Synthesis of a new series of biologically interesting 6′-chloro- 1′,1′-dioxospiro[4H-benzo[d][1,3,7]oxadiazocine-4, 3′(2′H)-[1,4,2]benzodithiazine]-2,6(1H,5H)dione derivatives

Article abstract of DOI:10.1007/s00706-013-1010-y

A series of 6′-chloro-1′,1′-dioxospiro[4H-benzo[d][1,3,7] oxadiazocine-4,3′(2′H)-[1,4,2]benzodithiazine]-2,6(1H,5H)dione derivatives have been synthesized from isatoic anhydride and 3-(R ²-amino)-1,4,2-benzodithiazine 1,1-dioxides. Some synthetic limitations are discussed on the basis of quantum chemical calculations performed by use of the Hartree-Fock method.

Full text of DOI:10.1007/s00706-013-1010-y

Monatsh Chem (2013) 144:1397–1405
DOI 10.1007/s00706-013-1010-y
ORIGINAL PAPER
Synthesis of a new series of biologically interesting 60-chloro-10,10-
dioxospiro[4H-benzo[d][1,3,7]oxadiazocine-4,30(20H)-
[1,4,2]benzodithiazine]-2,6(1H,5H)dione derivatives
_
Zdzisław Brzozowski Beata Zołnowska
•
•
´
Jarosław Sławinski
Received: 14 February 2013 / Accepted: 26 April 2013 / Published online: 11 June 2013
Ó The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract
A
series of 60-chloro-10,10-dioxospiro[4H-
otherwise not readily obtained 4-chloro-2-mercaptobenze-
nesulfonamide derivatives of type IV (Fig. 1). These
compounds have remarkable structure-dependent antitumor
activity [14–26], anti-HIV activity [14–17, 27–30], anti-
bacterial activity [31], or strong inhibitory activity of
human carbonic anhydrase (CA) isozymes I, II, IX, and XII
[32–34]. Some of the compounds have been reported to be
novel HIV-1 integrase inhibitors (MBSAs) [8, 11–13].
Recently, we have reported the synthesis and some
chemical properties of 60-chloro-10,10-dioxospiro[4H-benzo
[d][1,3,7]oxadiazocine-4,30(20H)-[1,4,2]benzodithiazine]-
2,6(1H,5H)dione derivatives of type V (Fig. 1) [35]. More
recently the compound V (R1 = 70-Me) and its potential
metabolite VI [35] have been tested in vitro at the National
Cancer Institute (Bethesda MD, USA) at a single dose
(10 lM) in the full NCI 60-cell lines panel. The most sus-
ceptible were lung cancer cells (HOP-92) and melanoma
(MALME-3 M) carcinoma cell lines whose growth was
inhibited by 34 and 28 % by compounds of type V (R1 = 70-
Me) and VI, respectively. In this work, the possibility of
using reaction of 3-amino-6-chloro-1,4,2-benzodithiazine
1,1-dioxide derivatives with isatoic anhydride for synthesis
of novel series of spiro compounds of type VII (Fig. 1) with
potential biological activity or as useful starting materials
for further chemical transformation has been investigated.
Synthesis of nitrogen-containing heterocyclic systems
from isatoic anhydrides has been reported in the literature
since 1981 [36, 37]. This work covers both direct trans-
formation of the anhydrides into such heterocyclic systems,
and processes leading initially to formation of anthranilic
acid derivatives which are then transformed into the het-
erocyclic compounds in one or several stages. It is
important that such transformations result in the formation
of new five and six-membered heterocyclic systems. Fur-
thermore, regioselective three-component reaction of
benzo[d][1,3,7]oxadiazocine-4,30(20H)-[1,4,2]benzodithiazine]-
2,6(1H,5H)dione derivatives have been synthesized from
isatoic anhydride and 3-(R2-amino)-1,4,2-benzodithiazine
1,1-dioxides. Some synthetic limitations are discussed on
the basis of quantum chemical calculations performed by
use of the Hartree–Fock method.
Keywords Benzodithiazine ꢀ Isatoic anhydride ꢀ
Synthesis ꢀ RHF ꢀ Spiro compounds ꢀ Quantum chemistry
Introduction
Compounds containing the 1,1-dioxo-1,4,2-benzodithi-
azine ring system were synthesized in our laboratories in
1984 and have attracted much attention for several years
because of their wide range of biological activity. It has
been demonstrated that many 6-chloro-1,4,2-benzodithi-
azine derivatives (Fig. 1, type I) have low acute toxicity to
mice and rats and, depending on their structure, act as
potential radio-protective [1, 2], diuretic [1–5], or chola-
gogue [5] agents. It has also been shown that some
6-chloro-1,1-dioxo-1,4,2-benzodithiazines have remark-
able antitumor activity (Fig. 1, types I [6–8] and II [9, 10])
or anti-HIV activity (Fig. 1, types I [11, 12], II [9], and III
[13]).
Furthermore, 6-chloro-3-methylthio-1,4,2-benzodithi-
azine 1,1-dioxides have attracted our investigative attention
because of their suitability for chemical transformation into
_
´
Z. Brzozowski ꢀ B. Zołnowska ꢀ J. Sławinski (&)
Department of Organic Chemistry, Medical University
´
of Gdansk, Gen. J. Hallera Str. 107, 80416 Gdansk, Poland
e-mail: jaroslaw@gumed.edu.pl
´
123

_
Z. Brzozowski B. Zołnowska J. Sławinski
´
1398
R2
Fig. 1 General structures of
6-chloro-1,4,2-benzodithiazine
1,1-dioxide derivatives I, II, III,
and VI, 2-mercaptobenzenesul
fonamides IV, and spiro [4H-
benzo[d][1,3,7]oxadiazocine-
4,30(20H)-[1,4,2]
Cl
R1
S
S
R2
Cl
R1
S
S
Cl
R1
S
S
N
Cl
R1
S
N
(CH2)n
R2
H
N
N
N
N
S
O O
R3
R2
O O
O O
O O
I
II
III (n = 1 or 2)
IV
benzodithiazine]-2,6(1H,5H)
dione derivatives V and VII
O
O
R2
H
S
H
N
N
N
Cl
S
S
Cl
S
Cl
R1
NH
O
NH
O
H
O
H
N
O
NH2
N
N
O
Me
S
O O
S
R1
O O
O O
VII
V
VI
Scheme 1
H
Cl
S
S
N
Cl
S
S
SMe
a
N
N
Me
Me
N
O O
O O
1i
H
Cl
S
S
N
O
Cl
S
S
NH2
b or c
N
R
N
Me
Me
O O
O O
1j, 1k
(a) aminoacetonitrile hydrochloride (1.0 molar equiv.),
4-dimethylaminopyridine (1.05 molar equiv.), dry
benzene, room temp. 4 h, 60 h, 81%; (b) acetic
anhydride (2.0 molar equiv.) dry toluene, reflux, 10 h,
80%; (c) benzoic anhydride (2.33 molar equiv.) 170-
175 °C, 3 h, dry toluene, reflux 2 h, 85%
Compd
R
Me
Ph
1j
1k
ꢀ
isatoic anhydride, primary amines, and isatins to spiroox-
indole derivatives has also been reported [38].
As shown in Scheme 2, synthesis of the target 60-chloro-
10,10-dioxospiro[4H-benzo[d][1,3,7]oxadiazocine-4,30(20H)-
[1,4,2]benzodithiazine]-2,6(1H,5H)dione derivatives 2–17
was achieved in good to excellent yield (81–97 %) by a
convenient procedure starting from isatoic anhydride and
benzodithiazines 1a–1p. However, reaction with benzodi-
thiazines 1r, 1s, and 1t failed. In these instances the
substrates, only, were recovered from the resulting reaction
mixture, i.e. isatoic anhydride (85–89 %) and the corre-
sponding 3-aminobenzodithiazines 1r (69 %), 1 s (59 %),
or 1t (69 %).
Results and discussion
Chemistry
Previously described methods were used for synthesis of
3-amino-6-chloro-1,4,2-benzodithiazine derivatives 1a-1e
[3], 1f, 1g [27], 1h [39], 1l–1p [9], 1r [40], 1s, and 1t [41].
Similar methods were used to prepare the new starting
benzodithiazines 1i, 1j, and 1k (Scheme 1).
It is supposed that reaction of isatoic anhydride with
benzodithiazines 1a–1t depends on the electronic effect of
123

Synthesis of a new series of biologically interesting spiro compounds
1399
Scheme 2
O
R2
R2
S
Isatoic anhydride
N
N
Cl
R1
S
S
N
(1.03 molar equiv.)
Cl
R1
H
NH
dry toluene
rt 2 h, reflux 42 h
O
N
S
O O
O
H
O O
1a-1p
A
8
O
7
9
10
R2
R2
6
N5
Cl
R1
S
S
N
Cl
R1
S
1
4
Isatoic anhydride (1.03 molar equiv.)
NH
3
H
4'
2
5'
8'
3'
2'
N
6'
7'
O
H
1'
S
O O
N
Dry toluene
rt 2 h, reflux 42 h
O
O O
1r-1t
2-17
1r (R1 = Me, R2 = Bu)
1s (R1 = Me, R2 = allyl
Substrates: 1r-1t (59-69%)
and isatoic anhydride
were recovered (85-89%)
1t (R1 = MeO2C, R2 = allyl)
R2
R1
Yield /%
Comp
R2
Me2N-
NC-CH2-
Me(C=O)-
Ph(C=O)-
4-FPh
4-ClPh
Ph
4-ClPh
R1
Comp
Yield /%
1a, 2
1b, 3
1c, 4
1d, 5
95
97
94
92
97
95
95
96
2-MeOPh
2-BrPh
4-ClPh
Me
Me
Me
Me
94
96
90
93
1h, 9
Me
Me
Me
Me
EtO2C
NC-
1i, 10
1j, 11
1k, 12
1l, 13
1m, 14
1n, 15
1o, 16
2,4-diClPh
Me
Me
Me
82
97
97
1e, 6
1f, 7
1g, 8
N
Cl
H2NCO-
H2NCO-
NH
N
Cl
95
1p, 17
O
Ph
H
Ph
N
NH
N
H
ꢀ
their substituents R2. Thus, only 3-aminobenzodithiazines
1r–1t, bearing substituents R2 with electron-donating
effects were unsuitable for formation of intermediate
compounds of type A (Scheme 2) and further conversion to
the desired spiro compounds of type 2–17 by cycloaddition
reaction. Trying to understand and to explain this phe-
nomenon we also undertook studies using ab-initio
calculations for molecules 1a–1t (in toluene), by use of the
Hartree–Fock method.
(C-4,30) in the upfield region d = 110.27–110.95 ppm, and
the presence of two carbonyl groups at positions 2 and 6 of
the benzo[d][1,3,7]oxadiazocine ring was indicated by
characteristic signals in the regions 153.58–160.57 and
160.00–166.32 ppm, respectively. The 1H NMR spectra
contained characteristic signals in the regions
d = 7.02–7.19 (d, J = 7.9–8.3 Hz) for H-10, 7.24–7.28 (t,
J = 7.1–8.1 Hz) for H-9, 7.56–7.75 (t, J = 7.1–8.3 Hz) for
H-8, 7.83–7.99 (d, J = 7.1–9.0 Hz) or 7.91 (dd,
Jortho = 7.9, Jmeta = 1.2 Hz) for H-7, 8.10–12.95 as singlet
for H-1, 8.10–11.82 (s) for H-20, 7.38–8.37 (s) for H-50, and
7.24 (s) for H-80. The IR spectra of compounds 2–17
contained strong absorption bands of the two carbonyl C=O
The structures of the new compounds were confirmed by
elemental analysis and by IR and NMR spectroscopy; the
results are given in the ‘‘Experimental’’ section. Inspection
of the 13C NMR spectra of spiro-cyclic compounds 2–17
revealed the characteristic signals of the spiro carbon atom
groups in the regions 1,720–1,730 and 1,765 cm-1
.
123

_
Z. Brzozowski B. Zołnowska J. Sławinski
´
1400
Molecular modeling studies
The plots of electrostatic potential as maps in Fig. 2 show
the electron charge density of representative compounds 1a
and 1s. Compound 1a has a region of high negative charge on
the N atom whereas compound 1s has less negative charge on
this nitrogen atom, which explains its low reactivity.
Quantum chemical calculations were performed by use of
Spartan 08 software [42] to study the molecular geometry
and electronic structure of 6-chloro-7-R1-3-(R2-amino)-
1,4,2-benzodithiazine 1,1-dioxides 1a–1t. The full opti-
mized geometries of compounds 1a–1t in toluene were
calculated by use of the ab-initio restricted Hartree–Fock
(RHF) method with the 6-31G* polarization basis set. The
calculated relative tautomer energies with the Boltzmann
distribution term equal to unity confirm experimental
results that 3-(R2-amino)-1,4,2-benzodithiazine is a low-
energy tautomer, more stable than the 3-(R2-imino)-1,4,2-
benzodithiazine isomer.
Conclusion
We have developed a method for preparation of new series
of 60-chloro-10,10-dioxospiro[4H-benzo[d][1,3,7]oxadiazo-
cine-4,30(20H)-[1,4,2]benzodithiazine]-2,6(1H,5H)dione
derivatives 2–17 by reaction of isatoic anhydride with
3-(R2-amino)-6-chloro-1,4,2-benzodithiazine 1,1-dioxide
derivatives bearing R2 substituents of diverse electronic
nature. For substrates 1a–1t geometry optimization was
performed, by use of Spartan 08 software and the ab-initio
restricted Hartree–Fock (RHF) method at the 6-31G* level.
Theoretical studies enabled explanation of the different
chemical behavior of 3-aminobenzodithiazines toward
isatoic anhydride. The unreactive substrates 1r–1t were
characterized by less negative charge and greater electro-
static potential on the nitrogen atom of the amine group
than the reactive compounds 1a–1p. Further structural
modification and biological evaluation of these compounds
are in progress and will be reported elsewhere.
The electrostatic atomic charges of the starting 3-am-
inobenzodithiazines 1a–1t (Table 1) and electrostatic
potential surface maps (Fig. 2), as affected by their R2
substituents, provide information about the reactivity of the
molecules in reactions with electrophiles.
The relative reactivity can be judged from the values of
the atomic charges calculated for the nucleophilic centers
of the compounds. Thus, the higher negative electrostatic
charges found on the nitrogen atom of the amine groups of
compounds 1a–1p explained the different chemical
behavior of 3-aminobenzodithiazines 1s–1t in reactions
with isatoic anhydride (Table 1).
Table 1 Electrostatic atomic charges of the heterocyclic rings and amine groups of the starting 6-chloro-7-R1-3-(R2-amino)-1,4,2-benzodi-
thiazine 1,1-dioxides 1a–1t
Compound
SO2
S-1
N-2
C-3
S-4
Amine group N
O-1
O-2
1a
1b
1c
1d
1e
1f
1.488
1.492
1.463
1.481
1.489
1.461
1.489
1.578
1.561
1.463
1.435
1.454
1.458
1.442
1.449
1.456
1.497
1.503
1.524
–0.677
–0.676
–0.670
–0.669
–0.676
–0.667
–0.674
–0.704
–0.699
–0.656
–0.651
–0.653
–0.661
–0.663
–0.671
–0.674
–0.682
–0.680
–0.685
–0.659
–0.659
–0.649
–0.653
–0.651
–0.644
–0.651
–0.676
–0.662
–0.649
–0.643
–0.647
–0.641
–0.645
–0.638
–0.642
–0.660
–0.662
–0.660
–0.756
–0.726
–0.747
–0.726
–0.737
–0.718
–0.720
–0.792
–0.740
–0.701
–0.703
–0.744
–0.738
–0.751
–0.743
–0.743
–0.782
–0.768
–0.760
0.617
0.590
0.642
0.570
0.632
0.585
0.550
0.508
0.616
0.519
0.629
0.600
0.628
0.621
0.652
0.658
0.579
0.559
0.486
–0.113
–0.113
–0.133
–0.110
–0.130
–0.077
–0.049
–0.148
–0.116
–0.056
–0.050
–0.120
–0.121
–0.142
–0.136
–0.142
–0.142
–0.146
–0.134
–0.550
–0.599
–0.637
–0.534
–0.614
–0.599
–0.572
–0.197
–0.341
–0.674
–0.600
–0.586
–0.628
–0.607
–0.647
–0.651
–0.386
–0.390
–0.260
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1r
1s
1t
123

Synthesis of a new series of biologically interesting spiro compounds
1401
Fig. 2 Electrostatic potential maps of representative benzodithiazines 1a and 1s. Color ranges, in kJ mol-1: 1a from red -118.650 to blue
?1,817.310, 1s from red -94.784 to blue ?1,903.035. RHF/6-31G* basis set (color figure online)
(6 9 5 cm3), dried, and purified by recrystallization from
40 cm3 glacial acetic acid. Yield: 4.9 g (81 %); m.p.: 228–
Experimental
229 °C; Rf = 0.76 (benzene–EtOH 4:1); IR (KBr):
The instrumentation and conditions used were: melting
ꢀ
m = 3,340 (NH), 2,255 (C:N), 1,560 (C=N), 1,345,
points Bu¨chi 535 apparatus; IR spectra: KBr pellets,
400–4,000 cm-1, Perkin Elmer 1600 FT-IR spectropho-
tometer; 1H NMR and 13C NMR: Varian Gemini 200
apparatus at 200 and 50 MHz, respectively; spectra were
recorded in dimethyl sulfoxide-d6 (DMSO-d6); chemical
shifts are expressed as d values relative to Me4Si as stan-
dard; coupling constants (J) are given in hertz; multiplicity
1,315, 1,165 (SO2) cm-1 1H NMR: d = 2.43 (s, 3H,
;
CH3), 4.52 (s, 2H, CH2), 7.96 (s, 1H, H-5), 8.03 (s, 1H,
H-8), 10.34 (s, 1H, NH) ppm; 13C NMR: d = 19.58, 30.88,
116.28, 126.88, 127.25, 128.47, 130.87, 137.63, 137.94,
163.83 ppm.
3-Acetylamino-6-chloro-7-methyl-1,4,2-benzodithiazine
1,1-dioxide (1j, C10H9ClN2O3S2)
1
in H NMR is reported as singlet (s), broad singlet (br s),
doublet (d), doublet of doublets (dd), triplet (t), quartet (q),
and multiplet (m). The results of elemental analysis for C,
H, and N were in agreement with calculated values within
0.3 %. Thin-layer chromatography (TLC) was performed
on Merck silica gel 60F254 plates and visualized by UV
illumination. The starting 6-chloro-7-methyl-3-methylthio-
1,4,2-benzodithiazine 1,1-dioxide and 3-amino-6-chloro-7-
methyl-1,4,2-benzodithiazine 1,1-dioxide were obtained by
use of previously described procedures [2, 43].
A mixture of 5.25 g 3-amino-6-chloro-7-methyl-1,4,2-ben-
zodithiazine 1,1-dioxide (0.02 mol) and 4.10 g acetic
anhydride (0.04 mol) in 50 cm3 dry toluene was stirred
under reflux for 10 h. After cooling to room temperature, the
precipitate was collected by filtration, washed successively
with toluene (3 9 5 cm3), methanol (2 9 5 cm3), and
acetonitrile (3 9 5 cm3), and dried. Yield: 4.9 g (80 %);
m.p.: 264–265 °C; Rf = 0.74 (benzene–EtOH 4:1); IR
ꢀ
(KBr): m = 3,220, 3,190 (NH), 1,710 (C=O), 1,555 (C=N),
1,345, 1,310, 1,160 (SO2) cm-1; 1H NMR: d = 2.19 (s, 3H,
CH3), 2.40 (s, 3H, CH3C=O), 8.00 (s, 1H, H-5), 8.06 (s, 1H,
H-8), 12.15 (s, 1H, NH) ppm; 13C NMR: d = 19.60, 23.95,
126.52, 128.42, 129.00, 129.35, 138.06, 138.91, 163.41,
172.27 ppm.
2-(6-Chloro-7-methyl-1,4,2-benzodithiazin-3-
ylamino)acetonitrile 1,1-dioxide (1i, C10H8ClN3O2S2)
A mixture of 5.88 g 6-chloro-7-methyl-3-methylthio-1,4,2-
benzodithiazin 1,1-dioxide (0.02 mol), 1.85 g aminoacetonitrile
hydrochloride (0.02 mol), and 2.56 g 4-dimethylaminopyridine
(0.021 mol) in 50 cm3 dry benzene was stirred at room
temperature for 4 h, followed by reflux until evolution of
CH3SH had ceased (55–60 h) (CAUTION: because of high
toxicity, CH3SH should be trapped in aqueous NaOH
solution). The solvent was evaporated under reduced
pressure to give an oily residue and 70 cm3 water was
added, with stirring. The resulting suspension (pH *7.8)
was acidified to pH 2 by addition of 1 % hydrochloric acid.
After stirring at room temperature for 6 h, the crude
product was collected by filtration, washed with water
3-Benzoylamino-6-chloro-7-methyl-1,4,2-benzodithiazine
1,1-dioxide (1k, C15H11ClN2O3S2)
A mixture of 3.94 g 3-amino-6-chloro-7-methyl-1,4,2-
benzodithiazine 1,1-dioxide (0.015 mol) and 7.92 g ben-
zoic anhydride (0.035 mol) was stirred at 170–175 °C for
3 h. After cooling to 105 °C, 60 cm3 dry toluene was
added to the reaction mixture. The resulting suspension
was further stirred under reflux for 2 h. After cooling to
room temperature and standing overnight, the precipitate
was collected by filtration, washed with toluene
123

_
Z. Brzozowski B. Zołnowska J. Sławinski
´
1402
(3 9 5 cm3) and ethanol (3 9 5 cm3), and dried. Yield:
Starting from 2.09 g 3-(2-bromophenylamino)-6-chloro-7-
methyl-1,4,2-benzodithiazine 1,1-dioxide (1b), the title
compound 3 was obtained. Yield: 2.8 g (96 %); m.p.:
222–223 °C (dec.); TLC: Rf = 0.78 (benzene–EtOH 4:1);
ꢀ
4.7 g (85 %); m.p.: 279–280 °C; IR (KBr): m = 3,260
(NH), 1,695 (C=O), 1,565 (C=N), 1,345, 1,305, 1,170
(SO2) cm-1 1H NMR: d = 2.46 (s, 3H, CH3), 7.58
;
ꢀ
(t, J = 7.8 Hz, 2H, H-3 and H-5, PhC=O), 7.70
(t, J = 7.3 Hz, 1H, H-4, PhC=O), 8.02 (d, J = 7.8 Hz,
2H, H-2 and H-6, PhC=O), 8.05 (s, 1H, H-5 benzodithi-
azine), 8.08 (s, 1H, H-8 benzodithiazine), 12.90 (s, 1H,
NH) ppm; 13C NMR: d = 19.56, 126.55, 128.47, 128.94,
129.20, 129.40, 129.64, 131.29, 134.07, 138.12, 138.96,
165.11, 168.46 ppm.
IR (KBr): m = 3,245, 3,185 (NH), 1,765, 1,725 (C=O),
1
1,365, 1,330, 1,155 (SO2) cm-1; H NMR: d = 2.13 (s,
3H, CH3), 7.15 (d, J = 8.2 Hz, 1H, H-10), 7.24 (t,
J = 8.1 Hz, 1H, H-9), 7.36–7.39 (m, 1H, arom),
7.46–7.52 (m, 2H, arom), 7.68–7.71 (m, 1H, arom), 7.74
(t, J = 7.8 Hz, 1H, H-8), 7.91 (dd, Jortho = 7.9 Hz,
Jmeta = 1.2 Hz, 1H, H-7), 7.97 (s, 1H, H-50), 8.00 (s, 1H,
H-80), 11.46 (s, 1H, NH), 11.73 (s, 1H, NH) ppm; 13C
NMR: d = 19.58, 110.53, 115.59, 123.78, 126.80, 127.52,
128.54, 129.11, 129.20, 129.79, 130.00, 130.16, 130.41,
130.87, 133.59, 137.20, 137.55, 137.95, 141.66, 147.36,
158.00, 160.14 ppm.
General procedure for the preparation of spiro-
[4H-benzo[d][1,3,7]oxadiazocine-4,30(20H)-
[1,4,2]benzodithiazine]-2,6(1H,5H)dione
derivatives 2–17
60-Chloro-5-(4-chlorophenyl)-70-methyl-10,10-dioxospiro-
[4H-benzo[d][1,3,7]oxadiazocine-4,30(20H)-[1,4,2]-
A mixture of 0.84 g isatoic anhydride (5.15 mmol) and the
corresponding 6-chloro-7-R1-3-(R2-amino)-1,4,2-benzodi-
thiazine 1,1-dioxide 1a–1p (5 mmol) in dry toluene
(15 cm3 for 1 g benzodithiazine) was stirred at room
temperature for 2 h, followed by reflux for 42 h. After
cooling to room temperature, the precipitate was collected
by filtration, and washed successively with toluene
(3 9 4 cm3), methanol (5 9 3 cm3), and petroleum ether
(3 9 3 cm3). In this manner, the following spiro com-
pounds were obtained (analogous reactions with 3-(R2-
amino)-1,4,2-benzodithiazine 1,1-dioxide 1r, 1s, and 1t,
bearing R2-substituents with strong or weak electron-
donating effect, failed).
benzodithiazine]-2,6(1H,5H)dione (4, C22H15Cl2N3O5S2)
Starting from 1.87 g 6-chloro-3-(4-chlorophenylamino)-7-
methyl-1,4,2-benzodithiazine 1,1-dioxide (1c), the title
compound 4 was obtained. Yield: 2.4 g (90 %); m.p.:
296–297 °C (dec.); TLC: Rf = 0.76 (benzene–EtOH 4:1);
ꢀ
IR (KBr): m = 3,270, 3,200, 3,125 (NH), 1,765, 1,725
(C=O), 1,315, 1,290, 1,145 (SO2) cm-1 1H NMR:
;
d = 2.44 (s, 3H, CH3), 7.15 (d, J = 8.1 Hz, 1H, H-10),
7.28 (t, J = 7.6 Hz, 1H, H-9), 7.50 (d, J = 8.8 Hz, 2H,
4-ClPh), 7.66 (d, J = 8.8 Hz, 2H, 4-ClPh), 7.73 (t,
J = 8.3 Hz, 1H, H-8), 7.91 (d, J = 7.0 Hz, 1H, H-7),
7.99 (s, 1H, H-50), 8.04 (s, 1H, H-80), 11.63 (s, 1H, NH),
11.66 (s, 1H, NH) ppm; 13C NMR: d = 19.34, 110.27,
115.34, 123.35, 123.52, 126.63, 127.53, 128.30, 128.94,
129.09, 129.67, 130.47, 136.60, 136.94, 137.40, 137.69,
141.41, 147.10, 159.88, 160.69 ppm.
60-Chloro-5-(2-methoxyphenyl)-70-methyl-10,10-dioxospi-
ro[4H-benzo[d][1,3,7]oxadiazocine-4,30(20H)-[1,4,2]ben-
zodithiazine]-2,6(1H,5H)dione (2, C23H18ClN3O6S2)
Starting from 1.85 g 6-chloro-7-methyl-3-(2-methoxy-
phenylamino)-1,4,2-benzodithiazine 1,1-dioxide (1a), the
title compound 2 was obtained. Yield: 2.5 g (94 %); m.p.:
200–201 °C (dec.); TLC: Rf = 0.95 (CHCl3–MeOH 16:3);
60-Chloro-5-(2,4-dichlorophenyl)-70-methyl-10,10-
dioxospiro[4H-benzo[d][1,3,7]oxadiazocine-4,30(20H)-[1,4,2]-
benzodithiazine]-2,6(1H,5H)dione (5, C22H14Cl3N3O5S2)
Starting from 2.04 g 6-chloro-3-(2,4-dichlorophenylami-
no)-7-methyl-1,4,2-benzodithiazine 1,1-dioxide (1d), the
title compound 5 was obtained. Yield: 2.6 g (93 %); m.p.:
213–214 °C (dec.); TLC: Rf = 0.77 (benzene–EtOH 4:1);
ꢀ
IR (KBr): m = 3,315, 3,240, 3,175 (NH), 1,765, 1,730
(C=O), 1,340, 1,310, 1,155 (SO2) cm-1 1H NMR:
;
d = 2.42 (s, 3H, CH3), 3.82 (s, 3H, CH3O), 7.02 (d,
J = 8.1 Hz, 1H, H-10), 7.15–7.24 (m, 2H, arom),
7.28–7.41 (m, 3H, arom), 7.74 (t, J = 7.6 Hz, 1H, H-8),
7.89 (d, J = 7.6 Hz, 1H, H-7), 7.93 (s, 1H, H-50), 7.99 (s,
1H, H-80), 11.06 (br s, 1H, NH), 11.70 (br s, 1H, NH) ppm;
13C NMR: d = 19.56, 56.08, 110.53, 112.76, 115.59,
120.83, 123.77, 124.00, 126.70, 126.90, 127.85, 127.92,
128.41, 128.92, 129.20, 131.14, 137.19, 137.39, 137.71,
141.66, 147.36, 153.58, 160.14 ppm.
ꢀ
IR (KBr): m = 3,335, 3,240, 3,175 (NH), 1,765, 1,730
(C=O), 1,365, 1,325, 1,165 (SO2) cm-1 1H NMR:
;
d = 2.43 (s, 3H, CH3), 7.19 (d, J = 8.1 Hz, 1H, H-10),
7.24 (t, J = 7.1 Hz, 1H, H-9), 7.56 (s, 2H, H-5 and H-6,
2,4-diClPh), 7.73 (t, J = 7.1 Hz, 1H, H-8), 7.83 (s, 1H,
H-3, 2,4-diClPh), 7.91 (d, J = 7.1 Hz, 1H, H-7), 7.99 (s,
1H, H-50), 8.01 (s, 1H, H-80), 11.50 (s, 1H, NH), 11.73 (s,
1H, NH) ppm; 13C NMR: d = 19.58, 110.53, 115.59,
123.79, 126.86, 128.41, 128.56, 128.64, 129.20, 130.00,
130.50, 130.75, 133.01, 133.11, 133.18, 137.20, 137.63,
138.04, 141.66, 147.36, 160.02, 163.68 ppm.
5-(2-Bromophenyl)-60-chloro-70-methyl-10,10-dioxospi-
ro[4H-benzo[d][1,3,7]oxadiazocine-4,30(20H)-[1,4,2]-
benzodithiazine]-2,6(1H,5H)dione (3, C22H15BrClN3O5S2)
123

Synthesis of a new series of biologically interesting spiro compounds
1403
60-Chloro-5-(2-chloro-3-pyridinyl)-70-methyl-10,10-
NH), 8.87 (t, J = 6.0 Hz, 1H, PhCH2NH), 11.73 (s, 1H,
C=NH) ppm; 13C NMR: d = 19.52, 44.49, 110.53, 115.60,
123.77, 126.35, 127.28, 127.35, 127.47, 127.64, 127.74,
128.79, 129.20, 130.89, 131.15, 136.16, 136.96, 137.19,
141.67, 147.36, 158.42, 160.00 ppm.
dioxospiro[4H-benzo[d][1,3,7]oxadiazocine-4,30(20H)-[1,4,2]-
benzodithiazine]-2,6(1H,5H)dione (6, C21H14Cl2N4O5S2)
Starting from 1.87 g 6-chloro-3-(2-chloro-3-pyridinyl-
amino)-7-methyl-1,4,2-benzodithiazine 1,1-dioxide (1e),
the title compound 6 was obtained. Yield: 2.2 g (82 %);
m.p.: 218–219 °C (dec.); TLC: Rf = 0.71 (benzene–EtOH
60-Chloro-5-(dimethylamino)-70-methyl-10,10-dioxospiro-
[4H-benzo[d][1,3,7]oxadiazocine-4,30(20H)-[1,4,2]-
ꢀ
4:1); IR (KBr): m = 3,285, 3,215, 3,175 (NH), 1,765, 1,730
benzodithiazine]-2,6(1H,5H)dione (9, C18H17ClN4O5S2)
Starting from 1.53 g 6-chloro-7-methyl-3-(2,2-dimethyl-
hydrazino)-1,4,2-benzodithiazine 1,1-dioxide (1h), the title
compound 9 was obtained. Yield: 2.2 g (95 %); m.p.: 207–
208 °C (dec.); TLC: Rf = 0.70 (benzene–EtOH 4:1); IR
1
(C=O), 1,620 (C=N), 1,365, 1,155 (SO2) cm-1; H NMR:
d = 2.43 (s, 3H, CH3), 7.15 (d, J = 7.9 Hz, 1H, H-10),
7.24 (t, J = 7.5 Hz, 1H, H-9), 7.58 (t, J = 5.8 Hz, 1H,
H-5, 3-pyridinyl), 7.73 (t, J = 7.3 Hz, 1H, H-8), 7.90 (d,
J = 7.5 Hz, 1H, H-7), 7.92–8.20 (m, 3H, H-4 and H-6,
3-pyridinyl, and H-50), 8.44 (s, 1H, H-80), 11.62 (s, 1H,
NH), 11.73 (s, 1H, NH) ppm; 13C NMR: d = 19.59,
110.51, 115.59, 123.77, 124.29, 126.89, 127.36, 128.57,
129.19, 130.66, 131.15, 137.19, 137.70, 138.11, 138.48,
141.66, 141.06, 147.36, 149.01, 160.13, 163.76 ppm.
ꢀ
(KBr): m = 3,240, 3,170 (NH), 1,765, 1,725 (C=O), 1,360,
1,315, 1,160 (SO2) cm-1; 1H NMR: d = 2.40 (s, 3H, CH3),
2.60 (s, 6H, CH3–N–CH3), 7.15 (d, J = 8.3 Hz, 1H, H-10),
7.26 (t, J = 7.3 Hz, 1H, H-9), 7.73 (t, J = 7.3 Hz, 1H,
H-8), 7.83 (d, J = 7.4 Hz, 1H, H-7), 7.88 (s, 1H, H-50),
7.94 (s, 1H, H-80), 10.98 (br s, 1H, NH), 11.62 (br s, 1H,
NH) ppm; 13C NMR: d = 19.52, 46.68, 110.52, 115.59,
123.77, 126.40, 128.36, 129.04, 129.20, 130.63, 137.11,
137.19, 137.33, 141.66, 147.35, 160.01, 166.63 ppm.
60-Chloro-5-[imino(piperidin-1-yl)methyl]-70-methyl-10,10-
dioxospiro[4H-benzo[d][1,3,7]oxadiazocine-4,30(20H)-
[1,4,2]benzodithiazine]-2,6(1H,5H)dione
(7, C22H22ClN5O5S2)
60-Chloro-70-methyl-10,10,2,6-tetraoxo-1,2-dihydrospiro-
[4H-benzo[d][1,3,7]oxadiazocine-4,30(20H)-[1,4,2]-
benzodithiazine]-5(6H)-acetonitrile
Starting from 1.64 g 6-chloro-7-methyl-3-(piperidine-1-
carboximidamino)-1,4,2-benzodithiazine 1,1-dioxide (1f),
the title compound 7 was obtained. Yield: 2.6 g (97 %);
m.p.: 211–212 °C (dec.); TLC: Rf = 0.75 (benzene–EtOH
4:1); IR (KBr): ꢀm = 3,370, 3,280, 3,210 (NH), 1,765, 1,725
(10, C18H13ClN4O5S2)
Starting from 1.51 g 2-(6-chloro-7-methyl-1,4,2-benzo-
dithiazin-3-ylamino)acetonitrile 1,1-dioxide (1i), the title
compound 10 was obtained. Yield: 2.3 g (97 %); m.p.:
194–195 °C (dec.); TLC: Rf = 0.70 (benzene–EtOH 4:1);
(C=O), 1,620 (C=N), 1,360, 1,345, 1,155 (SO2) cm-1; H
1
NMR: d = 1.58 (br s, 6H, piperidine), 2.39 (s, 3H, CH3),
3.51 (br s, 4H, piperidine), 7.15 (d, J = 8.0 Hz, 1H, H-10),
7.25 (t, J = 8.0 Hz, 1H, H-9), 7.69 (s, 1H, H-50), 7.73 (t,
J = 8.1 Hz, 1H, H-8), 7.89 (s, 1H, H-80), 7.93 (d,
J = 8.0 Hz, 1H, H-7), 8.22 (br s, 2H, NH), 11.73 (s, 1H,
C=NH) ppm; 13C NMR: d = 19.50, 23.64, 25.51, 45.94,
110.53, 115.60, 123.77, 126.28, 127.23, 129.20, 131.09,
131.31, 133.10, 135.97, 136.78, 137.20, 141.67, 147.36,
157.20, 164.77 ppm.
ꢀ
IR (KBr): m = 3,345, 3,240, 3,175 (NH), 2,245 (C:N),
1,765, 1,725 (C=O), 1,365, 1,320, 1,165 (SO2) cm-1; H
1
NMR: d = 2.43 (s, 3H, CH3), 4.51 (s, 2H, N:C–CH2N),
7.14 (d, J = 8.1 Hz, 1H, H-10), 7.20 (t, J = 8.0 Hz,
1H, H-9), 7.74 (t, J = 8.1 Hz, 1H, H-8), 7.91 (dd,
Jmeta = 1.2 Hz, Jortho = 7.9 Hz, 1H, H-7), 7.95 (s, 1H,
H-50), 8.02 (s, 1H, H-80), 10.32 (br s, 1H, NH), 11.72 (br s,
1H, NH) ppm; 13C NMR: d = 19.58, 30.90, 110.53,
115.59, 116.29, 123.77, 126.89, 127.27, 128.48, 129.20,
130.90, 137.20, 137.64, 137.95, 141.66, 147.36, 160.01,
163.82 ppm.
5-(N-Benzylcarbamimidoyl)-60-chloro-70-methyl-10,10-
dioxospiro[4H-benzo[d][1,3,7]oxadiazocine-4,30(20H)-
[1,4,2]benzodithiazine]-2,6(1H,5H)dione
(8, C24H20ClN5O5S2)
5-Acetyl-60-chloro-70-methyl-10,10-dioxospiro[4H-
benzo[d][1,3,7]oxadiazocine-4,30(20H)-[1,4,2]-
Starting from 1.98 g 3-(3-benzylguanidino)-6-chloro-7-
methyl-1,4,2-benzodithiazine 1,1-dioxide (1 g), the title
compound 8 was obtained. Yield: 2.7 g (97 %); m.p.: 194–
195 °C (dec.); TLC: Rf = 0.74 (benzene–EtOH 4:1); IR
benzodithiazine]-2,6(1H,5H)dione (11, C18H14ClN3O6S2)
Starting from 1.52 g 3-(acetylamino)-6-chloro-7-methyl-
1,4,2-benzodithiazine 1,1-dioxide (1j), the title compound
11 was obtained. Yield: 2.2 g (94 %); m.p.: 210–211 °C
(dec.); TLC: Rf = 0.70 (benzene–EtOH 4:1); IR (KBr):
ꢀ
(KBr): m = 3,425, 3,340, 3,285, 3,180 (NH and C=NH),
1,765, 1,730 (C=O), 1,620 (C=N), 1,360, 1,330, 1,140
(SO2) cm-1; 1H NMR: d = 2.40 (s, 3H, CH3), 4.42 (s, 2H,
PhCH2NH), 7.15 (d, J = 8.3 Hz, 1H, H-10), 7.24 (t,
J = 7.6 Hz, 1H, H-9), 7.30 (s, 5H, Ph), 7.38 (s, 1H, H-50),
7.71 (t, J = 7.6 Hz, 1H, H-8), 7.74 (s, 1H, H-80), 7.90 (d,
J = 7.6 Hz, 1H, H-7), 8.10 (br s, 1H, NH), 8.35 (br s, 1H,
ꢀ
m = 3,225, 3,185 (NH), 1,765, 1,730, 1,685 (C=O), 1,365,
1,310, 1,165 (SO2) cm-1; 1H NMR: d = 2.18 (s, 3H, CH3),
2.44 (s, 3H, CH3C=O), 7.14 (d, J = 8.1 Hz, 1H, H-10),
7.24 (t, J = 7.5 Hz, 1H, H-9), 7.73 (t, J = 7.7 Hz, 1H,
123

_
Z. Brzozowski B. Zołnowska J. Sławinski
´
1404
H-8), 7.90 (d, J = 7.7 Hz, 1H, H-7), 8.02 (s, 1H, H-50),
8.04 (s, 1H, H-80), 11.72 (s, 1H, NH), 12.48 (s, 1H, NH)
ppm; 13C NMR: d = 19.60, 23.97, 110.51, 115.59, 123.77,
126.53, 128.42, 129.02, 129.19, 129.39, 137.18, 138.06,
138.91, 141.66, 147.35, 160.02, 163.40, 172.29 ppm.
m.p.: 219–220 °C (dec.); TLC: Rf = 0.64 (benzene–EtOH
4:1); IR (KBr): m = 3,275, 3,195, 3,125 (NH), 2,238
ꢀ
(C:N), 1,765, 1,725 (C=O), 1,360, 1,320, 1,150 (SO2)
cm-1; 1H NMR: d = 7.14 (d, J = 8.1 Hz, 1H, H-10), 7.24
(t, J = 7.6 Hz, 1H, H-9), 7.62 (d, J = 8.7 Hz, 2H, 4-ClPh),
7.65 (d, J = 8.7 Hz, 2H, 4-ClPh), 7.73 (t, J = 7.7 Hz, 1H,
H-8), 7.90 (d, J = 7.6 Hz, 1H, H-7), 8.37 (s, 1H, H-50),
8.60 (s, 1H, H-80), 11.72 (s, 1H, NH), 11.87 (s, 1H, NH)
ppm; 13C NMR: d = 110.81, 112.97, 114.84, 115.58,
123.77, 123.93, 129.19, 129.43, 130.01, 130.22, 130.31,
130.71, 131.33, 136.71, 137.19, 138.93, 141.65, 147.34,
159.01, 160.15 ppm.
5-Benzoyl-60-chloro-70-methyl-10,10-dioxospiro[4H-
benzo[d][1,3,7]oxadiazocine-4,30(20H)-[1,4,2]-
benzodithiazine]-2,6(1H,5H)dione (12, C23H16ClN3O6S2)
Starting from 1.83 g 3-(benzoylamino)-6-chloro-7-methyl-
1,4,2-benzodithiazine 1,1-dioxide (1k), the title compound
12 was obtained. Yield: 2.4 g (92 %); m.p.: 230–232 °C
(dec.); TLC: Rf = 0.77 (benzene–EtOH 4:1); IR (KBr):
ꢀ
m = 3,240, 3,180 (NH), 1,765, 1,730, 1,695 (C=O), 1,365,
60-Chloro-10,10,2,6-tetraoxo-5-phenyl-1,2,5,6-
1
1,170 (SO2) cm-1; H NMR: d = 2.46 (s, 3H, CH3), 7.14
tetrahydrospiro[4H-benzo[d][1,3,7]oxadiazocine-
4,30(20H)-[1,4,2]benzodithiazine]-70-carboxamide
(15, C22H15ClN4O6S2)
(d, J = 8.1 Hz, 1H, H-10), 7.24 (t, J = 7.5 Hz, 1H, H-9),
7.56 (t, J = 7.4 Hz, 1H, H-8), 7.66–7.77 (m, 3H, H-3, H-4
and H-5, PhC=O), 7.91 (d, J = 7.8 Hz, 1H, H-7), 8.02 (d,
J = 7.6 Hz, 2H, H-2 and H-6, PhC=O), 8.02 (s, 1H, H-50),
8.07 (s, 1H, H-80), 11.73 (s, 1H, NH), 12.95 (s, 1H, NH)
ppm; 13C NMR: d = 19.64, 110.53, 115.59, 123.77,
126.56, 128.48, 128.95, 129.20, 129.41, 129.66, 131.32,
134.07, 137.19, 138.12, 141.66, 147.36, 160.02, 165.11,
168.49 ppm.
Starting from 1.84 g 6-chloro-1,1-dioxo-3-phenylamino-
1,4,2-benzodithiazine-7-carboxamide (1n), the title com-
pound 15 was obtained. Yield: 2.5 g (95 %); m.p.: 282–
283 °C (dec.); TLC: Rf = 0.54 (benzene–EtOH 4:1); IR
ꢀ
(KBr): m = 3,435, 3,325, 3,255, 3,200, 3,140 (NH2, NH),
1,765, 1,725, 1,675 (C=O), 1,365, 1,330, 1,140 (SO2)
cm-1; 1H NMR: d = 7.15 (d, J = 8.1 Hz, 1H, H-10), 7.24
(t, J = 7.4 Hz, 1H, H-9), 7.45 (t, J = 7.5 Hz, 1H, H-8),
7.61 (s, 2H, O=C–NH2), 7.65–7.77 (m, 3H, H-3, H-4, H-5
of Ph), 7.87 (d, J = 6.6 Hz, 2H, H-2 and H-6 of Ph), 7.95
(d, J = 8.2 Hz, 1H, H-7), 8.11 (s, 1H, H-50), 8.16 (s, 1H,
H-80), 11.58 (s, 1H, NH), 11.72 (s, 1H, NH) ppm; 13C
NMR: d = 110.53, 115.60, 122.19, 122.26, 122.44,
123.77, 124.49, 126.34, 129.20, 129.47, 129.71, 130.71,
131.51, 134.03, 137.20, 137.62, 141.66, 147.36, 160.00,
166.32 ppm.
Ethyl 60-chloro-5-(4-fluorophenyl)-10,10,2,6-tetraoxo-
1,2,5,6-tetrahydrospiro[4H-benzo[d][1,3,7]oxadiazocine-
4,30(20H)-[1,4,2]benzodithiazine]-70-carboxylate
(13, C24H17ClFN3O7S2)
Starting from 2.07 g ethyl 6-chloro-3-(4-fluorophenylami-
no)-1,1-dioxo-1,4,2-benzodithiazine-7-carboxylate (1l), the
title compound 13 was obtained. Yield: 2.8 g (97 %); m.p.:
216–217 °C (dec.); TLC: Rf = 0.71 (benzene–EtOH 4:1);
ꢀ
IR (KBr): m = 3,270, 3,265, 3,225 (NH), 1,765, 1,725,
60-Chloro-5-(4-chlorophenyl)-10,10,2,6-tetraoxo-1,2,5,6-
tetrahydrospiro[4H-benzo[d][1,3,7]oxadiazocine-
4,30(20H)-[1,4,2]benzodithiazine]-70-carboxamide
(16, C22H14Cl2N4O6S2)
1,685 (C=O), 1,365, 1,325, 1,170, 1,155 (SO2) cm-1; H
1
NMR: d = 1.34 (t, J = 7.1 Hz, 3H, CH3CH2O), 4.37 (q,
J = 7.1 Hz, 2H, CH3CH2O), 7.15 (d, J = 8.1 Hz, 1H,
H-10), 7.24 (t, J = 7.9 Hz, 1H, H-9), 7.33 (d, J = 8.9 Hz,
2H, H-2 and H-6 of 4-FPh), 7.62–7.68 (m, 2H, H-3 and H-5
of 4-FPh), 7.70 (t, J = 8.1 Hz, 1H, H-8), 7.91 (dd,
Jmeta = 1.2 Hz, Jortho = 7.9 Hz, 1H, H-7), 8.02 (s, 1H,
H-50), 8.35 (s, 1H, H-80), 11.61 (s, 1H, NH), 11.72 (s, 1H,
NH) ppm; 13C NMR: d = 14.21, 62.38, 110.53, 115.59,
116.01, 116.46, 123.77, 124.39, 124.57, 126.94, 129.20,
130.54, 130.81, 130.88, 134.31, 135.82, 137.19, 141.67,
147.36, 160.00, 160.17, 163.34 ppm.
Starting from 2.01 g 6-chloro-3-(4-chlorophenylamino)-
1,1-dioxo-1,4,2-benzodithiazine-7-carboxamide (1o), the
title compound 16 was obtained. Yield: 2.7 g (96 %);
m.p.: 286–287 °C (dec.); TLC: Rf = 0.54 (benzene–EtOH
ꢀ
4:1); IR (KBr): m = 3,455, 3,355 (O=C–NH2), 3,315, 3,190
(NH), 1,765, 1,730, 1,660 (C=O), 1,365, 1,315, 1,165
(SO2) cm-1 1H NMR: d = 7.15 (d, J = 8.2 Hz, 1H,
;
H-10), 7.24 (t, J = 7.5 Hz, 1H, H-9), 7.52 (d, J = 8.8 Hz,
2H, H-3 and H-5 of 4-ClPh), 7.67 (d, J = 8.8 Hz, 2H, H-2
and H-6 of 4-ClPh), 7.73 (t, J = 8.2 Hz, 1H, H-8), 7.87 (s,
2H, O=C–NH2), 7.95 (d, J = 9.0 Hz, 1H, H-7), 8.12 (s,
1H, H-50), 8.17 (s, 1H, H-80), 11.62 (s, 1H, NH), 11.74 (s,
1H, NH) ppm; 13C NMR: d = 110.53, 115.60, 123.68,
123.77, 124.55, 129.20, 129.29, 129.41, 129.73, 130.00,
130.55, 131.43, 134.11, 136.66, 137.19, 137.68, 141.66,
147.36, 160.05, 166.28 ppm.
60-Chloro-5-(4-chlorophenyl)- 10,10,2,6-tetraoxo-1,2,5,6-
tetrahydrospiro[4H-benzo[d][1,3,7]oxadiazocine-
4,30(20H)-[1,4,2]benzodithiazine]-70-carbonitrile
(14, C22H12Cl2N4O5S2)
Starting from 1.92 g 6-chloro-3-(4-chlorophenylamino)-
1,1-dioxo-1,4,2-benzodithiazine-7-carbonitrile (1m), the
title compound 14 was obtained. Yield: 2.8 g (95 %);
123

Synthesis of a new series of biologically interesting spiro compounds
1405
60-Chloro-N-(4-chlorophenyl)-10,10,2,6-tetraoxo-5-phenyl-
1,2,5,6-tetrahydrospiro[4H-benzo[d][1,3,7]oxadiazocine-
4,30(20H)-[1,4,2]benzodithiazine]-70-carboxamide
(17, C28H18Cl2N4O6S2)
11. Brzozowski Z, Sa˛czewski F, Sanchez T, Kuo CL, Gdaniec M,
Neamati N (2004) Bioorg Med Chem 12:3663
´
12. Brzozowski Z, Sa˛czewski F, Sławinski J, Sanchez T, Neamati N
(2009) Eur J Med Chem 44:190
13. Brzozowski Z, Sa˛czewski F, Neamati N (2006) Bioorg Med
Chem 16:5298
14. Brzozowski Z (1995) Acta Polon Pharm Drug Res 52:287
15. Brzozowski Z (1996) Acta Polon Pharm Drug Res 53:269
16. Brzozowski Z (1997) Acta Polon Pharm Drug Res 54:293
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18. Brzozowski Z, Sa˛czewski F (2002) Eur J Med Chem 37:285
Starting from 2.40 g 6-chloro-N-(4-chlorophenyl)-1,1-
dioxo-3-(phenylamino)-1,4,2-benzodithiazine-7-carboxa-
mide (1p), the title compound 17 was obtained. Yield:
3.1 g (95 %); m.p.: 278–279 °C (dec.); TLC: Rf = 0.64
ꢀ
(benzene–EtOH 4:1); IR (KBr): m = 3,285, 3,280, 3,205,
´
19. Sławinski J (2004) Eur J Med Chem 39:179
3,140 (NH), 1,765, 1,730, 1,675 (C=O), 1,360, 1,310, 1,145
(SO2) cm-1 1H NMR: d = 7.13 (d, J = 8.3 Hz, 1H,
;
´
20. Sławinski J, Gdaniec M (2005) Eur J Med Chem 40:377
´
21. Sławinski J, Brzozowski Z (2006) Eur J Med Chem 41:1180
22. Brzozowski Z, Sa˛czewski F, Sławinski J (2007) Eur J Med Chem
H-10), 7.21–7.24 (m, 2H, arom), 7.41–7.45 (m, 5H, arom),
7.63–7.72 (m, 5H, arom), 7.89 (d, J = 7.8 Hz, 1H, H-7),
8.19 (s, 1H, H-80), 10.83 (s, 1H, NH), 11.59 (s, 1H, NH),
11.71 (s, 1H, NH) ppm; 13C NMR: d = 110.95, 116.01,
122.08, 122.61, 124.19, 125.44, 126.73, 128.52, 129.48,
129.62, 129.72, 129.88, 130.17, 131.28, 132.66, 134.71,
137.41, 137.61, 138.15, 142.08, 147.79, 160.57, 160.99,
163.42 ppm.
´
42:1218
´
´
23. Sławinski J, Broz_ewicz K, Fruzinski A, Głowka ML (2011)
´
Heterocycles 83:1093
´
_
24. Brozewicz K, Sławinski J (2012) Monatsh Chem 143:975
25. Broz_ewicz K, Sławinski J (2012) Eur J Med Chem 55:384
´
_
´
26. Sławinski J, Zołnowska B, Orlewska Cz, Chojnacki J (2012)
Monatsh Chem 143:1705
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28. Brzozowski Z (1998) Acta Polon Pharm Drug Res 55:49
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Open Access This article is distributed under the terms of the
Creative Commons Attribution License which permits any use, dis-
tribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
30. Brzozowski Z, Sa˛czewski F (2007) J Heterocycl Chem 44:261
_
31. Sławinski J, Zołnowska B, Pirska D, Ke˛dzia A, Kwapisz E (2013)
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J Enzym Inhib Med Chem 28:41
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arnacka E, Innocenti A, Scozzafava A, Supuran CT (2006)
Bioorg Med Chem Lett 16:4846
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33. Sa˛czewski F, Innocenti A, Brzozowski Z, Sławinski J, Pom-
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