Novel benzopyridothiadiazepines as potential active antitumor agents

Article abstract of DOI:10.1021/jm0503897

The synthesis of novel thiadiazepine derivatives, that could be considered as constraint analogues of E-7010, are reported. These molecules were evaluated for their antiproliferative activity toward the murine L1210 leukemia cell line. Flow cytometric studies performed on L1210 cells with the most cytotoxic compounds showed an accumulation of the cells in the G2/M phases of the cell cycle with a significant percentage of tetraploid cells (8N DNA content). Submicromolar cytotoxicities were observed with compounds 2b, 4b, 4e, 4g, and 4i. Two of them, compounds 2b and 4b, were found to be potent inhibitors of tubulin polymerization with IC₅₀ of respectively 3.8 and 2.4 μM compared to 2.4 μM for desoxypodophyllotoxin. A 4-methoxyphenylethyl substitution on the pyridinyl nitrogen of the benzopyridothiadiazepine was found to be essential for the antiproliferative activity. The in vitro activities of compounds 2b and 4b make benzopyridothiadiazepine dioxides a promising new class of tubulin binders which warrant further in vivo evaluation.

Full text of DOI:10.1021/jm0503897

J. Med. Chem. 2005, 48, 7363-7373
7363
Novel Benzopyridothiadiazepines as Potential Active Antitumor Agents
Nicolas Lebegue,†,* Sebastien Gallet,† Nathalie Flouquet,† Pascal Carato,† Bruno Pfeiffer,‡ Pierre Renard,‡
Ste´phane Le´once,‡ Alain Pierre´,‡ Philippe Chavatte,† and Pascal Berthelot†
Laboratoire de Chimie The´rapeutique EA1043, Faculte´ des Sciences Pharmaceutiques et Biologiques de Lille, 3 rue du
Professeur Laguesse, B.P. 83 59006 LILLE Cedex, France, and Institut de Recherches Servier, Division Recherche Cance´rologie,
125 Chemin de Ronde, 78290 Croissy sur Seine, France
Received April 25, 2005
The synthesis of novel thiadiazepine derivatives, that could be considered as constraint
analogues of E-7010, are reported. These molecules were evaluated for their antiproliferative
activity toward the murine L1210 leukemia cell line. Flow cytometric studies performed on
L1210 cells with the most cytotoxic compounds showed an accumulation of the cells in the
G2/M phases of the cell cycle with a significant percentage of tetraploid cells (8N DNA content).
Submicromolar cytotoxicities were observed with compounds 2b, 4b, 4e, 4g, and 4i. Two of
them, compounds 2b and 4b, were found to be potent inhibitors of tubulin polymerization with
IC50 of respectively 3.8 and 2.4 µM compared to 2.4 µM for desoxypodophyllotoxin. A
4-methoxyphenylethyl substitution on the pyridinyl nitrogen of the benzopyridothiadiazepine
was found to be essential for the antiproliferative activity. The in vitro activities of compounds
2b and 4b make benzopyridothiadiazepine dioxides a promising new class of tubulin binders
which warrant further in vivo evaluation.
Introduction
One characteristic of cancer is uncontrolled cell
growth and proliferation. As numerous clinically ef-
ficient drugs and natural compounds are cytotoxic by
interfering with the mitotic spindle apparatus, micro-
tubules have been recognized as an attractive pharma-
cological target for anticancer drugs.1-4
Tubulin is a heterodimer of two closely related and
tightly linked globular polypeptides called R-tubulin and
â-tubulin.5,6 Tubulin molecules polymerize to form long
stiff microtubules that extend throughout the cytoplasm
and govern the location of membrane-bound organelles
and other cell components.7-9 At the onset of mitosis,
cytoplasmic microtubules disassemble, and the free
tubulin molecules rearrange to form the mitotic spindle,
which bridges between the chromosomes in the center
and the centrosomes at opposite poles of the cell. The
spindle remains in dynamic equilibrium with the pool
of free tubulin and therefore must constantly add
tubulin subunits to function properly. During anaphase,
controlled subtraction of tubulin subunits leads to
contraction of the mitotic spindle and concurent migra-
tion of the chromosomes to opposite poles of the dividing
cell.10-13 Interfering with the dynamic instability of
microtubules, spindle poisons arrest dividing cells in
G2/M phases of the cell cycle, causing mitotic catastro-
phy and finally apoptotic cell death.4
Figure 1. Antimitotic natural products.
The vinca alkaloids14 inhibit microtubule polymeri-
zation while the taxoids15 promote microtubule as-
combretastatins A-2 and A-4,21,22 share with colchicine
sembly. Colchicine16,17 is a well-known antimitotic agent
a common binding site on the tubulin (colchicine binding
that inhibits microtubule assembly.
A large number of natural antimitotic agents, such
Sulfonamide derivatives such as E7010 or ER-67865
as podophyllotoxin,18 cornigerine,19 steganacin,20 and
(Figure 2) were reported to inhibit tubulin polymeriza-
site) (Figure 1).
tion by interacting with tubulin at the colchicine binding
site.23-33 E7010 was found to cause cell cycle arrest and
apoptosis in M phase and was shown to inhibit micro-
tubule assembly owing to its reversible binding to the
* To whom correspondence should be addressed. Phone: +33 03 20
96 40 17. Fax: +33 03 20 96 49 13. e-mail: nlebegue@pharma.univ-
lille2.fr.
† Laboratoire de Chimie The´rapeutique EA1043.
‡ Institut de Recherches Servier.
10.1021/jm0503897 CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/25/2005

7364 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23
Lebegue et al.
these compounds followed by acetylation, in acetic
anhydride, led to acetamide derivatives 10 which were
converted, by heating under reflux in DMF in the
presence of copper and potassium carbonate, to the
corresponding substituted benzopyridothiadiazepine di-
oxide derivatives 11. Treatment with sodium hydride
in DMF and reaction with arylalkyl chlorides or meth-
anesulfonates 12, which were prepared as described in
Scheme 2, resulted in the obtention of the two regio-
isomers38,42 1 and 2 (in some cases, the regioisomers 1
could not be isolated from the reaction mixture). The
structures of the regioisomers 1 and 2 were unequivo-
cally determined by NMR spectra, including steady-
state NOE measurements. Analogous isomeric struc-
tures were also described for the synthesis of Nevirapine
derivatives.42
Figure 2. Sufonamides inhibitors of tubulin polymer-
ization.
The substituted thiadiazepine dioxide derivatives 1
and 2 were evaluated for their antiproliferative activity
toward the murine L1210 leukemia cell line. The results
expressed as IC50 are reported in Table 1. All the
compounds substituted on the thiadiazepine moiety,
1a-t, were found poorly cytotoxic with IC50 > 10 µM in
all cases. On the contrary, some of the compounds
substituted on the pyridine ring (structure 2) exhibited
significant cytotoxicity with IC50 values from 0.3 to 1.5
µM (2b, 2d, 2e, 2h, 2k).
Compounds 2 which were substituted by a 4-meth-
oxyphenylalkyl chain on the pyridinyl nitrogen were,
in numerous cases, clearly more active than their
counterpart substituted on the nitrogen at the 11
position of the thiadiazepine. The highest activities were
obtained whith a spacer of two carbon atoms (n ) 2,
2b, 2e, 2h, 2k) between the tricyclic heterocycle and
the phenyl group of the arylalkyl side chain.
Replacement of the 4-methoxyphenyl group with a
3,4,5-trimethoxybenzyl group, which is a common moi-
ety in many antimitotic agents such as podophyllotoxin,
colchicine, and combretastatin A4, resulted in a clear
decrease in activity (compouds 1s, 2s, 1t, 2t). Replace-
ment of the 4-methoxy group on the phenyl by a
4-benzyloxy (2u), a 4-hydroxy (2v), or a 4-dimethylami-
noethyloxy (2w) group led to poorly active compounds
(IC50 > 10 µM). Compounds substituted on the phenyl
moiety of the thiadiazepine by 2- or 3-Cl, 2-CH3, 2-CF3,
or 2-OCH3 were slightly less active than their unsub-
stituted counterpart 2b.
The structure-activity relationships obtained with
compouds of families 1 and 2 were then used to design
the benzo[c]pyrido[f]thiadiazepine dioxide analogues 3
and 4. These compounds were prepared by nearly the
same methodology described in Scheme 1, using 2-chloro-
3-pyridinesulfonyl chloride 14 and various nitroanilines
15 instead of 2-chloro-3-aminopyridine 7 and 2-ni-
trobenzenesulfonyl chlorides 6 (Scheme 3). 2-Chloro-3-
pyridinesulfonyl chloride 14 was prepared, as in Scheme
1, from 3-amino-2-chloropyridine 13 according to a
reported procedure. Condensation with substituted 2-ni-
troanilines 15 in the presence of pyridine led to the
corresponding sulfonamides 16.
Figure 3. Drug design.
cochicine binding site on tubulin. E7010 exhibited good
in vivo antitumor activity against various rodent tumors
and human tumor xenografts.30 Structure-activity
relationship studies showed that replacements of the
methoxy group, the hydroxy group of aniline, and the
pyridine moiety decreased both in vitro and in vivo
activity.28
As part of our program to identify novel cytotoxic
agents, we have decided to prepare and evaluate thia-
diazepine derivatives that could be considered as con-
straint analogues of E7010 (Template A, Figure 3).
Extensive pharmacomodulations starting from template
A (Figure 3) led us to the substituted benzopyridothia-
diazepines 1 and 2. Numerous substituted tricyclic
sulfonamides, with a thiadiazepine skeleton, were then
prepared and evaluated, leading to the identification of
potent and original cytotoxic antimitotic agents in both
structural families 1 and 2.
Chemistry and Biological Results
Benzo[f]pyrido[c]thiadiazepine derivatives 1 and 234
were prepared according to the general pathway35-38
described in Scheme 1. Various substituted 2-nitroben-
zenesulfonyl chlorides 6 were prepared from com-
mercially available substituted nitroanilines 5 according
to already described procedures.39-41 Condensation of
these compounds with 3-amino-2-chloropyridine in the
presence of pyridine at 60 °C led to the corresponding
sulfonamides 8, which were then reacted with sodium
hydride and iodomethane to give the N-methylated
products 9 in good yields. Catalytic hydrogenation of
Substitution of these sulfonamides with alkyls or
arylalkyls was obtained in good yields with sodium
hydride in DMF. Obtention of the 2-(N,N-diethylamino)-
ethylsulfonamide derivative was carried out in a bipha-
sic solution of toluene and water in the presence of

Benzopyridothiadiazepines as Antitumor Agents
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23 7365
Scheme 1a
a Reagents: (a) NaNO2, HCl, SO2, CuCl2, CH3COOH, 0 °C, 75-93%; (b) pyridine, 60 °C, 45-80%; (c) NaH, ICH3, DMF, 75%; (d) i: H2/Ni
Raney, EtOH; ii: (CH3CO)2O, 75%; (e) Cu, K2CO3, DMF, 60%; (f) NaH, DMF, 15-85%.
Scheme 2a
a Reagents: (a) THF, LiAlH4, 0 °C, 81-88%; (b) K2CO3, benzyl bromide, acetone, 85%; (c) triethylamine, methanesulfonyle chloride,
dichloromethane, 61-76%.
sodium hydroxide, benzyltriethylammonium chloride,
and 2-(N,N-diethylamino)ethyl chloride hydrochloride
with 52% yield. Reduction with iron in acidic conditions
of the nitro group into the primary amine, followed by
displacement of the chlorine by the amino group allowed
the cyclization into the tricyclic thiadiazepines 18.
Obtention of the two regioisomers 3 and 4 was per-
formed as in Scheme 1.
These compounds were also evaluated on L1210 cells
(Table 2). In most of the cases, compounds substituted
on the pyridine (4) were found more cytotoxic than their
counterpart substituted on the thiadiazepine moiety (3).
Four compounds, 4b, 4e, 4g, and 4i, were found mark-
edly cytotoxic with IC50 from 0.11 to 0.41 µM. Their
counterpart in family 3 (3b, 3e, 3g, and 3i) are all
inactive with IC50 >10 µM. As for compounds 1 and 2,
the best results are obtained when the benzopyrido-
thiadiazepine is substituted on the pyridine moiety by
a 4-methoxyphenylethyl chain with no substitution on
the benzenic part of the tricycle. To evaluate the
importance of substitution on the sulfonamide group,
we have replaced the methyl group by more bulky
substituents such as 4-methoxybenzyl (3l, 3m and 4l,
4m) or 2-(N,N-diethylamino)ethyl (3n and 4n). Those
changes in the sulfonamide substitution resulted in a
total loss of activity.
Compounds 2b and 4b were screened against respec-
tively six and one other tumor cell lines to further
determine their antitumor spectra. Cytotoxic activities
expressed in Table 3 showed that compounds 2b and
4b were potent antitumor agents with broader antitu-
mor spectra in the submicromolar range.
The perturbations of the cell cycle induced by the most
active compounds were studied on the L1210 cell line
by flow cytometry (Table 4). When exposed to the cells
for two doubling times (21 h), all these compounds
induced a marked accumulation of tetraploid cells. This
accumulation, which is observed for numerous tubulin
interacting drugs, prompted us to investigate the effects
of compounds 2b and 4b on tubulin polymerization.
These two compounds were found to be potent inhibitors
of tubulin polymerization with IC50 of respectively 3.8
and 2.4 µM compared to 2.4 µM for desoxypodophyllo-
toxin used as a reference compound. No effect was
observed on tubulin depolymerization. In comparison,
structurally related sulfonamides as E7010 and ER-
67865 were found to arrest P388 cells in the G2-M phase
and inhibited tubulin polymerization with IC50 of re-
spectively 2.2 and 2.5 µM.23,29 The low cytotoxicity of
these compounds considering their high inhibition of
tubulin polymerization can be explained by their weak
cell-penetrating properties. Prediction of lipophilicity43

7366 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23
Lebegue et al.
Table 1. In Vitro Antiproliferative Activity of Compounds 1a-t and 2a-w
no.
X
n
R
IC50a (µM)
no.
X
n
R
IC50a (µM)
1a
1b
H
H
1
2
4-OCH3
4-OCH3
>10
>10
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
H
H
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
1
2
2
2
2
4-OCH3
>10
0.3
4-OCH3
4-OCH3
>10
1.5
1d
1e
2-Cl
2-Cl
1
2
4-OCH3
4-OCH3
>10
>10
2-Cl
4-OCH3
2-Cl
4-OCH3
1.3
2-Cl
4-OCH3
>10
>10
1.3
3-Cl
4-OCH3
3-Cl
4-OCH3
3-Cl
4-OCH3
>10
9
1j
2-CH3
2-CF3
1
1
4-OCH3
4-OCH3
>10
>10
2j
2k
2l
2-CH3
2-CH3
2-CH3
2-CF3
2-CF3
2-CF3
2-OCH3
2-OCH3
2-OCH3
H
4-OCH3
4-OCH3
1.4
4-OCH3
>10
>10
>10
>10
>50
>10
>50
>10
>10
>10
>10
>10
1m
2m
2n
2o
2p
2q
2r
2s
2t
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
1s
1t
H
H
1
2
3,4,5-(OCH3)3
3,4,5-(OCH3)3
>10
>10
3,4,5-(OCH3)3
3,4,5-(OCH3)3
OCH2C6H5
OH
H
2u
2v
2w
H
H
H
O(CH2)2N(CH3)2
a Concentration inhibiting L1210 cell proliferation by 50% relative to untreated controls after 48 h of drug exposure.
Scheme 3a
a Reagents: (a) NaNO2, HCl, SO2, CuCl2, CH3COOH, 0 °C, 72%; (b) pyridine, 60 °C, 30-70%; (c) NaH, ICH3 or ClCH2C6H5OCH3, DMF,
60 °C, or NaOH, benzyltriethylammonium chloride, 2-(N,N-diethylamino)ethyl chloride hydrochloride, toluene, reflux, 50-90%; (d) iron,
CH3COOH, reflux; or iron, EtOH, H2O, CH3COOH, HCl, reflux, 35-80%; (e) NaH, DMF, 60 °C, 15-85%.
(logP) and aqueous solubility44 (logS) of compounds
2b,e,h,k and 4b,e,g,i was calculated using the ALOGPS
2.1 software.45 These compounds showed high lipophi-
licity with logP values in the range of 3.6 to 4.2 and
weak aqueous solubility with logS values in the range
of 2 to 9 mg/L in comparison with colchicine, podophillo-

Benzopyridothiadiazepines as Antitumor Agents
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23 7367
Table 2. In Vitro Antiproliferative Activity of Compounds 3a-n and 4a-n
no.
X
n
R
IC50a (µM)
no.
X
n
R
IC50a (µM)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
H
H
H
1
2
3
1
2
1
2
1
2
1
2
1
2
2
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
9.6
>10
>10
8.7
>100
9.8
>10
6.9
>10
8.3
>10
>100
>100
>10
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
H
H
H
1
2
3
1
2
1
2
1
2
1
2
1
2
2
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
>10
0.11
8.3
8-Cl
8-Cl
9-Cl
9-Cl
9-CH3
9-CH3
9-OCH3
9-OCH3
H
8-Cl
8-Cl
9-Cl
9-Cl
9-CH3
9-CH3
9-OCH3
9-OCH3
H
4.1
0.23
5.4
0.19
9.2
0.41
>10
1.5
>100
>100
>10
CH2C6H5OCH3
CH2C6H5OCH3
(CH2)2N(C2H5)2
CH2C6H5OCH3
CH2C6H5OCH3
(CH2)2N(C2H5)2
H
H
H
H
a Concentration inhibiting L1210 cell proliferation by 50% relative to untreated controls after 48 h of drug exposure.
Table 3. Antiproliferative Activity of 2b and 4b on Selected Tumoral Cell Lines
DU145 prostate
P388 leukemia
A549 lung
KB 3-1 skin
KB-A1a skin
IGROV1 ovarian
2b
4b
0.55
0.14
0.33
ntb
0.45
ntb
0.24
ntb
0.3
ntb
0.34
ntb
a KB-A1, adriamycin resistant. b Not tested.
Table 4. Effects on L1210 Cell Cycle
Experimental Section
% of L1210 cells in each phase of the cell cyclea
Melting points were determined on a BU¨ CHI B-540 ap-
paratus and are uncorrected. Infrared spectra were recorded
as thin films on potassium bromide disks on a Beckman
Acculab IV spectrophotometer. Mass spectra were performed
on a Finnigan MAT SSQ 710 Advantage spectrometer. 1H
NMR spectra (LARMN, Universite de Lille 2) were recorded
on a Bruker AC 300 P and 2D NMR spectra on a Bruker DPX
300, using tetramethylsilane as internal standard. Elemental
analyses were performed by C.N.RS-Vernaison and were in
agreement with the calculated values within (0.4%.
General Procedure for Synthesis of Substituted 2-Ni-
trobenzenesulfonyl Chlorides 6a-e. An aqueous solution
of sodium nitrite (15 mmol) is added dropwise to a suspension
of substituted 2-nitroaniline (10 mmol) in concentrated hy-
drochloric acid at 0 °C, and the reaction mixture is stirred for
45 min. The resulting solution is filtered, and the filtrate is
added at 5 °C to a saturated sulfur dioxide acetic acid solution
(10 mL) in the presence of CuCl2 (3 mmol). After stirring for
1.5 h, the precipitate is filtered, washed with water, and used
in the next step without further purification.
no.
G1
S
G2+M
8N
concn (µM)
2b
2e
2h
2k
4b
4e
4g
4i
6
7
4
5
5
3
8
2
5
8
32
26
24
19
17
21
19
12
17
54
61
66
68
70
70
63
84
71
1
5
2.5
5
0.2
0.5
1
2
5
6
6
8
8
6
10
2
4k
7
a Distribution of control cells in the cell cycle: 45% (G1), 31%
G2, 23% (G2 + M), 1% (8N).
toxin, E7010, and ER-67865 with logP and logS values
of respectively 1.6, 30 mg/L; 2.3, 120 mg/L; 3.4, 30 mg/
L; and 2.0, 150 mg/L.
Conclusion
4-Chloro-2-nitrobenzenesulfonyl chloride (6a): white
powder; yield 75%; mp: 74-76 °C. 1H NMR (CDCl3); IR (KBr).
5-Chloro-2-nitrobenzenesulfonyl chloride (6b): white
powder; yield 80%; mp: 60-64 °C. 1H NMR (CDCl3,); IR (KBr).
4-Methyl-2-nitrobenzenesulfonyl chloride (6c): white
powder; yield 82%; mp: 98-99 °C. 1H NMR (CDCl3); IR (KBr).
4-Methoxy-2-nitrobenzenesulfonyl chloride (6d): white
powder; yield 80%; mp: 74-75 °C. 1H NMR (CDCl3); IR (KBr).
4-Trifluoromethyl-2-nitrobenzenesulfonyl chloride
We have discovered new antimitotic compounds based
on a benzopyridothiadiazepine dioxide molecular skel-
eton with potent inhibitions of tubulin polymerization.
One of the most active compound of the series, 1-(4-
methoxyphenylethyl)-6-methylbenzo[c]-1,2-dihydropyrido-
[2,3-f][1,2,5]thiadiazepine 5,5-dioxide 4b, inhibits L1210
leukemia cell proliferation in the submicromolar range,
and tubulin polymerization in the micromolar range.
Determination of the site of interaction with tubulin as
well as the design of new compounds with improved
cytotoxicity, bioavailability, and water solubility is
under investigation.
1
(6e): white oil; yield 93%; mp: 74-75 °C. H NMR (CDCl3);
IR (KBr).
General Procedure for Synthesis of Substituted N-(3-
Pyridyl)-2-nitrobenzenesulfonamides 8a-f. Substituted
2-nitrobenzenesulfonyl chloride 6 (20 mmol) is added portion-
wise to a solution of 3-amino-2-chloropyridine 7 (20 mmol) in

7368 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23
Lebegue et al.
pyridine (2 mL) and heated at 70 °C for 2 h. After this time,
the residue is taken-up with water, extracted with ethyl
acetate, dried, filtered, evaporated under reduced pressure and
recrystallized from the appropriate solvent.
N-(2-Chloro-3-pyridyl)-2-nitrobenzenesulfonamide
(8a): beige powder; yield 80%; mp: 145-147 °C (ethanol). 1H
NMR (CDCl3); IR (KBr).
2-(Acetylamino)-N-(2-chloro-3-pyridyl)-N-methylben-
zenesulfonamide (10a). Synthesized from procedure A; beige
powder; yield 74%; mp: 116-118 °C (ethanol). 1H NMR
(CDCl3); IR (KBr).
2-(Acetylamino)-4-chloro-N-(2-chloro-3-pyridyl)-N-me-
thylbenzenesulfonamide (10b). Synthesized from procedure
1
B; brown powder; yield 64%; mp: 100-102 °C (ethanol). H
NMR (CDCl3); IR (KBr).
4-Chloro-N-(2-Chloro-3-pyridyl)-2-nitrobenzenesulfona-
2-(Acetylamino)-5-chloro-N-(2-chloro-3-pyridyl)-N-me-
mide (8b): beige powder; yield 72%; mp: 155-157 °C (etha-
1
thylbenzenesulfonamide (10c). Synthesized from procedure
nol). H NMR (CDCl3); IR (KBr).
1
A; brown powder; yield 77%; mp: 144-147 °C (ethanol). H
5-Chloro-N-(2-Chloro-3-pyridyl)-2-nitrobenzenesulfona-
NMR (CDCl3); IR (KBr).
mide (8c): beige powder; yield 45%; mp: 179-182 °C (etha-
1
2-(Acetylamino)-N-(2-chloro-3-pyridyl)-N-methyl-4-me-
nol). H NMR (CDCl3); IR (KBr).
thylbenzenesulfonamide (10d). Synthesized from procedure
N-(2-Chloro-3-pyridyl)-4-methyl-2-nitrobenzenesulfona-
1
A; brown powder; yield 65%; mp: 145-146 °C (ethanol). H
mide (8d): white powder; yield 78%; mp: 145-147 °C
NMR (CDCl3); IR (KBr).
1
(ethanol). H NMR (CDCl3); IR (KBr).
2-(Acetylamino)-N-(2-chloro-3-pyridyl)-4-methoxy-N-
N-(2-Chloro-3-pyridyl)-4-methoxy-2-nitrobenzene-
methylbenzenesulfonamide (10e). Synthesized from pro-
sulfonamide (8e): beige powder; yield 67%; mp: 183-184
1
cedure A; beige powder; yield 58%; mp: 102 °C (ethanol). H
1
°C (ethanol). H NMR (CDCl3); IR (KBr).
NMR (CDCl3); IR (KBr).
N-(2-Chloro-3-pyridyl)-4-trifluoromethyl-2-nitroben-
2-(Acetylamino)-N-(2-chloro-3-pyridyl)-4-trifluorometh-
yl-N-methylbenzenesulfonamide (10f). Synthesized from
procedure B; white powder; yield 50%; mp: 113-114 °C
zenesulfonamide (8f): white powder; yield 62%; mp: 151-
1
1524 °C (ethanol). H NMR (CDCl3); IR (KBr).
General Procedure for Synthesis of Substituted
N-Methyl-N-(3-pyridyl)-2-nitrobenzenesulfonamides 9a-
f. Substituted N-(3-pyridyl)-2-nitrobenzenesulfonamide 8 (10
mmol) dissolved in dimethylformamide (15 mL) is added
dropwise to a suspension of sodium hydride (20 mmol) in
dimethylformamide (5 mL) and stirred for 1 h at room
temperature. Iodomethane (30 mmol) in dimethylformamide
(5 mL) is added dropwise to the previous solution and stirred
for 12 h at room temperature. The resulting solution is
evaporated under reduced pressure, crystallized from water,
and filtered. The resulting powder is then recrystallized from
the appropriate solvent.
1
(ethanol). H NMR (CDCl3); IR (KBr).
General Procedure for Synthesis of Substituted
5,11-Dihydro-5-methylbenzo[f]pyrido
[3,2,c][1,2,5]-
thiadiazepine 6,6-Dioxide 11a-f. A solution of substituted
2-(acetylamino)-N-(2-chloro-3-pyridyl)-N-methylbenzenesulfona-
mide 10 (10 mmol) in dimethylformamide (30 mL) is treated
with potassium carbonate (20 mmol) and copper powder (5
mmol), stirred, and heated under reflux for 8 h. After this time,
the mixture is filtered and the solution is evaporated under
reduced pressure. The residue is diluted in dichloromethane,
washed with water, dried, evaporated, and crystallized from
the appropriate solvent.
N-(2-Chloro-3-pyridyl)-N-methyl-2-nitrobenzene-
5,11-Dihydro-5-methylbenzo[f]pyrido[3,2-c][1,2,5]-
sulfonamide (9a): yellow powder; yield 78%; mp: 127-128
thiadiazepine 6,6-dioxide (11a): beige powder; yield 67%;
1
°C (diisopropyl ether). H NMR (CDCl3); IR (KBr).
1
mp: 203-204 °C (ethanol). H NMR (CDCl3); IR (KBr).
4-Chloro-N-(2-chloro-3-pyridyl)-N-methyl-2-nitroben-
9-Chloro-5,11-dihydro-5-methylbenzo[f]pyrido[3,2-c]-
zenesulfonamide (9b): white powder; yield 78%; mp: 136-
[1,2,5]thiadiazepine 6,6-dioxide (11b): beige powder; yield
1
1
138 °C (ethanol). H NMR (CDCl3); IR (KBr).
68%; mp: 247-248 °C (ethanol). H NMR (CDCl3); IR (KBr).
5-Chloro-N-(2-Chloro-3-pyridyl)-N-methyl-2-nitroben-
8-Chloro-5,11-dihydro-5-methylbenzo[f]pyrido[3,2,c]-
zenesulfonamide (9c): beige powder; yield 77%; mp: 129-
[1,2,5]thiadiazepine 6,6-dioxide (11c): beige powder; yield
1
1
130 °C (2-propanol). H NMR (CDCl3); IR (KBr).
60%; mp: 315 °C (ethanol). H NMR (CDCl3); IR (KBr).
N-(2-Chloro-3-pyridyl)-N-methyl-4-methyl-2-nitroben-
5,11-Dihydro-5,9-dimethylbenzo[f]pyrido[3,2,c][1,2,5]-
ze`nesulfonamide (9d): white powder; yield 73%; mp: 139-
thiadiazepine 6,6-dioxide (11d): yellow powder; yield 37%;
1
1
140 °C (methanol). H NMR (CDCl3); IR (KBr).
mp: 202-203 °C (ethanol). H NMR (CDCl3); IR (KBr).
N-(2-Chloro-3-pyridyl)-4-methoxy-N-methyl-2-nitroben-
5,11-Dihydro-9-methoxy-5-methylbenzo[f]pyrido[3,2-
c][1,2,5]thiadiazepine 6,6-dioxide (11e): brown powder;
yield 62%; mp: 176-179 °C (ethanol). 1H NMR (CDCl3); IR
(KBr).
5,11-Dihydro-9-trifluoromethyl-5-methylbenzo[f]pyrido-
[3,2,c][1,2,5]thiadiazepine 6,6-dioxide (11f): white powder;
yield 62%; mp: 186-187 °C (ethanol). 1H NMR (CDCl3); IR
(KBr).
General Procedure for Synthesis of Alcohol Deriva-
tives (19b,c). A solution of the appropriate carboxylic acid (30
mmol) in THF (50 mL) is added dropwise to a suspension of
LiAlH4 (60 mmol) in THF (50 mL) at 0 °C. The reaction
mixture is stirred for 12 h at room temperature. A solution of
1 N hydrochloric acid is then added, and the solution is
extracted with diethyl ether. The organic layers are dried,
filtered, evaporated under reduced pressure, and used without
further purification for the next step.
zenesulfonamide (9e): beige powder; yield 82%; mp: 124-
1
127 °C (ethanol). H NMR (CDCl3); IR (KBr).
4-Trifluoromethyl-N-(2-Chloro-3-pyridyl)-N-methyl-2-
nitrobenzenesulfonamide (9f): white powder; yield 53%;
1
mp: 93-94 °C (ethanol). H NMR (CDCl3); IR (KBr).
General Procedure for Synthesis of Substituted
2-(Acetylamino)-N-(2-chloro-3-pyridyl)-N-methylbenze-
nesulfonamides 10a-f. Procedure A. Substituted N-meth-
yl-N-(3-pyridyl)-2-nitrobenzenesulfonamide 9 (20 mmol) is
stirred in ethanol (250 mL) with Raney nickel catalyst at room
temperature under an atmospheric pressure of hydrogen. The
catalyst is separated by filtration and the solvent evaporated
under reduced pressure. The intermediate amine is then
stirred, without purification, for 12 h in acetic anhydride (20
mL) at room temperature. After this time, the solution is
diluted with water, extracted with dichloromethane, dried,
filtered, evaporated under reduced pressure, and crystallized
from the appropriate solvent. Procedure B. Substituted
N-methyl-N-(3-pyridyl)-2-nitrobenzenesulfonamide 9 (20 mmol)
in acetic acid (50 mL) with iron powder (100 mmol) is refluxed
for 1 h. Then, the mixture is filtered, and the filtrate is added
to acetic anhydride (20 mL) and stirred for 12 h at room
temperature. After this time, the solution is diluted with water,
extracted with dichloromethane, dried, filtered, evaporated
under reduced pressure, and crystallized from the appropriate
solvent.
3-(4-Methoxyphenyl)propanol (19b): yellow oil; yield
1
81%; H NMR (CDCl3); IR (KBr).
2-(3,4,5-Trimethoxyphenyl)ethanol (19c): yellow oil;
1
yield 88%; H NMR (CDCl3); IR (KBr).
Synthesis of 2-(4-Benzyloxyphenyl)ethanol (19d). A
solution of 2-(4-hydroxyphenyl)ethanol (36 mmol), potassium
carbonate (43 mmol), and benzyl bromide (43 mmol) is heated
under reflux in acetone (50 mL) for 12 h. The reaction mixture
is filtered and the filtrate concentrated in vacuo. The residue
is dissolved in diethyl ether and washed with 2% NaOH, dried,

Benzopyridothiadiazepines as Antitumor Agents
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23 7369
evaporated under reduce pressure, and recrystallized from
hexane. White powder; yield 85%; mp: 86-87 °C; 1H NMR
(CDCl3); IR (KBr).
dioxide (1m): white powder; purified by chromatography
with petroleum ether/ethyl acetate/methanol (80:18:2); yield
1
7%; mp: 135-136 °C (ethanol). H NMR (CDCl3); IR (KBr);
MS (EI); Anal. (C21H18F3N3O3S): C, H, N.
General Procedure for Synthesis of Methanesulfonate
Derivatives (12a-d). A solution of methanesulfonyl chloride
(60 mmol) in dichloromethane (15 mL) is added dropwise to a
solution of the appropriate arylalkyl alcohol 19 (30 mmol) and
triethylamine (70 mmol) in dichloromethane (35 mL) at 0 °C
and stirred for 8 h at room temperature. The reaction mixture
is washed with water and saturated sodium bicarbonate
solution, and the organic layer is dried, filtered, concentrated
in vacuo, and crystallized from the appropriate solvent.
2-(4-Methoxyphenyl)ethyl methanesulfonate (12a):
white powder; yield 70%; mp: 35-36 °C (diisopropyl ether);
1H NMR (CDCl3); IR (KBr).
3-(4-Methoxyphenyl)propyl methanesulfonate (12b):
white powder; yield 61%; mp: 42-43 °C (diisopropyl ether);
1H NMR (CDCl3); IR (KBr).
5,11-Dihydro-11-(3,4,5-trimethoxybenzyl)-5-methyl-
benzo[f]pyrido[3,2,c][1,2,5]thiadiazepine
6,6-dioxide
(1s): white powder; purified by chromatography with petro-
leum ether/ethyl acetate/methanol (70:28:2); yield 14%; mp:
1
182-184 °C (ethanol). H NMR (CDCl3); IR (KBr); MS (EI);
Anal. (C22H23N3O5S): C, H, N.
5,11-Dihydro-11-[2-(3,4,5-trimethoxyphe´nyl)ethyl]-5-
methylbenzo[f]pyrido[3,2,c][1,2,5]thiadiazepine 6,6-di-
oxide (1t): white powder, purified by chromatography with
petroleum ether/ethyl acetate/methanol (80:18:2); yield 12%;
mp: 90-92 °C (ethanol). 1H NMR (CDCl3); IR (KBr); MS (EI);
Anal. (C23H25N3O5S): C, H, N.
1-(4-Methoxybenzyl)-5-methylbenzo[f]-1,5-dihydro-
pyrido[3,2,c][1,2,5]thiadiazepine 6,6-dioxide (2a): yellow
powder; purified by chromatography with petroleum ether/
ethyl acetate (75:25); yield 65%; mp: 174-177 °C (ethanol).
1H NMR (CDCl3); IR (KBr); MS (EI); Anal. (C20H19lN3O3S): C,
H, N.
2-(3,4,5-Trimethoxyphenyl)ethyl methanesulfonate
(12c): white powder; yield 76%; mp: 76-77 °C (diisopropyl
1
ether); H NMR (CDCl3); IR νmax (KBr).
2-(4-Benzyloxyphenyl)ethyl methanesulfonate (12d):
white powder; yield 54%; mp: 68-69 °C (propan-2-ol); 1H NMR
(CDCl3); IR (KBr).
1-(4-Methoxyphenylethyl)-5-methylbenzo[f]-1,5-
dihydropyrido[3,2,c][1,2,5]thiadiazepine
6,6-dioxide
(2b): yellow powder; purified by chromatography with dichlo-
romethane/ethyl acetate (98:2); yield 63%; mp: 181-183 °C
(ethanol). 1H NMR (CDCl3); IR (KBr); MS (EI); Anal.
(C21H21N3O3S): C, H, N.
General Procedure for Synthesis of Substituted 11-
(Arylalkyl)-5,11-dihydrobenzo[f]pyrido[3,2,c] [1,2,5]thia-
diazepine 6,6-Dioxides 1a-t and 1-(Arylalkyl)-5-meth-
ylbenzo[f]-1,5-dihydropyrido [3,2,c][1,2,5]thiadiazepine
6,6-Dioxides 2a-w. A solution of substituted 5,11-dihydro-
5-methylbenzo[f]pyrido [3,2,c][1,2,5]thiadiazepine 6,6-dioxide
11 (4 mmol) in dimethylformamide (10 mL) is added dropwise
to a suspension of sodium hydride (8 mmol) in dimethylfor-
mamide (5 mL) and stirred for 3 h at 60 °C. A solution of
arylalkyl chloride or methanesulfonate 12 (12 mmol) in
dimethylformamide (10 mL) is then added dropwise to the
previous solution and stirred for 24 h at 60 °C. The resulting
solution is evaporated under reduced pressure, the residue is
diluted in dichloromethane, washed with water, dried, evapo-
rated and the two regioisomers are purified by preparative
HPLC.
5,11-Dihydro-11-(4-methoxybenzyl)-5-methylbenzo[f]-
pyrido[3,2,c][1,2,5]thiadiazepine 6,6-dioxide (1a): white
powder; purified by chromatography with petroleum ether/
ethyl acetate/methanol (70:28:2); yield 11%; mp: 184.5-186
°C (ethanol). 1H NMR (CDCl3); IR (KBr); MS (EI); Anal.
(C20H19N3O3S): C, H, N.
5,11-Dihydro-11-[2-(4-methoxyphe´ nyl)ethyl]-5-
methylbenzo[f]pyrido[3,2,c][1,2,5]thiadiazepine 6,6-di-
oxide (1b): white powder; purified by chromatography with
petroleum ether/ethyl acetate/methanol (80:18:2); yield 12%;
mp: 115-118 °C (ethanol). 1H NMR (CDCl3); IR (KBr); MS
(EI); Anal. (C21H21N3O3S): C, H, N.
1-[1-(4-Me´thoxyphenyl)propyl]-5-methylbenzo[f]-1,5-
dihydropyrido[3,2,c][1,2,5]thiadiazepine
6,6-dioxide
(2c): yellow powder; purified by chromatography with petro-
leum ether/ethyl acetate (75:25); yield 50%; mp: 94-96 °C
(ethanol). 1H NMR (CDCl3); IR (KBr); MS (EI); Anal.
(C22H23N3O3S): C, H, N.
9-Chloro-1-(4-methoxybenzyl)-5-methylbenzo[f]-1,5-
dihydropyrido[3,2,c][1,2,5]thiadiazepine
6,6-dioxide
(2d): yellow powder, purified by chromatography with petro-
leum ether/ethyl acetate/methanol (80:18:2); yield 31%; mp:
1
131-132 °C (ethanol). H NMR (CDCl3); IR (KBr); MS (EI);
Anal. (C20H18ClN3O3S): C, H, N.
9-Chloro-1-(4-methoxyphenylethyl)-5-methylbenzo[f]-
1,5-dihydropyrido[3,2,c][1,2,5]thiadiazepine 6,6-dioxide
(2e): yellow powder; purified by chromatography with petro-
leum ether/ethyl acetate (80:20); yield 32%; mp: 130-131 °C
(ethanol). 1H NMR (CDCl3); IR (KBr); MS (EI); Anal. (C21H20-
ClN3O3S): C, H, N.
9-Chloro-[1-(4-methoxyphenyl)propyl]-5-methylbenzo-
[f]-1,5-dihydropyrido[3,2,c][1,2,5]thiadiazepine 6,6-diox-
ide (2f): yellow powder; purified by chromatography with
petroleum ether/ethyl acetate (75:25); yield 39%; mp: 112-
1
113 °C (ethanol). H NMR (CDCl3); IR (KBr); MS (EI); Anal.
(C22H22ClN3O3S): C, H, N.
8-Chloro-1-(4-methoxybenzyl)-5-methylbenzo[f]-1,5-
dihydropyrido[3,2,c][1,2,5]thiadiazepine
6,6-dioxide
9-Chloro-5,11-dihydro-11-(4-methoxybenzyl)-5-
methylbenzo[f]pyrido[3,2,c][1,2,5]thiadiazepine 6,6-di-
oxide (1d): white powder; purified by chromatography with
petroleum ether/ethyl acetate/methanol (80:18:2); yield 23%;
mp: 152-153 °C (ethanol). 1H NMR (CDCl3); IR (KBr); MS
(EI); Anal. (C20H18ClN3O3S): C, H, N.
(2g): yellow powder; purified by chromatography with petro-
leum ether/ethyl acetate/methanol (80:18:2); yield 13%; mp:
1
162-163 °C (ethanol). H NMR (CDCl3); IR (KBr); MS (EI);
Anal. (C20H18ClN3O3S): C, H, N.
8-Chloro-1-(4-methoxyphenylethyl)-5-methylbenzo[f]-
1,5-dihydropyrido[3,2,c][1,2,5]thiadiazepine 6,6-dioxide
(2h): yellow powder; purified by chromatography with petro-
leum ether/ethyl acetate (80:20); yield 37%; mp: 186-188 °C
(ethanol). 1H NMR (CDCl3); IR (KBr); MS (EI); Anal. (C21H20-
ClN3O3S): C, H, N.
9-Chloro-5,11-dihydro-11-(4-methoxyphe´nylethyl)-5-
methylbenzo[f]pyrido[3,2,c][1,2,5]thiadiazepine 6,6-di-
oxide (1e): white powder; purified by chromatography with
petroleum ether/ethyl acetate (80:20); yield 11%; mp: 172-
1
173 °C (ethanol). H NMR (CDCl3); IR (KBr); MS (EI); Anal.
8-Chloro-[1-(4-methoxyphenyl)propyl]-5-methylbenzo-
[f]-1,5-dihydropyrido[3,2,c][1,2,5]thiadiazepine 6,6-diox-
ide (2i): yellow powder; purified by chromatography with
petroleum ether/dichloromethane (50:50); yield 38%; mp: 112-
(C21H20ClN3O3S): C, H, N.
5,11-Dihydro-11-(4-methoxybenzyl)-5,9-dimethylbenzo-
[f]pyrido[3,2,c][1,2,5]thiadiazepine 6,6-dioxide (1j): white
powder; purified by chromatography with petroleum ether/
ethyl acetate (70:30); yield 5%; mp: 165-166 °C (ethanol). 1H
NMR (CDCl3); IR (KBr); MS (EI); Anal. (C21H21N3O3S): C, H,
N.
1
113 °C (ethanol). H NMR (CDCl3); IR (KBr); MS (EI); Anal.
(C22H22ClN3O3S): C, H, N.
1-(4-Methoxybenzyl)-5,9-dimethylbenzo[f]-1,5-
dihydropyrido[3,2,c][1,2,5]thiadiazepine
6,6-dioxide
5,11-Dihydro-9-trifluoromethyl-11-(4-methoxybenzyl)-
5-methylbenzo[f]pyrido[3,2,c][1,2,5]thiadiazepine 6,6-
(2j): yellow powder; purified by chromatography with petro-
leum ether/ethyl acetate (70:30); yield 21%; mp: 135-136 °C

7370 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23
Lebegue et al.
(ethanol). 1H NMR (CDCl3); IR (KBr); MS (EI); Anal.
(C21H21N3O3S): C, H, N.
sure. The crude product is crystallized in methanol/water (9/
1) and furnishes a yellow powder. Yield 60%; mp: 170-173
°C (ethanol). 1H NMR (CDCl3); IR (KBr); MS (EI); Anal.
(C20H19N3O3S): C, H, N.
1-(4-Methoxyphenylethyl)-5,9-dimethylbenzo[f]-1,5-
dihydropyrido[3,2,c][1,2,5]thiadiazepine
6,6-dioxide
Synthesis of 1-{2-[4-(2-Dimethylaminoethoxy)phenyl]-
ethyl}-5-methylbenzo[f]-1,5-dihydropyrido [3,2,c][1,2,5]-
thiadiazepine 6,6-Dioxide (2w). A solution of 2v (3 mmol),
potassium carbonate (6 mmol), and 2-(dimethylamino)ethyl
chloride hydrochloride (3 mmol) are warmed under relux in
acetone (40 mL) for 12 h. The reaction mixture is filtered and
the filtrate concentrated in vacuo. The residu is precipitated
into water, filtered, and recrystallized in ethanol. Yield 80%;
(2k): yellow powder; purified by chromatography with petro-
leum ether/ethyl acetate/methanol (80:18:2); yield 10%; mp:
128 °C (ethanol). 1H NMR (CDCl3); IR (KBr);; MS (CI - CH4);
Anal. (C22H23N3O3S): C, H, N.
1-(4-Methoxyphenyl)propyl-5,9-dimethylbenzo[f]-1,5-
dihydropyrido[3,2,c][1,2,5]thiadiazepine
6,6-dioxide
(2l): yellow powder; purified by chromatography with petro-
leum ether/ethyl acetate (75:25); yield 42%; mp: 130-131 °C
1
1
mp: 157-160 °C. H NMR (CDCl3); IR (KBr); MS (EI); Anal.
(ethanol). H NMR (CDCl3); IR (KBr);; MS (CI - CH4); Anal.
(C24H28N4O3S): C, H, N.
(C23H25N3O3S): C, H, N.
Syntesis of 2-Chloro-3-pyridinesulfonyl Chloride (14).
Prepared according to the procedure for series 6. White
powder; yield 72%; mp: 42-43 °C. 1H NMR (CDCl3); IR (KBr).
General Procedure for Synthesis of Substituted 2-Chlo-
ro-N-(2-nitrophenyl)-3-pyridinesulfonamides 16a-e. Pre-
pared according to the procedure for serie 8.
9-Trifluoromethyl-1-(4-methoxybenzyl)-5-methylben-
zo[f]-1,5-dihydropyrido[3,2,c][1,2,5]thiadiazepine 6,6-
dioxide (2m): yellow powder; purified by chromatography
with petroleum ether/ethyl acetate/methanol (80:18:2); yield
1
65%; mp: 142-143 °C (ethanol). H NMR (CDCl3); IR (KBr);
MS (EI); Anal. (C21H18F3N3O3S): C, H, N.
2-Chloro-N-(2-nitrophenyl)-3-pyridinesulfonamide
(16a): beige powder; yield 53%; mp: 148-149 °C (ethanol).
1H NMR (CDCl3); IR (KBr).
9-Trifluoromethyl-1-(4-methoxyphenylethyl)-5-meth-
ylbenzo[f]-1,5-dihydropyrido[3,2,c][1,2,5]thiadiazepine 6,6-
dioxide (2n): yellow powder; purified by chromatography
with petroleum ether/ethyl acetate (80:20); yield 35%; mp: 43-
2-Chloro-N-(4-chloro-2-nitrophenyl)-3-pyridinesulfona-
1
mide (16b): yellow powder; yield 70%; mp: 172-173 °C
44 °C (methanol). H NMR (CDCl3); IR (KBr); MS (EI); Anal.
1
(ethanol). H NMR (CDCl3); IR (KBr).
(C22H20F3N3O3S): C, H, N.
2-Chloro-N-(5-chloro-2-nitrophenyl)-3-pyridinesulfona-
9-Trifluoromethyl-1-(4-methoxyphenyl)propyl-5-meth-
ylbenzo[f]-1,5-dihydropyrido[3,2,c][1,2,5]thiadiazepine 6,6-
dioxide (2o): yellow powder; purified by chromatography
with petroleum ether/ethyl acetate/methanol (80:18:2); yield
mide (16c): yellow powder; yield 32%; mp: 153-154 °C
1
(ethanol). H NMR (CDCl3); IR (KBr).
2-Chloro-N-(4-methoxy-2-nitrophenyl)-3-pyridine-
1
48%; mp: 144-145 °C (ethanol). H NMR (CDCl3); IR (KBr);
sulfonamide (16d): yellow powder; yield 57%; mp: 121 °C
1
MS (EI); Anal. (C23H22F3N3O3S): C, H, N.
(ethanol). H NMR (CDCl3); IR (KBr).
2-Chloro-N-(4-methyl-2-nitrophenyl)-3-pyridinesulfona-
mide (16e): Beige powder; yield 67%; mp: 120 °C (ethanol).
1H NMR (CDCl3); IR (KBr).
9-Methoxy-1-(4-methoxybenzyl)-5-methylbenzo[f]-1,5-
dihydropyrido[3,2,c][1,2,5]thiadiazepine
6,6-dioxide
(2p): yellow powder; purified by chromatography with petro-
leum ether/ethyl acetate (70:30); yield 26%; mp: 179-180 °C
(ethanol). 1H NMR (CDCl3); IR (KBr); MS (EI); Anal.
(C21H21N3O4S): C, H, N.
9-Methoxy-1-(4-methoxyphenylethyl)-5-methylbenzo-
[f]-1,5-dihydropyrido[3,2,c][1,2,5]thiadiazepine 6,6-diox-
ide (2q): yellow powder; purified by chromatography with
petroleum ether/ethyl acetate/methanol (80:18:2); yield 14%;
mp: 65-68 °C (ethanol). 1H NMR (CDCl3); IR (KBr); MS (EI);
Anal. (C22H23N3O4S): C, H, N.
General Procedure for Synthesis of Substituted
N-Methyl-N-(2-nitrophenyl)- 3-pyridinesulfonamides 17a-
f. Prepared according to the procedure for serie 9.
2-Chloro-N-methyl-N-(2-nitrophenyl)-3-pyridinesulfona-
mide (17a): beige powder; yield 74%; mp: 125-126 °C
1
(ethanol/water 50:50). H NMR (CDCl3); IR (KBr).
2-Chloro-N-(4-chloro-2-nitrophenyl)-N-methyl-3-py-
ridinesulfonamide (17b): yellow powder; yield 91%; mp: 129
1
°C (ethanol). H NMR (CDCl3); IR (KBr).
9-Methoxy-[1-(4-methoxyphenyl)propyl]-5-methylben-
zo[f]-1,5-dihydropyrido[3,2,c][1,2,5]thia-diazepine 6,6-
dioxide (2r): yellow powder; purified by chromatography with
petroleum ether/ethyl acetate (75:25); yield 17%; mp: 128-
131 °C (2-propanol). 1H NMR (CDCl3); IR (KBr); MS (EI); Anal.
(C23H25N3O4S): C, H, N.
2-Chloro-N-(5-chloro-2-nitrophenyl)-N-methyl-3-py-
ridinesulfonamide (17c): yellow powder; yield 88%; mp:
1
139-140 °C (ethanol). H NMR (CDCl3); IR (KBr).
2-Chloro-N-(4-methoxy-2-nitrophenyl)-N-methyl-3-py-
ridinesulfonamide (17d): beige powder; yield 62%; mp:
1
145-146 °C (ethanol). H NMR (CDCl3); IR (KBr).
1-(3,4,5-Trimethoxybenzyl)-5-methylbenzo[f]-1,5-
2-Chloro-N-methyl-N-(4-methyl-2-nitrophenyl)-3-py-
ridinesulfonamide (17e): beige powder; yield 71%; mp: 87-
dihydropyrido[3,2,c][1,2,5]thiadiazepine
6,6-dioxide
1
(2s): yellow powder; purified by chromatography with petro-
88 °C (ethanol/water 50:50). H NMR (CDCl3); IR (KBr).
leum ether/ethyl acetate/methanol (70:28:2); yield 29%; mp:
2-Chloro-N-(4-methoxybenzyl)-N-(2-nitrophenyl)-3-
pyridinesulfonamide (17f). Using 4-methoxybenzyl chloride
instead of iodomethane. Yellow powder; yield 75%; mp: 109
1
178-180 °C (ethanol). H NMR (CDCl3); IR (KBr); MS (EI);
Anal. (C22H23N3O5S): C, H, N.
1
1-[2-(3,4,5-Trimethoxyphe´nyl)e´thyl]-5-methylbenzo[f]-
1,5-dihydropyrido[3,2,c][1,2,5]thiadiaze-pine 6,6-dioxide
(2t): yellow powder; purified by chromatography with dichlo-
romethane/ethyl acetate (98:2); yield 52%; mp: 165-166 °C
(ethanol). 1H NMR (CDCl3); IR (KBr); MS (EI); Anal.
(C23H25N3O5S): C, H, N.
°C (ethanol/water 50:50). H NMR (CDCl3); IR (KBr).
Synthesis of 2-Chloro-N-[2-(N,N-diethylamino)ethyl]-
N-(2-nitrophenyl)-3-pyridinesulfonamide (17g). 16a (6
mmol) is dissolved in a solution of toluene (50 mL) and water
(20 mL). Sodium hydroxide (60 mmol), benzyltriethylammo-
nium chloride (12 mmol), and 2-chloro-N,N-diethylethylamine
hydrochloride (6 mmol) are added. The mixture is refluxed for
20 h. After this time, the layer is separated and the water
phase is extracted with toluene. Then, all the organic layers
are dried, evaporated under reduced pression, and purified by
silica gel chromatography with dichloromethane/methanol (98:
1-[2-(4-Benzyloxyphenyl)ethyl]-5-methylbenzo[f]-1,5-
dihydropyrido[3,2,c][1,2,5]thiadiazepine
6,6-dioxide
(2u): yellow powder; purified by chromatography with petro-
leum ether/ethyl acetate/methanol (80:18:2); yield 60%; mp:
1
133-134 °C (ethanol). H NMR (CDCl3); IR (KBr); MS (EI);
1
Anal. (C27H25N3O3S): C, H, N.
2). Yellow oil; yield 52%. H NMR (CDCl3); IR (KBr).
Synthesis of 1-[2-(4-Hydroxyphenyl)ethyl]-5-methyl-
benzo[f]-1,5-dihydropyrido[3,2,c][1,2,5]thiadiazepine 6,6-
Dioxide (2v). A solution of 2u (6 mmol) in methanol (20 mL)
is stirred with 10% Pd/C catalyst at room temperature under
an atmospheric pressure of hydrogen. The catalyst is separated
by filtration and the solvent evaporated under reduced pres-
General Procedure for the Synthesis of Substituted
6,11-Dihydro-6-methylbenzo[c]pyrido[2,3,f][1,2,5]-
thiadiazepines 5,5-Dioxide (18a-e). A solution of 17 (5
mmol) in acetic acid (20 mL) with iron powder (25 mmol) is
refluxed for 1 h. Then, the mixture is filtered and the filtrate
is evaporated under reduced pressure. The residue is poured

Benzopyridothiadiazepines as Antitumor Agents
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23 7371
in water, extracted with ethyl acetate, dried, filtered, evapo-
rated under reduced pressure, and crystallized from the
appropriate solvent.
6,11-dihydro-11-[1-(4-methoxyphenyl)propyl]-6-meth-
ylbenzo[c]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-Dioxide
(3c). Using 3-(4-methoxyphenyl)propyl methanesulfonate
(10b). White powder; purified by chromatography with petro-
leum ether/ethyl acetate (85:15); yield 14%; mp: 138-140 °C
(hexane). 1H NMR (CDCl3); IR (KBr); MS (EI); Anal.
(C22H23N3O3S): C, H, N.
9-Chloro-6,11-dihydro-[11-(4-methoxybenzyl)]-6-meth-
ylbenzo[c]pyrido[2,3-f][1,2,5]thiadiaze-pine 5,5-Dioxide
(3d). Using 4-methoxybenzyl chloride. White powder; purified
by chromatography with petroleum ether (75:25); yield 44%;
mp: 173 °C (ethanol1H NMR (CDCl3); IR (KBr); MS (EI); Anal.
(C20H18ClN3O3S): C, H, N.
9-Chloro-6,11-dihydro-[11-(4-methoxyphenylethyl)]-6-
methylbenzo[c]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-Di-
oxide (3e). Using 4-methoxyphenylethyl methanesulfonate
(10a). White powder; purified by chromatography with petro-
leum ether/ethyl acetate/methanol (82.8:17:0.2); yield 4%;
mp: 187-188 °C (ethanol). 1H NMR (CDCl3); IR (KBr); MS
(EI); Anal. (C20H18ClN3O3S): C, H, N.
8-Chloro-6,11-dihydro-11-(4-methoxybenzyl)-6-methyl-
benzo[c]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-Dioxide (3f).
Using 4-methoxybenzyl chloride. White powder; purified by
chromatography with petroleum ether/ethyl acetate/methanol
(90:8:2); yield 31%: mp: 137-138 °C (ethanol). 1H NMR
(CDCl3); IR (KBr); MS (EI); Anal. (C20H18ClN3O3S): C, H, N.
6,11-Dihydro-6-methylbenzo[c]pyrido[2,3-f][1,2,5]-
thiadiazepine 5,5-dioxide (18a): white powder; yield 62%;
1
mp: 180 °C (ethanol). H NMR (CDCl3); IR (KBr).
9-Chloro-6,11-dihydro-6-methylbenzo[c]pyrido[2,3-f]-
[1,2,5]thiadiazepine 5,5-dioxide (18b): beige powder; yield
1
52%; mp: 258 °C (ethanol). H NMR (CDCl3); IR (KBr).
8-Chloro-6,11-dihydro-6-methylbenzo[c]pyrido[2,3-f]-
[1,2,5]thiadiazepine 5,5-dioxide (18c): beige powder; yield
1
60%; mp: 213-214 °C (ethanol). H NMR (CDCl3); IR (KBr).
6,11-Dihydro-6,9-dimethylbenzo[c]pyrido[2,3-f][1,2,5]-
thiadiazepine 5,5-dioxide (18d): white powder; yield 81%;
1
mp: 221 °C (ethanol). H NMR (CDCl3); IR (KBr).
6,11-Dihydro-9-methoxy-6-methylbenzo[c]pyrido[2,3-
f][1,2,5]thiadiazepine 5,5-dioxide (18e): white powder; yield
1
65%; mp: 216-217 °C (ethanol). H NMR (CDCl3); IR (KBr).
Synthesis of 6,11-Dihydro-6-(4-methoxybenzyl)benzo-
[c]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-Dioxide (18f). A
mixture of 17f (2 mmol) in ethanol (20 mL), water (10 mL),
acetic acid (20 mL), hydrochloric acid 12 N (0.5 mL), and iron
powder (18 mmol) is refluxed for 30 min. The reaction mixture
is filtered, and the filtrate is evaporated. The residue is diluted
with ethyl acetate and washed with a solution of sodium
bicarbonate and water. The organic layer is dried, filtered,
evaporated under reduced pressure, and crystallized from
ethanol. White powder; yield 35%; mp: 152-153 °C. 1H NMR
(CDCl3); IR (KBr).
8-Chloro-6,11-dihydro-[11-(4-methoxyphenylethyl)]-6-
methylbenzo[c]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-Di-
oxide (3g). Using 4-methoxyphenylethyl methanesulfonate
(10a). White powder; purified by chromatography with petro-
leum ether/ethyl acetate/methanol (90:8:2); yield 10%; mp: 146
°C (ethanol). 1H NMR (CDCl3); IR (KBr); MS (EI); Anal.
(C21H20ClN3O3S): C, H, N.
Synthesis of 6-[2-(N,N-Diethylamino)ethyl]-6,11-dihy-
drobenzo[c]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-Dioxide
(18g). A mixture of 17g (4 mmol) in ethanol (40 mL), water
(20 mL), acetic acid (40 mL), hydrochloric acid 12 N (1 mL),
and iron powder (24 mmol) is refluxed for 30 min. The reaction
mixture is filtered, and the filtrate is evaporated. The residue
is diluted with ethyl acetate and washed with a solution of
sodium bicarbonate and water. The organic layer is dried,
filtered, and evaporated under reduced pressure. The residue
is then added to acetic anhydride (40 mL) and stirred for 12 h
at 60 °C. The solution is evaporated, poured in water, extracted
with dichloromethane, dried, filtered, evaporated under re-
duced pressure, and purified by silica gel chromatography with
dichloromethane/methanol (98:2) to afford N-(2-acetamidophe-
nyl)-2-chloro-N-[2-(N,N-diethylamino)ethyl]-3-pyridinesulfona-
6,11-Dihydro-11-(4-methoxybenzyl)-6-methyl-9-meth-
ylbenzo[c]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-Dioxide
(3h). Using 4-methoxybenzyl chloride. White powder; purified
by chromatography with petroleum ether/ethyl acetate (75:
1
25); yield 36%; mp: 132-133 °C (ethanol). H NMR (CDCl3);
IR (KBr); MS (EI); Anal. (C21H21N3O3S): C, H, N.
6,11-Dihydro-11-(4-methoxyphenylethyl)-6-methyl-9-
methylbenzo[c]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-Di-
oxide (3i). Using 4-methoxyphenylethyl methanesulfonate
(10a). White powder; purified by chromatography with
petroleum ether/ethyl acetate (70:30); yield 19%; mp: 186-
1
1
188 °C (ethanol). H NMR (CDCl3); IR (KBr); MS (EI); Anal.
mide as a yellow oil. Yield 86%. H NMR (CDCl3); IR (KBr).
(C22H23N3O3S): C, H, N.
A solution of N-(2-acetamidophenyl)-2-chloro-N-[2-(N,N-
diethylamino)ethyl]-3-pyridinesulfonamide (29 mmol) in dim-
ethylformamide (20 mL) is treated with potassium carbonate
(59 mmol) and heated under reflux for 8 h. After this time,
the mixture is filtered and the solution is evaporated under
reduced pressure. The residue is diluted in dichloromethane,
washed with water, dried, evaporated, and crystallized from
isopropyl ether to afford 18g as a brown powder. Yield 56%;
6,11-Dihydro-9-methoxy-11-(4-methoxybenzyl)-6-me-
thylbenzo[c]pyrido[2,3-f][1,2,5]thiadiaze-pine 5,5-Diox-
ide (3j). Using 4-methoxybenzyl chloride. White powder,
purified by chromatography with petroleum ether/ethyl acetate
(80:20); yield 38%; mp: 159 °C (ethanol). 1H NMR (CDCl3);
IR (KBr); MS (EI); Anal. (C21H21N3O4S): C, H, N.
6,11-Dihydro-9-methoxy-11-(4-methoxyphenylethyl)-6-
methylbenzo[c]pyrido[2,3-f][1,2,5]thia-diazepine 5,5-Di-
oxide (3k). Using 4-methoxyphenylethyl methanesulfonate
(10a). White powder; purified by chromatography with petro-
leum ether/ethyl acetate (85:15); yield 33%; mp: 170 °C
(ethanol). 1H NMR (CDCl3); IR (KBr); MS (EI); Anal.
(C22H23N3O4S): C, H, N.
6,11-Dihydro-6-(4-methoxybenzyl)-11-(4-methoxyben-
zyl)benzo[c]pyrido[2,3-f][1,2,5]thiadiaze-pine 5,5-Diox-
ide (3l). Using 4-methoxybenzyl chloride. White powder;
purified by chromatography with petroleum ether/ethyl acetate/
methanol (80:19:1); yield 26%; mp: 134-135 °C (ethanol). 1H
NMR (CDCl3); IR (KBr); MS (EI); Anal. (C27H25N3O4S): C, H,
N.
1
mp: 107-108 °C. H NMR (CDCl3); IR (KBr).
General Procedure for the Synthesis of Substituted
6,11-Dihydro-11-(arylalkyl)-6-alkylbenzo[c]pyrido[2,3,f]-
[1,2,5]thiadiazepine 5,5-Dioxide (3a-n) and 1-(Aryla-
lkyl)-6-alkylbenzo[c]-1,2-dihydropyrido[2,3,f][1,2,5]-
thiadiazepine 5,5-Dioxide (4a-n). Prepared according to
the procedure for series 1 and 2.
6,11-Dihydro-11-(4-methoxybenzyl)-6-methylbenzo[c]-
pyrido[2,3-f][1,2,5]thiadiazepine 5,5-Dioxide (3a). Using
4-methoxybenzyl chloride. White powder; purified by chroma-
tography with petroleum ether/ethyl acetate (80:20); yield 31%;
mp: 160-161 °C (ethanol). 1H NMR (CDCl3); IR (KBr); MS
(EI); Anal. (C20H19N3O3S): C, H, N.
6,11-Dihydro-11-(4-methoxyphenylethyl)-6-methylben-
zo[c]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-Dioxide (3b).
Using 4-methoxyphenylethyl methanesulfonate (10a). White
powder; purified by chromatography with petroleum ether/
ethyl acetate (80:20); yield 11%; mp: 147-148 °C (ethanol).
1H NMR (CDCl3); IR (KBr); MS (EI); Anal. (C21H21N3O3S): C,
H, N.
6,11-Dihydro-6-(4-methoxybenzyl)-11-(4-methoxyphe-
nylethyl)benzo[c]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-
Dioxide (3m). Using 4-methoxyphenylethyl methanesulfonate
(10a). White powder; purified by chromatography with petro-
leum ether/ethyl acetate (70:30); yield 16%; mp: 134-135 °C
(ethanol). 1H NMR (CDCl3); IR (KBr); MS (EI); Anal.
(C28H27N3O4S): C, H, N.

7372 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23
Lebegue et al.
6-[2-(N,N-diethylamino)ethyl]-6,11-dihydro-11-(4-meth-
oxyphenylethyl)benzo[c]pyrido[2,3-f] [1,2,5]thiadiaz-
epine 5,5-Dioxide (3n). Using 4-methoxyphenylethyl meth-
anesulfonate (10a). White powder; purified by chromatography
with dichloromethane/methanol/water/acetic acid (78/20/1,3/
0,7); yield 11%; mp: 109 °C (ethanol). 1H NMR (CDCl3); IR
(KBr); MS (EI); Anal. (C26H32N4O3S): C, H, N.
ide (4k). Using 4-methoxyphenylethyl methanesulfonate (10a).
Yellow powder; purified by chromatography with petroleum
ether/ethyl acetate (85:15); yield 36%; mp: 146 °C (ethanol).
1H NMR (CDCl3); IR (KBr); MS (EI); Anal. (C22H23N3O4S): C,
H, N.
1-(4-Methoxybenzyl)-6-(4-methoxybenzyl)benzo[c]-1,2-
dihydropyrido[2,3-f][1,2,5]thiadiazepine 5,5-Dioxide (4l).
Using 4-methoxybenzyl chloride. Yellow powder; purified by
chromatography with petroleum ether/ethyl acetate/methanol
(80:19:1); yield 9%; mp: 95-98 °C (ethanol). 1H NMR (CDCl3);
IR (KBr); MS (EI); Anal. (C27H25N3O4S): C, H, N.
6-(4-methoxybenzyl)-1-(4-Methoxyphenylethyl)benzo-
[c]-1,2dihydropyrido[2,3-f][1,2,5]thiadiazepine 5,5-Diox-
ide (4m). Using 4-methoxyphenylethyl methanesulfonate
(10a). Yellow powder; purified by chromatography with pe-
troleum ether/ethyl acetate (70:30); yield 42%; mp: 67-68 °C
(ethanol). 1H NMR (CDCl3); IR (KBr); MS (EI); Anal.
(C28H27N3O4S): C, H, N.
1-(4-Methoxybenzyl)-6-methylbenzo[c]-1,2-dihydropy-
rido[2,3-f][1,2,5]thiadiazepine 5,5-Dioxide (4a). Using
4-methoxybenzyl chloride. Yellow powder; purified by chro-
matography with petroleum ether/ethyl acetate (80:20); yield
1
29%; mp: 127-129 °C (ethanol). H NMR (CDCl3); IR (KBr);
MS (EI); Anal. (C20H19N3O3S): C, H, N.
1-(4-Methoxyphenylethyl)-6-methylbenzo[c]-1,2-dihy-
dropyrido[2,3-f][1,2,5]thiadiazepine 5,5-Dioxide (4b). Us-
ing 4-methoxyphenylethyl methanesulfonate (10a). Yellow
powder; purified by chromatography with petroleum ether/
ethyl acetate (80:20); yield 16%; mp: 105-107 °C (ethanol).
1H NMR (CDCl3); IR (KBr); MS (EI); Anal. (C21H21N3O3S): C,
H, N.
1-[1-(4-Methoxyphenyl)propyl]-6-methylbenzo[c]-1,2-
dihydropyrido[2,3-f][1,2,5]thiadiazepine 5,5-Dioxide (4c).
Using 3-(4-methoxyphenyl)propyl methanesulfonate (10b).
Yellow powder; purified by chromatography with petroleum
ether/ethyl acetate (85:15); yield 29%; mp: 50-55 °C (2-
propanol). 1H NMR (CDCl3); IR (KBr); MS (EI); Anal.
(C22H23N3O3S): C, H, N.
6-[2-(N,N-diethylamino)ethyl]-1-(4-methoxyphenyl-
ethyl)-benzo[c]-1,2-dihydropyrido[2,3-f][1,2,5]-
thiadiazepine 5,5-Dioxide (4n). Using 4-methoxyphenyl-
ethyl methanesulfonate (10a). Yellow powder; purified by
chromatography with dichloromethane/methanol/water/acetic
1
acid (78/20/1,3/0,7); yield 16%;: 92-93 °C (ethanol). H NMR
(CDCl3); IR (KBr); MS (EI); Anal. (C26H32N4O3S): C, H, N.
Cell Culture and Cytotoxicity Assays. Cells were cul-
tivated in RPMI 1640 medium (Invitrogen Inc.) supplemented
with 10% fetal calf serum, 2 mM L-glutamine, 100 units/mL
penicillin, 100 µg/mL streptomycin, and 10 mM HEPES buffer
(pH 7.4). Cytotoxicity was measured by the microculture
tetrazolium assay (MTA). Briefly, L1210 cells were exposed
for 48 h to graded concentrations of drug. At the end of this
period, 15 µL of 5 mg/mL of 3-(4,5-dimethyl-2-yl)-2,5-diphe-
nyltetrazolium bromide (MTT, Sigma) were added to each well
and the plates were incubated for 4 h at 37 °C. The medium
was aspirated and the formazan solubilized by 100 µL of
DMSO. The IC50, concentration reducing by 50% the optical
density at 540 nm, was calculated by a linear regression
performed on the linear zone of the dose-reponse curve. All
the measurements were performed in triplicate.
8-Chloro-1-(4-methoxybenzyl)-6-methylbenzo[c]-1,2-di-
hydropyrido[2,3-f][1,2,5]thiadiazepine 5,5-Dioxide (4d).
Using 4-methoxybenzyl chloride. Yellow powder; purified by
chromatography with petroleum ether/ethyl acetate/methanol
1
(90:8:2); yield 27%; mp: 109 °C (ethanol). H NMR (CDCl3);
IR (KBr); MS (EI); Anal. (C20H18ClN3O3S): C, H, N.
8-Chloro-1-(4-methoxyphenylethyl)-6-methylbenzo[c]-
1,2-dihydropyrido[2,3-f][1,2,5]thiadiazepine 5,5-Dioxide
(4e). Using 4-methoxyphenylethyl methanesulfonate (10a).
Yellow powder; purified by chromatography with petroleum
ether/ethyl acetate/methanol (90:8:2); yield 44%; mp: 100-
101 °C (ethanol/water 90:10). 1H NMR (CDCl3); IR (KBr); MS
(EI); Anal. (C21H20ClN3O3S): C, H, N.
Cell Cycle Analysis.46,47 L1210 cells (2.5 × 105 cells/mL)
were incubated for 21 h with various concentrations of the
compounds. Cells were then fixed in 70% ethanol (v/v), washed
and incubated in Dulbecco’s phosphate buffered saline (D-PBS)
containing 100 mg/mL RNAse and 25 mg/mL propidium iodide
for 30 min. at 20 °C. For each sample, 104 cells were analyzed
on a Epics XL/MCL flow cytometer (Beckman Coulter, France).
Tubulin Test. Effects of the compounds on tubulin polym-
erization were evaluated as previously reported.48
9-Chloro-1-(4-methoxybenzyl)]-6-methylbenzo[c]-1,2-
dihydropyrido[2,3-f][1,2,5]thiadiazepine 5,5-Dioxide (4f).
Using 4-methoxybenzyl chloride. Yellow powder; purified by
chromatography with petroleum ether/ethyl acetate (75:25);
1
yield 49%; mp: 149 °C (ethanol). H NMR (CDCl3); IR (KBr);
MS (EI); Anal. (C20H18ClN3O3S): C, H, N.
9-Chloro-1-(4-methoxyphenylethyl)-6-methylbenzo[c]-
1,2-dihydropyrido[2,3-f][1,2,5]thiadiazepine 5,5-Dioxide
(4g). Using 4-methoxyphenylethyl methanesulfonate (10a).
Yellow powder; purified by chromatography with petroleum
ether/ethyl acetate/methanol (82.8:17:0.2); yield 24%; mp: 163
°C (ethanol). 1H NMR (CDCl3); IR (KBr); MS (EI); Anal.
(C21H20ClN3O3S): C, H, N.
1-(4-Methoxybenzyl)-6,9-dimethylbenzo[c]-1,2-dihy-
dropyrido[2,3-f][1,2,5]thiadiazepine 5,5-Dioxide (4h). Us-
ing 4-methoxybenzyl chloride. Yellow powder; purified by
chromatography with petroleum ether/ethyl acetate (75:25);
yield 9%; mp: 90-92 °C (ethanol). 1H NMR (CDCl3); IR (KBr);
MS (EI); Anal. (C21H21N3O3S): C, H, N.
1-(4-Methoxyphenylethyl)-6,9-dimethylbenzo[c]-1,2-di-
hydropyrido[2,3-f][1,2,5]thiadiazepine 5,5-Dioxide (4i).
Using 4-methoxyphenylethyl methanesulfonate (10a). Yellow
powder; purified by chromatography with petroleum ether/
ethyl acetate (70:30); yield 39%; mp: 156-157 °C (ethanol).
1H NMR (CDCl3); IR (KBr); MS (EI); Anal. (C22H23N3O3S): C,
H, N.
9-Methoxy-1-(4-methoxybenzyl)-6-methylbenzo[c]-1,2-
dihydropyrido[2,3-f][1,2,5]thiadiazepine 5,5-Dioxide (4j).
Using 4-methoxybenzyl chloride. Yellow powder; purified by
chromatography with petroleum ether/ethyl acetate (80:20);
yield 12%; mp: 95-96 °C (ethanol). 1H NMR (CDCl3); IR (KBr);
MS (EI); Anal. (C21H21N3O4S): C, H, N.
Supporting Information Available: Elemental analysis
for compounds 1a-t, 2a-w, 3a-n, 4a-n and spectroscopic
data for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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