Synthesis and Antioxidant Activity of N-Aminomethyl Derivatives of Ethosuximide and Pufemide Anticonvulsants

Article abstract of DOI:10.1134/S1070363220030093

Abstract: Aminomethylation of 3-methyl-3-ethylpyrrolidin-2,5-dione (ethosuximide) and 3-(4-isopropoxyphenyl)pyrrolidine-2,5-dione (pufemide) with a 25% aqueous formalin solution and alkyl(aryl)amines yielded corresponding N-aminomethyl derivatives. The antioxidant activity of the synthesized compounds and their effect on some parameters of the blood coagulation system were studied.

Full text of DOI:10.1134/S1070363220030093

ISSN 1070-3632, Russian Journal of General Chemistry, 2020, Vol. 90, No. 3, pp. 385–389. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Obshchei Khimii, 2020, Vol. 90, No. 3, pp. 403–408.
Synthesis and Antioxidant Activity of N-Aminomethyl
Derivatives of Ethosuximide and Pufemide Anticonvulsants
N. Z. Hakobyana, Z. A. Hovasyana, S. S. Hovakimyana, A. G. Melkonyana,
N. A. Pagutyana, G. A. Panosyana, and G. A. Gevorgyana,*
a Scientific and Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of the Republic of Armenia, Yerevan, 0014 Armenia
*e-mail: gyulgev@gmail.com
Received July 31, 2019; revised February 6, 2020; accepted February 8, 2020
Abstract—Aminomethylation of 3-methyl-3-ethylpyrrolidin-2,5-dione (ethosuximide) and 3-(4-isopropoxyphenyl)-
pyrrolidine-2,5-dione (pufemide) with a 25% aqueous formalin solution and alkyl(aryl)amines yielded correspond-
ing N-aminomethyl derivatives. The antioxidant activity of the synthesized compounds and their effect on some
parameters of the blood coagulation system were studied.
Keywords: N-aminomethylation, ethosuximide, pufemide, antioxidant activity, blood coagulation system
DOI: 10.1134/S1070363220030093
Imides are known to be physiologically active sub-
stances with a wide spectrum of activity, possessing
antimicrobial, antituberculous, antiviral, antitumor,
anticonvulsant and other types of activity [1]. The
most famous compounds of this type Ethosuximide
and Pufemide are used as effective anticonvulsant and
antiepileptic drugs [2]. On the other hand, it is known
that the Mannich N-bases show various pharmacological
activities (antibacterial, anticonvulsant, antioxidant,
etc.) [3, 4]. Based on the available literature data, in
order to expand the spectrum of biological activity, we
synthesized N-aminomethyl derivatives of Ethosuximide
and Pufemide; their antioxidant activity and the effect on
some parameters of the blood coagulation system were
investigated.
Structure of the obtained compounds was confirmed
by 1H, 13C NMR and IR spectroscopy. In the IR spectra
of compounds 3–7, 14, stretching vibrations of the
C=O group are observed in the regions of 1777–1766,
1713–1705 cm–1. The absorption at 3472–3442 cm–1 can
be attributed to their overtone [5].
Antioxidant activity (AOA) of the synthesized
compounds 6–8, 11–15, 17, 21, 24 and their effect on some
parameters of the blood coagulation system were studied.
According to the results obtained, the Ethosuximide
derivatives 6, 8, 10, 11, 12 and 21 exhibit a weak pro-
oxidant effect, whereas the Pufemide derivatives 15 and
24 show a weak antioxidant effect. Compounds 7, 14 and
17 do not possess activity (Table 1).
Aminomethylation of 3-methyl-3-ethylpyrrolidine-
2,5-dione (Ethosuximide) 1 and 3-(4-isopropoxyphenyl)-
pyrrolidine-2,5-dione (Pufemide) 2 with 25% aqueous
formalin and alkyl, aryl or cyclic amines in ethanol
(dioxane), the corresponding N-aminomethyl derivatives
3–19 were obtained (Scheme 1). Compounds 3, 4, 7, 8,
soluble in diethyl ether, were converted into oxalates
20–23 with an oxalic acid ethereal solution. The
corresponding hydrochloride 24 was obtained by reacting
compound 13 with a solution of hydrogen chloride in
diethyl ether.
The results of the study of the effect on some
parameters of the blood coagulation system led to the
conclusion that, in addition to substances 8, 10, 11 and 21,
which have procoagulant activity, the studied compounds
do not act on the blood coagulation system.
In summary, aminomethylation of Ethosuximide and
Pufemide with an aqueous solution of formalin and alkyl
(aryl) amines yielded the corresponding N-aminomethyl
derivatives, which did not exhibit noticeable antioxidant
activity.
385

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HAKOBYAN et al.
Scheme 1.
O
O
O
R2
R2
R2
CH2O, HNX
R1
R1
C2H2O4 (HCl)
NH
O
R1
N
N
. C2H2O4(HCl)
NX
NX
O
O
1, 2
3ꢀ19
20ꢀ24
R1 = CH3, R2 = C2H5, NX = dietylamino (3, 20), ethylbutylamino (4, 21), dicyclohexylamino (5), morpholin-4-yl
(6, 22), piperidin-1-yl (7, 23), (4-methylphenyl)amino (8), (4-isopropoxybenzyl)amino (9),
(4-carboxyphenyl)amino
2-yl)benzenesulfonamide (12), (1-benzylphenylcyclohexyl)ethyl]amino (13, 24); R1 = H, R2 = i-PrOC6H4, NX =
4-(4-fluorophenyl)piperazino (14), (4-carboxyphenyl)amino (15), (4-acetylphenyl)amino (16),
4-(ethoxycarboxyphenyl)amino (17), (3-bromophenyl)amino (18), (4-bromophenyl)amino (19).
(10),
(4-acetylphenyl)amino
(11),
4-amino-N-(5-ethyl-1,3,4-thiadiazol-
EXPERIMENTAL
N-Aminomethyl derivatives 3–19. A mixture of
0.01 mol of 3-methyl-3-ethylpyrrolidine-2,5-dione 1 or
3-(4-isopropoxyphenyl)pyrrolidine-2,5-dione 2, 1.3 g
(0.011 mol) of 25% formalin, 0.011 mol of amine in
15 mLof ethanol (dioxane) was heated at 70–80°С for 6–
7 h. After ethanol was removed, hexane was added to the
oily residue. The substance was triturated, then the solvent
was decanted.After some time, the substance crystallized.
Recrystallized from diethyl ether–ethanol mixture (3 : 1)
or acetone. Compounds 3, 4, and 6, which failed to
crystallize, were distilled under reduced pressure.
IR spectra were recorded on a Nicolet Avatar 330
FT-IR instrument from liquid paraffin. H and 13C
NMR spectra were recorded on a Mercury-300 Varian
spectrometer (300 and 75 MHz, respectively) from
DMSO-d6–CCl4 solutions relative to internal TMS.
Melting points were determined on a Boetius instrument.
1
The starting 3-methyl-3-ethylpyrrolidine-2,5-dione
(Ethosuximide) 1 and 3-(4-isopropoxyphenyl)pyrrolidine-
2,5-dione (Pufemide) 2 were synthesized according to the
known procedures [6] and [7], respectively.
Oxalates 20–23 and hydrochloride 24. An diethyl
ether solution of oxalic acid was slowly added dropwise to
an ether solution of compounds 3, 4, 7, 8, and an diethyl
ether solution of HCl to compound 13. The precipitate
was filtered off, and recrystallized from absolute acetone.
Table 1. Evaluation of intensity of lipid peroxidation processes
(I)a
Comp.
no.
Difference compared to control,
%
I
1-[(Diethylamino)methyl]-3-methyl-3-ethyl-
pyrrolidine-2,5-dione (3). Yield 77%, bp 105–107°C
(2 mmHg). IR spectrum, ν, cm–1: 3471, 1776, 1706
6
12.01
10.44
12.00
11.50
12.24
12.11
10.00
9.33
20.0
4.0
1
7
(CONCO). H NMR spectrum, δ, ppm: 0.87 t (3H,
CCH2CH3, J = 7.4 Hz), 1.06 t [6H, N(CH2CH3)2, J =
7.1 Hz], 1.25 s (3H, CCH3), 1.55 d. q (1H, CCH2CH3,
J = 13.7, 7.4 Hz), 1.67 d. q (1H, CCH2CH3, J = 13.7,
7.4 Hz), 2.38 d (1H, CH2, J = 18.1 Hz), 2.51 q [4H,
N(CH2)2, J = 7.1 Hz], 2.57 d (1H, CH2, J = 18.1 Hz),
4.34 s (2H, NCH2N). 13C NMR spectrum, δC, ppm:
8.2 (CH3CH2C), 12.6 [(CH3CH2)2N], 23.4 (CH3),
30.4 (CCH2CH3), 39.6 (CH2C), 43.3 (C*), 45.0
[N(CH2CH3)2], 55.5 (NCH2N). Found, %: C 63.60; H
9.93; N 12.32. C12H22N2O2. Calculated, %: C 63.68; H
9.80; N 12.38. Oxalate 20. Mp 169–170°C.
8
20.0
14.5
22.0
10.6
0.4
10
11
12
14
15
17
21
24
7.0
10.45
11.21
9.73
4.0
12.0
3.0
1-{[Butyl(ethyl)amino]methyl}-3-methyl-3-
ethylpyrrolidine-2,5-dione (4). Yield 48%, bp 115–
118°C (2 mmHg). IR spectrum, ν, cm–1: 3472, 1777,
1707 (CONCO). 1H NMR spectrum, δ, ppm: 0.87 t (3H,
a With respect to the content (nM.) of malonodialdehyde in 1 mg of
protein. Control is 10.04.
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SYNTHESIS AND ANTIOXIDANT ACTIVITY OF N-AMINOMETHYL DERIVATIVES
387
CCH2CH3, J = 7.4 Hz), 0.92 t (3H, CH3,Bu, J = 7.2 Hz),
1.05 t (3H, NCH2CH3, J = 7.1 Hz), 1.25 s (3H, CCH3),
1.23–1.36 m (2H, CH2CH3, Bu), 1.39–1.50 m (2H,
CH2C2H5, Bu), 1.55 d. q (1H, CCH2CH3, J = 13.7,
7.4 Hz), 1.67 d. q (1H, CCH2CH3, J = 13.7, 7.4 Hz), 2.38 d
(1H, CH2, J = 18.1 Hz), 2.43 t (2H, NCH2C3H7, J =
6.9 Hz), 2.50 q (2H, NCH2CH3, J = 7.1 Hz), 2.57 d
(1H, CH2, J = 18.1 Hz), 4.33 s (2H, NCH2N). 13C NMR
spectrum, δC, ppm: 8.2 (CH3CH2C), 12.7 (CH3), 13.5
(CH3), 19.7 (CH2), 23.4 (CH3), 29.3 (CH2), 30.4 (CH2),
39.6 (CH2), 43.2 (C), 45.4 (NCH2), 50.6 (NCH2), 56.0
(NCH2) 175.6 (CO), 182.4 (CO). Found, %: C 66.15; H
10.22; N 11.16. C14H26N2O2. Calculated, %: C 66.10; H
10.30; N 11.01. Oxalate 21. Mp 136–138°C.
1.68 d. q (1H, CH2CH3, J = 13.7, 7.4 Hz), 2.40 d (1H,
CH2, J = 18.1 Hz), 2.42–2.46 m (4H, α,α'-CH2Pip), 2.58 d
(1H, CH2, J = 18.1 Hz), 4.25 d (1H, J = 13.0 Hz), 4.27 d
(1H, NCH2, J = 13.0 Hz). Found, %: C 65.60; H 9.25; N
11.70. C13H22N2O2. Calculated, %: C 65.51; H 9.30; N
11.75. Oxalate 23. Mp 123–124°C.
3-Methyl-3-ethyl-1-{[(4-methylphenyl)amino]
methyl}pyrrolidine-2,5-dione (8). Yield 72%, mp 65°C.
IR spectrum, ν, cm–1: 3357 (NH), 1772, 1694 (CONCO).
1H NMR spectrum, δ, ppm: 0.71 t (3H, CH3CH2, J =
7.5 Hz), 1.18 s (3H, CCH3), 1.47 d. q (1H, CH2CH3,
J = 13.9, 7.5 Hz), 1.59 d. q (1H, CH2CH3, J = 13.9,
7.5 Hz), 2.19 s (3H, CH3-Ar), 2.34 d (1H, CH2, J =
18.1 Hz), 2.50 d (1H, CH2, J = 18.1 Hz), 4.80 d (2H,
NCH2, J = 7.7 Hz), 5.67 t (1H, NH, J = 7.7 Hz), 6.60–
6.65 m (2H, C6H4), 6.83–6.88 m (2H, C6H4). 13C NMR
spectrum, δC, ppm: 7.9 (CH3CH2), 19.9 (CH3-Ar), 23.1
(CCH3), 30.4 (CH2CH3), 39.6 (CH2), 43.2 (CCH3), 48.0
(NCH2), 113.0 (2CH), 125.8, 128.8 (2CH), 142.7, 174.9
(CON), 181.6 (CON). Found, %: C 69.28; H 7.65; N
10.69. C15H20N2O2. Calculated, %: C 69.20; H 7.74; N
10.76.
1-[(Dicyclohexylamino)methyl]-3-methyl-3-
ethylpyrrolidine-2,5-dione (5). Yield 48%, mp 69–70°C.
1
IR spectrum, ν, cm–1: 3442, 1773, 1706 (CONCO). H
NMR spectrum, δ, ppm: 0.85 t (3H, CH3CH2, J = 7.4 Hz),
1.20 s (3H, CH3), 0.94–1.43 m (10H, 11CH2), 1.47–1.79 m
(12H, 11CH2), 2.30 d (1H, CH2, J = 18.0 Hz), 2.50 d
(1H, CH2, J = 18.0 Hz), 2.66 t. t [2H, N(CH)2, J = 11.3,
6.7 Hz], 4.36 d (1H, NCH2N, J = 13.6 Hz), 4.40 d (1H,
NCH2N, J = 13.6 Hz). 13C NMR spectrum, δC, ppm: 8.1
(CH3CH2), 23.1 (CH3), 25.3, 26.0, 30.3, 32.2, 39.9, 42.8,
52.7, 57.4 (NCH), 174.9 (CO), 181.6 (CO). Found, %: C
71.90; H 10.18; N 8.35. C20H34N2O2. Calculated, %: C
71.81; H 10.25; N 8.37.
1-{[(4-Isopropoxybenzyl)amino]methyl}-3-methyl-
3-ethylpyrrolidine-2,5-dione (9). Yield 53%, mp
124–125°C. IR spectrum, ν, cm–1: 3455 (NH), 1771,
1703 (CONCO). 1H NMR spectrum, δ, ppm: 0.86 t (3H,
CH3CH2, J = 7.4 Hz), 1.22 s (3H, CCH3), 1.30 d (6H,
2CH3, J = 6.0 Hz), 1.54 d. q (1H, CH2CH3, J = 13.7,
7.4 Hz), 1.65 d. q (1H, CH2CH3, J = 13.7, 7.4 Hz), 2.36 d
(1H, CH2, J = 18.0 Hz), 2.55 d (1H, CH2, J = 18.0 Hz),
3.39 br. s (1H, NH), 3.60 br. s (2H, NCH2), 4.47 br. s (2H,
NCH2N), 4.50 septet (1H, OCH, J = 6.0 Hz), 6.69–6.74 m
(2H, C6H4), 7.14–7.19 m (2H, C6H4). 13C NMR spectrum,
δC, ppm: 8.2 (CH3CH2), 21.6 (CH3)2, 23.3 (CCH3), 30.4
(CH2CH3), 39.7 (CH2), 43.2 (CCH3), 55.1 (NCH2), 54.4
(NCH2), 68.6 (OCH), 114.7 (2CH), 129.3 (2CH), 130.5,
156.1, 175.7 (CO), 182.5 (CO). Found, %: C 67.79; H
8.28; N 8.85. C18H26N2O3. Calculated, %: C 67.90; H
8.23; N 8.80.
3-Methyl-3-ethyl-1-(morpholin-4-ylmethyl)-
pyrrolidine-2,5-dione (6). Yield 94%, bp 130–132°C
(2 mmHg). IR spectrum, ν, cm–1: 3470, 1775, 1706
1
(CONCO). H NMR spectrum, δ, ppm: 0.90 t (3H,
CH3CH2, J = 7.4 Hz), 1.28 s (3H, CCH3), 1.58 d. q (1H,
CH2CH3, J = 13.7, 7.4 Hz), 1.69 d. q (1H, CH2CH3, J =
13.7, 7.4 Hz), 2.44 d (1H, CH2, J = 18.1 Hz), 2.45–2.49 m
[4H, N(CH2)2], 2.61 d (1H, CH2, J = 18.1 Hz), 3.52–3.56 m
[4H, O(CH2)2], 4.27 d (1H, NCH2, J = 13.1 Hz), 4.29 d
(1H, NCH2, J = 13.1 Hz). 13C NMR spectrum, δC, ppm:
8.4 (CH3CH2), 23.5 (CH3C), 30.4 (CH2CH3), 39.5 (CH2),
43.5 (C), 50.4 [N(CH2)2], 59.1 (NCH2), 65.9 [O(CH2)2],
175.6 (CO), 182.3 (CO). Found, %: C 59.82; H 8.50; N
11.57. C12H20N2O3. Calculated, %: C 59.98; H 8.39; N
11.66. Oxalate 22. Mp 124–126°C.
4-{[(3-Methyl-3-ethyl-2,5-dioxopyrrolidin-1-yl)-
methyl]amino}benzoic acid (10). Yield 70%, mp
186–188°C. IR spectrum, ν, cm–1: 3358 (NH), 1775,
1698 (CONCO). 1H NMR spectrum, δ, ppm: 0.75 t (3H,
CH3CH2, J = 7.4 Hz), 1.21 s (3H, CH3), 1.43–1.69 m
(2H, CH2CH3), 2.40 d (1H, CH2, J = 18.2 Hz), 2.55 d
(1H, CH2, J = 18.2 Hz), 4.84 d (2H, NCH2, J = 7.1 Hz),
6.74–6.79 m (2H, C6H4), 6.89 br. t (1H, NH, J = 7.1 Hz),
7.67–7.72 m (2H, C6H4), 11.68 br. s (1H, COOH). 13C
3-Methyl-3-ethyl-1-(piperidin-1-ylmethyl)-
pyrrolidine-2,5-dione (7). Yield 94%, mp 65–67°C. IR
spectrum, ν, cm–1: 3450, 1772, 1705 (CONCO). 1H NMR
spectrum, δ, ppm: 0.89 t (3H, CH3CH2, J = 7.4 Hz), 1.26 s
(3H, CH3), 1.30–1.38 m (2H, γ-CH2Pip), 1.46–1.54 m (4H,
β,β'-CH2Pip), 1.56 d. q (1H, CH2CH3, J = 13.7, 7.4 Hz),
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HAKOBYAN et al.
NMR spectrum, δC, ppm: 8.0 (CH3), 23.0 (CH3), 30.5
(CH2CH3), 39.6 (CH2), 43.3 (CCH3), 46.7 (NCH2), 111.4
(2CH), 119.3, 130.7 (2CH), 149.4, 167.0 (COOH), 174.9
(CON), 181.5 (CON). Found, %: C 62.12; H 6.32; N 9.59.
C15H18N2O4. Calculated, %: C 62.06; H 6.25; N 9.65.
4.56br. s(2H, NCH2N), 7.11–7.25m(5H, C6H5), 10.24br. s
(2H, NH + HCl). 13C NMR spectrum, δC, ppm: 8.1
(CH3), 20.9, 22.4, 25.4, 30.2, 30.4, 34.3, 35.4, 39.9, 42.6,
43.4, 44.1, 48.0, 125.3 (CH), 127.3 (2CH), 130.2 (2CH),
137.2, 174.0, 180.8. Found, %: C 67.75; H 8.71; N 6.81.
.
C23H34N2O2 HCl. Calculated, %: C 67.88; H 8.67; N 6.88.
1-{[(4-Acetylphenyl)amino]methyl}-3-methyl-
3-ethylpyrrolidine-2,5-dione (11). Yield 78%, mp
110–112°C. IR spectrum, ν, cm–1: 3360 (NH), 1770, 1698
(CONCO), 1662 (C=O). 1H NMR spectrum, δ, ppm: 0.75 t
(3H, CH3CH2, J = 7.5 Hz), 1.22 s (3H, CH3), 1.52 d. q
(1H, CH2CH3, J = 13.8, 7.5 Hz), 1.63 d. q (1H, CH2CH3,
J = 13.8, 7.5 Hz), 2.40 s (3H, COCH3), 2.40 d (1H, CH2,
J = 18.2 Hz), 2.56 d (1H, CH2, J = 18.2 Hz), 4.84 d (2H,
NCH2, J = 6.8 Hz), 6.77–6.82 m (2H, C6H4), 7.09 br. t
(1H, NH, J = 6.8 Hz), 7.65–7.70 m (2H, C6H4). 13C NMR
spectrum, δC, ppm: 8.0 (CH3), 23.0 (CH3), 25.3 (CH3),
30.5 (CH2CH3), 39.6 (CH2), 43.3 (CCH3), 46.5 (NCH2),
111.4 (2CH), 126.6, 129.7 (2CH), 149.9, 174.8 (CON),
181.5 (CON), 193.7 (COCH3). Found, %: C 66.61; H
6.91; N 9.80. C16H20N2O3. Calculated, %: C 66.65; H
6.99; N 9.72.
3-(4-Isopropoxyphenyl)-1-{[4-(4-fluorophenyl)-
piperazin-1-yl]methyl}pyrrolidine-2,5-dione (14).
Yield 36%, mp 157–158°C. IR spectrum, ν, cm–1: 3333,
3177, 1792, 1766, 1713 (CONCO). 1H NMR spectrum,
δ, ppm: 1.30 d (6H, 2CH3, i-Pr, J = 6.0 Hz), 2.63–2.75 m
[4H, N(CH2)2], 2.72 d. d (1H, COCH2, J = 18.1, 5.1 Hz),
3.03–3.08 m [4H, N(CH2)2], 3.20 d. d (1H, COCH2, J =
18.1, 9.6 Hz), 4.05 d. d (1H, CH, J = 9.6, 5.1 Hz), 4.42 s
(2H, NCH2N), 4.53 septet (1H, ОCH, J = 6.0 Hz),
6.77–6.82 m (2H, C6H4О), 7.10–7.15 m (2H, C6H4О),
6.80–6.93 m (4H, C6H4F). 13C NMR spectrum, δC,
ppm: 21.5 (2CH3), 36.5 (CH2), 44.5 (CH), 49.2 and 49.8
(4CH2, piperazine), 59.2 (NCH2N), 68.7 (ОCH), 114.7 d
(2СH, JCF = 21.9 Hz), 115.4 (2CH), 117.0 d (2СH, JCF
=
7.5 Hz), 128.2 (2CH), 129.1, 147.4 d (JCF = 2.2 Hz),
156.0 d (JCF = 238.0 Hz), 156.6, 176.1 (CO), 178.1
(CO). Found, %: C 67.68; H 6.71; N 9.81. C24H28FN3O3.
Calculated, %: C 67.75; H 6.63; N 9.88.
4-{[(3-Methyl-3-ethyl-2,5-dioxopyrrolidin-1-yl)-
methyl]amino}-N-(5-ethyl-1,3,4-thiadiazol-2-yl)
benzenesulfonamide (12). Yield 27.45%, mp 257–
260°C. IR spectrum, ν, cm–1: 3379 (NH), 1770, 1689
4-({[3-(4-Isopropoxyphenyl)-2,5-dioxopyrrolidin-
1-yl]methyl}amino)benzoic acid (15). Yield 65%, mp
204–205°C. IR spectrum, ν, cm–1: 3345 (NH), 1768, 1686
(CONCO). 1H NMR spectrum, δ, ppm: 1.29 d (6H, 2CH3,
i-Pr, J = 6.0 Hz), 2.62 d. d (1H, CH2СН, J = 18.1, 4.9 Hz),
3.16 d. d (1H, CH2СН, J = 18.1, 9.5 Hz), 4.01 d. d (1H,
CH2CH, J = 9.5, 4.9 Hz), 4.51 septet (1H, ОCH, J =
6.0 Hz), 4.91 d (2H, NCH2, J = 7.2 Hz), 6.71–6.76 m
(2H, C6H4), 6.78–6.83 m (2H, C6H4), 6.96 br. t (1H, NH,
J = 7.2 Hz), 6.98–7.03 m (2H, C6H4), 7.68–7.73 m (2H,
C6H4), 11.70 br. s (1H, COOH). 13C NMR spectrum, δC,
ppm: 21.6 (2CH3), 36.8 (CH2), 44.5 (CH), 47.1 (NCH2),
68.8 (ОСН), 111.5 (2CH), 115.4 (2CH), 119.4, 128.3
(2CH), 129.0, 130.8 (2CH), 149.6, 156.6, 167.1 167.0
(CON), 175.4 (CON), 177.3 (COOH). Found, %: C 65.88;
H 5.85; N 7.28. C21H22N2O5. Calculated, %: C 65.96; H
5.80; N 7.33.
1
(CONCO). H NMR spectrum, δ, ppm: 0.72 t (3H,
CCH2CH3, J = 7.4 Hz), 1.19 s (3H, CCH3), 1.25 t (3H,
CH3CH2, J = 7.5 Hz), 1.49 d. q (1H, CCH2CH3, J = 13.7,
7.4 Hz), 1.60 d. q (1H, CCH2CH3, J = 13.7, 7.4 Hz), 2.41 d
(1H, CH2, J = 18.1 Hz), 2.55 d (1H, CH2, J = 18.1 Hz),
2.74 q (2H, CH2CH3, J = 7.5 Hz), 4.80 d (2H, NCH2, J =
7.3 Hz), 6.67 br. t (1H, NH, J = 7.3 Hz), 6.70–6.75 m
(2H, C6H4), 7.48–7.53 m (2H, C6H4). 13C NMR spectrum,
δC, ppm: 8.0 (CH3CH2C), 13.6 (CH3CH2), 23.0 (CH3C),
23.4 (CH2CH3), 30.4 (CCH2), 39.6 (CH2), 43.3 (C), 47.0
(NCH2), 111.1 (2CH), 127.4 (2CH), 133.4, 147.3, 159.1,
169.1, 175.1 (CO), 181.7 (CO). Found, %: C 49.50; H
5.35; N 16.11. C18H23N5O4S2. Calculated, %: C 49.41;
H 5.30; N 16.01.
1-({[2-(1-Benzylcyclohexyl)ethyl]amino}methyl)-
3-methyl-3-ethylpyrrolidine-2,5-dione (13). Yield
30%, viscous oil. Hydrochloride 24. Mp 154–155°C. IR
spectrum, ν, cm–1: 3361 (NH), 1773, 1702 (CONCO). 1H
NMR spectrum, δ, ppm: 0.92 t (3H, CH3CH2, J = 7.4 Hz),
1.19–1.37 m (5H, C6H10), 1.33 s (3H, CH3), 1.45–1.58 m
(5H, C6H10), 1.60–1.81 m (4H, CH2CH3 + CH2CH2N),
2.54 s (2H, CH2Ph), 2.55 d (1H, CH2, J = 18.1 Hz), 2.67 d
(1H, CH2, J = 18.1 Hz), 2.99 br. s (2H, NCH2CH2),
1-{[(4-Acetylphenyl)amino]methyl}-3-(4-
isopropoxyphenyl)pyrrolidine-2,5-dione (16). Yield
85%, mp 160–161°C. IR spectrum, ν, cm–1: 3342 (NH),
1766, 1693 (CONCO), 1663 (C=O). 1H NMR spectrum,
δ, ppm: 1.29 d (6H, 2CH3, i-Pr, J = 6.0 Hz), 2.41 s (3H,
COCH3), 2.63 d. d (1H, CH2СН, J = 18.1, 4.9 Hz),
3.17 d. d (1H, CH2СН, J = 18.1, 9.5 Hz), 4.01 d. d (1H,
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SYNTHESIS AND ANTIOXIDANT ACTIVITY OF N-AMINOMETHYL DERIVATIVES
389
CH2CH, J = 9.5, 4.9 Hz), 4.51 septet (1H, ОCH, J =
6.0 Hz), 4.91 d (2H, NCH2, J = 7.0 Hz), 6.71–6.76 m
(2H, C6H4), 6.81–6.86 m (2H, C6H4), 7.00–7.05 m (2H,
C6H4), 7.16 br. t (1H, NH, J = 7.0 Hz), 7.67–7.72 m (2H,
C6H4). 13C NMR spectrum, δC, ppm: 21.5 (2CH3), 25.3
(CH3), 36.7 (CH2), 44.4 (CH), 46.8 (NCH2), 68.7 (ОСН),
111.5 (2CH), 115.3 (2CH), 126.6, 128.2 (2CH), 128.9,
129.7 (2CH), 150.0, 156.5, 175.3 (CON), 177.2 (CON),
193.8 (COCH3). Found, %: C 69.52; H 6.30; N 7.40.
C22H24N2O4. Calculated, %: C 69.46; H 6.36; N 7.36.
21.5 (2CH3), 36.8, 44.4, 47.3, 68.7, 111.1, 115.3, 115.4,
119.5, 122.2, 128.2, 129.1, 129.8, 147.3, 156.5, 175.4,
177.3. Found, %: C 57.47; H 5.16; N 6.65. C20H21BrN2O3.
Calculated, %: C 57.56; H 5.07; N 6.71.
1-{[(4-Bromophenylamino)amino]methyl}-3-(4-
isopropoxyphenyl)pyrrolidine-2,5-dione (19). Yield
80%, mp 136–138°C. IR spectrum, ν, cm–1: 3328 (NH),
1772, 1693 (CONCO). 1H NMR spectrum, δ, ppm: 1.30 d
(6H, 2CH3, i-Pr, J = 6.0 Hz), 2.58 d. d (1H, CH2СН,
J = 18.2, 4.8 Hz), 3.15 d. d (1H, CH2СН, J = 18.2,
9.5 Hz), 3.98 d. d (1H, CH2CH, J= 9.5, 4.8 Hz), 4.51 septet
(1H, ОCH, J = 6.0 Hz), 4.85 d (2H, NCH2, J = 7.4 Hz),
6.44 br. t (1H, NH, J = 7.4 Hz), 6.70–6.76 m (4H, C6H4),
6.93–6.98 m (2H, C6H4), 7.13–7.18 m (2H, C6H4). Found,
%: C 57.68; H 5.10; N 6.64. C20H21BrN2O3. Calculated,
%: C 57.56; H 5.07; N 6.71.
Ethyl 4-({[3-(4-isopropoxyphenyl)-2,5-dioxo-
pyrrolidin-1-yl]methyl}amino)benzoate (17). Yield
89%, mp 144–146°C. IR spectrum, ν, cm–1: 3336 (NH),
1773, 1688 (CONCO). 1H NMR spectrum, δ, ppm: 1.29 d
(6H, 2CH3,i-Pr, J = 6.0 Hz), 1.34 t (3H, CH3, J = 7.1 Hz),
2.62 d. d (1H, CH2СН, J = 18.2, 4.9 Hz), 3.16 d. d (1H,
CH2СН, J = 18.2, 9.5 Hz), 4.00 d. d (1H, CH2CH, J =
9.5, 4.9 Hz), 4.23 q (2H, ОCH2, J = 7.1 Hz), 4.50 septet
(1H, ОCH, J = 6.0 Hz), 4.91 d (2H, NCH2, J = 7.2 Hz),
6.70–6.75 m (2H, C6H4), 6.79–6.84 m (2H, C6H4),
6.98–7.03 m (2H, C6H4), 7.04 br. t (1H, NH, J = 7.2 Hz),
7.70–7.75 m (2H, C6H4). 13C NMR spectrum, δC, ppm:
14.0 (CH3CH2), 21.5 (2CH3), 36.8 (CH2), 44.4 (CH),
46.9 (NCH2), 58.9 (ОСН2), 68.7 (ОСН), 111.5 (2CH),
115.3 (2CH), 118.4, 128.2 (2CH), 129.0, 130.5 (2CH),
149.8, 156.5, 165.1, 175.3, 177.2. Found, %: C 67.41;
H 6.45; N 6.87. C23H26N2O5. Calculated, %: C 67.30;
H 6.38; N 6.82.
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
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1769, 1699 (CONCO). 1H NMR spectrum, δ, ppm: 1.30 d
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18.1, 4.9 Hz), 3.16 d. d (1H, CH2СН, J = 18.1, 9.5 Hz),
4.00 d. d (1H, CH2CH, J = 9.5, 4.9 Hz), 4.51 septet
(1H, ОCH, J = 6.0 Hz), 4.85 d (2H, NCH2, J = 7.3 Hz),
6.60 br. t (1H, NH, J = 7.3 Hz), 6.70–6.78 m (4H, C6H4),
6.94–7.03 m (4H, C6H4). 13C NMR spectrum, δC, ppm:
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