Synthesis of novel 6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazin-3(2H)-one derivatives and their preliminary biological evaluation

Article abstract of DOI:10.3184/174751918X15389922302823

Simple and accessible pathways for the synthesis of a series of novel 6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazin-3(2H)-one derivatives including compounds with a combination of a pyrazolyl-pyridazine moiety with pyrimidine, 1,3,5-triazine and 1,3,4-oxadiazole rings in the same molecules were established. The tautomeric structures of 3-oxopyridazine and 5-thioxo-1,3,4-oxadiazole rings and also the position of their alkylation were shown. At preliminary screening the synthesised compounds showed pronounced plant growth stimulant activity. The most active compounds were selected for deeper studies and further field trials.

Full text of DOI:10.3184/174751918X15389922302823

JOURNAL OF CHEMICAL RESEARCH 2018
VOL. 42 OCTOBER, 535–539
RESEARCH PAPER 535
Synthesis of novel 6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazin-3(2H)-one
derivatives and their preliminary biological evaluation
Aleksandr P. Yengoyana,b , Roza S. Shainovaa,b*, Tiruhi A. Gomktsyanb and Armen V. Karapetyanb
aDepartment of General and Pharmaceutical Chemistry, Russian-Armenian University, 123, H. Emin str., Yerevan, 0051, Armenia
bLaboratory of Pesticides Synthesis and Plant Protection, National Agrarian University of Armenia, 74, Teryan str., Yerevan, 0009, Armenia
Simple and accessible pathways for the synthesis of a series of novel 6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazin-3(2H)-one derivatives
including compounds with a combination of a pyrazolyl-pyridazine moiety with pyrimidine, 1,3,5-triazine and 1,3,4-oxadiazole rings in the
same molecules were established. The tautomeric structures of 3-oxopyridazine and 5-thioxo-1,3,4-oxadiazole rings and also the position
of their alkylation were shown. At preliminary screening the synthesised compounds showed pronounced plant growth stimulant activity.
The most active compounds were selected for deeper studies and further field trials.
Keywords: 6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazin-3(2H)-one, N- and O-azinyl substituted pyridazines, heterocyclisation, [(5-alkylthio-1,3,4-
oxadiazol-2-yl)methyl]pyridazines, plant growth stimulant activity
On the basis of pyrazole and pyridazine heterocycles a large
number of compounds have been synthesised, which are widely
used not only in medical practice, but also in agriculture for plant
protection.1 Among the pyrazole derivatives there are effective
insecticides (acetoprole, chlorantraniliprole, cyantraniliprole,
dimetilan, ethiprole, fipronil, isolan, pyraclofos, pyrafluprole,
pyriprole, pyrolan, rizazole, tebufenpyrad, tolfenpyrad, vaniliprole)
and fungicides (bixafen, fenpyrazamine, fluxapyroxad,
furametpyr, isopyrazam, penflufen, penthiopyrad, pyraclostrobin,
pyrametostrobin, pyraoxystrobin, rabenzazole, sedaxane). The
arsenal of pesticides based on pyridazine includes mainly herbicides
(credazine, pyridafol, pyridate, brompyrazon, chloridazon,
dimidazon, flufenpyr, metflurazon, norflurazon, oxapyrazon,
pydanon). Because of the great interest in these heterocyclic
derivatives, in the last two decades studies on the series of pyrazole
and pyridazine derivatives have continued to find new compounds
with fungicidal,2–9 herbicidal10–17 and insecticidal5,15 activities.
Pyrazolyl-pyridazines obtained by cyclisation of 3-hydrazino-
pyridazines have hypotensive, anti-inflammatory, antibacterial
and antioxidant activities.18–21 At the same time, in the literature
there are practically no data on pesticidal or growth regulatory
properties of non-fused heterocyclic system derivatives with a
combination of pyrazolyl-pyridazines with azines or azoles, in
particular pyrimidine, 1,3,5-triazine or 1,3,4-oxadiazole, despite
the fact that on the basis of each of these heterocycles a number
of pesticides and plant growth regulators have been synthesised.1
Pyrimidine derivatives exhibit a wide spectrum of biological
activities. Some of the nucleic acids, vitamins, antibiotics
(amitsetin, bleomycin), certain drugs (barbiturates, pyrimidine
sulfonamides, ftorafur, orotic acid), a strong poison (tetrodotoxin)
and coenzymes (uridine diphosphate glucose) contain the
pyrimidine ring. As a result of continuing research on the series of
substituted pyrimidines, compounds possessing antitumour,22,23
anti-tuberculosis,24 cardiotonic,25 anti-HIV,26 antibacterial27 and
antiviral (hepatitis C)28 activities have been discovered. Some
derivatives are proposed as potential antagonists of adenosine
receptors29 and protein kinase inhibitors.30
Pyrimidine derivatives are also used in agriculture as
fungicides, insecticides and acaricides.1
1,3,5-Triazine-containing pesticides are widely used, mainly
to control weeds and include chloro-, fluoroalkyl-, methoxy- and
methylthio-substituted triazines and triazinone derivatives.1 In
the last two to three decades, a series of very active sulfonylurea
herbicides, based on pyrimidine and 1,3,5-triazine, has been
discovered.1 They have high efficiency, very low application
rates and low toxicity.
The spectrum of the pesticidal activity of 1,3,4-oxadiazole
derivatives is more limited. However, in recent years, derivatives
of this heterocycle have been the subject of many studies in
terms of searching for new biologically active compounds.
The increase in environmental requirements, as well as
the fact that harmful organisms can acquire resistance to
the chemical means of plant protection, make it necessary to
replenish systematically the arsenal of pesticides with new
more environmentally friendly preparations having different
mechanisms of action. In this regard, the targeted synthesis of
new compounds with a combination of listed pharmacophore
heterocycles in the same molecule could lead to new biologically
active derivatives, with respect to which the above-mentioned
resistance has not yet emerged.
The purpose of this work was to develop accessible and
effective methods for the synthesis of novel pyrazolyl-pyridazine
derivatives, as well as compounds in which the pyrazolyl-
pyridazine moiety is linked with pyrimidine, 1,3,5-triazine or
1,3,4-oxadiazole rings and to study their biological activities in
terms of searching for new environmentally friendly pesticides
or plant growth regulators.
Results and discussion
6-(3,5-Dimethyl-1H-pyrazol-1-yl)pyridazin-3-ol
(2)
was
synthesised by the reaction of previously obtained 3-chloro-6-
(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine (1)31 with acetic acid
(Scheme 1). Compound 2 can exist in two tautomeric forms,
depending on the position of the mobile hydrogen atom, and the
CH3
CH3
CH3
N
N
N
NH
N
N
CH3COOH
90%
KOH
95%
N
Cl
N
O
N
OK
N
N
N
H
3C
H
3C
H
3C
1
2
3
Scheme 1 Synthesis of 6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazin-3(2H)-one (2) and its potassium salt (3).
* Correspondent. E-mail: rozetta_11@mail.ru

536 JOURNAL OF CHEMICAL RESEARCH 2018
substitution reactions can occur both at the cyclic nitrogen atom,
adjacent to the carbonyl group, and the oxygen atom of the OH
group in the other tautomer. In the IR spectrum of tautomer 2,
an absorption at 1672 cm–1, corresponding to the double C=O
bond is observed, which agrees with the oxo-structure (2).
Compound 2 was converted into the corresponding potassium
salt (3), which was subjected to alkylation reactions (Scheme
2). In this case, an interesting regularity was discovered. It was
found that the reaction with alkyl halides proceeds through the
endocyclic nitrogen atom of the pyridazine ring, which leads
to N-substituted products (4a–d). This structure is supported
by the fact that in the IR spectra of compounds 4a,b the
absorptions of the double C=O bond at 1668 (4a) and 1671
cm–1 (4b) remained and in the IR spectra of compounds 4c,d
the signals of two carbonyl groups at 1709–1744 and 1664–1672
cm–1 were observed. The reaction of the potassium salt (3) with
2,4-dichloro-6-methylpyrimidine and 3,6-dichloropyridazine
also afforded products of N-substitution (5,6); the C=O
bond absorptions (1679 and 1678 cm–1) remained in their IR
spectra. It should be noted that the reaction with 2,4-dichloro-
6-methylpyrimidine is carried out at the chlorine atom of the
fourth position of the pyrimidine ring. This was proved in our
earlier work on the basis of 13C NMR spectra of compounds
with similar structures.32
occurs at the oxygen atom of the pyridazine ring to form the
O-substituted products (7a,b), since in the corresponding IR
spectra the absorption of the C=O bond disappears. Hindered
internal rotation around the N-heterocycle bond occurs in
these compounds and in 1H and 13C NMR spectra two signals
are observed due to protons of N-methyl groups. This process
was discussed in detail in a previous paper.33
To introduce the 1,3,4-oxadiazole ring into the structure,
the ester (4d) was at first converted into the corresponding
hydrazide (8) by reaction with hydrazine hydrate (see
Safety caution on hydrazine hydrate and hydrazines in the
Experimental section). The heterocyclisation of 8 with carbon
disulfide and KOH in an alcohol medium led to a target product
with a combination of three pharmacophore heterocyclic rings
(9) (Scheme 3).
The 5-thioxo-1,3,4-oxadiazole ring can exist in thione and
thiol tautomeric forms. In the 13C NMR spectrum of compound
9 a signal corresponding to the carbon atom of the C=S
double bond is observed at 178 ppm, which agrees with the
thionic structure of the tautomer (9). At the same time, when
it is alkylated with alkylating agents, the substitution proceeds
through the exocyclic sulfur atom of the 1,3,4-oxadiazole
ring. In the 13C NMR spectra of substituted products (10a–e),
the signal of the C=S bond carbon atom disappears and the
signals corresponding to S-alkyl substituents appear in the 1H
and 13C NMR spectra.
In contrast to chloro-azines, the reaction of the salt (3) with
the quaternary ammonium salts of substituted 1,3,5-triazines
Scheme 2 Substitution reactions of potassium salt (3). *See Safety caution on dimethyl sulfate in the Experimental section

JOURNAL OF CHEMICAL RESEARCH 2018 537
O
O
CH3
N
CH3
N
N
OCH3
N
N
NHNH2
NH2NH2 H
94%
CS2/KOH
2O
O
N
O
H
C2 5OH
N
N
H
3C
H
3C
4d
8
N
N
NH
N
CH3
N
CH3
N
O
O
N
N
N
N
SR3
R3Hal
S
KOH,
O
O
74%
67-80%
N
N
H
3C
H
3C
10a-e
9
3
a
b
c
d
e
R = CH3; CH2COOCH3; CH2COOH; CH2CONH2; CH2CH2OC6H5
Scheme 3 Synthesis of 6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-[(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl]pyridazin-3(2H)-one (9) and its S-substituted
derivatives.
Biological properties
mixture was evaporated on a hot water bath for 3–5 h until the salt
formed to give: Yellow crystals; yield 2.2 g (95%); m.p. >300 °C;
1H NMR: δ 2.20 (3H, s, 3-CH3-pyraz.), 2.50 (3H, d, J = 0.7 Hz, 5-CH3-
pyraz.), 5.93 (1H, brs, =CH), 6.90 (1H, d, J = 10.0 Hz, =CH pyrid.),
7.88 (1H, d, J = 10.0 Hz, =CH pyrid.).
Preliminary screening of the synthesised compounds showed
pronounced plant growth stimulant activity. The objects of study
were the seeds of the common bean (Phaseolus vulgaris L.).
The effect of aqueous suspension of compounds 2–10 and
heteroauxin [(indol-3-yl)acetic acid, IAA] in concentrations of
25 and 50 mg L–1 on the viability of seeds, germination and
seedlings was studied. The experimental data for suspensions
of the synthesised compounds were compared with similar
data from plants placed in IAA solutions and the activities of
preparations were determined in comparison with IAA (in %).
Eleven obtained compounds (2, 4a, 4d, 5, 6, 7a, 7b, 10a, 10c,
10d, 10e), which have shown activity higher than 70%, are
being prepared for deeper studies and further field trials.
Synthesis of compounds 4a–d; general procedure
CAUTION: Appropriate precautions must be taken when using
dimethyl sulfate which is carcinogenic, mutagenic and highly toxic.
Dimethyl sulfate, ethyl iodide or a chloroacetic acid derivative
(11 mmol) was added to a mixture of 6-(3,5-dimethyl-1H-pyrazol-
1-yl)pyridazin-3(2H)-one potassium salt (3) (10 mmol) in DMF (5
mL), at 0 °C with continuous stirring; then the mixture was stirred at
60–65 °C until it reached pH 7. The precipitate was washed, filtered off
and dried.
Experimental
IR spectra were obtained on an Avatar 330 FTIR (Thermo Nicolet)
spectrometer, using the attenuated total reflectance method. H and
6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-methylpyridazin-3(2H)-one
(4a): Yellow crystals; yield 1.2 g (60%); m.p. 85–87 °C; IR ν (cm–1):
1
1
1668 (C=O); H NMR: δ 2.20 (3H, s, 3-CH3-pyraz.), 2.51 3H, (d,
13C NMR spectra were recorded at 30 °C on a Varian Mercury-300
(300 and 75 MHz appropriately) spectrometer with standard pulse
sequences operating in a mixture of solvents [DMSO-d6 and CCl4
(1:3)], using tetramethylsilane (0.0 ppm) as internal standard. The
NMR multiplicities brs, s, d, t, q, and m stand for broad singlet, singlet,
doublet, triplet, quartet and multiplet respectively. The reaction
progress and purity of the obtained substances were checked using
TLC on “Silufol UV-254” plates and an acetone/hexane mixture (2:1)
as eluent. Elemental analysis was carried out on a Eurovector EA3000
elemental CHNS-O analyser. All melting points were determined in
open capillaries and are uncorrected.
J = 0.7 Hz, 5-CH3-pyraz.), 3.68 (3H, s, NCH3), 5.95 (1H, brs, =CH),
6.98 (1H, d, J = 10.0 Hz, =CH pyrid.), 7.93 (1H, d, J = 10.0 Hz, =CH
pyrid.); 13C NMR: δ 12.9, 13.3, 39.0, 108.6, 127.7, 130.7, 139.7, 141.2,
148.6, 157.6. Anal. calcd for C10H12N4O: C, 58.81; H, 5.92; N, 27.43;
found: C, 58.69; H, 5.81; N, 27.60%.
6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-ethylpyridazin-3(2H)-one
(4b): Yellow crystals; yield 1.5 g (70%); m.p. 58–60 °C; IR ν (cm–1):
1671 (C=O); 1H NMR: δ 1.37 (H, t, J = 7.2 Hz, 3CH3CH2N), 2.20 (3H,
s, 3-CH3-pyraz.), 2.51 (3H, d, J = 0.7 Hz, 5-CH3-pyraz.), 4.10 (3H, q,
J = 7.2 Hz, CH3CH2N), 5.96 (1H, brs, =CH), 6.97 (1H, d, J = 10.0 Hz,
=CH pyrid.), 7.92 (1H, d, J = 10.0 Hz, =CH pyrid.); 13C NMR: δ 12.9,
13.0, 13.4, 45.4, 108.6, 127.4, 131.0, 139.6, 141.4, 148.6, 157.2. Anal.
calcd for C11H14N4O: C, 60.53; H, 6.47; N, 25.67; found: C, 60.69; H,
6.57; N, 25.88%.
2-[3-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-oxopyridazin-1(6H)-yl]
acetamide (4c): Yellow crystals; yield 1.5 g (62%); m.p. 208–210 °C;
IR ν (cm–1): 1709, 1664 (C=O); 1H NMR: δ 2.21 (3H, s, 3-CH3-pyraz.),
2.49 (3H, d, J = 0.7 Hz, 5-CH3-pyraz.), 4.59 (2H, s, NCH2), 5.95 (1H,
brs, =CH), 6.97 (1H, brs, NH), 7.01 (1H, d, J = 10.0 Hz, =CH pyrid.),
7.40 (1H, brs, NH), 7.93 (1H, d, J = 10.0 Hz, =CH pyrid.); 13C NMR: δ
13.0, 13.2, 53.2, 108.4, 128.1, 130.9, 140.2, 141.2, 148.6, 157.8, 167.3.
Anal. calcd for C11H13N5O2: C, 53.43; H, 5.30; N, 28.32; found: C,
53.28; H, 5.14; N, 28.08%.
Synthesis of 6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazin-3(2H)-one
(2)
A mixture of 3-chloro-6-methylpyridazine (1) (10 mmol) and acetic acid
(15 mL) was stirred at 120 °C for 4 h and the residual acetic acid was
evaporated. Water (20 mL) was added to the mixture and after 0.5 h the
precipitate was filtered off and dried to give: Yellow crystals; yield 1.7 g
(90%); m.p. 250–252 °C; IR ν (cm–1): 1672 (C=O); 1H NMR: δ 2.20 (3H,
s, 3-CH3-pyraz.), 2.50 (3H, d, J = 0.7 Hz, 5-CH3-pyraz.), 5.93 (1H, brs,
=CH), 6.91 (1H, d, J = 10.0 Hz, =CH pyrid.), 7.89 (1H, d, J = 10.0 Hz,
=CH pyrid.), 12.72 (1H, brs, OH); 13C NMR: δ 13.0, 13.2, 108.4, 128.7,
131.6, 139.8, 141.9, 148.6, 159.2. Anal. calcd for C9H10N4O: C, 56.83; H,
5.30; N, 29.46; found: C, 56.69; H, 5.19; N, 29.22%.
Methyl 2-[3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-oxopyridazin-1(6H)-
yl]acetate (4d): Yellow crystals; yield 2.0 g (76%); m.p. 115–117 °C;
IR ν (cm–1): 1744, 1672 (C=O); 1H NMR: δ 2.21 (3H, s, 3-CH3-pyraz.),
2.50 (3H, d, J = 0.7 Hz, 5-CH3-pyraz.), 3.75 (3H, s, OCH3), 4.78 (2H,
s, NCH2), 5.95 (1H, brs, =CH), 7.04 (1H, d, J = 10.0 Hz, =CH pyrid.),
Synthesis of potassium salt of 6-(3,5-dimethyl-1H-pyrazol-1-yl)
pyridazin-3(2H)-one (3)
6-(3,5-Dimethyl-1H-pyrazol-1-yl)pyridazin-3(2H)-one (2) (10 mmol)
was added to a solution of KOH (10 mmol) in water (40 mL). The

538 JOURNAL OF CHEMICAL RESEARCH 2018
8.02 (1H, d, J = 10.0 Hz, =CH pyrid.); 13C NMR: δ 13.0, 13.3, 51.9,
108.8, 128.7, 131.0, 140.1, 141.6, 148.9, 157.57, 166.8. Anal. calcd for
C12H14N4O3: C, 54.96; H, 5.38; N, 21.36; found: C, 54.77; H, 5.30; N,
21.17%.
Preparation
oxopyridazin-1(6H)-yl]acetohydrazide (8)
of
2-[3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-
CAUTION: Appropriate precautions must be taken when using
hydrazine hydrate or hydrazines due to their toxicity and possible
explosive nature.
Synthesis of 2-(2-chloro-6-methylpyrimidin-4-yl)-6-(3,5-dimethyl-
1H-pyrazol-1-yl)pyridazin-3(2H)-one (5)
A
mixture of 6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazin-3(2H)-
Hydrazine hydrate (10 mmol) was added slowly with continuous
stirring to a mixture of compound 4d (10 mmol) and isopropanol
(5 mL), at 0 °C. The reaction mixture was stirred at room temperature
for 4 h and allowed to stand overnight. The mixture was treated with
water (8–10 mL) and then the precipitate was filtered off and dried to
give: White crystals; yield 2.5 g (94%); m.p. 183–185 °C; IR ν (cm–1):
one potassium salt (3) (10 mmol) in water (10 mL) was stirred until
the salt dissolved. Then at 0 °C acetone (15 mL) and 2,4-dichloro-6-
methylpyrimidine (10 mmol) were added. The mixture was stirred at
0–5 °C for 0.5 h, then at room temperature for 1 h. Later the mixture
was heated at 55–60 °C for 4 h, then at 65–70 °C for 6 h. The mixture
was treated with a dilute solution of potassium hydroxide to give a
solid which was filtered off, washed with water and dried: White
crystals; yield 2.0 g (63%); m.p. 188–190 °C; IR ν (cm–1): 1679 (C=O);
1H NMR: δ 2.23 (3H, s, 3-CH3-pyraz.), 2.62 (3H, d, J = 0.7 Hz, 5-CH3-
pyraz.), 2.63 (3H, s, CH3-pyrim.), 6.02 (1H, brs, =CH-pyraz.), 7.17
(1H, d, J = 10.0 Hz, =CH pyrid.), 7.93 (1H, s, CH-pyrim.), 8.16 (1H,
d, J = 10.0 Hz, =CH pyrid.); 13C NMR: δ 13.0, 13.7, 23.5, 109.4, 113.3,
128.8, 132.6, 141.0, 142.5, 149.4, 157.4, 159.4, 159.5, 171.5. Anal. calcd
for C14H13ClN6O: C, 53.09; H, 4.14; Cl, 11.19; N, 26.53; found: C,
52.88; H, 4.02; Cl, 11.00; N, 26.27%.
1
1691, 1679 (C=O); H NMR: δ 2.21 (3H, s, 3-CH3-pyraz.), 2.48 (3H,
d, J = 0.8 Hz, 5-CH3-pyraz.), 4.05 (2H, brs, NH2), 4.60 (2H, s, NCH2),
5.95 (1H, brs, =CH-pyraz.), 7.00 (1H, d, J = 10.0 Hz, =CH pyrid.), 7.94
(1H, d, J = 10.0 Hz, =CH pyrid.), 9.25 (1H, brs, NH); 13C NMR: δ 13.0,
13.3, 52.2, 108.5, 128.2, 130.9, 140.3, 141.3, 148.7, 157.8, 165.4. Anal.
calcd for C11H14N6O2: C, 50.38; H, 5.38; N, 32.04; found: C, 50.22; H,
5.27; N, 31.80%.
Preparation of 6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-[(5-thioxo-4,5-
dihydro-1,3,4-oxadiazol-2-yl)methyl]pyridazin-3(2H)-one (9)
A mixture of compound 8 (11 mmol), KOH (11 mmol), CS2 (20 mmol)
and absolute ethanol (10 mL) was stirred at 75–80 °C for 10 h. The
solvent was evaporated off at normal pressure and the residue was
treated with water and filtered off. The filtrate was acidified with a
concentrated solution of hydrochloric acid to pH 4. Then the precipitate
was filtered off, washed with water and dried to give: White crystals;
Preparation of 6′-chloro-3-(3,5-dimethyl-1H-pyrazol-1-yl)-6H-(1,3′-
bipyridazin)-6-one (6)
3,6-Dichloropyridazine (10 mmol) was added to a mixture of
potassium salt (3) (10 mmol) in DMF (20 mL). The mixture was stirred
at room temperature for 1 h then heated at 90–100 °C for 8–10 h. The
solvent was evaporated off at normal pressure and the residue was
washed with water, filtered off and dried to give: Yellow crystals; yield
1
yield 2.3 g (74%); m.p. 198–200 °C; H NMR: δ 2.20 (3H, s, 3-CH3-
pyraz.), 2.43 (3H, d, J = 0.8 Hz, 5-CH3-pyraz.), 5.31 (2H, s, NCH2),
5.97 (1H, brs, =CH-pyraz.), 7.09 (1H, d, J = 10.0 Hz, =CH pyrid.), 8.03
(1H, d, J = 10.0 Hz, =CH pyrid.), 14.32 (1H, brs, NH); 13C NMR: δ
13.0, 13.4, 44.6, 109.1, 128.6, 131.3, 140.4, 141.9, 149.1, 157.1, 157.7,
178.0. Anal. calcd for C12H12N6O2S: C, 47.36; H, 3.97; N, 27.62; found:
C, 47.24; H, 3.86; N, 27.39%.
2.3 g (76%); m.p. 233–235 °C; IR ν (cm–1): 1678 (C=O); H NMR: δ
1
2.24 (3H, s, 3-CH3-pyraz.), 2.54 (3H, d, J = 0.7 Hz, 5-CH3-pyraz.), 6.01
(1H, brs, =CH-pyraz.), 7.21 (1H, d, J = 10.0 Hz, =CH pyrid.), 7.93 (1H,
d, J = 10.0 Hz, =CH pyrid.), 8.13 (1H, d, J = 10.0 Hz, =CH pyrid.),
8.19 (1H, d, J = 10.0 Hz, =CH pyrid.). Anal. calcd for C13H11ClN6O: C,
51.58; H, 3.66; Cl, 11.71; N, 27.76; found: C, 51.39; H, 3.51; Cl, 11.55;
N, 27.50%.
Synthesis of compounds 10a–e; general procedure
KOH (10 mmol) and alkyl halide or haloacetic acid derivative
(11 mmol) were added to a mixture of compound 9 (10 mmol) and
DMF (10 mL) while stirring. The mixture was stirred at room
temperature for 1 h then at 60–65 °C for 4–6 h. The solvent was
evaporated off at normal pressure and then the residue was treated with
water, filtered off and dried.
Synthesis of compounds 7a,b; general procedure
The substituted 1,3,5-triazinyl-trimethyl ammonium chloride
(10 mmol) was added in portions to a suspension of 6-(3,5-dimethyl-
1H-pyrazol-1-yl)pyridazin-3(2H)-one potassium salt (3) (10 mmol)
in anhydrous acetone (10 mL), at 0–4 °C. The mixture was stirred at
room temperature for 5–6 h, then at 45–50 °C until the completion of
product formation which was monitored with hydrochloric acid. The
solvent was evaporated off at normal pressure and then the residue was
treated with ice-cold water, filtered off and dried.
6- (3,5-Dimethyl-1H-pyrazol-1-yl) -2-[(5-methylthio-1,3,4-
oxadiazol-2-yl)methyl]pyridazin-3(2H)-one (10a): Yellow crystals;
1
yield 2.4 g (77%); m.p. 118–120 °C; H NMR: δ 2.20 (3H, s, 3-CH3-
pyraz.), 2.39 (3H, d, J = 0.8 Hz, 5-CH3-pyraz.), 2.72 (3H, s, SCH3), 5.44
(2H, s, NCH2), 5.96 (1H, brs, =CH-pyraz.); 7.10 (1H, d, J = 10.0 Hz,
=CH pyrid.), 8.04 (1H, d, J = 10.0 Hz, =CH pyrid.); 13C NMR: δ 13.0,
13.3, 13.9, 44.3, 109.0, 128.5, 131.3, 140.3, 141.9, 149.1, 157.1, 161.9,
164.9. Anal. calcd for C13H14N6O2S: C, 49.05; H, 4.43; N, 26.40; found:
C, 49.18; H, 4.51; N, 26.27%.
6-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-[(2-amino-4-dimethylamino-
1,3,5-triazine-6-yl)oxy]-pyridazine (7a): White crystals; yield 2.3 g
(70%); m.p. 204–206 °C; IR ν (cm–1): 1655 (NH2); H NMR: δ 2.25
1
(3H, s, 3-CH3-pyraz.), 2.72 (3H, d, J = 0.7 Hz, 5-CH3-pyraz.), 3.00 (3H,
s, NCH3), 3.11 (3H, s, NCH3), 6.04 (1H, brs, =CH), 6.49 (1H, brs, NH),
6.67 (1H, brs, NH), 7.60 (1H, d, J = 10.0 Hz, =CH pyrid.), 8.18 (1H,
d, J = 10.0 Hz, =CH pyrid.); 13C NMR: δ 13.0, 14.3, 35.5, 35.7, 109.3,
122.5, 124.4, 141.0, 149.6, 154.7, 160.6, 166.2, 167.7, 169.5. Anal. calcd
for C14H17N9O: C, 51.37; H, 5.23; N, 38.51; found: C, 51.58; H, 5.37; N,
38.78%.
6-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-[(2,4-bis-dimethylamino-
1,3,5-triazine-6-yl)oxy]-pyridazine (7b): White crystals; yield 2.5 g
(71%); m.p. 166–168 °C; IR ν (cm–1): no C=O; 1H NMR: δ 2.25 (3H,
s, 3-CH3-pyraz.), 2.74 (3H, d, J = 0.7 Hz, 5-CH3-pyraz.), 3.02 (6H,
s, N(CH3)2), 3.13 (6H, s, N(CH3)2), 6.03 (1H, brs, =CH), 7.56 (1H,
d, J = 10.0 Hz, =CH pyrid.), 8.19 (1H, d, J = 10.0 Hz, =CH pyrid.);
13C NMR: δ 13.0, 14.4, 35.2, 35.4, 35.5, 35.6, 109.3, 122.0, 124.1, 141.1,
149.5, 154.7, 160.4, 165.7, 169.1. Anal. calcd for C16H21N9O: C, 54.07;
H, 5.96; N, 35.47; found: C, 54.20; H, 5.88; N, 35.61%.
Methyl 2-[(5-{[3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-oxopyridazin-
1(6H)-yl]methyl}-1,3,4-oxadiazol-2-yl)thio]acetate (10b): Yellow
1
crystals; yield 2.8 g (75%); m.p. 90–92 °C; H NMR: δ 2.20 (3H, s,
3-CH3-pyraz.), 2.37 (3H, d, J = 0.8 Hz, 5-CH3-pyraz.), 3.73 (3H, s,
OCH3), 4.12 (2H, s, SCH2), 5.45 (2H, s, NCH2), 5.97 (1H, brs, =CH-
pyraz.), 7.10 (1H, d, J = 10.0 Hz, =CH pyrid.), 8.03 (1H, d, J = 10.0 Hz,
=CH pyrid.); 13C NMR: δ 13.0, 13.3, 33.3, 44.3, 52.1, 109.0, 128.5,
131.3, 140.4, 141.9, 149.1, 157.1, 162.2, 163.4, 166.9. Anal. calcd for
C15H16N6O4S: C, 47.87; H, 4.28; N, 22.33; found: C, 47.71; H, 4.18; N,
22.08%.
2-[(5-{[3-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-oxopyridazin-1(6H)-
yl]methyl}-1,3,4-oxadiazol-2-yl)thio]acetic acid (10c): Yellow
1
crystals; yield 2.5 g (68%); m.p. 110–112 °C; H NMR: δ 2.20 (3H,
s, 3-CH3-pyraz.), 2.37 (3H, d, J = 0.7 Hz, 5-CH3-pyraz.), 4.03 (2H,
s, SCH2), 5.45 (2H, s, NCH2), 5.97 (1H, brs, =CH-pyraz.), 7.10 (1H,
d, J = 10.0 Hz, =CH pyrid.), 8.03 (1H, d, J = 10.0 Hz, =CH pyrid.),

JOURNAL OF CHEMICAL RESEARCH 2018 539
10.56 (1H, brs, COOH); 13C NMR: δ 13.0, 13.3, 34.0, 44.4, 109.1, 128.6,
131.3, 140.4, 142.0, 149.1, 157.2, 162.1, 163.8, 167.8. Anal. calcd for
C14H14N6O4S: C, 46.40; H, 3.89; N, 23.19; found: C, 46.21; H, 3.77; N,
23.36%.
8
9
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18 G. Szilagyi, E. Kasztreiner, L. Tardos, E. Kosa, L. Jaszlits, G. Cseh, I.
Kovacs, N. Szabo, P. Tolnay, S. Elek, I. Elekes and I. Polgari, US patent:
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19 G. Szilagyi, E. Kasztreiner, L. Tardos, E. Kosa, L. Jaszlits, A. Cseh,
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2-[(5-{[3-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-oxopyridazin-1(6H)-
yl]methyl}-1,3,4-oxadiazol-2-yl)thio]acetamide
(10d):
White
1
crystals; yield 2.4 g (67%); m.p. 206–208 °C; H NMR: δ 2.20 (3H,
s, 3-CH3-pyraz.), 2.38 (3H, d, J = 0.7 Hz, 5-CH3-pyraz.), 3.98 (2H,
s, SCH2), 5.44 (2H, s, NCH2), 5.97 (1H, brs, =CH-pyraz.), 7.08 and
7.55 (2H, brs, NH2), 7.10 (1H, d, J = 10.0 Hz, =CH pyrid.), 8.03 (1H,
d, J = 10.0 Hz, =CH pyrid.); 13C NMR: δ 13.0, 13.3, 35.9, 44.4, 109.0,
128.5, 131.3, 140.4, 141.9, 149.1, 157.2, 161.9, 164.4, 167.0. Anal. calcd
for C14H15N7O3S: C, 46.53; H, 4.18; N, 27.13; found: C, 46.39; H, 4.03;
N, 27.39%.
6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-{[5-(2-phenoxyethylthio)-
1,3,4-oxadiazol-2-yl]methyl}pyridazin-3(2H)-one (10e): Brown
crystals; yield 3.4 g (80%); m.p. 100–102 °C; 1H NMR: δ 2.20 (3H, s,
3-CH3-pyraz.), 2.36 (3H, d, J = 0.7 Hz, 5-CH3-pyraz.), 3.63 (t, J = 6.1
Hz, SCH2), 4.33 (t, J = 6.1 Hz, OCH2), 5.45 (2H, s, NCH2), 5.94 (1H,
brs, =CH-pyraz.), 6.85–7.26 (5H, m, C6H5), 7.09 (1H, d, J = 10.0 Hz,
=CH pyrid.), 8.03 (1H, d, J = 10.0 Hz, =CH pyrid.); 13C NMR: δ 13.0,
13.3, 31.1, 44.3, 65.1, 109.0, 114.0, 120.4, 128.5, 128.8, 131.3, 140.3,
141.9, 149.0, 157.1, 157.6, 162.1, 154.1. Anal. calcd for C20H20N6O3S: C,
56.59; H, 4.75; N, 19.80; found: C, 56.39; H, 4.61; N, 19.69%.
20 F. Yassin, J. Microbiol. Antimicrob., 2010, 2, 93.
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7743.
Acknowledgement
22 R. Jorda, L. Havlek, I.W. McNae, D.M. Walkinshaw, J. Voller, A. Sturc, J.
Navratilova, M. Kuzma, M. Mistrík, J. Bartek, M. Strnad and V. Krystof,
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23 Y.-S. Tung, M.S. Coumar, Y.-S. Wu, H.-Y. Shiao, J.-Y. Chang, J.-P. Liou, P.
Shukla, C.-W. Chang, C.-Y. Chang, C.-C. Kuo, T.-K. Yeh, C.-Y. Lin, J.-S.
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24 N. Shakya, N. C. Srivastav, N. Desroches, B. Agrawal, D.Y. Kunimoto and
R. Kumar, J. Med. Chem., 2010, 53, 4130.
This research was supported by the Russian-Armenian
University at the expense of the Ministry of Education and
Science of the Russian Federation.
Electronic Supplementary Information
The ESI (1H and 13C NMR spectra of compounds 2–10) is
available through
25 P. Dorigo, D. Fraccarollo, G. Santostasi, I. Maragno, M. Floreani, P.A.
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http://ingentaconnect.com/content/stl/jcr/2018/00000042/00000010/art00011
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29 V. Yaziji, D. Rodríguez, H. Gutiérrez-de-Terán, A. Coelho, O. Caamaño,
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31 T. Gomktsyan, R. Shainova, A. Karapetyan, A. Yengoyan, ChemXpress,
2016, 9, 183.
Received 14 June 2018; accepted 17 August 2018
Paper 1805473
https://doi.org/10.3184/174751918X15389922302823
Published online: 15 October 2018
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