Synthesis, structural characterization, and in vitro antitumor activity of novel N-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)arylsulfonamides

Article abstract of DOI:10.1016/j.bmc.2007.01.052

A new series of N-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)arylsulfonamides 23-48 have been synthesized as potential anticancer agents. All compounds were screened for their cytotoxic activity against six human tumor cell lines. The selected compound

Full text of DOI:10.1016/j.bmc.2007.01.052

Bioorganic & Medicinal Chemistry 15 (2007) 2560–2572
Synthesis, structural characterization, and in vitro
antitumor activity of novel N-(6-chloro-1,1-
dioxo-1,4,2-benzodithiazin-3-yl)arylsulfonamides
a
Zdzisław Brzozowski,a Franciszek Sa˛czewski,a, Jarosław Sławinski,
*
´
Patrick J. Bednarski,b Renate Grunertb and Maria Gdaniecc
¨
aDepartment of Chemical Technology of Drugs, Medical University of Gdan´sk, 80-416 Gdan´sk, Poland
bDepartment of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald,
D-17487 Greifswald, Germany
cFaculty of Chemistry, A. Mickiewicz University, 60-780 Poznan´, Poland
Received 6 September 2006; revised 25 January 2007; accepted 31 January 2007
Available online 2 February 2007
Abstract—A new series of N-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)arylsulfonamides 23–48 have been synthesized as poten-
tial anticancer agents. All compounds were screened for their cytotoxic activity against six human tumor cell lines. The selected com-
pounds 23–27, 30, 31, 33, 35, 38, 42, 45, and 46 were further tested at the US National Cancer Institute for their in vitro activities
against a panel of 53–59 human tumor cell lines. The compounds 23–26, 30, 31, 33, 38, 42, 45, and 46 showed 50% growth inhibitory
activity in low micromolar concentration (GI50 = 0.03–4.9 lM) against one or more human tumor cell lines (Table 3). The prom-
inent compound with remarkable activity (GI50 = 0.03 lM, TGI = 1.3 lM) and selectivity toward melanoma UACC-257 cell line
was N-(6-chloro-7-cyano-1,1-dioxo-1,4,2-benzodithiazin-3-yl)-N-(phenyl)-5-bromothiophene-2-sulfonamide 46.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
that cyclic analogues of 2-mercaptobenzenesulfon-
amides also showed remarkable cytotoxic properties
(Fig. 1, structures B,14,26,27 C,28 D,29, and E30). This
led us to an assumption that expansion of a series of
candidate anticancer agents of general formula F
(Fig. 1) may shed light on the structural features con-
tributing to the anticancer activity.
Sulfonamides are among a growing list of compounds
with desirable anticancer activity.1–16 Although they
have a common chemical motif of aromatic/heterocyclic
sulfonamide, there are a variety of mechanisms for their
anticancer action, such as disruption of microtubule
assembly, cell cycle arrest in the G1 phase, functional
suppression of the transcriptional activator NF-Y, angi-
ogenesis inhibition as well as carbonic anhydrase inhibi-
tion.1 Previously, we described the syntheses of various
2. Results and discussion
2.1. Chemistry
4-chloro-2-mercaptobenzenesulfonamide
derivatives
(Fig. 1, structure A) with the nitrogen atom of sulfon-
amide moiety attached to a variety of heterocyclic ring
systems. These compounds, depending on structure,
exhibited either anticancer9,15,17–22 or anti-HIV activi-
ties17–20,23 and have been described as a novel class of
potent HIV-1 integrase inhibitors.24,25 We further found
The previously described methods were employed for the
synthesis of 6-chloro-3-methylthio-1,1-dioxo-1,4,2-
benzodithiazine-7-carboxylic acid 131 and 3-amino-
6-chloro-1,1-dioxo-1,4,2-benzodithiazines 2 and 3,32
4
and 533, and 6–8.34 Similarly, we prepared the new
6-chloro-3-(4-fluoroanilino)-1,1-dioxo-1,4,2-benzodithi-
azine-7-carboxylic acid 9. The syntheses of the target
compounds 23–48 were achieved by a convenient one-,
three- or four-step procedure starting from 3-amino-
6-chloro-1,1-dioxo-1,4,2-benzodithiazines 2–9 as shown
Keywords: N-(6-Chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)aryl-
sulfonamides; Synthesis; Antitumor activity.
*
Corresponding author. Tel.: +48 58 349 3250; fax: +48 58 349
3257; e-mail: saczew@amg.gda.pl
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.01.052

Z. Brzozowski et al. / Bioorg. Med. Chem. 15 (2007) 2560–2572
2561
Cl
S
Cl
S
S
Cl
SH
N
N
N
H
NHPh
N
N
N
S
R2
R
S
O O
R1
N
O O
O O
A
B
C
Cl
Cl
O
O S
O
O S
O
Ar
Cl
S
S
Cl
S
S
N
Cl
R1
S
S
N
R2
N
N
N
N
Me
Me
HB
HB
O O
D (B = 4-DMAP)
Figure 1. Lead compounds among cyclic analogues of 2-mercaptobenzene sulfonamides.
O O
O O
E (B = 4-DMAP)
F
in Schemes 1–3 . First, the reaction of 3-(arylamino)-
6-chloro-1,1-dioxo-1,4,2-benzodithiazine-7-carboxylic
acids 6–9 with thionyl chloride was performed in boiling
benzene to give acid chlorides 10–13 in 87–89% yields.
Then, treatment of 10–13 with an excess of ethanol in
the presence of triethylamine afforded the expected ethyl
3-(arylamino)-6-chloro-1,1-dioxo-1,4,2-benzodithiazine-
7-carboxylates 14–17 in 78–98% yields (Scheme 1). The
reaction of acid chloride 13 with 8-hydroxyquinoline car-
ried out in p-dioxane at elevated temperature led to the
formation of 8-quinolyl 6-chloro-3-(4-fluoroanilino)-
1,1-dioxo-1,4,2-benzodithiazine-7-carboxylate hydro-
chloride 18ÆHCl in 94% yield. Then, on treatment of
18ÆHCl with KHCO3 in water the free ester 18 was ob-
tained in 75% yield (Scheme 2). Second, the reaction of
the 1,4,2-benzodithiazine-7-carbonyl chloride 10 and 11
with 28% ammonia aqua solution carried out in benzene
at temperatures 0–20 ꢁC led to the formation of carboxa-
mides 19 and 20 in excellent yield. Then upon treatment of
19 and 20 with an excess of boiling phosphorus oxychlo-
ride the target 1,4,2-benzodithiazine-7-carbonitriles 20
and 21 were obtained in 90–93% yields (Scheme 2). Final-
ly, the desired N-(6-chloro-1,1-dioxo-1,4,2-benzodithia-
zin-3-yl)arylsulfonamides 23–48 were obtained by
reacting the benzodithiazines 2–18, 21, and 22 with the
corresponding arylsulfonyl chlorides in pyridine in mod-
erate to good yield (Scheme 3).
The structures of the compounds 9–22 and the final
products 23–48 were confirmed by elemental analyses,
IR and NMR spectroscopic data presented in Section
4. It is worth noting, however, that the spectroscopic
data did not allow straightforward discrimination
between the actual N-(R2)-N-(6-chloro-1,1-dioxo-1,4,2-
benzodithiazin-3-yl)arylsulfonamide structure (23–48)
and the alternative 6-chloro-2-(arylsulfonyl)-3-(R2-im-
ino)-2,3-dihydro-1,1-dioxo-1,4,2-benzodithiazines. There-
fore, X-ray crystallography was undertaken on
representative compound 23 with a view to reveal some
more discrete structural features of these compounds.
Molecular structure of 23 with labeling scheme and
displacement ellipsoids at the 50% probability level is
shown in Figure 2. This structure confirms the location
of benzenesulfonyl moiety attached to the exocyclic N11
nitrogen atom.
2.2. Biological Results
The in vitro cytotoxic activity of all N-(6-chloro-1,1-di-
oxo-1,4,2-benzodithiazin-3-yl)arylsulfonamides 23–48
was evaluated35,36 using human bladder cancer cell lines
5637 and RT-4; human lung cancer cell lines A-427 and
LCLC-103H; human pancreatic cell line DAN-G and
human breast cancer cell line MCF-7. The assay was
H
H
Cl
S
S
N
Cl
S
S
N
a
b, c
HO
N
Cl
N
R
R
O O
O O
O
O
6-9
10-13
H
N
Compounds
6, 10, 14
7, 11, 15
8, 12, 16
9, 13, 17
R
Cl
S
H
EtO
N
S
O O
R
Cl
O
MeO
F
14-17
Scheme 1. Synthesis of 3-(arylamino)-6-chloro-1,1-dioxo-1,4,2-benzodithiazine-7-carbonyl chlorides (10–13) and ethyl 6-chloro-3-(arylamino)-1,
1-dioxo-1,4,2-benzodithiazine-7-carboxylates (14–17). Reagents, conditions, and yields: (a) SOCl2 (large excess), benzene, reflux, 16 h, 87–89%; (b)
ethanol (large excess), rt, 3 h; (c) Et3N (1.1 M equiv), rt, 1 h, reflux, 3 h, 78–97%.

2562
Z. Brzozowski et al. / Bioorg. Med. Chem. 15 (2007) 2560–2572
HCl
N
H
N
H
Cl
S
S
Cl
S
S
N
a
O
N
Cl
N
R
R
O O
O
O O
O
18.HCl
10, 11, 13
b
c
H
N
H
Cl
S
S
Cl
S
S
N
N
O
N
H2N
N
R
R
O O
O
O O
O
19-20
18
d
Compounds
R
H
N
Cl
S
13, 18.HCl, 18
10, 19, 21
F
H
Cl
N
S
R
N
O O
11, 20, 22
21-22
Scheme 2. Synthesis of 8-quinolyl 6-chloro-3-(4-fluoroanilino)-1,1-dioxo-1,4,2-benzodithiazine-7-carboxylate 18 and 3-(arylamino)-6-chloro-1,
1-dioxo-1,4,2-benzodithiazine-7-carbonitriles (21 and 22). Reagents, conditions, and yields: (a) 8-hydroxyquinoline (1.033 M equiv), p-dioxane, rt, 2
h, reflux, 4 h, 94%; (b) KHCO3 (1.14 M equiv), water, rt, 1 h, 75%; (c) 28% ammonia aqua solution (4 M equiv), benzene, 0–5 ꢁC, 1 h, rt, 10 h,
95–97%; (d) POCl3 (large excess), reflux, 25 h, 90–93%.
carried out in 96-well microtiter plates. Cells were seed-
ed into the plates and after 24 h they were treated with
the appropriate drug solutions. The cytotoxic effects of
the compounds were measured after a 96-h continuous
exposure to the substances. The cell growth inhibition
values were estimated by staining the adherent cells with
crystal violet. Only viable cells remained attached to the
plastic surface of the wells and bind the dye. The un-
bound dye was washed out with water and stain remain-
ing in the cells was redissolved with 70% ethanol. At the
end, the optical density (OD) was measured with a
microplate reader set at k = 570 nm.
the nitrogen atom, and a variously substituted aromatic
ring (Ar) attached to the sulfonyl group.
As shown in Table 1, compound 23 (R1 = Me) with
R2 = 4-ClPh and Ar = Ph showed a moderate activity
with mean GI50 value over all tested cancer cell lines
of 11.86 lM. The most sensitive were 5637, A-427,
DAN-G, and MCF-7 cell lines (GI50 in the range of
8.1–9.9 lM). A similar pattern was found for compound
25 incorporating R2 = 2-ClPh and Ar = 5-Br-thienyl
(mean GI50 = 12.01 lM). Replacement of phenyl ring
at R2 with Me2N group resulted in compound 26 with
slightly decreased antiproliferative activity (mean
GI50 = 18.43 lM). Other compounds with R2 = Me2N,
R1 = MeOCO and a variously substituted aromatic/het-
eroaromatic ring at Ar-position either did not pass the
preliminary test (28 and 29) or exhibited a moderate
activity (27 and 30) (mean GI50 = 14.71 and 16.31 lM,
respectively). These results indicate that lipophilic sub-
stituents are favored over Me2N group at position R2.
Therefore, further modifications with R2 = Me2N were
not pursued.
First, primary screening of the new compounds was
done to indicate whether a substance possesses enough
activity at the concentration of 20 lM to inhibit cell
growth by 50% (GI50 < 20 lM). The human tumor cell
lines used were 5637, LCLC-103H, MCF-7 and
DAN-G.
Then, for sulfonamides 25–27, 30, 31, 35–38, 41, and
42 that passed the preliminary test, a secondary
screening to determine their potency was performed
on a panel of six human cancer cell lines mentioned
above. Table 1 lists the GI50 values calculated from
the dose–response data obtained from 5 to 7 indepen-
dent experiments and reports the average GI50 value
and the relative standard deviation for the tested cell
lines.
With the goal of obtaining more SAR information we
then examined the antitumor activity of compounds
31–40 with EtOCO group at R1-position and lipophilic
substituents R2 and Ar. Compounds 32–34, 36, and 37
which incorporate aromatic/heteroaromatic rings substi-
tuted with electron-withdrawing groups (R1 = 4-ClPh,
4-FPh, and R2 = 4-O2NPh, 4-ClPh, 5-Br-thienyl) were
not active up to concentration of 20 lM. On the other
hand, compound 31 with R2 = Ph and Ar = 4-ClPh
retained a moderate antiproliferative activity (mean
GI50 = 15.10 lM). Likewise when R2 or Ar were
For a series of benzenesulfonamide derivatives obtained
(Scheme 3), the effects of structural modifications were
explored within three structural domains: substituent
R1 at 7-position of the phenyl ring, substituent R2 at

Z. Brzozowski et al. / Bioorg. Med. Chem. 15 (2007) 2560–2572
2563
Scheme 3. Synthesis of N-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)arylsulfonamides 23–48. Reagents, conditions, and yields: (a) arylsulfonyl
chloride (1.13 M equiv), pyridine, rt, 8 h; (b) 50–55 ꢁC, 3 h, 33–83%.
39 (R2 = 4-MeOPh, Ar = 2,4-diClPh) achieved the mean
GI50 value of 3.50 lM.
Interestingly, compounds 41 and 42 with electron-with-
drawing groups (R2 = 4FPh, Ar = 4-ClPh or 5-Br-thie-
nyl) carrying lipophilic quinolinoxycarbonyl group at
R1-position show a similar activity with 40 having EtO-
CO at R1, 4-MeOPh at R2 and unsubstituted phenyl
ring at Ar-position (mean GI50 = 7.73, 7.53, and
8.68 lM, respectively).
Compounds 23–27, 30, 31, 33, 35, 38, 42, 45, and 46
were also selected by the US National Cancer Institute
(Bethesda, USA) and tested for their in vitro anticancer
activity using 53–59 human tumor cell lines derived
from nine different cancer types: leukemia, lung, colon,
CNS, melanoma, ovarian, renal, prostate, and breast.
The compounds were tested at five concentrations at
10-fold dilution. A 48-h continuous drug exposure pro-
tocol was used and sulforhodamine B (SRB) protein as-
say was used to estimate cell growth. Details of this test
system have been published.37–39 The anticancer activity
of a test compound is reported for each cell line by three
parameters: GI50 value (GI50, molar concentration of
the compound that inhibits 50% net cell growth), TGI
Figure 2. ORTEP drawing of 23 with atom labeling scheme. Ellipsoids
are drawn at the 50% probability level.
replaced by 4-MeOPh, the resulting compounds 35, 38,
39, and 40 were more active, indicating the importance
of the electron-donating 4-methoxy group. Compound

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Z. Brzozowski et al. / Bioorg. Med. Chem. 15 (2007) 2560–2572
Table 1. GI50 values for the inhibition of in vitro cell growth of six human cancer cell lines by compounds 23, 25–27, 30, 31, 35–38, 41, and 42a
Compound
Meanb
Cell line/GI50 (lM)
5637
RT-4
22.0 8.5
28.6 21.8
>20.0
A-427
LCLC-103H
DAN-G
MCF-7
23
25
26
27
30
31
35
36
37
38
41
42
11.86
12.01
18.43
14.71
16.31
15.10
14.31
3.50
9.6 0.4
7.5 1.2
19.2 2.7
12.6 0.3
13.7 0.8
14.3 1.0
11.9 1.9
2.3 0.7
6.5 0.8
12.1 1.8
6.2 1.0
5.1 0.7
9.2 1.8
8.2 1.5
15.6 0.2
10.2 1.6
12.0 2.7
11.7 1.0
11.2 2.4
4.1 0.7
7.0 1.9
8.4 2.0
3.1 0.7
3.4 0.7
12.4 1.9
11.9 1.4
>20.0
9.9 3.1
9.4 3.4
23.5 5.0
18.7 2.9
23.7 10.7
14.8 4.9
12.3 2.9
3.1 0.6
7.6 2.6
12.0 3.2
9.3 4.4
8.2 2.9
8.1 2.2
6.5 1.0
12.3 0.5
8.7 0.9
10.9 1.0
9.8 1.8
8.1 1.4
2.4 0.7
4.9 1.6
5.8 1.8
3.2 0.5
3.2 1.3
18.5 2.2
18.5 1.3
19.6 5.1
19.1 1.2
>20.0
>20.0
23.1 8.9
6.3 0.6
19.3 3.3
2.8 0.4
9.3 1.3
17.5 5.2
4.6 1.1
5.3 0.5
8.68
16.8 8.0
19.0 5.2
12.46
7.73
7.53
>20.0
>20.0
a Values are averages standard deviation of five to seven independent determinations.
b Averaged GI50 values over all tested cancer cell lines.
value (TGI, molar concentration of the compound lead-
ing to total inhibition of net cell growth), and LC50 val-
ue (LC50, molar concentration of the compound leading
to 50% net cell death).
Analysis of the structure–activity relationships suggests
that electronic effects exerted by substituents R1, R2,
and Ar affect considerably their antitumor potency,
specificity, and selectivity. Thus, compound 23 exhibited
the highest inhibitory activity (GI50 in the range of 0.3–
4.5 lM) against 14 cell lines derived from eight different
human cancer types (Table 3). Substitution of the
phenyl ring at Ar-position with stronger electron-with-
drawing 5-Br-thienyl group produced compound 24
which showed a narrowed response range against three
cell lines only: RPMI-8226 of leukemia (GI50 = 2.1 lM)
and SF-539 of CNS (GI50 = 2.0 lM). Further replace-
ment of 4-ClPh at R2-position in compound 24 by even
stronger electron-withdrawing 2-ClPh yielded analogue
25 with antitumor activity limited to T-47D cell line of
breast cancer (GI50 = 4.9 lM). A similar pattern was
observed for compounds 31, 33, 45, and 46. Thus, com-
pound 31 (R1 = EtOCO, R2 = Ph, Ar = 4-ClPh) exhibit-
ed a high activity against five cell lines, including
leukemia CCRF-CEM (GI50 = 2.5 lM) and RPMI-
8226 (GI50 = 4.2 lM), skin cancer melanoma LOX
IMVI (GI50 = 3.1 lM) as well as breast cancer MCF-7
(GI50 = 4.3 lM) and T-470 (GI50 = 3.8 lM). Analogous
The following is to be noted regarding the tumor cell
growth inhibition data with the tested compounds. All
the compounds (i.e., 23–27, 30, 31, 35, 38, 42, 45, and
46) exhibited structure dependent high or reasonable
activity (GI50 = 0.03–80.8 lM) against most (91–
100%) of the 53–59 human tumor cell lines (Table 2).
The data of the most susceptible cell lines
(GI50 < 5.0 lM) recorded in Table 3 indicate the fol-
lowing rank order of potency: 23 (against 14 cell lines
i.e., leukemia, lung, colon, CNS, melanoma, ovarian,
renal, and breast), 45 (five cell lines i.e., lung, colon,
melanoma, ovarian, and renal), 31 (five cell lines of
leukemia, melanoma and breast), 33 (four cell lines
of leukemia and renal, 35 (three cell lines of leukemia,
lung, and breast), 24 (two cell lines of leukemia and
CNS), 46 (melanoma UACC-257), 30 (melanoma
SK-MEL-2), 26 (leukemia CCRF-CEM), 25 and 42
(against breast T-47D cell line).
Table 2. Overview of the results of the in vitro anticancer screening for compounds 23–27, 30, 31, 33, 35, 38, 42, 45, and 46a
Compound
No. of cell lines investigated
No. of the cell lines giving positive GI50, TGI, and LC50
TGIc (lM)
Range
LC50 (lM)
Range
b
d
GI50 (lM)
No.
Range
No.
No.
23
24
25
26
27
30
31
33
35
38
42
45
46
53
54
55
59
55
55
56
55
55
55
55
57
55
52
54
55
59
55
55
55
56
50
55
53
56
55
0.3–20.0
2.0–46.3
4.9–37.5
3.2–44.4
7.6–31.3
3.2–32.0
2.5–88.1
2.1–36.6
12.1–80.8
1.3–37.7
4.9–66.4
0.6–35.5
0.03–39.6
50
44
47
29
52
49
50
52
19
50
22
50
52
3.5–73.1
2.0–97.1
21.8–89.8
28.7–99.2
20.5–73.6
9.6–97.4
7.4–74.6
11.5–74.9
31.2–98.6
21.9–74.9
39.0–96.3
16.8–64.1
1.3–67.6
36
23
20
3
14.1-91.6
45.9–97.8
51.7–91.9
53.6–89.2
45.3–97.2
54.5–99.2
47.3–92.4
50.0–91.2
64.6–78.5
50.6–97.0
86.9–91.0
19.7–96.9
57.1–99.6
29
15
38
33
3
31
2
39
35
a Data obtained from the NCI’s in vitro disease-oriented human tumor cell screen37–39 (see Table 3 for details).
b The micromolar concentration that inhibits 50% net cell growth.
c The micromolar concentration giving total growth inhibition.
d The micromolar concentration leading to 50% net cell death.

Z. Brzozowski et al. / Bioorg. Med. Chem. 15 (2007) 2560–2572
2565
Table 3. Inhibition of the most susceptible tumor cell lines by selected
compounds 23–26, 30, 31, 33, 38, 42, 45, and 46 (GI50 < 5.0 lM)a
Table 3 (continued)
GI50 (lM) TGIc (lM)
0.03 1.3
b
Compound Panel cell line
b
Compound Panel cell line
GI50 (lM) TGIc (lM)
46
Melanoma
UACC-257
23
Leukemia
CCRF-CEM
RPMI-8226
SR
4.1
2.6
0.3
27.4
14.7
12.4
a Data obtained from NCI’s in vitro disease-oriented human tumor cell
screen.37–39
b The micromolar concentration that inhibits 50% net cell growth.
c The micromolar concentration giving total growth inhibition.
Non-small cell lung cancer
NCI-H226
Colon cancer
COLO 205
HCT-15
1.5
5.9
2.8
2.7
14.8
13.0
compound 33 with 5-Br-thienyl substituent at Ar-posi-
tion exhibited different biological profile and a high anti-
proliferative activity against four cell lines: leukemia
CCRF-CEM (GI50 = 4.5 lM), K-562 (GI50 = 4.7 lM),
MOLT-4 (GI50 = 4.3 lM), and renal cancer ACHN
(GI50 = 2.1 lM). Other modification of 31, consisting
in replacement of EtOCO at R1-position by CN group
with stronger electron-withdrawing properties, gave
compound 45 with high activity against five cell lines:
non-small cell lung cancer NCI-H522 (GI50 = 3.2 lM),
colon cancer HCT-116 (GI50 = 3.7 lM), melanoma
SK-MEL-2 (GI50 = 3.6 lM), ovarian cancer OVCAR-3
CNS cancer
SF-539
1.0
1.5
3.5
7.1
Melanoma
LOX IMVI
Ovarian cancer
IGROVI
2.5
1.5
4.4
31.7
7.1
OVCAR-3
OVCAR-5
Renal cancer
768-0
18.7
4.5
1.9
18.1
10.5
ACHN
Breast cancer
MDA-MB-231/ATCC 2.7
Leukemia
16.0
21.5
9.9
(GI50 = 4.9 lM), and renal cancer TK-10 (GI50
=
24
0.6 lM). Finally, when 4-ClPh at Ar-position in 45
was substituted with 5-Br-thienyl group, the resulting
compound 46 demonstrated significantly enhanced
RPMI-8226
CNS cancer
SF-539
3.7
2.0
4.9
3.2
3.2
potency against melanoma UACC-257 cell line (GI50
0.03 lM, TGI = 1.3 lM).
=
25
26
30
31
Breast cancer
T-47D
Leukemia
23.0
17.2
8.6
CCRF-CEM
Melanoma
SK-MEL-2
Leukemia
3. Conclusion
We have developed a method for the synthesis of new ser-
ies of N-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)aryl-
sulfonamides (23–48). The sulfonamides 23–26, 30, 31, 33,
38, 42, 45, and 46 depending on their structure exhibited
high (GI50 = 0.03–5.0 lM) or reasonable (GI50 = 5.0–
80.8 lM) activity against most of the tumor cell lines inves-
tigated. Compounds 23, 31, 45, and 46 were the most po-
tent of all derivatives tested. Moreover, the compound 46
acting as a potent inhibitor against melanoma UACC-257
cell line (GI50 = 0.03 lM and TGI = 1.3 lM) may serve as
useful lead compound for the search of more powerful
selective antineoplastic agents.
CCRF-CEM
RPMI-8226
Melanoma
LOX IMVI
Breast cancer
MCF-7
2.5
4.2
7.4
19.4
3.1
13.0
4.3
3.8
15.9
23.4
T-47D
Leukemia
33
38
CCRF-CEM
K-562
MOLT-4
4.5
4.7
4.3
18.8
21.1
17.9
Renal cancer
ACHN
Leukemia
2.1
1.3
4.8
4.8
4.9
3.2
3.7
3.6
4.9
0.6
11.5
32.2
18.3
81.9
39.0
17.3
18.0
16.8
17.9
3.6
4. Experimental
CCRF-CEM
Non-small cell lung cancer
HOP-92
The following instruments and parameters were used:
(melting points) Buchi 535 apparatus; (IR spectra) KBr
¨
Breast cancer
T-47D
pellets, 400–4000 cmÀ1 Perkin-Elmer 1600 FTIR spectro-
photometer; (1H and 13C NMR spectra) Varian Gemini
200 apparatus at 200 and 50 MHz, respectively (chemical
shifts are expressed at d values relative to Me4Si as stan-
dard). The starting 6-chloro-1,4,2-benzodithiazine 1,1-di-
oxides 1–8 were obtained according to methods described
previously: 1,31 2 and 3,32 4–633, and 7 and 8.34
42
45
Breast cancer
T-47D
Non-small cell lung cancer
NCI-H522
Colon cancer
HCT-116
Melanoma
SK-MEL-2
Ovarian cancer
OVCAR-3
Renal cancer
TK-10
4.1. 6-Chloro-3-(4-fluoroanilino)-1,1-dioxo-1,4,2-benzodi-
thiazine-7-carboxylic acid (9)
To an ice-cold suspension of 6-chloro-3-methylthio-1,1-
dioxo-1,4,2-benzodithiazine-7-carboxylic acid 1 (48.6 g,

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Z. Brzozowski et al. / Bioorg. Med. Chem. 15 (2007) 2560–2572
0.15 mol) in anhydrous methanol (180 mL) a solution of
triethylamine (15.2 g, 0.15 mol) and 4-fluoroaniline
(18.9 g, 0.17 mol) in anhydrous methanol (30 mL) was
added dropwise with stirring. After 0.5 h the ice bath
was removed and the reaction mixture was refluxed until
the evolution of MeSH had ceased (30–32 h) (caution:
due to a high toxicity, MeSH should be trapped into
an aq NaOH solution). The solvent was evaporated un-
der reduced pressure. The resulting residue was then dis-
solved in water (800 mL) and acidified to pH 6 with 1%
hydrochloric acid. After 6 h of stirring, a small amount
of insoluble side product was filtered out together with
charcoal added, and the filtrate was slowly acidified to
pH 1 with 0.5% hydrochloric acid. The title product,
which precipitated, was immediately collected by filtra-
tion, washed thoroughly with water and hot (50–
60 ꢁC) 2-propanol (4· 15 mL), and dried (40.3 g, 69%):
mp 317–319 ꢁC; IR (KBr) 3265, 3220 (NH, OH), 1715
(C@O), 1620 (C@N), 1325, 1305, 1155, 1140
compound 12 was obtained (22.6 g, 90%): mp 225–
227 ꢁC; IR (KBr) 3250 (NH), 1780, 1740 (O@CACl),
1340, 1315, 1155 (SO2) cmÀ1
.
Anal. Calcd for
C15H10Cl2N2O4S2 (417.30): C, 43.17; H, 2.40; N, 6.71.
Found: C, 43.10; H, 2.38; N, 6.74.
4.2.4. 6-Chloro-3-(4-fluoroanilino)-1,1-dioxo-1,4,2-benzo-
dithiazine-7-carbonyl chloride (13). Starting from benzo-
dithiazinecarboxylic acid 9 (23.2 g), the title compound
13 was obtained (21.3 g, 87%): mp 199–200 ꢁC; IR
(KBr) 3315 (NH), 1770, 1735 (O@CACl), 1335, 1160
(SO2) cmÀ1
.
Anal. Calcd for C14H7Cl2FN2O3S2
(405.27): C, 41.49; H, 1.74; N, 6.91. Found: C, 41.41;
H, 1.86; N, 6.92.
4.3. General procedure for the preparation of ethyl 3-(aryl-
amino)-6-chloro-1,1-dioxo-1,4,2-benzodithiazine-7-carb-
oxylates (14–17)
1
(SO2) cmÀ1; H NMR (DMSO-d6) d 7.23–7.36 (m, 2H,
The corresponding benzodithiazinecarbonyl chloride 10,
11, 12 or 13 (0.03 mol) was added portionwise to 99.9%
ethanol (90 mL), and this was stirred at room tempera-
ture for 3 h. Then to the stirred reaction mixture a solu-
tion of triethylamine (3.34 g, 0.033 mol) in ethanol
(15 mL) was added dropwise. The resulting reaction
mixture was further stirred at room temperature for
1 h, followed at reflux for 2 h. After cooling to room
temperature, the precipitate of the adequate carboxylate
formed was collected by filtration, washed successively
with ethanol (3 mL), water (3· 15 mL), 3% aq KHCO3
solution (3· 15 mL), water (5· 10 mL) and ethanol
(5 mL), and dried at temperatures gradually increasing
to 90 ꢁC.
4-FPh), 7.56–7.68 (m, 2H, 4-FPh), 8.19 (s, 1H, H-5),
8.33 (s, 1H, H-8), 11.63 (s, 1H, NH), 13.50 (s, 1H,
COOH) ppm. Anal. Calcd for C14H8ClFN2O4S2
(386.81): C, 43.47; H, 2.08; N, 7.24. Found: C, 43.50;
H, 2.19; N, 7.19.
4.2. General procedure for the preparation of 3-(aryl-
amino)-6-chloro-1,1-dioxo-1,4,2-benzodithiazine-7-carbonyl
chlorides (10–13)
To a suspension of the corresponding benzodithiazine-
carboxylic acid 6–9 (0.06 mol) in dry benzene (80 mL)
thionyl chloride (80 mL) was added. The reaction mix-
ture was stirred at reflux for 16 h. After cooling to room
temperature and standing overnight the precipitate of
the adequate benzodithiazinecarbonyl chloride was fil-
tered off washed successively with toluene (3· 8 mL)
and benzene (3· 10 mL), then dried at temperatures
gradually increasing to 100 ꢁC. In this manner, the fol-
lowing acyl chlorides were obtained.
In this manner, the following carboxylates were
obtained.
4.3.1. Ethyl 3-anilino-6-chloro-1,1-dioxo-1,4,2-benzodi-
thiazine-7-carboxylate (14). Starting from benzodithia-
zinecarbonyl chloride 10 (11.62 g), the title compound
14 was obtained (11.6 g, 97%): mp 222–223 ꢁC; IR
4.2.1. 3-Anilino-6-chloro-1,1-dioxo-1,4,2-benzodithiazine-
7-carbonyl chloride (10). Starting from benzodithiazine-
carboxylic acid 6 (22.13 g), the title compound 10 was
obtained (20.8 g, 89%): mp 233–235 ꢁC; IR (KBr) 3250
(KBr) 3285 (NH), 1720 (C@O), 1315, 1145 (SO2) cmÀ1
;
1H NMR (DMSO-d6)d 1.36 (t, J = 7.1 Hz, 3H, CH3),
4.39 (q, J = 7.1 Hz, 2H, CH2), 7.29–7.67 (m, 5H, Ph),
8.22 (s, 1H, H-5), 8.38 (s, 1H, H-8), 11.67 (s, 1H, NH)
ppm. Anal. Calcd for C16H13ClN2O4S2 (396.87): C,
48.42; H, 3.30; N, 7.05. Found: C, 48.60; H, 3.39; N, 6.99.
(NH), 1775, 1735 (O@CACl), 1320, 1310, 1195 (SO2) cmÀ1
.
Anal. Calcd for C14H8Cl2N2O3S2 (387.27): C, 43.42; H,
2.08; N, 7.23. Found: C, 43.47; H, 2.12; N, 7.30.
4.3.2. Ethyl 6-chloro-3-(4-chloroanilino)-1,1-dioxo-1,4,2-
benzodithiazine-7-carboxylate (15). Starting from benzo-
dithiazinecarbonyl chloride 11 (12.65 g), the title com-
pound 15 was obtained (12.5 g, 96%): mp 263–264 ꢁC;
IR (KBr) 3275 (NH), 1685 (C@O), 1350, 1155
4.2.2. 6-Chloro-3-(4-chloroanilino)-1,1-dioxo-1,4,2-ben-
zodithiazine-7-carbonyl chloride (11). Starting from ben-
zodithiazinecarboxylic acid
7
(24.2 g), the title
compound 11 was obtained (22.1 g, 87%): mp 215–
217 ꢁC dec; IR (KBr) 3270 (NH), 1780 (O@CACl),
1
(SO2) cmÀ1; H NMR (DMSO-d6)d 1.33 (t, J = 7.3 Hz,
1
1315, 1295, 1195 (SO2) cmÀ1; H NMR (Me2CO-d6) d
3H, CH3), 4.36 (q, J = 7.3 Hz, 2H, CH2), 7.51 (d,
J = 7.8 Hz, 2H, 4-ClPh), 7,67 (d, J = 7,8 Hz, 2H, 4-ClPh),
8.19 (s, 1H, H-5), 8.35 (s, 1H, H-8), 11.27 (s, 1H, NH)
ppm. Anal. Calcd for C16H12Cl2N2O4S2 (431,33): C,
44,55; H, 2.80; N, 6.49. Found: C, 44.62; H, 2.89; N, 6.47.
7.50 (d, J = 8.9 Hz, 2H, 4-ClPh), 7.78 (d, J = 8.9 Hz,
2H, 4-ClPh), 8.07 (s, 1H, H-5), 8.74 (s, 1H, H-8) ppm.
Anal. Calcd for C14H7Cl3N2O3S2 (471.72): C, 39.87;
H, 1.67; N, 6.44. Found: C, 39.76; H, 1.60; N, 6.46.
4.2.3.
6-Chloro-3-(4-methoxyanilino)-1,1-dioxo-1,4,2-
4.3.3. Ethyl 6-chloro-3-(4-methoxyanilino)-1,1-dioxo-
1,4,2-benzodithiazine-7-carboxylate (16). Starting from
benzodithiazinecarbonyl chloride 12 (12.52 g), the title
benzodithiazine-7-carbonyl chloride (12). Starting from
benzodithiazinecarboxylic acid 8 (23.9 g), the title

Z. Brzozowski et al. / Bioorg. Med. Chem. 15 (2007) 2560–2572
2567
compound 16 was obtained (10.1 g, 78%): mp 232–
233 ꢁC; IR (KBr) 3260 (NH), 1720 (C@O), 1305, 1160,
(200 mL) 28% ammonia solution (25 mL) was added
dropwise with stirring. After 1 h the ice-bath was re-
moved and the reaction mixture was stirred at room
temperature for 10 h. The precipitate of the adequate
carboxamide formed was filtered off, washed thoroughly
with water, and dried. In this manner, the following
carboxamides were obtained.
1145 (SO2) cmÀ1
;
1H NMR (DMSO-d6)d 1.34 (t,
J = 7.1 Hz, 3H, CH3), 3.77 (s, 3H, CH3O), 4.36 (q,
J = 7.1 Hz, 2H, CH2), 7.01 (d, J = 8.4 Hz, 2H, 4-MeOPh),
7,52 (d, J = 8.4 Hz, 2H, 4-MeOPh), 8.19 (s, 1H, H-5), 8.33
(s, 1H, H-8), 11.52 (s, 1H, NH) ppm. Anal. Calcd for
C17H15ClN2O5S2 (426.90): C, 47.93; H, 3.54; N, 6.56.
Found: C, 47.82; H, 3.68; N, 6.60.
4.5.1. 3-Anilino-6-chloro-1,1-dioxo-1,4,2-benzodithiazine-
7-carboxamide (19). Starting from benzodithiazinecar-
bonyl chloride 10 (19.4 g), the title compound 19 was
obtained (17.5 g, 95%): mp 307–308 ꢁC; IR (KBr)
3435, 3325, 3255, 3200 (NH2 and NH), 1675 (C@O),
4.3.4. Ethyl 6-chloro-3-(4-fluoroanilino)-1,1-dioxo-1,4,2-
benzodithiazine-7-carboxylate (17). Starting from ben-
zodithiazinecarbonyl chloride 13 (12.16 g), the title
compound 17 was obtained (11.5 g, 92%): mp 248–
249 ꢁC; IR (KBr) 3270 (NH), 1685 (C@O), 1325,
1610 (C@N), 1325, 1140 (SO2) cmÀ1
;
1H NMR
(DMSO-d6) d 7.38–7.67 (m, 5H, Ph), 7.87 (s, 1H, CON-
Ha), 7.99 (s, 1H, H-5), 8.14 (s, 1H, H-8), 8.19 (s, 1H,
CONHb), 11.60 (s, 1H, NH) ppm. Anal. Calcd for
C14H10ClN3O3S2 (367.84): C, 45.71; H, 2.74; N, 11.42.
Found: C, 45.66; H, 2.80; N, 11.47.
1170, 1155 (SO2) cmÀ1 1H NMR (DMSO-d6)d 1.34
;
(t, J = 7.1 Hz, 3H, CH3), 4.38 (q, J = 7.1 Hz, 2H,
CH2), 7.29–7.33 (m, 2H, 4-FPh), 7.50–7.65 (m, 2H,
4-FPh), 8.22 (s, 1H, H-5), 8.35 (s, 1H, H-8), 11.66
(s, 1H, NH) ppm. Anal. Calcd for C16H13ClFN2O4S2
(415.87): C, 46.21; H, 3.15; N, 6.73. Found: C, 46.32;
H, 3.21; N, 6.78.
4.5.2. 6-Chloro-3-(4-chloroanilino)-1,1-dioxo-1,4,2-ben-
zodithiazine-7-carboxamide (20). Starting from benzodi-
thiazinecarbonyl chloride 11 (21.1 g), the title
compound 20 was obtained (19.5 g, 97%): mp 317–
318 ꢁC dec; IR (KBr) 3440, 3340 (NH2), 3280 (NH),
1660 (C@O), 1610 (C@N), 1320, 1155, 1140 (SO2)
4.4. Synthesis of 8-quinolyl 6-chloro-3-(4-fluoroanilino)-
1,1-dioxo-1,4,2-benzodithiazine-7-carboxylate (18)
To a solution of 8-hydroxyquinoline (2.25 g, 0.0155 mol)
in anhyd p-dioxane (50 mL) benzodithiazinecarbonyl
chloride 13 (6.1 g, 0.015 mol) was added portionwise
with stirring. The reaction mixture was stirred at room
temperature for 2 h, followed at reflux for 4 h. After
cooling to room temperature and standing overnight
the precipitate of the crude benzodithiazine hydrochlo-
ride (18ÆHCl) was collected by filtration, washed with
p-dioxane (3· 5 mL), and dried (7.8 g, 94%); mp 171–
174 ꢁC dec; IR (KBr) 3245 (NH), 2850, 2560, 2435,
cmÀ1 1H NMR (DMSO-d 6) d 7.59 (d, J = 8.8 Hz,
;
2H, 4-ClPh), 7.69 (d, J = 8.8 Hz, 2H, 4-ClPh), 7.88 (s,
1H, CONHa), 8.00 (s, 1H, H-5), 8.15 (s, 1H, H-8),
8.19 (s, 1H, CONHb), 11.67 (s, 1H, NH) ppm. Anal.
Calcd for C14H9ClN3O3S2 (402.29): C, 41.80; H, 2.25;
N, 10.44. Found: C, 41.76; H, 2.41; N, 10.40.
4.6. Procedure for the preparation of 3-(arylamino)-6-
chloro-1,1-dioxo-1,4,2-benzodithiazine-7-carbonitriles
(21–22)
2320, 2250 (NH+), 1760 (C@O), 1315, 1160 (SO2) cmÀ1
.
Anal. Calcd for C23H14Cl2FN3O4S2 (550.42): N, 7.63.
Found: N, 7.36. The crude benzodithiazine hydrochlo-
ride 18ÆHCl (7.7 g, 0.014 mol) was added to a solution
of KHCO3 (1.6 g, 0.016 mol) in water (100 mL), and
the reaction mixture was stirred at room temperature
for 1 h. The precipitate of title product 18 was collected
by filtration, washed thoroughly with water and acetone
(2· 2 mL), and dried, at temperatures gradually increas-
ing to 100 ꢁC (5.8 g, 75%); mp 277–278 ꢁC dec; IR (KBr)
3265 (NH), 1760 (C@O), 1625 (C@N), 1320, 1160
A stirred mixture of the appropriate carboxamide 19
and 20 (0.04 mol) and phosphorus oxychloride
(130 mL) was refluxed for 25 h. After cooling to room
temperature the precipitate was collected by filtration
and then was poured onto crushed ice (700 g) with vig-
orously stirring for at least 1 h. The precipitate of the
adequate nitrile was filtered off, washed thoroughly with
several portions of cold water (pH 7) and acetone (4·
3 mL), and dried.
1
(SO2) cmÀ1; H NMR (DMSO-d6) d 7.33 (t, J = 8.3 Hz,
In this manner, the following nitriles were obtained.
2H, H-3, and H-6, quinoline), 7.63–7.67 (m, 4H, 4-
FPh), 8.02 (d, J = 8.3 Hz, 1H, quinoline), 8.37 (s, 1H,
H-5, benzodithiazine), 8.52 (d, J = 8.3 Hz, 1H, quino-
line), 8.83 (s, 1H, H-8, benzodithiazine) 8.92 (d,
J = 8.3 Hz, 1H, quinoline), 11.74 (s, 1H, NH) ppm. Anal.
Calcd for C23H13ClFN3O4S2 (513.75): C, 53.75; H, 2.55;
N, 8.17. Found: C, 53.70; H, 2.64; N, 8.19.
4.6.1. 3-Anilino-6-chloro-1,1-dioxo-1,4,2-benzodithiazine-
7-carbonitrile (21). Starting from carboxamide 19 (14.7
g), the title compound 21 was obtained (13.1 g, 93%):
mp 292-294 ꢁC; IR (KBr) 3285 (NH), 2230 (C „ N),
1
1610 (C @ N), 1330, 1310, 1150 (SO2) cmÀ1; H NMR
(DMSO-d6) d 7.44–7.66 (m, 5H, Ph), 8.39 (s, 1H, H-5),
8.61 (s, 1H, H-8), 11,74 (s, 1H, NH) ppm. Anal. Calcd
for C14H8ClN3O2S2 (349.82): C, 48.07; H, 2.30; N,
12.01. Found: C, 48.12; H, 2.41; N, 12.02.
4.5. Procedure for the preparation of 3-(arylamino)-6-
chloro-1,1-dioxo-1,4,2-benzodithiazine-7-carboxamides
(19 and 20)
4.6.2. 6-Chloro-3-(4-chloroanilino)-1,1-dioxo-1,4,2-ben-
zodithiazine-7-carbonitrile (22). Starting from carboxam-
ide 20 (16.1 g), the title compound 22 was obtained
(13.9 g, 90%): mp 281–282 ꢁC; IR (KBr) 3275 (NH),
To an ice-cold suspension of the appropriate 3-
(arylamino)-6-chloro-1,1-dioxo-1,4,2-benzodithiazine-7-
carbonyl chloride 10 and 11 (0.05 mol) in benzene

2568
Z. Brzozowski et al. / Bioorg. Med. Chem. 15 (2007) 2560–2572
2235 (C@N), 1608 (C@N), 1345, 1320, 1150 (SO2) cmÀ1
;
50%): mp 217–218 ꢁC; IR (KBr) 1585 (C@N), 1385,
1
1H NMR (DMSO-d6) d 7.52 (d, J = 8.8 Hz, 2H, 4-
ClPh), 7.66 (d, J = 8.8 Hz, 2H, 4-ClPh), 8.37 (s, 1H,
H-5), 8.60 (s, 1H, H-8), 11,82 (s, 1H, NH) ppm. Anal.
Calcd for C14H7Cl2N3O2S2 (384.28): C, 43.75; H, 1.84;
N, 10.93. Found: C, 43.68; H, 2.00; N, 10.90.
1350, 1335, 1180, 1165 (SO2) cmÀ1; H NMR (DMSO-
d6) d 2.44 (s, 3H, CH3), 7.53 (d, J = 3.9 Hz, 1H, H-4,
thiophene), 7.60–7.62 (m, 1H, 2-ClPh), 7.70-7.74 (m,
1H, 2-ClPh), 7.79–7.82 (m, 2H, 2-ClPh), 7.84 (d,
J = 3.9 Hz, 1H, H-3, thiophene), 7.92 (s, 1H, H-5, ben-
zodithiazine), 8.14 (s, 1H, H-8, benzodithiazine) ppm.
Anal. Calcd for C18H11BrCl2N2O4S4 (598.37): C,
36.13; H, 1.85; N, 4.68. Found: C, 36.02; H, 1.98; N, 4.63.
4.7. General procedure for the preparation of N-(6-chloro-
1,1-dioxo-1,4,2-benzodithiazin-3-yl)arylsulfonamides
(23–48)
4.7.4. N-(Dimethylamino)-N-(6-chloro-7-methyl-1,1-
dioxo-1,4,2-benzodithiazin-3-yl)-4-chlorobenzenesulfon-
amide (26). Starting from hydrazinobenzodithiazine 4 (2.4
g) and 4-chlorobenzenesulfonyl chloride (1.9 g) the title
compound 26 was obtained (1.5 g, 50%): mp 170–171 ꢁC
dec; IR (KBr) 1575 (C@N), 1370, 1345, 1180, 1160
To a suspension of the corresponding 3-aminobenzodi-
thiazine 2–5, 14–20 (8 mmol) in dry pyridine (1.8 mL/
1 g) the appropriate arylsulfonyl chloride (9 mmol) was
added with stirring.
1
The solution obtained was stirred at room temperature
for 8 h, followed at 50–55 ꢁC for 3 h. After cooling to
room temperature the suspension was left overnight.
The precipitate was collected by filtration, washed succes-
sively with pyridine (2· 1 mL), and toluene (4· 4 mL),
dried, and purified by crystallization from acetonitrile.
(SO2) cmÀ1; H NMR (DMSO-d6) d 2.39 (s, 3H, CH3-7),
3.11 (s, 6H, CH3NCH3), 7.78 (d, J = 8.9 Hz, 2H,
4-ClPh), 7.95 (s, 1H, H-5), 7.98 (s, 1H, H-8), 8.08 (d,
J = 8.9 Hz, 2H, 4-ClPh) ppm; 13C NMR (DMSO-d6)d
19.56, 44.98, 126.86, 127.13, 128.52, 128.79, 129.83,
131.67, 136.02, 138.14, 138.84, 140.61, 164.59, ppm. Anal.
Calcd for C16H15Cl2N3O4S3 (480.40): C, 40.00; H, 3.14;
N, 8.75. Found: C, 40.12; H, 3.11; N, 8.90.
In this manner, the following sulfonamides were
obtained.
4.7.5. Methyl 6-chloro-3-[N-(dimethylamino)-4-chloro-
benzenesulfonamido]-1,1-dioxo-1,4,2-benzodithiazine-7-car-
boxylate (27). Starting from hydrazinobenzodithiazine 5
(2.8 g) and 4-chlorobenzenesulfonyl chloride (1.9 g) the
title compound 27 was obtained (1.5 g, 43%): mp 180–
181 ꢁC dec; IR (KBr) 1740 (C@O), 1590 (C@N), 1360,
4.7.1. N-(4-Chlorophenyl)-N-(6-chloro-7-methyl-1,1-
dioxo-1,4,2-benzodithiazin-3-yl)benzenesulfonamide (23).
Starting from aminobenzodithiazine 2 (2.99 g) and ben-
zenesulfonyl chloride (1.6 g) the title compound 23 was
obtained (2.8 g, 68%): mp 233–235 ꢁC; IR (KBr) 1590
1
1
(C@N), 1365, 1345, 1325, 1180, 1155 (SO2) cmÀ1; H
1340, 1330, 1185, 1170 (SO2) cmÀ1; H NMR (DMSO-
NMR (CDCl3)
d
2.43 (s, 3H, CH3), 7.27 (d,
d6) d 3.13 (s, 6H, CH3NCH3), 3.88 (s, 3H, CH3O), 7.79
(d, J = 8.8 Hz, 2H, 4-ClPh), 8.09 (d, J = 8.8 Hz, 2H,
4-ClPh), 8.17 (s, 1H, H-5), 8.31 (s, 1H, H-8) ppm; 13C
NMR (DMSO-d6) d 44.98, 53.38, 127.05, 127.19,
127.51, 129.88, 130.89, 131.74, 135.47, 135.79, 136.09,
140.76, 163.54, 164.31 ppm. Anal. Calcd for
C17H15Cl2N3O6S3 (524.43): C, 38.96; H, 2.88; N, 8.02.
Found: C, 36.91; H, 2.90; N, 8.16.
J = 8.7 Hz, 2H, 4-ClPh), 7.55 (d, J = 8.7 Hz, 2H,
4-ClPh), 7.60–7.66 (m, 3H, PhSO2 and H-5), 7.73 (t,
J = 7.4 Hz, 1H, PhSO2), 7.96 (s, 1H, H-8), 8.13 (d,
J = 7.4 Hz, 2H, PhSO2) ppm. Anal. Calcd for
C20H14Cl2N2O4S3 (513.44): C, 46.78; H, 2.75; N, 5.45.
Found: C, 46.71; H, 2.82; N, 5.49.
4.7.2. N-(4-Chlorophenyl)-N-(6-chloro-7-methyl-1,1-
dioxo- 1,4,2-benzodithiazin-3-yl)-5-bromothiophene-2-sul-
fonamide (24). Starting from aminobenzodithiazine 2
(2.99 g) and 5-bromothiophene-2-sulfonyl chloride (2.35 g)
the title compound 24 was obtained (3.8 g, 79%): mp
192–194 ꢁC; IR (KBr) 1590 (C@N), 1385, 1355, 1335,
1170 (SO2) cmÀ1; 1H NMR (CDCl3)d 2.45 (s, 3H, CH3),
7.19 (d, J = 3.9 Hz, 1H, H-4, thiophene), 7.25 (s, 1H, H-
5, benzodithiazine), 7.35 (d, J = 8.7 Hz, 2H 4-ClPh),
7.54 (d, J = 8.7 Hz, 2H, 4-ClPh), 7.83 (d, J = 3.9 Hz,
1H, H-3, thiophene), 8.01 (s, 1H, H-8, benzodithiazine)
ppm; 13C NMR (CDCl3)d 20.34, 125.30, 127.27, 127.78,
127.89, 127.94, 131.01, 131.22, 132.11, 132.73, 136.89,
138.46, 138.85, 139.40, 139.72, 162.37 ppm.
4.7.6. Methyl 6-chloro-3-[N-(dimethylamino)-2,4-dichloro-
benzenesulfonamido]-1,1-dioxo-1,4,2-benzodithiazine-7-car-
boxylate (28). Starting from hydrazinobenzodithiazine 5
(2.8 g) and 2,4-dichlorobenzenesulfonyl chloride (2.21 g)
the title compound 28 was obtained (1.5 g, 33%): mp
236–238 ꢁC dec; IR (KBr) 1730 (C@O), 1580 (C@N),
1375, 1345, 1335, 1175, 1140 (SO2) cmÀ1 1H NMR
;
(DMSO-d6)d 3.18 (s, 6H, CH3NCH3), 3.87 (s, 3H,
CH3O), 7.99 (dd, Jortho = 8.8 Hz, Jmeta = 2.1 Hz, 1H, H-
5, 2,4-doClPh), 8.00 (d, Jmeta = 2.1 Hz, H-3, 2,4-diClPh),
8.19 (d, Jortho = 8.8 Hz, 1H, H-6, 2,4-diClPh), 8.21 (s, 1H,
H-5), 8.27 (s, 1H, H-8) ppm; 13C NMR (DMSO-d6)d
45.14, 53.38, 127.19, 127.57, 128.76, 130.98, 131.16,
132.04, 133.10, 134.69, 135.12, 135.21, 136.14, 141.26,
163.53, 164.83 ppm. Anal. Calcd for C17H14Cl3N3O6S3
(558.87): C, 36.53; H, 2.52; N, 7.52. Found: C, 36.54; H,
2.70; N, 7.61.
Anal. Calcd for C18H11BrCl2N2O4S4 (598.37): C, 36.13;
H, 1.85; N, 4.68. Found: C, 36.18; H, 1.96; N, 4.72.
4.7.3. N-(2-Chlorophenyl)-N-(6-chloro-7-methyl-1,1-
dioxo-1,4,2-benzodithiazin-3-yl)-5-bromothiophene-2-sul-
fonamide (25). Starting from aminobenzodithiazine 3
(2.99 g) and 5-bromothiophene-2-sulfonyl chloride
(2.35 g) the title compound 25 was obtained (2.4 g,
4.7.7.
Methyl
6-chloro-3-[N-(dimethylamino)benze-
nesulfonamido]-1,1-dioxo-1,4,2-benzodithiazine-7-carbox-
ylate (29). Starting from hydrazinobenzodithiazine 5
(2.8 g) and 2,4-dichlorobenzenesulfonyl chloride

Z. Brzozowski et al. / Bioorg. Med. Chem. 15 (2007) 2560–2572
2569
(1.59 g) the title compound 29 was obtained (3.1 g,
79%): mp 234–236 ꢁC dec; IR (KBr) 1740 (C@O),
C20H14BrClN2O6S4 (621.95): C, 38.62; H, 2.26; N,
4.50. Found: C, 48.54; H, 2.35; N, 4.50.
1585 (C@N), 1370, 1325, 1170, 1140 (SO2) cmÀ1 1H
;
NMR (DMSO-d6)d 3.14 (s, 6H, CH3NCH3), 3.87 (s,
3H, CH3O), 7.68–7.87 (m, 3H, PhSO2), 8.07-8.12 (m,
2H, PhSO2), 8.16 (s, 1H, H-5), 8.30 (s, 1H, H-8) ppm.
Anal. Calcd for C17H16ClN3O6S3 (489.98): C, 46.67;
H, 3.29; N, 8.57. Found: C, 46.65; H, 3.36; N, 8.56.
4.7.12. Ethyl 6-chloro-3-[N-(4-chlorophenyl)-5-bromothio-
phene-2-sulfonamido]-1,1-dioxo-1,4,2-benzodithiazine-7-
carboxylate (34). Starting from aminobenzodithiazine
15 (3.45 g) and 5-bromothiophene-2-sulfonyl chloride
(2.35 g) the title compound 34 was obtained (4.0 g,
76%): mp 245–246 ꢁC dec; IR (KBr) 1730 (C@O),
1370, 1345, 1185, 1165 (SO2) cmÀ1; 1H NMR (DMSO-
d6) d 1.33 (t, J = 7.1 Hz, 3H, CH3), 4.36 (q, J = 7.1 Hz,
2H, CH2), 7.54 (d, J = 4.1 Hz, 1H, H-4, thiophene),
7.68 (d, J = 9.6 Hz, 2H, 4-ClPh), 7.73 (d, J = 9.6 Hz,
2H, 4-ClPh), 7.80 (d, J = 4.1 Hz, 1H, H-3, thiophene),
8.11 (s, 1H, H-5), 8.41 (s, 1H, H-8) ppm. Anal. Calcd
for C20H13BrCl2N2O6S4 (656.40): C, 35.59; H, 1.99; N,
4.26. Found: C, 35.57; H, 2.10; N, 4.28.
4.7.8. Methyl 6-chloro-3-[N-(dimethylamino)-5-bromothio-
phene-2-sulfonamido]-1,1-dioxo-1,4,2-benzodithiazine-7-
carboxylate (30). Starting from hydrazinobenzodithi-
azine
5
(2.8 g) and 5-bromothiophene-2-sulfonyl
chloride (2.35 g) the title compound 30 was obtained
(1.9 g, 41%): mp 185–187 ꢁC dec; IR (KBr) 1745
(C@O), 1585 (C@N), 1380, 1330, 1175, 1165, 1135
(SO2) cmÀ1
;
1H NMR (DMSO-d6)d 3.08 (s, 6H,
CH3NCH3), 3.89 (s, 3H, CH3O), 7.52 (d, J = 4.2 Hz,
1H, H-4, thiophene), 7.89 (d, J = 4.2 Hz, 1H, H-3, thio-
phene), 8.20 (s, 1H, H-5), 8.37 (s, 1H, H-8) ppm; 13C
NMR (DMSO-d6) d 44.75, 53.39, 125.26, 127.14,
127.58, 130.94, 131.11, 132.09, 135.56, 136.15, 137.35,
138.83, 163.56, 164.31 ppm. Anal. Calcd for
C15H13BrClN3O6S4 (574.90): C, 31.34; H, 2.28; N,
7.31. Found: C, 31.30; H, 2.35; N, 7.52.
4.7.13. Ethyl 6-chloro-3-[N-(4-methoxyphenyl)-4-chloro-
benzenesulfonamido]-1,1-dioxo-1,4,2-benzodithiazine-7-car-
boxylate (35). Starting from aminobenzodithiazine 16
(3.44 g) and 4-chlorobenzenesulfonyl chloride (1.9 g) the
title compound 35 was obtained (3.9 g, 81%): mp 261–
263 ꢁC; IR (KBr) 1730 (C@O), 1605 (C@N), 1370,
1345, 1185, 1165 (SO2) cmÀ1 1H NMR (DMSO-d6)d
;
1.31 (t, J = 7.0 Hz, 3H, CH3), 3.88 (s, 3H, CH3O), 4.34
(q, J = 7.0 Hz, 2H, CH2), 7.16 (d, J = 9.0 Hz, 2H,
4-MeOPh), 7.57 (d, J = 9.0 Hz, 2H, 4-MeOPh), 7.82 (d,
J = 8.8 Hz, 2H, 4-ClPhSO2), 8.04 (d, J = 8.8 Hz, 2H,
4-ClPhSO2), 8.08 (s, 1H, H-5), 8.33 (s, 1H, H-8) ppm.
Anal. Calcd for C23H18Cl2N2O7S3 (601.51): C, 45.92; H,
3.01; N, 4.65. Found: C, 45.90; H, 3.12; N, 4.71.
4.7.9. Ethyl 6-chloro-3-[N-phenyl-4-chlorobenzenesulfo-
namido]-1,1-dioxo-1,4,2-benzodithiazine-7-carboxylate (31).
Starting from aminobenzodithiazine 14 (3.17 g) and 4-
chlorobenzenesulfonyl chloride (1.9 g) the title compound
31 was obtained (3.2 g, 70%): mp 236–237 ꢁC; IR (KBr)
1730 (C@O), 1380, 1370, 1345, 1185, 1165 (SO2) cmÀ1
;
1H NMR (DMSO-d6)d 1.31 (t, J = 7.0 Hz, 3H, CH3),
4.36 (q, J = 7.0 Hz, 2H, CH2), 7.67 (s, 5H, Ph), 7.82 (d,
J = 8.4 Hz, 2H, 4-ClPh), 8.04 (s, 1H, H-5), 8.08 (d,
J = 8.4 Hz, 2H, 4-ClPh), 8.34 (s, 1H, H-8) ppm. Anal.
Calcd for C22H16Cl2N2O6S4 (571.49): C, 46.23; H, 2.82;
N, 4.90. Found: C, 46.32; H, 2.97; N, 4.97.
4.7.14. Ethyl 6-chloro-3-[N-(4-methoxyphenyl)-2,4-di-
chlorobenzenesulfonamido]-1,1-dioxo-1,4,2-benzodithiazine-
7-carboxylate (36). Starting from aminobenzodithiazine
16 (3.44 g) and 2,4-dichlorobenzenesulfonyl chloride
(2.21 g) the title compound 36 was obtained (3.3 g,
64%): mp 229–231 ꢁC; IR (KBr) 1720 (C@O), 1600
1
(C@N), 1380, 1340, 1180, 1165, 1145 (SO2) cmÀ1; H
4.7.10. Ethyl 6-chloro-3-[N-phenyl-4-nitrobenzenesulfon-
amido]-1,1-dioxo-1,4,2-benzodithiazine-7-carboxylate (32).
Starting from aminobenzodithiazine 14 (3.17 g) and 4-
nitrobenzenesulfonyl chloride (2.0 g) the title compound
32 was obtained (3.7 g, 79%): mp 200–201 ꢁC; IR (KBr)
1740 (C@O), 1535, 1260 (NO2), 1380, 1350, 1185, 1175
NMR (DMSO-d6)d 1.31 (t, J = 7.1 Hz, 3H, CH3), 3.88
(s, 3H, CH3O), 4.34 (q, J = 7.1 Hz, 2H, CH2), 7.20 (d,
J = 9.0 Hz, 2H, 4-MeOPh), 7.67 (d, J = 9.0 Hz, 2H,
4-MeOPh), 7.83 (d, Jortho = 8.5 Hz, 1H, 2,4-diClPhSO2),
7.95 (dd, Jortho = 8.5 Hz, Jmeta = 2.6 Hz, 1H, 2,4-di-
ClPhSO2), 8.09 (s, 1H, H-5), 8.29 (d, Jmeta = 2.6 Hz,
1H, 2,4-diClPhSO2), 8.30 (s, 1H, H-8) ppm. Anal. Calcd
for C23H17Cl3N2O7S3 (635.95): C, 43.44; H, 2.69; N,
4.40. Found: C, 43.48; H, 2.76; N, 4.50.
(SO2) cmÀ1 1H NMR (DMSO-d6)d 7.74 (s, 5H, Ph),
;
8.07 (s, 1H, H-5), 8.35 (s, 1H, H-8), 8.37 (d, J = 8.8 Hz,
2H, 4-O2NPh), 8.53 (d, J = 8.8 Hz, 2H, 4-O2NPh) ppm.
Anal. Calcd for C22H16ClN3O8S3 (582.04): C, 45.40; H,
2.77; N, 7.22. Found: C, 45.49; H, 2.90; N, 7.11.
4.7.15. Ethyl 6-chloro-3-[N-(4-methoxyphenyl)benze-
nesulfonamido]-1,1-dioxo-1,4,2-benzodithiazine-7-carbox-
ylate (37). Starting from aminobenzodithiazine 16
(3.44 g) and benzenesulfonyl chloride (1.59 g) the title
compound 37 was obtained (3.8 g, 83%): mp 219–
221 ꢁC; IR (KBr) 1730 (C@O), 1605 (C@N), 1370,
4.7.11. Ethyl 6-chloro-3-[N-phenyl-5-bromothiophene-2-
sulfonamido]-1,1-dioxo-1,4,2-benzodithiazine-7-carboxyl-
ate (33). Starting from aminobenzodithiazine 14 (3.17 g)
and 5-bromothiophene-2-sulfonyl chloride (2.35 g) the
title compound 33 was obtained (4.0 g, 80%): mp 209–
210 ꢁC; IR (KBr) 1735 (C@O), 1390, 1380, 1345, 1165
1
1340, 1185, 1170, 1150 (SO2) cmÀ1; H NMR (DMSO-
1
(SO2) cmÀ1; H NMR (DMSO-d6)d 1.33 (t, J = 7.1 Hz,
d6) d 1.31 (t, J = 7.0 Hz, 3H, CH3), 3.89 (s, 3H,
CH3O), 4.34 (q, J = 7.0 Hz, 2H, CH2), 7.19 (d,
J = 9.0 Hz, 2H, 4-MeOPh), 7.55 (d, J = 9.0 Hz, 2H,
4-MeOPh), 7.69–7.85 (m, 3H, PhSO2), 8.04 (m, 2H,
PhSO2), 8.08 (s, 1H, H-5), 8.32 (s, 1H, H-8) ppm. Anal.
3H, CH3), 4.36 (q, J = 7.1 Hz, 2H, CH2), 7.54 (d,
J = 4.2 Hz, 1H, H-4, thiophene), 7.36–7.68 (m, 5H,
Ph), 7.80 (d, J = 4.2 Hz, 1H, H-3, thiophene), 8.07 (s,
1H, H-5), 8.40 (s, 1H, H-8) ppm. Anal. Calcd for

2570
Z. Brzozowski et al. / Bioorg. Med. Chem. 15 (2007) 2560–2572
Calcd for C23H19ClN2O7S3 (567.06): C, 48.72; H, 3.37;
N, 4.94. Found: C, 48.82; H, 3.44; N, 4.87.
4-ClPhSO2) ppm. Anal. Calcd for C29H16Cl2FN3O6S3
(688.57): C, 50.58; H, 2.34; N, 6.10. Found: C, 50.63;
H, 2.29; N, 6.26.
4.7.16. Ethyl 6-chloro-3-[N-(4-fluorophenyl)-4-methoxy-
benzenesulfonamido]-1,1-dioxo-1,4,2-benzodithiazine-7-car-
boxylate (38). Starting from aminobenzodithiazine 17
(3.33 g) and 4-methoxybenzenesulfonyl chloride (1.86 g)
the title compound 38 was obtained (3.3 g, 70%): mp
223–224 ꢁC; IR (KBr) 1725 (C@O), 1590 (C@N), 1365,
4.7.20. 8-Quinolyl 6-chloro-3-[N-(4-fluorophenyl)-5-
bromothiophene-2-sulfonamido]-1,1- dioxo-1,4,2-benzodi-
thiazine-7-carboxylate (42). Starting from aminobenzo-
dithiazine 18 (4.11 g) and 5-bromothiophene-2-sulfonyl
chloride (2.35 g) the title compound 42 was obtained
(3.3 g, 55%): mp 234–235 ꢁC; IR (KBr) 1750 (C@O),
1600 (C@N), 1395, 1385, 1330, 1175, 1175, 1165 (SO2)
cmÀ1; 1H NMR (DMSO-d6) d 7.47–7.83 (m, 9H, arom.),
7.88 (dd, Jortho = 8.2 Hz, Jmeta = 1.6 Hz, 1H, quinoline),
8.24 (s, 1H, H-5, benzodithiazine), 8.51 (dd,
Jortho = 8.2 Hz, Jmeta = 1.6 Hz, 1H, quinoline), 8.87
(s, 1H, H-8, benzodithiazine), 8.91 (dd, Jortho = 4.2 Hz,
Jmeta = 1.6 Hz, 1H, quinoline) ppm. Anal. Calcd for
C27H14BrClFN3O6S4 (739.04): C, 43.88; H, 1.91; N,
5.68. Found: C, 43.81; H, 2.03; N, 5.75.
1
1340, 1170, 1135 (SO2) cmÀ1; H NMR (DMSO-d6) d
1.32 (t, J = 7.1 Hz, 3H, CH3), 3.89 (s, 3H, CH3O), 4.35
(q, J = 7.1 Hz, 2H, CH2), 7.23 (d, J = 9.1 Hz, 2H, 4-
MeOPh), 7.46–7.54 (m, 2H, 4-FPh), 7.66–7.73 (m, 2H,
4-FPh), 7.99 (d, J = 9.1 Hz, 2H, 4-MeOPh), 8.06 (s, 1H,
H-5), 8.35 (s, 1H, H-8) ppm; 13C NMR (DMSO-d6) d
14.17, 56.39, 62.50, 115.02, 117.54, 118.00, 127.22,
127.46, 128.01, 131.18, 131.70, 132.49, 133.74, 133.94,
136.10, 162.44, 163.15, 164.81, 166.30 ppm. Anal. Calcd
for C23H18ClFN2O7S3 (585.05): C, 47.22; H, 3.10; N,
4.78. Found: C, 47.20; H, 3.16; N, 4.85.
4.7.21. N-(6-Chloro-7-cyano-1,1-dioxo-1,4,2-benzodithia-
zin-3-yl)-N-phenyl-4-nitrobenzenesulfonamide (43). Start-
ing from aminobenzodithiazine 21 (2.8 g) and 4-
nitrobenzenesulfonyl chloride (2.0 g) the title compound
43 was obtained (2.7 g, 63%): mp 270–271 ꢁC; IR (KBr)
2235 (C@N), 1605 (C@N), 1375, 1350, 1335, 1170 (SO2)
4.7.17. Ethyl 6-chloro-3-[N-(4-fluorophenyl)-4-chloro-
benzenesulfonamido]-1,1-dioxo-1,4,2-benzodithiazine-7-
carboxylate (39). Starting from aminobenzodithiazine 17
(3.33 g) and 4-chlorobenzenesulfonyl chloride (1.9 g) the
title compound 39 was obtained (3.0 g, 61%): mp 235–
237 ꢁC; IR (KBr) 1730 (C@O), 1605 (C@N), 1370,
1
cmÀ1; H NMR (DMSO-d6)d 7.42 (s, 5H, Ph), 8.25 (s,
1
1345, 1180, 1165 (SO2) cmÀ1; H NMR (DMSO-d6)d
1H, H-5), 8.36 (d, J = 8.4 Hz, 2H, 4-O2NPh), 8.54 (d,
J = 8.4 Hz, 2H, 4-O2NPh), 8.71 (s, 1H, H-8) ppm. Anal.
Calcd for C20H11ClN4O6S3 (534.98): C, 44.90; H, 2.07;
N, 10.42. Found: C, 45.06; H, 2.11; N, 10.52.
1.31 (t, J = 7.1 Hz, 3H, CH3), 4.34 (q, J = 7.1 Hz, 2H,
CH2), 7.47–7.56 (m, 2H, arom.), 7.74–7.83 (m, 4H,
arom.), 8.06 (d, J = 9.8 Hz, 2H, 4-ClPhSO2), 8.09 (s,
1H, H-5), 8.34 (s, 1H, H-8) ppm; 13C NMR (DMSO-
d6)d 14.14, 62.51, 117.61, 118.07, 127.29, 129.97,
131.18, 131.77, 133.58, 133.92, 134.12, 135.97, 136.17,
140.77, 161.45, 162.65, 163.12, 166.43 ppm. Anal. Calcd
for C22H15Cl2FN2O6S3 (589.48): C, 48.82; H, 2.56; N,
4.75. Found: C, 48.79; H, 2.61; N, 4.77.
4.7.22. N-(6-Chloro-7-cyano-1,1-dioxo-1,4,2-benzodithia-
zin-3-yl)-N-phenyl-3-nitrobenzenesulfonamide (44). Start-
ing from aminobenzodithiazine 21 (2.8 g) and 3-
nitrobenzenesulfonyl chloride (2.0 g) the title compound
44 was obtained (3.1 g, 72%): mp 244–246 ꢁC; IR (KBr)
2230 (CtbondN), 1375, 1355, 1340 (SO2) cmÀ1 1H
;
4.7.18. Ethyl 6-chloro-3-[N-(4-fluorophenyl)-5-bromothio-
phene-2-sulfonamido]-1,1-dioxo-1,4,2-benzodithiazine-7-
carboxylate (40). Starting from aminobenzodithiazine
17 (3.33 g) and 5-bromothiophene-2-sulfonyl chloride
(2.35 g) the title compound 40 was obtained (3.2 g,
65%): mp 211–212 ꢁC; IR (KBr) 1730 (C@O), 1600
NMR (DMSO-d6)d 7.74 (s, 5H, Ph), 8.05 (t,
J = 8.1 Hz, 1H, 3-O2NPh), 8.24 (s, 1H, H-5), 8.47 (dd,
Jortho 8.1 Hz, Jmeta = 1.8 Hz, 1H, 3-O2NPh), 8.68 (dd,
Jortho = 8.1 Hz, Jmeta = 1.8 Hz, 1H, 3-O2NPh), 8.71 (s,
1H, H-8), 8.77 (t, Jmeta 1.8 Hz, 1H, 3-O2NPh) ppm.
Anal. Calcd for C20H11ClN4O6S3 (534.98): C, 44.90;
H, 2.07; N, 10.42. Found: C, 44.91; H, 2.10; N, 10.59.
1
(C@N), 1370, 1340, 1175, 1165 (SO2) cmÀ1; H NMR
(DMSO-d6)d 1.33 (t, J = 7.1 Hz, 3H, CH3), 4.36 (q,
J = 7.1 Hz, 2H, CH2), 7.44–7.53 (m, 2H, 4-FPh), 7.54
(d, J = 4.2 Hz, 1H, H-4, thiophene), 7.69–7.76 (m, 2H,
4-FPh), 7.80 (d, J = 4.2 Hz, 1H, H-3, thiophene), 8.09
(s, 1H, H-5), 8.41 (s, 1H, H-8) ppm. Anal. Calcd for
C20H13BrClFN2O6S3 (607.87): C, 39.52; H, 2.15; N,
4.60. Found: C, 39.49; H, 2.18; N, 4.59.
4.7.23. N-(6-Chloro-7-cyano-1,1-dioxo-1,4,2-benzodithia-
zin-3-yl)-N-phenyl-4-chlorobenzenesulfonamide (45). Start-
ing from aminobenzodithiazine 21 (2.8 g) and 4-
chlorobenzenesulfonyl chloride (1.9 g) the title compound
45 was obtained (3.5 g, 83%): mp 256–258 ꢁC; IR (KBr)
2235 (C„N), 1380, 1345, 1335, 1175, 1160 (SO2) cmÀ1
;
1H NMR (DMSO-d6) d 7.69 (s, 5H, Ph), 7.85 (d,
J = 8.9 Hz, 2H, 4-ClPh), 8.09 (d, J = 8.9 Hz, 2H, 4-ClPh),
8.23 (s, 1H, H-5), 8.69 (s, 1H, H-8) ppm. Anal. Calcd for
C20H11Cl2N3O4S3 (524.43): C, 45.80; H, 2.11; N, 8.01.
Found: C, 45.84; H, 2.15; N, 8.20.
4.7.19. 8-Quinolyl 6-chloro-3-[N-(4-fluorophenyl)-4-chlo-
robenzenesulfonamido]-1,1-dioxo-1,4,2-benzodithiazine-7-
carboxylate (41). Starting from aminobenzodithiazine 18
(4.11 g) and 4-chlorobenzenesulfonyl chloride (1.9 g) the
title compound 41 was obtained (3.0 g, 54%): mp 236–
237 ꢁC; IR (KBr) 1760 (CP@O), 1590 (C@N), 1385,
4.7.24. N-(6-Chloro-7-cyano-1,1-dioxo-1,4,2-benzodithia-
zin-3-yl)-N-phenyl-5-bromothiophene-2-sulfonamide (46).
Starting from aminobenzodithiazine 21 (2.8 g) and
5-bromothiophene-2-sulfonyl chloride (2.35 g) the
title compound 46 was obtained (3.3 g, 71%): mp
1
1340, 1175, 1170, 1155 (SO2) cmÀ1; H NMR (DMSO-
d6) d 7.45–7.85 (m, 8H, arom.), 7.99–8.17 (m, 4H,
arom.), 8.22 (s, 1H, H-8, benzodithiazine), 8.50 (d,
J = 8.3 Hz, 1H, quinoline), 8.86 (d, J = 11.4 Hz, 2H,

Z. Brzozowski et al. / Bioorg. Med. Chem. 15 (2007) 2560–2572
2571
246–247 ꢁC dec; IR (KBr) 2235 (C„N), 1390, 1380,
Branch, Developmental Therapeutic of the National
Cancer Institute for some of the in vitro anticancer
testing.
1
1345, 1180, 1170 (SO2) cmÀ1; H NMR (DMSO-d6)d
7.57 (d, J = 4.2 Hz, 1H, H-4, thiophene), 7.62–7.73 (m,
5H, Ph), 7.83 (d, J = 4.2 Hz, 1H, H-3, thiophene), 8.25
(s, 1H, H-5), 8.77 (s, 1H, H-8) ppm. Anal. Calcd for
C18H9BrClN3O4S4 (574.90): C, 37.60; H, 1.58; N, 7.31.
Found: C, 37.58; H, 1.64; N, 7.33.
References and notes
1. Casini, A.; Scozzafava, A.; Mastrolorenzo, A.; Supuran,
C. T. Curr. Cancer Drug Targets 2002, 2, 55.
2. Scozzafava, A.; Casini, A.; Supuran, C. T. Curr. Med.
Chem. 2002, 9, 1167.
3. Supuran, C. T.; Casini, A.; Scozzafava, A. Med. Res. Rev.
2003, 23, 535.
4. Scozzafava, A.; Owa, T.; Mastrolorenzo, A.; Supuran, C.
T. Curr. Med. Chem. 2003, 10, 925.
5. Labb, K. L.; Hipskind, P. A.; Aikins, J. A.; Alvarez, E.;
Cheung, Y. Y.; Considine, E. L.; De Dios, A.; Durst, G.
L.; Ferritto, R.; Grossman, C. S.; Giera, D. D.; Hollister,
B. A.; Huang, Z.; Iversen, P. W.; Law, K. L.; Li, T.; Lin,
H. S.; Lpoez, B.; Lopez, J. E.; Martin Cabrejas, L. M.;
McCann, D. J.; Molero, V.; Reilly, J. E.; Riched, M. E.;
Shih, C.; Teicher, B.; Wikel, J. H.; White, W. T.; Mader,
M. M. J. Med. Chem. 2004, 47, 5367.
6. Villar, R.; Encio, I.; Migliaccio, M.; Gil, M. J.; Martinez-
Merino, V. Bioorg. Med. Chem. 2004, 12, 963.
7. Reddy, N. S.; Mallireddigari, M. R.; Cosenza, S.; Gumir-
eddy, K.; Bell, S. C.; Reddy, P.; Reddy, M. V. R. Bioorg.
Med. Chem. 2004, 12, 4093.
4.7.25. N-(4-Chlorophenyl)-N-(6-chloro-7-cyano-1,1-
dioxo-1,4,2-benzodithiazin-3-yl)-4-chlorobenzenesulfon-
amide (47). Starting from aminobenzodithiazine 22
(3.07 g) and 4-chlorobenzenesulfonyl chloride (1.9 g)
the title compound 47 was obtained (3.1 g, 69%): mp
280–281 ꢁC; IR (KBr) 2235 (C„N), 1375, 1345, 1330,
1
1170, 1160 (SO2) cmÀ1; H NMR (DMSO-d6)d 7.74 (s,
4H, 4-ClPhN), 7.82 (d, J = 8.8 Hz, 2H, 4-ClPhSO2),
8.06 (d, J = 8.8 Hz, 2H, 4-ClPhSO2), 8.24 (s, 1H, H-5),
8.69 (s, 1H, H-8) ppm. Anal. Calcd for
C20H10Cl3N3O4S3 (558.87): C, 42.98; H, 1.80; N, 7.52.
Found: C, 43.06; H, 1.83; N, 7.54.
4.7.26. N-(4-Chlorophenyl)-N-(6-chloro-7-cyano-1,1-
dioxo-1,4,2-benzodithiazin-3-yl)-3-chloro-4-fluorobenzene-
sulfonamide (48). Starting from aminobenzodithiazine 22
(3.07 g) and 3-chloro-4-fluorobenzenesulfonyl chloride
(2.06 g) the title compound 48 was obtained (3.3 g,
71%): mp 253–255 ꢁC; IR (KBr) 2235 (C„N), 1390,
8. Encio, I.; Morre, D. J.; Villar, R.; Gil, M. J.; Martinez-
Merino, V. Br. J. Cancer 2005, 92, 690.
1
1380, 1340, 1180, 1140 (SO2) cmÀ1; H NMR (DMSO-
d6)d 7.76 (s, 4H, 4-ClPhN), 7.83 (d, Jortho = 8.8 Hz, 1H,
H-5, 3-Cl-4-FPh), 8.02-8.10 (m, 1H, H-2, 3-Cl-4-FPh),
8.26 (s, 1H, H-5, benzodithiazine), 8.31 (dd,
Jortho = 8.8 Hz, Jmeta = 2.4 Hz, 1H, H-6, 3-Cl-4-FPh),
8.72 (s, 1H, H-8) ppm. Anal. Calcd for
C20H9Cl3FN3O4S3 (576.86): C, 41.64; H, 1.57; N, 7.28.
Found: C, 41.58; H, 1.69; N, 7.23.
´
9. Sławinski, J.; Gdaniec, M. Eur. J. Med. Chem. 2005, 40,
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4.8. X-ray structure analysis of 23
Crystal data for C20H14Cl2N2O4S3: triclinic, space group
13. Pomarnacka, E.; Bednarski, P. J.; Reszka, P.; Dziemido-
˚
˚
P-1, a = 9.5300 (7) A, b = 10.5007 (7) A, c = 12.5199
´
wicz-Borys, E.; Bienczak, A.; Werel, W.; Hałasa, R. Eur.
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˚
(10) A, a = 66.112 (7)ꢁ, b = 77.284 (7)ꢁ, c = 68.496 (7)ꢁ,
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3
˚
14. Brzozowski, Z.; Sa˛czewski, F.; Neamati, N. Bioorg. Med.
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´
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Ka) = 0.633 mmÀ1, T = 130 K. Data were collected for
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KumaCCD diffractometer using graphite monochro-
mated Mo Ka radiation. Final R indices for 3630 reflec-
tions with I > 2r(I) and 280 refined parameters are:
R1 = 0.0327, wR2 = 0.0844 (R1 = 0.0392, wR2 = 0.0881
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Supporting information available: Crystallographic data
for compound23havebeendepositedatCambridge Crys-
tallographic Data Centre and allocated the deposition
number CCDC 619225). Copies of the data can be ob-
tained upon request from CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK, quoting the deposition number.
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Acknowledgments
Authors thank the Polish State Committee for Scientific
Research for financial support (Grant No. 2 P05F
03527). We thank the Drug Synthesis and Chemistry
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