Synthesis of new Schiff bases and polycyclic fused thiopyranothiazoles containing 4,6-dichloro-1,3,5-triazine moiety

Article abstract of DOI:10.1002/jhet.890

New aromatic aldimines, isatine substituted ketimines based on (4,6-dichloro-1,3,5-triazin-2-yl)-hydrazine scaffold and polycyclic fused thiopyranothiazoles formed using hetero-Diels-Alder reactions starting from 4-thioxo-2-thiazolidinones and 5-norbornene-2,3-dicarboxylic acid triazino-derivatives synthetic approach is described. The application of condensation and cyclocondensation reactions of N-nucleophiles and carbonyl agents for synthesis a number of biologically active triazine derivatives is reported. Screening of anticancer activity in vitro yielded the most active compounds 3a, 8b, and 8f for different cell lines.

Full text of DOI:10.1002/jhet.890

Month 2013
Synthesis of New Schiff Bases and Polycyclic Fused
Thiopyranothiazoles Containing 4,6-Dichloro-1,3,5-Triazine
Moiety
a
a
a
*
Svyatoslav V. Polovkovych, Andrew I. Karkhut, Natalia G. Marintsova,
Roman B. Lesyk,b Borys S. Zimenkovsky,b and Volodymyr P. Novikova
aDepartment of Technology of Biologically Active Substances, Pharmacy and Biotechnology,
National University “Lviv Polytechnic,” Bandera 12, Lviv 79013, Ukraine
bDepartment of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv
National Medical University, Pekarska 69, Lviv 79010, Ukraine
*
E-mail: spolovkovych@ukr.net
Received August 17, 2010
DOI 10.1002/jhet.890
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
New aromatic aldimines, isatine substituted ketimines based on (4,6-dichloro-1,3,5-triazin-2-yl)-hydra-
zine scaffold and polycyclic fused thiopyranothiazoles formed using hetero-Diels-Alder reactions starting
from 4-thioxo-2-thiazolidinones and 5-norbornene-2,3-dicarboxylic acid triazino-derivatives synthetic
approach is described. The application of condensation and cyclocondensation reactions of N-nucleophiles
and carbonyl agents for synthesis a number of biologically active triazine derivatives is reported. Screening
of anticancer activity in vitro yielded the most active compounds 3a, 8b, and 8f for different cell lines.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
Thiazolidone fragment also has a high pharmacological
potential. It is an interesting scaffold used in the rational
design of “drug-like” compounds as innovative drugs
prototypes. 4-Thiazolidone derivatives are a well-known
group of biologically active compounds with anticancer
activity that possessed low acute toxicity and cytotoxicity
[30–34]. Published information prove the affinity of such
derivatives to biological targets involved in the biochemi-
cal processes of tumor cell growth (antiapoptic proteins
complex Bcl-XL-BH3, PPARγ receptors, TNFα-TNFRc-1
complex, etc.) [35–37]. Biological studies of thiopyrano
[2,3-d ]thiazole derivatives showed that they are a good
basis for the synthesis of compounds rows with high
biological potential [33], [38], [39], so the aim of this study
was to synthesize a number of new thiazolidone and
sim-triazine containing heterocyclic compounds with
anticancer activity.
The triazine derivatives are well-known biologically
active agents; therefore, the development of effective and
convenient methods of their synthesis with subsequent
modification is the perspective direction of drug-like
substances design in modern medicinal chemistry.
2,4,6-Trichloro-1,3,5-triazine (cyanuric chloride) is an
important reagent in chemistry of triazine derivatives
considering its low cost and its utilization in selective
modification reactions. This is a commercially available
product synthesized by trimerization of cyanchloride [1].
Reactions of cyanuric chloride with amines, alcohols,
thiols, and phenols are widely used in the synthesis of
dyes, herbicides, insecticides, fungicides, pesticides, and
drugs [2], [3]. They have displayed a wide range of biolog-
ical activity, such as antitumor [4–7], antimetastatic [8],
antibacterial [9–13], anti-inflammatory [14–16], and herbi-
cidal [17–20], as well as therapeutic for menopausal symp-
toms and postmenopausal osteoporosis treatment [21],
[22]. Nowadays, 1,3,5-triazines with aromatic N-substitu-
ents are identified as effective HIV replication inhibitors
and are clinically used for prevention and treatment of
HIV infection [23–28]. Moreover three-substituted
sim-triazine derivatives are proved to be antimalarial and
antibacterial agents [29].
RESULTS AND DISCUSSION
In this article, the synthesis of new aromatic
aldimines, isatine-substituted ketimines (Scheme 1) and
polycyclic condensed thiopyranothiazoles (Scheme 2)
based on of (4,6-dichloro-1,3,5-triazin-2-yl)-hydrazine
2 is described.
© 2013 HeteroCorporation

S. V. Polovkovych, A. I. Karkhut, N. G. Marintsova, R. B. Lesyk, B. S. Zimenkovsky,
and V. P. Novikov
Vol 000
Scheme 1. Synthesis of Schiff bases based on (4,6‐dichloro‐1,3,5‐triazin‐2‐yl)‐hydrazine 2.
Starting material (4,6-dichloro-1,3,5-triazin-2-yl)-hydra-
zine 2 was obtained by nucleophilic substitution of chlo-
rine atom in the molecule of 2,4,6-trichloro-1,3,5-triazine
1 by a hydrazine in anhydrous acetonitrile at −7°C during
1 h stirring with the use of amine excess [Scheme 1(b)].
Synthesis of corresponding Schiff bases was carried out
by condensation reaction of equimolar quantities of
isatines or aromatic aldehydes with (4,6-dichloro-1,3,5-
triazin-2-yl)-hydrazine 2 in DMF medium during 2 h
heating at 110°C [Scheme 1(b)].
with bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride
(endic anhydride) in acetic acid medium in the presence
of catalytic amount of hydroquinone [Scheme 2(c)]. Subse-
quent condensation of 6(a–i) with (4,6-dichloro-1,3,5-
triazin-2-yl)-hydrazine 2 in toluene medium with the
following addition of thionyl chloride [Scheme 2(d)]
allowed us to obtain target compounds 8(a–i).
Also, we report an alternative two-step synthesis of
compounds 8(a–i): condensation (4,6-dichloro-1,3,5-
triazin-2-yl)-hydrazine 2 with endic anhydride in DMF
medium at 110°C [Scheme 2(e)], resulting in 4-(4,6-
Compounds 6(a–i) were obtained by hetero-Diels–Alder
reaction of 5-arylidene-4-thioxo-2-thiazolidinones 5(a–i)
dichloro-1,3,5-triazin-2-ylamino)-4-azatricyclo[5.2.1.02,6
]
Scheme 2. Synthesis of polycyclic fused thiopyranothiazoles based on (4,6‐dichloro‐1,3,5‐triazin‐2‐yl)‐hydrazine 2.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Synthesis of New Schiff Bases and Polycyclic Fused Thiopyranothiazoles
Containing 4,6-Dichloro-1,3,5-Triazine Moiety
Table 1
Percent of cancer cell lines growth [GP (%)] in comparison with control.
Middle
mitotic activity
of 60 lines (%)
A range of mitotic
activity of 60
lines (%)
Most sensible
cell lines and their
mitotic activity [GP(%)]
Compounds
3a
104.94
108.51
108.63
73.63–137.55
71.85–180.30
75.95–142.34
HOP‐92 (nonsmall cell lung cancer): 73.63
SR (leukemia): 78.50
CCRF‐CEM (leukemia): 80.84
SR (leukemia): 71.85
HL‐60(TB) (leukemia): 78.97
HOP‐92 (nonsmall cell lung cancer): 80.79
SR (leukemia): 77.95
8b
8f
LOX IMVI (melanoma): 82.58
The progress of the reaction was monitored by TLC. The solid
product formed was collected by filtration.
dec-8-ene-3,5-dione 7, which reacted with 5-arylidene-
4-thioxo-2-thiazolidinones 5(a–i) and yielded the
corresponding [4+2]-cycloaddition products 8(a–i)
[Scheme 2(f)].
The yields of products 8(a–i) from the initial (4,6-
dichloro-1,3,5-triazin-2-yl)-hydrazine 2 by the route d in
3-[(4,6-Dichloro-1,3,5-triazin-2-yl)-hydrazono]-1,3-dihydroindol-
1
2-one (3 a). Yield 76%, mp = 150–152°C. H NMR (300 MHz,
DMSO-d6) δ: 12.87 (s, 1H, NH), 11.30 (s, 1H, NH); 7.65 (d, 1H, J
= 7.6 Hz, arom.), 7.37 (t, 1H, arom.), 7.11 (t, 1H, arom.), 6.96 (d,
1H, J = 7.6 Hz, arom.). 13C NMR (100 MHz, DMSO-d6): 172.12
(triazine C–Cl); 161.79 (CO izatine); 161.53 (triazine C–NH);
135.71 (N C isatine); 114–148 (Ar); Anal. Calcd. for
C11H6Cl2N6O (309.12): C, 42.74; H, 1.96; N, 27.19. Found: C,
42.59; H, 1.82; N, 27.05.
1-Methyl-3-[(4,6-dichloro-1,3,5-triazin-2-yl)-hydrazono]-1,3-
dihydroindol-2-one (3b). Yield 76%, mp = 162–164°C. 1H NMR
(300 MHz, DMSO-d6) δ: 10.67 (s, 1H, NH); 7.95 (d, 1H, J = 7.6
Hz, arom.), 7.49 (t, 1H, arom.), 7.13 (t, 1H, arom.), 6.99 (d, 1H, J
= 7.6 Hz, arom.); 3.53 (s, 3H, CH3). 13C NMR (100 MHz,
DMSO-d6): 172.18 (triazine C–Cl); 161.71 (CO isatine); 161.13
(triazine C–NH); 143.66 (N C isatine); 117–146 (Ar); 25,51 (N–
CH3); Anal. Calcd. for C12H8Cl2N6O (323.14): C, 44.60; H,
2.50; N, 26.01. Found: C, 44.57; H, 2.43; N, 25.91.
5-Bromo-3-[(4,6-dichloro-1,3,5-triazin-2-yl)-hydrazono]-1,3-
dihydroindol-2-one (3c). Yield 76%, mp = 134–135°C. 1H NMR
(300 MHz, DMSO-d6) δ: 12.76 (s, 1H, NH), 10.37 (s, 1H, NH);
8.51 (s, 1H, arom.), 7.62 (d, 1H, J = 7.5 Hz, arom.), 6.89 (d,
1H, J = 7.5 Hz, arom.). 13C NMR (100 MHz, DMSO-d6):
172.15 (triazine C–Cl); 162.34 (CO isatine); 161.67 (triazine C–
NH); 134.45 (N C isatine); 111.73 (C–Br); 112–148 (Ar); Anal.
Calcd. for C11H5BrCl2N6O (388.01): C, 34.05; H, 1.30; N,
21.66. Found: C, 33.89; H, 1.32; N, 21.05.
N-[1-(Phenyl)-methylidene]-N’-(4,6-dichloro-1,3,5-triazin-2-
yl)-hydrazine (4a). Yield 86%, mp = 132–134°C. 1H NMR (300
MHz, DMSO-d6) δ: 10.07 (s, 1H, NH); 8.33 (s, 1H, NCH); 7.65
(d, 2H, J = 8.6 Hz, arom.), 7.33 (t, 2H, arom.), 7.11 (t, 1H,
arom.). 13C NMR (100 MHz, DMSO-d6): 172.15 (triazine C–
Cl); 168.64 (triazine C–NH); 145.53 (N=CH-Ar); 126–134 (Ar);
Anal. Calcd. for C10H7Cl2N5 (268.11): C, 44.80; H, 2.63; N,
26.12. Found: C, 44.70; H, 2.57; N, 26.05.
comparison with two-stage route e–f are nearly equal.
Anticancer activity of the synthesized compounds.
Compounds 3a, 8b, and 8f were passed on for evaluation
in the panel of 60 human tumor cell lines in
concentration 10−5M. Compound 3a showed the highest
antitumor cytotoxicity against HOP-92 (nonsmall cell
lung cancer), CCRF-CEM, and SR (leukemia) cell lines;
8b: NCI-H522 (nonsmall cell lung cancer), SR
(leukemia) cell lines; and 8f: SR (leukemia), LOX IMVI
(melanoma) cell lines correspondingly (Table 1). These
preliminary results are promising and need further
investigation of antitumor activity spectrum of mentioned
and related compounds.
EXPERIMENTAL
Melting points were determined in open capillary tubes. IR
spectrums were recorded on a Specord-80M spectrophotometer
in potassium bromide pellets as described elsewhere. H1 NMR
spectra were recorded on a Varian VXR (300 MHz), and 13C
NMR spectra on Varian Gemini 100 MHz in DMSO-d6. The
reaction progress was monitored by thin layer chromatography
on 0.2-mm silica gel (Silufol UV-254).
(4,6-Dichloro-1,3,5-triazin-2-yl)-hydrazine (2). To a suspension of
10 mmol of cyanuric chloride 1 in 15 mL of anhydrous
acetonitrile, 25 mmol 80% hydrazine hydrate was added, and
the mixture was stirred at temperature −7°C for 1 h. The
progress of the reaction was monitored by TLC. The precipitate
obtained was filtered and washed with cold water.
Yield 86%, mp = 190–193°C. Anal. Calcd. for C4H4Cl2N6S
(239,09): C, 20.10; H, 1.69; N, 35.15; S, 13.41. Found: C,
20.00; H, 1.60; N, 35.07; S, 13.35.
General procedure of preparation of compounds 3a–c
and 4a–j. A solution of appropriate carbonyl compounds
(10 mmol) and (4,6-dichloro-1,3,5-triazin-2-yl)-hydrazine 2 (10
mmol) in DMF (20 mL) stirred at temperature 110°C for 2 h.
N-[1-(4-Methoxyphenyl)-methylidene]-N’-(4,6-dichloro-1,3,5-
triazin-2-yl)-hydrazine (4b). Yield 81%, mp = 124–125°C. 1H
NMR (300 MHz, DMSO-d6) δ: 10.09 (s, 1H, NH); 8.50 (s, 1H,
NCH); 7.25 (d, 2H, J = 8.1 Hz, arom.), 6.96 (d, 2H, J = 8.1 Hz
arom.), 3.77 (s, 3H, OCH3). 13C NMR (100 MHz, DMSO-d6):
172.37 (triazine C–Cl), 168.68 (triazine C–NH), 144.17 (N CH-
Ar), 114–160 (Ar); 55,20 (OCH3); Anal. Calcd. for
C11H9Cl2N5O (298.13): C, 44.32; H, 3.04; N, 23.49. Found: C,
44.28; H, 3.00; N, 23.43.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. V. Polovkovych, A. I. Karkhut, N. G. Marintsova, R. B. Lesyk, B. S. Zimenkovsky,
and V. P. Novikov
Vol 000
N-[1-(3,4-Dimetoxyphenyl)-methylidene]-N’-(4,6-dichloro-1,3,5-
triazin-2-yl)-hydrazine (4c). Yield 85%, mp = 143–145°C. 1H NMR
(300 MHz, DMSO-d6) δ: 10.11 (s, 1H, NH); 8.41 (s, 1H, NCH); 6.92
(d, 1H, J = 8.1 Hz, arom.), 6.83 (m, 2H, arom.); 3.76 (s, 3H, OCH3),
3.73 (s, 3H, OCH3). 13C NMR (100 MHz, DMSO-d6): 172.40
(triazine C–Cl), 168.67 (triazine C–NH), 142.29 (N CH-Ar), 108–
151 (Ar); 56,32; 56,13 (OCH3); Anal. Calcd. for C12H11Cl2N5O2
(328.16): C, 43.92; H, 3.38; N, 21.34. Found: C, 43.88; H, 3.30;
N, 21.23.
N-[1-Anthracen-9-yl-methylidene]-N’-(4,6-dichloro-1,3,5-
triazin-2-yl)-hydrazine (4j). Yield 87%, mp = 198–199°C. H
1
NMR (300 MHz, DMSO-d6) δ: 10.08 (s, 1H, NH); 8.96 (s,
1H, NCH); 8.79 (d, 2H, J = 8.5 Hz, arom.), 8.61 (s, 1H, J =
8.5 Hz, arom.), 8.01 (d, 2H, J = 8.5 Hz, arom.), 7.74 (t, 2H, J
= 8.5 Hz, arom.), 7.63 (t, 2H, J = 8.5 Hz, arom.). 13C NMR
(100 MHz, DMSO-d6): 172.40 (triazine C–Cl), 168.64
(triazine C–NH), 136.13 (N CH-Ar), 121–132 (Antracene);
Anal. Calcd. for C18H11Cl2N5 (368.23): C, 58.71; H, 3.01; N,
19.02. Found: C, 58.50; H, 2.81; N, 19.09.
N-[1-(3-Ethoxy-4-hydroxyphenyl)-methylidene]-N’-(4,6-dichloro-
1
4-(4,6-Dichloro-1,3,5-triazin-2-ylamino)-4-azatricyclo[5.2.1.02,6
]
1,3,5-triazin-2-yl)-hydrazine (4d). Yield 65%, mp = 156–157°C. H
NMR (300 MHz, DMSO-d6) δ: 10.01 (s, 1H, NH); 8.86 (s, 1H,
OH); 8.32 (s, 1H, NCH); 6.73 (d, 1H, J = 8.0 Hz, arom.), 6.71
(s, 1H, arom.), 6.63 (d, 1H, J = 8.0 Hz, arom.); 4.02 (qu, 2H,
CH2CH3); 1.19 (t, 3H, CH2CH3). 13C NMR (100 MHz,
DMSO-d6): 172.41 (triazine C–Cl), 168,70 (triazine C–NH),
141,33 (N CH-Ar), 110–150 (Ar); 65,70 (OCH2CH3); 15,19
(OCH2CH3); Anal. Calcd. for C12H11Cl2N5O2 (328,16): C,
43.92; H, 3.38; N, 21.34. Found: C, 43.52; H, 3.24; N, 21.31.
N-[1-(3,5-tert-Butyl-4-hydroxyphenyl)-methylidene]-N’-(4,6-
dichloro-1,3,5-triazin-2-yl)-hydrazine (4e). Yield 85%, mp >
250°C. 1H NMR (300 MHz, DMSO-d6) δ: 9.83 (s, 1H, NH);
8.33 (s, 1H, NCH); 8.02 (s, 1H, OH); 7.68 (s, 2H, arom.); 1.42
(s, 18H, 2 × C(CH3)3). 13C NMR (100 MHz, DMSO-d6):
172,39 (triazine C–Cl), 168,69 (triazine C–NH), 141,45 (N CH-
Ar), 124–152 (Ar); 33,25 (C(CH3)3); 30,99 (C(CH3)3); Anal.
Calcd. for C18H23Cl2N5O (396,32): C, 54.55; H, 5.85; N,
17.67. Found: C, 54.26; H, 5.80; N, 17.57.
N-[1-(4-Dimetylaminophenyl)-methylidene]-N’-(4,6-dichloro-
1,3,5-triazin-2-yl)-hydrazine (4f). Yield 87%, mp = 121–123°C.
1H NMR (300 MHz, DMSO-d6) δ: 10.1 (s, 1H, NH); 8.53 (s, 1H,
NCH); 7.25 (d, 2H, J = 8.1 Hz, arom.), 6.96 (d, 2H, J = 8.1 Hz,
arom.); 2.77 (s, 6H, N(CH3)2). 13C NMR (100 MHz, DMSO-d6):
172.46 (triazine C–Cl), 168.66 (triazine C–NH), 143.56 (N CH-
Ar), 112–151 (Ar); 40,42 (N(CH3)2); Anal. Calcd. for
C12H12Cl2N6 (311.18): C, 46.32; H, 3.89; N, 27.01. Found: C,
46.28; H, 3.80; N, 27.00.
dec-8-ene-3,5-dione (7). A solution of bicyclo[2.2.1]hept-5-ene-2,3-
dicarboxylic anhydride (10 mmol) and (4,6-dichloro-1,3,5-triazin-2-
yl)-hydrazine 2 (10 mmol) in DMF (20 mL) stirred at temperature
110°C for 2 h. The progress of the reaction was monitored by TLC.
The solid product that formed was collected by filtration.
1
Yield 71%, mp > 250°C. H NMR (300 MHz, DMSO-d6) δ:
10.09 (s, 1H, NH); 6.52 (d, 2H, J = 8.6 Hz), 2.97 (s, 4H, J =
4.9 Hz), 1.54–1.45 (m, 2H); norbornene fragment. Anal. Calcd.
for C12H9Cl2N5O2 (326.14): C, 44.19; H, 2.78; N, 21.47. Found:
C, 44.21; H, 2.69; N, 21.37.
General procedure of preparation of compounds 8
(a–i). Way d. A solution of 9-aryl-6,13,14,15-tetraoxo-3,
7-dytia-5-azapentacyclo[9.5.1.02,10.012,16]heptadec-4(8)-en-thiazol-2-
one 6(a–i) (10 mmol) and (4,6-dichloro-1,3,5-triazin-2-yl)-hydrazine
2 (10 mmol) in toluene (20 mL) was stirred. After 1.75 h, SOCl2
was added and refluxed for 15 min. The progress of the reaction
was monitored by TLC. The obtained precipitate was filtered off
and washed with cold water.
Way f. A solution of 4-(4,6-dichloro-1,3,5-triazin-2-ylamino)-
4-azatriciclo[5.2.1.02,6]dec-8-ene-3,5-dione 7 (12 mmol) and 5-
arylidene-4-thioxo-2-thiazolidinone 5(a–i) (10 mmol) refluxed
in toluene (20 mL) in the presence of a catalytic amount of
hydroquinone for 1 h. The progress of the reaction was
monitored by TLC. The obtained precipitate was filtered.
9-Phenyl-14-(4,6-dichloro-1,3,5-triazin-2-yl-amino)-6,13,15-
trioxo-3,7-dithia-5-azapentacyclo[9.5.1.02,10.012,16]heptadec-4(8)-
N-[1-(4-Fluorophenyl)-methylidene]-N’-(4,6-dichloro-1,3,5-
1
en-thiazol-2-one (8a). Yield 76%, mp > 250°C. H NMR (300
1
triazin-2-yl)-hydrazine (4g). Yield 88%, mp = 110–113°C. H
MHz, DMSO-d6) δ: 11.47 (s, 1H, NH), 10.09 (s, 1H, NH); 7.65
(d, 2H, arom.), 7.33 (t, 2H, arom.), 7.11 (t, 1H, arom.); 3.50 (m,
3H), 3.26 (m, 1H), 2.71 (d, 1H, J = 4.9 Hz), 2.52 (m, 1H), 2.41
(d, 1H, J = 5.3 Hz), 2.30 (t, 1H, J = 8.6 Hz), 1.70 (d, 1H, J =
10.0 Hz); norbornane fragment, CHAr. 13C NMR (100 MHz,
DMSO-d6): 172.81; 173.56 (N–CO–CH); 171.25 (triazine C–Cl);
169.89 (triazine C–NH); 169.72 (NH–CO–S); 126–139 (Ar); 37–
51 (norbornane fragment); Anal. Calcd. for C22H16Cl2N6O3S2
(547.45): C, 48.27; H, 2.95; N, 15.35. Found: C, 48.19; H, 2.90;
N, 15.30.
NMR (300 MHz, DMSO-d6) δ: 10.09 (s, 1H, NH); 8.73 (s,
1H, NCH); 7.94 (t, 2H, J = 8.3 Hz, arom.), 7.33 (t, 2H, J =
8.3 Hz, arom.). 13C NMR (100 MHz, DMSO-d6): 172.42
(triazine C–Cl), 168.72 (triazine C–NH), 144.31 (N CH-Ar),
116–150 (Ar); 149.80 (C–F); Calcd. for C10H6Cl2FN5
(286.10): C, 41.98; H, 2.11; N, 24.48. Found: C, 41.50; H,
2.01; N, 24.39.
N-[1-(4-Chlorophenyl)-methylidene]-N’-(4,6-dichloro-1,3,5-
1
triazin-2-yl)-hydrazine (4h). Yield 81%, mp = 115–116°C. H
NMR (300 MHz, DMSO-d6) δ: 10.11 (s, 1H, NH); 8.21 (s, 1H,
NCH); 7.16 (d, 2H, J = 8.5 Hz, arom.), 6.92 (d, 2H, J = 8.5 Hz,
arom.). 13C NMR (100 MHz, DMSO-d6): 172.45 (triazine C–Cl),
168.65 (triazine C–NH), 144.68 (N CH-Ar), 127–134 (Ar);
133.14 (C–Cl); Anal. Calcd. for C10H6Cl3N5 (302.55): C, 39.70;
H, 2.00; N, 23.15. Found: C, 39.59; H, 1.91; N, 23.09.
N-[1-(4-Bromophenyl)-methylidene]-N’-(4,6-dichloro-1,3,5-
triazin-2-yl)-hydrazine (4i). Yield 87%, mp = 123–124C. 1H
NMR (300 MHz, DMSO-d6) δ: 10.1 (s, 1H, NH); 8.46 (s, 1H,
NCH); 7.19 (d, 2H, J = 8.5 Hz, arom.), 6.98 (d, 2H, J = 8.5
Hz, arom.). 13C NMR (100 MHz, DMSO-d6): 172.39 (triazine
C–Cl), 168.69 (triazine C–NH), 145.89 (N CH-Ar), 125–133
(Ar); 124.97 (C–Br); Anal. Calcd. for C10H6BrCl2N5 (347.00):
C, 34.61; H, 1.74; N, 20.18. Found: C, 34.50; H, 1.71; N, 20.09.
9-(4-Methoxyphenyl)-14-(4,6-dichloro-1,3,5-triazin-2-yl-amino)-
6,13,15-trioxo-3,7-dithia-5-azapentacyclo[9.5.1.02,10.012,16]heptadec-4
1
(8)-en-thiazol-2-one (8b). Yield 71%, mp = 145°C. H NMR (300
MHz, DMSO-d6) δ: 11.57 (s, 1H, NH), 10.09 (s, 1H, NH); 7.25 (d,
2H, J = 8.1 Hz, arom.), 6.96 (d, 2H, J = 8.1 Hz, arom.); 3.77 (s, 3H,
OCH3); 3.50 (m, 3H), 3.26 (m, 1H), 2.71 (d, 1H, J = 4.9 Hz), 2.52
(m, 1H), 2.41 (d, 1H, J = 5.3 Hz), 2.30 (t, 1H, J = 8.6 Hz), 1.70 (d,
1H, J = 10.0 Hz); norbornane fragment, CHAr. 13C NMR (100 MHz,
DMSO-d6): 172.82; 173.55 (N–CO–CH); 171.28 (triazine C–Cl);
169.84 (triazine C–NH); 169.67 (NH–CO–S); 112–157 (Ar);
55,32 (OCH3); 37–51 (norbornane fragment); Anal. Calcd. For
C23H18Cl2N6O4S2 (577.47): C, 47.84; H, 3.14; N, 14.55.
Found: C, 48.68; H, 3.00; N, 14.23.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Synthesis of New Schiff Bases and Polycyclic Fused Thiopyranothiazoles
Containing 4,6-Dichloro-1,3,5-Triazine Moiety
9-(3,4-Dimethoxyphenyl)-14-(4,6-dichloro-1,3,5-triazin-2-yl-
NMR (300 MHz, DMSO-d6) δ: 11.57 (s, 1H, NH), 10.07
(s, 1H, NH); 7.96 (t, 2H, J = 8.4 Hz, arom.), 7.35 (t,
2H, J = 8.4 Hz, arom.); 3.50 (m, 3H), 3.26 (m, 1H),
2.71 (d, 1H, J = 4.9 Hz), 2.52 (m, 1H), 2.41 (d, 1H, J
= 5.3 Hz), 2.30 (t, 1H, J = 8.6 Hz), 1.70 (d, 1H, J =
10.0 Hz); norbornane fragment, CHAr. 13C NMR (100
MHz, DMSO-d6): 172.82; 173.53 (N–CO–CH); 171.26
(triazine C–Cl); 169.87 (triazine C–NH); 169.76 (NH–CO–
S); 159.70 (C–F); 113–137 (Ar); 37–51 (norbornane
fragment); Anal. Calcd. for C22H15Cl2FN6O3S2(565.44): C,
46.73; H, 2.67; N, 14.86. Found: C, 46.70; H, 2.61; N,
14.79.
9-(4-Chlorophenyl)-14-(4,6-dichloro-1,3,5-triazin-2-yl-amino)-
6,13,15-trioxo-3,7-dithia-5-azapentacyclo[9.5.1.02,10.012,16]heptadec-
4(8)-en-thiazol-2-one (8h). Yield 71%, mp = 226–228°C. 1H
NMR (300 MHz, DMSO-d6) δ: 11.53 (s, 1H, NH), 10.11
(s, 1H, NH); 7.16 (d, 2H, J = 8.5 Hz, arom.), 6.92 (d, 2H,
J = 8.5 Hz, arom.); 3.50 (m, 3H), 3.26 (m, 1H), 2.71 (d,
1H, J = 4.9 Hz), 2.52 (m, 1H), 2.41 (d, 1H, J = 5.3 Hz),
2.30 (t, 1H, J = 8.6 Hz), 1.70 (d, 1H, J = 10.0 Hz);
norbornane fragment, CHAr. 13C NMR (100 MHz, DMSO-
d6): 172.78; 173.57 (N–CO–CH); 171.24 (triazine C–Cl);
169.83 (triazine C–NH); 169.71 (NH–CO–S); 127–140 (Ar);
133.42 (C–Cl); 37–51 (norbornane fragment); Anal. Calcd.
for C22H15Cl3N6O3S2 (581.89): C, 45.41; H, 2.60; N, 14.44.
Found: C, 45.37; H, 2.58; N, 14.39.
9-(4-Bromophenyl)-14-(4,6-dichloro-1,3,5-triazin-2-yl-amino)-
6,13,15-trioxo-3,7-dithia-5-azapentacyclo[9.5.1.02,10.012,16]heptadec-
4(8)-en-thiazol-2-one (8i). Yield 67%, mp = 242–244°C. 1H
NMR (300 MHz, DMSO-d6) δ: 11.51 (s, 1H, NH), 10.21 (s,
1H, NH); 7.19 (d, 2H, J = 8.5 Hz, arom.), 6.98 (d, 2H, J = 8.5
Hz, arom.); 3.50 (m, 3H), 3.26 (m, 1H), 2.71 (d, 1H, J = 4.9
Hz), 2.52 (m, 1H), 2.41 (d, 1H, J = 5.3 Hz), 2.30 (t, 1H, J =
8.6 Hz), 1.70 (d, 1H, J = 10.0 Hz); norbornane fragment,
CHAr. 13C NMR (100 MHz, DMSO-d6): 172.86; 173.51 (N–
CO–CH); 171.29 (triazine C–Cl); 169.85 (triazine C–NH);
169.69 (NH–CO–S); 119–141 (Ar); 119.89 (C–Br); 37–51
(norbornane fragment); Anal. Calcd. for C22H15BrCl2N6O3S2
(626.34): C, 42.19; H, 2.41; N, 13.42. Found: C, 42.13; H,
2.37; N, 13.40.
amino)-6,13,15-trioxo-3,7-dithia-5-azapentacyclo[9.5.1.02,10.012,16
]
1
heptadec-4(8)-en-thiazol-2-one (8c). Yield 73%, mp = 156°C. H
NMR (300 MHz, DMSO-d6) δ: 11.57 (s, 1H, NH), 10.11 (s, 1H,
NH); 6.92 (d, 1H, arom.), 6.83 (m, 2H, arom.); 3.76 (s, 3H, OCH3),
3.73 (s, 3H, OCH3); 3.50 (m, 3H), 3.26 (m, 1H), 2.71 (d, 1H, J =
4.9 Hz), 2.52 (m, 1H), 2.41 (d, 1H, J = 5.3 Hz), 2.30 (t, 1H, J =
8.6 Hz), 1.70 (d, 1H, J = 10.0 Hz); norbornane fragment, CHAr.
13C NMR (100 MHz, DMSO-d6): 172.80; 173.55 (N–CO–CH);
171.27 (triazine C–Cl); 169.86 (triazine C–NH); 169.73
(NH–CO–S); 111–149 (Ar); 56,21; 56,03 (OCH3); 37–51
(norbornane fragment); Anal. Calcd. for C24H20Cl2N6O5S2
(607.50): C, 47.45; H, 3.32; N, 13.83. Found: C, 47.38; H,
3.20; N, 13.73.
9-(3-Ethoxy-4-hydroxyphenyl)-14-(4,6-dichloro-1,3,5-triazin-
2-yl-amino)-6,13,15-trioxo-3,7-dithia-5-azapentacyclo[9.5.1.02,10.012,16
]
heptadec-4(8)-en-thiazol-2-one (8d). Yield 65%, mp = 131°C.
1H NMR (300 MHz, DMSO-d6) δ: 11.35 (s, 1H, NH), 10.21 (s,
1H, NH); 8.86 (s, 1H, OH); 6.73 (d, 1H, J = 8.0 Hz, arom.),
6.71 (s, 1H, arom.), 6.63 (d, 1H, J = 8.0 Hz, arom.); 4.02
(qu, 2H, CH2CH3); 3.50 (m, 3H), 3.26–3.38 (m, 1H), 2.71
(d, 1H, J = 4.9 Hz), 2.52 (m, 1H), 2.41 (d, 1H, J = 5.3
Hz), 2.30 (t, 1H, J = 8.6 Hz), 1.70 (d, 1H, J = 10.0 Hz);
norbornane fragment, CHAr; 1.19 (t, 3H, CH2CH3). 13C
NMR (100 MHz, DMSO-d6): 172.79; 173.56 (N–CO–CH);
171.20 (triazine C–Cl); 169.82 (triazine C–NH); 169.70
(NH–CO–S); 113–146 (Ar); 65,82 (OCH2CH3); 37–51
(norbornane fragment); 15,13 (OCH2CH3); Anal. Calcd. for
C24H20Cl2N6O5S2 (607.50): C, 47.45; H, 3.32; N, 13.83.
Found: C, 47.42; H, 3.29; N, 13.80.
9-(3,5-tert-Butyl-4-hydroxyphenyl)-14-(4,6-dichloro-1,3,5-triazin-
2-yl-amino)-6,13,15-trioxo-3,7-dithia-5-azapentacyclo[9.5.1.02,10.012,16
]
heptadec-4(8)-en-thiazol-2-one (8e). Yield 55%, mp = 187°C.
1H NMR (300 MHz, DMSO-d6) δ: 11.55 (s, 1H, NH), 10.01 (s,
1H, NH); 8.06 (s, 1H, OH); 7.68 (s, 2H, arom.); 3.50 (m, 3H),
3.26–3.38 (m, 1H), 2.71 (d, 1H, J = 4.9 Hz), 2.52 (m, 1H), 2.41
(d, 1H, J = 5.3 Hz), 2.30 (t, 1H, J = 8.6 Hz), 1.70 (d, 1H, J =
10.0 Hz); norbornane fragment, CHAr; 1.42 (s, 18H, 2 × C(CH3)
3). 13C NMR (100 MHz, DMSO-d6): 172.87; 173.52 (N–CO–
CH); 171.23 (triazine C–Cl); 169.89 (triazine C–NH); 169.68
(NH–CO–S); 125–151 (Ar); 37–51 (norbornane fragment); 32,98
(C(CH3)3); 31,45 (C(CH3)3); Anal. Calcd. for C30H32Cl2N6O4S2
(675.66): C, 53.33; H, 4.77; N, 12.44. Found: C, 53.26; H,
4.70; N, 12.37.
General procedure of study of anticancer activity
in vitro.
performed [40] for compounds 3a, 8b, and 8f according to
NCI (USA) standard protocol [41], [42]. study of
Preliminary antitumor activity studies were
A
9-(4-Dimethylaminophenyl)-14-(4,6-dichloro-1,3,5-triazin-2-
anticancer activity in vitro were carried out for 60 lines of
cancer cells: Nonsmall cell lung cancer (A549/ATCC, EKVX,
HOP-62, HOP-92, NCI-H226, NCI-H23, NCI-H322M, NCI-
H460, and NCI-H522), leukemia (CCRF-CEM, HL-60(TB),
K-562, MOLT-4, and RPMI-8226), breast cancer (MCF7,
NCI/ADR-RES, MDA-MB-231/ATCC, HS 578T, MDA-MB-
435, BT-549, and T-47D), Ovarian cancer (IGROV-1,
OVCAR-3, OVCAR-4, OVCAR-5, and SK-OV-3), renal
cancer (786–0, A498, ACHN, CAKI-1, RXF-393, SN12C,
TK-10, and UO-31), colon cancer (COLO 205, HCT-116,
yl-amino)-6,13,15-trioxo-3,7-dithia-5-azapentacyclo[9.5.1.02,10.012,16
]
heptadec-4(8)-en-thiazol-2-one (8f). Yield 77%, mp = 182–184°
C. 1H NMR (300 MHz, DMSO-d6) δ: 11.67 (s, 1H, NH),
10.19 (s, 1H, NH); 7.25 (d, 2H, J = 8.1 Hz, arom.), 6.96
(d, 2H, J = 8.1 Hz, arom.); 3.50 (m, 3H), 3.26 (m, 1H),
2.71 (d, 1H, J = 4.9 Hz), 2.52 (m, 1H), 2.41 (d, 1H, J =
5.3 Hz), 2.30 (t, 1H, J = 8.6 Hz), 1.70 (d, 1H, J = 10.0
Hz); norbornane fragment, CHAr; 2.77 (s, 6H, N(CH3)2).
13C NMR (100 MHz, DMSO-d6): 172.83; 173.55 (N–CO–
CH); 171.21 (triazine C–Cl); 169.86 (triazine C–NH);
169.72 (NH–CO–S); 113–148 (Ar); 40,46 (N(CH3)2); 37–51
(norbornane fragment); Anal. Calcd. for C24H21Cl2N7O3S2
(590.51): C, 48.82; H, 3.58; N, 16.60. Found: C, 48.68; H,
3.50; N, 16.53.
HCT-15, HT29, KM12, and
SW-620), melanoma (LOX
IMVI, MALME-3M, M14, SK-MEL-2, SK-MEL-28, SK-
MEL-5, UACC-257, and UACC-62), prostate cancer (PC-3
and Du-145), CNS cancer (SF-268, SF-295, SF-539, SNB-19,
SNB-75, and U251) in
Percent of cancer cell lines growth [GP (%)] in comparing
a
concentration of 10−5 mol/L.
9-(4-Fluorophenyl)-14-(4,6-dichloro-1,3,5-triazin-2-yl-amino)-
6,13,15-tryoxo-3,7-dithia-5-azapentacyclo[9.5.1.02,10.012,16]heptadec-
4(8)-en-thiazol-2-one (8g). Yield 78%, mp = 223–225°C. 1H
with control was calculated as
of activity.
a quantitative parameter
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. V. Polovkovych, A. I. Karkhut, N. G. Marintsova, R. B. Lesyk, B. S. Zimenkovsky,
and V. P. Novikov
Vol 000
[23] Ludovici, D. W.; Kavash, R. W.; Kukla, M. J.; Ho, C. Y.; Ye,
H.; De Corte, B. L.; Andries, K.; de Bethune, M. P.; Azijn, H.; Pauwels,
R.; Moereels, H. E.; Heeres, J.; Koymans, L. M.; de Jonge, M. R.; Van
Aken, K. J.; Daeyaert, F. F.; Lewi, P. J.; Das, K.; Arnold, E.; Janssen,
P. A. Bioorg Med Chem Lett 2001, 11, 2229.
Acknowledgments. The authors thank V. L. Narayanan from
Drug Synthesis and Chemistry Branch, National Cancer Institute
(Bethesda, MD), for in vitro evaluation of anticancer activity.
[24] Van Herrewege, Y.; Vanham, G.; Michiels, J.; Fransen, K.;
Kestens, L.; Andries, K.; Janssen, P.; Lewi, P. Antimicrob Agents
Chemother 2004, 48, 3684.
REFERENCES AND NOTES
[25] Vzorov, A. N.; Bhattacharyya, D.; Marzilli, L. G.; Compans, R. W.
Antiviral Res 2005, 65, 57.
[26] Guillemont, J. E. G.; Pasquier, E. T. J.; Heeres, J.; Hertogs, K.;
Bettens, E.; Lewi, P. J.; De Jonge, M. R.; Koymans, L. M. H.;
Daeyaert, F. F. D.; Vinkers, H. M.; Arts, F. X. J. H. US Pat.0,142,571,
2006.
[27] Guillemont, J. E. G.; Pasquier, E. T. J.; Heeres, J.; Hertogs, K.;
Bettens, E.; Lewi, P. J.; De Jonge, M. R.; Koymans, L. M. H.;
Daeyaert, F. F. D.; Vinkers, A. J.; Janssen, H. M.; Arts, F. X. J. H.
US Pat.0,194,804, 2006.
[1] Kaminski, Z. J.; Biopolymers (Pept Sci) 2000, 55, 140.
[2] Menicagli, R.; Malanga, C.; Peluso, P. Synth Commun 1994,
24, 2153.
[3] Srinivas, K.; Srinivas, U.; Rao, V. J.; Bhanuprakash, K.;
Kishore, K. H.; Murty, U. S. N. Bioorg Med Chem Lett 2005, 4, 1121.
[4] Goldin, A.; Wolpert-Defilippes, M. K. Bull Cancer 1979,
66, 61.
[5] Foster, B. J.; Harding, B. J.; Leyland-Jones, B.; Hoth, D.
Cancer Treatment Rev 1986, 13, 197.
[6] Menicagli, R.; Samaritani, S.; Signore, G.; Vaglini, F.; Via, L.
D. J Med Chem 2004, 47, 4649.
[28] Agarwal, A.; Srivastava, K.; Puri, S. K.; Chauhan, P. M. S.
Bioorg Med Chem Lett 2005, 15, 3130.
[7] Saczewski, F.; Bulakowska, A.; Bednarski, P.; Grunert, R. Eur
J Med Chem 2006, 41, 219.
[29] Atamanyuk, D.; Zimenkovsky, B.; Lesyk, R. J Sulfur Chem
2007, 29, 151.
[8] Maeda, M.; Iogo, M.; Tsuda, H.; Fujita, H.; Yonemura, Y.;
Nakagawa, K.; Endo, Y.; Sasaki, T. Anticancer Drug Des 2000, 15, 217.
[9] Kreutzberger, A.; Richter, B. Archiv der Pharmazie 1983, 316, 213.
[10] Arenas, J. E.; Cload, S. T.; Fleming, E. S. WO Patent99/
36410, 1999.
[11] Ghaib, A.; Menager, S.; Verite, P.; Lafont, O.; Farmaco
(Societa Chimica Italiana, 1989), 2002, 57, 109.
[12] Srinivas, K.; Srinivas, U.; Bhanuprakash, K.; Harakishore, K.;
Murthy, U. S.; Jayathirtha Rao, V.; Eur J Med Chem 2006, 41, 1240.
[13] Zhou, Y.; Sun, Z.; Froelich, J. M.; Hermann, T.; Wall, D.
Bioorg Med Chem Lett 2006, 16, 5451.
[14] Bhalla, M.; Srivastava, V. K.; Bhalla, T. N.; Shanker, K. Boll
Chim Farm 1994, 133, 521.
[15] Dianzani, C.; Collino, M.; Gallicchio, M.; Samaritani, S.;
Signore, G.; Menicagli, R.; Fantozzi, R. J Pharm Pharmacol 2006, 58, 219.
[16] Ruckle, T.; Schwarz, M. K.; Rommel, C. Nat Rev Drug
Discov 2006, 5, 903.
[30] Lesyk, R.; Vladzimirska, O.; Holota, S.; Zaprutko, L.;
Gzella, A. Eur J Med Chem 2007, 42, 641.
[31] Kaminskyy, D. V.; Roman, O. M.; Atamanyuk, D. V.; Lesyk, R.
B. Zh Org Farm Khim (in Ukrainian). 2006, 4, 41; Kaminskyy, D. V.;
Roman, O. M.; Atamanyuk, D. V.; Lesyk, R. B. Chem Abstr 2007, 148,
33653.
[32] Lesyk, R. B.; Zimenkovsky, B. S.; Yarmoluk, S. M.;
Subtelna, I. Yu. Farm Zh 2003, 1, 51; Lesyk, R. B.; Zimenkovsky, B. S.;
Yarmoluk, S. M.; Subtelna, I. Chem Abstr 2003, 140, 42071.
[33] Lesyk, R.; Zimenkovsky, B.; Atamanyuk, D. Jensen, F.; Kiec-
Kononowicz, K.; Gzella, A. Bioorg Med Chem 2006, 14, 5230.
[34] Zimenkovsky, B.; Kazmirchuk, G.; Zaprutko, L.;
Paraskiewicz, A.; Melzer, E.; Lesyk, R. Ann Polish Chem Soc 2005,
1, 69.
[35] Carter, P. H.; Scherle, P. A.; Muckelbauer, J. A. Voss, M. E.;
Liu, R-Q.; Thompson, L. A.; Tebben, A. J.; Solomon, K. A.; Lo, Y. C.;
Li, Z.; Proc Natl Acad Sci USA 2001, 98, 11879.
[36] Liu, W.; Bulgaru, A.; Haigentz, M.; Stein, C. A.; Perez-Soler, R.;
Mani. S. Curr Med Chem: Anti-Cancer Agents 2003, 3, 217.
[37] Theocharis, S.; Margeli, A.; Kouraklis, G. Curr Med Chem:
Anti-Cancer Agents. 2003, 3, 239.
[38] Luk’yanchuk, V. D.; Renzyak, S. Ya.; Atamanyuk, D. V.,
Lesyk, R. B. Liky (in Ukrainian) 2006, 3, 56.
[39] Lesyk, R. B.; Zimenkovsky, B. S. Curr Org Chem 2004, 8,
1547.
[40] Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.;
Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A. J Natl
Cancer Inst 1991, 83, 757.
[41] Boyd, M. R.; Paull, K. D. Drug Dev Res 1995, 34, 91.
[42] Monks, A.; Scudiero, D. A.; Johnson, G. S.; Paull, K. D.;
Sausville, E. A. Anti-Cancer Drug Des 1997, 12, 533.
[17] Omokawa, H.; Tabei, A. Biosci Biotechnol Biochem 2002, 66,
1959.
[18] Dinku, W.; Megersa, N.; Raju, V. J. T.; Solomon, T.; Jonsson,
J. A.; Retta, N. Bull Chem Soc Ethiopia 2003, 17, 35.
[19] Silverman, F. P.; Petracek, P. D.; Heiman, D. F.; Ju, Z.;
Fledderman, C. M.; Warrior, P. J Agric Food Chem 2005, 53, 9769.
[20] Cosman, F.; Lindsay, R. Endocr Rev 1999, 20, 418.
[21] Henke, B. R.; Consler, T. G.; Go, N.; Hale, R. L.; Hohman, D.
R.; Jones, S. A.; Lu, A. T.; Moore, L. B.; Moore, J. T.; Orband-Miller, L.
A.; Robinett, R. G.; Shearin, J.; Spearing, P. K.; Stewart, E. L.; Turnbull,
P. S.; Weaver, S. L.; Williams, S. P.; Wisely, G. B.; Lambert, M. H. J Med
Chem 2002, 45, 5492.
[22] Desai, N. C.; Bhatt, J. J.; Shah, B. R.; Trivedi, P. B.; Undavia,
N. K. Indian J Exp Biol 1996, 34, 584.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet