A new type of mixed anhydride and its applications to the synthesis of 7-substituted 8-chloro-5,5-dioxoimidazo[1,2-b][1,4,2]benzodithiazines with in vitro antitumor activity

Article abstract of DOI:10.1021/jm010953n

A new series of 8-chloro-5,5-dioxoimidazo[1,2-b][1,4,2]benzodithiazine derivatives 8-25 with heteroaryloxycarbonyl or heteroarylcarbamoyl substituents at position 7 have been synthesized as potential antitumor agents. In this procedure a novel type of mix

Full text of DOI:10.1021/jm010953n

430
J . Med. Chem. 2002, 45, 430-437
A New Typ e of Mixed An h yd r id e a n d Its Ap p lica tion s to th e Syn th esis of
7-Su bstitu ted 8-Ch lor o-5,5-d ioxoim id a zo[1,2-b][1,4,2]ben zod ith ia zin es w ith in
Vitr o An titu m or Activity
Zdzisław Brzozowski and Franciszek Sa¸czewski*
Department of Chemical Technology of Drugs, Medical University of Gdan´sk, 80-416 Gdan´sk, Poland
Received J une 13, 2001
A new series of 8-chloro-5,5-dioxoimidazo[1,2-b][1,4,2]benzodithiazine derivatives 8-25 with
heteroaryloxycarbonyl or heteroarylcarbamoyl substituents at position 7 have been synthesized
as potential antitumor agents. In this procedure a novel type of mixed anhydride 7 was prepared
from 8-chloro-5,5-dioxoimidazo[1,2-b][1,4,2]benzodithiazine-7-carboxylic acid 6 and methane-
sulfonyl chloride, which in turn was condensed either with heteroarylamines or heteroaryl-
hydroxy compounds. All the compounds prepared were screened at the National Cancer Institute
(NCI) for their activities against a panel of 60 tumor cell lines, and relationships between
structure and antitumor activity in vitro are discussed. The amides 8, 10, 12, 13, 21, and ester
25 were inactive, whereas the other compounds exhibited rather moderate activity against
one or more human tumor cell lines. The prominent compound with remarkable activity (log GI50
< -8) and selectivity for the leukemia HL-60(TB) cell line was 2-methyl-8-quinolyl 8-chloro-
5,5-dioxoimidazo[1,2-b][1,4,2]benzodithiazine-7-carboxylate 24.
In tr od u ction
Recently, arylsulfonamides have attracted attention
as anticancer1-11 and anti-HIV12-15 agents. We further
found that cyclic analogues of 2-mercaptobenzene-
sulfonamides (2 and 3, Figure 1) also showed anti-HIV31
and anticancer32 properties. This led us to the assump-
tion that expansion of a series of candidate antineoplas-
tic agents of general formula 3 in which groups of
varying sizes and electronic properties are placed at
position 7 of 8-chloro-5,5-dioxoimidazo[1,2-b][1,4,2]-
benzodithiazine ring may shed light on the structural
features contributing to the antitumor activity. We
reasoned that a relatively broad diversity of the struc-
ture 3 could be achieved by introducing either the
heteroarylcarbamoyl or heteroaryloxycarbonyl at posi-
tion 7. We also described the syntheses of various
4-chloro-2-mercaptobenzenesulfonamide derivatives 1
(MBSAs, Figure 1) with the nitrogen atom of sulfona-
mide moiety attached to a variety of heterocyclic ring
systems. These compounds, depending on structure,
exhibited either anticancer18-27 or anti-HIV activi-
ties18,21,25,26,28,29 and have been described by Neamati
et al.30 as a novel class of potent HIV-1 integrase
inhibitors.
F igu r e 1.
Sch em e 1. Previously Described Synthesis of the
Compounds 3a
a
Reagents and yields: (a) H2NCH2CH(OMe)2 (1 molar equiv),
dry toluene or benzene, reflux, 14-20 h, 51-79%; (b) 98% H2SO4,
20-37 °C, 8-10 h, 92-97%.
Resu lts a n d Discu ssion
ethylacetal, we obtained compound 5, which upon
treatment with 98% sulfuric acid at room temperature
for 18 h afforded the expected 8-chloro-5,5-dioxoimidazo-
[1,2-b][1,4,2]benzodithiazine-7-carboxylic acid 6 in 96%
yield (Scheme 2).
The reaction of a carboxylic acid with methanesulfo-
nyl chloride in the presence of base usually gives rise
to the corresponding mixed sulfonic-carboxylic anhy-
dride.34 However, when we treated 6 (1 equiv) with
methanesulfonyl chloride (0.75 equiv) in methylene
chloride at -15 °C in the presence of triethylamine (1.25
Our initial attempt was to obtain the desired com-
pounds by the method described previously31 and de-
picted in Scheme 1, but this strategy was not successful.
Therefore, we have developed a method in which a new
type of mixed anhydride 7 of the hypothetical methyl-
eneorthosulfonic acid was a key intermediate. Starting
from 6-chloro-3-methylthio-1,1-dioxo-1,4,2-benzodithi-
azine-7-carboxylic acid 433 and aminoacetaldehyde dim-
* To whom correspondence should be addressed. Phone: +48-58-
3493250. Fax: +48-58-3493206. E-mail: saczew@farmacja.amg.gda.pl.
10.1021/jm010953n CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/06/2001

New Mixed Anhydride
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 2 431
Sch em e 2. Synthesis of the 8-Chloro-5,5-dioxoimidazo-
[1,2-b][1,4,2]benzodithiazine-7-carboxylic Acid 6a
ration of the central sulfur atom of 7. It should also be
emphasized that anhydride 7 proved to be stable for ca.
1 month, but upon prolonged storage for 1 year, it slowly
decomposed to a complex mixture of products.
The desired imidazobenzodithiazinecarboxamides 8-22
and heteroaroyl imidazobenzodithiazinecarboxylates 23-
25 were obtained by reacting the anhydride 7 with
corresponding heteroarylamines (Scheme 4) and het-
eroarylols (Scheme 5), respectively. It is worthy noting
that only two of four acyl groups of 7 are available for
the formation of the desired products. Therefore, for the
best results, the molar ratio of mixed anhydride 7/pri-
mary or secondary amine/triethylamine was generally
1:2:2. In this way, the two remaining acyl groups could
be recovered in the form of the corresponding carboxylic
acid 6 by quenching the reaction mixture with water
(pH 8-9) and filtering off the resulting amide. Acid 6
precipitated from the filtrate upon treatment with
diluted hydrochloric acid (see Experimental Section).
a
Reagents and yields: (a) H2NCH2CH(OMe)2 (2 molar equiv),
MeOH, reflux, 12 h; (b) H2O, HCl, pH 1.5, 89%; (c) 98% H2SO4,
20-38 °C, 18 h, 96%.
Sch em e 3. Proposed Mechanism of the Formation of
the Mixed Anhydride 7
We have also developed methods for the syntheses of
the 8-(3,4-dihydro-4-oxo)quinazoline derivative 26 and
the previously not described 2-substituted 4,4,6-trioxo-
5,6-dihydro-3,4,1,5-benzaoxathiadiazocine 27 (Scheme
6).
Compounds 8-13, 16, 18, 19, 21, 22, and 24-27 were
submitted to the National Cancer Institute (Bethesda,
MD) for testing against a panel of approximately 60
tumor cell lines. Details of this test system and the
information, which is encoded by the activity pattern
over all cell lines, have been published.37-39 The anti-
tumor activity of a test compound is given by three
parameters for each cell line: log GI50 value (GI50
)
molar concentration of the compound that inhibits 50%
net cell growth), log TGI value (TGI ) molar concentra-
tion of the compound leading to total inhibition of net
cell growth), and log LC50 value (LC50 ) molar concen-
tration of the compound leading to 50% net cell death).
Furthermore, a mean graph midpoint (MG_MID) is
calculated for each of the mentioned parameters, giving
an averaged activity parameter over all cell lines. For
the calculation of the MG_MID, insensitive cell lines are
included with the highest concentration tested. The
discovery of compounds with new selectivity patterns
is one of the intentions of the screening program.
Selectivity of a compound with respect to one or more
cell lines of the screen is characterized by a high
deviation of the particular cell line parameter compared
to the MG_MID value.
equiv), a crystalline product was formed in 87% yield,
which was analyzed for the methyleneorthosulfonic
t et r a k is(8-ch lor o-5,5-dioxoim ida zo[1,2-b][1,4,2]-
benzodithiazine-7-carboxylic) anhydride (7) (Scheme 3).
The following is to be noted regarding the tumor cell
growth inhibition data with the tested compounds: (i)
Compounds 8, 10, 12, 13, 21, and 25 were inactive
(log GI50 > -4), whereas the other compounds 9, 11, 16,
18, 19, 22, 24, 26, and 27 exhibited moderate activity
against one or more human tumor cell lines (Table 1).
(ii) Generally, the most active compounds were 22, 24,
and 19 (Table 1). (iii) Different cancer cell lines of the
same tumor type possessed a variable response to
inhibition of growth in the presence of the new deriva-
tives (Table 2). For example, the NCI-522 lung cancer
1
The H NMR spectrum of the product 7, containing a
nonstandard functional group, showed a lack of methyl
protons, but the presence of a two-proton singlet at δ
5.76 and the correlation between this methylene proton
and the carbon atom at δ 54.20 (1J (13C,1H) ) 181 Hz)
was found in the 1H-13C heterocorrelated spectrum
(HSQC, heteronuclear single quantum coherence spec-
trum). Moreover, the 1D distortionless enhancement by
polarization transfer-heteronuclear multiple-quantum
coherence (DEPT-HMQC) experiment35 confirmed the
presence of the methylene group of the mixed anhydride
7. Hence, results from spectral as well as elemental
analyses are fully consistent with the proposed struc-
ture. Quantum chemical calculations performed at the
ab initio level36 revealed a square pyramidal configu-
cells were susceptible to inhibition by 19 (log GI50
)
-5.91, log TGI ) -5.55, log LC50 ) -5.18), whereas
other lung cancer cell lines (such as A549/ATCC, EKVX,
etc.) showed a much lower level of inhibition (log GI50
ranged from -4.83 to -4.62). The same situation has

432 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 2
Brzozowski and Sa¸ czewski
Sch em e 4. Synthesis of the 8-Chloro-5,5-dioxoimidazo[1,2-b][1,4,2]benzodithiazine-7-carboxamides 8 and 9-22a
a
Reagents: (a) 5H-dibenzo[b,f]azepine or (b) primary amine X-NH2, Et3N, p-dioxane, reflux; (c) K2CO3, H2O, 20 °C; (d) HCl, 71-90%.
Sch em e 5. Synthesis of the Heteroaryl 8-Chloro-5,5-
dioxoimidazo[1,2-b][1,4,2]benzodithiazine-7-carboxylates
23-25a
Sch em e 6. Synthesis of
8-Chloro-5,5-dioxoimidazo-[1,2-b][1,4,2]benzodithiazine
Derivatives 26 and 27 by Cyclocondensation Reactions
of Imidazobenzodithiazinecarboxamide 10a
a
Reagents: (a) thionyl chloride, reflux, 10 h, 71%; (b) sulfuric
a
Reagents: (a) hydroxy compounds Y-OH, p-dioxane, reflux;
acid, room temperature, 12 h, 74%.
(b) KHCO3, H2O, 20 °C; (c) HCl, 87-90%.
cancer, HO-31 renal cancer, and MCF7 and T-470 breast
cancer (Table 2).
been evidenced in the case of diverse leukemia cell lines,
with compound 24 acting selectively as a potent inhibi-
tor (log GI50 < -8.00, log TGI < -8.00, log LC50
)
Su m m a r y
-5.42) against the HL-60(TB) line, whereas other
leukemia cell lines such as CCRF-CEM, K-62, and
MOLT-4 did not reach the LC50 level. Other cell lines
of this tumor, such as RMPI-8226 and SR, had an
activity between the two extremes (log LC50 ) -5.07
and -4.56) reported above . Also some of the tumors
responded moderately to inhibition with compound 22.
This included HL-60(TB) and RMPI-8226 leukemia,
UACC-257 melanoma, EKVX, HOP-62, NCIH322M, and
NCI-460 non-small-cell lung cancer, OVCAR-3 ovarian
We have developed a method for the synthesis of a
new series of 7-substituted 8-chloro-5,5-dioxoimidazo-
[1,2-b][1,4,2]benzodithiazine derivatives with antitumor
activity, using a nonstandard mixed anhydride of a
hypothetical methyleneorthosulfonic acid 7. Compounds
22 and 24 were the most potent of all derivatives tested,
and the latter displayed a high degree of selectivity
against leukemia HL-60(TB) cells. The mechanism of
the antitumor activity and further variations of the

New Mixed Anhydride
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 2 433
Ta ble 1. Overview of the Results of the in Vitro Antitumor Screening for Compounds 8-13, 16, 18, 19, 21, 22, and 24-27a,e
b
d
no. of the cell lines giving positive log GI50 [M], log GTI c [M], and log LC50 [M]
b
d
log GI50 [M]
log GTI c [M]
range
log LC50 [M]
no. of the cell
lines investigated
compound
no.
range
no.
no.
range
9
11
16
18
19
22
24
26
27
57
58
57
57
60
60
60
57
54
50
58
57
56
60
60
60
46
52
-5.19 to -4.06
10
11
55
52
60
57
57
35
27
-4.52 to -4.02
-4.51 to -4.02
-4.77 to -4.06
-4.70 to -4.04
-5.55 to -4.04
-5.49 to -4.31
<-8.00 to -4.01
-4.81 to -4.07
-4.59 to -4.04
0
1
-4.90 to -4.15
-5.40 to -4.47
-5.48 to -4.40
-5.91 to -4.55
-5.77 to -4.34
<-8.00 to -4.01
-5.38 to -4.05
-5.33 to -4.09
-4.23
35
18
50
46
39
19
4
-4.35 to -4.00
-4.27 to -4.00
-5.18 to -4.01
-5.24 to -4.02
-5.42 to -4.04
-4.63 to -4.07
-4.20 to -4.04
a
Data obtained from the NCI’s in vitro disease-oriented human tumor cells screen (see Table 2 and refs 37-39 for details). Compounds
8, 10, 12, 13, 21, and 25 were inactive. The log of the molar concentration that inhibitis 50% net cell growth. c The log of the molar
concentration giving total growth inhibition. The log of the molar concentration leading to 50% net cell death.
b
d
g, 0.1 mol) in anhydrous CH2Cl2 (75 mL) was added with
stirring triethylamine (12.65 g, 0.125 mol). The solution
obtained was cooled to -15 °C in an ice-NaCl bath, and to
this was added dropwise over 45 min a solution of methane-
sulfonyl chloride (8.6 g, 0.075 mol) in anhydrous CH2Cl2 (50
mL). The reaction mixture was stirred for an additional 3 h
at -12 to -6 °C. The cooling bath was removed, and the
reaction mixture was allowed to warm to 18 °C. The solid that
precipitated was collected by filtration and washed successively
with CH2Cl2 (5 × 10 mL), cold water (6 × 20 mL), and acetone
(4 × 10 mL), CH2Cl2 (2 × 10 mL). Drying under vacuum gave
anhydride 7 (28.5 g, 87%): mp 257-259 °C dec; IR (KBr) 1800,
1740 (CdO, anhydride), 1370, 1195, 1175 (SO2), and other
characteristics at 1580, 1530, 1505, 1430, 1325, 1290, 1095,
parent structure are currently being investigated to
improve both potency and selectivity and to get more
detailed information on the SAR.
Exp er im en ta l Section
The following instruments and parameters were used:
(melting points) Buchi 535 apparatus; (IR spectra) KBr pellets,
400-4000 cm-1 Perkin-Elmer 1600 FTIR spectrometer; (1H
NMR spectra) Varian Gemini 200 apparatus (chemical shifts
are expressed as δ values relative to Me4Si as standard). HSQC
and DEPT-HMQC spectra were taken on a Varian Unity 500
spectrometer. Hydrogen and carbon spectral widths were 3749
and 18 518 Hz, respectively. Analyses of C, H, N were within
(O.4% of the theoretical values.
1030, 1005, 905, 875, 765, 685, 670, 610 cm-1 1H NMR
;
(DMSO-d6,) δ 5.76 (s, 2H, SdCH2), 7.37 (d, J ) 1.6 Hz, 4H,
2-H), 8.16 (d, J ) 1.6 Hz, 4H, H-3), 8.37 (s, 4H, 9-H), 8.54 (s,
4H, 6-H) ppm; 13C NMR (DMSO-d6) δ 54.20 (SdC), 164.18 (Cd
O), 117.53, 127.61, 130.58, 130.79, 131.93, 134.52, 137.77,
138.25 ppm. Anal. (C41H18Cl4N8O16S9) C, H, N.
Syn th esis of 6-Ch lor o-3-(2,2-d im eth oxyeth yla m in o)-
1,1-d ioxo-1,4,2-ben zo-d ith ia zin e-7-ca r boxylic Acid (5). To
an ice-cold suspension of 6-chloro-3-methylthio-1,1-dioxo-1,4,2-
benzodithiazine-7-carboxylic acid 433 (32.4 g, 0.1 mol) in
anhydrous methanol (140 mL) was added with stirring ami-
noacetaldehyde dimethylacetal (21.03 g, 02 mol). After 0.5 h,
the ice bath was removed and the reaction mixture was
refluxed until the evolution of MeSH had ceased (10-12 h)
(CAUTION: because of high toxicity, MeSH should be trapped
in an aqueous NaOH solution). The solvent was evaporated
under reduced pressure. The residue was dissolved in water
(400 mL) and acidified to pH 3.5 with 1% hydrochloric acid.
After 0.5 h of stirring, a small amount of insoluble side product
was filtered out together with charcoal added, and the filtrate
was slowly acidified to pH 1.5 with 0.5% hydrochloric acid.
The title product, which precipitated, was immediately col-
lected by filtration, washed thoroughly with water, and dried
at temperatures gradually increasing to 105 °C: yield 34.0 g,
89%; mp 166-168 °C dec; IR (KBr) 3385, 3285 (OH, NH), 1710
(CdO), 1570 (CdN), 1310, 1160 (SO2) cm-1; 1H NMR (DMSO-
d6) δ 3.29 (s, 6H, 2OCH3), 3.50 (t, J ) 5.3 Hz, 2H, CH2), 4.52
(t, J ) 5.3 Hz, CH-O), 8.09 (s, 1H, 5-H), 8.29 (s, 1H, 8-H),
10.00 (t, 1H, NH) ppm. Anal. (C12H13ClN2O6S2) C, H, N.
Syn th esis of 8-Ch lor o-5,5-d ioxoim id a zo[1,2-b][1,4,2]-
ben zod ith ia zin e-7-ca r boxylic a cid (6). The benzodithiazine
5 (32.4 g 0.085 mol) was added portionwise at room temper-
ature to 98% sulfuric acid (100 mL). After the exothermic
reaction was complete (1 h, 36-38 °C), the reaction mixture
was kept at room temperature for 18 h. The solution obtained
was poured onto a water-crushed ice mixture (800-900 g, 0-3
°C) and stirred at room temperature for 3 h. The precipitated
solid was collected by filtration, washed with water, and dried
at 100 °C to afford the acid 6 (26.1 g, 96%): mp 305-310 °C
dec; IR (KBr) 3155, 3130, 3080 (C-H, arom), 2920, 2860, 2805,
2730, 2625, 2550, 2490, 1722 (COOH), 1580 (CdN), 1375, 1195,
Gen er a l P r oced u r e for th e P r ep a r a tion of Im id a -
zoben zod ith ia zin eca r boxa m id es 8 a n d 9-22. To a sus-
pension of anhydride 7 (3.27 g, 0.0025 mol) and the appropriate
amine (0.005 mol) in anhydrous p-dioxane (70 mL) was added
triethylamine (0.5 g, 0.005 mol). The reaction mixture was
stirred at room temperature for 1 h, followed by reflux for 12
h. The solvent was evaporated under reduced pressure. To the
residue a solution of K2CO3 (2.2 g) in water (150 mL) was
added, and this was stirred at room temperature for 1 h. The
precipitate of the adequate carboxamide obtained was filtered
out, washed successively with water (6 × 5 mL) and ethanol
(5 × 4 mL), and dried. The water-filtrates (pH 9-10) mixture
was acidified with 1% hydrochloric acid to pH 1. Carboxylic
acid 6 thus obtained as a side product (yield: 0.9-1.2 g, 57-
76%) was filtered out, washed with water, and dried at
temperatures gradually increasing to 105 °C.
In this manner the following carboxamides were obtained.
5-(8-C h lo r o -5,5-d io x o im id a z o [1,2-b ][1,4,2]b e n z o -
dith iazin -7-yl-car bon yl)-5H-diben zo[b,f]azepin e (8). Start-
ing from 5H-dibenzo[b,f]azepine (0.97, 0.005 mol), the title
compound 8 was obtained (2.2 g, 89%): mp 241-242 °C; IR
(KBr) 1675 (CdO), 1375, 1355, 1190 (SO2) cm-1 1H NMR
;
(DMSO-d6) δ 7.14 (d, J ) 12 Hz, 2H), 7.19-7.26 (m, 2H), 7.36
(d, J ) 1.7 Hz, 1H), 7.40-7.48 (m, 4H), 7.55 (s, 1H), 7.59-
7.83 (m, 2H), 8.12 (s, 1H), 8.17 (d, J ) 1.7 HZ, 1H) ppm. Anal.
(C24H14ClN3O3S2) C, H, N.
N-(2-An th r yl)-8-ch lor o-5,5-d ioxoim id a zo[1,2-b][1,4,2]-
ben zod ith ia zin e-7-ca r boxa m id e (9). Starting from 2-ami-
noanthracene (0.97 g), the title compound 9 was obtained (2.0
g, 81%): mp 298-300 °C dec; IR (KBr) 3280 (NH), 1665 (Cd
O), 1370, 1360, 1190, 1175 (SO2) cm-1; 1H NMR (DMSO-d6) δ
7.39-7.67 (m, 4H), 8.05-8.20 (m, 4H), 8.44-8.63 (m, 5H),
10.98 (s, 1H, NH) ppm. Anal. (C24H14ClN3O3S2) C, H, N.
N-[2-(P h en ylcar boam oyl)ph en yl]-8-ch lor o-5,5-dioxoim -
id a zo[1,2-b][1,4,2]b en zod it h ia zin e-7-ca r b oxa m id e (10).
Starting from 2-aminobenzanilide (1.06 g), the title compound
1
1180 (SO2) cm-1; H NMR (DMSO-d6) δ 7.37 (d, J ) 1.7 Hz,
1H, 2-H), 8.17 (d, J ) 1.7 Hz, 3-H), 8.38 (s, 1H, 9-H), 8.55 (s,
1H, 6-H) ppm. Anal. (C10H5ClN2O4S2) C, H, N.
Syn th esis of Meth ylen eor th osu lfon ictetr akis(8-ch lor o-
5,5-d ioxoim id a zo[1,2-b][1,4,2]ben zod ith ia zin e-7-ca r boxy-
lic) An h yd r id e (7). To a suspension of carboxylic acid 6 (31.7

434 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 2
Brzozowski and Sa¸ czewski
Ta ble 2. Inhibition of in Vitro Cancer Cell Lines by Selected Imidazo [1,2-b][1,4,2]benzodithiazine derivatives 19, 22, and 24a
b
d
response parameters: (A) log GI50 [M], (B) log TGI c [M], (C) log LC50 [M], and MG_MIDe
compd 19
compd 22
compd 24
panel cell line
leukemia
A
B
C
A
B
C
A
B
C
CCRF-CEM
HL-60 (TB)
K-562
MOLT-4
RMPI-8226
SR
-5.30
-4.87
-4.80
-4.72
-5.03
-5.52
-4.61
-4.51
-4.33
-4.38
-4.63
-4.92
-4.02
-4.15
-4.06
-4.03
-4.24
-4.33
-5.49
-5.73
-5.39
-5.56
-5.68
-5.70
-4.87
-5.43
-4.70
-5.03
-5.39
-5.32
e
-5.60
<-8.00
-5.39
-5.34
-5.77
-5.65
-4.77
<-8.00
-4.42
-4.70
-5.42
-5.23
e
5.13
e
-4.08
-5.10
e
-5.42
e
e
-5.07
-4.56
non-small-cell lung cancer
A 549/ATCC
EKVX
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-46-
-4.62
-4.69
-4.83
-4.82
-4.71
-4.77
-4.76
-4.8-
-5.91-
-4.20
-4.35
-4.52
-4.40
-4.45
-4.47
-4.47
-4.53
-5.55
e
-4.90
-5.64
-5.78
-5.23
-4.72
-4.93
-5.75
-5.69
-5.27
-4.41
-5.33
-5.42
-4.59
-4.48
-4.60
-5.49
-5.37
-4.65
e
-4.91
-4.77
-7.31
-4.84
-4.82
-4.86
-4.92
-5.58
-4.98
-4.59
-4.59
-4.79
-4.17
-4.24
-4.25
-4.61
-5.11
4.58
-4.20
-4.11
-4.40
e
e
e
-4.30
-4.57
-4.18
-4.01
-4.21
e
-4.19
-4.17
-4.19
-4.26
-5.18
-5.01
-5.06
-4.02
-4.23
-4.26
-5.24
-5.05
-4.05
NCI-522
colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
-4.77
-4.80
-4.79
-4.91
-4.70
-4.91
-4.77
-4.51
-4.53
-4.53
-4.47
-4.33
-4.58
-4.38
-4.25
-4.27
-4.26
-4.03
e
-4.24
e
-4.76
-5.47
-5.59
-5.28
-5.65
-5.69
-4.92
-4.51
-4.93
-5.27
-4.67
-5.28
-5.41
-4.33
-4.25
-4.26
-4.89
-4.14
-4.54
-5.13
e
-4.77
-5.74
-5.34
-5.32
-5.02
-5.18
-5.11
-4.51
-5.33
-4.77
-4.56
-4.25
-4.72
-4.63
-4.26
-4.84
-4.39
e
e
-4.36
-4.23
SW-620
melanoma
LOX IMVI
MALME 3M
M14
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
prostate cancer
PC-3
PU-145
CNS cancer
SF-268
SF-295
SF-539
SNB-19
SNB-75
U251
ovarian cancer
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
SK-OV-3
renal cancer
768-0
A498
ACHN
CAKI-1
RXF 393
SN12C
TK-10
UO-31
breast cancer
MCF 7
NCI/ADR-RES
MDA-MB-231/ATCC
HS 578T
MDA-MB-435
MDA-N
BT 549
T-470
MG_MID
-4.96
-4.70
-4.75
-4.76
-4.70
--4.78
-4.86
-4.84-
-4.59
-4.43
-4.46
-4.48
-4.42
-4.52
-4.57
-4.56
-4.22
-4.16
-4.17
-4.20
-4.15
-4.26
-4.28
-4.28
-5.28
-4.18
-4.76
-5.00
-5.61
-4.80
-5.74
-5.27
-4.39
e
e
e
-5.30
-4.77
-5.14
-4.88
-5.02
-4.97
-4.86
-4.84
-4.74
-4.48
4.64
-4.49
-4.57
-4.63
-4.57
4.51
-4.34
-4.19
-4.24
-4.11
-4.12
-4.30
-4.29
-4.17
-4.33
-4.59
-5.17
-4.47
-5.47
-4.75
-4.16
-4.19
-4.33
-4.14
-5.20
-4.38
-4.77
-4.79
-4.48
-4.52
-4.18
-4.56
-5.72
-5.76
-5.45
-5.49
-5.19
-5.22
-5.57
-5.26
-4.98
-4.75
-4.49
-4.37
-4.72
-4.74
-4.71
-4.72
-4.73
-4.76
-4.33
-4.46
-4.43
-4.43
-4.45
-4.51
e
-5.47
-4.95
-5.65
-4.92
-5.41
-5.34
-4.79
-4.60
-5.31
-4.61
-4.57
-4.80
e
-5.02
-4.94
-5.74
-4.99
-5.16
-5.46
e
e
-4.19
-4.14
-4.14
-4.18
-4.25
-4.26
-4.81
-4.30
e
-4.61
-5.31
-4.47
-4.51
4.84
-4.27
-4.59
e
e
-4.35
-4.42
-4.93
-4.82
-4.79
-4.66
-4.76
-4.61
-4.53
-4.55
-4.41
-4.34
4.43
-4.12
-4.27
-4.04
-4.01
-4.10
e
-5.26
-5.75
-5.56
-4.53
-5.63
-4.34
-4.63
-5.46
-4.99
-4.08
-5.15
e
4.10
-5.18
-4.06
e
4.42
e
-5.49
-5.53
-4.96
-4.79
-5.42
-4.57
-5.16
-4.94
-4.61
-4.43
-4.84
-4.01
-4.63
-4.46
-4.21
-4.04
-4.27
e
-4.19
-4.80
-4.72
-4.75
-5.07
-4.72
-4.77
-4.72
-5.36
-4.53
-4.46
-4.49
-4.43
-4.40
-4.49
-4.46
-4.83
-4.27
-4.20
-4.23
e
-4.08
-4.20
-4.20
-4.33
-4.78
-4.87
-4.90
-5.32
-5.33
-4.82
-4.98
-5.68
-4.52
-4.58
-4.44
-4.72
-4.54
-4.54
-4.64
-5.36
-4.26
-4.20
e
-4.29
-4.25
-4.25
-4.30
-4.30
-4.79
-4.79
-5.07
-4.63
-5.02
-4.91
-5.07
-5.99
-4.42
-4.39
-4.47
-4.20
-4.60
e
-4.04
e
e
e
-4.19
e
-4.34
e
-4.68
-4.37
-5.17
-4.72
-4.71
-4.55
-4.76
-4.75
-4.74
-4.63
-4.83
-4.70
-4.35
-4.44
-4.04
-4.50
-4.48
-4.45
-4.19
-4.48
-4.35
e
-4.17
e
-4.24
-4.21
-4.16
e
-5.76
-4.75
-5.22
-5.38
-5.09
-4.87
-4.91
-5.77
-5.23
-5.47
-4.41
-4.61
e
-4.31
-4.56
-4.49
-5.24
-4.75
5.18
-4.08
-4.27
e
-5.49
-4.84
-4.94
-4.87
-5.10
-4.86
-4.94
-5.62
-5.10
-4.83
-4.38
-4.62
e
-4.64
-4.04
-4.22
-5.20
-4.54
-4.41
e
-4.31
e
-4.26
e
e
-4.42
-4.16
-4.25
-4.07
-5.11
-4.34
-4.17
a
b
Data obtained from the NCI’s in vitro disease-oriented human tumor cells screen (see refs 37-39 for details). The log of the molar
concentration that inhibits 50% net cell growth. c The log of the molar concentration giving total growth inhibition. The log of the molar
d
concentration leading to 50% net cell death. MG_MID ) mean graph midpoint ) arithmetical mean value for all tested cancer cell lines.
If the indicated effect was not attainable within the used concentration interval, the highest tested concentration was used for the
calculation. e The values of log TGI or log LC50 > -4.00.

New Mixed Anhydride
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 2 435
10 was obtained (2.1 g, 82%): mp 265-265.5 °C dec; IR (KBr)
3280, 32235 (NH), 1665, 1660, 1640, (CdO, CdN), 1375, 1195,
4H), 8.14 (d, J ) 8 Hz, 1H), 8.57 (d, 7.75 (t, J ) 7.9 Hz, 1H),
7.91-8.12 (m, 4H), 8.14 (d, J ) 8 Hz, 1H), 8.57 (d, J ) 5.9 Hz,
1H), 8.78 (s, 1H), 9.36 (s, 1H), 10.86 (s, 1H, NH) ppm. Anal.
(C19H11ClN4O3S2) C, H, N.
1
1180 (SO2) cm-1; H NMR (DMSO-d6) δ 7.07-8.00 (m, 10H),
8.19 (s, 1H), 8.37 (s, 1H), 8.52 (s, 1H), 10.47 (s, 1H, NH), 10.98
(s, 1H, NH) ppm; 13C NMR (DMSO-d6) δ 117.60, 120.22,
120.49, 123.72, 125.00, 125.87, 128.03, 128.46, 128.55, 128.88,
130.57, 131.10, 131.16, 131.25, 133.21, 135.64, 135.94, 136.10,
139.00, 162.15, 166.14 ppm. Anal. (C23H15ClN4O4S2) C, H, N.
N-(2-P yr id yl)-8-ch lor o-5,5-d ioxoim id a zo[1,2-b][1,4,2]-
ben zod ith ia zin e-7-ca r boxa m id e (11). Starting from 2-ami-
nopyridine 0.48 g), the title compound 11 was obtained (1.4 g,
71%): mp 358-360 °C dec; IR (KBr) 3140 (NH), 1650, 1625
(CdO, CdN), 1375, 1175 (SO2) cm-1; 1H NMR (CDCl3) δ 7.47
(s, 1H), 7.56-7.70 (m, 2H), 7.79 (s, 1H), 8.30 (t, J ) 7.8 Hz,
1H), 8.96 (s, 1H), 9.10 (s, 1H), 9.19 (d, J ) 6.8 Hz), 11.28 (s,
1H, NH) ppm. Anal. (C15H9ClN4O3S2) C, H, N.
N-(2-Th ia zolyl)-8-ch lor o-5,5-d ioxoim id a zo[1,2-b][1,4,2]-
ben zod ith ia zin e-7-ca r boxa m id e (19). Starting from 2-ami-
nothiazole (0.5 g), the title compound 19 was obtained (1.8 g,
90%): mp 367-370 °C dec; IR (KBr) 3240 (NH), 1660 (CdO),
1
1375, 1190, 1175 (SO2) cm-1; H NMR (DMSO-d6) δ 7.38 (s,
3H), 7.59 (s, 1H), 8.19 (s, 1H), 8.40 (s, 1H), 8.65 (s, 1H, NH)
ppm; 13C NMR (DMSO-d6) δ 114.35, 117.59, 126.89, 130.61,
130,90, 130.95, 133.70, 133.85, 136.60, 137.41, 138.46, 157.99,
162.24 ppm. Anal. (C13H7ClN4O3S2) C, H, N.
N-(4-P h en yl-2-t h ia zolyl)-8-ch lor o-5,5,-d ioxoim id a zo-
[1,2-b][1,4,2]ben zod ith ia zin e-7-ca r boxa m id e (20). Starting
from 2-amino-4-phenylthiazole (0.9 g), the title compound 20
was obtained (2.1 g, 89%): mp 182-185 °C dec; IR (KBr) 3150
N-(4-Meth yl-2-p yr id yl)-8-ch lor o-5,5-d ioxoim id a zo[1,2-
b][1,4,2]ben zodith iazin e-7-car boxam ide (12). Starting from
2-amino-4-methylpyridine (0.55 g), the title compound 12 was
obtained (1.6 g, 77%): mp 355-357 °C dec; IR (KBr) 3135
(NH), 1685 (CdO), 1375, 1185, 1175 (SO2) cm-1 1H NMR
;
(DMSO-d) δ 7.30-7.48 (m, 4H), 7.77-7.94 (m, 3H), 8.19 (s,
1H), 8.40 (s, 1H), 8.68 (s, 1H), 13.12 (s, 1H, NH) ppm. Anal.
(C19H11ClN4O3S3) C, H, N.
(NH), 1655, 1625 (CdO, CdN), 1360, 1190, 1180 (SO2) cm-1
;
1H NMR (CDCl3) δ 2.46 (s, 3H, CH3), 7.41 (d, J ) 6.7 Hz, 1H),
7.45 (s, 2H), 7.78 (s, 1H), 8.88 (s, 1H), 9.00 (d, J ) 6.7 Hz,
N-(Ben zot h ia zol-5-yl)-8-ch lor o-5,5,-d ioxoim id a zo[1,2-
b][1,4,2]ben zodith iazin e-7-car boxam ide (21). Starting from
5-aminobenzothiazole (0.75 g), the title compound 21 was
obtained (2.0 g, 89%): mp 308-309 °C dec; IR (KBr) 3285
(NH), 1665 (CdO), 1605 (CdN, arom ring), 1370, 1190, 1175
(SO2) cm-1; 1H NMR (DMSO-d6) δ 7.38 (t, J ) 2 Hz, 1H), 7.67-
7.73 (m, 1H), 8.09 (d, J ) 8.8 Hz, 1H), 8.19 (d, J ) 1.6 Hz,
1H), 8.43 (s, 1H), 8.60 (s, 1H), 8.65 (d, J ) 1.6 Hz, 1H), 9.33
(s, 1H), 10.99 (s, 1H, NH) ppm. Anal. (C17H9ClN4O3S3) C, H,
N.
N-(Ben zo-2,1,3-th iod ia zol-4-yl)-8-ch lor o-5,5-d ioxoim i-
d a zo[1,2-b][1,4,2]b en zod it h ia zin e-7-ca r b oxa m id e (22).
Starting from 4-aminobenzo-2,1,3-thiadiazole (0.76 g), the title
compound 22 was obtained (1.8 g, 80%): mp 224-226 °C; IR
(KBr) 3400 (NH), 1685 (CdO), 1610 (CdN), 1370, 1185, 1175
(SO2) cm-1; 1H NMR (DMSO-d6) δ 7.38 (s, 1H), 7.73-7.90 (m,
2H), 8.19 (s, 1H), 8.44 (t, J ) 7.3 Hz, 2H), 8.57 (s, 1H), 11.34
(s, 1H, NH) ppm; 13C NMR (DMSO-d6) δ 116.94, 117.64,
118.10, 126.40, 128.31, 129.85, 130.61, 130.68, 130.76, 132.92,
135.97, 136.35, 138.65, 148.04, 154.70, 163.25 ppm. Anal.
(C16H8ClN5O3S3) C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ar yl Im i-
d a zoben zod ith ia zin eca r boxyla tes 23-25. A stirred mix-
ture of anhydride 7 (2.62 g, 0.002 mol), the appropriate
heteroaromatic hydroxy compound (0.005 mol), and anhydrous
p-dioxane (25 mL) was refluxed for 8 h. The solvent was
evaporated under reduced pressure. To the residue a solution
of KHCO3 (1 g) in water (100 mL) was added, and this was
stirred at room temperature for 2 h. The precipitate of the
adequate crude ester 20, 21, or 22 was filtered out, washed
with water, dried, and recrystallized from acetone. The water-
filtrates (pH 7.5-8.5) mixture was acidified with 1% hydro-
chloric acid to pH 1. The precipitate thus obtained was filtered
out, washed with water, and dried at temperatures gradually
increasing to 105 °C, giving 0.9-1.0 g (71-79%) of carboxylic
acid 6 formed as a byproduct.
1H), 9.07 (s, 1H), 11.29 (s, 1H, NH) ppm. Anal. (C16H11
ClN4O3S2) C, H, N.
-
N-(3-Meth yl-2-p yr id yl)-8-ch lor o-5,5-d ioxoim id a zo[1,2-
b][1,4,2]ben zodith iazin e-7-car boxam ide (13). Starting from
2-amino-3-methylpyridine (0.55 g), the title compound 13 was
obtained (1.8 g, 88%): mp 341-342 °C dec; IR (KBr) 3135
(NH), 1630, 1610 (CdO, CdN), 1375, 1185, 1175 (SO2) cm-1
;
1H NMR (CDCl3) δ 2.48 (s, 3H, CH3), 7.20-7.54 (m, 4H), 7.89
(d, J ) 7.5 Hz, 1H), 8.99 (d, J ) 7.5 Hz, 1H), 9.22 (s, 1H, NH)
ppm. Anal. (C16H11ClN4O3S2) C, H, N.
N-(2-Qu in olyl)-8-ch lor o-5,5-d ioxoim id a zo[1,2-b][1,4,2]-
ben zod ith ia zin e-7-ca r boxa m id e (14). Starting from 2-ami-
noquinoline (0.72 g), the title compound 14 was obtained (1.7
g, 77%): mp 219-221 °C dec; IR (KBr) 3200 (NH), 1690 (Cd
-1
O), 1615 (CdN), 1385, 1190, 1175 (SO2) cm
;
1H NMR
(DMSO-d6) δ 7.39 (s, 1H), 7.51-7.81 (m, 3H), 7.98 (d, J ) 8.2
Hz, 1H), 8.38-8.49 (m, 3H), 8.61 (s, 1H), 11.64 (s, 1H, NH)
ppm. Anal. (C19H11ClN4O3S2) C, H, N.
N-(3-Qu in olyl)-8-ch lor o-5,5-d ioxoim id a zo[1,2-b][1,4,2]-
ben zod ith ia zin e-7-ca r boxa m id e (15). Starting from 3-ami-
noquinoline (0.72 g), the title compound 15 was obtained (1.8
g, 81%): mp 232-234 °C; IR (KBr) 3305 (NH), 1670 (CdO),
1
1610 (CdN), 1380, 1190, 1170 (SO2) cm-1; H NMR (DMSO-
d6) δ 7.39 (d, J ) 1.6 Hz, 1H), 7.58-7.74 (m, 2H), 7.99-8.04
(m, 2H), 8.20 (d, J ) 1.6 Hz), 8.44 (s, 1H), 8.68 (s, 1H), 8.84 (s,
1H), 9.00 (s, 1H), 11.23 (s, 1H, NH); 13C NMR (DMSO-d6) δ
117.62, 123.18, 126.17, 127.26, 127.64, 127.90, 128.36, 128.60,
130.62, 131.03, 131.16, 132.19, 133.33, 135.63, 136.34, 138.55,
144.61, 149.02, 162.76 ppm. Anal. (C19H11ClN4O3S2) C, H, N.
N-(6-Qu in olyl)-8-ch lor o-5,5-d ioxoim id a zo[1,2-b][1,4,2]-
ben zod ith ia zin e-7-ca r boxa m id e (16). Starting from 6-ami-
noquinoline (0.72 g), the title compound 16 was obtained (2.0
g, 90%): mp 255-257 °C dec; IR (KBr) 3240 (NH), 1675 (Cd
O), 1625 (CdN), 1365, 1190, 1175 (SO2) cm-1; 1H NMR (DMSO-
d6) δ 739 (s, 1H), 7.50-7,56 (m, 1H), 7.86-8.07 (m, 2H), 8.20
(s, 1H), 8.37-8.63 (m, 4H), 8.84 (d, J ) 3.4 Hz, 1H), 11.06 (s,
1H, NH). Anal. (C19H11ClN4O3S2) C, H, N.
In this manner the following esters were obtained.
8-Qu in olyl
8-Ch lor o-5,5-d ioxoim id a zo[1,2-b][1,4,2]-
ben zod ith ia zin e-7-ca r boxyla te (23). Starting from 8-hy-
droxyquinoline (0.73 g), the title compound 23 was obtained
(1.6 g, 90%): mp 216-217 °C; IR (KBr) 1742 (CdO), 1620 (Cd
N), 1375, 1175 (SO2) cm-1; 1H NMR (DMSO-d6) δ 7.41 (d, J )
1.8 Hz, 1H), 7.62-7.86 (m, 3H), 8.0-8.05 (m, 1H), 8.22 (d, J
) 1.8 Hz, 1H), 8.49-8.55 (m, 2H), 8.91-8.94 (m, 1H), 9.00 (s,
1H) ppm. Anal. (C19H10ClN3O4S2) C, H, N.
N-(2-Meth yl-6-qu in olyl)-8-ch lor o-5,5-d ioxoim id a zo[1,2-
b][1,4,2]ben zodith iazin e-7-car boxam ide (17). Starting from
6-amino-3-methylquinoline (0.8 g), the title compound 17 was
obtained (2.0 g, 88%): mp 286-288 °C dec; IR (KBr) 3300
(NH), 1665 (CdO), 1625 (CdN), 1375, 1190, 1175 (SO2) cm-1
;
H NMR (DMSO-d6) δ 3.36 (s, 3H, CH3), 7.37-7.40 (m, 2H),
7.42-7.95 (m, 2H), 8.17-8.26 (m, 2H), 8.42 (s, 2H), 8.60 (s,
1H), 10.98 (s, 1H, NH) ppm. Anal. (C20H13ClN4O3S2) C, H, N.
N-(5-Isoqu in olyl)-8-ch lor o-5,5-dioxoim idazo[1,2-b][1,4,2]-
bn ezod ith ia zin e-7-ca r boxa m id e (18). Starting from 5-ami-
noisoquinoline (0.72 g), the title compound 18 was obtained
(1.7 g, 77%): mp 256-257 °C dec; IR (KBr) 3220 (NH), 1685
2-Meth yl-8-qu in olyl 8-Ch lor o-5,5-d ioxoim id a zo[1,2-b]-
[1,4,2]ben zod ith ia zin e-7-ca r boxyla te (24). Starting from
8-hydroxy-2-methylquinoline (0.8 g), the title compound 24 was
obtained (1.6 g, 87%): mp 185-186 °C; IR (KBr) 1745 (CdO),
1
1370, 1190, 1175 (SO2) cm-1; H NMR (DMSO-d6) δ 2.64 (s,
3H, CH3), 7.40 (d, J ) 1.7 Hz, 1H), 7.50-7.95 (m, 4 H), 8.23
(d, J ) 1.7 Hz, 1H), 8.36 (d, J ) 8.5 Hz, 1H), 8.52 (s, 1H), 9.13
(s, 1H). Anal. (C20H12ClN3O4S2) C, H, N.
(CdO), 1360, 1190, 1170 (SO2) cm-1 1H NMR (DMSO-d6) δ
;
7.38 (d, J ) 8 Hz, 1H), 7.75 (t, J ) 7.9 Hz, 1H), 7.91-8.12 (m,

436 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 2
Brzozowski and Sa¸ czewski
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2-P h en yl-4-oxo-4H-ch r om en -3-yl 8-Ch lor o-5,5-d ioxoim -
id a zo[1,2-b][1,4,2]b en zod it h ia zin e-7-ca r b oxyla t e (25).
Starting from 3-hydroxyflavone (1.2 g), the title compound 25
was obtained (1.9 g, 88%): mp 249-251 °C; IR (KBr) 1765
(CdO, ester), 1640 (CdO, ketone), 1625, 1610 (CdN, CdC),
1
1360, 1190 (SO2) cm-1; H NMR (DMSO-d6) δ 7.36-7.41 (m,
2H), 7.58-7.65 (m, 4H), 7.86-7.99 (m, 3H), 8.14-8.21 (m, 2H),
8.53 (s, 1H), 8.69 (s, 1H) ppm. Anal. (C25H13ClN2O6S2) C, H,
N.
Syn th esis of 8-Ch lor o-7-(3,4-d ih yd r o-4-oxoqu in oa zo-
lin -2-yl)-5,5-dioxoim idazo[1,2-b][1,4,2]ben zodith iazin e (26).
A mixture of carboxamide 10 (2.04 g, 0.004 mol) and thionyl
chloride (15 mL) was refluxed for 10 h. The thionyl chloride
was evaporated in vacuo. The dry residue was dissolved in
boiling toluene (40 mL), a small amount of insoluble side
products was filtered out, and the filtrate was concentrated
in vacuo. The resulting residue was recrystallized from ethanol
(15 mL) to give 26 (1.4 g, 71%): mp 230-232 °C dec; IR (KBr)
1685 (CdO), 1625 (CdN), 1375, 1190, 1180 (SO2) cm-1 1H
;
NMR (DMSO-d6) δ 7.11-7.39 (m, 6H), 7.59-7.81 (m, 3H),
8.18-8.27 (m, 2H), 8.38 (s, 1H), 8.60 (s, 1H) ppm; 13C NMR
(DMSO-d6) δ 117.60, 119.17, 122.09, 124.13, 126.13, 126.98,
128.02, 128.74, 129.57, 129.66, 130.63, 131.11, 131.97, 134.30,
134.38, 137.58, 141.67, 144.93, 144.98, 151.70 ppm. Anal.
(C23H13ClN4O3S2) C, H, N.
Syn th esis of 8-Ch lor o-7-(5-p h en yl-4,4,6-tr ioxo-5,6-d i-
h ydr o-3,4,1,5-ben zoxath iadiazocyn -2-yl)-5,5-dioxoim idazo-
[1,2-b][1,4,2]ben zod ith ia zin e (27). The carboxamide 10 (2.04
g, 0.004 mol) was added portionwise to 98% sulfuric acid (10
mL), and this was stirred at room temperature for 12 h. The
solution obtained was poured into a water-crushed ice mix-
ture (180-200 g, 0-3 °C). The resulting white precipitate was
collected by filtration, washed thoroughly with water, dried,
and recrystallized from toluene (130 mL) to give 27 (1.7 g,
74%): mp 261-262 °C; IR (KBr) 1765 (CdO), 1620 (CdN),
1380, 1190, 1180 (SO2) cm-1; 1H NMR (DMSO-d6) δ 7.40 (d, J
) 1.4 Hz, 2H), 7.71-8.25 (m, 9H), 8.50 (s, 1H), 8.72 (s, 1H)
ppm; 13C NMR (DMSO-d6) δ 117.05, 117.55, 127.30, 128.16,
129.78, 129.85, 130.67, 131.26, 132.01, 134.61, 137.16, 137.51,
145.48, 153.43, 158.36 ppm. Anal. (C23H13ClN4O6S3) C, H, N.
(14) Turner, S. R.; Strohbach, W. J .; Tommasi, R. A.; Aristoff, P. A.;
J ohnson, P. D.; Skulnick, H. I.; Dolak, L. A.; Seest, E. P.; Tomich,
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Dihydro-4-hydroxy-2-pyrone Sulfonamide Class. J . Med. Chem.
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C.; Balzarini, J .; Clercq, E.; Vega, S. Novel 1,1,3-Trioxo-2H,4H-
thieno[3,4-e][1,2,4]thadiazine Derivatives as Non-Nucleoside
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Ack n ow led gm en t. This work was supported by the
Polish State Committee for Scientific Research (Grant
4 P05F 007 19). We also thank Dr. V. L. Narayanan
from NCI (Bethesda, MD) for the in vitro screening.
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(5-amino-1,2,4-triazol-3-yl)benzene-sulphonamide derivatives with
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