N-(2-Acetylaminoethyl)glycourils
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 3, March, 2020
565
10 mmol) in water (10 mL), and the mixture was heated at 80 С
for 1 h. The solvent was evaporated in vacuo. The formed oily
residue was treated with propan-2-ol and methanol. The formed
precipitate of compound 2 was filtered. Yield 51% (cf. Ref. 16:
yield 51%), m.p. 257 С (cf. Ref. 16: m.p. 255—257 С). 1H NMR,
: 1.78 (s, 6 H, 2 Ac); 2.94—2.98 (m, 2 H, NCH2); 3.05—3.09
(m, 2 H, NCH2); 3.20—3.28 (m, 4 H, 2 NCH2); 5.25 (s, 2 H,
2 CH); 7.49 (s, 2 H, 2 NH); 7.83 (t, 2 H, 2 NHAc, J = 4.9 Hz)
(cf. Ref. 16).
the memory consolidation in the development of CRPA
are shown in Table 1.
Thus, a detailed study of the effects of N-(acetylamino-
ethyl)glycolurils on CNS was carried out, which showed
that compound 1а is the most promising one. This com-
pound is non-toxic, has no depressive effect on CNS
and exhibits a definite nootropic activity. In the whole
range of the used doses (from 50 to 250 mg kg–1), this
compound stimulated memorizing processes in 90% of
mice. This effect exceeds the efficiency of the reference
drug Mebicar and the known nootropic drug Piracetam
(Nootropil).
All experiments with animals were carried out in accordance
with the EU Directive (86/609/EEC), the experimental protocol
was approved by the IPAC RAS Bioethics Commission. Outbred
white mice (males, 1.5—2 months, 20—25 g) were obtained from
the nursery of the Institute of Bioorganic Chemistry of the Russian
Academy of Sciences (Pushchino) and were quarantined for five
days before the start of the experiment. The animals were kept
in ventilated plastic cages at 2—22 С with a 12-hour day/night
cycle, 40—70% humidity, and free access to water and food.
The experiments were carried out strictly from 11.00 to
13.00 h, 10 mice per day were tested. Compounds were administered
intraperitoneally in physiological saline with additions of
tween-80. The effects were observed in 1 h after administration
the compounds.
Experimental
Compounds 3a,b were synthesized by N-carbamoylation of
N-acetylethylenediamine with potassium cyanate and methyl
isocyanate, respectively.15,16 N-Acetylethylenediamine was
prepared from ethylenediamine and ethyl acetate.22 Dihydr-
oxyimidazolidinones 4a,b were obtained according to known
procedures by the reaction of glyoxal or benzil with urea or
1,3-dimethylurea.23,24 The yields, melting points, and physico-
chemical characteristics of glycolurils 1а,b15 and 216 and starting
compounds 3a,b15,16 and 4a,b23,24 correspond to those reported
earlier.
Acute toxicity21 of compounds 1a,b and 2 was measured
after their intraperitoneal administration at the doses of 500 and
1000 mg kg–1
.
The open-field test.17,18 The effect of the compounds under
study on the motor activity was assessed by the number of squares
crossed by a mouse for 3 min. The effect of the compounds on
the research activity was determined by the number of holes
examined in 3 min. The data were compared with those obtained
for the control group.
1H NMR spectra were recorded using a Bruker AM-250
spectrometer (250.13 MHz) in DMSO-d6, chemical shifts are
given relative to Me4Si used as an internal standard. Melting
points were measured using a GALLENKAMP apparatus (Sanyo).
Synthesis of N-{2-(hexahydro-1-methyl-2,5-dioxoimidazo-
[4,5-d]imidazol-3(6aH)-yl)ethyl}acetamide (1а) and N-{2-(hexa-
hydro-1,3-dimethyl-2,5-dioxo-3a,6a-diphenylimidazo[4,5-d]-
imidazol-6(6aH)-yl)ethyl}acetamide (1b) (general procedure).
Concentrated HCl was added dropwise (to рН 1) under stirring
and heating at 50 С to a solution of compound 4a or 4b
(10.1 mmol) and corresponding urea 3a or 3b (10 mmol) in
water—propan-2-ol mixture (10 mL, 2 : 3) (for 1a) or in metha-
nol (20 mL, for 1b), and stirring was continued at 80 С for 1 h
(for 1a) or 1.5 h (for 1b). Solvent was evaporated using a rotary
evaporator; the obtained oily residue was triturated with propan-
2-ol (for1a) or water (for 1b). The formed precipitates of com-
pounds 1a and 1b were filtered and recrystallized from dioxane
and acetone.
The elevated plus maze test.17,18 The degree of anxiety was
determined by the time spent by a mouse in the open hands of
the maze during 3 min of the experiment. The data were compared
with those obtained for the control group.
The hot plate method.20 A mouse was placed on a plate
warmed to 55 С, and the time of the appearance of the defensive
reflex consisting in licking the hind foot was measured. The results
were assessed by increasing the time of the onset of the defensive
reflex compared with the initial data. Statistical data processing
was carried out according to Student’s test. The effect was con-
sidered significant at р ≤ 0.05.25
The CRPA test.19 The compounds were administered imme-
diately after mice received a 50 V electric shock in the dark
compartment of a dark-light chamber. Each group of mice con-
sisted of 10 animals. The elaboration of the conditioned reflex
was checked in 24 h. The percentage of mice that did not enter
the dark compartment for 3 min on the second day of the study
was calculated. Statistical data processing was carried out ac-
cording to Pearson´s 2 test.25
Compound 1а•H2O. Yield 45% (cf. Ref. 15: yield 43—45%),
1
m.p. 128 С (cf. Ref. 15: m.p. 126—128 С). H NMR, : 1.77
(s, 3 Н, СОМе); 2.63 (s, 3 Н, NМе); 2.93—3.11 (m, 2 Н, СН2);
3.12—3.32 (m, 2 Н, СН2); 5.10 (d, 1 Н, СН, J = 8.1 Hz); 5.27
(d, 1 Н, СН, J = 8.1 Hz); 7.49 (br.s, 1 Н, NH); 7.56 (br.s, 1 Н,
NH); 7.86 (t, 1 Н, NH, J = 5.1 Hz) (cf. Ref. 15).
Compound 1b. Yield 67% (cf. Ref. 15: yield 65—67%), m.p.
267 С (cf. Ref. 15: m.p. 265—267 С). 1H NMR, : 1.74 (s, 3 Н,
COMe); 2.61 (s, 3 H, NMe); 2.86 (s, 3 H, NMe); 2.77—2.91
(m, 1 Н, СН2); 3.21—3.38 (m, 3 Н, СН2); 6.79 (m, 2 Н, Ph);
6.89 (m, 2 Н, Ph); 7.09 (m, 6 Н, Ph); 7.95 (br.s, 1 Н, NH); 8.52
(s, 1 H, NH) (cf. Ref. 15).
Synthesis of 1,4-di(2-acetylaminoethyl)tetrahydroimidazo-
[4,5-d]imidazole-2,5(1H,3H)-dione (2). (2-Acetylaminoethyl)-
urea (3b) (20 mmol) and concentrated HCl (to pH 1) were added
to a 40% aqueous solution of glyoxal (d = 1.265 g mL–1, 1.15 mL,
References
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