Synthesis, characterization and biological activity of some 1,2,4-triazine derivatives

Article abstract of DOI:10.1002/jhet.5570420528

4-Amino-6-methyl-3-(2H)-thioxo-5-(4H)-oxo-1,2,4-triazine (1) was condensed with 2-methyl (or phenyl)-4H-3,1-benzoxazin-4-one (5a,b) in boiling acetic acid to give compounds 8-11. Reacting 1 with chloroacetyl chloride afforded the corresponding chloroaceta

Full text of DOI:10.1002/jhet.5570420528

Jul-Aug 2005
935
Synthesis, Characterization and Biological Activity
of Some 1,2,4-Triazine Derivatives
A. A. El-Barbary*, M. A. Sakran, A. M. El-Madani
Chemistry Department, Faculty of Science, Tanta University, Tanta, Egypt
Claus Nielsen
Retrovirus Laboratory, Department of Virology, State Serum Institute, DK-2300 Copenhagen, Denmark
Received August 25, 2004
4-Amino-6-methyl-3-(2H)-thioxo-5-(4H)-oxo-1,2,4-triazine (1) was condensed with 2-methyl (or
phenyl)-4H-3,1-benzoxazin-4-one (5a,b) in boiling acetic acid to give compounds 8-11. Reacting 1 with
chloroacetyl chloride afforded the corresponding chloroacetamido and triazinothiadiazine derivatives 12 and
13. Condensing 2 with succinic anhydride and/or phthalic anhydride yielded compounds 14 and 15.
Benzoylation of 4-amino-6-methyl-3-(2H)-thioxo-5-(4H)-oxo-2-(2,3,4,5-tetra-O-acetyl-α-D-glucopyra-
nosyl)-1,2,4-triazine (19) afforded the corresponding 4-N,N-dibenzoyl derivative 20. Deblocking of the N-2
glycoside 21 and the S-glycoside 22 by methanolic ammonia gave compounds 23 and 24. Acetylation of
4-amino glycoside 25a afforded the corresponding 4-mono- and 4-diacetyl derivatives 26 and 27.
Deamination of 25a,b yielded compounds 28a,b. Methylation of compound 28b afforded the corresponding
N4- and S-methyl derivatives 29 and 30.
J. Heterocyclic Chem., 42, 935 (2005).
1,2,4-Triazines are important classes of compounds that
act as antimicrobial [1], antiviral [2], anti-inflammatory
[3-5] and antimalarial [6] agents. Some of them are used as
antibacterial [7-9] and antidiabetics [10]. 3-Sulfanilamido-
5-dimethylethyl-1,2,4-triazine is manufactured and used as
a sulfa drug [11]. 6-Azacytidine derivatives show antiviral
effects on the adenovirus genome [12], whereas some tri-
azinone derivatives are used as antiulcer agents [13].
Fluorene containing substituted-3-thioxo-1,2,4-triazine-5-
ones exhibit antihuman immune virus activity [14].
Moreover, some substituted 1,2,4-triazino[5,6-b]indole
derivatives act as antiviral and anticancer agents [15]. This
prompted us to make further investigation in this area.
Some of 1,2,4-triazine derivatives 1-4 were prepared
according to the reported methods [16].
afforded 6-methyl-4-(2-phenyl-4-(3H)-oxo-N3-quina-
zolinyl)-3-(2H)-thioxo-5-(4H)-oxo-1,2,4-triazine (10) and
6-methyl-4-acetylamino-3-(2H)-thioxo-5-(4H)-oxo-1,2,4-
triazine (11) (Figure 1).
1
2
R
R
1
2
3
4
Me
4-MeOC H -CH=CH-
NH
NH
NH
2
2
2
6
4
4-ClC H -CH=CH-
6
4
Me
N=CHPh
4-Amino-6-methyl-3-(2H)-thioxo-5-(4H)-oxo-1,2,4-tri-
azine (1) was condensed with 2-methyl-4H-3,1-benzox-
azin-4-ones (5a,b) in boiling acetic acid to give 6-methyl-
4-(2-methyl-4-(3H)-oxo-N3-quinazolinyl)-3-(2H)-thioxo-
5-(4H)-oxo-1,2,4-triazine (8) and 6-methyl-4-(2-diacety-
laminobenzoyl)amino-3-(2H)-thioxo-5-(4H)-oxo-1,2,4-
triazine (9). Condensing 1 with 2-phenyl-4H-3,1-benzox-
azin-4-one (5b) in the same above reaction conditions
Figure 1
The formation of compound 8 was explained according
to the following postulated mechanism: the reaction pro-

936
A. A. El-Barbary, M. A. Sakran, A. M. El-Madani
Vol. 42
ceeds by nucleophilic attack of 4-aminotriazine 1 on C-4
of compound 5a leading to the intermediate 6 which
rearranged to the open ring structure 7 which then,
cyclized with elimination of water to give compound 8.
Compound 7 undergoes acetylation by acetic acid to afford
compound 9. Compound 11 was formed due to acetylation
of 1 by acetic acid (Figure 2).
Figure 4
Some glycosides of 1,2,4-triazine have been reported to
have biological and medicinal activities [17-20].
Mansour et al [21-23] have reported that stirring 4,6-
diaryl-3-thioxo-5-oxo-2,3,4,5-tertrahydro-1,2,4-triazines
(16) at room temperature with 2,3,4,6-tetra-O-acetyl-α-D-
glucopyranosyl bromide (17) in aqueous acetone contain-
ing one equivalent of KOH afforded only the correspond-
ing N-2 glucosyl derivative (18) (Figure 5).
Figure 2
Treatment of 1 with chloroacetylchloride in dioxane
in the presence of triethylamine at 10 °C gave 6-methyl-
4-(N-chloroacetamido)-3-thioxo-5-oxo-2,3,4,5-tetrahy-
dro-1,2,4-triazine (11) and 3-methyl-4,7-dioxo-4,6,7,8-
tetrahydro-1,2,4-triazino[3,4-b][1,3,4]thiadiazine (12)
(Figure 3).
Figure 5
We've reported recently [24] that when 1 was treated
with 17 under the same reaction condition it afforded the
corresponding N-2 glucosyl derivative 19 which on ben-
zoylation yielded the corresponding 4-N,N-dibenzoy-
lamino derivative 20 (Figure 6).
Coupling 4-benzylideneamino-6-methyl-3-(2H)-
thioxo-5-(4H)-oxo-1,2,4-triazine (4) with 17 under the
same reaction conditions described above afforded 4-ben-
zylideneamino-6-methyl-3-(2H)-thioxo-5-(4H)-oxo-2-
(2,3,4,5-tetra-O-acetyl-α-D-glucopyranosyl)-1,2,4-tri-
azine (21) and 4-benzylideneamino-6-methyl-5-(4H)-
Figure 3
Fusion of 4-amino-6-(4-methoxystyryl)-3-(2H)-thioxo-
5-(4H)-oxo-1,2,4-triazine (2) with succinic anhydride at
155 ° afforded 6-(4-methoxystyryl)-4-(N-succinimido)-3-
(2H)-thioxo-5-(4H)-oxo-1,2,4-triazine (14). Similarly,
with phthalic anhydride it afforded 6-(4-methoxystyryl)-4-
(N-phthalimido)-3-(2H)-thioxo-5-(4H)-oxo-1,2,4-triazine
(15) (Figure 4).

Jul-Aug 2005
Synthesis, Characterization and Biological Activity
937
Figure 6
oxo-3-(2,3,4,5-tetra-O-acetyl-α-D-glucopyranosyl)thio-
1,2,4-triazine (22). Treatment of the N-2 glycoside (21)
with methanolic ammonia at 0° gave the corresponding
4-benzylideneamino-6-methyl-3-(2H)-thioxo-5-(4H)-
oxo-2-(2,3,4,5-tetrahydro-α-D-glucopyranosyl)-1,2,4-tri-
azine (23). While, the S-glycoside 22 in the same reaction
conditions undergoes cleavage and desulfurization to give
3,5-dioxo-1,2,4-triazine derivative 24 (Figure 7).
expected molecular formula.
On the other hand, when 4-amino-6-substituted 3-
thioxo-5-oxo-2,3,4,5-tetrahydro-1,2,4-triazines 2 and 3
were treated with 17 in DMF containing one equivalent
of aqueous K CO they gave the corresponding N-glyco-
2
3
1
sides 25a,b. The H-nmr spectrum of 25a showed a dou-
blet at δ 6.89 ppm assigned to the anomeric proton of the
glucose moiety with J = 9.90 Hz corresponding to a
diaxial orientation of H-1' and H-2' protons, which indi-
The mass spectrum of compound 23 showed the molec-
13
+
cates the β-configuration of the glycoside. Its C-nmr
ular ion peak M at 230.00, which corresponds to the
Figure 7
Figure 8

938
A. A. El-Barbary, M. A. Sakran, A. M. El-Madani
Vol. 42
(growth medium). Culture supernatant was filtered (0.45
spectrum showed a signal at δ 86.78 ppm corresponding
to the C-1' atom of the β-configuration. Similarly, com-
pound 25b was established to have the N-glycosidic
linkage with β-configuration. Compounds 25a,b were
readily deaminated by nitrous acid in acetic acid to give
compounds 26a,b (Figure 8).
nm), aliquotted and stored at
−80 °C until use. Both HIV-
1 strains were obtained from NIH AIDS.
EXPERIMENTAL
Acetylation of compound 25a by acetic anhydride in
pyridine at r.t. afforded the corresponding mono- and di-
acetyl derivatives 27 and 28 (Figure 9).
All melting points are uncorrected and performed by the open
capillary melting point apparatus Microanalyses were performed
by Microanalysis Unit, Faculty of Science, Cairo University,
Figure 9
Stirring compound 26b with MeI in a mixture of DMF
and K CO gave the corresponding N-4 and S-methyl
derivatives 29 and 30 (Figure 10).
Egypt. IR spectra were recorded with a Perkin-Elmer spectro-
meter. The nmr spectra were recorded on a Bruker AC 250 FT
nmr spectrometer using TMS as an internal standard DMSO as a
2
3
Figure 10
The test for activity against HIV-1 was performed in
MT4 cell cultures infected with either wild type HIV-1
(strain IIIB) or non nucleoside reverse transcriptase
inhibitors (NNRTIs) resistant HIV-1 (strain N119) that
harbored a substitution of cysteine for the tyrosine at
position 181 in the reverse transcriptase enzyme
(Cys181Tyr mutant strain). Compounds 8, 11, 12, 19, 22,
25a, 25b, 26b and 28 have been tested against HIV-1.
None of them have showed any activity against HIV-1 at
100 µM. The HIV-1 strains HTLV-IIIB [25] and the
NNRTI resistant strain N119 [26] were propagated in H9
solvent. Mass spectra (MS) were recorded using electron ioniza-
tion (E.I.) on a Varian Mat 311A spectrometer.
Condensation of 1 with 2-methyl-4H-3,1-benzoxazin-4-one:
Formation of 8 and 9.
A mixture of 1 (1.60 g., 0.01 mole) and 5a (0.01 mole) was
refluxed in glacial acetic acid (30 ml) for 24 hr (tlc). The reaction
mixture was cooled and poured on ice. The solid obtained was
collected by filtration and chromatographed on a column of silica
gel with chloroform:methanol (10:1, v/v) to give 8 and 9.
6-Methyl-4-(2-methyl-4-(3H)-oxo-N3-quinazolinyl)-3-(2H)-
thioxo-5-(4H)-oxo-1,2,4-triazine (8).
cells [27] at 37°, 5% CO using RPMI 1640 with 10%
heat-inactivated fetal calf serum (FCS) and antibiotics
2
This compound was obtained in 40 % yield (1.21 g); mp
1
217-218°; H-nmr (DMSO-d ): δ 2.39 (s, 3H, CH ), 2.5 (s,
6
3

Jul-Aug 2005
Synthesis, Characterization and Biological Activity
939
3H, CH ), 7.60 (t), 7.70 (d), 7.90 (t), 8.10 (d) (m, 4H, H
);
arom
6-Methyl-4-(N-chloroacetamido)-3-(2H)-thioxo-5-(4H)-oxo-
1,2,4-triazine (12).
3
13
C-nmr (DMSO-d ): δ 16.29 (CH ), 19.88 (CH ) 127.82, 128.86,
6
3
3
129.48, 131.97, 133.87, 135.95, 147.9, 150.4, 153.4, 156.2, 172.8
This compound was obtained in 45 % yield (1.05 g); mp 150-
(quinazolinone C's, triazine C's and O=C's); EI MS: m/z 301.00
1
151°; H-nmr (DMSO-d ): δ 2.15 (s, 3H, triazine CH ), 4.30 (d,
6
3
+
-1
(M ); ir (KBr): ν (cm ) 1606 (C=N), 1683 (CO), 3367 (NH).
Anal. Calcd. for C H N O S: C, 51.82; H, 3.68; N, 23.24.
2H, CH ), 13.74 (s, 1H, triazine NH), 11.43 ( s, 1H, NHCO);
C-nmr (DMSO-d ): δ 16.65 (CH ), 40.55 (CH ), 147.67 (C-3),
151.21 (C-6), 164.30 (C-5), 174.74 (NHCO); EI MS: m/z 234.00
(M ); ir (KBr): ν (cm ) 1609 (C=N), 1694 (CO, amide), 1726
(CO, acetyl), 3219 (NH).
2
13 11
5
2
13
6
3
2
Found: C, 51.62; H, 3.45; N, 23.33.
+
-1
6-Methyl-4-(2-diacetylaminobenzoyl)amino-3-(2H)-thioxo-5-
(4H)-oxo-1,2,4-triazine (9).
Anal. Calcd. for C H ClN O S: C, 30.71; H, 3.01; N, 23.88;
Cl, 15.11. Found: C, 30.60; H, 2.97; N, 23.84; Cl, 14.94.
6
7
4 2
This compound was obtained in 25 % yield (0.90 g); mp 207-
1
209°; H-nmr (DMSO-d ): δ 2.01, 2.30, 2.39 (9H, 3CH ) 7.54
6
3
13
(d), 7.70 (t), 7.86 (t), 8.13 (d) (m, 4H, H
); C-nmr (DMSO-
3-Methyl-4,7-dioxo-4,6,7,8-tetrahydro-1,2,4-triazino[3,4-b]-
[1,3,4]thiadiazine (13).
arom
d ): ν 10.16, 14.37 (2CH CO), 16.61 (CH ), 127.82, 128.86,
6
3
3
129.48, 131.97, 133.87, 135.57, 141.53, 147.56 (quinazolinone
C's), 152.69, 157.83 (C-3 and C-6), 161.09, 165.26 (2CO); EI
This compound was obtained in 25 % yield 0.49 g (25%); mp
1
187-189°; H-nmr (DMSO-d ): δ 2.36 (s, 3H, CH ), 3.86 (s, 2H,
+
-1
6
3
MS: m/z 361.30 (M ); ir (KBr): ν (cm ) 1610 (C=N), 1996
13
CH ), 12.50 (broad s, 1H, NH); C-nmr (DMSO-d ): δ 17.31
(CH ), 45.24 (C-8), 147.30 (C-10), 151.19 (C-3), 155.46 (C-7)
and 164.96 (C-4) ; EI MS: m/z 197.90 (M ); ir (KBr): ν (cm )
1528 (C=N), 1675 (CO), 3219 (NH).
2
6
(CO), 3213 (NH).
3
Anal. Calcd. for C H N O S: C, 49.85; H, 4.18; N, 19.38;
15 15
5 4
+
-1
Found: C, 49.92; H, 3.98; N, 19.36.
Condensation of 1 with 2-Phenyl-4H-3,1-benzoxazin-4-one:
Formation of 10 and 11.
Anal. Calcd. for C H N O S: C, 36.36; H, 3.05; N, 28.27.
Found: C, 36.47; H, 2.96; N, 28.17.
6
6 4 2
A mixture of 1 (1.60 g., 0.01 mole) and 5b (2.07 g., 0.015
mole) was refluxed in glacial acetic acid (30 ml) for 24 hr (tlc).
The reaction mixture was cooled and poured on ice. The solid
obtained was collected by filtration and chromatographed on a
column of silica gel with chloroform:methanol (10:1, v/v) to give
10 and 11.
Synthesis of 6-(4-Methoxystyryl)-4-(N-succinimido)-3-(2H)-
thioxo-5-(4H)-oxo-1,2,4-triazine (14).
A mixture of 2 (0.01 mole) and succinic anhydride (0.01 mole)
was fused at 155 °C in an oil bath for 3 hr (tlc). The reaction mix-
ture was cooled and poured on ice-cold water. The solid obtained
was collected by filtration and chromatographed on a column of
silica gel with petroleum ether:ethyl acetate (3:1, v/v) to give 14.
6-Methyl-4-(2-phenyl-4-(3H)-oxo-N3-quinazolinyl)-3-(2H)-
thioxo-5-(4H)-oxo-1,2,4-triazine (10).
1
Yield 1.43 g (40%); mp 236-238°; H-nmr (DMSO-d ): δ 2.90
6
(m, 4H, 2CH ), 3.60 (s, 3H, MeO), 6.71-7.70 (m, 6H, H
13.90 (s, broad, 1H, NH); %); ir (KBr): ν (cm ) 1599 (C=N),
),
This compound was obtained in 50% yield (1.82 g); mp 172-
2
arom
-1
1
174°; H-nmr (DMSO-d ): δ 3.44 (s, 1H, CH ), 7.24-8.29 (m,
6
3
13
1738 (CO), 3298 (NH).
9H, H
); C-nmr (DMSO-d ): δ 16.00 (CH ), 117.60, 119.76,
arom
6 3
Anal. Calcd. for C H N O S: C, 53.62; H, 3.94; N, 15.63.
122.85, 127.21, 129.63, 131.44, 132.15, 133.92, 134.75 (C
141.26, 164.79 (C-3 and C-6), 170.51 (2C=O); ir (KBr): ν (cm )
1638 (C=N), 1679 (CO), 3040 (NH).
),
16 14
4 4
arom
-1
Found: C, 53.60; H, 3.86; N, 15.49.
Synthesis of 6-(4-Methoxystyryl)-4-(N-phthalimido)-3-(2H)-
thioxo-5-(4H)-oxo-1,2,4-triazine (15).
Anal. Calcd. for C H N O S: C, 59.49; H, 3.61; N, 19.27.
18 13
5 2
Found: C, 59.54; H, 3.57; N, 19.23.
A mixture of 2 (0.01 mole) and phthalic anhydride (0.01 mole)
was fused at 198 °C in an oil bath for 3 hr (tlc). The reaction mix-
ture was cooled to r.t. and treated with cold water. The solid
obtained was collected by filtration and chromatographed on a
column of silica gel with petroleum ether:ethyl acetate (3:1, v/v)
6-Methyl-4-acetylamino-3-(2H)-thioxo-5-(4H)-oxo-1,2,4-tri-
azine (11).
This compound was obtained in 30 % yield (0.6 g); mp 222-
1
224°; H-nmr (DMSO-d ): δ 1.90 (s, 3H,CH CO), 2.10 (s, 3H, tri-
6
3
1
13
to give (15). Yield 3.08 g (48 %); mp 292-293°; H-nmr (DMSO-
azine CH ), 10.90 (s, 1H, NHCO), 13.70 (s, 1H, triazine NH); C-
3
d ): δ 3.80 (s, 3H, OCH ), 6.80-8.10 (m, 10H, H
and
nmr (DMSO-d ): δ 16.60 (CH ), 20.20 (CH CO), 147.60, 151.50,
6
3
arom
-1
6
3
3
CH=CH), 14.40 (broad s, 1H, NH); %); ir (KBr): ν (cm ) 1599
(C=N), 1750 (CO), 3288 (NH).
167.40, (C-3, C-6, C-5), 175.20 (COCH ); EI MS: m/z 200.00
3
+
-1
(M ); ir (KBr): ν (cm ) 1609 (C=N), 1680 (CO), 3228 (NH).
Anal. Calcd. for C H N O S: C, 35.99; H, 4.03; N, 27.98.
Anal. Calcd. for C H N O S: C, 59.11; H, 3.47; N, 13.79.
20 14
4 4
6
8 4 2
Found: C, 59.18; H, 3.37; N, 13.71.
Found: C, 35.46; H, 4.00; N, 27.79.
Action of Methanolic Ammonia on Compounds 21 and 22:
Reaction of 1 with Chloroacetylchloride: Formation of 12 and 13.
Formation of 23 and 24.
Compound 1 (0.01 mole) was dissolved in dioxane (15 ml),
then chloroacetyl chloride (1.20 g, 0.01 mole) was added with
cooling to 10 °C. Triethylamine (1.0 g., 0.01 mole) dissolved in
dioxane (5 ml) was added dropwise with stirring at 10 °C. The
mixture was stirred for 6 hr at r.t. (tlc). The solvent was evapo-
rated till dryness under reduced pressure and the residual solid
was chromatographed on a column of silica gel with petroleum
ether:ethyl acetate ( 5:1, v/v) to give 12 and 13.
To a suspension of each of compounds 21 and/or 22 (0.005
mole) in anhydrous methanol (15 ml), a saturated solution of
ammonia in anhydrous methanol (20 ml) was added. The reaction
mixture was stirred at r.t. for 1 hr and left overnight in the refrig-
erator. The solvent was evaporated under reduced pressure and
the residue was purified over a column of silica gel with chloro-
form:methanol (5:1, v/v) to afford 23 and 24, respectively.

940
A. A. El-Barbary, M. A. Sakran, A. M. El-Madani
Vol. 42
4-Benzylideneamino-6-methyl-3-(2H)-thioxo-5-(4H)-oxo-2-
(2,3,4,5-tetrahydro-α-D-glucopyranosyl)-1,2,4-triazine (23).
This compound was obtained ain 60 % yield (3.54 g); mp 241-
1
242°; H-nmr (DMSO-d ): δ 1.90-2.03 (4s, 12H, 4CH CO), 3.81
6
3
(s, 3H, CH O), 4.02 (d, 1H, H-6'), 4.22 (m, 1H, H-5'), 5.02 (t, 1H,
3
This compound was obtained ain 67 % yield (1.36 g); mp 168-
H-4'), 5.54 (t, 1H, H-3'), 5.63 (t, 1H, H-2'), 6.88-7.79 (m, H-1',
1
169 °C; H-nmr (DMSO-d ): δ 2.10 (s, 3H, CH ), 3.20-3.70 (m,
6
3
13
CH=CH, H
); C-nmr (DMSO-d ): δ 20.30 (4CH CO),
arom
6
3
2H, H-6', H-5'), 3.44 (m, 1H, H-4'), 3.66 (m, 2H, H-3', H-2'), 4.51
(s,1H, HO-6') 4.97 (s, 1H, HO-4'), 5.16 (s, 1H, HO-3'),5.27 (d,
55.45 (CH O), 85.90, 73.63, 72.72 69.09, 68.18, 61.81 (C-1', C-
3
2', C-3', C-4', C-5', C-6'), 114.55, 128.64, 129.55, 141.37 (C
arom
1H, H-1'), 5.34 (s, 1H, HO-2'), 7.44-7.65 (m, 5H, H
), 8.34 (s,
arom
and CH=CH), 147.73, 160.91, 169.55 (C-3, C-6, C-5), 170.16,
13
1H, CH=N); C-nmr (DMSO-d ): δ 11.28 (CH ), 82.81, 81.64,
6
3
-1
170.46, 170.91 (4COCH ); g. 42); ir (KBr): ν (cm ) 1603
3
78.80, 71.76, 69.70, 60.58 (C-1', C-2', C-3', C-4', C-5'and C-6'),
+
(C=N), 1747 (CO), 3427 (NH); EI Hrms m/z 591.2200 (M ,
126.68, 129.01, 130.00, 134.34 (C
), 142.96 151.53, 160.74,
arom
C H N O S) requires 591.1590.
+
26 29
3 11
167.11 (C-3, C-6, CH=N, C-5); EI MS: m/z 408.00 (M ); ir
-1
(KBr): ν (cm ) 1611 (C=N), 1673 (CO), 3409 (OH).
6-(4-Chlorostyryl)-3-(2H)-thioxo-5-(4H)-oxo-2-(2,3,4,5-tetrahy-
dro-O-acetyl-α-D-glucpyranosyl)-1,2,4-triazine (26b).
Anal. Calcd. for C H N O S: C, 49.99; H, 4.94; N, 13.72; S,
17 20
4 6
7.84. Found: C, 49.83; H, 4.98; N, 13.68; S, 7.81.
This compound was obtaineda in 70 % yield (4.16 g); mp 260-
1
261°; H-nmr (DMSO-d ): δ 1.86, 1.89, 1.93, 1.95 (4s,
4-Benzylideneamino-6-methyl-3,5-(2H,4H)-dioxo-1,2,4-triazine
(24).
6
4CH CO), 4.01 (d, 2H, H-6'), 4.16-4.30 (m, 1H, H-5'), 5.01 (t,
3
1H, H-4'), 5.52 (t, 1H, H-3'), 5.61 (t, 1H, H-2'), 6.86 (d, 1H, H-1'),
This compound was obtained in 58 % yield (0.66 g); mp 198-
13
7.06-7.77 (m, 6H, H
and CH=CH), 13.50 (s, 1H, NH); C-
arom
1
199°; H-nmr (DMSO-d ): δ 2.18 (s, 3H, CH ), 7.58-7.95 (m,
6
3
nmr (DMSO-d ): δ 20.28 (4CH CO), 84.90, 72.91, 72.84, 68.58,
6
3
13
5H, H
), 8.78 (s, 1H, CH=N), 12.52 (bs, 1H, NH); C-nmr
arom
67.61, 61.50 (C-1', C-2', C-3', C-4', C-5'and C-6'), 118.99,
128.12, 129.66, 133.93, 134.59, 135.87 (C and CH=CH),
(DMSO-d ): δ 16.62 (CH ), 129.23, 129.78, 132.10, 133.01
6
3
arom
(C
), 142.69, 147.46, 153.46, 171.65 (C-3, C-6, CH=N, C-5);
arom
144.52, 151.62, 174.67 (C-3, C-6, C-5), 168.94, 169.40, 169.70,
+
EI MS: m/z 231.00 (M , 100 %), 203.70 (C H N O, 1.70 %),
10 11
4
-1
170.35 (4COCH acetyl); ir (KBr): ν (cm ) 1624 (C=N), 1747
3
+
126.90 (C H N O , 23.60 %), 103.90 (C H N , 16.90 %). ir
4
4
3
2
7 6
+
(CO), 3215 (NH); EI Hrms m/z 595.1018 (M
,
-1
(KBr): ν (cm ) 1602 (C=N), 1721 (CO), 2934 (NH).
Anal. Calcd. for C H N O : C, 57.39; H, 4.38; N, 24.34.
C H ClN O S) requires 595.1027.
25 26
3 10
11 10
4 2
Found: C, 57.26; H, 4.39; N, 24.37.
Acetylation of Compound 25a: Formation of compounds 27 and
28.
Synthesis of 4-N,N-Dibenzoylamino-6-methyl-3-(2H)-thioxo-5-
(4H)-oxo-2-(2,3,4,5-tetra-O-acetyl-α-D-glucopyranosyl)-1,2,4-
triazine (20).
To a solution of 25a (0.01 mole) in anhydrous pyridine (25
ml), acetic anhydride (5 ml) was added dropwise with stirring
and cooling to 0 °C. The stirring was then continued at r.t.
overnight (tlc). The reaction mixture was poured onto ice and the
solid obtained was collected by filtration and chromatographed
on a column of silica gel with petroleum ether:ethylacetate (3:1,
v/v) to give 27 and 28, respectively.
To a solution of compound 19 (0.01 mole) in anhydrous pyri-
dine (25 ml), benzoyl chloride (5 ml) was added dropwise with
stirring and cooling to 0°. The stirring was then continued at r.t.
overnight (tlc). The reaction mixture was poured onto ice. The
solid obtained was collected by filtration and chromatographed on
a column of silica gel with petroleum ether:ethyl acetate (3:1, v/v)
4-Acetylamino-6-(4-methoxystyryl)-3-(2H)-thioxo-5-(4H)-oxo-2-
(2,3,4,5-tetra-O-acetyl-α-D-glucopyranosyl)-1,2,4-triazine (27).
1
to give (20). Yield 5.29 (76 %); mp 170-171 ºC; H-nmr (DMSO-
d ): δ 1.89-2.00 (4s, 12H, 4CH CO), 2.28 (s, 1H, CH ), 4.05 (d,
6
3
3
This compound was obtaineda in 40 % yield (2.59 g); mp 198-
1H, H-6'), 4.19-4.39 (m, 1H, H-5'), 5.00 (t, 1H, H-4'), 5.43 (t, 1H,
1
199 °C; H-nmr (DMSO-d ): δ 1.88-2.10 (m, 15H, 5CH CO), 3.80
6
3
H-3'), 5.65 (t, 1H, H-2'), 6.94 (d, 1H, H-1'), 7.34-7.73 (m, 5H,
(s, 1H, CH O), 4.00-4.32 (m, 2H, H-6' and H-5'), 5.04 (t, 1H, H-4'),
3
13
H
); C-nmr (DMSO-d ): δ 16.69 (CH ), 20.06, 20.19, 20.32,
arom
6
3
5.62 (tt, 2H, H-3'and H-2'), 6.94 (d, 1H, H-1'), 6.98-7.82 (4H,
20.48 (4CH CO), 86.75, 73.06, 72.13, 69.06, 67.50, 61.38 (C-1',
3
13
H
and CH=CH), 11.10 (d, 1H, NH); C-nmr (DMSO-d ): δ
arom
6
C-2', C-3', C-4', C-5', C-6'), 128.71, 129.07, 132.93, 133.36
20.02, 20.14, 20.18, 20.23, 20.37 (5CH CO), 55.19 (CH O),
3
3
(C
), 147.21, 149.86, 168.25 (C-3, C-6, C-5), 168.88, 169.50,
arom
87.04, 73.15, 72.78, 69.07, 67.59, 61.48 (C-1', C-2', C-3', C-4', C-
5', C-6'), 114.58, 115.35, 128.27, 129.52, 138.00 (C and
-1
169.68, 170.17 (4COCH ), 175.15 (2COPh); ir (KBr): ν (cm )
3
arom
1743 (CO, acetyl), 1696 (CO, amide), 1631 (C=N); EI Hrms m/z
CH=CH), 149.52, 160.77, 167.15 (C-3, C-6, C-5), 168.96, 169.35,
+
696.4450 (M , C H N O S) requires 696.1729.
32 32
4 12
+
169.54, 169.92, 175.44 (5COCH ); EI MS: m/z 648.00 (M ); ir
(KBr): ν (cm ) 1602 (CO, amide), 1746 (CO, acetyl).
3
-1
Deamination of Compounds 25a,b: Formation of 26a,b.
Anal. Calcd. for C H N O S: C, 51.85; H, 4.97; N, 8.64.
28 32
4 12
To a solution of each of compounds 25a,b (0.01 mole) in
acetic acid (15 ml) was added dropwise a solution of sodium
nitrite (1.4 g, 0.02 mole in 1 ml water) with stirring and cooling
to 5 °C. The reaction mixture was then stirred at r.t. overnight
(tlc). After dilution with cold water, the solid obtained was col-
lected by filtration and chromatographed on a column of silica
gel with petroleum ether:ethyl acetate (3:1, v/v) to give 26a,b,
respectively.
Found: C, 51.88; H, 5.11; N, 8.55.
4-N,N-Diacetylamino-6-(4-methoxystyryl)-3-(2H)-thioxo-5-
(4H)-oxo-2-(2,3,4,5-tetra-O-acetyl-α-D-galucpyranosyl)-1,2,4-
triazine (28).
This compound was obtained in 30 % yield (2.07 g); mp 184-
1
186°; H-nmr (DMSO-d ): δ 1.92-2.05 (4s, 12H, 4CH CO),
6
3
2.39, 2.43 (2s, 6H, (CH CO) N), 3.83 (s, 3H, CH O), 4.08 (d,
3
2
3
6-(4-Methoxystyryl)-3-(2H)-thioxo-5-(4H)-oxo-2-(2,3,4,5-tetra-
O-acetyl-α-D-glucpyranosyl)-1,2,4-triazine (26a).
1H, H-6'), 4.14-4.42 (m, 1H, H-5'), 5.11 (t, 1H, H-4'), 5.64 (tt,
13
2H, H-3'and H-2'), 7.04-7.92 (H-1', H
and CH=CH); C-nmr
arom

Jul-Aug 2005
Synthesis, Characterization and Biological Activity
941
[1] A. K. Mansour, S. B. Awad and S. Antown, Z. Naturforsch.,
B29, 792 (1974).
[2] W. M. Davidson and W. D. Boykin, J. Pharm. Sci., 65, 737
(1978).
[3] P. W. Hielman, R. D. Gielman, A. J. Scozzie, R. J. Wayner, M.
J. Gollo and S. Z. Ariyan, J. Pharm. Sci, 69, 282 (1980).
[4] M. J. Gollo, P. W. Iteillman, R. J. Wayner and E. G. Robert,
German Offen, 2, 84, 381; Chem. Abstr., 90, 121664m (1979).
[5] W. B. Lacefield, French Demande, 2, 243, 479; Chem. Abstr.,
89, 24372m (1979).
[6] L. C. March, G. S. Bajwa, J. Lee, K. Wasti and M. M. Joullie,
J. Med. Chem., 19 (6), 845 (1976).
[7] I. Saikawa, Y. Suzaki and T. Osada, Japanese Patent, 7026,
294; Chem. Abstr., 73, 131036w (1970).
[8] I. Saikawa and T. Osada, Japanese Patent, 7026, 109; Chem.
Abstr., 73, 131037x (1970).
[9] I. Saikawa, S. Kuroda and T. Osada, Japanese Patent, 7026,
108; Chem. Abstr., 73, 131038y (1970).
[10] I. Saikawa and T. Maeda, Japanese Patent, 7026, 106; Chem.
Abstr., 73, 131039z (1970); ibid, 7026, 107; Chem. Abstr., 73, 131040t
(1970); ibid, 7026, 903; Chem. Abstr., 73, 131041z (1970).
[11] S. Kono, S. Zoga and T. Komaki, Japanese Patent, 6720, 313;
Chem. Abstr., 69, 36183a (1968).
[12] L. N. Nosach, I. S. Dyachenko, S. I. Butenko, V. L.
Zhovnovataya, M. Ya. Timofeeva, L. A. Tarasishin, I. V. Alekseeva and
V. P. Chernetskii, Nov. Podkhody Khimioter Virusn. Infekts., 87, 389
(1991); Chem. Abstr., 116, 227707y (1992).
(DMSO-d ): δ 20.11, 20.17, 20.28, 20.39 (4CH CO, sugar),
6
3
23.83, 24.33 (2CH CO amide) , 55.30 (CH O), 87.10, 73.20,
3
3
72.30, 69.20, 67.54, 61.40 (C-1', C-2', C-3', C-4', C-5', C-
6'),114.57, 115.43, 128.06, 129.71, 138.57, 144.00 (C and
arom
CH=CH), 149.71, 160.86, 168.57 (C-3, C-6, C-5), 169.00,
-1
169.57, 169.71, 170.14, 174.57 (6COCH ); ir (KBr): ν (cm )
3
1602 (CO, amide), 1746 (CO, acetyl).EI Hrms m/z 690.4010
+
(M , C H N O S) requires 690.1834.
30 34
4 13
Methylation of Compound 26b: Formation of 29 and 30.
Compound 26b (0.01 mole) was dissolved in a mixture
of DMF (20 ml) and aq. K CO (1.38 g, 0.01mole in 10 ml
2
3
water) and stirred for 10 min. Methyl iodide (1.42 g, 0.01 mole)
was added and the mixture was stirred overnight at r.t. (tlc). The
reaction mixture was poured onto ice and the solid obtained was
collected by filtration and chromatographed on a column of silica
gel with petroleum ether:ethyl acetate (3:1, v/v) to give 29 and
30, respectively.
4-Methyl-6-(4-chlorostyryl)-5-(4H)-oxo-3-(2H)-thioxo-2-
(2,3,4,5-tetra-O-acetyl-α-D-glucopyranosyl)-1,2,4-triazine (29).
This compound was obtained ain 35 % yield (2.13 g); mp 200
1
°C; H-nmr (DMSO-d ): δ 1.97-2.15 (4s, 12H, 4CH CO), 2.66
6
3
(s, 3H, CH -N), 4.13 (d, 1H, H-6'), 4.27-4.51 (m, 1H, H-5'), 5.13
3
(t, 1H, H-4'), 5.81 (tt, 1H, H-3' and H-2'), 6.26 (d, 1H, H-1'), 7.15-
13
7.97 (m, 6H, H
and CH=CH); C-nmr (DMSO-d ): δ 20.11,
[13] K. Hirai, H. Sugimoto and T. Mizushima, Japanese Patent,
61, 134; Chem. Abstr., 106, 67353j (1987).
arom
6
20.23, 20.38 (4CH CO), 30.61 (CH -N), 119.92, 129.17, 129.33,
3
3
[14] R. M. Abdel-Rahman, Farmaco, 46 (2), 379 (1991); Chem.
Abstr., 120, 134427z (1994).
[15] N. H. Eshba, H. M. Salama, I. M. Labouta and A. Mohsen M.
Omar, Pharmazie, 42, 664 (1987).
[16] A. Dornow, H. Menzel and P. Marx, Chem. Ber., 97, 2173
(1964).
134.0, 134.67, 136.5 (C
165.96 (C-3, C-6, C-5), 168.89, 169.45, 169.82, 170.22
and CH=CH), 144.67, 157.96,
arom
-1
(4COCH ); ir (KBr): ν (cm ) 1616 (C=N), 1660 (CO, amide),
3
+
1744 (CO, acetyl); EI Hrms m/
z
609.2820 (M ,
C H ClN O S) requires 609.1176.
26 28
3 10
Methylthio-6-(4-chlorostyryl)-5-(2H)-oxo-2-(2,3,4,5-tetra-O-
acetyl-α-D-glucopyranosyl)-1,2,4-triazine (30).
[17] U. Niedballa and H. Vorbrüggen, Angew. Chem. Internat. Ed.,
9, 461 (1970); Chem. Abstr., 73, 66854v (1970).
[18] H. Vorbrüggen, K.H. Kolbe, U. Nieballa and P. Strehlke, Ger.
Patant 1, 955, 695 (1971); Chem. Abstr., 75, 49513g (1971).
[19] U. Niedballa and H. Vorbrüggen, Ger Patent 1, 943, 428
(1971); Chem. Abstr., 74, 100361g (1971).
[20] U. Niedballa and H. Vorbrüggen, J. Org. Chem., 39, 36654
(1974).
[21] A. K. Mansour, Y. A. Ibrahim and M. M. Eid, Z. Naturforsch.,
316, 505 (1976).
This compound was obtained in 25 % yield (1.52 g); mp 267-
1
269 °C; H-nmr (DMSO-d ): δ 1.91-2.04 (4s, 12H, 4CH CO),
6
3
2.52 (s, 3H, CH -S), 4.05-4.4 (m, 2H, H-6' and H-5'), 5.08 (t, 1H,
3
H-4'), 5.75 (tt, 2H, H-3' and H-2'), 6.22 (d, 1H, H-1'), 7.10-7.91
-1
(m, 6H, H
and CH=CH); ir (KBr): δ (cm ) 1625 (C=N),
arom
1665 (CO, amide), 1747 (CO, acetyl).
Anal. Calcd. for C H ClN O S: C, 51.26; H, 4.63; N, 6.90;
26 28
3 10
[22] A. K. Mansour, Y. A. Ibrahim, M. M.Eid and S. A. L. Abdel-
Hady, J. Carbohydrate Nucleosides-Nucleotides, 8, 81 (1981).
[23] M. M. Eid, S. A. L. Abdel-Hady and H. A. W. Ali, Arch.
Pharmazie, 323, 243 (1990).
[24] M. A. Sakaran, A. A. El-Barbary, and A. M. El-Madani, Delta
J. Sci, 22, 30 (1998).
Found: C, 51.29; H, 4.58; N, 6.80.
Acknowledgment.
The authors are thankful to the Danish International
Development Agency (DANIDA) for their support.
[25] M. Popovic, M. G. Sarngadharan, E. Read and R. C. Gallo,
Science, 224, 497 (1984).
REFERENCES AND NOTES
[26] S. Harada, V. Kovanani and O. N. Vamamoto, Science, 229,
563 (1985).
[*] Author to whom correspondence should be addressed: Fax
+20 40 3350804; e-mail: aaelbarbary@hotmail.com.
[27] T. Mosmann, J. Immunol. Methods, 65, 55 (1983).