Synthesis and Biological Activity of Pyrazolo[1,5-c][1,3]benzoxazines Containing a Thiazolidin-4-one Fragment

Article abstract of DOI:10.1134/S1070428020040053

Abstract: 5-[4-(2-Aryl-1,10b-dihydropyrazolo[1,5-c][1,3]benzoxazin-5-yl)benzylidene]-1,3-thiazolidin-4-ones weresynthesized by reactions of4-[(3-R-2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzaldehydes with2-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)phenols and evaluated for antitumor andanti-inflammatory activities.

Full text of DOI:10.1134/S1070428020040053

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 4, pp. 588–595. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Organicheskoi Khimii, 2020, Vol. 56, No. 4, pp. 538–546.
Synthesis and Biological Activity
of Pyrazolo[1,5-c][1,3]benzoxazines Containing
a Thiazolidin-4-one Fragment
V. Y. Horishnya, L. Z. Mandzyukb, R. Z. Lytvync, O. V. Bodnarchukb,
V. S. Matiychukc, and M. D. Obushakc,*
a Danylo Halitsky Lviv National Medical University, Lviv, 79010 Ukraine
b Ivano-Frankivsk National Medical University, Ivano-Frankivsk, 76018 Ukraine
c Ivan Franko National University of Lviv, Lviv, 79005 Ukraine
*e-mail: mykola.obushak@lnu.edu.ua
Received September 13, 2019; revised January 17, 2020; accepted January 17, 2020
Abstract—5-[4-(2-Aryl-1,10b-dihydropyrazolo[1,5-c][1,3]benzoxazin-5-yl)benzylidene]-1,3-thiazolidin-4-
ones were synthesized by reactions of 4-[(3-R-2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzaldehydes with
2-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)phenols and evaluated for antitumor and anti-inflammatory activities.
Keywords: pyrazolo[1,5-c][1,3]oxazines, 1,3-benzoxazines, thiazolidine-2,4-diones, rhodanine, antitumor
activity, anti-inflammatory activity
DOI: 10.1134/S1070428020040053
Fused aza heterocycles possess a combination of
practically useful properties and therefore constantly
attract researchersʼ attention. They exhibit various bio-
logical activities and are used as pharmaceuticals [1].
Many natural compounds, e.g., alkaloids, also contain
fused aza heterocycles as structural fragments [2, 3]. In
continuation of our studies [4–9] of the synthesis and
biological properties of fused nitrogen heterocycles,
we have developed a synthetic approach to 1,10b-dihy-
dropyrazolo[1,5-c][1,3]benzoxazines with a pharmaco-
phoric 4-oxothiazolidine moiety, and the synthesized
compounds have been evaluated for antitumor and
anti-exudative activities. It should be noted that
1,10b-dihydropyrazolo[1,5-c][1,3]benzoxazines consti-
tute a poorly explored heterocyclic system. The reac-
tion of 2-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)phenols
with carbonyl compounds is virtually the only accept-
able preparative method of synthesis of these hetero-
cycles. Reactions of pyrazolylphenols with aromatic
aldehydes and ketones [10–12] and cyclic ketones
[12–14] have been reported. Biological activity of
1,10b-dihydropyrazolo[1,5-c][1,3]benzoxazines also
remains poorly studied. In particular, there are
published data on their antimicrobial [14] and mol-
luscicidal properties [15], and some derivatives have
been found to act as 5-HT2B serotonin receptor antag-
onists [13].
The present study was aimed at synthesizing thia-
zolidin-4-one–pyrazolo[1,5-c][1,3]benzoxazine con-
jugates and evaluating them for antitumor and anti-
inflammatory activities. In contrast to pyrazolo-
[1,5-c][1,3]benzoxazine derivatives, biological activity
of compounds containing a 4-oxothiazolidine moiety
has been well documented. These compounds exhibit
a broad spectrum of biological activity, and some
derivatives are used as medicines; therefore, 4-oxothia-
zolidine fragment is considered a privileged structure
in medicinal chemistry [16–18]. It should also be em-
phasized that both antitumor and anti-inflammatory
agents have been found among 5-arylmethylidene
derivatives of thiazolidin-4-ones [16–18]. A combina-
tion of the privileged 4-oxothiazolidine fragment with
pyrazolo[1,5-c][1,3]benzoxazine system could give
rise to novel pharmacologically active compounds with
important properties.
In the first stage of our study we developed a proce-
dure for the synthesis of 4-[(4-oxo-1,3-thiazolidin-5-
ylidene)methyl]benzaldehydes 3a–3c. For this purpose,
terephthalaldehyde (1) was reacted with 1,3-thiazoli-
dine-2,4-dione (2a), 3-methyl-2-sulfanylidene-1,3-thia-
588

SYNTHESIS AND BIOLOGICAL ACTIVITY OF PYRAZOLO[1,5-c][1,3]BENZOXAZINES
589
Scheme 1.
X
CHO
O
O
O
S
AcOH
N
R
+
R
N
+
N
R
R
N
S
CHO
S
S
O
X
X
CHO
X
1
2a–2c
3a–3c (60–73%)
4a–4c (7.5–12%)
2–4, R = H, X = O (a), R = Me, X = S (b), R = 4-MeOC6H4CH2CH2, X = S (c).
zolidin-4-one (2b), and 3-[2-(4-methoxyphenyl)ethyl]-
2-sulfanylidene-1,3-thiazolidin-4-one (2c). The reac-
tions were carried out in acetic acid using a slight
excess of dialdehyde 1. Apart from the target aldehydes
3a–3c, minor 1 : 2 condensation products 4a–4c were
formed (Scheme 1). Compounds 3 and 4 were separat-
ed by crystallization from acetic acid due to significant
difference in their solubilities.
We then studied reactions of aldehydes 3a–3c with
2-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)phenols 5a–5e
which were prepared from salicylaldehyde and substi-
tuted acetophenones [14]. By heating equimolar
amounts of 3a–3c and 5a–5e in boiling ethanol (or
ethanol–DMF, 1 : 1) for 0.5–1 h we obtained
5-[4-(2-aryl-1,10b-dihydropyrazolo[1,5-c][1,3]benz-
oxazin-5-yl)benzylidene]-1,3-thiazolidin-4-ones 6–8
Scheme 2.
R
R
R
O
N
NH
O
3a
3b
3c
S
N
O
6a–6e
R
O
Me
N
N
S
S
N
N
N
O
H
OH
5a–5e
7a–7e
O
N
OMe
N
S
S
N
O
8a–8e
5–8, R = H (a), 4-Me (b), 3-MeO (c), 4-MeO (d), 4-Cl (e).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 4 2020

HORISHNY et al.
590
(Scheme 2). The products were isolated as high-
melting white (6) or light yellow (7, 8) solids readily
soluble on heating in DMF and DMSO and sparingly
soluble in acetic acid.
carrageenan in the control group and test sample-
treated group, respectively. For comparison, the anti-
exudative effect of standard anti-inflammatory drugs
(diclofenac, ketorolac, indomethacin, and phenylbuta-
zone) was evaluated under similar conditions. The
results are summarized in Table 2. The anti-exudative
effect of compounds 6a and 6d was comparable with
those of indomethacin and ketorolac but slightly
weaker than the effect of diclofenac and phenyl-
butazone.
Molecules 6–8 possess two chiral centers, and they
could be formed as different diastereoisomers or their
mixtures. In fact, some compounds were individual
isomers, while the others were mixtures of diastereo-
isomers at different ratios. No distinct relations in the
stereochemical results were found. This suggests pos-
sible interconversion of the isomers, which could be
favored by the presence of traces of acids [10]. The
diastereoisomer ratios were determined from the inten-
sities of the 10b-H and 5-H signals whose positions
were significantly different for the different isomers.
One isomer was characterized by a doublet at δ 4.76–
4.82 (10b-H) and a singlet at δ 6.7–6.9 ppm (5-H), and
the other displayed a doublet at δ 5.39–5.46 (10b-H)
and a singlet at δ 6.30– 6.35 ppm (5-H).
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian
Mercury spectrometer at 400 MHz using DMSO-d6 as
solvent and tetramethylsilane as internal standard. The
elemental analyses were obtained with a Carlo Erba
1106 analyzer. The melting points were measured on
a Boetius melting point apparatus.
Commercially available reagents (Merck, Acros
Organics) with a purity of no less than 97% were used.
Compounds 6–8 were subjected to highly efficient
antitumor screening according to the Developmental
Therapeutic Program of the US National Institutes of
Health (National Cancer Institute, Bethesda, Maryland,
USA) [19–21]. The antitumor activity was assayed in
vitro in 60 cancer cell lines covering almost all human
malignancies at a single dose concentration of 10–5 M.
The antitumor activity was evaluated as cancer cell
growth percentage (GP, %) relative to control (Table 1)
[19–21]. The most active were rhodanine derivatives
7a and 8a against CCRF-CEM leukemia with GP
values of 37.38, and 36.63%, respectively. Substitution
in the benzene ring led to loss of cytostatic effect on
that cancer cell line. Renal cancer cell line UO-31
turned out to be one of the most sensitive to all tested
compounds (GP 62.51–84.00%).
4-[(2,4-Dioxo-1,3-thiazolidin-5-ylidene)methyl]-
benzaldehyde (3a). Thiazolidine-2,4-dione (2a), 9.4 g
(80 mmol), terephthalaldehyde (1), 13.4 g (0.1 mol),
and fused sodium acetate, 6.6 g (80 mmol), were
dissolved in 100 mL of hot acetic acid with stirring.
The mixture was slowly cooled to 45–50°C and kept
for 10 days at that temperature. The mixture was
cooled, and the precipitate was filtered off, washed
with acetic acid and ethanol, and dried. The product
was heated in 600 mL of boiling acetic acid and filtered
while hot to separate undissolved compound 4a. The
filtrate was cooled, and the precipitate of aldehyde 3a
was filtered off and recrystallized from propan-2-ol.
1
Yield of 3a 13.4 g (71%), mp 249–251°C. H NMR
spectrum, δ, ppm: 7.80 d (2H, C6H4, J = 8.4 Hz), 7.85 s
(1H, CH=), 8.02 d (2H, C6H4, J = 8.4 Hz), 10.04 s (1H,
CHO), 12.77 br.s (1H, NH). Found, %: C 56.38;
H 2.87; N 6.13. C11H7NO3S. Calculated, %: C 56.64;
H 3.03; N 6.01.
The anti-inflammatory activity of compounds 6a–
6e was evaluated using the rat paw edema assay [22].
Outbred white rats with a weight of 180–250 g were
injected under aseptic conditions with 0.1 mL of
a 2% carrageenan solution under the hind paw
aponeurosis (subplantar injection), and the paw volume
was measured by the oncometric method before the
injection and 4 h after the injection. Test compounds
were administered intraperitoneally 1 h before carra-
geenan injection. The percent inhibition of edema was
calculated by the formula
(5Z,5′Z)-5,5′-[1,4-Phenylenedimethylidene]di-
(1,3-thiazolidine-2,4-dione) (4a) was recrystallized
from DMF–AcOH. Yield 1.0 g (7.5%), mp ˃ 270°C.
1H NMR spectrum, δ, ppm: 7.71 s (4H, C6H4), 7.79 s
(2H, CH=), 12.70 br.s (2H, NH). Found, %: 50.70;
H 2.58; N 8.32. C14H8N2O4S2. Calculated, %: C 50.59;
H 2.43; N 8.43.
4-[(3-Methyl-4-oxo-2-sulfanylidene-1,3-thiazoli-
din-5-ylidene)methyl]benzaldehyde (3b) was synthe-
sized as described above for 3a; the mixture was heated
at 45–50°C for 48 h. Yield 15.36 g (73%), mp 192–
(ΔVcontr – ΔVtest)/ΔVcontr × 100%,
where ΔVcontr and ΔVtest are the average differences in
the paw volumes before and after the injection of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 4 2020

SYNTHESIS AND BIOLOGICAL ACTIVITY OF PYRAZOLO[1,5-c][1,3]BENZOXAZINES
591
Table 1. Cytotoxicity of compounds 6a–6e, 7a–7e, and 8a–8e at a single-dose concentration of 10–5 M against most sensitive
cancer cell lines
Mitotic activity
Compound no.
GP range, %
Most sensitive cancer cell lines; GP, %
LOX IMVI (melanoma); 67.87
UO-31 (renal cancer); 74.75
6a
6b
67.87–112.01
CHB-75 (CNS cancer); 86.96
LOX IMVI (melanoma); 69.02
UO-31 (renal cancer); 68.55
T-47D (breast cancer); 81.49
68.55–114.17
EKVX (non-small-cell lung cancer); 85.43
LOX IMVI (melanoma); 70.48
UO-31 (renal cancer); 73.17
6c
70.48–118.50
67.40–112.15
LOX IMVI (melanoma); 67.40
UO-31 (renal cancer); 71.63
6d
EKVX (non-small-cell lung cancer); 77.55
LOX IMVI (melanoma); 68.61
IGROV1 (ovarian cancer); 76.70
UO-31 (renal cancer); 62.51
6e
62.51–121.22
CCRF-CEM (leukemia); 37.38
CHB-75 (CNS cancer); 78.49
CAKI-1 (renal cancer); 77.24
UO-31 (renal cancer); 69.39
7a
7b
37.38–137.62
66.30–113.67
CHB-75 (CNS cancer); 76.22
CAKI-1 (renal cancer); 73.60
UO-31 (renal cancer); 66.30
MOLT-4 (leukemia); 81.81
CHB-75 (CNS cancer); 81.26
UO-31 (renal cancer); 77.59
7c
7d
7e
8a
8b
77.59–123.58
71.88–118.48
71.76–119.33
36.63–117.37
78.59–116.61
CAKI-1 (renal cancer); 71.88
UO-31 (renal cancer); 72.23
NCI-H522 (non-small-cell lung cancer); 83.96
CAKI-1 (renal cancer); 83.84
UO-31 (renal cancer); 71.76
CCRF-CEM (leukemia); 36.63
UO-31 (renal cancer); 80.71
CHB-75 (CNS cancer); 81.93
CAKI-1 (renal cancer); 83.76
UO-31 (renal cancer); 78.59
8c
82.05–107.32
84.00–113.65
UO-31 (renal cancer); 82.05
EKVX (non-small-cell lung cancer); 88.77
UO-31 (renal cancer); 84.00
8d
EKVX (non-small-cell lung cancer); 81.45
CHB-75 (CNS cancer); 77.16
8e
68.13–118.06
UO-31 (renal cancer); 68.13
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 4 2020

HORISHNY et al.
Table 2. Anti-exudative activity of compounds 6a–6e and some reference drugs
592
Compound no.
Dose, mg/kg
Paw volume increase after 4 h, %
Inflammation inhibition, %
6a
50
50
50
50
50
–
82.0
120.7
96.2
82.7
90.2
131.7
74.3
80.9
84.4
72.4
37.7
8.4
6b
6c
27.0
37.2
31.6
–
6d
6e
Control
Diclofenac
Ketorolac
Indomethacin
Phenylbutazone
8
43.6
38.6
35.9
45.0
10
10
50
1
5-[4-(2-Aryl-1,10b-dihydropyrazolo[1,5-c]-
[1,3]benzoxazin-5-yl)benzylidene]-1,3-thiazolidin-4-
ones 6–8 (general procedure). Aldehyde 3, 1 mmol,
was dissolved in 30 mL of boiling ethanol (3a) or
DMF–ethanol (1:1, 3b, 3c), and 1 mmol of 2-(3-aryl-
4,5-dihydro-1H-pyrazol-5-yl)phenol 5a–5e was added
with stirring to the hot solution. The mixture was
refluxed for 0.5–1 h, and the precipitate was filtered off
from the hot mixture, washed with ethanol, dried, and
recrystallized from DMF–ethanol.
193°C (from AcOH). H NMR spectrum, δ, ppm:
3.42 s (3H, CH3), 7.85 d (2H, C6H4, J = 8.0 Hz), 7.88 s
(1H, CH=), 8.04 d (2H, C6H4, J = 8.0 Hz), 10.06 s
(1H, CHO). Found, %: C 54.58; H 3.31; N 5.47.
C12H9NO2S2. Calculated, %: C 54.73; H 3.44; N 5.32.
(5Z,5′Z)-5,5′-[1,4-Phenylenedimethylidene]di-
(3-methyl-2-sulfanylidene-1,3-thiazolidine-2,4-
dione) (4b) was isolated as described above for 4a.
Yield 1.7 g (11%), mp ˃ 270°C (from DMF). 1H NMR
spectrum, δ, ppm: 3.44 s (6H, CH3), 7.75 s (4H, C6H4),
7.91 s (2H, CH=). Found, %: 49.15; H 3.18; N 6.95.
C16H12N2O2S4. Calculated, %: C 48.96; H 3.08; N 7.14.
5-[4-(2-Phenyl-1,10b-dihydropyrazolo[1,5-c]-
[1,3]benzoxazin-5-yl)benzylidene]-1,3-thiazolidine-
2,4-dione (6a). Yield 0.38 g (84%), mp 220–221°C.
1H NMR spectrum, δ, ppm: 3.31–3.35 m (1H, CH2),
3.50–3.61 m (1H, CH2), 4.80 d (0.4H, 10b-H, J =
9.4 Hz), 5.44 d (0.6H, 10b-H, J = 9.1 Hz), 6.33 s (0.4H,
5-H), 6.83–6.95 m (1.6H, Harom, 5-H), 7.01–7.06 m
(1H, Harom), 7.12–7.19 m (1H, Harom), 7.25–7.56 m
(6H, H, Harom), 7.61 d (0.6H, Harom, J = 8.5 Hz), 7.65–
7.79 m (3H, Harom), 7.86–7.87 m (1.4H, Harom, CH=),
12.68 br.s (1H, NH). Found, %: C 68.75; H 4.17;
N 9.20. C26H19N3O3S. Calculated, %: C 68.86; H 4.22;
N 9.27.
4-({3-[2-(4-Methoxyphenyl)ethyl]-4-oxo-2-sul-
fanylidene-1,3-thiazolidin-5-ylidene}methyl)benz-
aldehyde (3c) was synthesized as described above for
3b. Yield 18.4 g (60%), mp 165–166°C (from i-PrOH).
1H NMR spectrum, δ, ppm: 2.89 t (2H, CH2, J =
7.6 Hz), 3.71 s (3H, CH3O), 4.20 t (2H, CH2N, J =
7.6 Hz), 6.85 d (2H, C6H4, J = 8.4 Hz), 7.13 d (2H,
C6H4, J = 8.4 Hz), 7.84 d (2H, C6H4, J = 8.4 Hz),
7.85 s (1H, CH=), 8.04 d (2H, C6H4, J = 8.4 Hz),
10.06 s (1H, CHO). Found, %: C 62.53; H 4.35;
N 3.72. C20H17NO3S2. Calculated, %: C 62.64; H 4.47;
N 3.65.
5-{4-[2-(4-Methylphenyl)-1,10b-dihydropyra-
zolo[1,5-c][1,3]benzoxazin-5-yl]benzylidene}-1,3-
thiazolidine-2,4-dione (6b). Yield 0.38 g (81%),
(5Z,5′Z)-5,5′-[1,4-Phenylenedimethylidene]bis-
{3-[2-(4-methoxyphenyl)ethyl]-2-sulfanylidene-1,3-
thiazolidine-2,4-dione} (4c) was isolated as described
above for 4a. Yield 3.0 g (12%), mp 263–264°C (from
1
mp 218–219°C. H NMR spectrum, δ, ppm: 2.26 s
(1H, CH3), 2.31 s (2H, CH3), 3.26–3.34 m (1H, CH2),
3.47–3.58 m (1H, CH2), 4.78 d (0.67H, 10b-H, J =
9.4 Hz), 5.41 d (0.33H, 10b-H, J = 9.4 Hz), 6.31 s
(0.33H, 5-H), 6.85–6.94 m (2.33H, Harom, 5-H), 6.99–
7.08 m (1H, Harom), 7.10–7.29 m (3.33H, Harom), 7.40 d
(0.67H, Harom, J = 8.1 Hz), 7.56–7.62 m (2.67H, Harom),
7.65–7.73 m (2H, Harom), 7.76 s (0.67H, CH=), 7.82–
1
DMF). H NMR spectrum, δ, ppm: 2.92 t (4H, CH2,
J = 7.2 Hz), 3.73 s (6H, CH3O), 4.25 t (4H, CH2N, J =
7.2 Hz), 6.86 d (4H, C6H4, J = 8.4 Hz), 7.14 d (4H,
C6H4, J = 8.4 Hz), 7.75–7.77 m (6H, C6H4, CH=).
Found, %: C 60.85; H 4.51; N 4.29. C32H28N2O4S4.
Calculated, %: C 60.73; H 4.46; N 4.43.
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SYNTHESIS AND BIOLOGICAL ACTIVITY OF PYRAZOLO[1,5-c][1,3]BENZOXAZINES
593
7.89 m (1H, Harom, CH=), 12.67 br.s (1H, NH).
Found, %: C 69.19; H 4.50; N 8.81. C27H21N3O3S.
Calculated, %: C 69.36; H 4.53; N 8.99.
(1H, CH2, J = 16.4, 9.5 Hz), 5.44 d (1H, 10b-H, J =
9.1 Hz), 6.34 s (1H, 5-H), 6.87 d (1H, Harom, J =
8.1 Hz), 7.03 t (1H, Harom, J = 7.4 Hz), 7.17 t (1H,
Harom, J = 7.8 Hz), 7.28 d (1H, Harom, J = 7.5 Hz),
7.30–7.36 m (3H, Harom), 7.50–7.54 m (2H, Harom),
7.76 d (2H, Harom, J = 8.2 Hz), 7.87–7.91 m (3H,
Harom, CH=). Found, %: C 67.14; H 4.30; N 8.81.
C27H21N3O2S2. Calculated, %: C 67.06; H 4.38;
N 8.69.
5-{4-[2-(3-Methoxyphenyl)-1,10b-dihydropyra-
zolo[1,5-c][1,3]benzoxazin-5-yl]benzylidene}-1,3-
thiazolidine-2,4-dione (6c). Yield 0.42 g (87%),
1
mp 222–223°C. H NMR spectrum, δ, ppm: 3.31–
3.35 m (1H, CH2), 3.52–3.55 m (1H, CH2), 3.71 s
(1.38H, OCH3), 3.78 s (1.62H, OCH3), 4.80 d (0.54H,
10b-H, J = 9.5 Hz), 5.43 d (0.46H, 10b-H, J = 9.0 Hz),
6.32 s (0.46H, 5-H), 6.82–7.36 m (8.54H, Harom, 5-H),
7.61 d (1H, Harom, J = 8.4 Hz), 7.68 d (1H, Harom, J =
8.4 Hz), 7.71 d (1H, Harom, J = 8.4 Hz), 7.76 s (0.54H,
CH=), 7.85–7.87 m (1.46H, Harom, CH=), 12.67 br.s
(1H, NH). Found, %: C 67.15; H 4.47; N 8.48.
C27H21N3O4S. Calculated, %: C 67.07; H 4.38; N 8.69.
3-Methyl-5-{4-[2-(4-methylphenyl)-1,10b-dihy-
dropyrazolo[1,5-c][1,3]benzoxazin-5-yl]benzyli-
dene}-2-sulfanylidene-1,3-thiazolidin-4-one (7b).
1
Yield 0.48 g (96%), mp 232–234°C. H NMR spec-
trum, δ, ppm: 2.25 s (3H, CH3), 3.31 d (1H, CH2, J =
16.7 Hz), 3.42 s (3H, NCH3), 3.50 d.d (1H, CH2, J =
16.7, 9.2 Hz), 5.41 d (1H, 10b-H, J = 9.2 Hz), 6.33 s
(1H, 5-H), 6.87 d (1H, Harom, J = 8.2 Hz), 7.02 t (1H,
Harom, J = 7.8 Hz), 7.10–7.20 m (3H, Harom), 7.27 d
(1H, Harom, J = 7.6 Hz), 7.40 d (2H, Harom, J = 8.1 Hz),
7.76 d (2H, Harom, J = 8.4 Hz), 7.84–7.92 m (3H,
Harom, CH=). Found, %: C 67.38; H 4.61; N 8.32.
C28H23N3O2S2. Calculated, %: C 67.58; H 4.66;
N 8.44.
5-{4-[2-(4-Methoxyphenyl)-1,10b-dihydropyra-
zolo[1,5-c][1,3]benzoxazin-5-yl]benzylidene}-1,3-
thiazolidine-2,4-dione (6d). Yield 0.40 g (83%),
1
mp 216–217°C. H NMR spectrum, δ, ppm: 3.31–
3.34 m (1H, CH2), 3.43–3.57 m (1H, CH2), 3.72 s
(1.2H, OCH3), 3.77 s (1.8H, OCH3), 4.76 d (0.6H,
10b-H, J = 9.2 Hz), 5.39 d (0.4H, 10b-H, J = 9.1 Hz),
6.30 s (0.4H, 5-H), 6.83–6.98 m (4H, Harom, 5-H),
6.99–7.06 m (1H, Harom), 7.11–7.19 m (1H, Harom),
7.26 d (0.6H, Harom, J = 7.4 Hz), 7.45 d (1H, Harom, J =
8.9 Hz), 7.58–7.73 m (4H, Harom), 7.76 s (0.6H, CH=),
7.83–7.88 m (1.4H, Harom, CH=), 12.67 br.s (1H, NH).
Found, %: C 66.92; H 4.24; N 8.67. C27H21N3O4S.
Calculated, %: C 67.07; H 4.38; N 8.69.
5-{4-[2-(3-Methoxyphenyl)-1,10b-dihydropyra-
zolo[1,5-c][1,3]benzoxazin-5-yl]benzylidene}-3-
methyl-2-sulfanylidene-1,3-thiazolidin-4-one (7c).
1
Yield 0.46 g (89%), mp 201–203°C. H NMR spec-
trum, δ, ppm: 3.32–3.35 m (1H, CH2), 3.39 s (1H,
NCH3), 3.42 s (2H, NCH3), 3.47–3.60 m (1H, CH2),
3.71 s (2H, OCH3), 3.78 s (1H, OCH3), 4.79 d (0.33H,
10b-H, J = 9.2 Hz), 5.43 d (0.67H, 10b-H, J = 9.2 Hz),
6.34 s (0.67H, 5-H), 6.84–7.37 m (7.33H, Harom, 5-H),
7.65–7.72 m (1H, Harom), 7.75–7.81 m (2H, Harom),
7.85–7.91 m (3H, Harom, CH=). Found, %: C 65.27;
H 4.41; N 8.09. C28H23N3O3S2. Calculated, %:
C 65.48; H 4.51; N 8.18.
5-{4-[2-(4-Chlorophenyl)-1,10b-dihydropyra-
zolo[1,5-c][1,3]benzoxazin-5-yl]benzylidene}-1,3-
thiazolidine-2,4-dione (6e). Yield 0.44 g (90%),
1
mp 223–224°C. H NMR spectrum, δ, ppm: 3.31–
3.36 m (1H, CH2), 3.50–3.61 m (1H, CH2), 4.82 d
(0.6H, 10b-H, J = 9.4 Hz), 5.46 d (0.4H, 10b-H, J =
5-{4-[2-(4-Methoxyphenyl)-1,10b-dihydropyra-
zolo[1,5-c][1,3]benzoxazin-5-yl]benzylidene}-3-
methyl-2-sulfanylidene-1,3-thiazolidin-4-one (7d).
9.2 Hz), 6.34 s (0.4H, 5-H), 6.85–6.97 m (2.4H, Harom
,
5-H), 7.01–7.05 m (1H, Harom), 7.12–7.20 m (1H,
Harom), 7.27 d (0.4H, Harom, J = 7.6 Hz), 7.39 d (0.8H,
Harom, J = 8.5 Hz), 7.47 d (1.2H, Harom, J = 8.5 Hz),
1
Yield 0.48 g (94%), mp 225–227°C. H NMR spec-
trum, δ, ppm: 3.31–3.36 m (1H, CH2), 3.40 s (1H,
NCH3), 3.42 s (2H, NCH3), 3.46–3.58 m (1H, CH2),
3.73 s (2H, OCH3), 3.78 s (1H, OCH3), 4.77 d (0.33H,
10b-H, J = 9.3 Hz), 5.40 d (0.67H, 10b-H, J = 9.1 Hz),
6.30 s (0.67H, 5-H), 6.84–6.98 m (3.67H, Harom, 5-H),
7.01–7.07 m (1H, Harom), 7.12–7.19 m (1H, Harom),
7.27 d (0.67H, Harom, J = 7.8 Hz), 7.43–7.48 m (1.33H,
7.52 d (0.8H, Harom, J = 8.6 Hz), 7.61 d (1.2H, Harom
,
J = 8.3 Hz), 7.65–7.74 m (3H, Harom), 7.76 s (0.6H,
CH=), 7.83–7.88 m (1.2H, Harom, CH=), 12.66 br.s
(1H, NH). Found, %: C 64.13; H 3.59; N 8.46.
C26H18ClN3O3S. Calculated, %: C 64.00; H 3.72;
N 8.61.
3-Methyl-5-[4-(2-phenyl-1,10b-dihydropyra-
zolo[1,5-c][1,3]benzoxazin-5-yl)benzylidene]-2-
sulfanylidene-1,3-thiazolidin-4-one (7a). Yield 0.46 g
(95%), mp 222–224°C. H NMR spectrum, δ, ppm:
3.34–3.36 m (1H, CH2), 3.43 s (3H, CH3), 3.54 d.d
Harom), 7.60–7.73 m (2H, Harom), 7.75 d (1.33H, Harom
,
J = 8.4 Hz), 7.79 s (0.33H, CH=), 7.89 m (2H, Harom
,
CH=). Found, %: C 65.57; H 4.40; N 8.12.
C28H23N3O3S2. Calculated, %: C 65.48; H 4.51;
N 8.18.
1
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HORISHNY et al.
594
5-{4-[2-(4-Chlorophenyl)-1,10b-dihydropyra-
zolo[1,5-c][1,3]benzoxazin-5-yl]benzylidene}-3-
3.53 d.d (1H, CH2, J = 16.9, 9.6 Hz), 3.72 s (6H,
CH3O), 4.22 t (2H, CH2N, J = 6.9 Hz,), 5.44 d (1H,
10b-H, J = 9.6 Hz), 6.33 s (1H, 5-H), 6.80–7.33 m
(12H, Harom), 7.75 d (2H, Harom, J = 7.9 Hz), 7.84 s
(1H, CH=), 7.89 d (2H, Harom, J = 7.7 Hz). Found, %:
C 68.08; H 4.84; N 6.47. C36H31N3O4S2. Calculat-
ed, %: C 68.22; H 4.93; N 6.63.
methyl-2-sulfanylidene-1,3-thiazolidin-4-one (7e).
1
Yield 0.50 g (97%), mp 246–248°C. H NMR spec-
trum, δ, ppm: 3.37 d (1H, CH2, J = 16.4 Hz), 3.43 s
(3H, CH3), 3.54 d.d (1H, CH2, J = 16.4, 9.7 Hz), 5.46 d
(1H, 10b-H, J = 9.7 Hz), 6.35 s (1H, 5-H), 6.88 d (1H,
H
arom, J = 8.1 Hz), 7.03 t (1H, Harom, J = 7.5 Hz), 7.18 t
5-{4-[2-(4-Methoxyphenyl)-1,10b-dihydropyra-
zolo[1,5-c][1,3]benzoxazin-5-yl]benzylidene}-3-[2-
(4-methoxyphenyl)ethyl]-2-sulfanylidene-1,3-thia-
zolidin-4-one (8d). Yield 0.53 g (84%), mp 203–
(1H, Harom, J = 7.9 Hz), 7.27 d (1H, Harom, J = 8.0 Hz),
7.39 d (2H, Harom, J = 8.6 Hz), 7.52 d (2H, Harom, J =
8.5 Hz), 7.76 d (2H, Harom, J = 8.3 Hz), 7.84–7.91 m
(3H, Harom, CH=). Found, %: C 62.41; H 3.77; N 7.98.
C27H20ClN3O2S2. Calculated, %: C 62.60; H 3.89;
N 8.11.
1
205°C. H NMR spectrum, δ, ppm: 2.82–2.94 m (2H,
NCH2CH2), 3.28–3.34 m (1H, CH2), 3.43–3.58 m (1H,
CH2), 3.70 s (3H, CH3O), 3.77 s (3H, CH3O), 4.14–
4.26 m (2H, CH2N), 4.76 d (0.8H, 10b-H, J = 9.2 Hz),
5.40 d (0.2H, 10b-H, J = 9.4 Hz), 6.31 s (0.2H, 5-H),
3-[2-(4-Methoxyphenyl)ethyl]-5-[4-(2-phenyl-
1,10b-dihydropyrazolo[1,5-c][1,3]benzoxazin-5-yl)-
benzylidene]-2-sulfanylidene-1,3-thiazolidin-4-one
6.21–7.76 m (11.2H, Harom, 5-H), 7.27 d (0.2H, Harom
,
1
(8a). Yield 0.57 g (94%), mp 204–206°C. H NMR
J = 7.5 Hz), 7.45 d (0.4H, Harom, J = 8.6 Hz), 7.58–
7.91 m (6H, Harom, CH=). Found, %: C 68.13; H 4.79;
N 6.58. C36H31N3O4S2. Calculated, %: C 68.22;
H 4.93; N 6.63.
spectrum, δ, ppm: 2.91 t (2H, NCH2CH2, J = 7.7 Hz),
3.31–3.35 m (1H, CH2), 3.54 d.d (1H, CH2, J = 16.4,
9.4 Hz), 3.72 s (3H, CH3O), 4.22 t (2H, CH2N, J =
7.7 Hz), 4.81 d (0.1H, 10b-H, J = 9.3 Hz), 5.44 d
(0.9H, 10b-H, J = 9.4 Hz), 6.34 s (0.9H, 5-H), 6.83–
6.94 m (3.1H, Harom), 7.03 t (1H, Harom, J = 7.6 Hz),
7.11–7.19 m (3H, Harom), 7.25–7.36 m (3H, Harom),
7.47–7.54 m (2H, Harom), 7.65–7.69 m (1H, Harom),
7.76 d (2H, Harom, J = 8.0 Hz), 7.85 s (1H, CH=),
7.89 d (2H, Harom, J = 8.1 Hz). Found, %: C 69.50;
H 4.65; N 6.91. C35H29N3O3S2. Calculated, %:
C 69.63; H 4.84; N 6.96.
5-{4-[2-(4-Chlorophenyl)-1,10b-dihydropyra-
zolo[1,5-c][1,3]benzoxazin-5-yl]benzylidene}-3-[2-
(4-methoxyphenyl)ethyl]-2-sulfanylidene-1,3-thia-
zolidin-4-one (8e). Yield 0.56 g (88%), mp 208–
1
210°C. H NMR spectrum, δ, ppm: 2.91 t (2H,
NCH2CH2, J = 7.7 Hz), 3.31–3.34 m (1H, CH2),
3.54 d.d (1H, CH2, J = 17.5, 9.7 Hz), 3.71 s (3H,
CH3O), 4.22 t (2H, CH2N, J = 7.7 Hz), 5.46 d (1H,
10b-H, J = 9.3 Hz), 6.35 s (1H, 5-H), 6.85–6.95 m (3H,
Harom), 7.03 t (1H, Harom, J = 7.1 Hz), 7.11–7.20 m (3H,
Harom), 7.27 d (1H, Harom, J = 7.8 Hz), 7.38 d (2H,
Harom, J = 8.4 Hz), 7.52 d (2H, Harom, J = 8.2 Hz),
7.75 d (2H, Harom, J = 8.2 Hz), 7.81–7.93 m (3H,
Harom, CH=). Found, %: C 66.04; H 4.48; N 6.51.
C35H28ClN3O3S2. Calculated, %: C 65.87; H 4.42;
N 6.58.
3-[2-(4-Methoxyphenyl)ethyl]-5-{4-[2-(4-methyl-
phenyl)-1,10b-dihydropyrazolo[1,5-c][1,3]benzoxa-
zin-5-yl]benzylidene}-2-sulfanylidene-1,3-thiazoli-
din-4-one (8b). Yield 0.51 g (83%), mp 204–206°C.
1
NMR spectrum H, δ, ppm: 2.26 s (3H, CH3), 2.85–
2.96 m (2H, NCH2CH2), 3.31–3.35 m (1H, CH2),
3.51 d.d (1H, CH2, J = 16.6, 9.2 Hz), 3.72 s (3H,
CH3O), 4.18–4.25 m (2H, CH2N), 5.42 d (1H, 10b-H,
J = 9.3 Hz), 6.31 s (1H, 5-H), 6.81–6.92 m (3H, Harom),
7.02 t (1H, Harom, J = 7.4 Hz), 7.12–7.23 m (5H, Harom),
7.27 d (1H, Harom, J = 7.6 Hz), 7.40 d (2H, Harom, J =
7.8 Hz), 7.75 d (2H, Harom, J = 7.8 Hz), 7.84 s (1H,
CH=), 7.89 d (2H, Harom, J = 8.0 Hz). Found, %:
C 70.12; H 5.14; N 6.67. C36H31N3O3S2. Calculat-
ed, %: C 69.99; H 5.06; N 6.80.
CONFLICT OF INTEREST
The authors declare the absence of conflict of interest.
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