Synthesis and antitumor activity of 2-aryl-7-fluoro-6-(4-methyl-1-piperazinyl)-4(3H)-quinazolinones

Article abstract of DOI:10.3987/COM-05-10387

A series of new 2-aryl-7-fluoro-6-(4-methyl-1-piperazinyl)-4(3H)-quinazolinones were prepared by the oxidative cyclization of the corresponding 2-arylidineamino-4-fluoro-5-(4-methyl-1-piperazinyl)benzamides. The new quinazolinones were evaluated for their

Full text of DOI:10.3987/COM-05-10387

HETEROCYCLES, Vol. 65, No. 9, 2005
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HETEROCYCLES, Vol. 65, No. 9, 2005, pp. 2061 - 2070
Received, 1st March, 2005, Accepted, 4th August, 2005, Published online, 5th August, 2005
SYNTHESIS AND ANTITUMOR ACTIVITY OF 2-ARYL-7-FLUORO-
6-(4-METHYL-1-PIPERAZINYL)-4(3H)-QUINAZOLINONES
Raid J. Abdel-Jalil,1* Hani M. Aldoqum,1 Mikdad T. Ayoub,1 and Wolfgang
Voelter2*
1Chemistry Department, Faculty of Science and Arts, Hashemite University,
Zarka-Jordan. E-mail: jalil@hu.edu.jo
2 Abteilung für Physikalische Biochemie des Physiologisch-chemischen Instituts
der Universität Tübingen, Hoppe-Seyler Strasse 4, D-72076 Tübingen, Germany.
E-mail: wolfgang.voelter@uni-tuebingen.de
Abstract – A series of new 2-aryl-7-fluoro-6-(4-methyl-1-piperazinyl)-4(3H)-
quinazolinones were prepared by the oxidative cyclization of the corresponding
2-arylidineamino-4-fluoro-5-(4-methyl-1-piperazinyl)benzamides.
The
new
quinazolinones were evaluated for their antitumor activity.
INTRODUCTION
The synthesis of quinazolinone derivatives is an area of research that has attracted a great deal of attention
in recent years as they possess a wide range of pharmacological activities,1 such as fungicidal2
anti-inflammatory,3 antimalarial,4 antitumor,5 antihypertension,6 cholecystokinin receptor antagonist7 or
anticonvulsant activities.8 Recently, some of the quinazolinones are used as chemotherapeutic agents for
various diseases, e.g., mecloqualone9 or metolazone10 are applied as sedative or diuretic drugs, respectively.
To the best of our knowledge, quinazolinones incorporating both fluorine and N-piperazine substituents are
undescribed in the literature. The presence of both substituents has enhanced considerably the antimicrobial
potency of the quinolone drugs,11 such as Ciprofloxacin® (1). Based on these findings, quinazolinone
derivatives incorporating fluorine and piperazine as appendages might have potential biological activities.
In this paper, we describe a multi-step synthesis and antitumor activity of new quinazolinones bearing
fluorine and piperazine moieties (2).

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RESULTS AND DISCUSSION
The starting material 2-nitro-4-fluoro-5-(4-methyl-1-piperazinyl)aniline (3) was prepared using a standard
O
N
O
Me
N
O
F
OH
N
F
NH
N
HN
N
Ar
1
2
methodology12 from commercially available 3-chloro-4-fluoroaniline by a sequence of steps involving
acylation, nitration, deacylation and piperazinylation. The starting nitroaniline was diazotized using
sulfuric acid and potassium nitrite and then coupled with copper(I) cyanide (generated in situ by reaction of
copper(I) chloride with potassium cyanide) yielding the substituted benzonitrile (4). Acidic hydrolysis at
room temperature gave 5 in moderate yield. Subsequent reduction of 5 using tin(II) chloride in hydrochloric
acid afforded the key intermediate 2-amino-4-fluoro-5-(4-methyl-1-piperazinyl)benzamide (6) as shown in
Scheme 1.
Me
Me
N
N
N
F
NH2
NO2
N
F
CN
H2SO4, rt, 24 h
(i) KNO2/H2SO4
(ii) CuCN
NO2
3
4
Me
Me
N
O
N
O
N
N
F
SnCl2/HCl, rt
NH2
NO2
NH2
NH2
F
6
5
Scheme 1
The latter was then treated with the appropriate aldehyde to offer the Schiff’s bases (7a-h) in high yields.
Recently,13 we have reported a new method for the synthesis of quinazolinones using CuCl2 as a cyclizing
agent. This cyclization reaction was conducted under various equivalents of CuCl2, it was fastest (2 h),
when the equivalents of CuCl2 were threefold. With this standard reaction condition in hand, we turned our
attention towards the simplification of the work up. In our first attempt to purify 2a, the reaction mixture
was evaporated under reduced pressure and the residue subjected to column chromatography using 30%
methanol/dichloromethane. Thereafter, 2a was still contaminated with traces of copper salts, and therefore

HETEROCYCLES, Vol. 65, No. 9, 2005
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the column purification was repeated twice. To simplify the purification, hydrogen sulfide gas was bubbled
through the hot reaction mixture for 5 min and the black copper sulfide was filtered off. Upon cooling and
standing, the filtrate gave the quinazolinones in high purity which were further recrystallized from
methanol yielding the desired products in 83-93 % yields.
Me
Me
N
O
N
O
N
F
N
F
ArCHO/EtOH. rt
NH2
NH2
reflux, 3 h
N
NH2
Ar
7a-h
CuCl2/MeOH
6
reflux, 3 h
Me
N
O
N
N
F
NH
Ar
2a-h
e
No.
g
h
a
d
f
b
c
p-Me-C6H4
2-thienyl 2-furyl
p-MeO-C6H4
p-F-C6H4 p-Cl-C6H4
p-Br-C6H4
Ar C6H5
Scheme 2
In the 1H NMR spectra of 2a-h, the aromatic proton signals (H-5 and H-8) appear as two doublets around δ
7.70-7.90 ppm and δ 7.58-7.70 ppm, respectively. The H-5 protons are more deshielded and show a
smaller coupling with the adjacent fluorine atom (JH-F = 8.00-9.60 Hz) than those of H-8 (JH-F
=
11.40-13.80 Hz). The N-CH3 methyl protons appear as singlets around δ 2.90 ppm. The methylene proton
signals of the piperazine moiety appear as two broad singlets at δ 3.40-3.70 ppm. The N-H protons give
rise to broad singlets around δ 10.50-11.50 ppm. Moreover, the disappearance of the methine signals
(around δ 8.31-8.5 ppm) and the appearance of the N-H signals at low field (around δ 10.50-11.50 ppm)
1
in the H NMR spectra of 2 and 7, respectively, illustrate clearly the successful formation of the
quinazolinone derivatives.
ANTITUMOR ACTIVITY
Compounds (2a-h), selected by the National Cancer Institute (NCI, USA), were tested using a one dose
primary anticancer in vitro assay14 against tumor in a three-cell line panel consisting of MCF7 (breast),
NCI-H460 ( lung) and SF-268 (CNS), identifying 2b, d, g as active compounds (Table 1). Based on the
requirement for cell line screening set by NCI, the percent growth of tumor cells PG% (calculated on a

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HETEROCYCLES, Vol. 65, No. 9, 2005
plate-by-plate basis for test wells relative to control wells and expressed as the ratio of fluorescence of test
well (T) to average fluorescence of control wells (C) x 100 or T/C x 100) is 30% or less in at least one of
the three cell lines. From the results obtained, compounds (2b, g) are active against NCI-H460 (lung) while
compound (2d) is active against all three cell lines.
Table 1. Percent growth of tumor cells in a three-cell line panel.
Growth (%)
Compound
(Lung)
(Breast)
MCF7
56
(CNS)
SF-268
52
H460
2b
2d
2g
18
9
25
6
1
52
58
CONCLUSION
We have successfully prepared a new series of substituted quinazolinones incorporating fluorine and
piperazine substituents. The primary biological evaluation shown clearly a reasonable tumor activities.
Further studies on the utilization of the new intermediates and the detailed antitumor activities are in
progress and will be published in a due course.
EXPERIMENTAL
3-Chloro-4-fluoroaniline was purchased from Acros, N-methylpiperazine was acquired from Aldrich and
all aldehydes used were obtained from Acros. Melting points were determined on SMP2 Stuart apparatus
and are uncorrected. Elemental analyses were performed using a Perkin-Elmer elemental analyser, model
240. The El MS spectra were recorded on a Finnigan MAT 312 mass spectrometer.
1H NMR spectra were measured with a Bruker WM 400-spectrometer (400 MHz) using TMS as internal
standard. The chemical shifts are reported in parts per million (ppm).
BIOLOGICAL EVALUATION
Antitumor activity of all test compounds was tested primarily on a three-cell line panel, NCI-H460 (lung),
MCF7 (breast) and SF-268 (CNS). In this prescreening procedure, cells were plated in a microtiter plate at
a density of 1000 cells/well (NCI-H460), 5000 cells/well (MCF7) and 7500 cells/well (SF-268). Cells
were suspended in 50µl RPMI-1640 culture media supplemented with 5% fetal bovine serum and 2mM

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L-glutamine . Each plate contained all three cell lines in separate wells, total kill wells and untreated
control wells. After 24 hours of incubation at 37oC, 5% CO2, 95% air and 100% humidity, test compounds
were separately added at a final concentration of 10-4M. Cells were then incubated for an additional 48
hours at the indicated conditions. Alamar Blue was added at 10 µl/well, incubated for 4 hours and
fluorescence was measured at an excitation wavelength of 530nm and an emission wavelength of 590nm.
Percent growth was calculated on a plate-by-plate basis for test wells relative to control wells and expressed
as the ratio of fluorescence of test well (T) to average fluorescence of control wells (C) x 100 or T/C x 100.
4-Fluoro-5-(4-methyl-1-piperazinyl)-2-nitrobenzonitrile (4)
Sulfuric acid (15 mL) was treated over 1 h at 5-10 °C with sodium nitrite (1.7 g, 24.6 mmol) and the mixture
was slowly heated to 70 °C. The nitrosylsulfuric acid thus obtained was cooled to 10 °C and was treated
under stirring for 30 min with a solution of 4-fluoro-5-(4-methyl-1-piperazinyl)- 2-nitroaniline (3, 5.0g,
19.7 mmol) in acetic acid (19.5 mL) at 15-20 °C. The mixture was stirred at the same temperature for 3 h
and then added dropwise (30 min) with stirring to a solution of CuCN [prepared by treatment of a
suspension of CuCl (3.3 g, 33.3 mmol) in water (17 mL) with a solution of KCN (6.8 g, 69.0 mmol) in water
(24 mL)]. The solution was heated to 60 °C followed by the addition of a solution of Na2CO3 (40.5 g, 0.38
mol) in water (95 mL) at the same temperature, whereby CO2 gas developed. The reaction mixture was
heated to 85-90 °C for 30 min and cooled to rt. The precipitate obtained was filtered, washed with water,
dried, dissolved in benzene (100 mL) at 70 °C and the undissolved material filtered off. The filtrate was
dried and evaporated under vacuum to give a brown solid which was further crystallized from benzene /
petroleum ether (40-60 °C) to give 4 (2.8 g, 54 %) as brown crystals, mp 153-155 °C. 1H NMR (400 MHz,
CDCl3): δ 7.93 (d, J = 13.1 Hz, 1H, H-3), 7.19 (d, J = 8.2 Hz, 1H, H-6), 3.37, 2.54 (each t, each J = 4.9, Hz,
each 4H, piperazine), 2.31 (s, 3H, N-CH3). IR (KBr): 2223 , 1591, 1330 cm-1. Anal. Calcd for C12H13N4O2F:
C, 54.54; H, 4.96; N, 21.20. Found: C, 54.43; H, 4.92; N, 21.13.
4-Fluoro-5-(4-methyl-1-piperazinyl)-2-nitrobenzamide (5)
A mixture of 4-fluoro-5-(4-methyl-1-piperazinyl)-2-nitrobenzonitrile (4) (5.0 g, 18.9 mmol) in conc.
sulfuric acid (62 mL) was stirred at rt for three days. The reaction mixture was then poured slowly into
ice water (100 mL) and was treated with a 50 % sodium hydroxide solution to a pH of 10. The mixture
was extracted with ethyl acetate (3 x 50 mL) and the combined ethyl acetate extracts were dried (Na2SO4),
1
evaporated under vacuum and crystallized (ethanol) to give 5 (3.9 g, 73 %), mp 194-196 °C. H NMR
(400 MHz, CDCl3): δ 7.80 (d, J = 13.1 Hz, 1H, H-3), 6.88 (d, J = 8.2 Hz, 1H, H-6), 3.32, 2.55 (each t,
each J = 4.9, Hz, each 4H, piperazine), 2.33 (s, 3H, N-CH3). IR (KBr): 3560, 3303, 2223, 1660 cm-1. Anal.
Calcd for C12H15N4O3F: C, 51.06; H, 5.36; N, 19.85. Found: C, 51.00; H, 5.33; N, 19.79.

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2-Amino-4-fluoro-5-(4-methyl-1-piperazinyl)benzamide (6)
To a solution of 4-fluoro-5-(4-methyl-1-piperazinyl)-2-nitrobenzamide (5) (5.0 g, 17.8 mmol) in conc. HCl
(100 mL), stannous chloride ( 22.4 g, 0.12 mol) was slowly added (10 min) at rt. Stirring was continued for
additional 30 min, then water (100 mL) was added and stirring was continued for 1 h. The reaction mixture
was cooled (ice-water bath) and treated gradually with a solution of 40% NaOH until the solution is
strongly alkaline (pH = 13), then the resulting precipitate was filtered, dried and crystallized (methanol) to
give 6 (3.8 g, 85 %), mp 175-177 °C. 1H NMR (400 MHz, CDCl3): δ 6.96 (d, J = 9.0 Hz, 1H, H-6), 6.36 (d,
J = 13.5 Hz, H-3), 2.96, 2.56 (each t, each J = 4.9, Hz, each 4H, piperazine), 2.31 (s, 3H, N-CH3), 5.52, 5.80
(each br s, each 2H, NH2, O=C-NH2). IR (KBr): 3448, 3213, 1643 cm-1. Anal. Calcd for C12H17N4O3F: C,
57.13; H, 6.79; N, 22.21. Found: C, 57.02; H, 6.72; N, 22.15.
2-Arylidinamino-4-fluoro-5-(4-methyl-1-piperazinyl)benzamides (7a-h)
General procedure: To a stirred solution of 2-amino-4-fluoro-5-(4-methyl-1-piperazinyl)benzamide (6)
(1.26 g, 5 mmol) in dry ethanol (20 mL) was added the appropriate aldehyde (15 mmol) and the reaction
mixture was refluxed for 6 h. The resulting precipitate was collected and crystallized (ethanol) to give the
corresponding Shiff’s bases (7a-h).
2-Benzylidenamino-4-fluoro-5-(4-methyl-1-piperazinyl)benzamide (7a)
Yield (82 %), mp 178-180 °C. 1H NMR (400 MHz, CDCl3): δ 8.42 (s, 1H, CH=Ar), 7.50-7.82 (m, 5H,
C6H5), 7.94 (d, J = 9.8 Hz, H-6), 6.88 (d, J = 13.2 Hz, 1H, H-3), 3.21, 2.63 (each t, each J = 4.9, Hz, each 4H,
piperazine), 2.35 (s, 3H, N-CH3), 9.10, 5.93 (each br s, each 1H, NH2). IR (KBr): 3273 , 3116, 1670, 1592,
1603 cm-1. Anal. Calcd for C19H21N4OF: C, 67.04; H, 6.22; N, 16.46. Found: C, 66.92; H, 6.19; N, 16.39.
4-Fluoro-2-[4-fluorobenzylidinamino]-5-(4-methyl-1-piperazinyl)benzamide (7b)
Yield (81%); mp 222-224 °C. 1H NMR (CDCl3, 400 MHz): δ 8.50 (s, 1H, CH=Ar), 7.29-7.95 (m, 4H,
C6H4F), 8.05 (d, J = 9.5 Hz, H-6), 6.97 (d, J = 12.9 Hz, 1H, H-3), 3.32, 2.71 (each t, each J = 4.9, Hz, each
4H, piperazine), 2.71 (s, 3H, N-CH3), 9.06, 6.04 (each br s, each 1H, NH2). IR (KBr): 3283 , 3126, 1668,
1595, 1608 cm-1. Anal. Calcd for C19H20N4OF2: C, 63.68; H, 5.62; N, 15.63. Found: C, 63.52; H, 5.59; N,
15.59.
4-Fluoro-2-[4-chlorobenzylidineamino]-5-(4-methyl-1-piperazinyl)benzamide (7c)
Yield (92 %), mp 228-230 °C. 1H NMR (CDCl3, 400 MHz): δ 8.37 (s, 1H, CH=Ar), 7.46, 7.76 (each d, each
J = 8.2, Hz, each 2H, C6H4Cl), 7.93 (d, J = 9.9 Hz, H-6), 6.86 (d, J = 13.1 Hz, 1H, H-3), 3.20, 2.34 (each t,
each J = 4.9, Hz, each 4H, piperazine), 2.34 (s, 3H, N-CH3), 8.91, 5.92 (each br s, each 1H, NH2). IR (KBr):

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3308 , 3196, 1654, 1587, 1606 cm-1. Anal. Calcd for C19H21N4OClF: C, 60.88; H, 5.38; N, 14.95. Found: C,
60.72; H, 5.36; N, 14.89.
4-Fluoro-2-[4-methoxybenzylidineamino]-5-(4-methyl-1-piperazinyl)benzamide (7d)
Yield (78 %), mp 250-251 °C. 1H NMR (CDCl3, 400 MHz): δ 8.49 (s, 1H, CH=Ar), 7.03, 7.48 (each d, each
J = 8.9 Hz, each 2H, C6H4OCH3), 7.36(d, J = 9.5 Hz, H-6), 6.60 (d, J = 13.1 Hz, 1H, H-3), 3.82 (s, 3H,
C6H4OCH3), 2.94, 2.58 (each t, each J = 4.9, Hz, each 4H, piperazine), 2.29 (s, 3H, N-CH3), 8.26, 5.76
(each br s, each 1H, NH2). IR (KBr): 3288 , 3124, 1675, 1598, 1609 cm-1. Anal. Calcd for C20H23N4O2F: C,
64.85; H, 6.26; N, 15.13. Found: C, 64.69; H, 6.22; N ,15.09.
4-Fluoro-2-[4-methoxybenzylidinamino]-5-(4-methyl-1-piperazinyl)benzamide (7e)
Yield (85 %), mp 248-249 °C. 1H NMR (CDCl3, 400 MHz): δ 8.49 (s, 1H, CH=Ar), 7.41, 7.84 (each d, each
J = 8.0 Hz, each 2H, C6H4CH3), 8.06 (d, J = 9.9 Hz, H-6), 6.98 (d, J = 13.3 Hz, 1H, H-3), 3.31, 2.71 (each t,
each J = 4.9, Hz, each 4H, piperazine), 2.54 (s, 3H, N-CH3), 2.46 (s, 3H, C6H4CH3), 9.23, 6.03 (each br s,
each 1H, NH2). IR (KBr): 3283 , 3119, 1670, 1588, 1609 cm-1. Anal. Calcd for C20H23N4OF: C, 67.78; H,
6.54; N, 15.81. Found: C, 67.68; H, 6.50; N ,15.79.
4-Fluoro-2-[4-bromobenzylidinamino]-5-(4-methyl-1-piperazinyl)benzamide (7f).
Yield (83 %), mp 230-232 °C. 1H NMR (CDCl3, 400 MHz): δ 8.41 (s, 1H, CH=Ar), 7.43, 8.03 (each d, each
J = 8.2 Hz, each 2H, C6H4Br), 7.99 (d, J = 9.9 Hz, H-6), 7.02 (d, J = 13.1 Hz, 1H, H-3), 3.22, 2.61 (each t,
each J = 4.9, Hz, each 4H, piperazine), 2.35 (s, 3H, N-CH3), 8.95, 5.96 (each br s, each 1H, NH2). IR
(KBr): 3330 , 3107, 1667, 1559, 1628 cm-1. Anal. Calcd for C19H20N4OBrF: C, 54.43; H, 4.81; N, 13.36.
Found: C, 54.29; H, 4.79; N , 13.29.
4-Fluoro-2-[2-thionylmethylenamino]-5-(4-methyl-1-piperazinyl)benzamide (7g).
Yield (78 %), mp 206-208 °C. 1H NMR (CDCl3, 400 MHz): δ 8.51 (s, 1H, CH=Ar), 7.92 (d, J = 9.7 Hz,
H-6), 7.53 (m, 2H, thienyl), 7.14 (dd, J = 3.5, 4.8 Hz, 1H, thienyl), 6.87 (d, J = 13.1 Hz, 1H, H-3), 3.17, 2.57
(each t, each J = 4.9, Hz, each 4H, piperazine), 2.35 (s, 3H, N-CH3), 9.05, 6.00 (each br s, each 1H, NH2). IR
(KBr): 3360 , 3176, 1664, 1572, 1602 cm-1. Anal. Calcd for C17H19N4OFS: C, 58.94; H, 5.53; N, 16.17.
Found: C, 58.80; H, 5.49; N , 16.11.
4-Fluoro-2-[2-furylmethylenamino]-5-(4-methyl-1-piperazinyl)benzamide (7h)
Yield (90 %), mp 208-209 °C. 1H NMR (CDCl3, 400 MHz): δ 8.33 (s, 1H, CH=Ar), 8.06 (d, J = 9.7 Hz,
H-6), 7.74 (dd, J = 0.9, 1.8 Hz, 1H, furyl), 7.10 (dd, J = 2.0, 4.1 Hz, 1H, furyl), 6.59 (dd, J = 0.7, 4.2 Hz,

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1H, furyl), 7.00 (d, J = 13.1 Hz, 1H, H-3), 3.31, 2.69 (each t, each J = 4.9, Hz, each 4H, piperazine), 2.45
(s, 3H, N-CH3), 9.49, 6.16 (each br s, each 1H, NH2). IR (KBr): 3312 , 3133, 1666, 1569, 1603 cm-1.
Anal. Calcd for C17H19N4O2F: C, 61.81; H, 5.80; N, 16.96. Found: C, 61.69; H, 5.77; N , 16.89.
2-Aryl-7-fluoro-6-(4-methyl-1-piperazinyl)-4(3H)-quinazolinones (2)
General procedure: A mixture of 2-arylidineamino-4-fluoro-5-(4-methyl-1-piperazinyl)benzamide (7) (3
mmol), CuCl2 (1.2 g, 9 mmol) in methanol (100mL) was refluxed for 3 h. Hydrogen sulfide gas was then
bubbled into the boiling mixture for 10 min. The black precipitate was filtered off and the filtrate allowed
to cool to rt. The resulting precipitate was then collected, washed with cold methanol and further
crystalized (methanol) to affored the desired quinazolinones (2) in good yields.
7-Fluoro-6-(4-methyl-1-piperazinyl)-2-phenyl-4(3H)quinazolinone (2a)
Yield (83 %), mp 288-290 °C. 1H NMR (400 MHz, DMSO- d6): δ 11.21 (s, 1H, N-H), 7.65-8.23 (m, 5H,
C6H5), 7.76 (d, J = 9.5 Hz, H-5), 7.63 (d, J = 13.7 Hz, 1H, H-8), 3.64, 3.35 (each t, each J = 4.9, Hz, each 4H,
piperazine), 2.92 (s, 3H, N-CH3). IR (KBr): 3380, 1709, 1630, 1649 cm-1. Anal. Calcd for C19H19N4OF: C,
67.04; H, 6.22; N, 16.46. Found: C, 66.92; H, 6.19; N, 16.39.
7-Fluoro-2-(4-fluorophenyl)-6-(4-methyl-1-piperazinyl)-4(3H)-quinazolinone (2b)
Yield (88 %), mp 300 °C (decomp). 1H NMR (400 MHz, DMSO- d6): δ 11.64 (s, 1H, N-H), 7.46-7.84 (m,
4H, C6H4F), 7.74 (d, J = 9.2 Hz, H-5), 7.69 (d, J = 11.5 Hz, 1H, H-8), 3.64, 3.36 (each t, each J = 4.9, Hz,
each 4H, piperazine), 2.89 (s, 3H, N-CH3). IR (KBr): 3386, 1652, 1593, 1610 cm-1. Anal. Calcd for
C19H18N4OF2: C, 64.04; H, 5.09; N, 15.72. Found: C, 63.92; H, 5.11; N, 15.70.
7-Fluoro-6-2-(4-chlorophenyl)-(4-methyl-1-piperazinyl)-4(3H)-quinazolinone (2c)
Yield (88 %), mp 300 °C (decomp).1H NMR (400 MHz, DMSO- d6): δ 11.44 (s, 1H, N-H), 7.70, 8.24 (each
d, each J = 8.0 Hz, each 2H, C6H4Cl), 7.75 (d, J = 9.2 Hz, H-5), 7.66 (d, J = 13.0 Hz, 1H, H-8), 3.65, 3.36
(each t, each J = 4.9, Hz, each 4H, piperazine), 2.90 (s, 3H, N-CH3). IR (KBr): 3441, 1711, 1602, 1634 cm-1.
Anal. Calcd for C19H18N4OClF: C, 61.21; H, 4.87; N, 15.03. Found: C, 61.08; H, 4.82; N, 14.95.
7-Fluoro-6-2-(4-methoxyphenyl)-(4-methyl-1-piperazinyl)-4(3H)-quinazolinone (2d)
Yield (83 %), mp 257-258 °C. 1H NMR (400 MHz, DMSO- d6): δ 11.34 (s, 1H, N-H), 7.24, 8.03 (each d,
each J = 9.0 Hz, each 2H, C6H4OCH3), 7.88 (d, J = 8.8 Hz, H-5), 7.60 (d, J = 12.5 Hz, 1H, H-8), 3.95 (s, 3H,
C6H4OCH3), 3.76, 3.35 (each t, each J = 4.9, Hz, each 4H, piperazine), 3.01 (s, 3H, N-CH3). IR (KBr): 3442,
1664, 1600, 1624 cm-1. Anal. Calcd for C20H21N4O2F: C, 65.20; H, 5.75; N, 15.21. Found: C, 65.03; H,

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5.70; N, 15.16.
7-Fluoro-6-2-(4-methylphenyl)-(4-methyl-1-piperazinyl)-4(3H)-quinazolinone (2e)
Yield (93 %), mp 220 °C (decomp).1H NMR (400 MHz, DMSO- d6): δ 10.82 (s, 1H, N-H), 7.44, 8.12 (each
d, each J = 8.0 Hz, each 2H, C6H4CH3), 7.74 (d, J = 9.2 Hz, H-5), 7.65 (d, J = 12.9 Hz, 1H, H-8), 3.65, 3.31
(each t, each J = 4.9, Hz, each 4H, piperazine), 2.93 (s, 3H, N-CH3). IR (KBr): 3447, 1706, 1615, 1645 cm-1.
Anal. Calcd for C20H21N4OF: C, 68.16; H, 6.01; N, 15.90. Found: C, 68.05; H, 5.99; N, 15.85.
7-Fluoro-6-2-(4-bromophenyl)-(4-methyl-1-piperazinyl)-4(3H)-quinazolinone (2f)
Yield (90 %), mp 304 °C (decomp).1H NMR (400 MHz, DMSO- d6): δ 11.00 (s, 1H, N-H), 7.84, 8.18 (each
d, each J = 8.0 Hz, each 2H, C6H4Cl), 7.76 (d, J = 9.6 Hz, H-5), 7.65 (d, J = 13.0 Hz, 1H, H-8), 3.66, 3.34
(each t, each J = 4.9, Hz, each 4H, piperazine), 2.93 (s, 3H, N-CH3). IR (KBr): 3390, 1659, 1580, 1607 cm-1.
Anal. Calcd for C19H18N4OBrF: C, 54.69; H, 4.35; N, 13.43. Found: C, 54.58; H, 4.29; N, 13.39.
7-Fluoro-(4-methyl-1-piperazinyl)-6-(2-thienyl)-4(3H)-quinazolinone (2g)
Yield (88 %), mp 320 °C (decomp). 1H NMR (400 MHz, DMSO- d6): δ 10.98 (s, 1H, N-H), 8.29 (br s, 1H,
thienyl), 7.94 (br d, J = 5.4 Hz, 1H, thienyl), 7.31 (br s, 1H, thienyl), 7.74 (d, J = 9.2 Hz, H-5), 7.57 (d, J =
13.0 Hz, 1H, H-8), 3.69, 3.32 (each t, each J = 4.9, Hz, each 4H, piperazine), 2.92 (s, 3H, N-CH3). IR (KBr):
3437, 1655, 1587, 1629 cm-1. Anal. Calcd for C17H17N4OFS: C, 59.28; H, 4.98; N, 16.27. Found: C, 59.11;
H, 4.93; N, 16.19.
7-Fluoro-6-(2-furyl)-(4-methyl-1-piperazinyl)-4(3H)-quinazolinone (2h)
Yield (85 %), mp 205 °C (decomp). 1H NMR (400 MHz, DMSO- d6): δ 10.90 (s, 1H, N-H), 8.05 (br d, J =
5.9 Hz, 1H, furyl), 7.66 (br t, J = 4.7 Hz, 1H, furyl), 6.80 (m, 1H, furyl), 7.71 (d, J = 9.2 Hz, H-5), 7.58 (d,
J = 12.7 Hz, 1H, H-8), 3.54, 3.32 (each t, each J = 4.9, Hz, each 4H, piperazine), 2.92 (s, 3H, N-CH3). IR
(KBr): 3345, 1662, 1587, 1605 cm-1. Anal. Calcd for C17H17N4O2F: C, 62.19; H, 5.22; N, 17.06. Found: C,
62.05; H, 5.19; N, 16.99.
ACKNOWLEDGEMENTS
We acknowledge the financial support from the Hashemite University and the NCI for the antitumor
evaluation of the new compounds.
REFERENCES

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HETEROCYCLES, Vol. 65, No. 9, 2005
1. P. S. Reddy, P. P. Reddy, and T. Vasantha, Heterocycles, 2003, 60, 183.
2. J. Bartroli, E. Turmo, M. Algueró, E. Boncompete, M. L. Vericat, L. Conte, J. Ramis, M. Merlos,
J. G. R, and J. Forn, J. Med. Chem., 1998, 41, 1869.
3. J. A. Lowe, R. L. Archer, D. S. Chapin, J. B. Cheng, D. Helweg, J. L. Johnson, B.-K. Koe, L. A.
Lebel, P. F. Moore, J. A. Nielsen, L. L. Russo, and J. T. Shirley, J. Med. Chem., 1991, 34, 624.
4. S. Hirai, H. Kikuchi, H-S. Kim, K. Begum, Y. Wataya, H. Tasaka, Y. Miyazawa, K. Yamamoto,
and Y. Oshima, J. Med. Chem., 2003, 46, 4351.
5. V. Bavetsias, L. A. Skelton, F. Yafai, F. Mitchell, S. C. Wilson, B. Allan, and A. L. Jackman, J.
Med. Chem., 2002, 45, 3692.
6. H. J. Havera and H. Vidrio, J. Med. Chem., 1979, 22, 1548.
7. J. K. Padia, M. Field, J. Hinton, K. Meecham, J. Pablo, R. Pinnock, B. D. Roth, L. Singh, N.
Suman-Chauhan, B. K. Trivedi, and L. Webdale, J. Med. Chem., 1998, 41, 1042.
8. M. Hori, R. Iemura, H. Hara, A. Ozaki, T. Sukamoto, and H. Ohtaka, Chem. Pharm. Bull., 1990,
38, 1286.
9. J. F. Wolfe, T. L. Rathman, M. C. Sleevi, J. A. Campbell, and T. D. Greenwood, J. Med. Chem.,
1990, 33, 161.
10. D. C. Brater, R. H. Pressley, and S. A. Anderson, J. Pharm. Exp. Therap. 1985, 233, 70.
11. J. P. Sanchez, J. M. Domagala, S. E. Hagen, C. L. Heifetz, M. P. Hutt, J. B. Nichols, and A. K.
Trehan, J. Med. Chem., 1988, 31, 983.
12. (a) M. M. El-Abadelah, S. S. Sabri, M. Abu Zarga, and R. J. Abdel-Jalil, Heterocycles, 1995, 41,
2713. (b) R. J. Abdel-Jalil, R. R. Al-Qawasmeh, W. Voelter, and P. Heeg, J. Heterocyl. Chem.,
2000, 37, 1275. (c) R. J. Abdel-Jalil and W. Voelter, J. Heterocyl. Chem., 2005, 42, 1.
13. R. Abdel-Jalil, W. Voelter, and M. Saeed, Tetrahedron Lett., 2004, 45, 3475.
14. Monks, P. Scudiero, R. Skeham, K. Shoemaker, and D. Paull, J. Natl. Cancer Inst., 1991, 83, 757.