Synthesis, isomerism, and hypotensive activity of thiethane-containing hydrazones of uracilylacetic acid

Article abstract of DOI:10.1134/S1068162014030108

By the reaction of 2-[6-methyl-1-(thiethane-3-yl)uracil-3-yl]acetic acid hydrazide with aryl aldehydes and acetophenone derivatives, acylhydrazones have been obtained, which exist in DMSO solutions as a mixture of two stereoisomers of an E_C=N-isomer, due to the hindered internal rotation around the hydrazide bond. It has been found that the compounds synthesized exhibit a hypotensive activity.

Full text of DOI:10.1134/S1068162014030108

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2014, Vol. 40, No. 3, pp. 300–307. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © S.A. Meshcheryakova, V.A. Kataev, K.V. Nikolaeva, V.N. Perfilova, D.D. Borodin, I.N. Tyurenkov, 2014, published in Bioorganicheskaya Khimiya, 2014,
Vol. 40, No. 3, pp. 327–334.
Synthesis, Isomerism, and Hypotensive Activity
of ThiethaneꢀContaining Hydrazones of Uracilylacetic Acid
S. A. Meshcheryakovab, V. A. Kataevb, K. V. Nikolaevab,
1
V. N. Perfilovaa, , D. D. Borodina, and I. N. Tyurenkova
a Volgograd State Medical University, pl. Pavshikh Bortsov 1, Volgograd, 400131 Russia
b Bashkirian State Medical University, Ufa, Bashkirtostan, Russia
Received October 15, 2013; in final form, November 11, 2013
Abstract—By the reaction of 2ꢀ[6ꢀmethylꢀ1ꢀ(thiethaneꢀ3ꢀyl)uracilꢀ3ꢀyl]acetic acid hydrazide with aryl
aldehydes and acetophenone derivatives, acylhydrazones have been obtained, which exist in DMSO solutions
as a mixture of two stereoisomers of an EC=Nꢀisomer, due to the hindered internal rotation around the
hydrazide bond. It has been found that the compounds synthesized exhibit a hypotensive activity.
Keywords: uracil, thiethane, acylhydrazones, E,Zꢀisomers, hypotensive activity
DOI: 10.1134/S1068162014030108
1
INTRODUCTION
Uracil is present, as a structural fragment, in moleꢀ
cules of many biologically active compounds having a
wide spectrum of pharmacological activity; novel
drugs are being successfully synthesized by its modifiꢀ
cations. On the other hand, thiethanes and their derivꢀ
atives found in the plants of Berkheya angustifolia and
Cullumia squarrossa and in glands of some mammals
of the Mustelid family, which exhibit antiꢀinflammaꢀ
tory, sedative, and insecticide activities, are promising
objects for the synthesis of potentially biologically
active compounds. The goal of the present study was
the synthesis of thiethaneꢀcontaining hydrazones of
uracilylacetic acid and a search for compounds posꢀ
sessing a hypotensive activity in this series.
The role of arterial hypertension as one of the key
risk factors in the development of stroke, myocardial
infarction, cardiac insufficiency, myocardial ischemia,
and cardiac death has been well studied and is beyond
question [1, 2]. According to the data of epidemiologiꢀ
cal studies, AH accounts for 30 to 50% of the global
burden of disease in the world; this indicator among the
population of the Russian Federation is 38% [3]. AH in
our country has been and remains one of the most
important medical and social problems since it is the
main factor determining the high mortality in Russia.
According to the data of the Ministry of Health, it was
the cause of 18.3% of lethal outcomes in 2012 [4, 5].
Despite the fact that to date there is a wide selecꢀ
tion of hypotensive drugs, the number of persons with
high AP who are nonsusceptible to pharmacotherapy
steadily increases [6]. About 60% of patients with AH
in Russia take hypotensive drugs; however, positive
results are observed only in 21.5% [7, 8]. Many
hypotensive drugs used in medicinal practice are charꢀ
acterized by a slow development of the clinically sigꢀ
nificant decrease in AP and have limitations owing to
side effects or the impairment of quality of life, which
largely restricts their use. A search for, and the develꢀ
opment of, novel highly effective and lowꢀtoxic
hypotensive drugs of longꢀterm action remain urgent
problems in modern pharmacology and pharmaceutiꢀ
cal chemistry.
RESULTS AND DISCUSSION
Thiethaneꢀcontaining acylhydrazones (IV)–(XII
were synthesized from 6ꢀmethylꢀ1ꢀ(thiethaneꢀ3ꢀ
yl)uracil ( ) obtained by the thiirane–thiethane rearꢀ
)
I
rangement in the reaction of equimolar amounts of 6ꢀ
methyluracil and 2ꢀchloromethylthiirane in water in
the presence of potassium hydroxide [10]. The
Nꢀ
alkylation of compound ( ) by the ethyl ether of
I
monochloroacetic acid in the presence of potassium
carbonate in acetone led to ether (II), which readily
reacted with a fivefold molar excess of hydrazine
hydrate in ethanol to form hydrazide (III) with a yield
of 53%. Acylhydrazones (IV)–(XII) were synthesized
by the reaction of hydrazide (III) with aryl aldehydes
and aryl ketones without the use of acid catalyzers with
yields of 48–89% (Scheme).
Abbreviations: AH, arterial hypertension; AP, arterial pressure;
SAP, systolic arterial pressure; HR, heart rate.
Corresponding author: phone: +7 (905) 395ꢀ54ꢀ51; fax: +7
1
(8442) 97ꢀ81ꢀ80; eꢀmail: vnperfilova@mail.ru.
300

SYNTHESIS, ISOMERISM, AND HYPOTENSIVE ACTIVITY
O
301
O
OEt
N
OEt
NH
Cl
K CO
2
+
3
O
Me
N
S
O
O
Me
N
S
O
(I)
(II)
O
R
O
H
H
N
O
R
N
NH2
N
N
Ar
N
+
Ar
O
O
Me
N
S
O
Me
N
S
O
(III)
(IV)–(XII)
(IV) R = H, Ar = Ph; (V) R = H, Ar = Ph(4NMe2); (VI) R = H, Ar = Ph(2OH); (VII) R = H, Ar = Ph(4OMe);
(VIII) R = H, Ar = Ph(5Br, 2OH); (IX) R = Me, Ar = Ph; (X) R = Me, Ar = Ph(4Cl); (XI) R = Me, Ar = Ph(4Br);
(XII) R = Me, Ar = Ph(4NH2).
Scheme. Synthesis of thiethaneꢀcontaining acylhydrazones
.
The structures of the compounds synthesized were isomerism (E',Z') owing to the hindered rotation
confirmed by spectral methods (IR, 1Н, and 13C NMR
around the NꢀCO bond. According to the literature
data, acylhydrazones of aryl aldehydes [12] and aceꢀ
tophenones [13, 14] occur only in the single form of
spectroscopies) and the data of elemental analysis.
1
Thus, H NMR spectra of compounds (II)–(IV),
the Еꢀisomer relative to the multiple C=N bond. Conꢀ
(
VII), and (X)–(XII) indicate the retention of the thiꢀ
1
sequently, the doubling of signals in the H NMR
spectra is caused by the hindered rotation around the
ethane cycle; they contain two characteristic pseudotꢀ
riplets in the ranges of 3.07–3.14 and 4.12–4.21 and a
multiplet in the range of 6.02–6.12 ppm, which belong N–CO bond. The signals from protons of the СН2СО
to the protons of the thiethane group and NCH,
respectively [10]. In the 13C NMR spectra of (VIII
and (IX), signals of thiethane carbon atoms are also the signals of protons of the HC=N or СН3С=N
group of the
Z'ꢀconformer of acylhydrazones (IV),
(
VII), and ( )–(XII) are shifted to a higher field, and
X
)
recorded [11]. Signals at 31.40–31.47 and 46.95–
47.01 ppm belong to C2, C4, and C3 atoms of the thiꢀ
ethane cycle, respectively.
groups, to a lower field compared with the correꢀ
sponding signals of ꢀconformer [14, 15]. The signal
from the proton of the NH group of the ꢀconformer
of compounds ( )–(XII) is recorded in the highꢀfield
region [15], and that of compounds (IV) and (VII), in
the lowꢀfield region compared with the corresponding
Е
'
Z
'
X
1
The H NMR spectrum of compound (III) conꢀ
tains a double set of resonance signals, indicating the
E,Zꢀisomerism due to the hindered rotation around
the C–N bond, which is typical of hydrazides. The
chemical shifts of protons of CH2CO and NH2 groups
of the Zꢀconformer are in a stronger field, and the sigꢀ
nals of the hydrazide proton of NH, the methyl group,
and the proton in position 5 of the uracil fragment are
in a weaker field compared with the signals of the
signal of Е'ꢀisomer [14], which probably depends on
the structure of the hydrazone fragment.
The screening of compounds with hypotensive
action among the thiethaneꢀcontaining hydrazones of
uracilylacetic acid revealed that compounds (
V
) and
VI) do not affect SAP; compounds (VII), (VIII),
IX), ( ), and (XII) have a weakly pronounced
(
(
Еꢀisomer (Table 1). The sterically more stable
Zꢀisoꢀ
X
mer prevails.
hypotensive effect and reduce SAP from 4.1 to 5.8%.
Compounds (III), (IV), and (XI) most significantly
reduce SAP, to the maximal extent at 90 min of observaꢀ
tion, by 13.9, 14.3, and 21.2%, respectively, compared
with the initial parameters. In the control group of aniꢀ
The spectra of compounds (IV), (VII), (X)–(XII
)
also contain two sets of resonance signals (Table 1). Howꢀ
ever, it is known that acylhydrazones can exist as four steꢀ
reoisomeric forms, due to the geometric E, Zꢀisomerism
relative to the C=Nꢀbond and the conformational mals, no changes in SAP were observed (Table 2).
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 40
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2014

302
Table 1. Chemical shifts in 1H NMR spectra of compounds (II)–(IV), (VII), and (
Chemical shift, , ppm, , Hz
6CH3, s CH3C=N, s CH2C=H, s CHC=N, s NH, br s
MESHCHERYAKOVA et al.
X
)–(XII)
δ
J
Comꢀ
pound
Еꢀisoꢀ
mer, %
Other signals
(II)
2.17
–
–
–
–
4.62
–
–
1.27 (3 H, t, CH3, Et, 7.1); 3.10–3.14 [2 H,
J
–
m, S(CH)2]; 4.12–4.16 [2 H, m, S(CH)2];
4.25 (2 H, q, OCH2, Et, 7.1); 5.69 (1 H, s,
H5); 6.02–6.08 m (1 H, s, NCH)
J
(III)
(IV)
2.08 (E
)
)
4.42 (Z
)
)
–
8.77 (
9.36 (Z)
E
), 3.07–3.11 [2
H
, m, S(CH)2]; 4.15–4.19
12
78
79
[2 H, m, S(CH)2]; 4.29 ( ), 4.54 ( ) (2H,
br s, CH2); 5.64 ( ), 5.66 ( ) (1 H, s, H5);
6.03–6.07 (1 H, m, NCH)
Z
E
2.14 (Z
4.79 (E
E
Z
2.15 (E
)
)
4.57 (Z
)
)
8.03 (
8.20 (
E
Z)
)
11.79 (
11.82 (Z)
E
)
3.08–3.11 [2 H, m, S(CH)2]; 4.14–4.17
[2 H, m, S(CH)2]; 5.68 (1 H, s, H5); 6.02–
6.08 (1 H, m, NCH); 7.43–7.45 (3 H, m,
arom); 7.69–7.72 (2 H, m, arom)
2.18 (Z
5.01 (E
(VII)
2.16 (E
)
)
4.57 (Z
)
)
7.99 (
8.16 (
E
)
11.63 (
11.66 (
E
Z)
)
3.09–3.14 [2 H, m, S(CH)2]; 3.81 (3 H, s,
OCH3); 4.15–4.21 [2 H, m, S(CH)2]; 5.69
(1 H, s, H5);6.04–6.11(1H, m, NCH);7.01
2.19 (Z
5.01 (E
Z)
(2 H, d, arom,
8.6)
J 8.6); 7.67 (2 H, d, arom,
J
(X)
2.17
2.24 (
E
)
)
4.68 (
Z
)
)
–
–
–
10.73 (
Z
)
)
3.08–3.11 [2 H, m, S(CH)2]; 4.14–4.17
[2 H, m, S(CH)2]; 5.67 (1 H, s, H5); 6.02–
6.10 (1 H, m, NCH); 7.42 (2 H, d, arom,
76
78
85
2.29 (Z
5.04 (E
10.98 (
E
J
8.5); 7.63 (2 H, d, arom, J 8.5 )
(XI)
(XII)
2.14 (E
)
)
2.25 (E
)
)
4.69 (Z
)
10.84 (
Z
)
)
3.08–3.11 [2 H, m, S(CH)2]; 4.14–4.17
[2 H, m, S(CH)2]; 5.68 (1 H, s, H5); 6.02–
6.10 (1 H, m, NCH); 7.61 (2 H, d, arom,
2.16 (Z
2.29 (Z
5.04 (E
)
11.09 (
E
J
8.6); 7.77 (2 H, d, arom, J 8.6)
2.16
2.17 (E
)
Z)
4.69 (Z
)
10.54 (
Z
)
3.09–3.14 [2 H, m, S(CH)2]; 4.16–4.21
[2 H, m, SCH2]; 5.46 (2 H, s, NH2); 5.68
(1 H, s, H5);6.04–6.12(1H, m, NCH);6.57
2.20 (
5.04 (E
)
10.73 (
E
)
(2 H, d, arom,
8.5)
J 8.5); 7.54 (2 H, d, arom, J
Then we studied the hypotensive action of the most after 8 h and by 6.4 and 7.3% 24 h after the administraꢀ
tion, respectively (Table 3).
active compounds, which were administered orally at
a dose that exceeded twice the effective dose used
upon intravenous injection. It was found that comꢀ
pound (III) (20 mg/kg) lowered SAP by a maximum
of 6.9% after 8 h; 24 h later SAP returned to the initial
level. Compound (IV) (24 mg/kg) on peroral adminisꢀ
tration lowered SAP after 5 h of observation by 8.7%
relative to the initial level; however, after 24 h, the
A study of the dose–effect dependence upon the
oral administration of the most active compound
ylidene hydrazide showed that compound (XI) at a
dose of 15 mg/kg has a mild hypotensive action with a
maximum effect by 6 h after the administration. SAP
decreased by 10.8% and after 24 h remained by 7.1%
lower than the initial values. Increasing the dose of
readings returned to the initial values. Compound (XI
)
(
XI) to 60 mg/kg did not increase the hypotensive
(30 mg/kg) exhibited the most pronounced longꢀterm
hypotensive activity: SAP slowly decreased by the
action of the compound and was after 8 h by 12.9%
lower than the initial values (Table 3). In a group of
animals to which the reference preparation normoꢀ
dipine was administered at a dose of 1 mg/kg, SAP
decreased by a maximum of 12.6% after 8 h of obserꢀ
vation to return almost to the initial value 24 h after the
administration. In animals receiving lisinopril at a
dose of 10 mg/kg and nebilet at a dose of 2 mg/kg, SAP
action, and SAP reduced by 8 h of the experiment by
8.3% relative to the initial value; after 24 h of observaꢀ
tion, the decrease was 6.3% (Table 4). In this case,
compound (XI) has almost no effect on HR.
Thus, compound (XI) injected intravenously at a
dose of 15 mg/kg lowers AP by 21.2% compared with
the initial level. When administered orally, this comꢀ
pound is most effective at a dose of 30 mg/kg; in the
magnitude of the effect, it is as good as amlodipine and
decreased relative to the initial level by 17.9 and 19.2% is comparable with lisinopril and nebivolol, which
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SYNTHESIS, ISOMERISM, AND HYPOTENSIVE ACTIVITY
303
Table 2. Changes in SAP in rats* after intravenous injection of thiethaneꢀcontaining uracilylacetic acid hydrazones
Time, min
Compound, dose,
mg/kg
Initial value
30
60
90
Control, –
(II), 11.4
(III), 10
122.1 6.8
–
124.3 5.5
122.3 2.5
122.9 2.6
1.8
0.2
0.6
127.0 3.5
123.0 3.2
126.7 5.9
125.0 6.4
–3.1
–0.3
112.0 4.9#
–1.6
110.6 1.1#
128.4 3.2
–
117.7 10.8
–8.4
–12.8
–13.9
(IV), 12
134.0 9.8
–
129.9 10.1#
124.0 9.9#
114.8 9.5#
–3.0
–7.5
–14.3
(V), 13.4
(VI), 12.4
(VII), 13
(VIII), 15
124.6 10.1
–
124.9 22.7
125.4 22.7
124.2 24.0
0.3
0.7
–0.3
124.6 5.6
–
126.8 8.3
128.1 11.3
126.6 10.8
2.9
1.6
1.8
125.8 6.6
–
121.8 14.8
120.2 14.9
119.0 12.3
–3.2
–4.4
–5.4
138.6 19.0
–
134.9 13.5
136.1 15.5
132.9 18.3
–2.6
–1.8
–4.1
(
IX), 12
), 12.5
124.7 5.2
–
115.7 16.7
115.6 27.6
118.9 25.2
–7.2
–7.3
–4.6
(X
134.7 7.0
–
135.7 7.5
128.8 14.5
129.0 8.7
0.7
–4.3
–4.2
(XI), 15
125.7 5.5
–
116.5 10.6#
108.1 10.1#
99.0 12.5#
–7.3
–14.0
–21.2
(XII), 13
122.7 11.4
–
120.6 9.1
120.4 12.5
115.6 13.7
–1.7
–1.8
–5.8
* The upper line shows SAP (M S, where M is the average value, and S is the standard deviation) and the lower line shows changes in SAP
in percent of the initial value.
The data are confident relative to the control group (p < 0.05).
#
enables one to consider a further study of its effect on ature was determined in a capillary on a PTP(M)
the cardiovascular system promising.
device. TLC was carried out on Silufix plates using
ethanol as a mobile phase; the detection was with UV
light and iodine vapors.
EXPERIMENTAL
6ꢀMethyluracil (OOO Polisintez, Russia) and
1H NMR spectra were recorded on a Bruker AMXꢀ300
spectrometer (Germany) with a working frequency of
300 MHz and a Bruker Avence IIIꢀ500 device (Gerꢀ
many) with a working frequency of 500.13 MHz. 13C
NMR spectra were recorded on a Bruker AMXꢀ300
spectrometer (Germany) with a working frequency of
6ꢀmethylꢀ1ꢀ(thiethaneꢀ3ꢀyl)uracil (29
3%) [10]
were used.
The data of 1H NMR spectra of compounds (II)–
(
IV), (VII), and ( )–(XII) are given in Table 1.
X
Ethyl ether of 2ꢀ[6ꢀmethylꢀ1ꢀ(thiethaneꢀ3ꢀ
75 MHz with complete proton decoupling and moduꢀ yl)uracilꢀ3ꢀyl]acetic acid (II). A suspension of comꢀ
lation of the CꢀH coupling constant. Residual signals pound ( ) (4.0 g, 20 mmol) and calcined ground
I
of the solvent DMSOꢀd6 were used as an internal stanꢀ potassium carbonate (4.14 g, 30 mmol) in acetone
dard. IR spectra were measured on an Infralum FTꢀ02 (125 mL) were boiled on a flask heater for 30 min, and
device (Russia) in KBr disks, and the melting temperꢀ the ethyl ether of monochloroacetic acid (2.45 g,
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304
MESHCHERYAKOVA et al.
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SYNTHESIS, ISOMERISM, AND HYPOTENSIVE ACTIVITY
305
Table 4. Dose dependence of the effect of compound (XI) on SAP upon peroral administration to rats
Time after the onset of the experiment, h
Dose,
mg/kg
initial
value
1 h
2 h
3 h
4 h
5 h
6 h
8 h
24 h
Control, – 123.4 1.4 123.6 2.2 123.9 1.5 123.6 1.5 123.3 2.3 123.7 1.8 123.9 1.0 125.0 0.6 124.9 1.3
0.1 0.4 0.1 –0.1 0.2 0.4 1.3 1.2
125.4 1.3 122.4 1.8 119.0 4.5 114.4 7.5 114.0 2.8 114.3 3.6 111.9 6.7 112.9 4.2 116.6 6.9
–2.4 –5.1 –8.8 –9.1 –8.9 –10.8 –10.0 –7.1
128.0 3.8 125.5 2.1 119.8 0.2 116.3 3.8 112.0 3.8 109.2 1.2 106.3 9.0 111.5 2.1 119.3 16.0
–2.0 –6.4 –9.1 –12.5 –14.7 –16.9 –12.9 –6.8
130.3 1.5 127.9 2.2 125.4 2.3 122.2 1.9 121.3 1.7 119.6 3.2 120.2 3.0 119.6 2.3 122.1 5.8
–1.9 –3.8 –6.2 –6.9 –8.3 –7.8 –8.3 –6.3
15
30
60
#
#
#
#
#
#
* The upper line shows SAP (M S, where M is the average value, and S is the standard deviation) and the lower line shows changes in SAP
in percent of the initial value.
The data are confident relative to the control group (p < 0.05).
#
20 mmol) was added. After 2 h, more monochloroaceꢀ H 4.99, N 15.81. С17Н18N4О3S. Calculated, %: C
tic acid ethyl ether (1.23 g, 10 mmol) was added, and 56.97, H 5.06, N 15.63.
the boiling was continued for 5 h. The reaction mass
was cooled, and the sediment was filtered. The solvent
was removed in a vacuum, and the residue was recrysꢀ
2ꢀ[6ꢀMethylꢀ1ꢀ(thiethaneꢀ3ꢀyl)uracilꢀ3ꢀyl]acetic
acid (4ꢀdimethylaminophenyl)methylidene hydrazide (V).
A reaction mixture was boiled for 2 h. Yield 53%;
tallized from hexane. Yield 4.24 g (74%); Rf 0.54; mp
Rf 0.46; mp 241–243°С (iꢀPrOH); IR (ν
, cm–1): 3172,
40–42°С; IR (ν
, cm–1): 1750 (C=O), 1703 (C2=O),
3053, 2946 (NH), 1734 (C2=O), 1678, 1646 (C4=O,
C=O, C=N), 1611 (C=C), 1527, 1411 (C–N).
Found, %: C 57.02, H 5.64, N 17.29. С19Н23N5О3S
1656 (C4=O), 1626 (C=C), 1418, 1389 (C–N), 1208
(C–O–C). Found, %: C 50.81, H 5.59, N 9.97.
С12Н16N2О4S. Calculated, %: C 50.69, H 5.67, N 9.85.
.
Calculated, %: C 56.84, H 5.77, N 17.44.
2ꢀ[6ꢀMethylꢀ1ꢀ(thiethaneꢀ3ꢀyl)uracilꢀ3ꢀyl]acetic
acid hydrazide (III). A 85% solution of hydrazine
hydrate (2.94 g, 50 mmol) was added to a solution of
compound (II) (2.84 g, 10 mmol) in EtOH (50 mL)
and boiled for 3 h. The reaction mixture was cooled at
2ꢀ[6ꢀMethylꢀ1ꢀ(thiethane 3ꢀyl)uracilꢀ3ꢀyl]acetic
acid (2ꢀhydroxyphenyl)methylidene hydrazide (VI).
A
reaction mixture was boiled for 2 h. Yield 53%;
Rf 0.66; mp 262–264 С ( ꢀPrOH); IR (
°
i
ν
, cm–1):
3221, 3057 (OH, NH), 1712 (C2=O), 1664, 1657
(C4=O, C=O, C=N), 1615 (C=C), 1438, 1409, 1299
(C–N). Found, %: C 54.58, H 5.01, N 14.73.
С17Н19N4О4S. Calculated, %: C 54.39, H 5.10, N
14.92.
0°С
for 12 h, and the sediment was filtered, washed
with water, and dried. Yield 1.43 g (53%); Rf 0.35; mp
199–201 (EtOH); IR (
, cm–1): 3211, 3322 (NH),
°С
ν
1692 (C2=O), 1654 (C4=O, C=O), 1609 (C=C),
1464, 1439, 1385 (C–N). Found, %: C 44.44, H 5.19,
2ꢀ[6ꢀMethylꢀ1ꢀ(thiethaneꢀ3ꢀyl)uracilꢀ3ꢀyl]acetic
N
20.74. С10Н14N4О3S. Calculated, %: C 44.71, H
acid (4ꢀmethoxyphenyl)methylidene hydrazide (VII).
A
5.11, N 20.89.
reaction mixture was boiled for 3 h. Yield 88%; Rf
0.82; mp 214–215 (PrOH); IR (
°С
ν
, cm–1): 3181,
A general method for obtaining acylhydrazones
(IV)–(XII) Aryl aldehyde or acetophenone (2.4 mmol)
was added to a solution of hydrazide (III) (0.54 g,
2 mmol) in EtOH (15 mL). The mixture was boiled
and cooled. The sediment was filtered, washed with
EtOH, and dried.
3084 (NH), 1716 (C2=O), 1663, 1654 (C4=O, C=O,
C=N), 1607 (C=C), 1419, 1411, 1388 (C–N), 1274,
1261 (C–O). Found, %: C 55.74, H 5.03, N 14.27.
С18Н20N4О4S. Calculated, %: C 55.66, H 5.19, N
14.42.
2ꢀ[6ꢀMethylꢀ1ꢀ(thiethaneꢀ3ꢀyl)uracilꢀ3ꢀyl]acetic
2ꢀ[6ꢀMethylꢀ1ꢀ(thiethaneꢀ3ꢀyl)uracilꢀ3ꢀyl]acetic
acid phenylmethylidene hydrazide (IV). A reaction acid (5ꢀbromoꢀ2ꢀhydroxyphenyl)methylidene hydraꢀ
mixture was boiled for 3 h. Yield 89%; Rf 0.67; mp zide (VIII). A reaction mixture was boiled for 2 h.
233–235°С (PrOH); IR (ν °С (iꢀPrOH); IR (ν,
, cm–1): 3198, 3067 (NH), Yield 59%; Rf 0.65; mp 176–178
1712 (C2=O), 1664, 1657 (C4=O, C=O, C=N), 1615 cm–1): 3224, 3068 (OH, NH), 1706 (C2=O), 1670,
(C=C), 1438, 1409, 1299 (CꢀN). Found, %: C 57.11, 1653 (C4=O, C=O, C=N), 1623 (C=C), 1477, 1418,
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306
MESHCHERYAKOVA et al.
1383 (C–N), 1273 (C–O); 13C NMR (
δ, ppm): 19.10 Health and SR of the Russian Federation of
(6 СН3); 31.40 [S(CH2)2)]; 45.69 (3 СН2); 46.95 23.08.2010 no. 708n “Approval of laboratory practice
(NCH); 100.11 (C5); 110.78 (C5arom); 118.39 regulations,” GOST Rꢀ53434ꢀ2009 “Principles of
(C3arom); 122.38 (C1arom); 127.59 (C6arom); 133.52 proper laboratory practice,” and the regulations of the
(C4arom); 139.54 (N=CH); 151.58 (C2arom); 153.95 European convention on the protection of vertebrate
(C6); 155.60 (C2); 161.17 (C4); 168.24 (3 СН2– animals used for experimental and other research purꢀ
С=О). Found, %: C 45.16, H 3.86, N 12.47. poses (1986).
С17Н17BrN4О4S. Calculated, %: C 45.04, H 3.78, N
For measuring SAP and HR, an animal was placed
12.36.
in a box, and a blood pressure cuff with an inꢀbuilt
2ꢀ[6ꢀMethylꢀ1ꢀ(thiethaneꢀ3ꢀyl)uracilꢀ3ꢀyl]acetic acid
photosensitive probe was put on the tail. The air was
delivered to the cuff under pressure (by 10—15 mmHg
higher than the supposed AP) and then slowly let out.
The SAP and HR values were automatically fixed on a
personal computer connected to a IITC 29 device for
the invasive blood pressure measurement (IITC Life
Science Inc., United States). The values recorded
prior to the administration of compounds under study
phenylethylidene hydrazide (IX). A reaction mixture
was boiled for 6 h. Yield 72%; Rf 0.79; mp 192–194°С
(iꢀPrOH); IR (ν
, cm–1: 3307): 3307 (NH), 1687
(C2=O), 1662, 1621 (C4=O, C=O, C=N, C=C),
1426, 1399, 1364 (C–N). Found, %: C 58.10, H 5.36,
15.10. С18Н20N4О3S. Calculated, %: C 58.05,
H 5.41, N 15.04.
N
2ꢀ[6ꢀMethylꢀ1ꢀ(thiethaneꢀ3ꢀyl)uracilꢀ3ꢀyl]acetic acid were taken to be the initial level. The statistical proꢀ
(4ꢀchlorophenyl)ethylidene hydrazide (X). A reaction cessing of the data was performed by the program
mixture was boiled for 5 h. Yield 57%; Rf 0.68; mp Microsoft Excel 2007 using the paired Student’s test.
201–203°С (iꢀPrOH); IR (ν
, cm–1): 3125, 3083 (NH),
The screening of substances with the hypotensive
activity in the series of thiethaneꢀcontaining hydraꢀ
zones of uracilylacetic acid was carried out on 72 aniꢀ
mals. Twelve groups (six animals in each) were formed:
1, control group of intact animals, which received a
50% aqueous DMSO solution intravenously (iv) in a
volume of 0.3 mL per 100 g weight; and 2–12, experiꢀ
mental groups of animals to which the compounds
under study were injected iv at a dose that amounted to
1718 (C2=O), 1662, 1647, 1607 (C4=O, C=O, C=N,
C=C), 1480, 1413, 1349 (C–N). Found, %: C 53.07,
H 4.68, N 13.91. С18Н19ClN4О3S. Calculated, %:
C 53.13, H 4.71, N 13.77.
2ꢀ[6ꢀMethylꢀ1ꢀ(thiethaneꢀ3ꢀyl)uracilꢀ3ꢀyl]acetic
acid (4ꢀbromophenyl)ethylidene hydrazide (XI).
A
reaction mixture was boiled for 4 h. Yield 82%;
Rf 0.73; mp 251–253 (BuOH); IR (
, cm–1): 3191,
3075 (NH), 1718 (C2=O), 1661, 1627 (C4=O, C=O,
C=N, C=C), 1435, 1417, 1364 (CꢀN); 13C NMR (
°С
ν
1/30 of the molecular weight: (II) 11.4 mg/kg, (III
10 mg/kg, (IV) 12 mg/kg, ( ) 13.4 mg/kg, (VI
12.4 mg/kg, (VII) 13 mg/kg, (VIII) 15 mg/kg, (IX
12 mg/kg, ( ) 12.5 mg/kg, (XI) 15 mg/kg, and (XII
)
)
)
)
δ
,
V
ppm): 13.55 (N=С–СН3); 19.15 (6 СН3); 31.47
[S(CH2)2)]; 46.16 (3 СН2); 47.01 (NCH); 100.24
(C5); 122.80 (C4arom); 128.25 (C3,5arom); 131.32
(C2,6arom); 137.06 (C1arom); 148.02 (N=СꢀСН3);
151.68 (C6); 153.95 (C2); 161.23 (C4); 169.32
X
13 mg/kg. A 50% DMSO solution was used as a solꢀ
vent. The SAP and HR values were recorded 30, 60,
and 90 min after the injection of the compounds.
(
3 СН2–С=О). Found, %: C 47.99, H 4.18, N 12.29.
To study the dose–hypotensive effect dependence
and the duration of action of compound (XI), a leader
upon oral administration, in comparison with referꢀ
ence preparations, seven groups of animals were
formed, six animals in each: group 1, a control group
of intact animals to which a 2% starch mucus (0.2 mL
per 100 g weight) was administered; groups 2–4,
experimental groups of animals that received comꢀ
pound (XI) at a dose of 15, 30, and 60 mg/kg, respecꢀ
tively; groups 5–7, experimental groups of animals to
which the reference preparations were administered:
nebivolol (nebilet, BerlinꢀChemie AG, Germany) at a
dose of 2 mg/kg, lisinopril (diroton; Gedeon–Richter,
Hungary) at a dose of 10 mg/kg, and normodipine
(normodipine; Gedeon–Richter, Hungary) at a dose
of 1 mg/kg, respectively. Prior to administration, subꢀ
stances at doses examined and reference preparations
were suspended in a 2% starch mucus. The parameters
were recorded at 1ꢀh intervals over a period of 8 h and
24 h after the administration of substances using a
С18Н19BrN4О3S. Calculated, %: C 47.90, H 4.24,
N 12.41.
2ꢀ[6ꢀMethylꢀ1ꢀ(thiethaneꢀ3ꢀyl)uracilꢀ3ꢀyl]aceꢀ
tic acid (4ꢀaminophenyl)ethylidene hydrazide (XII).
A
reaction mixture was boiled for 3 h. Yield 48%;
Rf 0.59; mp 198–200 with decomposition (EtOH :
Н2О, 1 : 1); IR (
, cm–1): 3314, 3174 (NH), 1699
°С
ν
(C2=O), 1662, 1643, 1621 (C4=O, C=O, C=N,
C=C), 1518, 1438, 1394 (C–N). Found, %: C 55.87,
H 5.49, N 17.99. С18Н21N5О3S. Calculated, %: C
55.80, H 5.46, N 18.07.
Hypotensive activity of compounds (III)—(XII).
Experiments were performed on 3.5–4ꢀmonthꢀold
white nonlinear pubertal female rats weighing 280–
320 g, obtained from the Rappolovo Nursery of Laboꢀ
ratory Animals (Russian Academy of Medical Sciꢀ
ences). Rats were maintained in a vivarium under
standard conditions and received a diet balanced
according to GOST 50258ꢀ92.
The study was performed according to the stanꢀ IITC 29 device for the noninvasive arterial pressure
dardized documents: the Order of the Ministry of measurement (IITC Life Science Inc., United States).
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SYNTHESIS, ISOMERISM, AND HYPOTENSIVE ACTIVITY
307
Eur. J. Cardiovasc. Prev. Rehabil., 2011, vol. 18,
pp. 224–232.
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Translated by S. Sidorova
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 40
No. 3
2014