Synthesis and Antinociceptive Activity of N-Substituted 4-Aryl-4-oxo-2-[(3-thiophen-2-yl)amino]but-2-enamides

Article abstract of DOI:10.1134/S1070363220040040

Abstract: 2-{[5-Aryl-2-oxofuran-3(2H)-ylidene]amino}thiophene-3-carboxylic acid derivatives reacted with substituted amines to give new N-substituted 4-aryl-4-oxo-2-[(3-thiophen-2-yl)amino]but-2-enamides. Antinociceptive activity of the synthesized compou

Full text of DOI:10.1134/S1070363220040040

ISSN 1070-3632, Russian Journal of General Chemistry, 2020, Vol. 90, No. 4, pp. 583–589. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Obshchei Khimii, 2020, Vol. 90, No. 4, pp. 513–521.
Synthesis and Antinociceptive Activity of N-Substituted
4-Aryl-4-oxo-2-[(3-thiophen-2-yl)amino]but-2-enamides
S. A. Shipilovskikha,b,*, V. Y. Vaganova, R. R. Makhmudova, and A. E. Rubtsova
aPerm State University, Perm, 614990 Russia
bUral Federal University, Yekaterinburg, 620002 Russia
*e-mail: shipilovskikh@psu.ru
Received November 25, 2019; revised November 25, 2019; accepted November 28, 2019
Abstract—2-{[5-Aryl-2-oxofuran-3(2H)-ylidene]amino}thiophene-3-carboxylic acid derivatives reacted with
substituted amines to give new N-substituted 4-aryl-4-oxo-2-[(3-thiophen-2-yl)amino]but-2-enamides. Antinoci-
ceptive activity of the synthesized compounds was studied.
Keywords: antinociceptive activity, Gewald reaction, 2,4-dioxobutanoic acids, 3-(thiophen-2-yl)iminofuran-
2(3H)-one
DOI: 10.1134/S1070363220040040
Substituted Gewald aminothiophene derivatives are
important heterocycles found in numerous biologically
active and natural compounds [1–10]. Interest in this
type of heterocycle starts from the chemistry of dyes to
the modern design of drugs and much more. Generally,
substituted 2-aminothiophenes with an electron-
withdrawing group, such as cyano, ester or amide at
position 3 and alkyl, aryl or hetaryl groups at position 4
or 5, can be obtained using the Gewald reaction [11–13].
2-enoic acids [20]. Herein, we proposed studies in
the synthesis of new 3-thienylimino-3H-furan-2-ones
and studied their reactions with aliphatic, aromatic,
heteroaromatic and disubstituted amines.
The starting 3-thienylimino-3H-furan-2-ones 2a–2e
were prepared according to the known methods [16] by
intramolecular cyclization of the corresponding 4-aryl-
4-oxo-2-thienylaminobut-2-enoic acids 1a–1e in acetic
anhydride. Compounds 2d and 2e were obtained for the
first time (Scheme 1).
Compounds containing 3-imino-3H-furan-2-one in
their structure are represented in the literature by few
examples of their preparation [14, 15]. Previously, we
have proposed a simple method for the preparation of a
number of ethyl esters of 2-[5-aryl-2-oxofuran-3(2H)-
ylideneamino]-4,5,6,7-tetrahydrobenzo[b]thiophene-
3-carboxylic acids by intramolecular cyclization
of (Z)-4-aryl-4-oxo-2-[3-(ethoxycarbonyl)-4,5,6,7-
tetrahydrobenzo[b]thiophen-2-ylamino]but-2-enoic acids
under the action of acetic anhydride [16], and also their
chemical properties were studied [17–19]. At the same
time, this rare type of derivatives of 3-thienylimino-3H-
furan-2-one seems to be very promising from the point
of view of high reactivity and the possible presence of
biologically active compounds in the series of furan
derivatives.
The IR spectra of compounds 2d and 2e contain
absorption bands of stretching vibrations of the lactone
carbonyl group of the furan ring at 1791–1794 cm–1 and
C=N bonds at 1599–1606 cm–1. In the 1H NMR spectra,
the singlet of the vinyl C4H proton of the furan ring is
observed at 7.22–7.23 ppm.
The reaction of 3-thienylimino-3H-furan-2ones
2a–2e with alkyl, aryl, hetaryl, and disubstituted amines
in an inert aprotic solvent proceeds with the formation
of N-substituted butenoic acid amides 4a–4n in yields
of up to 97% (Scheme 1). It was found that the reaction
proceeded through attack of the amino group at the carbon
atom of the lactone C=O group of compounds 2a–2e and
led to the products of the furan ring opening. The ester
group does not participate in the reaction with amines,
which does not contradict the literature data [21–23].
It has been previously shown that 3-thienylimino-3H-
furan-2-ones recyclize upon reaction with aliphatic amines
to form amides of 4-aryl-4-oxo-2-thienylaminobut-
Compounds 4a–4n are crystalline orange or yellow
substances. In the IR spectra of amides 4a–4n, there is an
583

584
SHIPILOVSKIKH et al.
Scheme 1.
absorption band of the NH group of the amide fragment
in the 3123–3395 cm–1 region and an absorption band of
the carbonyl group at 1652–1694 cm–1.
In CDCl3 solutions, compounds 4a and 4b are in two
forms, A and B. The presence of two forms in solutions of
deuterated chloroform seems to be associated with greater
thermodynamic stability due to several intramolecular
hydrogen bonds of form B, which are destroyed by the
more polar DMSO-d6, and the gain in energy becomes
predominant for solvated form B. Form A is characterized
by a proton singlet of the NH group involved into a
strong intramolecular hydrogen bond (13.14–14.86 ppm),
proton of the CH group (6.20–7.23 ppm) and a proton
signal of the NHCO group (5.91–9.73 ppm). Form B is
We studied the 1H NMR spectra of compounds 4a–4n
in DMSO-d6 and CDCl3 solutions. It was found that
compounds 4a, 4e, 4g–4i, 4k–4n in DMSO-d6 solutions
exist in form A and are characterized by a proton singlet
of the NH group involved into a strong intramolecular
hydrogen bonding (12.38–13.58 ppm), proton signals of
the group NHCO (8.13–10.94 ppm) and a singlet of the
proton of the CH group (6.12–6.48 ppm).
Table 1. Antinociceptive activity of compounds 4a–4g, 4i, 4j, 4l–4na
Compound
Dosage, mg/kg
The latent period of the defensive reflex (120 min), s
4a
4b
4d
4d
4e
4f
4g
4i
4j
50
50
50
50
50
50
50
50
50
19.80 ± 1.24
14.80 ± 0.49
15.60 ± 0.75
23.70 ± 3.23
19.00 ± 1.22
17.20 ± 1.77
15.60 ± 1.33
16.20 ± 1.71
18.20 ± 0.20
19.00 ± 0.84
16.10 ± 1.50
24.90 ± 1.18
16.33 ± 3.02
p < 0.1
4l
4m
4n
50
50
50
Metamizole sodium
93 (ED50)
Diclofenac sodium
Control
a Reliability compared to control p < 0.05.
10
–
26.20 ± 0.96
10.30 ± 0.60
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SYNTHESIS AND ANTINOCICEPTIVE ACTIVITY OF N-SUBSTITUTED
585
characterized by a singlet of the proton of the NH group
(12.31–13.89 ppm), a signal of the proton of the amide
group (12.22–12.41 ppm), and a singlet of a proton of
the CH group (6.06–7.05 ppm).
procedure described in [26]; compounds 1a–1d have
been described previously.
2-[(3-(Aminocarbonyl)-4,5,6,7-tetrahydrobenzo[b]-
thiophen-2-yl)amino]-4-(4-methylphenyl)-4-oxobut-2-
enoic acid (1e). Yield 3.08 g (80%), red crystals, mp 150–
151°С (dioxane). IR spectrum, ν, cm–1: 1634 (CONH2),
According to 1H NMR data, in a DMSO-d6 solution,
disubstituted amides 4f and 4l exist in two conformations,
mainly in a conformation with a larger group in a transoid
1
3189, 3396 (NH2). Н NMR spectrum (DMSO-d6), δ,
1
ppm: 1.57 m (2Н, CH2), 1.91 m (2Н, CH2), 2.45 s (3Н,
CH3), 2.79 m (4Н, CH2), 5.89 br. s (2H, NH2), 7.01 s
(1H, C=CH), 7.33 m (2Н, HAr), 7.94 m (2Н, HAr), 12.65
s (1Н, NH). Found, %: С 62.45; Н 5.25; N 7.31; S 8.36.
С20H20N2O4S. Calculated, %: С 62.48; Н 5.24; N 7.29;
S 8.34.
position with respect to the oxygen atom. In H NMR
spectra, the Z-conformation is characterized by the NH
proton singlet at 13.53–13.57 ppm involved into the
intramolecular hydrogen bond and the CH proton singlet
at 6.21–6.24 ppm. The proton singlet corresponds to the
E-conformer NH groups at 13.46–13.49 ppm involved
into the intramolecular hydrogen bond, and a proton
singlet of the CH group at 6.16–6.19 ppm.
The substituted 3-thienylimino-3H-furan-2-ones 2a–
2e were obtained according to the procedure described in
[16]; compounds 2a–2c have been described previously.
Earlier, antinociceptive activity has been detected
in similar compounds [24, 25]; therefore, some of the
obtained compounds were also studied on antinociceptive
activity (Table 1). From the data obtained it follows that
all the studied compounds have a pronounced analgesic
effect. The most active compounds 4d and 4n are
comparable in action to diclofenac sodium. It was found
that the introduction of an antipyryl substituent into
the amide fragment increases the activity of compound
4d, while the introduction of a benzocaine fragment
led to a significant decrease in activity. However, the
replacement of the ester substituent at position 3 of the
thiophene ring with an amide also led to a significant
increase in the analgesic effect of compound 4n. The data
presented indicate the feasibility of further study of the
antinociceptive activity of the obtained amides in order to
search for substances with a pronounced analgesic effect.
Ethyl 4,5-dimethyl-2-{[2-oxo-5-phenylfuran-3(2H)-
ylidene]amino}thiophene-3-carboxylate (2d). Yield
2.91 g (82%), dark red crystals, mp 169–170°С (toluene).
IR spectrum, ν, cm–1: 1606 (С=N), 1715 (COOEt), 1794
(COlactone). 1Н NMR spectrum (DMSO-d6), δ, ppm: 1.31 t
(3H, CH3CH2O, J = 6.6 Hz), 2.13 s (3Н, CH3), 2.44 s
(3Н, CH3), 4.31 q (2H, CH3CH2O, J = 6.6 Hz), 7.23 s
(1H, HAr), 7.61 m (3Н, HAr), 8.02 m (2Н, HAr). 13C NMR
spectrum (DMSO-d6), δС, ppm: 12.1, 13.6, 14.1, 60.9,
98.3, 126.6, 126.7, 129.2, 132.5, 132.9, 135.3, 137.4,
145.2, 146.1, 162.6, 164.1, 165.6. Found, %: C 64.20; H
4.85; N 3.93; S 9.00. C19H17NO4S. Calculated, %: 64.21;
H 4.82; N 3.94; S 9.02.
2-{[5-(4-Methylphenyl)-2-oxofuran-3(2H)-ylidene]-
amino}-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxamide (2e). Yield 3.08 g (84%), red crystals, mp
231–232°C (toluene). IR spectrum, ν, cm–1: 1599 (С=N),
1658 (CONH2), 1791 (COlactone), 3165, 3348 (NH2). 1Н
NMR spectrum (DMSO-d6), δ, ppm: 1.78 m (2H, СН2),
1.84 m (2H, СН2), 2.44 s (3H, CH3), 2.84 m (4H, 2СН2),
7.22 s (1H, HAr), 7.31 br. s (1Н, NH2), 7.42 m (2Н, HAr),
7.92 m (2Н, HAr), 8.08 br. s (1Н, NH2). Found, %: C
65.57; H 4.97; N 7.63; S 8.75. C20H18N2O3S.Calculated,
%: C 65.55; H 4.95; N 7.64; S 8.75.
EXPERIMENTAL
IR spectra were recorded on an FSM-1202 instrument
1
from liquid paraffin. H and 13C NMR spectra were
recorded on a Bruker Avance III instrument (400 and
100 MHz) from CDCl3 and DMSO-d6 solutions relative to
residual signals of the non-deuterated solvent. Elemental
analysis was performed on a Leco CHNS-932 instrument.
Reaction progress and individuality of obtained
compounds was monitored by TLC on Sorbfil plates,
eluting with a diethyl ether–benzene–acetone system
(10 : 9 : 1); detecting in UV light and iodine vapor.
Melting points were determined on an SMP40 instrument.
General procedure forthe synthesis ofN-substituted
amides of 4-aryl-4-oxo-2-[(3-thiophen-2-yl)amino]-
but-2-enoic acids 4a–4n. A mixture of 0.001 mol of
compound 2a–2e and 0.001 mol of the corresponding
amine 3a–3k in anhydrous toluene (20 mL) was stirred
at 50°С for 2 h. After cooling the precipitate was filtered
off and recrystallized.
The initial substituted 4-aryl-4-oxo-2-thienylaminobut-
2-enoic acids 1a–1e were obtained according to the
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SHIPILOVSKIKH et al.
Ethyl 2-{[1-(adamantylamino)-1,4-dioxo-4-phenyl-
HAr), 7.35 m (2H, HAr), 7.69 m (3H, HAr), 8.09 m (2H,
HAr), 10.35 s (1Н, NН), 13.78 s (1Н, NH). Found, %: С
65.90; Н 5.57; N 5.15; S 5.82. C30H30N2O6S. Calculated,
%: С 65.92; Н 5.53; N 5.12; S 5.86.
but-2-en-2-yl]amino}-4,5,6,7-tetrahydrobenzo[b]thio-
phene-3-carboxylate (4a). Yield 0.52 g (97%), orange
crystals, mp 200–201°C (acetonitrile). IR spectrum,
ν, cm–1: 1665 br (CONH, COOEt), 3179, 3280 (NH).
1Н NMR spectrum (DMSO-d6), δ, ppm: 1.39 t (3H,
CH3CH2O, J = 7.1 Hz), 1.70 m (6H, CH2), 1.74 m (7H,
2CH2 + 3CH), 2.11 m (6H, CH2), 2.63 m (2H, CH2), 2.75 m
(2H, CH2), 4.39 q (2H, CH3CH2O, J = 7.1 Hz), 6.20 s
(1H, C=CH), 7.57 m (2H, HAr), 7.65 m (1H, HAr), 8.03 m
(2H, HAr), 8.58 s (1H, NH), 13.27 s (1H, NH). 1Н NMR
spectrum (CDCl3), δ, ppm: form A (46%), 1.38 m (3H,
Ме), 1.78 m (6H, CH2), 2.10 m (7H, 2CH2 + 3CH), 2.23 m
(6H, CH2), 2.72 m (4H, CH2), 4.40 m (2H, CH3CH2O),
5.91 s (1H, NH), 6.17 s (1H, C=CH), 7.48 m (3H, HAr),
7.96 m (2H, HAr), 13.14 s (1H, NH); form B (54%), 1.38 m
(3H, Ме), 1.78 m (6H, CH2), 2.10 m (7H, 2CH2 +
3CH), 2.23 m (6H, CH2), 2.72 m (4H, CH2), 4.40 m
(2H, CH3CH2O), 7.05 s (1H, C=CH), 7.48 m (3H, HAr),
7.96 m (2H, HAr), 12.22 s (1H, NH), 12.31 s (1H, NH).
Found, %: С 69.93; Н 6.80; N 5.22; S 6.07. C31H36N2O4S.
Calculated, %: С 69.90; Н 6.81; N 5.26; S 6.02.
Ethyl 2-{[1,4-dioxo-1-(4-antipyrylamino)-4-phenyl-
but-2-en-2-yl]amino}4,5,6,7-tetrahydrobenzo[b]-
thiophen-3-carboxylate (4d). Yield 0.41 g (70%), orange
crystals, mp 203–204°C (toluene). IR spectrum, ν, cm–1:
1664 (CONH), 1712 (COOEt), 3123, 3236 br (NH). 1Н
NMR spectrum (CDCl3), δ, ppm: 1.40 t (3H, CH3CH2O,
J = 7.1 Hz), 1.78 m (4Н, СН2), 2.08 s (3H, Me), 2.59 m
(2H, CH2), 2.79 m (2H, CH2), 3.06 s (3H, NCH3), 4.36 q
(2H, CH3CH2O, J = 7.1 Hz), 6.27 s (1Н, С=CH), 7.37 m
(10H, HAr), 8.39 s (1H, NH), 10.33 s (1Н, NH). Found,
%: С 65.70; Н 5.53; N 9.55; S 5.47. C32H32N4O5S.
Calculated, %: С 65.73; Н 5.52; N 9.58; S 5.48.
Ethyl 2-{[1,4-dioxo-1-(piperidin-1-yl)-4-phenylbut-
2-en-2-yl]amino}-4,5,6,7-tetrahydrobenzo[b]thio-
phene-3-carboxylate (4e). Yield 0.31 g (67%), orange
crystals, mp 128–129°С (acetonitrile). IR spectrum, ν,
cm–1: 1681 (CONH), 1726 (COOEt), 3370 br (NH).
1Н NMR spectrum (DMSO-d6), δ, ppm: 1.36 t (3H,
CH3CH2O, J = 7.1 Hz), 1.56 m (6Н, СН2), 1.73 m (4Н,
СН2), 2.72 m (2H, CH2), 3.61 m (4H, NCH2), 4.39 q (2H,
CH3CH2O, J = 7.1 Hz), 6.22 s (1Н, С=CH), 7.52 m (2H,
HAr), 7.60 m (1H, HAr), 8.01 m (2H, HAr), 13.61 s (1Н,
NH). Spectral data coincided with those reported in [6].
Ethyl 2-{[1,4-dioxo-1-(phenylamino)-4-phenylbut-
2-en-2-yl]amino}-4,5,6,7-tetrahydrobenzo[b]thiophene-
3-carboxylate (4b). Yield 0.42 g (89%), orange crystals,
mp188–190°С(isopropanol).IRspectrum,ν,cm–1:1675br
(CONH, COOEt), 3188, 3312 (NH). 1Н NMR spectrum
(CDCl3), δ, ppm: form А (50%), 1.25 t (3H, CH3CH2O,
J = 7.1 Hz), 1.66 m (4H, CH2), 2.37 m (2H, CH2), 2.54 m
(2H, CH2), 4.15 m (2Н, CH3CH2O), 7.23 m (1Н, С=CH;
2H, HAr), 7.52 m (4H, HAr), 7.84 m (2H, HAr), 8.08 m
(2H, HAr), 9.73 s (1Н, NН), 14.86 s (1Н, NH); form B
(50%), 1.44 t (3H, CH3CH2O, J = 7.1 Hz), 1.87 m (4H,
CH2), 2.75 m (2H, CH2), 2.87 m (2H, CH2), 4.45 m (2Н,
CH3CH2O), 6.06 s (1Н, С=CH), 7.23 m (2H, HAr), 7.52 m
(4H, HAr), 7.84 m (2H, HAr), 8.08 m (2H, HAr), 12.41 s
(1Н, NН), 13.89 s (1Н, NH). Found, %: С 68.30; Н 5.56;
N 5.92; S 6.75. C27H26N2O4S. Calculated, %: С 68.33;
Н 5.52; N 5.90; S 6.76.
Ethyl 2-({1-[benzyl(ethyl)amino]-1,4-dioxo-
4-phenylbut-2-en-2-yl}amino)-4,5,6,7-tetrahydro-
benzo[b]thiophen-3-carboxylate (4f). Yield 0.32 g
(62%), yellow crystals, mp 119–120°C (acetonitrile).
IR spectrum, ν, cm–1: 1652 (CONH), 1715 (COOEt),
3380 br (NH). 1Н NMR spectrum (DMSO-d6), δ, ppm:
Z-conformer (57%), 1.13 m (3H, CH3), 1.33 m (3H,
CH3), 1.73 m (4H, CH2), 2.48 m (2H, CH2), 2.71 m (2H,
CH2), 3.32 m (2H, CH2N), 4.36 m (2H, CH2O), 4.61 m
(2H, CH2Ph), 6.24 s (1H, C=CH), 7.37 m (5H, HAr),
7.57 m (3H, HAr), 8.02 m (2H, HAr), 13.57 s (1H, NH);
E-conformer (43%), 1.13 m (3H, CH3), 1.33 m (3H, CH3),
1.73 m (4H, CH2), 2.48 m (2H, CH2), 2.62 m (2H, CH2),
3.25 m (2H, CH2N), 4.36 m (2H, CH2O), 4.71 m (2H,
CH2Ph), 6.19 s (1H, C=CH), 7.37 m (5H, HAr), 7.57 m
(3H, HAr), 7.76 m (2H, HAr), 13.49 s (1H, NH). Spectral
data coincided with those reported in [6].
Ethyl 2-[(1,4-dioxo-1-{[4-(ethoxycarbonyl)phenyl]-
amino}-4-phenylbut-2-en-2-yl)amino]-4,5,6,7-
tetrahydro-benzo[b]thiophene-3-carboxylate (4c).
Yield 0.38 g (70%), orange crystals, mp 179–180°С
(isopropanol). IR spectrum, ν, cm–1: 1688 (CONH), 1706,
1
1719 (COOEt), 3223, 3389 (NH). Н NMR spectrum
Ethyl 2-{[1-(adamantylamino)-1,4-dioxo-4-
(4-methoxyphenyl)but-2-en-2-yl]amino}-4,5,6,7-
tetrahydrobenzo[b]thiophen-3-carboxylate (4g).
Yield 0.47 g (83%), orange crystals, mp 200–202°С
(CDCl3), δ, ppm: 1.31 m (3H, CH3), 1.39 m (3H, CH3),
1.73 m (4H, CH2), 2.50 m (2H, CH2), 2.69 m (2H, CH2),
4.27 m (4Н, CH2O), 5.98 s (1Н, С=CH), 7.19 m (2H,
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SYNTHESIS AND ANTINOCICEPTIVE ACTIVITY OF N-SUBSTITUTED
587
(acetonitrile). IR spectrum, ν, cm–1: 1686 br (CONH,
COOEt), 3311 (NH). 1Н NMR spectrum (DMSO-d6), δ,
ppm: 1.37 t (3H, CH3CH2O, J = 7.1 Hz), 1.69 m (6H,
CH2), 1.76 m (7H, 2CH2 + 3CH), 2.09 m (6H, CH2),
2.59 m (2H, CH2), 2.73 m (2H, CH2), 3.87 s (3H, ОCH3),
4.37 q (2H, CH3CH2O, J = 7.1 Hz), 6.12 s (1H, C=CH),
7.05 m (2H, HAr), 7.97 m (2H, HAr), 8.13 s (1H, NH),
13.00 s (1H, NH). 13C NMR spectrum (DMSO-d6), δC,
ppm: 14.1, 22.1, 22.5, 24.1, 25.9, 28.9, 36.0, 40.5, 113.9,
114.3, 126.9, 129.5, 131.3, 132.5, 148.0, 151.3, 162.4,
162.6, 163.0, 188.4. Found, %: С 68.33; Н 6.80; N 4.95;
S 5.72. C32H38N2O5S. Calculated, %: С 68.30; Н 6.81;
N 4.98; S 5.70.
Yield 0.53 g (97%), yellow crystals, mp 113–115°С
(acetonitrile). IR spectrum, ν, cm–1: 1694 br (COOEt,
CONH2), 3370 br (NH). 1Н NMR spectrum (DMSO-d6),
δ, ppm: Z-conformer (57%), 1.13 m (3H, CH3), 1.33 m
(3H, CH3), 1.72 m (4H, CH2), 2.46 m (2H, CH2), 2.69 m
(2H, CH2), 3.31 m (2H, CH2N), 3.86 s (3H, OCH3),
4.35 m (2H, OCH2), 4.65 m (2H, CH2Ph), 6.21 s (1H,
C=CH), 7.05 m (2H, HAr), 7.36 m (5H, HAr), 8.01 m
(2H, HAr), 13.53 s (1H, NH); E-conformer (43%), 1.13 m
(3H, CH3), 1.33 m (3H, CH3), 1.72 m (4H, CH2), 2.61 m
(2H, CH2), 2.69 m (2H, CH2), 3.31 m (2H, CH2N), 3.84 s
(3H, OCH3), 4.35 m (2H, OCH2), 4.65 m (2H, CH2Ph),
6.16 s (1H, C=CH), 7.05 m (2H, HAr), 7.36 m (5H, HAr),
7.77 m (2H, HAr), 13.46 s (1H, NH). 13C NMR spectrum
(DMSO-d6), δC, ppm: Z-conformer, 12.6, 14.1, 22.0, 22.3,
23.9, 25.9, 46.5, 55.4, 60.1, 94.2, 113.9, 114.5, 126.3,
127.4, 128.2, 129.0, 129.5, 130.8, 132.8, 135.8, 146.8,
150.3, 162.6, 162.8, 163.5, 187.9; E-conformer, 10.9,
14.1, 22.0, 22.4, 24.0, 26.0, 42.6, 50.1, 60.1, 94.7, 113.8,
114.4, 126.2, 127.1, 127.3, 128.2, 129.4, 130.7, 132.9,
135.9, 146.9, 159.8, 162.6, 162.8, 163.8, 187.8. Spectral
data coincided with those reported in [6].
Ethyl 2-{[1,4-dioxo-4-(4-methoxyphenyl)-1-
(cyclohexylamino)but-2-en-2-yl]amino}-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (4h).
Yield 0.36 g (70%), yellow crystals, mp 177–179°С
(acetonitrile). IR spectrum, ν, cm–1: 1660 (CONH), 1719
(COOEt), 3270 br (NH). 1Н NMR spectrum (DMSO-d6),
δ, ppm: 1.26 m (6H, CH2), 1.36 t (3H, CH3CH2O, J =
7.2 Hz), 1.73 m (8H, CH2), 2.58 m (2H, CH2), 2.71 m
(2H, CH2), 3.69 m (1H, CH), 3.86 s (3Н, ОCH3), 4.36 q
(2H, CH3CH2O, J = 7.2 Hz), 6.18 s (1H, C=CH), 7.06 m
(2H, HAr), 7.99 m (2H, HAr), 8.85 d (1H, NH J = 7.7 Hz),
13.13 s (1H, NH). 13C NMR spectrum (DMSO-d6), δC,
ppm: 14.2, 22.1, 22.4, 24.0, 24.4, 25.1, 25.9, 31.5, 48.2,
55.4, 60.0, 96.6, 113.9, 125.8, 129.6, 130.9, 132.4, 148.1,
150.5, 162.2, 162.6, 163.1, 188.3. Found, %: С 65.90,
H 6.76, N 5.47, S 6.28. C28H34N2O5S. Calculated, %: С
65.86, H 6.71, N 5.49, S 6.28.
Ethyl (Z)-2-{[1,4-dioxo-1-(diethylamino)-4-
(4-methoxyphenyl)but-2-en-2-yl]amino}-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate
(4k). Yield 0.30 g (62%), orange crystals 99–101°С
(acetonitrile). IR spectrum, ν, cm–1: 1677 br (CON), 1710
(COOEt), 3368 br (NH). 1Н NMR spectrum (DMSO-d6),
δ, ppm: 1.13 t (3H, CH3CH2N, J = 7.0 Hz), 1.20 t (3H,
CH3CH2N, J = 7.1 Hz), 1.36 t (3H, CH3CH2O, J =
7.1 Hz), 1.73 m (4H, CH2), 2.58 m (2H, CH2), 2.71 m
(2H, CH2), 3.35 q (2H, CH3CH2N, J = 7.0 Hz), 3.46 m
(2H, CH3CH2N), 3.85 s (3H, OCH3), 4.38 q (2H,
CH3CH2O, J = 7.1 Hz), 6.13 s (1H, C=CH), 7.04 m (2H,
HAr), 8.00 m (2H, HAr), 13.58 s (1H, NH). 13C NMR
spectrum (DMSO-d6), δC, ppm: 11.6, 13.0, 14.1, 22.0,
22.3, 23.9, 25.9, 38.6, 42.7, 55.4, 60.1, 94.2, 113.9,
114.0, 126.1, 129.5, 130.8, 132.8, 147.1, 150.2, 162.6,
162.9, 163.0, 187.8. Found, %: С 64.44, H 6.68, N 5.81,
S 6.65. C26H32N2O5S. Calculated, %: С 64.44, H 6.66,
N 5.78, S 6.62.
Ethyl 2-{[1,4-dioxo-1-morpholino-4-(4-methoxy-
phenyl)but-2-en-2-yl]amino}-4,5,6,7-tetrahydro-
benzo[b]thiophene-3-carboxylate (4i). Yield 0.33 g
(67%), yellow crystals, mp 104–106°С (acetonitrile). IR
spectrum, ν, cm–1: 1679 (CONH2), 1712 (COOEt), 3395
br (NH). 1Н NMR spectrum (DMSO-d6), δ, ppm: 1.36 t
(3H, CH3CH2O, J = 7.1 Hz). 1.74 m (4H, CH2), 2.60 m
(2H, CH2), 2.70 m (2H, CH2), 3.60 m (8H, CH2), 3.86 s
(3H, OCH3), 4.38 q (2H, CH3CH2O, J = 7.1 Hz), 6.25 s
(1H, C=CH), 7.04 m (2H, HAr), 8.01 m (2H, HAr), 13.53 s
(1H, NH). 13C NMR spectrum (DMSO-d6), δC, ppm: 14.1,
22.0, 22.4, 23.9, 26.0, 41.5, 46.8, 55.4, 60.1, 65.1, 65.2,
94.9, 113.8, 113.9, 126.0, 129.7, 130.8, 132.8, 148.8,
147.1, 162.1, 162.6, 163.0, 187.9. Spectral data coincided
with those reported in [6].
Ethyl 2-{[1,4-dioxo-4-(4-chlorophenyl)-1-
(cyclohexylamino)but-2-en-2-yl]amino}-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (4l).
Yield 0.27 g (53%), dark orange crystals, mp 164–166°С
(isopropanol). IR spectrum, ν, cm–1: 1679 (CONH), 1708
(COOEt), 3310 br (NH). 1Н NMR spectrum (DMSO-d6),
δ, ppm: 1.32 m (6H, CH2), 1.37 t (3H, CH3CH2O, J =
Ethyl 2-({1-[benzyl(ethyl)amino]-1,4-dioxo-4-
(4-methoxyphenyl)but-2-en-2-yl}amino)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (4j).
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SHIPILOVSKIKH et al.
7.1 Hz), 1.73 m (8H, CH2), 2.59 m (2H, CH2), 2.71 m
(2H, CH2), 3.69 m (1H, CH), 4.36 q (2H, CH3CH2O, J =
7.1 Hz), 6.19 s (1H, C=CH), 7.59 m (2H, HAr), 8.02 m
(2H, HAr), 8.89 d (1H, NH, J = 7.7 Hz), 13.20 s (1H,
NH). 13C NMR spectrum (DMSO-d6), δC, ppm: 14.1,
22.0, 22.4, 24.0, 24.37, 25.1, 25.90, 31.5, 48.3, 60.1, 96.2,
114.4, 126.6, 128.7, 129.2, 132.5, 136.9, 137.2, 147.4,
151.6, 161.9, 163.0, 188.0. Found, %: С 62.92; H 6.10;
N 5.41; S 6.24. C27H31ClN2O4S. Calculated, %: С 62.96;
H 6.07; N 5.44; S 6.22.
The indicator of the change in pain sensitivity was
the length of time the animals stay on the hot plate until
a defensive pain reflex occurs—licking the hind legs or
trying to tear off all four paws from the surface of the
plate. The time of onset of this reflex from the beginning
of the placement of the animal on the plate was measured
in sec (latent period). The maximum duration of the latent
period is the interval of 40 s. In the experiment we used
animals with the initial time of the onset of the defensive
reflex of no more than 15 sec. Each compound was tested
on 6 animals. The results were evaluated by increasing
the time of the onset of the defensive reflex compared
with the initial data.
Ethyl 2-({1,4-dioxo-1-[(4-methoxyphenyl)amino]-
but-2-en-2-yl}amino-4-phenyl)-4,5-dimethyl-
thiophene-3-carboxylate (4m). Yield 0.38 g (80%),
orange crystals, mp 210–211°С (acetonitrile). IR
spectrum, ν, cm–1: 1668 (CONH), 1702 (COOEt), 3288 br
(NH). 1Н NMR spectrum (DMSO-d6), δ, ppm: 1.39 t (3H,
CH3CH2O, J = 7.2 Hz), 2.16 s (3H, CH3), 2.18 s (3H,
CH3), 3.75 s (3H, ОCH3), 4.39 q (2H, CH3CH2O, J =
7.2 Hz), 6.48 s (1H, C=CH), 6.96 m (2H, HAr), 7.32 m
(2H, HAr), 7.56 m (3H, HAr), 8.06 m (2H, HAr), 10.94 s
(1H, NH), 13.28 s (1H, NH). Found, %: С 65.28; H 5.44;
N 5.87; S 6.72. C26H26N2O5S. Calculated, %: С 65.25;
H 5.48; N 5.85; S 6.70.
The control group of animals was injected with 2%
starch mucus. Metamizole sodium (Farmkhimkomplekt
LLC) at a dose of 93 mg/kg (ED50), ibuprofen (EnSiFarm)
at a dose of 50 mg/kg, diclofenac sodium (AlfaAesar®) at
a dose of 10 mg/kg were used as comparison compounds.
Statistical processing of experimental data was carried
out using Student's confidence criteria. The effect was
considered significant at p <0.05 [29].
The studies are carried out in accordance with all
applicable international, national and institutional
guidelines for the care and use of animals.
2-{[1-(Benzylamino)-1,4-dioxo-4-(4-methoxy-
phenyl)but-2-en-2-yl]amino}-4,5,6,7-tetra-
hydrobenzo[b]thiophene-3-carboxamide (4n). Yield
0.43 g (87%), yellow crystals, mp 215–217°C (toluene).
IR spectrum, ν, cm–1: 1652 (CONH2, CONH), 3191 br
(NH), 3291, 3373 (NH2). 1Н NMR spectrum (DMSO-d6),
δ, ppm: 1.71 m (4H, CH2), 2.50 m (2H, CH2), 2.57 m
(2H, CH2), 3.82 s (3H, OCH3), 4.37 d (2Н, СН2N, J =
5.8 Hz), 6.19 s (1Н, С=CH), 7.01 m (2H, HAr), 7.59 m
(5H, HAr), 7.44 br. s (2H, NH2), 7.96 m (2H, HAr), 9.55 t
(1H, NH, J = 5.8 Hz), 12.38 s (1Н, NH). Found, %: С
66.25; Н 5.53; N 8.59; S 6.52. C27H27N3O4S. Calculated,
%: С 66.24; Н 5.56; N 8.58; S 6.55.
FUNDING
This work was financially supported by the Russian
Foundation for Basic Research (project no. 19-43-590023).
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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