Synthesis and anti-HIV activity of N-(3-amino-3,4-dihydro-4-oxopyrimidin-2- yl)-4-chloro-2-mercapto-5-methylbenzenesulfonamide derivatives

Article abstract of DOI:10.1002/jhet.5570440144

(Chemical Equation Presented) A series of N-(3-amino-3,4-dihydro-4- oxopyrimidin-2-yl)-4-chloro-2-mercapto-5-methylbenzenesulfonamide derivatives 10-17 have been synthesized as potential anti-HIV agents. The in vitro anti-HIV-1 activity of these compounds

Full text of DOI:10.1002/jhet.5570440144

Jan-Feb 2007
261
Synthesis and Anti-HIV Activity of N-(3-Amino-3,4-dihydro-4-
oxopyrimidin-2-yl)-4-chloro-2-mercapto-5-
methylbenzenesulfonamide Derivatives
Zdzisꢀaw Brzozowski and Franciszek Sꢁczewski*
Department of Chemical Technology of Drugs, Medical University of Gdaꢂsk, Al. Gen. Hallera 107, 80-416
Gdaꢂsk, Poland, e-mail: saczew@amg.gda.pl
Received April 4, 2006
Cl
S
S
SMe
Cl
SH
S
H
N
N
N
O
Me
Me
O
O
X
O
O
N
H2N
1
X = aromatic or heteroaromatic ring
A series of N-(3-amino-3,4-dihydro-4-oxopyrimidin-2-yl)-4-chloro-2-mercapto-5-methylbenzenesulfon-
amide derivatives 10-17 have been synthesized as potential anti-HIV agents. The in vitro anti-HIV-1
activity of these compounds has been tested at the national Cancer Institute (Bethesda, MD), and the
structure-activity relationships are discussed. The selected N-[3-amino-3,4-dihydro-6-(tert-butyl)-4-
oxothieno[2,3-e]pyrimidin-2-yl]-4-chloro-2-metcapto-5-methylbenzenesulfonamide (14) showed good
anti-HIV-1 activity with 50% effective concentration (EC50) value of 15 μM and weak cytotoxic effect
(IC50 = 106 μM).
J. Heterocyclic Chem., 44, 261 (2007).
INTRODUCTION
RESULTS AND DISCUSSION
Synthesis. The syntheses of the target compounds 10-
17 were achieved by a convenient two step procedure
starting from 4-chloro-5-methyl-3-methylthio-1,4,2-
benzodithiazine 1,1-dioxide 1 as shown in Schemes 1 and
2. First, the reaction of 1 with the appropriate alkyl o-
amino-arylcarboxylates carried out in boiling toluene in
the presence of pyridine led to the formation of alkyl o-(6-
chloro-7-methyl-1,1-dioxo-1,4,2-benzodithiazin-3-ylamino)-
arylcarboxylates 2-9 which were obtained in good yields
(55-91%, Scheme 1). Then, upon treatment of 2-9 with
hydrazine hydrate in methanol at room temperature (2-6,
Method A) or in boiling toluene (7-9, Method B), the
desired 2-mercaptobenzenesulfonamides 10-17 were
obtained in 41-96% yield.
We propose a reaction sequence for the transformations
as shown in Scheme 2. Nucleophilic attack of hydrazine
at the carbon C-3 of benzodithiazine ring results in
aminoguanidine intermediate A, which undergoes a
spontaneous cyclocondensation reaction leading to the
formation of final oxopyrimidine product 10-17.
Sulfonamides are among a growing list of compounds
with desirable anticancer and anti-HIV activities [1-5].
Previously, we have described the syntheses of various 4-
chloro-2-mercaptobenzenesulfonamide derivatives with
the nitrogen atom of sulfonamide moiety attached to a
variety of heterocyclic ring systems (I, Figure 1) [6-13].
Recently we have also reported on the syntheses of cyclic
analogues of 4-chloro-2-mercaptobenzenesulfonamide (II
and III, Figure 1) [22-26]. These compounds, depending on
their structure, exhibited pronounced either anticancer [6-
9,11,12,6-12,14-16,18] or anti-HIV [13,17,18] activities.
Some of the compounds were described as novel class
HIV-1 integrase inhibitors (MBS As) [13,17,19]. To
better understand the nature of their anticancer versus
their antiviral property we extended our studies to the
synthesis of new series of 4-chloro-2-mercaptobenzene-
sulfonamides (IV, Figure 1) as potential anti-HIV agents.
Cl
R1
S
S
Cl
R1
SH
S
Cl
R1
S
R3
N
H
N
N
N
R2
S
The structures of the compound 2-17 were confirmed
by elemental analysis (C, H, N) and spectroscopic data
presented in the experimental section. For example, in the
ir spectra of esters 2-9 the C=O vibrations appear at 1675-
1690 cm-1, while characteristic feature of the ir spectra of
o-mercaptobenzenesulfonamides 10-17 is the presence of
S-H vibrations at 2550-2570 cm-1.
R3
R2
O
O
R2
O O
O
O
I
II
III
Cl
SH
S
H
N
N
O
Me
X
O
O
N
IV X = aromatic or heteroaromatic ring
H2N
It should be pointed out that 3-amino-2-arylsulfon-
amidoquinazolin-4(3H)-ones have not been described
previously. However, it was found [20] that the amino-
Figure 1

262
Z. Brzozowski and F. Sꢀczewski
Vol 44
Scheme 1
O
OMe
O
OMe
H
H
N
Cl
S
S
N
Cl
S
S
N
N
S
Me
R
Me
O
O
O
O
R
4
Compd
R
H
Me
2
3
c
a, b
O
OMe
H
N
Cl
S
Cl
S
S
SMe
d, e
S
N
N
Me
S
Me
R
O
O
O
O
1
R
H
Compd
5
6
f, g
t-butyl
h
O
O
OEt
R1
OEt
H
H
Cl
S
S
N
Cl
S
S
N
N
S
N
N
NH
Me
Me
R2
O
O
O
O
9
Compd
R1 R2
7
8
Me
Me Me
H
Synthesis of alkyl o-(6-chloro-7-methyl-1,1-dioxo-1,4,2-benzodithiazin-3-ylamino)arylcarboxylates 2-9. Reagents and yields: (a) methyl 2-
aminobenzoate (1 molar equiv), pyridine (1.33 molar equiv), toluene, reflux, 60%; (b) methyl 2-amino-4,5-dimethoxybenzoate (1 molar equiv),
pyridine (1.33 molar equiv), toluene, reflux, 55%; (c) methyl 4-aminothiophene-3-carboxylate (1 molar equiv), pyridine (1.33 molar equiv),
toluene, reflux, 91%; (d) 3-aminothiophene-2-carboxylate (1 molar equiv), pyridine (1.33 molar equiv), toluene, reflux, 79%; (e) 3-amino-5-(tert-
butyl)thiophene-2-carboxylate (1 molar equiv), toluene, reflux, 61%; (f) ethyl 2-amino-4-methylthiophene-3-carboxylate (1 molar equiv), pyridine
(1.33 molar equiv), toluene, reflux, 74%; (g) ethyl 2-amino-4,5-dimethylthiophene-3-carboxylate (1 molar equiv), pyridine (1.33 molar equiv),
toluene, reflux, 76%; (h) ethyl 3-aminopyrazole-4-carboxylate (1 molar equiv), pyridine (1.33 molar equiv), toluene, reflux, 89%.
guanidine compounds of type A generated by the
treatment of 2-phenyliminomethyleneamino-benzoic acid
esters with hydrazine underwent a facile cycloconden-
sation at room temperature giving rise to the formation of
corresponding 3-amino-2-phenylamino-3H-quinoxalin-4-
ones.
suspended in complete medium to yield the desired
multiplicity of infection (ꢁ 0.1) and added to the microtiter
wells, resulting in a 1:200 final dilution of the compound.
Uninfected cells with the compound serve as a toxicity
control, and infected and uninfected cells without the
compound serve as basic controls. Cultures are incubated at
37°C in a 5% CO2 atmosphere for 6 days. The tetrazolium
salt, XTT [2,3-bis(2-methoxy-4-nitro-5-sulfenyl)-2H-tetra-
zolium-5-carboxamide] was added to all wells, and cultures
are incubated to allow formazan colour development by
viable cells. Individual wells were analyzed spectrophoto-
metrically to quantitate formazan production and in addition
are viewed microscopically for detection of viable cells and
confirmation of protective activity.
Biology. The final compounds 10-17 were tested for anti-
HIV-1 activities at the National Cancer Institute (Bethesda,
USA). The anti-HIV drug testing performed at NCI is based
on a protocol described by Wieslow et al [21]. In brief, all
compounds were dissolved in DMSO and diluted in 1:100 in
cell culture medium. Exponentially growing T4 lymphocytes
(CEM cell line) were added at 5000 cells per well. Frozen
virus stock solution were thawed immediately before use,

Jan-Feb 2007
Synthesis and Anti-HIV Activity of N-(3-Amino-3,4-dihydro-4-oxopyrimidin-
2-yl)-4-chloro-2-mercapto-5-methylbenzenesulfonamide Derivatives
263
Scheme 2
X
Cl
SH
Cl
SH
S
Cl
S
S
N
H
Method A
Method B
H
H
N
N
N
N
Me
S
Me
Y
Me
X
O
O
O O
O
O
NH
H2N
2-9
10-17
X
Y
Compd
2, 10
Method
A
N
O
N
N
H2N
H2N
OMe
O
N
OMe
OMe
OMe
OMe
A
3, 11
4, 12
O
OMe
O
N
S
S
A
A
A
O
N
N
N
H2N
H2N
H2N
OMe
O
N
O
5, 13
6, 14
S
S
OMe
O
N
O
S
S
S
OMe
O
N
OEt
O
Me
Me
B
N
N
N
7, 15
8, 16
9, 17
H2N
H2N
Me
S
O
N
OEt
O
S
Me
B
B
Me
Me
S
O
N
N
N
NH
NH
O
H2N
OEt
O
Synthesis of 2-mercaptobenzenesulfonamides 10-17. Reagents, conditions, and yields: (Method A) hydrazine hydrate
(3.4 molar equiv), methanol, room temperature 60-64 h, 90-96%; (Method B) hydrazine hydrate (2.2 molar equiv),
toluene, room temperature 12 h, reflux 8 h, 41-81%.
The compound 15 proved to be inactive in the anti-HIV
tests. However, other compounds exhibited good (14),
moderate (11, 12 and 16) or weak (10, 13 and 17) activity
(Table 1). It is noteworthy that the anti-HIV activity
showed the compounds with substuituents varying in size
and electronic properties such as quinazoline (10-11)
thieno[3,4-e]pyrimidine (12), thieno[2,3-e]pyrimidine
(13,14), thieno[3,2-e]pyrimidine (16) and pyrazolo[4,3-
e]pyrimidine (17). The most potent compound 14
inhibited the replication of HIV-1 at EC50 of 15.0 μM,
which is 7-fold below the cytotoxicity threshold.
The geometry of the most active compound 14
was optimized (Figure 2) by quantum-chemical
calculations at ab initio level using HF/6.31**
method [22]. Although the mechanism of anti-HIV
action of this compound has not been investigated,
it seems possible that it acts as a non-nucleoside
reverse transcriptase inhibitor due to the butterfly-
like conformation, similar to those found for Cl-ꢀ-
APA and other flexible reverse transcriptase
inhibitors [23].

264
Z. Brzozowski and F. Sꢀczewski
Vol 44
Table 1
General Procedure for the Preparation of Alkyl o-(6-chloro-
7-methyl-1,1-dioxo-1,4,2-benzodithiazin-3-ylamino)aryl-
carboxylates 2-9.
In vitro anti-HIV-1 drug screening results for N-(3-amino-3,4-
dihydro-4-oxopyri-midin-2-yl)-6-chloro-2-mercapto-5-
methylbenzenesulfonamide derivatives 10-17.a
To
a
solution of 6-chloro-7-methyl-3-methylthio-1,4,2-
benzodithiazine 1,1-dioxide 1 (4.4 g, 0.015 mol) and the
appropriate alkyl o-aminoarylcarboxylate (0.015 mol) in dry
toluene (15 ml) was added anhydrous pyridine (1.6 g, 0.02 mol).
The reaction mixture was refluxed with stirring until the evolution
of MeSH had ceased (42-65 h) (CAUTION: due to a high toxicity,
MeSH should be trapped into aqueous NaOH salution). After
cooling to room temperature the suspension was left overnight.
The precipitate was collected by filtration, washed with toluene (4
x 2.5 ml) and methanol (4 x 2.5 ml), dried and recrystallized from
DMF (12-25 ml). In this manner, the following products were
obtained:
d
Compound
EC50 (μM)b
41.1
29.8
29.7
41.1
15.0
>200.0
29.6
97.6
IC50c (μM)
87.7
>200.0
129.0
>200.0
106.0
113.0
TI50
2.13
>6.90
4.36
> 4.87
7.06
-
Commentse
10
11
12
13
14
15
16
17
M
A
A
M
A
I
135.0
>200.0
4.56
>2.05
A
M
a
b
Data obtained from the NCI’s in vitro anti-HIV primary screen;
Effective concentration 50% (protection of HIV-1 infected CEM cells); c
Cytotoxic concentration 50% (toxicity to uninfected CEM cells);
Therapeutic index = IC50/EC50; e NCI designated activity: A (confirmed
active); M (confirmed moderate); I (confirmed inactive).
Methyl 2-(6-chloro-7-methyl-1,1-dioxo-1,4,2-benzodithiazin-
3-ylamino)benzoate (2).
Starting from methyl 2-aminobenzoate (2.27 g), the title
compound 2 was obtained (3.6 g, 60%): mp 225-226°; ir (KBr)
d
Figure 2. Shape of compound 14.
3215 (NH), 1685 (C=O), 1325, 1160 (SO2) cm-1; 1H nmr (CDCl3)
ꢀ 2.27 (s, 3H, CH3), 3.37 (s, 3H, CH3O), 6.96-7.04 (m, 1H, arom.),
7.06 (s, 1H, H-5, benzodithiazine), 7.39-7.48 (m, 1H, arom.), 7.84
(s, 1H, H-8, benzodithiazine), 7.89 (d, J = 1.6 Hz, 1H, arom.), 8.62
(d, J = 8.4 Hz, 1H, arom.), 11.72 ppm (s, 1H, NH); 13C nmr
(CDCl3) ꢀ 19.97, 52.86, 115.80, 121.68, 124.48, 127.20, 127.61,
130.06, 130.96, 135.03,138.20, 138.60, 139.95, 147.20, 160.02,
168.92 ppm. Anal. Calcd. for C16H13ClN2O4S2 (396.85): C, 48.42,
H, 3.30, N, 7.06. Found: C, 48.48, H, 3.34, N, 7.11.
CONCLUSION
We have demonstrated that the anti-HIV activity is
characteristic for a variety of N-(3-amino-3,4-dihydro-
4-oxopyrimidin-2-yl)-4-chloro-2-mercapto-5-methyl-
benzenesulfonamide derivatives containing the
pyrimidine moiety fused with an aromatic or hetero-
aromatic ring. Further structural modifications aimed at
optimization of their potency are in progress.
Methyl 2-(6-chloro-7-methyl-1,1-dioxo-1,4,2-benzodithia-
zin-3-ylamino)-4,5-dimethoxy-benzoate (3). Starting from
methyl 2-amino-4,5-dimethoxybenzoate (3.17 g), the title
compound 3 was obtained (3.8 g, 55%): mp 223-225°; ir (KBr)
3200, 3115 (NH), 1685 (C=O), 1615 (C=N), 1360, 1165 (SO2)
cm-1; 1H nmr (CDCl3) ꢀ 2.48 (s, 3H, CH3), 3.88 (s, 3H, 5-
CH3OPh), 3.91 (s, 3H, 4-CH3OPh), 4.03 (s, 3H, CH3O-CO),
7.47 (s, 1H, H-3, Ph), 7.48 (s, 1H, H-6, Ph), 8.04 (s, 1H, H-5,
benzodithiazine), 8.51 (s, 1H, H-8, benzodithiazine), 12.04 ppm
(s, 1H, NH); 13C nmr (CDCl3) ꢀ 20.28, 52.91, 56.41, 56.70,
105.00, 107.96, 112.15, 127.64, 127.89, 127.96, 130.60, 136.24,
138.47, 138.90, 145.51, 154.25, 159.94, 168.98 ppm. Anal.
Calcd. For C18H17ClN2O6S2 (456.91); C, 47.31, H, 3.75, N, 6.13.
Found: C, 47.30; H, 3.79; N, 6.18.
EXPERIMENTAL
The following instruments and parameters were used:
(melting points) Büchi 535 apparatus; (IR Spectra) KBr pellets,
400-4000 cm-1 Perkin-Elmer 1600 FTIR spectrometer; (1H- and
13C NMR spectra) Varian Gemini 200 spectrometer at 200 and
50 MHz, respectively (chemical shifts are expressed as ꢀ values
relative to Me4Si as standard). The starting 6-chloro-7-methyl-3-
methylthio-1,4,2-benzodithiazine-1,1-dioxide (1) was prepared
according to a know method [24].

Jan-Feb 2007
Synthesis and Anti-HIV Activity of N-(3-Amino-3,4-dihydro-4-oxopyrimidin-
2-yl)-4-chloro-2-mercapto-5-methylbenzenesulfonamide Derivatives
265
Methyl 4-(6-chloro-7-methyl-1,1-dioxo-1,4,2-benzodithia-
zin-3-ylamino)thiophene-3-carboxylate (4). Starting from
methyl 4-aminothiophene-3-carboxylate (2.36 g), the title
compound 4 was obtained (5.5 g, 91%): mp 261-262°; ir (KBr)
3180 (NH), 1680 (C=O), 1570 (C=N), 1340, 1315, 1160 (SO2)
C17H17ClN2O4S3 (444.97): C, 45.88; H, 3.85; N, 6.29. Found: C,
45.85; H, 3.92; N, 6.39.
Ethyl 3-(6-chloro-7-methyl-1,1-dioxo-1,4,2-benzodithiazin-
3-ylamino)-1H-pyrazole-4-carboxylate (9). Starting from ethyl
3-aminopyrazole-4-carboxylate (2.32 g), the title compound 9
was obtained (5.3 g, 88%): mp. 272-273 °C; ir (KBr) 3240, 3140
(NH), 1690 (C=O), 1580 (C=N), 1325, 1160 (SO2) cm-1; 1H nmr
(DMSO-d6) ꢀ 1.13 (t, J = 7.1 Hz, 3H, CH3 of EtO), 2.47 (s, CH3-
7), 4.14 (q, J = 7.1 Hz, 2H of EtO), 7.93 (s, 1H, H-5,
benzodithiazine), 8.00 (s, 1H, H-8, benzodithiazine), 8.44 (s, 1H,
H-5, pyrazole), 11.46 (s, 1H, H-1, pyrazole), 13.60 ppm (s, 1H,
NH). Anal. Calcd. for C14H13ClN4O4S2 (400.84): C, 41.94; H,
3.27; N, 13.97. Found: C, 41.91; H, 3.30; N, 13.95.
1
cm-1; H Nnmr (CDCl3) ꢀ 2.48 (s, 3H, CH3-7), 3.95 (s, 3H,
CH3O), 7.47 (s, 1H, H-5, benzodithiazine), 8.05 (s, 1H, H-8,
benzodithiazine), 8.11 (d, J = 3.5 Hz, 1H, H-5, thiophene), 8.30
(d, J = 3.5 Hz, 1H, H-2, thiophene), 10.73 ppm (s, 1H, NH); 13
C
nmr (CDCl3) ꢀ 19.68, 52.13, 114.24, 120.71, 126.72, 127.35,
129.99, 132.85, 134.49, 137.89, 138.29, 158.47, 164.44 ppm.
Anal. Calcd. For C14H11ClN2O4S3 (402.89): C, 41.73; H, 2.75; N,
6.95. Found: C, 47.80; H, 2.91; N, 6.99.
Procedures for the Preparation of 4-Chloro-2-mercapto-
benzenesulfonamide derivatives 10-17. Method A (for 10-14).
A mixture of the corresponding methyl carboxylate 2-6 (0.0075
mol) and 99-100% hydrazine hydrate (1.3 g, 0.026 mol) in
methanol (30 ml) was stirred at room temperature for 60-64 h.
The precipitate hydrazinium salt of the desired product obtained
was collected by filtration, washed with methanol (3 x 1,5 ml)
and then mixed with 1% hydrochloric acid (100 ml). The
reaction mixture was kept at room temperature for 2 h. The
product that precipitated was again collected by filtration,
washed with plenty of water until neutral pH was achieved, and
dried initially at room temperature and then at 90°C. In this
manner the following 2-mercaptobenzenesulfonamides were
obtained:
Methyl 3-(6-chloro-7-methyl-1,1-dioxo-1,4,2-benzodithia-
zin-3-ylamino)thiophene-2-carboxylate (5). Starting from
methyl 3-aminothiophene-2-carboxylate (2.36 g), the title
compound 5 was obtained (4.8 g, 79%): mp 278-279°; ir (KBr)
3190 (NH), 1675 (C=O), 1575 (C=N), 1340, 1320, 1155 (SO2)
cm-1; 1H nmr (CDCl3) ꢀ 2.49 (s, 3H, CH3-7), 2.95 (s, 3H, CH3O),
7.48 (s, 1H, H-5, benzodithiazine), 7.56 (d, J = 5.5 Hz, 1H, H-4,
thiophene), 8.06 (s, 1H, H-8, benzodithiazine), 8.29 (d, J = 5.5
Hz, 1H, H-5, thiophene), 10.79 ppm (s, 1H, NH); 13C nmr
(CDCl3) ꢀ 20.05, 52.49, 112.71, 123.17, 126.82, 127.68, 127.74,
130.00, 132.03, 138.79, 142.93, 159.31, 164.93 ppm. Anal.
Calcd. for C14H11ClN2O4S3 (402.89): C, 41.73; H, 2.75; N, 6.95.
Found: C, 41.70; H, 2.82; N, 6.92.
Methyl 5-(tert-butyl)-3-(6-chloro-7-methyl-1,1-dioxo-1,4,2-
benzodithiazin-3-ylamino)thiophene-2-carboxylate (6).
Starting from 3-amino-5-(tert-butyl)thiophene-2-carboxylate
(3.2 g), the title compound 6 was obtained (4.2 g, 61%): mp
261-262°; ir (KBr) 3185 (NH), 1680 (C=O), 1585 (C=N), 1350,
N-(3-Amino-3,4-dihydro-4-oxoquinazolin-2-yl)-4-chloro-2-
mercapto-5-methylbenzene-sulfonamide (10). Starting from
methyl 2-(6-chloro-7-methyl-1,1-dioxo-1,4,2-benzodithiazin-3-
ylamino)benzoate 2 (2.98 g), the title compound 10 was
obtained (2.7 g, 91%): mp 284-286° dec., ir (KBr) 3350, 3300,
3265 (NH2 and NH), 2550 (SH), 1670 (C=O), 1345, 1130 (SO2)
1
1325, 1170 (SO2) cm-1; H nmr (CDCl3) ꢀ 1.42 (s, 9H, tert-
butyl), 2.49 (s, 3H, CH3-7), 3.91 (s, 3H, CH3O), 7.48 (s, 1H, H-
4, thiophene), 8.01 (s, 1H, H-5, benzodithiazine), 8.06 (s, 1H, H-
8, benzodithiazine), 10.84 ppm (s, 1H, NH). Anal. Calcd. for
C18H19ClN2O4S3 (458.99): C, 47.09; H, 4.17; N, 6.10. Found: C,
47.15; H, 4.21; N, 6.21.
1
cm-1; H nmr (DMSO-d6) ꢀ 2.34 (s, 3H, CH3), 3.55 (s, 1H, SH),
5.30 (s, 2H, NH2), 7.40 (t, J = 7.3 Hz, 1H, H-8, quinazoline),
7.73 (s, 1H, H-3, Ph SO2), 7.77-7.84 (m, 2H, H-6 and H-7,
quinazoline), 7.89-8.06 (m, 2H, H-6 of PhSO2 and H-3 of
quinazoline), 10.92 ppm (s, 1H, NH). Anal. Calcd. for
C15H13ClN4O3S2 (396.85): C, 45.39; H, 3.30; N, 14.12. Found:
C, 35.31; H, 3.41; N, 14.10.
Ethyl 2-(6-chloro-7-methyl-1,1-dioxo-1,4,2-benzodithiazin-
3-ylamino)-4-methylthio-phene-3-carboxylate (7). Starting
from ethyl 2-amino-4-methylthiophene-3-carboxylate (2.8 g),
the title compound 7 was obtained (4,8 g, 74%): mp 244-245°; ir
(KBr) 3120 (NH), 1670 (C=O), 1625 (C=N), 1320, 1160 (SO2)
N-(3-Amino-3,4-dihydro-6,7-dimetoxy-4-oxoquinazolin-2-
yl)-4-chloro-2-mercapto-5-methylbenzenesulfonamide (11).
Starting from methyl 2-(6-chloro-7-methyl-1,1-dioxo-1,4,2-
benzodithiazin-3-ylamino)-4,5-dimethoxybenzoate 3 (3.43 g),
the title compound 11 was obtained (3.2 g, 93%); mp 194-195°
dec.; ir (KBr) 3335, 3325, 3270, (NH2 and NH), 2565 (SH),
1
cm-1; H nmr (CDCl3) ꢀ 1.43 (t, J = 7.1 Hz, 3H., CH3 of EtO),
2.38 (s, 3H, CH3-4 of thiophene), 2.48 (s, 3H, CH3-7), 4.42 (q, J
= 7.1 Hz, 2H, CH2 of EtO), 6.57 (s, 1H, H-5, thiophene) 7.48 (s,
1H, H-5, benzodithiazine), 8.07 (s, 1H, H-8, benzodithiazine),
12,17 ppm (s, 1H, NH).; 13C nmr (CDCl3) ꢀ 16.19, 19.87, 22.05,
63.45, 116.16, 117.39, 128.70, 129.72, 129.79, 132.32, 137.31,
140.49, 140.77, 150.92, 159.33, 168.90 ppm. Anal. Calcd. for
C16H15ClN2O4S3 (430.94): C, 44.59; H, 3.50; N, 6.50. Found: C,
44.64; H, 3.51; N, 6.55.
1
1670 (C=O), 1360, 1130 (SO2) cm-1; H nmr (CDCl3) ꢀ 2.37 (s,
3H, CH3), 3.96 (s, 3H, CH3O), 4.01 (s, 3H, CH3O), 4.59 (s, 1H,
SH), 6.71 (s, 2H, NH2), 7.28 (s, 1H, H-7, quinazoline), 7.40 (s,
1H, H-5, quinazoline), 7.49 (s, 1H, H-3, PhSO2), 7.97 (s, 1H,
H-6, Ph SO2), 10.86 ppm (s, 1H, NH). Anal. Calcd. for
C17H17ClN4O5S2 (456.91): C, 44.68; H, 3.75; N, 12.26. Found:
C, 44,70; H, 3.83; N, 12.30.
N-(3-Amino-3,4-dichydro-4-oxothieno[3,4-e]pyrimidin-2-yl)-
4-chloro-2-mercapto-5-methylbenzenesulfoamide (12). Starting
from methyl 4-(chloro-7-methyl-1,1-dioxo-1,4,2-benzodithiazin-
Ethyl 2-(6-chloro-7-methyl-1,1-dioxo-1,4,2-benzodithiazin-
3-ylamino)-4,5-dimethyl-thiophene-3-carboxylate (8). Starting
from ethyl 2-amino-4,5,-dimethylthiophene-3-carbo-xylate (3.0
g), the title compound 8 was obtained (5.1 g, 76%): mp 229-
231°; ir (KBr) 3200 (NH), 1675 (C=O), 1550 (C=N), 1330, 1165
3-yloamin)thiophene-3-carboxylate
compound 12 was obtained (2.8 g, 92%): mp 197-198° dec.; ir
4
(3.02 g), the title
1
(SO2) cm-1; H nmr (CDCl3) ꢀ 1.42 (t, J = 7.1 Hz, 3H, CH3 of
EtO), 2.25 (s, 3H, CH3-4 of thiophene), 2.30 (s, 3H, CH3-5 of
thiophene), 2.47 (s, 3H, CH3-7), 4.39 (q, J = 7.1 Hz, 2H, CH2 of
EtO), 7.46 (s, 1H, H-5, benzodithiazine), 8.06 (s, 1H, H-8,
benzodithiazine), 12.16 ppm (s, 1H, NH). Anal. Calcd. for
(KBr) 3345, 3240 (NH2 and NH), 2560 (SH), 1695 (C=O), 1360,
1
1140 (SO2) cm-1; H nmr (DMSO-d6) ꢀ 2.34 (s, 3H, CH3), 3.84
(s, 1H, SH), 5.75 (s, 2H, NH2), 7.60 (d, J = 3.4 Hz, 1H, H-7,
thienopyrimidine), 7.73 (s, 1H, H-3, Ph SO2), 8.06 (s, 1H, H-6,

266
Z. Brzozowski and F. Sꢀczewski
Vol 44
PhSO2), 8.53 (d, J = 3.4 Hz, 1H, H-5, thienopyrimidine), 11.08
ppm (s, 1H, NH); 13C nmr (DMSO-d6) ꢀ 18.89, 108.88, 120.74,
126.75, 130.03, 130.64, 133.00, 133.72, 134.79, 138.00, 138.82,
145.90, 154.18 ppm. Anal. Calcd. for C13H11ClN4O3S3 (402.89):
C, 38.75; H, 2.75; N, 13.90. Found: C, 38.81; H, 2.84; N, 13.91.
N-(3-Amino-3,4-dihydro-4-oxothieno[2,3-e]pyrimidin-2-
yl)-4-chloro-2-mercapto-5-methylbenzenesulfonamide (13).
Starting from methyl 3-(6-chloro-7-methyl-1,1-dioxo-1,4,2-
benzodithiazin-3-ylamino)thiophene-2-carboxylate 5 (3.02 g),
the title compound 13 was obtained (2.9 g, 96%): mp 256-258°
dec.; ir (KBr) 3345, 3260, 3215 (NH2 and NH), 2565 (SH), 1675
(C=O), 1345, 1335, 1165 (SO2) cm-1; 1H nmr (DMSO-d6) ꢀ 2.33
(s, 3H, CH3), 3.68 (s, 1H, SH), 5.20 (s, 2H, NH2), 7.45 (d, J =
5.3 Hz, 1H, H-7, thienopyrimidine), 7.71 (s, 1H, H-3, PhSO2),
7.99 (s, 1H, H-6, PhSO2), 8.15 (d, J = 5.3 Hz, 1H, H-6, thieno-
pyrimidine), 10.94 ppm (s, 1H, NH); 13C nmr (DMSO-d6) ꢀ
18.89, 113.47, 119.98, 130.45, 130.58, 132.08, 132.47, 136.24,
136.81, 137.59, 143.42, 146.02, 153.99 ppm. Anal. Calcd. for
C13H11ClN4O3S3 (402. 89): C, 38.75; H, 2.75; N, 13.90. Found:
C, 38,69; H, 2.88; N, 13.89.
N-(3-Amino-3,4-dihydro-5,6-dimethyl-4-oxothieno[3,2-e]-
pyrimidin-2-yl)-4-chloro-2-mercapto-5-methylbenzene-
sulfonamide (16). Starting from ethyl 2-(6-chloro-7-methyl-1,1-
dioxo-1,4,2-benzodithiazin-3-ylamino)-4,5-dimethylthiophene-
3-carboxylate 8 (2.23 g), the title compound 16 was obtained
(1.7 g, 79%): mp 220-221° dec.; ir (KBr) 3285, 3230, 3190
(NH2 and NH), 2565 (SH), 1660 (C=O), 1350, 1160 (SO2) cm-1;
1H nmr (DMSO-d6) ꢀ 2.21 (s, 3H, CH3), 2.26 (s, 3H, CH3), 2.31
(s, 3H, CH3), 3.65 (s, 1H, SH), 4.30 (s, 2H, NH2), 7.50 (s, 1H,
H-3, PhSO2), 7.93 (s, 1H, H-6, PhSO2), 10.72 ppm (s, 1H, NH).
Anal. Calcd. for C15H15ClN4O3S3 (430.94): C, 41.80; H, 3.51; N,
13.00. Found: C, 41.78; H, 3.62; N, 13.07.
N-(3-Amino-3,4-dihydro-4-oxo-6H-pyrazolo[4,3-e]pyrimidin-
2-yl)-4-chloro-2-mer-capto-5-methylbenzenesulfonamide (17).
Starting from ethyl 2-(6-chloro-7-methyl-1,1-dioxo-1,4,2-
benzodithiazin-3-ylamino-1H-pyrazole-4-carboxylate 9 (2.0
g), the title compound 17 was obtained (0.8 g, 41.%): mp
236-239° dec.; ir (KBr) 3560, 3450, 3315, 3220 (NH2 and
1
NH) 2570 (SH), 1670 (C=O), 1350, 1140 (SO2) cm-1; H nmr
(DMSO-d6) ꢀ 2.40 (s, 3H, CH3), 3.72 (s, 1H, SH), 4.96 (s,
2H, NH2), 7.76 (s, 1H, H-3, PhSO2), 7.81 (s, 1H, H-5,
pyrazolopyrimidine), 8.17 (s, 1H, H-6, PhSO2), 10.80 (s, 1H,
H-6, pyrazolopyrimidine), 11.47 ppm (s, 1H, NH). Anal.
Calcd. for C12H11ClN6O3S2 (386.84): C, 37.25; H, 2.86; N,
21.72. Found: C, 37.22; H, 2.91; 21.70.
N-[3-Amino-3,4-dihydro-6-(tert-butyl)-4-oxothieno[2,3-e]-
pyrimidin-2-yl]-4-chlor-2-mercapto-5-methylbenzenesulfon-
amide (14). Starting from methyl 5-(tert-butyl)-3-(6-chloro-7-
methyl-1,1-dioxo-1,4,2-benzodithiazin-3-ylamino)thiophene-2-
carboxylate 6 (3.44 g), the title compound 14 was obtained (3.0
g, 90%), mp 203-204° dec.; ir (KBr) 3320, 3270, 3225, (NH2
1
and NH), 2560 (SH), 1700 (C=O), 1345, 1130 (SO2) cm-1; H
ACKNOWLEDGEMENT
nmr (CDCl3) ꢀ 1.42 (s, 9H, tert-butyl), 2.37 (s, 3H, CH3), 4.60
This work was supported by the Polish State Committee for
Scientific Research (Grant No. 2 PO5F 035 27). We would like to
thank the Drug Synthesis and Chemistry Branch, Developmental
Therapeutics of the National Cancer Institute for antiviral testing.
(s, 1H, SH) 5.47 (s, 2H, NH2), 6.85 (s, 1H,
H-7, thieno-
pyrimidine), 7.41 (s, 1H, H-3, PhSO2) 7 97 (s, 1H, H-6, PhSO2)
11-20 ppm (s, 1H, NH). Anal. Calcd. for C17H19ClN4O3S3
(459.02): C, 44.48; H, 4.17; N, 12.20. Found: C, 44.53; H, 4.22;
N, 12.28.
Method B (for 15-17). A mixture of the corresponding ethyl
carboxylate 7, 8, or 9 (0.005 mol) and 99-100% hydrazine
hydrate (0.55 g, 0.011 mol) in dry toluene (30 ml) was stirred at
room temperature for 12 h, followed by refluxing for 8 h. After
cooling to room temperature the precipitate hydrazinium salt of
the appropriate product obtained was collected by filtration,
washed with toluene (3 x 1.5 ml) and immediately was acidified
by refluxed in glacial acetic acid (20 ml) for 3 min. After
cooling to room temperature, the precipitate was collected by
filtration, washed successively with acetic acid (2 x 2 ml) and
toluene (4 x 1.5 ml), and dried at temperatures gradually
increasing to 90°C. In this manner the following 2-mercapto-
benzenesulfonamides were obtained:
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1
NH), 2565 (SH), 1665 (C=O), 1350, 1160 (SO2) cm-1; H nmr
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(416.91): C, 40.33; H, 3.14; N, 13.43. Found: C, 40.28; H, 3.19;
N, 13.45.

Jan-Feb 2007
Synthesis and Anti-HIV Activity of N-(3-Amino-3,4-dihydro-4-oxopyrimidin-
2-yl)-4-chloro-2-mercapto-5-methylbenzenesulfonamide Derivatives
267
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