Synthesis of heterobicyclic nitrogen systems bearing a 1,2,4-triazine moiety as anticancer drugs: Part IV

Article abstract of DOI:10.1080/10426500390228738

Some new isolated and fused heterobicyclic nitrogen systems such as thiazolidinone, imidazolone, pyrimidinone, quinazolone, as-triazolone, as-triazinones, tetrazino-as-triazines, and the related compounds 3,4-diaminotriazine and sulfa derivatives 2-27 have been synthesized via treatment of 4-amino-6-styryl-3-thioxo-1,2,4-triazin-5(2,4H)ones (1) with cyclic and acyclic oxygen and nitrogen compounds. The structures of the products have been established from their elemental and spectral analyses. Some new compounds exhibited significant anticancer activities, where compounds 11j > 2a > 6 and 11I > 14 > 11k showed a moderate activity toward leukemia, ovarian cancer, and non-small cell lung cancer.

Full text of DOI:10.1080/10426500390228738

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of Heterobicyclic Nitrogen Systems Bearing a
1,2,4-Triazine Moiety as Anticancer Drugs: Part IV
Z. El-Gendy a , J. M. Morsy a , H. A. Allimony a , W. R. Abdel-Monem a & R. M. Abdel-Rahman
a
a Ain Shams University , Roxy, Cairo, Egypt
Published online: 23 Aug 2006.
To cite this article: Z. El-Gendy , J. M. Morsy , H. A. Allimony , W. R. Abdel-Monem & R. M. Abdel-Rahman (2003) Synthesis of
Heterobicyclic Nitrogen Systems Bearing a 1,2,4-Triazine Moiety as Anticancer Drugs: Part IV, Phosphorus, Sulfur, and Silicon
and the Related Elements, 178:9, 2055-2071, DOI: 10.1080/10426500390228738
To link to this article: http://dx.doi.org/10.1080/10426500390228738
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Phosphorus, Sulfur, and Silicon, 178:2055–2071, 2003
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500390228738
SYNTHESIS OF HETEROBICYCLIC NITROGEN
SYSTEMS BEARING A 1,2,4-TRIAZINE MOIETY
AS ANTICANCER DRUGS: PART IV
Z. El-Gendy, J. M. Morsy, H. A. Allimony, W. R. Abdel-Monem,
and R. M. Abdel-Rahman
Ain Shams University, Roxy, Cairo, Egypt
(Received February 18, 2002; accepted February 18, 2003)
Some new isolated and fused heterobicyclic nitrogen systems such as
thiazolidinone, imidazolone, pyrimidinone, quinazolone, as-triazolone,
as-triazinones, tetrazino-as-triazines, and the related compounds 3,4-
diaminotriazine and sulfa derivatives 2–27 have been synthesized via
treatment of 4-amino-6-styryl-3-thioxo-1,2,4-triazin-5(2,4H)ones (1)
with cyclic and acyclic oxygen and nitrogen compounds. The structures
of the products have been established from their elemental and spectral
analyses. Some new compounds exhibited significant anticancer activ-
ities, where compounds 11j > 2a > 6 and 11I > 14 > 11k showed a
moderate activity toward leukemia, ovarian cancer, and non-small cell
lung cancer.
Keywords: 1,2,4-Triazines; biological activity; condensed heterocycles
Among 1,2,4-triazine derivatives; Sencor [4-amino-3-methylthio-6-tert-
butyl-1,2,4-triazin-5(4H)one] is being used as a commercial herbicide
for the control of weeds in potato crops.1 Some heterocyclic systems such
as thiazolidinone, imidazolone, and quinazolinone derivatives exhibited
remarkable pharmacological activity.2,3
Also, some 3-thioxo-1,2,4-triazin-5-one derivatives are used as anti-
cancer and anti-HIV drugs.4–6 During the search for new chemothera-
peutic agents, some new heterobicyclic nitrogen systems derived from 4-
amino-3-thioxo-1,2,4-triazin-5-ones (1) have been synthesized, in view
of potential anticancer activities (Schemes 1–5).
The authors are very grateful to Prof. Dr. Johan P. Bader, Chief Antiviral Evaluations
Branch and Prof. Dr. V. L. Narayanan, Chief Drug Synthesis, Chemistry Branch National
Cancer Institute, Bethesda, Maryland, USA for evalution of the vitro antitumor tests as
development program. Thanks also are due to the members of the NCl staff.
Address correspondence to R. M. Abdel-Rahman, Ain Shams University, Department
of Chemistry, Faculty of Education, Roxy, Cairo, Egypt.
2055

2056
Z. El-Gendy et al.
INVESTIGATIONS AND RESULTS
Chemistry
Condensation of the 4-amino-6-styryl-3-thioxo-1,2,4-triazin-5-ones 1
with aromatic aldehydes7 in the presence of absolute ethanol con-
centrated sulfuric acid produced the hydrazone 2, which upon
cyclo-addition with mercaptoacetic acid in dry dioxan, yielded the
3-thiazolidinyl-1,2,4-triazine derivative 3. Treatment of 2d with
monochloroacetic acid in DMF gave the carboxymethyl derivative 4 by
electrophilic attack on sulfur atom (Scheme 1).
SCHEME 1

1,2,4-Triazines as Anticancer Drugs
2057
SCHEME 2
On the other hand, condensation of compound 1a with heterocyclic
carbonyl compounds such as oxazolinone 5, pyridine-2,3-dicarboxylic
anhydride 7, and 3,1-benzoxazin-4-one 9 in dry pyridine furnished
1,2,4-triazine derivatives connected with imidazolinone (6) pyridine-
2,3-dicarboximide (8) and quinazolinone (10) moieties (Scheme 2).
The structures of 8 and 10 were deduced from elemental and spec-
troscopic analyses. The mass spectrum showed the correct molecular
ion peak of 8 at m/z 443 and, in addition, the base peak at m/z = 169
attributable to the 2-hydroxynapthylethenyl moiety. The absorptions
at 3543 (OH), 3060 (NH), 1764, 1660 (2C O), 1594 (C N), 1175 (C S),
756 (phenyl CH), and 681 cm−1 (C Cl) in the IR spectrum; the display
of a molecular ion peak at m/z (Int., M) = 551 (6.05; C29H18N5ClSO2)
and the base peak at 57 (100, CHN2O+), in addition to the ions at 111
(96.13, +C6H4Cl), 169 (4.97, 2-hydroxynapthylethylene ion) and 102
(20.34; +C6H4CN) supported the structure 10 (Figure 1).

2058
Z. El-Gendy et al.
FIGURE 1 Mass fragmentation of compound 10.
3,4-Diamino-1,2,4-triazin-5-ones are used as starting materials for
the preparation of fused heterobicyclic systems as herbicides.8,9 Thus,
nucleophilic displacement reactions of compound 1 with primary amino
compounds yielded 3,4-diamino-1,2,4-triazin-5-ones (11a–g), which
upon heterocyclization, afforded fused heterobicyclic systems. Reflux-
ing compound 1 with 3,5-diaminobenzoic acid in DMF yielded 3,5-
disubstituted aminobenzoic acid 11 l.
The 1,2,4-triazolidino [5,1-c]-1,2,4-triazine-4,7-dione (12) was ob-
tained from the heterocyclization reaction of 11d with ethyl chloro-
formate in DMF (Scheme 3).
Various types of sulfa drugs containing heterocyclic rings have
been prepared and their biological activities have been studied. Thus,
several new sulfa compounds (11h–k) bearing 1,2,4-triazine and/or
1,2,4-triazinotriazine moieties have been synthesized by reaction of
compound 1 with sulfa drugs such as sulfanilamide, sulfadiazine, sul-
fadimidine, and sulfisoxazole in the presence of DMF. Heterocyclization
reactions of compounds 11h and 11j on refluxing with monochloroacetic
acid and/or 1,1-diethoxy-2-bromoethane in basic medium led to the di-
rect formation of the 1,2,4-triazino[4,3-b]-1,2,4-triazine (13) and the
1,2,4-triazino [4,3-b]-1,2,4-triazin-4-one (14) respectively (Scheme 3).
The structures of 11 and 14 were assigned on the basis of IR, 1HNMR,
and mass spectral data. The absorptions at 3546 (OH), 3445 (NH2),
3182, 3052 (NH, NH), 1683 (C O), 1319, 1178 cm−1 (SO2) in the IR
spectrum, the display of signals at δ 1.8 (Me2), 3.8 (NHSO2), 4.4 (NH2),
7.1-7.5 (4H, aromatic), 7.6–7.7 (CH CH), 8.3 (C5 H of pyrimidine),

1,2,4-Triazines as Anticancer Drugs
2059
SCHEME 3
9.7 ppm (OH) protons in the 1H NMR spectrum are in agreement with
the proposed structure of 11g.
On the other hand, the 1H NMR spectrum of 14 revealed a signal at
δ 3.8 (CH2), in addition to the spectrum of 11. The mass fragmentation
of 14 followed several pathways involving the fission of one or more
bonds of the 1,2,4-triazinotriazine ring and showed the molecular ion

2060
Z. El-Gendy et al.
SCHEME 4
at m/z (Int., M) = 582 (0.01, C19H19N5O3S), the base peak at 527 (100,
M HCON2), and 145 (29.92, C6H4N2O), 128 (C3H2N3S).
Similarly, fusion of compound 1 with bifunctional nitrogen com-
pounds such as cyanamide and ethanolamine afforded the 1,2,4-
triazolino[5,1-c]1,2,4-trazin-4-one 15, and the 1,2,4-triazino[4,3-b]-
1,2,4-triazin-4-one 16 respectively (Scheme 4).
On the other hand, treatment of compound 1 with diethanolamine in
DMF yielded 4-amino-3-[bis(2-hydroxyethyl)amino]-1,2,4-triazin-5-one
17, which, upon heterocyclization with acetic anhydride, led to the for-
mation of 4-acetamido-3-morpholino-1,2,4-triazin-5-one 18. The struc-
ture of compound 18 was elucidated from the lindependent reaction of
compound 1 with morpholine in DMF to give 19 followed by acylation
(Scheme 4).
Nucleophilic displacement at the thiocarbonyl carbon atom of 1 us-
ing bis-amino reagents such as hydrazine hydrate, 2,4-dinitrophenyl-
hydrazine and thiocarbohydrazide in isopropyl alcohol afforded the 1,2-
disubstituted hydrazines 20a–c (Scheme 5).
Some 1,2,4-triazino-1,2,4,5-tetrazine derivatives also were obtained
by heterocyclization reactions of compound 20. Thus, acylation
of compound 20a with ethyl chloroformate in DMF afforded the
1,2,4,triazino[4,3-e]-1,2,4,5-tetrazin-3,6-dione 21 while refluxing 20a,b
with carbon disulfide in ethanolic potassium hydroxide yielded the iso-
meric thiones 22 and 23 respectively (Scheme 5).
The structures of 20a and 21 were confirmed on the basis
of spectral data. The IR spectrum of 20a showed characteristic

1,2,4-Triazines as Anticancer Drugs
2061
SCHEME 5
absorptions at ν 3566 (OH), 3416 (NH2), 3291 (NH2NH), 3052 (NH),
1742 cm−1 (C O), while that of 21 showed the absorptions at ν 3524
(OH), 3551 (OH), 3034 (NH, NH), 1679 (C O) with disappearance of
the NH2 group. The 1H NMR spectrum of 21 displayed signals at

2062
Z. El-Gendy et al.
δ 7.0–7.5 (Ar CH), 7.8–7.9 (CH CH), 8.3, 8.4 (NH), 9.8 and 12.5 ppm
(OH).
Aroylation of compound 20a,b using furoyl chloride and 4-
chlorobenzoylchloride in DMF resulted in the formation of the 1,2,4-
triazino[3,4-c]-1,2,4,5-tetraazin-6-ones 24–26 (Scheme 5). The struc-
ture of 20b and 25 was elucidated from elemental and spectroscopic
data. The IR spectrum of 20b showed the presence of absorption bands
at ν 3267 (NH2), 3089 (NH, NH), 1744 (C O), 1612 (def. NH2), 1511,
1
1329 cm−1 (asy. and sy. NO2). H NMR of 20b revealed the signals at
6.7–7.5 (furan and Ar CH), 7.6–8.0 (cis CH CH), 8.0–8.7 (Ar CH of
2,4-dinitrophenyl), 9.4, 9.7 (NH, NH) and at 12.5 ppm (OH) while that of
25 at 6.7–7.6 (furan and Ar CH), 7.7–8.0 (cis CH CH), 8.2–8.4 (Ar CH
of 2,4-dinitrophenyl), 9.3–9.7 (OH), and 12.5 ppm (NH).
An inspection of the mass spectra of compounds 20a and 25 reveals
that the fragmentation process common to all compounds involves:
i) splitting of both side chaine styrl and/or 2,4-dinitrophenyl moieties,
and ii) fission of the 1,2,4-triazinone nucleus, base peaks of 20a at m/z
112 (100, C3H4N4O) and at 170 (100, C12H10O) for 25 iii) formation of
ions involving some kind of rearrangement (Figure 2).
FIGURE 2 Mass fragmentation of compound 25.

1,2,4-Triazines as Anticancer Drugs
2063
FIGURE 3 Mass fragmentation of compound 27.
Finally, refluxing compound 20c with carbon disulfide in ethano-
lic potassium hydroxide led to the direct formation of the tris-
thioxotriazine compound 27 (Scheme 5). The structure of 27 was derived
from elemental and spectroscopic data. The UV absorption spectrum
showed λmax at 410, 325, and 270 nm. The IR spectrum of 27 showed
ν at 3542 (OH), 3679, 3619 (NH, NH), 1744, 1708 (2C O), 1177 (C S),
and 787, 749 cm−1. The high resolution mass spectrum of compound 27
(Figure 3) shows that the molecular ion constitutes the base peak at
m/z 170 (100%) and suffers cleavage of C C and C N with hydrogen
transfer giving rise to differ heterobicyclic ions.
Pharmacology
In Vitro Antitumor Testing
Most of the newly synthesized compounds have been evaluated in
vitro for antitumor activity according to the described method10,11 in
different concentrations: a sulforhodamine B (SRB) protein assay was
used to estimate cell viability or growth. The primary and fine results

2064
Z. El-Gendy et al.
obtained for the tested compounds are outlined in Tables II and III were
carried out in the National Cancer Institute, Bethesda, Maryland, USA.
DISCUSSION
In continuation of our program directed to the development of an effec-
tive drug for the treatment of cancer,12–14 various heterocycles contain-
ing sulfur and a 1,2,4-triazine moiety have been synthesized and the
results of the antitumor screening of the synthesized compounds are
recorded in Tables I and II.
Quantitative Relation Between Structure and Activity
at the Primary Anticancer Activity
Most of the tested compounds showed a moderate in vitro model pri-
mary anticancer activity especially towards Lung cancer (NCI-H460),
Breast cancer (MCF7) and central nervous system cancer SF268 in
the following order 11j > 2a > 6 and 11i > 14 > 11k. Only compound
11j highly reduced the growth of any one of the cell lines towards
all tested cancers, which seems to be due to the conjugation between
the sulfadimidine and the 4-amino-5-oxo-1,2,4-triazin-3-yl substituent
(Table I).
TABLE I The in vitro Model Primary Anticancer Data of Some New
Compoundsa
Growth percentagesb
(Lung)
NCI-H460
(Breast)
MCF7
(CNS)
SF 268
Compd. no.
Concentration
Activityc
2a
3d
6
11.00E-04 Molar
11.00E-04 Molar
11.00E-04 Molar
11.00E-04 Molar
11.00E-04 Molar
11.00E-04 Molar
11.00E-04 Molar
11.00E-04 Molar
11.00E-04 Molar
11.00E-04 Molar
11.00E-04 Molar
30
−52
46
126
120
−47
0
28
−3
72
−23
26
109
120
−11
4
active
active
active
inactive
inactive
active
active
active
active
inactive
active
−28
11a
11b
11i
11j
11k
11l
11m
11n
84
88
−60
1
−5
−100
−13
40
−18
−76
−26
100
−25
3
98
−5
aResults for each test agent are reported as the percent of growth of the treated cells
when compound to the untreated control cells.
bActive compounds reduce the growth of any one of the cell lines to 32%.
cNegative numbers indicate cell kill.

1,2,4-Triazines as Anticancer Drugs
2065
Quantitative Relation Between Structure and Activity
at the In Vitro Anticancer Activity
In view of the in vitro anticancer activity, we showed that most of the
tested compounds exhibited a moderate anticancer activity in the order
11h > 2a > 3c > 6 > 11k > 1b especially toward leukemia (Table IIa).
Quantitative relation between sulfur element percentage and allular
sensitivity ꢀ of each tested compound were recorded (Table IIb). By,
increasing of sulfur percentage record increasing of ꢀ values in the
following order 2a > 3a > 1b > 14 > 11j, and increasing of sulfur
percentage afforded decreasing the ꢀ values in the order 20c > 11h >
6 > 11k (Table IIb).
In view of these facts we report that:
i) Hydrazone 2 is more active than compound 1, due to the extension
of electronic conjugation between the heterocyclic moiety and the
unsaturated N CH group.
TABLE IIa In vitro Antitumor Activity Data of Some New Compounds
Selectivity
Different allular
Different subpanel
sensitivity
Compd.
GI50
sensitivity (ꢀb)
a
1c
−4.41
−4.54
−4.69
−4.92
−4.80
−4.65
−4.92
−4.45
−4.49
−4.50
1.44
2.15
2.07
2.25
2.06
3.65
1.19
1.59
2.08
2.57
0.27
0.82
0.76
1.21
1.52
2.11
0.41
0.96
2.80
2.95
leukemia, non-small cell lung cancer,
ovarian cancer, breast cancer
leukemia, ovarian cancer
2a
3c
leukemia, non-small cell lung cancer,
colon cancer, ovarian cancer
leukemia, breast cancer
6
11h
11i
11j
11k
14
leukemia, ovarian cancer
leukemia
leukemia
leukemia, colon cancer
colon, renal, breast cancers
leukemia
20c
aGI50 concentration giving 50% inhibition.
bThe reported data represent the logarithmic difference between the parameter value
referred to the most sensible cell line and the same mean parameter.
ꢀ is considered low if <1, moderate if >1 and <3, high if >3.

2066
Z. El-Gendy et al.
TABLE IIb The Sulfur Percentage and ꢀ Values for Some
Tested Compounds
Compd.
Sulfur %
ꢀ
Compd.
Sulfur %
ꢀ
2a
3a
1b
14
11j
11.80
11.80
10.25
7.72
2.07
2.06
1.44
0.41
0.76
11i
11k
6
11h
20c
6.06
8.24
7.81
7.11
4.83
0.27
1.52
1.19
2.08
2.80
5.75
ii) The presence of a thiazolidinone moiety in compound 3 caused a
higher activity than an imidazolone moiety in the compound 6.
iii) The allular sensitivity increased by replacement of SH group in
compound 1 by sulfa groups in compounds 11h–k.
iv) Also, the results reveal that the compounds 2a, 3d, and 11h (ꢀ > 2)
are more active than the compounds 1c, 6, and 11k (ꢀ < 2), which
is mainly due to the presence of indole, thiazolidinone, and sulfanil-
amide moieties.
In conclusion, the anticancer activities were improved when com-
pounds that contain a 1,2,4-triazine moiety were connected with other
heterocyclic rings, such as thiazolidinone and imidazolone or a sulfa
moiety.
EXPERIMENTAL
M.p. are uncorrected. IR spectra in KBr were recorded on a Perkin-
Elmer 293 FT spectrophotometer (νmax in cm−1). UV absorption spec-
tra in DMF were recorded on a Perkin-Elmer, Lambda 4B controller
1
accessory interface UV-VIS spectrophotometer (λmax in nm). HNMR
spectra were recorded on an EM NMR spectrometer 200 MHz PMR us-
ing DMSO as a solvent and TMS as internal reference (Chemical shifts
in ppm) and MS were recorded on a Gas Chromatographic GCMSqp
1000ex Shimadzu instrument at 70 eV. Compounds 1a,b were prepared
following a reported procedure.15 The physical data of the synthesized
compounds are given in Table III.
4-Arylidene-6-styryl-3-thioxo-1,2,4-triazin-5(2H)-ones
(2a--d)
A mixture of 1a or 1b (0.01 mmol) and indol-3-carboxaldehyde,
furan-2-carboxaldehyde, pyridin-2-carboxaldehyde, or 2-hydroxynaph-
thaldehyde (0.01 mmol) in EtOH (20 ml) and conc. H2SO4 (2 drops)

1,2,4-Triazines as Anticancer Drugs
2067
TABLE III Physical Data of the New Heterobicyclic Nitrogen Systems
Sulfur analysis
Found/calcd.%
Compd.
no.a
Crystallized
from
m.p.
(◦C)
Mol. formula
M. Wt.
2a
2b
2c
2d
3a
3b
3c
4
6
MeOH
MeOH
MeOH
MeOH
MeCO2Et
MeCO2Et
MeCO2Et
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
Dil DMF
MeOH
MeOH
Dil DMF
Dil DMF
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DMF
230
165
225
200
200
285
250
260
115
170
140
190
270
320
180
135
265
295
195
215
235
185
220
170
230
285
240
180
295
280
140
198
280
170
205
195
350
140
160
150
240
210
310
C12H9N5OS
C8H6N4O2S
C9H7N5OS
C26H20N4O3S
C10H8N4O3S2
C11H9N5O2S2
C28H20N4O4S2
271
222
233
468
296
307
540
524
409.5
443
551.5
311
325
375
378
386
387
431
450
528
556
388
531
532
404
490
412
152
320
312
383
407
365
310
476
662
336
352
518
386
552
431
746
11.1
14.3
13.3
5.9
21.1
20.9
11.2
5.9
7.3
7.1
5.6
—
—
—
8.0
—
—
11.80
14.41
13.73
6.83
21.62
20.84
11.85
6.10
7.80
7.22
5.79
—
—
—
8.46
—
—
C
28H20N4O5S
C19H12N5O2SCl
C22H13N5O4S
8
10
C29H18N5O3SCl
C15H13N5O3
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
11m
12
13
14
15a
15b
16
17
18
19
20a
20b
20c
21
22
23
24
25
26
27
C
15H15N7O2
C20H17N5O3
C18H14N6O2S
C21H18N6O2
C
21H17N5O3
C22H17N5O5
C21H18N6O4S
—
—
6.4
5.7
5.6
7.4
5.7
—
7.4
5.9
7.1
—
—
—
—
—
—
—
—
4.2
—
7.11
6.06
5.75
8.24
6.02
—
7.92
6.53
7.76
—
—
—
—
—
—
—
—
4.83
—
C
25H20N8O4S
C27H24N8O4S
15H16N8O3S
C25H21N7O5S
C
C
C
23H20N10O6
19H12N6O3S
C23H18N6O5S
C17H18N8O3S
C4H4N6O
C16H12N6O2
C17H15N5O2
C19H21N5O4
C
C
21H21N5O4
19H19N5O3
C15H14N6O2
21H16N8O6
C
C31H26N12O4S
C16H12N6O3
C
C
16H12N6O2S
22H14N8O6S
8.2
6.1
—
—
—
9.09
6.17
—
—
—
C20H14N6O3
C26H16N8O7
C
22H15N6O2Cl
C33H22N12O4S3
12.3
12.86
aYield = 40–70%.
bElemental analysis (C,H,N) are within 0.5% of the theoretical values.
cChlorine elemental analysis: 6 = Found: 8.2, Calcd.: 8.65%; 10 = Found: 6.2, Calcd.:
6.43%; 26 = Found: 7.3, Calcd.: 8.23%.

2068
Z. El-Gendy et al.
was refluxed for 4 h. The reaction mixture was cooled and poured onto
ice. The solid obtained was filtered off and recrystallized to give 2a–d
(Table III).
2-Aryl-3-(5-oxo-6-substituted-3-thioxo(2H-1,2,4-triazin-4-
yl))-1,3-thiazolidin-4-ones (3a--c)
A mixture of 2 (0.01 mmol) and thioglycolic acid (10 ml) in dry dioxane
(20 ml) was refluxed for 12 h, the reaction mixture was concentrated
and neutralized with K2CO3 solution. The solid obtained was filtered
off and recrystallized to give 3a–c (Table III).
Carboxymethyl Derivative 4
A mixture of 2d (0.01 mmol) and monochloroacetic acid (0.01 mmol) in
DMF (20 ml) was refluxed for 4 h, cooled, and poured onto ice. The solid
obtained was filtered and crystallized to give 4 (Table III).
Imidazolinone 6
A mixture of 1a (0.01 mmol) and oxazolidin-4-one 5 (0.01 mmol) in dry
pyridine (10 ml) was refluxed for 4 h, cooled, and poured onto ice-HCl.
The solid obtained was filtered and crystallized to give 6 (Table III).
Pyridine-2,3-dicarboximide Derivative 8
A mixture of 1b (0.01 mmol) and pyridine-2,3-dicarboxylic anhydride 7
(0.01 mmol) in glacial acetic acid (20 ml) was heated under reflux for
4 h, cooled, and poured onto ice. The solid obtained was filtered off and
crystallized to give 8 (Table III).
Quinazolinone 10
A mixture of 1b (0.01 mmol) and quinazolin-4-one 9 (0.01 mmol) in dry
pyridine (15 ml) was heated under reflux for 8 h, cooled, and poured
onto ice and HCl. The solid obtained was filtered off and crystallized to
give 10 (Table III).
3,4-Diamino-1,2,4-triazin-5-ones 11a--k &
3,5-Disubstituted Amino Benzoic Acid 11l
A mixture of 1a and/or 1b (0.01 mmol) and primary amines, such as,
hydroxylamine hydrochloride, cyanoguanidine, furylamine, 2-amino-
thiazole, 2-amino-6-methylpyridine, 4-aminophenol, 4-aminosalicylic

1,2,4-Triazines as Anticancer Drugs
2069
acid, sulfanilamide, sulfapyrimidine, sulfadimidine, sulfaisoxazole, and
3,5-diaminobenzoic acid (0.01 mmol) in DMF (20 ml) was refluxed for
12 h, cooled, and poured onto ice. The solid obtained was filtered off and
recrystallized to give 11a–m (Table III).
1,2,4-Triazolidino[5,1-c][1,2,4]triazin-4,7-dione 12
A mixture of 11d (0.01 mmol) and ethyl chloroformate (0.01 mmol) in
DMF (20 ml) was refluxed for 8 h, cooled, and poured onto ice. The solid
obtained was filtered off and crystallized to give 12 (Table III).
1,2,4-Triazino[4,3-b][1,2,4]triazine 13
A mixture of 11h (0.01 mmol) and monochloroacetic acid (0.01 mmol)
in aq. NaOH (10%) was refluxed for 4 h, cooled, and poured onto ice
and HCl. The solid obtained was filtered off and crystallized to give 13
(Table III).
1,2,4-Triazino[4,3-b][1,2,4-triazin-4-one 14
A mixture of 11j (0.01 mmol) and bromoacetaldehyde diethyl acetal
(0.01 mmol) in sodium ethoxide (0.02 mmol Na, 20 ml abs. EtOH) was
refluxed for 4 h, cooled, and poured onto ice and HCl. The solid obtained
was filtered off and crystallized to give 14 (Table III).
1,2,4-Triazino[5,1-c][1,2,4]triazin-one 15
A mixture of 1a and/or 1b (0.01 mmol) and cyanamide (0.01 mmol) in
DMF (20 ml) was refluxed for 12 h, cooled, and poured onto ice. The
solid obtained was filtered off and crystallized to give 15a,b (Table III).
Perhydro 1,2,4-Triazino[4,3-b][1,2,4]triazin-4-one 16
A mixture of 1b (0.01 mmol) and ethanolamine (0.01 mmol) was re-
fluxed for 8 h, cooled, and poured onto ice-MeOH. The solid obtained
was filtered off and crystallized to give 16 (Table III).
4-Amino-3-[bis(2-hydroxyethyl)amino][1,2,4]triazin-
5-one 17
A mixture of 1b (0.01 mmol) and diethanolamine (0.01 mmol) in DMF
(20 ml) was refluxed for 4 h, cooled, and poured onto ice. The solid
obtained was filtered off and crystallized to give 17 (Table III).

2070
Z. El-Gendy et al.
4-Acetamido-3-morpholino-1,2,4-triazin-5-one 18
A mixture of 17 (0.01 mmol) and Ac2O (0.01 mmol) in dry pyridine
(10 ml) was refluxed for 6 h, cooled, and poured onto ice. The solid
obtained was filtered off and crystallized to give 18 (Table III).
4-Amino-3-morpholino-1,2,4-triazin-5-one 19
A mixture of 1b (0.01 mmol) and morpholine (0.01 mmol) in DMF (10 ml)
was refluxed for 8 h, cooled, and poured onto ice. The solid obtained was
filtered off and crystallized to give 19 (Table III).
Formation of 18 From 19
A mixture of 19 (0.01 mmol) and Ac2O (0.01 mmol) was refluxed for
4 h, cooled, and poured onto ice. The solid obtained was filtered off and
crystallized to give 18 (Table III).
1,2-Disubstituted Hydrazines 20a--c
A mixture of 1b (0.01 mmol) and hydrazine hydrate (0.04 mmol) in
EtOH (30 ml) and/or 2,4-dinitrophenyl hydrazine (0.01 mmol) in DMF
(20 ml) and/or thiocarbohydrazide (0.005 mmol) in DMF (20 ml) was
refluxed for 4 h, cooled, and poured onto ice. The solid obtained was
filtered off and crystallized to give 20 (Table III).
1,2,4-Triazino[4,3-b][1,2,4,5]tetrazin-3,6-dione 21
A mixture of 20a (0.01 mmol) and ethyl chloroformate (0.02 mmol) in
DMF (20 ml) was refluxed for 8 h, cooled, and poured onto ice. The solid
obtained was filtered off and crystallized to give 21 (Table III).
2,7-Disubstituted-3-thioxo-1H,4H-1,2,4-triazino[4,3-e]-
1,2,4,5-tetra-azaperhydroin-6-ones (22 and 23)
A mixture of 20a and 20b (0.01 mmol) and carbon disulfide (0.02 mmol)
in EtOH (20 ml) and KOH (10%), was refluxed for 4 h, cooled, and poured
onto ice-HCl. The solid obtained was filtered off and crystallized to give
22 and 23 (Table III). UV absorptions of 22 were observed at λmax 430,
410, 380, 325, and 268 nm while that of 23 at 439, 412, 389, 330, and
270 nm.

1,2,4-Triazines as Anticancer Drugs
2071
1,2,4-Triazino[3,4-c][1,2,4,5]tetrazin-6-one 24--26
A mixture of 20a and/or 20b (0.01 mmol) and furyl benzoyl chloride or
4-chlorobenzoyl chloride (0.01 mmol) in DMF (20 ml) was refluxed for
6 h, cooled, and poured onto ice. The solid obtained was filtered off and
crystallized to give 24, 25 and 26 respectively (Table III).
Tris-thioxotriazine 27
A mixture of 20c (0.01 mmol) and carbondisulfide (0.04 mmol) in EtOH
(20 ml) and KOH (10%), was refluxed for 4 h, cooled, and poured onto
ice-HCl. The solid obtained was filtered off and crystallized to give 27
(Table III).
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