RCHH HARM
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Arch. Pharm. Chem. Life Sci. 2015, 348, 338–346
Pyridazin-3(2H)-one Derivatives as Anticancer Agents
Archiv der Pharmazie
human cancer cell lines by MTT assay, the results revealed that,
the compounds 4g and 4i were the most promising cytotoxic
agents. Therefore, these compounds were further evaluated
for inhibition of selected cytokines and found that 4g was
potent antiangiogenic agent against TNFa, VEGF, FGFb, and
TGFb, whereas 4i showed potent antiangiogenic activity
against TNFa, VEGF, FGFb, and leptin. Furthermore, com-
pound 4f showed better OH radical scavenging activity than
the standard AA. Finally, it is conceivable that further
derivatization of such compounds will be of interest with
hope to get more selective agents.
4H), 1.65–1.61 (m, 6H); 13C NMR (CDCl3, 300 MHz): d 158.48 (C-
Ar), 154.55 (CO), 147.64 (C-Ar), 136.53 (C-Ar), 132.39 (C-Ar),
125.46 (C-Ar), 123.98 (C-Ar), 121.42 (C-Ar), 128.37 (C-Ar),
106.31 (C-Ar), 45.70 (2, CH2), 25.74 (3, CH2); LC–MS: m/e 342
(Mþ1). Anal. calcd. for C15H14Cl2FN3O: C, 52.65; H, 4.12; N,
12.28. Found: C, 52.87; H, 4.31; N, 12.73%.
4-Chloro-[2-(3-chloro-4-fluorophenyl)]-5-(4-methyl-1,4-
diazepan-1-yl)-pyridazin-3(2H)-one (4b)
Light brown solid; m.p.: 100–101°C; IR (KBr) cmꢄ1: 3335, 3075,
2942, 2765, 1645, 1493; 1H NMR (DMSO-d6, 400 MHz): d 8.06 (s,
1H), 7.81 (d, J ¼ 4.0 Hz, 1H), 7.54 (d, J ¼ 8.8 Hz, 2H), 3.76–3.73
(m, 4H), 2.70–2.66 (m, 4H), 2.28 (s, 3H), 1.91–1.90 (m, 2H);
13C NMR (CDCl3, 400 MHz): d 158.20 (C-Ar), 155.88 (CO), 146.71
(C-Ar), 137.88 (C-Ar), 130.84 (C-Ar), 127.52 (C-Ar), 124.90
(C-Ar), 120.80 (C-Ar), 116.22 (C-Ar), 110.51 (C-Ar), 58.52
(CH2), 57.37 (CH2), 51.33 (CH2), 51.16 (CH2), 46.43 (CH3),
28.34 (CH2); LC–MS: m/e 371 (Mþ1). Anal. calcd. for
Experimental
Chemistry
All the chemicals were purchased from Aldrich Chemical Co.
(USA). All the solvents were purchased from S. D. Fine
Chemicals. IR spectra (KBr disks) were recorded using a
Perkin-Elmer 237 spectrophotometer. 1H NMR spectra were
recorded on Bruker Advance (300 and 400 MHz) spectrometer
using DMSO-d6 and CDCl3 as solvent, with TMS as an internal
reference. Mass spectra were recorded on a Shimadzu LC–MS-
QP 1000 EX. Thin layer chromatography (TLC) was performed
on silica gel-coated plates for monitoring the reactions. The
spots could be visualized easily under UV light.
C
16H17Cl2FN4O: C, 51.77; H, 4.62; N, 15.09. Found: C, 51.43;
H, 4.83; N, 15.63%.
4-Chloro-[2-(3-chloro-4-fluorophenyl)]-5-(4-ethylpiperazin-
1-yl)-pyridazin-3(2H)-one (4c)
Brown solid; m.p.: 110–111°C; IR (KBr) cmꢄ1: 3055, 2941, 2750,
2710, 2261, 1643; 1H NMR (DMSO-d6, 400 MHz): d 8.10 (s, 1H),
7.81 (d, J ¼ 5.6 Hz, 1H), 7.55 (d, J ¼ 6.0 Hz, 2H), 3.50–3.48 (m,
4H), 2.50–2.46 (m, 4H), 2.38 (q, J ¼ 7.2 Hz, 2H), 1.02 (t, 3H); 13
C
Synthesis of [2-(3-chloro-4-fluorophenyl)]-4,5-
dichloropyridazin-3-one (3)
NMR (CDCl3, 400 MHz): d 158.52 (C-Ar), 156.03 (CO), 147.11 (C-
Ar), 137.82 (C-Ar), 131.88 (C-Ar), 127.61 (C-Ar), 125.10 (C-Ar),
121.94 (C-Ar), 120.85 (C-Ar), 116.26 (C-Ar), 52.61 (2, CH2), 52.24
(2, CH2), 48.85 (CH2), 11.88 (CH3); LC–MS: m/e 371 (Mþ1). Anal.
calcd. for C16H17Cl2FN4O: C, 51.77; H, 4.62; N, 15.09. Found: C,
51.46; H, 4.33; N, 15.57%.
To a solution of mucochloric acid 1 (14.99 g, 88.75 mmol) in
EtOH (150 mL) was added 3-chloro-4-fluorophenyl hydrazine 2
(14.25 g, 88.75 mmol), and MSA (20 mL) at 25°C. The solution
was refluxed for 2 h. After completion of reaction as indicated
by TLC, the suspension was filtered, washed with water, and
dried under high vacuum to afford crude solid compound 3.
Yield: 90%; 1H NMR (DMSO-d6, 400 MHz): d 8.36 (s, 1H), 7.86 (d,
J ¼ 6.4 Hz, 1H), 7.61 (d, J ¼ 6.8 Hz, 2H); LC–MS: m/e 293 (Mþ1).
5-Chloro-1-(3-chloro-4-fluorophenyl)-1,6-dihydro-4-(4-
methylpiperazin-1-yl)-pyridazine (4d)
White solid; m.p.: 130–131°C; IR (KBr) cmꢄ1: 3150, 2941, 2835,
2810, 2371, 1661; 1H NMR (DMSO-d6, 400 MHz): d 8.11 (s, 1H),
7.81 (d, J ¼ 5.6 Hz, 1H), 7.56 (d, J ¼ 6.0 Hz, 2H), 3.50–3.48 (m,
4H), 2.46–2.41 (m, 4H), 2.22 (s, 3H); 13C NMR (CDCl3, 300 MHz): d
158.78 (C-Ar), 155.45 (CO), 146.99 (C-Ar), 137.61 (C-Ar), 131.89
(C-Ar), 127.46 (C-Ar), 124.98 (C-Ar), 124.88 (C-Ar), 120.90 (C-Ar),
116.31 (C-Ar), 54.70 (2, CH2), 48.74 (2, CH2), 45.92 (CH3); LC–MS:
m/e 357 (Mþ1). Anal. calcd. for C15H15Cl2FN4O: C, 50.44; H,
4.23; N, 15.68. Found: C, 50.91; H, 4.02; N, 15.98%.
Synthesis of 4-chloro-2-(3-chloro-4-fluorophenyl)-5-
(aliphatic/cyclic saturated amino)pyridazin-3(2H)-one (4a–i)
To the solution of crude [2-(3-chloro-4-fluorophenyl)]-4,5-
dichloropyridazin-3-one 3 (2.30 g, 7.84 mmol) in acetonitrile
(20 mL) was added amine (10 mmol) and anhydrous potassium
carbonate (1.08 g, 7.84 mmol) at 25°C. The reaction mixture
was then refluxed for 1.5–2.5 h. After completion of reaction
(TLC), reaction mixture was poured over crushed ice, extracted
with ethyl acetate (30 mL ꢃ 3), washed with water (30 mL ꢃ 2),
brine (30 mL), dried (anhydrous Na2SO4), and concentrated
under reduced pressure. The crude product was purified by
recrystallization with diethyl ether.
4-Chloro-[2-(3-chloro-4-fluorophenyl)]-5-
(cyclopentylamino)-pyridazin-3(2H)-one (4e)
Light brown solid; m.p.: 106–107°C; IR (KBr) cmꢄ1: 2935, 2770,
2830, 2345, 1549, 1525; 1H NMR (DMSO-d6, 400 MHz): d 8.13 (s,
1H), 7.81 (d, J ¼ 6.0 Hz, 1H), 7.53 (d, J ¼ 8.40 Hz, 2H), 6.52 (d,
4-Chloro-[2-(3-chloro-4-fluorophenyl)]-5-(piperidin-1-yl)-
pyridazin-3(2H)-one (4a)
1H), 4.19–4.17 (m, 1H), 1.98–1.96 (m, 2H), 1.71–1.55 (m, 6H) 13
C
NMR (CDCl3, 400 MHz): d 158.46 (C-Ar), 156.00 (CO), 155.87 (C-
Ar), 143.43 (C-Ar), 137.83 (C-Ar), 127.55 (C-Ar), 125.14 (C-Ar),
120.78 (C-Ar), 116.22 (C-Ar), 107.25 (C-Ar), 54.84 (CH), 34.22 (2,
CH2), 23.81 (2, CH2); LC–MS: m/e 342 (Mþ1). Anal. calcd. for
White solid; m.p.: 140–141°C; IR (KBr) cmꢄ1: 2950, 2740, 2830,
2350, 1649, 1475; 1H NMR (DMSO-d6, 400 MHz): d 8.08 (s, 1H),
7.81 (d, J ¼ 5.6 Hz, 1H), 7.55 (d, J ¼ 8.0 Hz, 2H), 3.46–3.42 (m,
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