Synthesis and cytotoxicity testing of novel 2-(3-substituted-6-chloro-1,1- dioxo-1,4,2-benzodithiazin-7-yl)-3-phenyl-4(3H)-quinazolinones

Article abstract of DOI:10.1002/ardp.200700258

A new series of thirteen 2-[3-(substituted amino)-6-chloro-1,1-dioxo-1,4,2- benzodithiazin-7-yl]-3-phenyl-4(3H)-quinazolinones 4-16 were prepared in order to evaluate their cytotoxic activity against 12 human cancer cell lines. The bioassay indicated that the quinazolinone derivatives 5, 8-12, 15, and 16 possess cancer-cell growth-inhibitory properties. Compounds 5 and 12 showed a high level of selectivity for certain cell lines. The most active compounds 9, 10, 15, and 16 showed moderate antiproliferative activity and were approximately 4-fold less potent than cisplatin.

Full text of DOI:10.1002/ardp.200700258

Arch. Pharm. Chem. Life Sci. 2008, 341, 485–490
E. Pomarnacka et al.
485
Full Paper
Synthesis and Cytotoxicity Testing of Novel 2-(3-Substituted-6-
chloro-1,1-dioxo-1,4,2-benzodithiazin-7-yl)-3-phenyl-4(3H)-
quinazolinones
Elzbieta Pomarnacka1, Magdalena Maruszak1, 2, Karolina Langowska1, 2, Przemyslaw Reszka2,
and Patrick J. Bednarski2
1 Department of Chemical Technology of Drugs, Medical University of Gdansk, Poland
2 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald,
Greifswald, Germany
A new series of thirteen 2-[3-(substituted amino)-6-chloro-1,1-dioxo-1,4,2-benzodithiazin-7-yl]-3-
phenyl-4(3H)-quinazolinones 4-16 were prepared in order to evaluate their cytotoxic activity
against 12 human cancer cell lines. The bioassay indicated that the quinazolinone derivatives 5,
8–12, 15, and 16 possess cancer-cell growth-inhibitory properties. Compounds 5 and 12 showed
a high level of selectivity for certain cell lines. The most active compounds 9, 10, 15, and 16
showed moderate antiproliferative activity and were approximately 4-fold less potent than cis-
platin.
Keywords: Cytotoxic activity / 2-Substituted-3-phenyl-4(3H)-quinazolinones / Synthesis /
Received: December 12, 2007; accepted: January 21, 2008
DOI 10.1002/ardp.200700258
Introduction
Quinazolinone derivatives have drawn attention due to
their broad range of pharmacological activities, among
others antifungal, anti-Parkinsonism, antimalarial, anti-
inflammatory, anticonvulsant, antibacterial, antihyper-
tensive [1–5], and anticancer activities [6–8]. Moreover,
quinazolinone drugs with antiproliferative activity are
known to bind to tubulin and interfere with its polymer-
Figure 1. Structures of cytotoxic cyclic 2-mercaptobenzenesul-
fonamides.
ization [9–11]. Our systematic studies on the synthesis of
1,4,2-benzodithiazine 1,1-dioxides and their subsequent
transformation into N-(azolyl or azinyl)-2-mercaptoben-
zenesulfonamides have resulted in promising anticancer
agents [12–14] or potent inhibitors of HIV–1 integrase
(MBSAs) [15]. We also found that cyclic sulfonamide deriv-
atives of 2-amino-8-chloro-5,5-dioxo[1,2,4]triazolo[2,3-
b][1,4,2]benzodithiazine (I, Fig. 1) [16] or of type II–IV
(Fig. 1) possess interesting in-vitro anticancer properties
[17–21]. The putative mechanism of antitumor action
appears to be involved in cell cycle arrest in the G0/G1
phase [22]. Therefore, the antiproliferative activity associ-
ated with both, quinazolinone and cyclic 2-mercaptosul-
fonamide moieties prompted us to synthesize new deriv-
Correspondence: Elzbieta Pomarnacka, Department of Chemical Tech-
nology of Drugs, Medical University of Gdansk, Al. Gen. J. Hallera 107,
80-416 Gdansk, Poland.
E-mail: zopom@amg.gda.pl
Fax: +48 58 349-3257
Patrick J. Bednarski, Department of Pharmaceutical and Medicinal Chem-
istry, Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-
Jahn Str. 17, D-17487 Greifswald, Germany.
E-mail: bednarsk@uni-greifswald.de
Fax: +49 3834 864-874
Abbreviation: relative standard deviation (RSD)
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

486
E. Pomarnacka et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 485–490
In turn, nucleophilic displacement of the 3-methyl-
thiol group of 3 by the appropriate amine in boiling
methanol proceeded with elimination of methyl mercap-
tan, leading to the target quinazolinones 4–16 in 40–
65% yields (Scheme 1). All the final products were charac-
1
terized by IR and H-NMR spectroscopy, and all active
compounds were further characterized by 13C-NMR as
detailed in the experimental protocols. Elemental analy-
ses of all products were in accordance with the proposed
structures.
Biology
A microtiter based assay on the staining of adherent cells
with crystal violet was used to quantify the antiprolifera-
tive potential of the new compounds on human cancer
cell lines. Details of this test have been published else-
where [25, 26]. Primary screening of compounds 4–16 for
antiproliferative activity took place on six human cancer
cell lines. Compounds that showed inhibition of cell
growth by more than 50% at 20 lM in one or more of the
cell lines were investigated further. Secondary screening
to determine potency was performed on a panel of 12
human cancer cell lines: three bladder cell lines: RT-4, RT-
112, and 5637; three esophagus cell lines: KYSE-70, -510,
and –520; two pancreas lines: YAPC and DAN-G; two lung
cancer cell lines: LCLC-103H and A-427, one cervical can-
cer line: SISO, and the breast cancer cell line: MCF-7.
Table 1 lists the average IC50 values calculated from the
dose-response data obtained from three independent
experiments. The IC50 is the concentration required to
inhibit cell growth by 50% compared to the untreated
control over a 96 h-treatment period [25].
Reagents: (i) 2-aminobenzanilide, pyridine, toluene; (ii) excess of thionyl chloride; (iii)
the appropriate amine, dry benzene, or dry methanol.
Scheme 1. Synthesis of 2-(3-substituted amino-6-chloro-1,1-
dioxo-1,4,2-benzodithiazin-7-yl)-3-phenyl-4(3H)-quinazolinones
4–16.
The compounds 4, 6, 7, 13, and 14 were inactive up to a
concentration of 20 lM. Generally, the IC50 values for the
active compounds were all greater than those of cisplatin
(Table 1). However, some compounds showed similar (12
in KYSE-520) or even greater (9 – YAPC; 15 - KYSE-520)
activity than cisplatin in specific cell lines (Table 1).
The following conclusion may be drawn from the
structure-activity relationship study. No correlations
were found between the calculated logP values (ClogP
ranged between 3.65 for 9 and 6.67 for 13, calculated
with Pallas 3.0, prolog P 6.0 module) and the IC50 values
of the compounds in any of the cell lines. In the series of
quinazolinone derivatives, the electronic character of
the benzodithiazine ring substituent at position-3
appears to be an important factor influencing cytotoxic-
ity. The most active compounds are 9, 10, 15, and 16,
which maybe due to the moderate electron-donating
nature of substituent at position-3. It was found that
incorporation of phenylethylamino group (ionization
constant of ß-phenylethylamine Ka = 6.75610– 5) into
atives with the objective of obtaining bi-heterocycles of
type V (Fig. 1). Here, we report the synthesis of 13 new
compounds of type V and the results of their in-vitro eval-
uation for cytotoxic activity.
Results and discussion
Chemistry
The previously described methods were employed for the
synthesis of 6-chloro-3-methylthio-1,1-dioxo-1,4,2-benzo-
dithiazin-7-carbonyl chloride 1 [23, 24]. The reaction of 1
with the 2-aminobenzanilide was carried out in boiling
toluene in the presence of pyridine and afforded the
expected
N-[2-(phenylcarbamoyl)phenyl]-6-chloro-1,1-
dioxo-3-methylthio-1,4,2-benzodithiazin-7-carboxamide
2 in 87% yield. Treatment of 2 with an excess of thionyl
chloride under reflux gave rise to the novel 2-(6-chloro-
1,1-dioxo-3-methylthio-1,4,2-benzodithiazin-7-yl)-3-phe-
nyl-3H-quinazolin-4-one 3 (Scheme 1).
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Arch. Pharm. Chem. Life Sci. 2008, 341, 485–490
Novel 2-Substituted-3-phenyl-4(3H)-quinazolinones
487
Table 1. IC50 values (lM) for the inhibition of in-vitro cell growth of human cancer cell lines by compounds 5, 8–12, 15, and 16a).
Tumor cell
line
IC50 (lM) for compounds
5
8
9
10
11
12
15
6.3 l 3.7
16
Cisplatinb)
RT-4
RT-112
5637
KYSE-70
KYSE-510
KYSE-520
YAPC
DAN-G
LCLC-103H 30.2 l 9.3
A-427
28.1 l 6.5
58.6 l 13.0 13.9 l 2.9
10.5 l .2
7.8 l 1.0
7.2 l 3.5
4.4 l 0.4
5.3 l 0.4
5.7 l 0.9
7.2 l 5.1
3.7 l 0.1
4.7 l 2.1
5.8 l 1.5
4.2 l 0.1
4.31.4
8.9 l 3.3
7.6 l 0.4
5.2 l 1.9
7.4 l 4.8
8.2 l 2.2
8.7 l 1.3
10.5 l 3.8
4.2 l 0.5
3.9 l 1.8
3.1 l 1.7
7.7 l 1.4
5.7 l 2.6
6.79
11.2 l 4.0
10.7 l 2.0
12.1 l 7.6
4.9 l 2.7
12.3 l 1.6
13.3 l 1.5
16.6 l 2.3
6.0 l 0.3
9.7 l 4.3
7.3 l 2.8
8.1 l 1.1
12.7 l 6.5
10.43
4.1 l 1.9
6.2 l 1.0
Nc)
6.5 l 1.4
1.61
1.22
0.35
0.63
0.44
3.61
4.09
0.73
0.90
1.96
1.38
0.24
1.43
5.1 l 1.9
7.7 l 0.5
9.3 l 2.8
4.8 l 1.2
6.5 l 0.3
8.8 l 2.1
11.5 l 3.2
3.1 l 0.1
13.6 l 4.5
5.4 l 1.6
3.5 l 0.8
7.7 l 0.7
2.9 l 0.5
7.3 l 1.9
2.6 l 1.4
7.8 l 2.4
2.8 l 0.9
12.3 l 0.3
28.8 l 1.8
13.3 l 4.6
5.6 l 0.8
13.3 l 0.8
6.8 l 2.5
6.9 l 1.4
9.2 l 4.9
10.9
6.2 l 2.3
8.4 l 0.3
Nc)
Nc)
9.2 l 1.7
29.6 l 9.4
10.1 l 2.7
4.7 l 0.6
7.7 l 7.7
4.6 l 2.8
4.8 l 0.7
20.6 l 9.8
5.1 l 0.4
40.0 l 12.7 17.2 l 13.6
10.38
105
Nc)
Nc)
5.9 l 0.04
3.3 l 0.2
5.2 l 0.3
6.4 l 0.7
4.5 l 0.7
5.84
8.0 l 3.4
6.4 l 3.3
MCF-7
SISO
Nc)
5.33.1
5.48
24
Averaged)
RSDe) (%)
19.0
92
7.64
59
61
34
32
24
83
a)
Values were averages of three independent determinations l 1 SD.
Values were from ref. [25].
Not determined.
Averaged IC50 values over all tested cancer cell lines.
Relative standard deviation.
b)
c)
d)
e)
position-3 resulted in inactive 13. On the other hand, fold, which promises to be useful in the search for more
introduction of a benzylamino group (ionization con- selective antineoplastic agents. It can be stated that the
stant of benzylamine, Ka = 2.0610– 5) led to 12 with mod- electronic character of substituents at position-3 of the
erate activity. Similarly, replacement of the allylamino benzodithiazine ring system influences the cytotoxicity
group in 10 by propargylamino in 11 caused a reasonable of compounds 4–16. Moreover, further structural modifi-
decrease of sensitivity towards all cell lines.
cation of compounds 9, 10, and 15 may lead to the discov-
A characteristic of anticancer drugs (e.g., cisplatin) ery of even more active quinazolinones with good selec-
tested in our panel of cancer cell lines is that the relative tivity against various cancer types.
standard deviation (RSD) of the IC50 values tend to be large
(i.e. A80%). Thus, we calculated the RSD of the new com- We wish to thank the EU for Erasmus scholarships to M. M. and
pounds (Table 1). Both compounds 5 and 12 showed RSD K. L.
greater than 80%, indicating that these compounds havea
characteristic spectrum of activity, with some cell lines The authors have declared no conflict of interest.
intrinsically resistant and other cell lines more sensitive
to the compounds. For example, compound 12 had a large
RSD because two cell lines, A-427 and SISO, are insensitive
Experimental
to the compound while the other cell lines show modest
activity. By replacing the phenyl for a pyridinyl ring, in15,
an overall increase in activity results, but a decrease in the
RSD was observed; this is because the A-427 and SISO cell
lines are more sensitive to 15 than 12. Nevertheless, the
increased cell selectivity, as evidenced by the larger RSD
for 5 and 12, stands in contrast to the relatively low RSDs
found with the very same cell lines for the compounds of
theseries types I [21] and III [20].
Chemistry
Melting points are uncorrected and were determined on a B(chi
SMP-20 apparatus (Bꢀchi Labortechnik, Flawil, Switzerland). The
IR spectra were recorded on 1600 FTIR Perkin Elmer (Perkin
Elmer, Norwalk, CT, USA) spectrometer using potassium bro-
mide pellets and frequencies were expressed in cm– 1. The 13C-
1
NMR and H-NMR spectra were obtained on a Varian Gemini
(50 MHz and 200 MHz) or Varian Unity Plus (125 MHz and
500 MHz) spectrometers (Varian Inc., Palo Alto, CA, USA). The
chemical shift values d were expressed in ppm relative to the
residual solvent signal at 2.50 or 7.26 ppm and 39.5 or 77 ppm,
respectively. MS spectra were recorded on a Finnigan MAT-95
spectrometer at 70 eV (Finnigan MAT, Bremen, Germany). The
analytical results for C, H, and N were within l 0.4% of the theo-
retical values. The starting 6-chloro-3-methylthio-1,1-dioxo-1,4,2-
Conclusion
The above data demonstrate the usefulness of connecting
quinazolinone and benzodithiazine rings to form a scaf-
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488
E. Pomarnacka et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 485–490
benzodithiazin-7-carboxylic acid [23] and 6-chloro-3-methylthio-
1,1-dioxo-1,4,2-benzodithiazin-7-carbonyl chloride 1 [24] were
obtained by the previously described methods.
7.6 Hz, 1H, aromat.), 8.62 (s, 1H, H-8 benzodit.) ppm. Anal.
(C26H21ClN4O3S2) C, H, N.
2-(6-Chloro-1,1-dioxo-3-morpholin-4-yl-1,4,2-
N-[2-(Phenylcarbamoyl)phenyl]-6-chloro-1,1-dioxo-3-
methylthio-1,4,2-benzodithiazin-7-carboxamide 2
benzodithiazin-7-yl)-3-phenyl-4(3H)-quinazolinone 5
Starting from morpholine (0.096 g) in benzene, the title 5 was
obtained (0.30 g, 55%); mp. 223–2258C. IR (KBr, cm– 1) 1675 (CO),
1620 (C=N), 1320, 1160 (SO2). 1H-NMR (200 MHz, CDCl3): d 3.66–
4.10 (m, 8H, CH2), 7.05–7.44 (m, 5H, phenyl), 7.51 (s, 1H, H-5 ben-
zodit.), 7.53–7.65 (m, 2H, aromat.), 7.68–7.78 (m, 1H, aromat.),
8.30–8.55 (m, 1H, aromat.), 8.62 (s, 1H, H-8 benzodit.). 13C-NMR
(50 MHz, CDCl3): d 48.38 (2 C, H2C-N-CH2), 66.56 (2 C, H2C-O-CH2),
122.75, 124.24, 125.21, 127.23, 127.42, 127.83, 129.03, 129.43
(two overlapping signals), 130.05, 130.47, 130.52, 131.71, 132.12,
132.20, 134.74, 137.12, 142.60 (18 C, aromat.), 152.86, 152.03
(C=N), 162.73 (CO) ppm. Anal. (C25H19ClN4O4S2) C, H, N.
To a suspension of compound 1 (3.42 g, 10 mmol) and 2-amino-
benzanilide (2.33 g, 11 mmol) in anhydrous toluene (120 mL),
pyridine (0.8 mL, 10 mmol) in anhydrous toluene (50 mL) was
added. The reaction mixture was stirred at reflux for 48 h and
then left overnight at room temperature. The precipitate was fil-
tered off, washed with toluene (5 mL), dried, and suspended in
0.5% aqueous K2CO3 (200 mL). The mixture was stirred for 1 h, fil-
tered off, washed successively with water (2650 mL), methanol
(20 mL) and dried. Yield: 4.5 g, 87%, mp. 248–2508C; IR (KBr,
cm– 1) 3300, 3230 (NH), 1665, 1645 (CONH), 1605 (C=N), 1330,
1170 (SO2); 1H-NMR (200 MHz, DMSO-d6): d 2.72 (s, 3H, SCH3), 7.07
(t, J = 7.3 Hz, 1H, aromat.), 7.25-7.42 (m, 3H, aromat.), 7.59 (ddd, J
= 6.6 Hz, J = 1.3 Hz, J = 7.7 Hz, 1H, aromat.), 7.67–7.82 (m, 3H, aro-
mat.), 7.99 (d, J = 8 Hz, 1H, aromat.), 8.15 (s, 1H, H-5 benzodit.),
8.34 (s, 1H, H-8 benzodit.), 10.46 (s, 1H, NH), 11.03 (s, 1H, NH).
Anal. (C22H16ClN3O4S3) C, H, N.
2-(6-Chloro-1,1-dioxo-3-pyrrolidin-1-yl-1,4,2-
benzodithiazin-7-yl)-3-phenyl-4(3H)-quinazolinone 6
Starting from pyrrolidine (0.078 g) in benzene, the title 6 was
obtained (0.25 g, 48%); mp. 250–2518C. IR (KBr, cm– 1) 1677 (CO),
1625 (C=N), 1315, 1160 (SO2). 1H-NMR (500 MHz, CDCl3): d 1.99–
2.18 (m, 4H, 26CH2), 3.60 (s, 2H, N-CH2), 3.80 (s, 2H, N-CH2), 7.1–
7.42 (m, 5H, phenyl), 7.49 (s, 1H, H-5 benzodit.), 7.5–7.62 (m, 2H,
aromat.), 7.68–7.76 (m, 1H, aromat.), 8.28–8.48 (m, 1H, aro-
mat.), 8.64 (s, 1H, H-8 benzodit.) ppm. Anal. (C25H19ClN4O3S2) C, H,
N.
2-(6-Chloro-1,1-dioxo-3-methylthio-1,4,2-benzodithiazin-
7-yl)-3-phenyl-4(3H)-quinazolinone 3
A mixture of carboxamide 2 (5.0 g, 10 mmol) and thionyl chlor-
ide (50 mL) was refluxed for 20 h. The thionyl chloride was dis-
tilled off (808C), then toluene was added to the residue
(2640 mL) and distilled off (1118C). The dry residue was recrys-
tallized from anhydrous toluene (200 mL) to give compound 3.
Yield: 3.0 g, 60%, mp. 254–2568C. IR (KBr, cm– 1) 1670 (CO), 1628
2-[6-Chloro-3-(4-phenylpiperazin-1-yl)-1,1-dioxo-1,4,2-
benzodithiazin-7-yl]-3-phenyl-4(3H)-quinazolinone 7
Starting from 1-phenylpiperazine (0.18 g) in benzene, the title 7
was obtained (0.25 g, 40%); mp. 229–2318C. IR (KBr, cm– 1) 1675
1
(C=N), 1350, 1170 (SO2); H-NMR (200 MHz, CDCl3): d 2.72 (s, 3H,
CH3), 7.09–7.44 (m, 5H, phenyl), 7.47 (s, 1H, H-5 benzodit.), 7.53–
7.8 (m, 3H, aromat.), 8.44 (d, J = 7.5 Hz, 1H, aromat), 8.64 (s, 1H,
H-8 benzodit.). 13C-NMR (CDCl3): d 16.92 (SCH3), 122.77, 125.34,
127.56, 127.89, 129.32, 129.4 (two overlapping signals), 129.77,
129.98, 130.09, 130.22, 130.26, 132.30, 134.68, 134.80, 134.96,
138.20, 142.54 (aromat.), 152.47, 152.56 (C=N), 180.17 (C=O).
Anal. (C22H14ClN3O3S3) C, H, N.
1
(CO), 1625 (C=N), 1325, 1160 (SO2). H-NMR (200 MHz, CDCl3): d
3.15–3.40 (m, 4H, 26CH2), 3.85–4.28 (m, 4H, 26CH2), 6.82–
7.45 (m, 10H, 26phenyl), 7.53 (s, 1H, H-5 benzodit.), 7.54–7.65
(m, 2H, aromat.), 7.68 (d, J = 6.7 Hz, 1H, aromat.), 8.32 (d, J =
7.5 Hz, 1H, aromat.), 8.63 (s, 1H, H-8 benzodit.) ppm. Anal.
(C31H24ClN5O3S2) C, H, N.
General procedure for preparation of 2-[6-chloro-3-
2-(6-Chloro-3-isopropylamino-1,1-dioxo-1,4,2-
(substituted amino)-1,1-dioxo-1,4,2-benzodithiazin-7-yl]-
3-phenyl-4(3H)-quinazolinones 4–16
benzodithiazin-7-yl)-3-phenyl-4(3H)-quinazolinone 8
Starting from 2-aminopropane (0.07 g) in methanol, the title 8
was obtained (0.30 g, 59%); mp. 275-2778C. IR (KBr, cm– 1) 3265
(NH), 1676 (CO), 1628 (C=N), 1317, 1150 (SO2). 1H-NMR (200 MHz,
DMSO-d6): d 1.17 (d, J = 6.2 Hz, 6H, 26CH3), 4.0–4.22 (m, 1H, CH),
7.0–7.38 (m, 5H, phenyl), 7.52–7.68 (m, 2H, aromat.), 7.72–7.84
(m, 1H, aromat.), 8.05 (s, 1H, H-5 benzodit.), 8.23 (d, J = 7.6 Hz, 1H,
aromat.), 8.39 (s, 1H, H-8 benzodit.), 9.76 (s, 1H, NH) ppm. 13C-
NMR (50 MHz, DMSO-d6): d 21.39 (2 C, 26CH3), 46.13 (CH),
119.15, 122.11 (two overlapping signals), 124.03, 126.08, 126.86,
127.16, 128.68 (two overlapping signals), 129.42, 129.97, 130.12,
131.47, 133.47, 134.23, 134.98, 141.80, 144.97 (18 C, aromat.),
145.03, 152.37 (C=N), 160.38 (CO) ppm. Anal. (C24H19ClN4O3S2) C,
H, N.
A mixture of 3 (0.5 g, 1 mmol) and the appropriate amine
(1.1 mmol) in the appropriate solvent (20 mL) was stirred at
room temperature for 20 h and then refluxed until the forma-
tion of MeSH had ceased (20–30 h) [Caution: because of high tox-
icity, MeSH should be trapped in an aqueous NaOH solution].
The precipitate was filtered off, washed successively with solvent
(5 mL), chloroform (5 mL), and dried. In this manner, the follow-
ing compounds were obtained.
2-(6-Chloro-1,1-dioxo-3-piperidin-1-yl-1,4,2-
benzodithiazin-7-yl)-3-phenyl-4(3H)-quinazolinone 4
Starting from piperidine (0.094 g) in benzene, the title 4 was
obtained (0.31 g, 58%); mp. 213–2148C. IR (KBr, cm– 1) 1670 (CO),
1625 (C=N), 1310, 1160 (SO2). 1H-NMR (200 MHz, CDCl3): d 1.74 (s,
6H, 36CH2 piper.), 3.73 (s, 2H, H2C-N-piper.), 3.94 (s, 2H, H2C-N-
piper.), 7.05–7.44 (m, 5H, phenyl), 7.49 (s, 1H, H-5 benzodit.)
7.50–7.78 (m, 3H, aromat.), 8.36 (ddd, J = 7 Hz, J = 3.3 Hz, J =
2-[6-Chloro-3-(3-hydroxypropylamino)-1,1-dioxo-1,4,2-
benzodithiazin-7-yl]-3-phenyl-4(3H)-quinazolinone 9
Starting from 3-amino-1-propanol (0.083 g) in methanol, the
title 9 was obtained (0.30 g, 57%); mp. 210–2128C. IR (KBr, cm– 1
)
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Arch. Pharm. Chem. Life Sci. 2008, 341, 485–490
Novel 2-Substituted-3-phenyl-4(3H)-quinazolinones
489
3380 (NH), 1675 (CO), 1625 (C=N), 1320, 1155 (SO2). 1H-NMR
(200 MHz, DMSO-d6): d 1.69 (q, J = 6.6 Hz, 2H, CH2), 3.38–3.49 (m,
4H, CH2N, CH2OH), 4.57 (t, J = 4.8 Hz, 1H, OH), 7.08 (t, J = 7.2 Hz,
1H, phenyl), 7.19 (d, J = 7.2 Hz, 2H, phenyl), 7.26-7.39 (m, 2H, phe-
nyl), 7.55-7.66 (m, 2H, aromat.), 7.79 (ddd, J = 1.5 Hz, J = 7.6 Hz, J =
6.4 Hz, 1H, aromat.), 8.05 (s, 1H, H-5 benzodit.), 8.25 (dd, J =
1.5 Hz, J = 6.8 Hz, 1H, aromat.), 8.39 (s, 1H, H-8 benzodit.), 9.83 (s,
1H, NH) ppm. 13C-NMR (50 MHz, DMSO-d6): d 31.37 (-CH2-), 41.2
(CH2N), 58.32 (CH2OH), 119.47, 122.43 (two overlapping signals),
124.35, 126.39, 127.17, 127.49, 129.0 (two overlapping signals),
129.74, 130.29, 130.39, 131.76, 133.74, 134.55, 134.83, 135.30,
142.12 (18 C, aromat.), 145.29, 152.69 (C=N), 161.70 (CO) ppm.
Anal. (C24H19ClN4O4S2) C, H, N.
126.39, 127.18, 127.55, 127.88, 128.04 (two overlapping signals),
128.86 (two overlapping signals), 129.01 (two overlapping sig-
nals), 129.74, 130.37, 130.49, 131.64, 133.65, 134.55, 135.38,
136.78, 142.11, 145.28 (aromat.), 145.39, 152.67 (C=N), 162.21
(C=O) ppm. Anal. (C28H19ClN4O3S2) C, H, N.
2-(6-Chloro-1,1-dioxo-3-phenethylamino-1,4,2-
benzodithiazin-7-yl)-3-phenyl-4(3H)-quinazolinone 13
Starting from phenethylamine (0.13 g) in methanol, the title 13
was obtained (0.36 g, 63%); mp. 175–1778C. IR (KBr, cm– 1) 3370,
3270 (NH), 1674 (CO), 1628 (C=N), 1320, 1160 (SO2). 1H-NMR
(200 MHz, DMSO-d6): d 2.87 (t, J = 6.3 Hz, 2H, CH2), 3.49–3.69 (m,
2H, CH2), 7.02–7.42 (m, 10H, 26phenyl), 7.52–7.86 (m, 3H, aro-
mat.), 8.03 (s, 1H, H-5 benzodit.), 8.22 (d, J = 7.3 Hz, 1H, aromat.),
8.40 (s, 1H, H-8 benzodit.), 9.91 (s, 1H, NH) ppm. Anal.
(C29H21ClN4O3S2) C, H, N.
2-(3-Allylamino-6-chloro-1,1-dioxo-1,4,2-benzodithiazin-
7-yl)-3-phenyl-4(3H)-quinazolinone 10
Starting from allylamine (0.063 g) in benzene, the title 10 was
obtained (0.34 g, 68%); mp. 236–2388C. IR (KBr, cm– 1) 3300 (NH),
1674 (CO), 1628 (C=N), 1320, 1150 (SO2). 1H-NMR (200 MHz,
DMSO-d6): d 4.06 (br s, 2H, NCH2), 5.20 (dd, J = 1.3 Hz, J = 6.0 Hz,
1H, =CH2), 5.27 (dd, J = 1.3 Hz, J = 13.1 Hz, 1H, =CH2), 5.8–6.0 (m,
1H, CH=), 7.12 (t, J = 7.2 Hz, 1H, phenyl), 7.23 (d, J = 7.2 Hz, 2H,
phenyl), 7.31–7.44 (m, 2H, phenyl), 7.58–7.70 (m, 2H, aromat.),
7.83 (ddd, J = 1.4 Hz, J = 7.0 Hz, J = 7.6 Hz, 1H, aromat.), 8.11 (s,
1H, H-5 benzodit.), 8.27 (d, J = 7.0 Hz, 1H, aromat), 8.44 (s, 1H, H-8
benzodit.), 10.07 (s, 1H, NH) ppm. 13C-NMR (DMSO-d6): d 45.36
(NHCH2), 117.29 (=CH2), 119.16, 122.11 (two overlapping signals),
124.03, 126.08, 126.86, 127.22, 127.66, 128.69 (two overlapping
signals), 129.43, 130.06, 130.13, 131.31, 132.42, 133.32, 134.23,
135.05 (aromat.), 141.80 (CH=), 144.98, 152.36 (C=N), 161.65
(C=O) ppm. EIMS m/z 508.1 [M+] (65.7). Anal. (C24H17ClN4O3S2) C, H,
N.
2-(6-Chloro-1,1-dioxo-3-p-tolylamino-1,4,2-
benzodithiazin-7-yl)-3-phenyl-4(3H)-quinazolinone 14
Starting from tolylamine (0.11 g) in benzene, the title 14 was
obtained (0.15 g, 27%); mp. 251–2538C. IR (KBr, cm– 1) 3270,
3210 (NH), 1676 (CO), 1622 (C=N), 1320, 1140 (SO2) cm– 1. 1H-NMR
(200 MHz, DMSO-d6): d 2.30 (s, 3H, CH3), 7.02–7.40 (m, 7H, phe-
nyl), 7.42–7.70 (m, 4H, 2H phenyl and 2H aromat.), 7.71–7.85
(m, 1H, aromat.), 8.14 (s, 1H, H-5 benzodit.), 8.23 (d, J = 7.6 Hz, 1H,
aromat.), 8.44 (s, 1H, H-8 benzodit.), 11.50 (br s, 1H, NH) ppm.
Anal. (C28H19ClN4O3S2) C, H, N.
2-{6-Chloro-1,1-dioxo-3-[(pyridin-3-ylmethyl)amino]-
1,4,2-benzodithiazin-7-yl}-3-phenyl-4(3H)-quinazolinone
15
Starting from 3-(aminomethyl)pyridine (0.12 g) in methanol, the
title 15 was obtained (0.21 g, 37%), mp. 228–2308C. IR (KBr, cm–
1): 3240 (NH), 1670 (CO), 1628 (C=N), 1325, 1155 (SO2); 1H-NMR
(200 MHz, DMSO-d6): d 4.63 (s, 2H, NCH2), 7.08 (t, J = 7.1 Hz, 1H,
phenyl), 7.19 (d, J = 7.3 Hz, 2H, phenyl), 7.31 (d, J = 7.3 Hz, 2H,
phenyl), 7.33–7.41 (m, 1H, H-5 pyrid.), 7.52–7.68 (m, 3H, aro-
mat.), 7.71–7.85 (m, 1H, H-4 pyrid.), 8.08 (s, 1H, H-5 benzodit.),
8.23 (d, J = 7.3 Hz, 1H, aromat), 8.41 (s, 1H, H-8 benzodit.), 8.50 (d,
J = 3.6 Hz, 1H, H-6 pyrid.), 8.55 (s, 1H, H-2 pyrid.), 10.33 (s,1H, NH)
ppm. 13C-NMR (DMSO-d6): d 44.53 (NCH2), 119.46, 122.42 (two
overlapping signals), 126.39, 127.18, 127.58, 129.01 (two overlap-
ping signals), 129.76, 130.40, 130.51, 131.52, 132.49, 133.59,
134.55, 135.42, 135.60, 142.10 (aromat.), 123.93, 124.35 (C-3 and
5 pyrid.), 135.96 (C-4 pyrid), 149.11, 149.45 (C-2 and 6 pyrid.),
145.32, 152.65 (C=N), 162.37 (C=O) ppm. Anal. (C27H18ClN5O3S2) C,
H, N.
2-(6-Chloro-1,1-dioxo-3-prop-2-ynylamino-1,4,2-
benzodithiazin-7-yl)-3-phenyl-4(3H)-quinazolinone 11
Starting from propargylamine (0.06 g) in benzene, the title 11
was obtained (0.32 g, 63%); mp. 240–2428C. IR (KBr, cm– 1): 3300,
3260 (NH), 1674 (CO), 1628 (C=N), 1320, 1150 (SO2). 1H-NMR
(500 MHz, DMSO-d6): d 3.36 (s, 1H, CH), 4.21 (d, J = 1.9 Hz, 2H,
CH2), 7.09 (t, J = 7.3 Hz, 1H, phenyl), 7.20 (d, J = 7.8 Hz, 2H, phe-
nyl), 7.33 (t, J = 7.8 Hz, 2H, phenyl), 7.58–7.64 (m, 2H, aromat.),
7.79 (t, J = 7.8 Hz, 1H, aromat.), 8.07 (s, 1H, H-5 benzodit.), 8.23 (d,
J = 7.8 Hz, 1H, aromat), 8.42 (s, 1H, H-8 benzodit.), 10.30 (s, 1H,
NH) ppm. 13C-NMR (DMSO-d6): d 33.14 (CH2), 75.84 (CH), 79.21 (C),
119.90, 122.86 (two overlapping signals), 124.79, 126.83, 127.61,
128.03, 129.22, 129.44 (two overlapping signals), 130.19, 130.93,
131.81, 133.94, 134.98, 135.88, 142.53, 145.72 (aromat.), 145.78,
153.06 (C=N), 162.46 (C=O) ppm. EIMS m/z 506.1 [M+] (77.8). Anal.
(C24H15ClN4O3S2) C, H, N.
2-[6-Chloro-1,1-dioxo-3-(2-pyridin-2-ylethylamino)-1,4,2-
benzodithiazin-7-yl]-3-phenyl-4(3H)-quinazolinone 16
Starting from 2-(2-aminoethyl)pyridine (0.11 g) in methanol, the
title 16 was obtained (0.30 g, 52%), mp. 237–2388C. IR (KBr, cm–
1): 3190 (NH) 1676 (CO), 1626 (C=N), 1325, 1155 (SO2) cm– 1. 1H-
NMR (200 MHz, DMSO-d6): d 3.03 (t, J = 7 Hz, 2H, CH2), 3.75 (t, J =
7 Hz, 2H, CH2), 7.08 (t, J = 7.3 Hz, 1H, phenyl), 7.15–7.38 (m, 6H,
4H phenyl, H-3 and H-5 pyrid.), 7.54–7.64 (m, 2H, aromat), 7.65
(m, 2H, aromat and H-4 pyrid.), 8.03 (s, 1H, H-5 benzodit.), 8.22 (d,
J = 7.3 Hz, 1H, aromat.), 8.40 (s, 1H, H-8 benzodit.), 8.50 (d, J =
4.4 Hz, 1H, H-6 pyrid.), 9.93 (br s, 1H, NH) ppm. 13C-NMR (DMSO-
d6): d 35.71 (CH2), 42.87 (NCH2), 119.53, 121.75, 122.11 (two over-
2-(6-Chloro-3-benzylamino-1,1-dioxo-1,4,2-
benzodithiazin-7-yl)-3-phenyl-4(3H)-quinazolinone 12
Starting from benzylamine (0.12 g) in methanol, the title 12 was
obtained (0.38 g, 67%); mp. 236–2388C. IR (KBr, cm– 1) 3290 (NH),
1674 (CO), 1628 (C=N), 1315, 1140 (SO2). 1H-NMR (200 MHz,
DMSO-d6): d 4.6 (s, 2H, CH2), 7.03–7.42 (m, 10H, 26phenyl),
7.54–7.65 (m, 2H, aromat.), 7.73–7.85 (m, 1H, aromat.), 8.07 (s,
1H, H-5 benzodit.), 8.23 (d, J = 8.0 Hz, 1H, aromat), 8.41 (s, 1H, H-8
benzodit.), 10.33 (s, 1H, NH) ppm. 13C-NMR (DMSO-d6): d 46.85
(NHCH2), 119.47, 122.42 (two overlapping signals), 124.35,
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

490
E. Pomarnacka et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 485–490
lapping signals), 124.03, 126.08, 126.86, 127.21, 128.69 (two
overlapping signals), 129.43, 130.0, 130.10, 131.35, 134.23,
135.01, 141.79, 144.97 (aromat.), 122.06, 123.93, (C-3 and 5
pyrid.), 136.57 (C-4 pyrid), 149.10, 149.22 (C-2 and 6 pyrid.),
145.02, 157.89 (C=N), 161.56 (C=O) ppm. Anal. (C28H20ClN5O3S2) C,
H, N.
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Braunschweig, Germany). Stock solutions of compounds were
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i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com