = 4.89 (s, 2H, D2O exchangeable,
NH2), 6.68 (s, 1H, CH=N), 7.20-7.36 (m, 10H, 2C6H5), 8.22 (s, 1H, D O
exchangeable, NH). Calcd for C16H14N6O(306.32): C, 62.74; H, 4.61; N, 27.244
%. Found: C, 62.44; H, 4.52; N, 27.71 %. MS m/z: 306 (M+).
Compound 19a: Orange crystals from 1,4-dioxan, yield (2.76 g, 72 %),
°
m.p. 70 C. IR (KBr): υ/cm-1 = 3487-3335 (2NH), 3055 (CH aromatic), 2225
(CN), 1685 (CO), 1630 (C=C), 1623 (C=N). 1HNMR (DMSO) δ = 2.85, 3.03
(2s, 6H, 2CH ), 5.99 (s, 1H, pyrazole H-4), 6.73 (s, 1H, CH=N), 7.29-7.37
(m, 10H, 2C63H5), 8.19, 8.25 (2s, 2H, D O exchangeable, 2NH). Calcd for
C22H20N6O (384.43): C, 68.73; H, 5.24; N,221.86 %. Found: C, 68.52; H, 5.46;
N, 22.04%. MS m/z: 384 (M+).
5-Amino-2,4-diphenyl-3-thioxo-6-N-benzalcarbohydrazido-1,3,4-
triazine (12)
To a solution of compound 5 (1.91 g, 0.01 mol) in 1,4-dioxan (40 mL),
phenylisothiocyanate (1.35 g, 0.01 mol) was added. The reaction mixture was
heated under reflux for 4 h then poured onto ice/water containing few drops of
hydrochloric acid. The formed solid product was collected by filtration.
Compound 19b: Pale yellow crystals from 1,4-dioxan, yield (2.56 g, 66 %),
m.p.100 °C. IR (KBr): υ/cm-1 = 3592-3330 (OH, 2NH), 3058 (CH aromatic),
1120

J. Chil. Chem. Soc., 57, Nº 2 (2012)
2223 (CN), 1688 (CO), 1633 (C=C), 1620 (C=N). 1H NMR (DMSO) δ = 2.89
(s, 3H, CH ), 5.97 (s, 1H, pyrazole H-4), 6.71 (s, 1H, CH=N), 7.26-7.39 (m,
10H, 2C6H53), 8.15, 8.22 (2s, 2H, D2O exchangeable, 2NH), 10.22 (s, 1H, D O
exchangeable, OH). Calcd for C21H18N6O2 (386.41): C, 65.27; H, 4.70; N, 21.275
%. Found: C, 65.31; H, 5.02; N, 22.01%. MS m/z: 386 (M+).
3. M.A. Khalil, O.A. El-Sayed, H.A. El-Shamy, Arch. Pharm. (Weinheim)
326, 489 (1993).
4. N. Ulusoy, G. .Capan, G. O. Tuk, M. Kiraz, Boll. Chim. Farmac. 139, 167
(2000).
5. N. Ulusoy, N. Ergenc¸, G. .O¨ tu¨k, M. Kiraz, Boll. Chim. Farmac. 140,
417 (2001).
a-Cyano-b-phenylamino-b-(3,5-diaminopyrazol-1-yl)-N-
benzalacrylo-hydrazide (20a) and a-Cyano-b-phenylamino-b-(3-hydroxy-
5-aminopyrazol-1-yl)-N-benzalacrylohydrazide (20b)
6. S. Rollas, N. Gulerman, H. Erdeniz, Farmaco 57, 171 (2002).
7. S.G. Kucukgu zel, E. E. Oruc¸, S. Rollas, F. Sahin, A. .O¨ zbek, Eur. J.
Med. Chem. 37, 197 (2002).
General procedure: To a solution of compound 14 (3.20 g, 0.01 mol)
in 1,4-dioxan (30 mL) either malononitrile (0.66 g, 0.01 mol) or ethyl
cyanoacetate (1.25 g, 0.01 mol) was added. The reaction mixture was heated
under reflux for 4 h then the solvent was evaporated under reduced pressure.
The remaining residue was triturated with ethanol and the formed solid product
was collected by filtration.
8. N. Ulusoy, N. Ergenc¸, A. C. Ekinci, H. .Ozer, Monatsh. Chem 127 1197
(1996).
9. B. .Cakir, E. Yildirim, T. Ercanli, K. Erol, M. F. Sahin, Farmaco 54, 842
(1999).
10. J. R. Dimmock, S. C. Vashishtha, J. P. Stables, Eur. J. Med. Chem. 35, 241
(2000).
11. S. N. Pandeya, H. Manjula, J.P. Stables, Pharmazie 56, 121 (2001).
12. E. M. Sah., D.J. Drain, M. Seiler, J. Pharm. Pharmacol. 4, 844 (1952)
13. J. M. Patel, M.P. Dave, N.A. Langalia, K.A. Thaker, J. Indian Chem. Soc.
61, 718 (1984).
14. L. Bukowski, M. Janowiec, Pharmazie 51, 27 (1996).
15. S. G. Kuc¸I. K. zel, S. Rollas, I. Ku¨c¸u¨kgu¨ zel, M. Kiraz, Eur. J. Med.
Chem. 34 1093 (1999).
Compound 20a: Orange crystals from 1,4-dioxan, yield (2.76 g, 66 %),
m.p. 60 °C. IR (KBr): υ/cm-1 = 3487-3335 (2NH), 3058 (CH aromatic), 2228 (
CN), 1689 (CO), 1633 (C=C), 1622 (C=N). 1H NMR (DMSO) δ = 4.66, 5.23
(2s, 4H, D O exchangeable, 2NH2), 5.63 (s, 1H, pyrazole H-4), 6.80 (s, 1H,
CH=N), 7.226-7.39 (m, 10H, 2C6H5), 8.20, 8.29 (2s, 2H, D O exchangeable,
2NH). Calcd for C20H18N8O (386.41): C, 62.17; H, 4.70; N, 229.00 %. Found:
C, 60.93; H, 5.83; N, 28.37%. MS m/z: 386 (M+).
16. L. Bukowski, M. Janowiec, Z. Zwolska-Kwiek, Z. Andrzejczyk,
Pharmazie 54 651 (1999).
Compound 20b: Buff crystals from ethanol, yield (2.56 g, 66 %), m.p. 70
°C. IR (KBr): υ/cm-1 = 3569-3324 (OH, 2NH & NH2), 3056 (CH aromatic),
2222 (CN), 1690 (CO), 1630 (C=C), 1622 (C=N). 1HNMR (DMSO) δ = 4.66
(s, 2H, D2O exchangeable, NH ), 5.89 (s, 1H, pyrazole H-4), 6.69 (s, 1H,
CH=N), 7.24-7.40 (m, 10H, 2C26H5), 8.18, 8.26 (2s, 2H, D2O exchangeable,
2NH), 10.09 (s, 1H, D O exchangeable, OH). Calcd for C20H17N7O2 (387.39):
C, 62.01; H, 4.42; N, 225.31 %. Found: C, 61.89; H, 4.63; N, 25.44%. MS m/z:
387 (M+).
17. S. G. Komurcu , S. Rollas, M. .Ulgen, J.W. Gorrod, Boll. Chim. Farmac.
134, 375 (1995).
18. B. Colvin, J. Pharm. Sci. 58 (12), 1433 (1969).
19. B. Durgun, G. .Capan, N. Ergenc, S. Rollas, Pharmazie 48, 942 (1993).
a-Cyano-b-phenylamino-b-(3-amino-4-cyano-5-phenylpyrazol-1-
yl)-N-benzalacrylohydrazide (22a) and a-Cyno-b-phenylamino-b-(3-
hydroxy-3-cyano-5-phenylpyrazol-1-yl)-N-benzalacrylohydrazide (22b)
General procedure: To a solution of compound 14 (3.20 g, 0.01 mol) in
1,4-dioxan (30 mL) either a-cyanocinnamonitrile (1.54 g, 0.01 mol) or ethyl
a-cyanocinnamate (2.01 g, 0.01 mol) was added. The reaction mixture was
heated under reflux for 4 h then evaporated under vacuum. The remaining
product was triturated with ethanol and the formed solid product was collected
by filtration.
Compound 22a: Pale yellow crystals from 1,4-dioxan, yield (4.17 g, 88
%), m.p. 60 °C IR (KBr): υ/cm-1 = 3463-3324 (2NH& NH2), 3056 (CH
aromatic), 2224 (CN), 1689 (CO), 1631 (C=C), 1620 (C=N). 1H NMR
(DMSO) δ = 4.69 (s, 2H, D O exchangeable, NH2), 6.77 (s, 1H, CH=N), 7.30-
7.42 (m, 15H, 3C6H5), 8.21, 28.32 (2s, 2H, D2O exchangeable, 2NH). Calcd for
C27H20N8O(472.18): C, 68.63; H, 4.27; N, 23.72 %. Found: C, 68.41; H, 4.08;
N, 23.68 %. MS m/z: 472 (M+).
Compound 22b : Pale brown crystals from ethanol, yield (3.83 g, 60 %),
m.p.70 °C. IR (KBr): υ/cm-1 = 3584-3348 (OH, 2NH), 3051 (CH aromatic),
2220 (CN), 1690 (CO), 1630 (C=C), 1622 (C=N). 1HNMR (DMSO) δ = 6.59 (s,
1H, CH=N), 7.27-7.37 (m, 15H, 3C6H ), 8.22, 8.29 (2s, 2H, D2O exchangeable,
2NH), 10.32 (s, 1H, D O exchangeab5le, OH). Calcd for C27H19N7O2 (473.49):
C, 68.49; H, 4.04; N, 220.71 %. Found: C, 68.72; H, 4.28; N, 20.94%. MS m/z:
473 (M+).
CONCLUSIONS
The work described showed the uses of the phenylhydrazone derivative 5
in a series of heterocyclic transformations to form pyridazine, 1,2,4-triazine
and pyrazole derivatives. The antitumor evaluation of the synthesized products
showed that the pyrazole derivative 20b has the maximum inhibitory effect
towards the cancer cell lines.
REFERENCES
1. E. Szarvasi, L. Fontaine, A. Betbeder-Matibet, J. Med. Chem. 16, 281
(1973).
2. H.M. Eisa, A.S. Tantawy, M.M. El-Kerdawy, Pharmazie 46 182 (1991).
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