UDK 547.792ʼ532ʼ367ʼ857.4.03/.04.057
Gotsulya
A. S., Gnatov N. I.
Zaporozhye State Medical
University
The study of properties of 2-[5-R-4-(2-methoxyphenyl)-1,2,4-triazoles
3-ylthio]-1-aryletanones
Keywords: 1,2,4-triazole, physical and chemical properties
Introduction. Searching of the biologically active substances among heterocyclic nitrogen
containing compounds causes a considerable interest and attention of many
researchers. This is not surprising. Because an amount of highly efficient
drugs always supplements with derivatives of such heterocyclic systems.
Derivatives of 1,2,4-triazoles are characterized by a number of valuable
properties, namely low toxicity, reactionary ability, expressed biological
activity. Therefore, the combination of this kind of molecule with various
sintons is an actual task for modern pharmacy and medicine.
The aim of our research
was a purposeful search of new substances among
2-(1,2,4-triazoles-3-ylthio)-1-aryletanone, research of their physical,
chemical and biological properties.
Materials
and methods. Research of physical and chemical properties of obtained compounds performed,
using methods that are listed in the State Pharmacopoeia of Ukraine. The
melting point determined by open capillary method on the device PTP (M). The
structure of compounds was confirmed by elemental analysis on the Elementar
Vario L cube (CHNS) device, IR-spectra (4000 - 400 cm-1) were removed
on a module of the ALPHA-T spectrometer Bruker ALPHA FT-IR. 1H NMR
spectra of compounds were recorded, using a spectrometer «Mercury 400» (solvent
- DMSO-d6, internal standard - tetramethylsilane). Chromatographic and mass spectral researches performed on the instrument
Agilent 1100 Series LC/MSD System, ionization method - chemical ionization at
atmospheric pressure (APCI).
Results and discussion. To the alkylation of 1,2,4-triazoles-3-thiones by α-halogen ketone is
devoted several works of national and foreign authors.
Established
that the reaction of 1,2,4-triazoles-3-thiones with α-halogen ketones
proceeds exclusively using sulfur atom with a formation of 2-(1,2,4-triazoles-3-ylthio)-1-aryletanones.
During
the alkylation of 4-(2-methoxyphenyl)-5-methyl-1,2,4-triazoles-3-thione and
4-(2-methoxyphenyl)-5-phenyl-1,2,4-triazoles-3-thione by α-halogen ketones
in ethanol medium with an addition of equimolecular amount of sodium hydroxide
occurs a formation of corresponding 2-[5-R-4-(2-methoxyphenyl)-1,2,4-triazoles
3-ylhtio]-1-aryletanones (Pic. 1).
R= СН3,
С6Н5; R1=Н, С6Н5;
R2=C6H5, C6H5-C6H5, C6H4NO2-4, C6H4Сl-4, C6H4ОСН3-4
Pic. 1. The scheme of synthesis of
2-[5-R-4-(2-methoxyphenyl)-1,2,4-triazoles-3-ylthio]-1-aryletanones.
Obtained 2-[5-R-4-(2-methoxyphenyl)-1,2,4-triazoles-3-ylthio]-1-aryl-ethanones
(1-15) - white (1-3 , 6-11, 14, 15), yellow (4, 5, 12, 13) crystalline
substance, practically insoluble in water, soluble in alcohol and dimethyl formamide.
For analysis compounds recrystallized from methanol (2, 10), a mixture of
acetate acid: water (2:1) (4); ethanol, n-propanol (1: 1) (3) or n-propanol (1,
5-9, 11-15).
Individuality
of compounds 1-15 confirmed by the method of thin layer chromatography in
different solvent systems.
IR-spectrum
of 1-15 compounds characterized by vibrational bands of the NH-groups within
the ranges 3500-3300 cm-1; C = N-groups within the ranges 1660-1470
cm-1; O2N groups within 1650-1620 cm-1
(νas) and 1345-1310 cm-1 (νs)
(compounds 5, 13). CO-groups within the ranges 1725-1700 cm-1, also
available vibrational bands between 1600-1460 cm-1 and below 1050 cm-1,
which is typical for an aromatic ring. Planar deformational C-H vibrations in
areas 1025-1005 cm-1 and 775-744 cm-1, also an additional
band among 2845-2865 cm-1 demonstrate the presence of
2-methoxyphenyle fragment. The aromatic protons in 1H NMR spectra of
compounds 1-15 observed as two single-proton doublets (at 7,38-7,34 ppm and at
7,17-7,13 ppm) and two single–proton triplets (at 7, 13- ppm and 7.06 ppm at
7,56-7,51). CH3O-group resonates in area 3,77-3,62 ppm, CH3
signal appears as singlets at 2,22-2,09 ppm.
In
1H NMR spectrum of compounds available signals of single-proton
aromatic doublets at 7.34 ppm ( 1H, H-6, J = 7,8 Hz) and at 7.29 ppm (1H, H-2,
J = 8,3 Hz) and signals of aromatic single-proton triplets at 7.56 ppm ( H-4, J
= 8,1 Hz) and at 7.13 ppm (1H, H-5, J = 7,6 Hz). Registered also a singlet of
methoxy group at 3.77 ppm (2-CH3O) and the methyl group at 2.09 ppm
(5-CH3). In a strong part of magnetic area present resonating
protons of methoxy group at 3.83 ppm. 2-methoxyphenyle balance has two proton
doublets (H-6 at 7.34 ppm, H-3 at 7.24 ppm) and two proton triplets: H-5 at
7.51 ppm, H-4 resonates at 7.14 ppm.
Table 1
2-[5-R-4-(2-methoxyphenyle)-1,2,4-triazole-3-ylthio]-1-аrylethanones (1–15)
|
Compound |
R |
R1 |
R2 |
Т m., °С |
Formula |
Yield, % |
|
1 |
H |
С6Н5 |
102 - 104 |
79 |
||
|
2 |
CH3 |
H |
67 - 69 |
C19H19N3O2S |
83 |
|
|
3 |
CH3 |
H |
C6H4OСН3-3 |
182 - 184 |
C19H19N3O3S |
65 |
|
4 |
CH3 |
H |
177 - 179 |
C19H19N3O3S |
69 |
|
|
5 |
CH3 |
Н |
201 - 202 |
C18H16N4O4S |
73 |
|
|
6 |
CH3 |
H |
С6Н3СН3-2-СН3-4 |
124-125 |
C20H21N3O2S |
86 |
|
7 |
CH3 |
H |
121 |
76 |
||
|
8 |
Н |
С6Н5-С6Н4 |
112 - 114 |
C24H21N3O2S |
88 |
|
|
9 |
С6Н5 |
162 - 163 |
C24H21N3O2S |
71 |
||
|
10 |
H |
С6Н5 |
123 - 125 |
59 |
||
|
11 |
С6Н5 |
Н |
C6H4OСН3-3 |
208 |
C24H21N3O3S |
66 |
|
12 |
С6Н5 |
Н |
С6Н4ОСН3-4 |
188 - 191 |
C24H21N3O3S |
60 |
|
13 |
С6Н5 |
H |
C6H4NO2-4 |
230 |
C23H18N4O4S |
76 |
|
14 |
Н |
С6Н5-С6Н4 |
164 - 166 |
C29H23N3O2S |
85 |
|
|
15 |
С6Н5 |
229 - 231 |
C29H23N3O2S |
82 |
Table 2
The data of synthesized compounds elemental analysis
|
Compound |
Found, % |
Calculated, % |
||||||
|
C |
H |
N |
S |
C |
H |
N |
S |
|
|
1 |
63,73 |
5,02 |
12,41 |
9,48 |
63,70 |
5,05 |
12,38 |
9,45 |
|
2 |
64,55 |
5,45 |
11,92 |
9,04 |
64,57 |
5,42 |
11,89 |
9,07 |
|
3 |
61,79 |
5,15 |
11,40 |
8,65 |
61,77 |
5,18 |
11,37 |
8,68 |
|
4 |
61,79 |
5,16 |
11,40 |
8,65 |
61,77 |
5,18 |
11,37 |
8,68 |
|
5 |
56,27 |
4,16 |
14,59 |
8,31 |
56,24 |
4,20 |
14,57 |
8,34 |
|
6 |
65,39 |
5,74 |
11,47 |
8,71 |
65,37 |
5,76 |
11,44 |
8,73 |
|
7 |
60,11 |
5,27 |
10,49 |
8,06 |
60,13 |
5,30 |
10,52 |
8,03 |
|
8 |
69,35 |
5,12 |
10,09 |
7,76 |
69,37 |
5,09 |
10,11 |
7,72 |
|
9 |
70,12 |
4,74 |
10,14 |
8,73 |
69,37 |
5,09 |
10,11 |
7,72 |
|
10 |
68,79 |
4,75 |
10,49 |
7,98 |
68,81 |
4,77 |
10,47 |
7,99 |
|
11 |
66,81 |
4,87 |
9,74 |
7,43 |
66,80 |
4,91 |
9,74 |
7,43 |
|
12 |
66,77 |
4,94 |
9,71 |
7,45 |
66,80 |
4,91 |
9,74 |
7,43 |
|
13 |
61,89 |
4,09 |
12,51 |
7,15 |
61,87 |
4,06 |
12,55 |
7,18 |
|
14 |
72,96 |
4,83 |
8,77 |
6,74 |
72,93 |
4,85 |
8,80 |
6,71 |
|
15 |
72,96 |
4,88 |
8,79 |
6,67 |
72,93 |
4,85 |
8,80 |
6,71 |
Acute toxicity of
the synthesized compounds
On
the first stage of biological research of synthesized compounds examines mainly
an acute toxicity, which significantly allows to reduce the number and
intensity of the adverse reactions manifestations in terms of their clinical
application.
The
aim of toxicological research of compounds, derivatives of 1,2,4-triazoles, was
identification of the character and severity of their damaging effects on the
organism of experimental animals and evaluation of their safety.
Researches
performs, using tabulated express-method of V. B. Prozorovskiy on white rats of
the Wistar line.
Were
used four groups of animals, 2 observations in each each with an additional
application of previous and subsequent dose. Water-soluble compounds dissolved
in 1.5 ml of purified water and injected in compliance with the rules of
aseptic and antiseptic intraperitoneally. Water-insoluble compounds stabilized
with twin-80 and introduced through a metal tube into the stomach. The
observations performed after 24 hours.
Table 2
Acute toxicity of 2- [5-R-4-(2-methoxyphenyl)-1,2,4-triazoles
3-iltio]-1-aryletanones (4, 5, 9, 13-15)
|
Compound |
LD50, mg/kg |
Compound |
LD50, mg/kg |
|
4 |
421 (415 – 445) |
13 |
490 (475 – 505) |
|
5 |
474 (455 – 480) |
14 |
564 (540 – 575) |
|
9 |
740 (720 – 755) |
15 |
790 (760 – 805) |
On
a quantity of the toxicity of these compounds, affect substituents with phenyl
group of the ketone residue. Yes, substituents of 4-methoxy and 4-nitro
significantly increase the toxic properties of
2-[5-R-4-(2-methoxyphenyl)-1,2,4-triazoles-3-iltio]-1-aryletanones. It should
be noted that the increase in acute toxicity is observed at the recovery of
2-[5-R-4-(2-methoxyphenyl)-1,2,4-triazoles 3-ylthio]-1-aryletanones to
2-[5-R-4-(2-methoxyfenyl)-1,2,4-triazoles-3-ylthio]-1-aryletanoles. Also established
that the transition from
2-[5-methyl-4-(2-methoxyphenyl)-1,2,4-triazole-3-ylthio]-1-аrylethanones to
2-[5-phenyl-4-(2-methoxyphenyl)-1,2,4-triazole-3-ylthio]-1-аrylethanones do not
allows to clearly form the correlation dependence between the influence of
radicals in fifth position of the nucleus of 1,2,4-triazoles and between a
modification of the acute toxicity.
Conclusions
Established the optimal conditions of synthesis of
2-[5-R-4-(2-methoxyphenyl)-1,2,4-triazoles-3-ylthio]-1-aryletanones with 4-(2-methoxyphenyl)-5-R-1,2,4-triazoles-3-thiones. It is proved that the major outputs of the reaction
products were observed using ethanol as a solvent. Researched general physical
and chemical properties of the compounds.
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