Synthesis and antihypoxic activity of 5-aryl-4-aroyl-3-hydroxy-1-[2-(2-hydroxyethoxy)ethyl]-3-pyrrolin-2-ones

Article abstract of DOI:10.1134/S1070363215110109

Reactions of 2-(2-aminoethoxy)ethanol with mixtures of an aromatic aldehyde and aroylpyruvic acid methyl ester have afforded 5-aryl-4-aroyl-3-hydroxy-1-[2-(2-hydroxyethoxy)ethyl]-3-pyrrolin-2-ones. Antihypoxic activity of the synthesized compounds has bee

Full text of DOI:10.1134/S1070363215110109

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 11, pp. 2568–2570. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © V.L. Gein, S.N. Rogachev, A.A. Bobyleva, D.Yu. Apushkin, G.A. Veikhman, O.E. Nasakin, 2015, published in Zhurnal Obshchei
Khimii, 2015, Vol. 85, No. 11, pp. 1826–1829.
Synthesis and Antihypoxic Activity of 5-Aryl-4-aroyl-
3-hydroxy-1-[2-(2-hydroxyethoxy)ethyl]-3-pyrrolin-2-ones
V. L. Geina, S. N. Rogacheva, A. A. Bobylevaa,
D. Yu. Apushkina, G. A. Veikhmana, and O. E. Nasakinb
a Perm State Pharmaceutical Academy, Ministry of Health of the Russian Federation,
ul. Polevaya 2, Perm, 614990 Russia
e-mail: geinvl48@mail.ru
b Ulyanov Chuvash State University, Cheboksary, Russia
Received April 27, 2015
Abstract—Reactions of 2-(2-aminoethoxy)ethanol with mixtures of an aromatic aldehyde and aroylpyruvic
acid methyl ester have afforded 5-aryl-4-aroyl-3-hydroxy-1-[2-(2-hydroxyethoxy)ethyl]-3-pyrrolin-2-ones.
Antihypoxic activity of the synthesized compounds has been studied.
Keywords: 5-aryl-4-aroyl-3-hydroxy-1-[2-(2-hydroxy)ethyl]-3-pyrrolin-2-one, antihypoxic activity
DOI: 10.1134/S1070363215110109
Search for substances enhancing the body resistance
to negative environmental factors is a topical issue
nowadays. Study of antihypoxic activity of pyrrole-
2,3-diones derivatives is of interest, since represen-
tatives of this class exhibit nootropic activity [1], and
combination of these two properties would be
promising for practical applications.
solubility in water and antihypoxic activity of the
obtained compounds.
Using the known method [2], we performed
reactions of 2-(2-aminoethoxy)ethanol with mixtures
of an aromatic aldehyde and methyl aroylpyruvate
taken in equimolar ratio, in dioxane medium at room
temperature. Under those conditions, 5-aryl-4-aroyl-3-
hydroxy-1-[2-(2-hydroxyethyl)ethyl]-3-pyrrolin-2-ones
1–6 were obtained as the only reaction products
(Scheme 1, Table 1).
We targeted at preparation of tetrahydropyrrole-2,3-
diones with a hydrophilic 2-(2-hydroxyethoxy)ethyl
substituent at the position 1 of the heterocycle and at
elucidation of the structural changes effects on
Scheme 1.
O
O
O
OMe
O
R1
+
+
R2
H
H2N
OH
OH
O
O
R1
R2
N
O
O
OH
1_6
R1 = 4-СH3 (1, 3, 4), H (2), 4-Cl (5, 6); R2 = 2,4-Cl2C6H3 (1), 3-OHC6H4 (2), 3-pyridyl (3), 2-FC6H4 (4), 4-FC6H4 (5),
2-CH3OC6H4 (6).
2568

SYNTHESIS AND ANTIHYPOXIC ACTIVITY
Table 1. Physico-chemical parameters of compounds 1–6
2569
Found, %
Calculated, %
Comp. Yield,
mp, °С
Formula
no.
%
C
H
N
C
H
N
1
2
3
4
5
6
61.5
75.2
64.8
61.6
70.7
58.8
215–217 (EtOH)
193–195 (EtOH)
191–193 (EtOH)
232–234 (EtOH)
231–233 (EtOH)
174–176 (EtOH)
59.28
65.80
66.05
66.08
60.14
61.22
5.34
5.54
5.70
5.47
4.55
5.15
3.05
3.68
7.35
3.50
3.29
3.17
С23H25Cl2NO5
C21H21NO6
59.24
65.79
65.96
66.16
60.08
61.19
5.40
5.52
5.80
5.55
4.56
5.13
3.00
3.65
7.33
3.51
3.34
3.24
C21H22N2O5
C22H22FNO5
C21H19ClFNO5
C22H22ClNO6
Table 2. 1Н NMR (DMSO-d6) data for compounds 1–6
δ, ppm
Comp.
no.
Н
Ar (m)
ОН (s)
11.90
11.90
12.00
11.80
12.00
11.70
C1HAHB (m)
3.80
C1HAHB (m) CH2OCH2CH2OH (m)
other signals (s)
2.35 (3H1, CH3)
1
2
3
4
5
6
7.20
7.25
7.20
7.25
7.25
6.80
2.80
2.80
2.70
2.80
2.75
2.70
3.40
3.45
3.40
3.50
3.40
3.35
3.80
3.80
2.34 (3H1, CH3)
2.34 (3H1, CH3)
3.80
3.75
3.80
2.35 (3H1, CH3O)
The resulting compounds 1–6 were white crystal-
line substances, soluble in ethanol, dimethyl
sulfoxide, and dimethylformamide and insoluble in
water (Table 1).
All the synthesized compounds were assayed for
antihypoxic activity. The results revealed the highest
antihypoxic activity of compounds 4 and 6. The results
of 5-aryl-4-aroyl-3-hydroxy-1-[2-(2-hydroxyethoxy)-
ethyl]-3-pyrrolin-2-ones 1–6 assay under normobaric
hypoxia conditions are shown in Table 4.
The products structure was confirmed by the data
1
1
of IR and H NMR spectroscopy (Table 2). H NMR
spectra of compounds 1–6 contained the signals of
aromatic protons (6.80–7.25 ppm), two multiplets of
enantiotopic protons of the methylene group at
position 1 (2.75–2.80, 3.75–3.80 ppm), a multiplet of
other methylene protons (3.35–3.50 ppm), and a
singlet assigned to the hydroxyl group at position 3 of
the pyrroline ring (11.70–12.00 ppm) (Table 2).
EXPERIMENTAL
1H NMR spectra of the solutions in DMSO-d6 were
recorded using a Bruker AM-500 instrument at operat-
Table 3. IR spectral data for compounds 1–6
ν, cm–1
Comp.
IR spectra of compounds 1–6 (Table 3) contained
absorption bands due stretching of the lactam (1652–
1696 cm–1), ketone (1620–1632 cm–1), enol (3096–
3128 cm–1), and alcohol (3400–3470 cm–1) groups.
no.
CO
CОN
1692
1696
1652
1682
1692
1664
ОН
CH2OH
3400
3470
3430
3450
3432
3470
1
2
3
4
5
6
1620
1624
1624
1625
1632
1632
3096
3120
3112
3128
3118
3112
Solutions of all the obtained compounds revealed
deep cherry coloration after treatment with alcoholic
solution of iron(III) chloride. That reaction along with
the spectroscopy data indicated existence of com-
pounds 1–6 in the enol form.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 11 2015

2570
GEIN et al.
Table 4. 5-Aryl-4-aroyl-3-hydroxy-1-[2-(2-hydroxyethoxy)ethyl]-3-pyrrolin-2-ones 1–6 towards antihypoxic activity under
normobaric hypoxia conditions
Exp. no.
1
Reference
25.00
1
2
3
4
5
6
30.00
32.00
22.00
32.00
26.00
32.00
2
3
4
5
6
26.00
25.00
30.00
22.00
29.00
26.17
25.00
24.00
23.00
20.00
24.00
24.33
28.00
25.00
29.00
35.00
30.00
29.83
24.00
21.00
23.00
25.00
25.00
23.33
31.00
28.00
30.00
29.00
33.00
30.50
28.00
24.00
25.00
27.00
29.00
26.50
34.00
30.00
29.00
31.00
32.00
31.33
Average
Confidence interval
% increase relative to the reference group
23.10–29.24 20.91–27.76 26.23–33.43 21.62–25.05 28.54–32.46 24.54–28.46 29.50–33.17
–7.01 14.01 –10.83 16.56 1.27 19.75
ing frequency of 500 MHz relative to internal TMS. IR
spectra of the suspensions in mineral oil were
registered with a SPECORD M-80 spectrometer.
Melting points were determined using a Melting-
PointM-565 apparatus. Elemental analysis was per-
formed with a Perkin Elmer 2400 instrument.
was injected with a required amount of 0.9% sodium
chloride solution. Lifetime of the mice (in minutes)
was determined.
ACKNOWLEDGMENTS
This work was financially supported by the Russian
Science Foundation (project no. 15-13-10029).
5-Aryl-4-aroyl-3-hydroxy-1-[2-(2-hydroxyethoxy)-
ethyl]-3-pyrrolin-2-ones (1–6). A solution of 0.05 mol
of methyl aroylpyruvate in 10 mL of dioxane was
mixed with equimolar amounts of an aromatic
aldehyde and 2-(2-aminoethoxy)ethanol and incubated
at room temperature during 1 day. The precipitate
formed was filtered off, recrystallized from ethanol,
and dried.
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(Tetrahydropyrrole- and Tetrahydrofuran-2,3-diones),
Perm: PGFA, 2004.
Antihypoxia activity was studied taking advantage
of the model of normobaric hypoxia with hypercapnia
[3]. The experiments were performed with white mice
(18–20 g) kept under standard vivarium conditions.
The tested compounds were injected intraperitoneally
30 min prior to the experiment at a dose of 100 mg kg–1
as a suspensions with isotonic sodium chloride
solution. Depending on the weight, the reference group
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 11 2015