Synthesis and neurotropic activity of 6,8-diamino derivatives of pyrano[3,4-c]pyridines

Article abstract of DOI:10.1134/S1068162016020102

New diamino derivatives of pyrano[3,4-c]pyridines were synthesized by the pyridine ring recyclization. The presence of the intramolecular hydrogen bond in 6-[(4-methoxyphenyl)amino]-3,3-dimethyl8-methylamino-3,4-dihydro-1H-pyrano[3,4-c]pyridin-5-carbonitrile was identified by X-ray diffraction. A pharmacological study of the synthesized compounds was carried out in known tests, such as assay for antagonism induced by corazole subcutaneous injection and the open field test. The method of rotating rod was used to evaluate neurotoxicity. The diamino derivatives of pyrano[3,4-c]pyridines were found to possess neutrotropic properties. The synthesized compounds, as well as diazepam, prevent the occurrence of clonic seizures and clonic corazoleinduced convulsions in animals; however, they cause a behavior-depressing sedative effect.

Full text of DOI:10.1134/S1068162016020102

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2016, Vol. 42, No. 2, pp. 215–223. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © E.G. Paronikyan, Sh.Sh. Dashyan, I.A. Dzhagatspanyan, R.G. Paronikyan, I.M. Nazaryan, A.G. Akopyan, N.S. Minasyan, A.G. Ayvazyan,
R.A. Tamazyan, E.V. Babaev, 2016, published in Bioorganicheskaya Khimiya, 2016, Vol. 42, No. 2, pp. 238–246.
Synthesis and Neurotropic Activity of 6,8ꢀDiamino Derivatives
of Pyrano[3,4ꢀc]pyridines
, 1
E. G. Paronikyana, Sh. Sh. Dashyana , I. A. Dzhagatspanyana, R. G. Paronikyana, I. M. Nazaryana,
A. G. Akopyana, N. S. Minasyanb, A. G. Ayvazyanb, R. A. Tamazyanb, and E. V. Babaevc
aMndzhoyan Institute of Fine Organic Chemistry, Scientific and Technological Center of Organic and Pharmaceutical
Chemistry, National Academy of Sciences of Armenia, pr. Azatutyan 26, Yerevan, 0014 Armenia
bMolecular Structure Research Center, Scientific and Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of Armenia, pr. Azatutyan 26, Yerevan, 0014 Armenia
cMoscow State University, Moscow, 119991 Russia
Received August 11, 2015; in final form, September 22, 2015
Abstract—New diamino derivatives of pyrano[3,4ꢀ
clization. The presence of the intramolecular hydrogen bond in 6ꢀ[(4ꢀmethoxyphenyl)amino]ꢀ3,3ꢀdimethylꢀ
8ꢀmethylaminoꢀ3,4ꢀdihydroꢀ1 ꢀpyrano[3,4ꢀ ]pyridinꢀ5ꢀcarbonitrile was identified by Xꢀray diffraction. A pharꢀ
macological study of the synthesized compounds was carried out in known tests, such as assay for antagonism
induced by corazole subcutaneous injection and the open field test. The method of rotating rod was used to evaluꢀ
ate neurotoxicity. The diamino derivatives of pyrano[3,4ꢀ ]pyridines were found to possess neutrotropic properties.
c]pyridines were synthesized by the pyridine ring recyꢀ
H
c
c
The synthesized compounds, as well as diazepam, prevent the occurrence of clonic seizures and clonic corazoleꢀ
induced convulsions in animals; however, they cause a behaviorꢀdepressing sedative effect.
Keywords: pyrano[3,4ꢀc]pyridines, rearrangement, neurotropic activity
DOI: 10.1134/S1068162016020102
INTRODUCTION
medicine. Thus, alkaloids of the pyrano[3,4ꢀс]pyriꢀ
dine series extracted from plants, such as gentianine
and gentianadine exert a universal effect: hypotensive,
anticonvulsant, antipsychotic, antiꢀinflammatory, and
hypothermic [1–4]. Furthermore, derivatives of pyrꢀ
Synthesis of pharmaceuticals for the treatment of
neuropsychiatric disorders, in particular epilepsy, is a
serious challenge for synthetic organic chemistry. In
recent years, the pharmacopoeia of antiepileptic
agents has expanded significantly. However, most of
them are not active enough, and the most effective
agents often cause toxic side responses from different
organs and systems, emotional disturbances, impaired
memory, etc. In this regard, the search and study of
anticonvulsants possessing the combined psychotroꢀ
pic properties is of unquestionable interest. In experiꢀ
mental psychopharmacology, while searching for new
neurotrophic compounds, it is important and relevant
to model both the pathology itself and its individual manꢀ
ifestations in animals. Such an approach of differentiated
(application of interoceptive stimuli, such as corazole)
and integrative (for example, “open field”) modeling,
biostatistical evaluation of the spectrum of pharmacologꢀ
ical action of substances, and comparison of the major
and side effects make it possible to carry out a more
detailed selection of promising pharmaceutical agents
among newly synthesized compounds.
ano[3,4ꢀс]pyridines are the starting compounds for
the synthesis of indole alkaloids, in particular campꢀ
tothecin exhibiting antitumor activity [5, 6]. Information
about the synthetic methods for preparation of pyrꢀ
ano[3,4ꢀ
Previously, we synthesized oxo, thio and amino
derivatives of pyrano[3,4ꢀ ]pyridines [10–13]. In the
present work, in continuation of these studies we carꢀ
ried out the synthesis of new pyrano[3,4ꢀ ]pyridine
с]pyridine derivatives is also available [7–9].
c
c
derivatives and studied their neurotropic properties.
RESULTS AND DISCUSSION
6ꢀAminopyrano[3,4ꢀ
used as the starting compounds in the synthesis of
diamino derivatives of pyrano[3,4ꢀ ]pyridines (Va – o
(Scheme 1). Compounds (IIIa–g) were obtained via
the interaction of thiopyrilium salt ( ) [14] with substiꢀ
tuted anilines, which resulted in imino compounds
IIa–g) that were further subjected to the Dimroth
rearrangement under the action of sodium ethylate to
afford 6ꢀaminopyrano[3,4ꢀ ]pyridines IIIa–g).
Then, to increase the electrophilicity of the C8 atom
c]pyridines (IIIa–g) were
c
)
I
The derivatives of condensed pyridines are of interꢀ
est as biologically active substances and widely used in
(
1
c
(
Corresponding author: phone: +374 (10) 287789; eꢀmail:
shdashyan@gmail.com.
215

216
PARONIKYAN et al.
C16
N15
C1
C9
N8
O2
C10
C11
C22
C23
O24
C7
C21
C3
C18
C5
C12
C6
C4
N17
C25
C20
C19
C13
N14
Fig. 1. Crystal structure and the numbering scheme of atoms in compound (Vl) accepted in structural experiment. Thermal ellipꢀ
soids of 50% probability are shown.
0
a
b
c
N14i
N14
H15ii
N15ii
H15
N15
Fig. 2. The chain along [0 1 0] formed by intermolecular hydrogen bonds; symmetry code (i = x; y – 1; z, ii = x; y + 1; z). Hydrogen
bonds are depicted by dashed lines.
of the pyridine ring, we obtained pyridinium salts respectively. Analysis of the molecule packing in the
crystal lattice showed that the molecules bind via
intermolecular hydrogen bonding N15–H15⋅⋅⋅N14i
(length of the donorꢀacceptor bond 2.924(19) Å) to
form infinite chains along the [0 1 0] (Fig. 2).
(
IVa–g) in the reaction of thiones (III–g) with dimeꢀ
thyl sulfate. The interaction of compounds (IVa–g
with primary amines is accompanied by rearrangeꢀ
ment [15] that affords diamino derivatives (Va – o ).
)
Structures of compounds (Va – o ) were confirmed
by the data of 1H and 13C NMR spectroscopy and Xꢀ
ray diffraction (Fig. 1). While studying the structure of
compound (Vl) it was shown that the dihydropyran
ring has a halfꢀchair conformation; the atoms C1, C4,
C5, and C10 are located in the plane (maximum
deflection 0.0028(3) Å), and the atoms O2 and C3 are
Neurotropic Activity
We studied the neurotropic activity of 15 newly
synthesized 6,8ꢀdiamino derivatives of pyrano[3,4ꢀ
]pyridines (Va – o ) and the reference drug diazepam
by indicators characterizing the anticonvulsant, sedaꢀ
tive, and antianxiety activity, as well as the central
с
deflected from the plane by 0.2736(3) and 0.4652(3) Å, muscle relaxant effect. The study was carried out in
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 42
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SYNTHESIS AND NEUROTROPIC ACTIVITY OF 6,8ꢀDIAMINO DERIVATIVES
217
Table 1. Comparative anticorazole activity of compounds
anticonvulsant effect. Administration of the comꢀ
pounds to mice starting from a dose of 25 mg/kg was
accompanied by prevention of corazole seizures, and
ED50 in these animals varied from 30 to 60 mg/kg
(Table 1). At these doses, coordination of movements
in mice was not substantially violated, the muscle
relaxation phenomena were not observed. The excepꢀ
tion was compounds (Vi, m, n) that possess a proꢀ
nounced anticonvulsive activity and induce muscle
relaxation in animals at therapeutic doses. Therefore,
these compounds were not used in the open field
model. The diazepam effective dose (ED50) by anticꢀ
orazole action in mice was 0.5 mg/kg (Table 1).
(Ve
,
g
,
i,
l–o) and diazepam
Antagonism to corazole*
(ED50 mg/kg)
Compound
(
Ve
)
)
30.0(17.1–45.6)
32.0(20.0–51.2)
56.0(36.0–80.3)
33.0(24.8–43.8)
50.5(30.0–72.5)
43.0(25.2–73.9)
41.0(23.5–68.0)
0.5(0.4–0.7)
(
(
(
(
(
(
Vg
Vi
)
)
Vl
Vm
Vn
Vo
)
)
)
In the openꢀfield behavioral model, the number of
horizontal movements was 18.6 and 22.5; vertical
movements, 1.1 and 6.5; and the number of examined
chambers, 2.1 and 4.8 in rats of the control group to
diazepam and the control group to compounds (Ve, g,
l, o), respectively (Table 2). Compounds under invesꢀ
tigation caused some changes of the behavior indicaꢀ
tors compared to the control: a slight tendency to inhiꢀ
bition of horizontal movements of animals was
observed when compounds (Ve) and (Vg ) were
injected; and compounds (Vl) and (Vo) reduced the
ability of animals to rise on the hind legs and to examꢀ
ine the chambers, which may be associated with the
manifestations of mild sedation induced by these
compounds (Table 2). Diazepam (2 mg/kg) caused a
significant increase in these parameters, i.e., there was
its antianxiety and activating effect.
Diazepam
*Confidence intervals at a probability level
P = 0.05.
200 white mice weighing 18–24 g and 64 male Wistar
rats weighing 120–140 g.
In the study of anticonvulsant action, it was found
that not all synthesized derivatives have the same proꢀ
nounced anticorazole activity. Thus, the compound
(
Vj) at a dose of 50 mg/kg, (Va – d , f , h , k ) at a dose of
100 mg/kg warned convulsions in 20ꢀ40% of animals.
In the study of anticonvulsant action, it was found that
not all of the synthesized derivatives have the same
pronounced anticorazole activity. Thus, compounds
(Vj) at a dose of 50 mg/g and (Va – d , f , h , k ) at a dose
of 100 mg/kg prevented convulsions in 20–40% of
animals. At the above mentioned doses, the adverse
Study of the relationship between structure of the
side effects were observed in animals: coordination of investigated compounds and their biological activity
movements was violated and muscle relaxation showed that compounds (Ve, g, i, l–o) with the methꢀ
appeared. Other regularities were observed for comꢀ oxy group in positions 2, 3, and 4 of the aniline residue
pounds (Ve, g, i, l–o). All of them have a pronounced exhibit anticonvulsant activity. Compounds (Ve, g, l
)
Table 2. The effect of compounds (Ve
,
g,
l,
o) and diazepam in the openꢀfield test
Number of (in absolute values for 5 min)*
Compound
horizontal movements
vertical movements
examined chambers
Control to compounds
22.5(19.3–25.7)
14.0(10.2–17.8)
15.2(10.4–18.3)
18.3(12.0–24.6)
24.3(18.2–39.9)
18.6(13.7–23.5)
33.6(29.4–37.8)
6.5(4.8–8.2)
7.8(5.8–9.9)
3.2(2.8–3.6)
7.6(5.7–9.5)
4.3(2.9–5.7)
1.1(0.7–1.5)
6.4(5.4–7.4)
4.8(4.0–5.6)
3.6(2.3–4.9)
2.6(1.0–4.1)
3.5(2.4–4.6)
2.8(1.1–5.4)
2.1(1.0–3.2)
5.0(3.7–6.3)
(
(
(
(
Ve
)
)
Vg
Vl
)
Vo
)
Control to diazepam
Diazepam
*Confidence intervals at a probability level
P = 0.05.
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218
PARONIKYAN et al.
Table 3. Basic crystallographic characteristics and experiꢀ
SigmaꢀAldrich (United States). The solvents were
purified according to standard protocols. The melting
points were determined on a Boetius microtable. Eleꢀ
mental analysis was performed on a Euro EA 3000
Elemental Analyzer (Germany). The IR spectra were
recorded on a Nicolet Avatar 330 FTꢀIR spectrometer
(United States) in mineral oil. The 1H and 13C NMR
mental data for the crystal structure of compound (Vl
)
Crystallographic characteristics
Chemical formula sum
Chemical formula weight
Crystal system
C19H22N4O2
338.40
Triclinic
Pꢀ1
spectra ( , ppm; J, Hz) were measured on a Mercury
δ
Space group
Vx 300 instrument (United States) at an operating freꢀ
quency of 300 and 75.462 MHz, respectively, in
DMSOꢀd6 with tetramethylsilane as internal standard.
Basic crystallographic characteristics and experimenꢀ
tal data for compound (VI) are reported in Table 3.
The Xꢀray diffraction study of compound (Vl) sinꢀ
gle crystal was performed in a EnrafꢀNonius CADꢀ4
automatic diffractometer (graphite monochromator,
a
,
b
,
c, Å
8.4531(17), 9.0608(18),
12.057(2)
a, b, g, deg
99.97(3), 103.72(3), 90.92(3)
V
Z
, Å3
882.0(3)
2
Density (calc.), g/cm3
(Mo
), mm–1
1.274
0.085
360
μ
K
Мо
К
radiation,
θ
/2
ture. Monoclinic unit cell parameters were deterꢀ
mined and refined by 24 reflexes with 10.09
16.67 . The structure was decoded by the direct
θ
scanning) at ambient temperaꢀ
α
α
F(000)
°
<
θ
<
Crystal size, mm
Experimental data
Temperature, K
Radiation, Å
0.25
×
0.30
×
0.36
°
method, the coordinates of the hydrogen atoms were
determined from the difference Fourier syntheses. The
structure was refined using the fullꢀmatrix method of
least squares in the anisotropic approximation for
nonhydrogen atoms; and isotropic approximation for
the hydrogen atoms. All structural calculations were
performed using SHELXTL software [21].
293
0.71073
1.8; 30.0
θmin; θmax, deg
Scanning area
0
≤
h
≤
11, –12
≤
k ≤ 12,
–16 ≤ l ≤ 16
Number of collected
reflections
5443
3703
Crystallographic data for compound (Vl) were
deposited with the Cambridge Crystallographic Data
Center (CCDC no. 1411701).
Number of observed
reflections with
Compounds (IIa–e)–(IVa–e) were obtained as
described in [15, 22].
[I
> 2.0 σ(I)]
Calculated data
Nref, Npar
Compounds (IIf, g). General procedure. Substiꢀ
tuted aniline (10 mmol) was added to a suspension of
5120, 314
R
,
wR2,
S
0.0476, 0.1399, 1.02
compound (
(10 mL) with stirring. The reaction mixture was kept at
75 for 1.5 h, then cooled to room temperature, and
I) [14] (1.9 g, 5 mmol) in absolute ethanol
2
Weighing scheme
W
= 1/[
σ
(
F
o2) + (0.0696P)2
],
= (Fo2 + 2Fc2)/3
+ 0.1397
P
°С
where
P
poured into cold water. The precipitate was filtered
off, washed with water, dried, and recrystallized from
ethanol.
containing both the methylamine fragment in position 8
6ꢀAminoꢀ3,3ꢀdimethylꢀ8ꢀ[(2ꢀmethylphenyl)imino]ꢀ
of pyrano[3,4ꢀ
most active.
c]pyridine and methoxy group were the
4,8ꢀdihydroꢀ1
bonitrile (IIf). Yield 70%, mp 129–130
C 66.48, H 5.81, N 12.87, S 9.79. С18Н19N3OS. Calꢀ
culated, %: C 66.43, H 5.88, N 12.91, S 9.85. IR (
cm–1: 1660 (C=N), 2192 (CN), 3198, 3305 (NH2)
H,3Hꢀthiopyrano[3,4ꢀ
c
]pyranꢀ5ꢀcarꢀ
°C. Found, %:
Thus, while studying neurotropic properties of 6,8ꢀ
diamino derivatives of pyrano[3,4ꢀ ]pyridines it was
c
ν
,
found that some of them possess anticorazole and cenꢀ
tral myorelaxant effects that were not previously
described. However, in contrast to the tranquilizer
diazepam that possesses anxiolytic and behaviorꢀactiꢀ
vating effects in the openꢀfield test, the sedative effect
was observed in some compounds studied.
.
1H NMR: 1.30 (s, 6 H, C(С
2.41 (t, 2 H, 1.8, 4ꢀ 2), 4.45 (t, 2 H,
6.66 (dd, 1 H,
1 7.8, 2 1.2,
2 1.2,
), 7.11–7.21 (m, 2 H, 2C
H2).
6ꢀAminoꢀ8ꢀ[(3ꢀmethoxyphenyl)imino]ꢀ3,3ꢀdimeꢀ
thylꢀ4,8ꢀdihydroꢀ1 ,3 ꢀthiopyrano[3,4ꢀ ]pyranꢀ5ꢀ
. Found,
reagents purchased from Fluka (Germany) and %: C 63.38, H 5.66, N 12.27, S 9.34. С18Н19N3O2S
Н3)2), 2.08 (s, 3 H,
СН3),
J
C
J
H
J
1.8, 1ꢀC
H
2),
J
CH
), 6.95 (td, 1 H,
J
1 7.5,
J
CH
H), 7.50 (br. s, 2 H,
N
EXPERIMENTAL
H
H
c
In this work we used commercially available carbonitrile (IIg). Yield 94%, mp 207–209°C
.
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SYNTHESIS AND NEUROTROPIC ACTIVITY OF 6,8ꢀDIAMINO DERIVATIVES
219
Calculated, %: C 63.32, H 5.61, N 12.31, S 9.39. IR 15.9, 1ꢀC
, cm–1): 1660 (C=N), 2190 (CN), 3195, 3308 7.66 (m, 4 H, 4CH), 8.38 (br. s, 2 H,
(NH2). 1H NMR: 1.29 (s, 6 H, C(С
3)2), 2.39 (t, 2 H,
1.7, 4ꢀ 2), 3.77 (s, 3 H, OСН3), 4.39 (t, 2 H, 1.7,
1ꢀ H2), 6.29–6.37 (m, 2 H, 2C
), 6.58 (ddd, 1 H, J1
8.3, ), 7.22 (t, 1 H, 8.0, ), 7.52
2 2.5, 3 0.8,
(br. s, 2 H, H2).
H
H), 4.79 (d, 1 H,
J
15.9, 1ꢀCH
H2).
6ꢀAminoꢀ5ꢀcyanoꢀ3,3ꢀdimethylꢀ8ꢀmethylthioꢀ7ꢀ
(3ꢀmethoxyphenyl)ꢀ3,4ꢀdihydroꢀ1 ꢀpyrano[3,4ꢀ ]pyriꢀ
H
), 7.47–
(
ν
N
Н
J
C
H
J
H
c
C
H
diniumꢀ7ꢀmethanesulfonate (IVg). Yield 74%, mp
186–187°C. Found, %: C 51.45, H 5.47, N 8.92, S
13.67. С20Н25N3O6S2. Calculated, %: C 51.38, H 5.39,
J
J
CH
J
CH
N
Compounds (IIIf, g). General procedure. Correꢀ N 8.99, S 13.72. IR (
sponding compound (IIf, g) (10 mmol) was added to a (NH2). 1H NMR: 1.37 (s, 6 H, C(С
solution of sodium ethylate obtained from sodium SСН3), 2.94 (d, 1 H, 18.2, 4ꢀCH
(253 mg, 11 mmol) and absolute ethanol (25 mL). The 18.2, 4ꢀCH ), 3.58 (s, 3 H, SOСН3), 3.89 (s, 3 H,
reaction mixture was kept at 50 C for 30 min, then COC 3), 4.71 (d, 1 H, 15.9, 1ꢀCH ), 4.79 (d, 1 H,
cooled to room temperature, and poured into cold 15.9, 1ꢀCH ), 7.15–7.20 (m, 2 H, 2C ), 7.56–7.67
), 8.45 (br. s, 2 H, H2).
ν
, cm–1): 2230 (CN), 3217, 3315
Н
3)2), 2.23 (s, 3 H,
), 3.01 (d, 1 H, J
J
H
H
°
H
J
H
J
H
H
water. The precipitate was filtered off, washed with (m, 2 H, 2C
water, dried, and recrystallized from nitromethane.
H
N
Compounds (Va–c, f, h–k, m–o). General proceꢀ
6ꢀAminoꢀ3,3ꢀdimethylꢀ7ꢀ(2ꢀmethylphenyl)ꢀ8ꢀ
dure. A mixture of pyridinium salt (IVa, b, d, e, g)
thioxoꢀ3,4,7,8ꢀtetrahydroꢀ1 ꢀpyrano[3,4ꢀ ]pyriꢀ (5 mmol) and corresponding amine (50 mmol) in
H
c
dineꢀ5ꢀcarbonitrile (IIIf). Yield 68%, mp 296–297°C. MeOH (20 mL) was refluxed for 2 h, then cooled to room
Found, %: C 66.50, H 5.83, N 12.96, S 9.77. temperature. The precipitate formed was filtered off,
С18Н19N3OS. Calculated, %: C 66.43, H 5.88, N washed with water, dried, and recrystallized from ethanol.
12.91, S 9.85. IR (
3205, 3308 (NH2). 1H NMR: 1.31 (s, 6 H, C(С
2.07 (s, 3 H, Н3), 2.55 (br. s, 2 H, 4ꢀ H2), 4.35 (d, 1
H, 16.5, 1ꢀC H), 4.41 (d, 1 H, 16.5, 1ꢀCH ),
6.48 (br. s, 2 H, 2), 7.03–7.08 (m, 1 H, Ar),
.38–7.43 (m, 3 H,3CHAr).
6ꢀAminoꢀ3,3ꢀdimethylꢀ7ꢀ(3ꢀmethoxyphenyl)ꢀ8ꢀ
thioxoꢀ3,4,7,8ꢀtetrahydroꢀ1 ꢀpyrano[3,4ꢀ ]pyriꢀ s, 2 H, 4ꢀ
ν
, cm–1): 1245 (C=S), 2204 (CN),
3)2)
6ꢀAnilinoꢀ3,3ꢀdimethylꢀ8ꢀ[(3ꢀmethoxypropyl)amino]ꢀ
3,4ꢀdihydroꢀ1 ꢀpyrano[3,4ꢀ ]ꢀpyridineꢀ5ꢀcarboniꢀ
trile (Va). Yield 69%, mp 116–117 . Found, %: C
68.77, H 7.08, N 15.34. С21Н26N4O2. Calculated, %:
C 68.83, H 7.15, N 15.29. IR (
, cm–1): 2200 (CN),
3370 (NH), 3395 (NH). H NMR: 1.27 (s, 6 H,
C(С 3)2), 1.76–1.85 (m, 2 H, NHCH2CH2), 2.57 (br.
Н2), 3.27 (s, 3 H, OC 3), 3.36–3.41 (m, 4
2OCH3), 4.31 (br. s, 2 H, 1ꢀС 2),
5.4, N CH2), 6.86–6.93 (m, 1 H,
), 7.58–7.63 (m, 2 H,
Н
,
H
c
С
C
°C
J
H
J
H
NH
CH
ν
7
1
Н
H
c
С
H
dineꢀ5ꢀcarbonitrile (IIIg). Yield 97%, mp 298– H, NHCH2 and
300°C. Found, %: C 63.37, H 5.68, N 12.25, S 9.33. 6.31 (br. t, 1 H,
C
J
H
Н
H
С18Н19N3O2S. Calculated, %: C 63.32, H 5.61, N
12.31, S 9.39. IR (
, cm–1): 1250 (C=S), 2220 (CN), 2C
3200, 3290 (NH2). 1H NMR: 1.31 (s, 6 H, C(С
3)2)
2.54 (br. s, 2 H, H2), 3.84 (s, 3 H, OСН3), 4.36 (br. s,
2 H, 1ꢀ H2), 6.54 (br. s, 2 H, 2), 6.70–6.75 (m, 2
H, 2C Ar), 7.01–7.05 (m, 1 H, Ar), 7.45–7.52 (m,
1 H,
). 13C NMR: 25.8, 25.9, 37.4, 54.8, 61.6, 68.7,
C
H
H
), 7.15–7.21 (m, 2 H, 2C
), 7.83 (br. s, 1 H, N ).
6ꢀAnilinoꢀ8ꢀ{[3ꢀ(dimethylamino)propyl]amino}ꢀ
3,3ꢀdimethylꢀ3,4ꢀdihydroꢀ1 ꢀpyrano[3,4ꢀ ]ꢀpyriꢀ
dineꢀ5ꢀcarbonitrile (Vb). Yield 61%, mp 150–151
Found, %: C 69.68, H 7.75, N 18.37. С22Н29N5O. Calꢀ
culated, %: C 69.63, H 7.70, N 18.45. IR (
, cm–1):
2206 (CN), 3365 (NH), 3405 (NH). H NMR: 1.27
(s, 6 H, C(С 3)2), 1.67–1.76 (m, 2 H, NHCH2C 2),
3)2), 2.38 (t, 2 H, 6.8, NCH2),
of corresponding thione (IIIf, g) (10 mmol), dimethꢀ 2.56 (br. s, 2 H, 4ꢀСН2), 3.41 (td, 2 H, J1 6.9, J2 5.2,
ylsulfate (1.9 g, 15 mmol), and toluene (20 mL) was NHCH2), 4.26 (br. s, 2 H, 1ꢀСН2), 6.75 (br. t, 1 H,
refluxed for 10–15 min. After cooling, the precipitate 5.2, CH2), 6.85–6.92 (m, 1 H, C ), 7.18–7.24
was filtered off, washed with cold MeOH, dried, and (m, 2 H, 2C ), 7.58–7.65 (m, 2 H, 2C ), 7.79 (br. s,
H
ν
H
Н
,
C
H
c
C
H
H
NH
CH
°C.
C
ν
78.5, 113.4, 115.1, 115.2, 119.7, 122.7, 130.6, 138.5,
141.5, 153.9, 160.7, 177.9.
1
Н
H
Compounds (IVf, g). General procedure. A mixture 2.18 (s, 6 H, N(
СН
J
J
NH
H
H
H
recrystallized from 1,4ꢀdioxane.
1 H, N
6ꢀAnilinoꢀ3,3ꢀdimethylꢀ8ꢀ[(tetrahydrofuranꢀ2ꢀ
ylmethyl)amino]aminoꢀ3,4ꢀdihydroꢀ1 ꢀpyrano[3,4ꢀ
]ꢀpyridineꢀ5ꢀcarbonitrile (Vc). Yield 62%, mp 166–
mp 198–200°C. Found, %: C 53.26, H 5.63, N 9.27, 168°C. Found, %: C 69.88, H 6.87, N 14.73.
H).
6ꢀAminoꢀ3,3ꢀdimethylꢀ7ꢀ(2ꢀmethylphenyl)ꢀ8ꢀ
methylthioꢀ5ꢀcyanoꢀ3,4ꢀdihydroꢀ1
H
ꢀpyrano[3,4ꢀ
H
c]pyridiniumꢀ7ꢀmethanesulfonate (IVf). Yield 78%,
c
S
14.14. С20Н25N3O5S2. Calculated, %: C 53.20, H С22Н26N4O2. Calculated, %: C 69.82, H 6.92, N
5.58, N 9.31, S 14.20. IR (
ν
, cm–1): 2220 (CN), 3220, 14.80. IR (
ν
, cm–1): 2210 (CN), 3330 (NH), 3405
3)2), 1.58–1.83
3318 (NH2). 1H NMR: 1.38 (s, 3 H, C(С
Н
3)2), 1.39 (s, (NH). H NMR: 1.27 (s, 6 H, C(С
Н
1
3 H, C(С
SСН3), 2.94 (d, 1 H,
18.1, 4ꢀCH ), 3.58 (s, 3 H, OСН3), 4.71 (d, 1 H,
Н
3)2), 2.10 (s, 3 H,
СН3), 2.25 (s, 3 H, (m, 4 H, 2CH2), 2.55 (br. s, 2 H, 4ꢀСН2), 3.24–4.03
J
18.1, 4ꢀ
C
HH), 3.01 (d, 1 H,
J
J
(m, 5 H,
CH2,CH, NHCH2), 4.35 (br. s, 2 H, 1ꢀСН2),
H
6.33 (br. t, 1 H,
J
5.4, CH2), 6.85–6.94 (m, 1 H,
NH
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 42
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220
PARONIKYAN et al.
C
2C
H
H
), 7.18–7.23 (m, 2 H, 2C
H
), 7.56–7.61 (m, 2 H, (t, 1 H,
J
J
5.1, OH), 4.31 (br. s, 2 H, 1ꢀСН2), 6.33 (br.
5.1, CH2), 6.79–7.05 (m, 2 H, 2C ),
), 7.70 (br. s, 1 H, N ).
8ꢀ[(2ꢀMethoxyethyl)amino]ꢀ3,3ꢀdimethylꢀ6ꢀ[(4ꢀ
methylphenyl)amino]ꢀ3,4ꢀdihydroꢀ1 ꢀpyrano[3,4ꢀ
]ꢀpyridineꢀ5ꢀcarbonitrile (Vk). Yield 68%, mp 195–
), 7.84 (br. s, 1 H, N ).
H
t, 1 H,
7.46–7.54 (m, 2 H, 2C
NH
H
H
H
8ꢀ[(2ꢀFuranylmethyl)amino]ꢀ3,3ꢀdimethylꢀ6ꢀ[(3ꢀ
methylphenyl)amino]ꢀ3,4ꢀdihydroꢀ1 ꢀpyrano[3,4ꢀ
]ꢀpyridineꢀ5ꢀcarbonitrile (Vf). Yield 71%, mp 193–
H
H
c
c
194°C. Found, %: C 71.18, H 6.27, N 14.50.
196°C. Found, %: C 68.87, H 7.22, N 15.23.
С23Н24N4O2. Calculated, %: C 71.11, H 6.23, N 14.42.
IR (
, cm–1): 2200 (CN), 3365 (NH), 3387 (NH).
1H NMR: 1.28 (s, 6 H, C(С
3)2), 2.24 (s, 3 H, Н3),
2.55 (s, 2 H, 4ꢀСН2), 4.37 (s, 2 H, 1ꢀСН2), 4.54 (d, 2
H, 5.6, NHC 2), 6.00 (dd, 1 H,
1 3.2, 2 0.8, C
furyl), 6.24 (dd, 1 H, ꢀfuryl), 6.70 (br.
1 3.1, 2 1.8, C
d, 1 H, 7.3, C ), 6.85 (br. t, 1 H, 5.6, CH2),
7.04 (dd, 1 H, J1 8.2, J2 7.3, C
8.2, C ), 7.36 (dd, 1 H,
1 1.8,
(br. s, 1 H, C
С21Н26N4O2. Calculated, %: C 68.83, H 7.15, N 15.29.
IR (
, cm–1): 2203 (CN), 3328 (NH), 3356 (NH).
1H NMR: 1.27(s, 6 H, C(С
3)2), 2.30 (s, 3 H, H3), 2.54
(br. s, 2 H, 4ꢀСН2), 3.41–3.53 (m, 4 H, NHC 2СН2),
4.32 (br. s, 2 H, 1ꢀСН2), 6.29 (br. t, 1 H, 5.2,
CH2), 6.96–7.03 (m, 2 H, 2C ), 7.42–7.48 (m,
2 H, 2CH), 7.75 (br. s, 1 H, NH). C NMR: 20.2,
25.8, 37.5, 40.3, 57.8, 58.2, 69.0, 70.5, 78.3, 103.9,
116.9, 120.3, 128.0, 130.1, 137.4, 144.2, 153.8, 155.2.
ν
ν
Н
С
Н
C
H
J
H
J
H
J
Hꢀ
J
J
J
NH
H
J
H
J
NH
13
H
J
), 7.29 (br. d, 1 H, J
H
J
2 0.8, CHꢀfuryl), 7.42
13
H
), 7.85 (br. s, 1 H, N
H
). C NMR:
20.9, 25.8, 37.3, 37.5, 58.2, 69.0, 79.1, 104.2, 106.0,
109.8, 116.7, 117.3, 120.8, 122.1, 127.4, 136.6, 139.7,
140.6, 144.5, 152.8, 153.4, 155.0.
8ꢀ[(2ꢀMethoxyethyl)amino]ꢀ6ꢀ[(4ꢀmethoxypheꢀ
nyl)amino]ꢀ3,3ꢀdimethylꢀ3,4ꢀdihydroꢀ1
pyridineꢀ5ꢀcarbonitrile (Vm). Yield 70%, mp 225–
226 C. Found, %: C 65.89, H 6.91, N 14.70.
С21Н26N4O3. Calculated, %: C 65.95, H 6.85, N 14.65.
IR (
, cm–1): 2210 (CN), 3345 (NH), 3380 (NH).
1H NMR: 1.27 (s, 6 H, C(С
3)2), 2.53 (br. s, 2 H, 4
Н2), 3.31 (s, 3 H, OC 3), 3.51–3.62 (m, 4 H,
NHC 2СН2), 3.76 (s, 3 H, CH2ОCH3), 4.35 (br. s,
2 H, 1ꢀСН2), 6.22 (t, 1 H, 5.2, CH2), 6.85–6.90
), 7.53–7.65 (m, 2 H, 2C ), 7.83 (br. s,
Hꢀpyrano[3,4ꢀc]ꢀ
°
6ꢀ[(3ꢀMethoxyphenyl)amino]ꢀ3,3ꢀdimethylꢀ8ꢀ
[(pyridineꢀ3ꢀylmethyl)amino]ꢀ3,4ꢀdihydroꢀ1
ano[3,4ꢀ ]ꢀpyridineꢀ5ꢀcarbonitrile (Vh). Yield 63%,
mp 200–202 C. Found, %: C 67.49, H 6.62, N 16.50.
C24H25N5O2. Calculated, %: C 69.38, H 6.06, N 16.86.
Hꢀpyrꢀ
ν
c
Н
ꢀ
°
С
H
, cm–1): 2205 (CN), 3386 (NH), 3401 (NH).
3)2), 2.56 (br. s, 2 H, 4
3), 4.40 (br. s, 2 H, 1ꢀСН2),
2), 6.44 (dt, 1 H,
1 7.1, J2
CH2), 6.93–7.05 (m, 3 H, 3C ), 7.10–7.16
(m, 2 H, 2C ), 7.52 (dt, 1 H, ), 7.92
1 7.8, 2 2.0, C
(s, 1 H, N ), 8.33 (dd, 1 H, ), 8.41
1 6.2, 2 1.5, C
(d, 1 H, 2.0, C ).
H
IR (
ν
1H NMR: 1.28 (s, 6 H, C(С
Н
ꢀ
J
NH
(m, 2 H, 2C
1 H, NH).
H
H
СН2), 3.70 (s, 3 H, OCH
4.56 (d, 2 H,
2.1,
J
5.8, NHC
H
J
N
H
H
8ꢀ{[(2ꢀDimethylamino)ethyl]amino}ꢀ6ꢀ[(4ꢀmethꢀ
oxyphenyl)amino]ꢀ3,3ꢀdimethylꢀ3,4ꢀdihydroꢀ1 ꢀpyrꢀ
ano[3,4ꢀ ]ꢀpyridineꢀ5ꢀcarbonitrile (Vn). Yield 72%,
mp 163–165 C. Found, %: C 66.87, H 7.32, N 17.65.
С22Н29N5O2. Calculated, %: C 66.81, H 7.39, N 17.71.
IR (
, cm–1): 2207 (CN), 3370 (NH), 3400 (NH). 1H
NMR: 1.27 (s, 6 H, C(С 3)2), 2.16 (s, 6 H, N( Н3 2),
2.39 (t, 2 H, 6.8, NCH2), 2.53 (br. s, 2 H, 4ꢀСН2),
3.35–3.43 (m, 2 H, NHСН2), 3.77 (s, 3 H, OC 3),
4.31 (br. s, 2 H, 1ꢀСН2), 5.97 (br. t, 1 H, 5.4,
CH3), 6.71–6.78 (m, 2 H, 2C ), 7.43–7.50 (m, 2
H, 2C ), 7.70 (br. s, 1 H, N ).
H
H
J
J
J
J
H
H
H
c
J
H
°
6ꢀ[(3ꢀMethoxyphenyl)amino]ꢀ3,3ꢀdimethylꢀ8ꢀ
[(2ꢀmorpholinꢀ4ꢀylethyl)amino]ꢀ3,4ꢀdihydroꢀ1 ꢀpyrꢀ
ano[3,4ꢀ ]ꢀpyridineꢀ5ꢀcarbonitrile (Vi). Yield 67%,
mp 165–166 C. Found, %: C 65.82, H 7.20, N 16.15.
С24Н31N5O3. Calculated, %: C 65.88, H 7.14, N 16.01.
IR (
, cm–1): 2200 (CN), 3376 (NH), 3394 (NH).
1H NMR: 1.27 (s, 6 H, C(С
3)2), 2.33–2.37 (m, 4 H,
N(С 2)2), 2.47 (t, 2 H, 6.9, NC 2), 2.55 (br. s, 2 H,
ꢀСН2), 3.44–3.51 (m, 2 H, NHСН2), 3.52–3.57 (m,
4 H, O(С 2)2), 3.77 (s, 3 H, OC 3), 4.32 (br. s, 2 H,
ꢀСН2), 6.15 (br. t, 1 H, 5.2, CH2), 6.45 (ddd, 1
), 7.06 (t, 1 H, 8.0, C ),
2 2.9, 3 1.0, C
), 7.26 (t, 1 H,
).
ν
H
Н
С
)
c
J
°
H
J
ν
N
H
H
Н
H
H
Н
J
H
4
6ꢀ[(4ꢀMethoxyphenyl)amino]ꢀ3,3ꢀdimethylꢀ8ꢀ
[(tetrahydrofuranꢀ4ꢀylmethyl)amino]ꢀ3,4ꢀdihydroꢀ
Н
H
1
J
H
NH
1H
ꢀpyrano[3,4ꢀ
67%, mp 158–159
17.65. С23Н28N4O3. Calculated, %: C 67.63, H 6.91, N
13.72. IR (
, cm–1): 2205 (CN), 3378 (NH), 3395
(NH). H NMR: 1.26 (s, 6 H, C(С 3)2), 1.56–1.81
(m, 4 H, 2СН2), 2.54 (br. s, 2 H, 4ꢀСН2), 3.38–3.64
(m, 5 H, NHС 2, СН2, C ), 3.78 (s, 3 H, OC 3),
4.36 (br. s, 2 H, 1ꢀСН2), 6.12 (br. t, 1 H, 5.1,
CH2), 6.73–6.78 (m, 2 H, 2C ), 7.43–7.51 (m, 2
H, 2C ), 7.76 (br. s, 1 H, N ).
c
]ꢀpyridineꢀ5ꢀcarbonitrile (Vo). Yield
H,
7.15 (ddd, 1 H,
2.2, C
J
1 8.0,
J
2 3.5,
J
3 1.0, C
J
H
°
C. Found, %: C 66.87, H 7.32, N
J
1 8.0,
J
J
H
J
H
), 7.86 (br. s, 1 H, N
H
ν
1
Н
8ꢀ[(3ꢀHydroxypropyl)amino]ꢀ3,3ꢀdimethylꢀ6ꢀ[(4ꢀ
methylphenyl)amino]ꢀ3,4ꢀdihydroꢀ1 ꢀpyrano[3,4ꢀ
]ꢀpyridineꢀ5ꢀcarbonitrile (Vj). Yield 65%, mp 217–
H
Н
H
H
c
J
218°C. Found, %: C 68.89, H 7.20, N 15.24.
N
H
H
C21H26N4O2. Calculated, %: C 68.83, H 7.15, N 15.29.
IR (
, cm–1): 2208 (CN), 3280–3350 (NH, OH).
1H NMR: 1.27 (s, 6 H, C(С
3)2), 1.64–1.77 (m, 2 H,
NHCH2СН2), 2.30 (s, 3 H, H3), 2.52 (br. s, 2 H, 4
Н2), 3.40–3.52 (m, 4 H, NHСН2 and СН2OH), 4.13 methanolic solution of methylamine (30 mL) was kept
H
H
ν
Н
Compounds (Vd, e, g, l). General procedure. A mixꢀ
ture of pyridinium salt (IVc, e, f, g) (5 mmol) and 7 M
C
ꢀ
С
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 42
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SYNTHESIS AND NEUROTROPIC ACTIVITY OF 6,8ꢀDIAMINO DERIVATIVES
221
at 40–50°C for 1 h and then cooled to room temperaꢀ ponent induced by subcutaneous injection of corazole
ture. The resulting precipitate was filtered off, washed
(90 mg/kg) to mice, i.e., by antagonism to corazole.
Unwanted side effects in these animals, namely the
central myorelaxant effect and impaired motor coorꢀ
dination were examined by the rotating rod method
[16]. The compounds under investigation were
injected in a dose range of 25, 50, and 100 mg/kg; refꢀ
erence drug diazepam (Polfa, Poland), at doses of
0.1–0.3 and 1.0 mg/kg intraperitoneally 45 min before
injection of corazole (Acros Organics, United States)
in the form of a suspension with carboxymethyl celluꢀ
lose (ViadiꢀIngredienti, Russia) and Tween 80 (Ferak
Berlin, Germany). Control animals were administered
an emulsifier before corazole injection. A 50% effecꢀ
tive dose (ED50) of the tested compounds, i.e., dose
causing anticonvulsant effect in 50% of animals, was
determined by anticonvulsant effect according the
Litchfield and Wilcoxon method [17].
with water, dried, and recrystallized from a CHCl3
–
EtOH mixture (1 : 2).
3,3ꢀDimethylꢀ8ꢀmethylaminoꢀ6ꢀ[(2ꢀmethylpheꢀ
nyl)amino]ꢀ3,4ꢀdihydroꢀ1 ꢀpyrano[3,4ꢀ ]pyridineꢀ
5ꢀcarbonitrile (Vd). Yield 65%, mp 134–135 C.
Found, %: C 70.85, H 6.83, N 17.34. С19Н22N4O. Calꢀ
culated, %: C 70.78, H 6.88, N 17.38. IR (
, cm–1):
2205 (CN), 3372 (NH), 3395 (NH). H NMR: 1.27
(s, 6 H, C(С 3)2), 2.31 (s, 3 H, Н3), 2.54 (br. s, 2 H,
ꢀСН2), 2.92 (d, 3 H, 4.5, NHCH3), 4.32 (br. s, 2 H,
ꢀСН2), 6.38 (q, 1 H, 4.5, CH2), 6.87–6.93 (m,
), 7.05–7.17 (m, 3 H, 3C ), 7.86 (br. s, 1 H,
H
c
°
ν
1
Н
С
4
1
J
J
NH
1 H, C
).
6ꢀ[(2ꢀMethoxyphenyl)amino]ꢀ3,3ꢀdimethylꢀ8ꢀ
methylaminoꢀ3,4ꢀdihydroꢀ1 ꢀpyrano[3,4ꢀ ]pyridineꢀ
5ꢀcarbonitrile (Ve). Yield 61%, mp 173–174 C.
Found, %: C 67.51, H 6.49, N 16.62. С19Н22N4O2
Calculated, %: C 67.44, H 6.55, N 16.56. IR (
, cm–1):
2200 (CN), 3365 (NH), 3387 (NH). 1H NMR: 1.27 (s,
6 H, C(С 3)2), 2.53 (br. s, 2 H, 4ꢀСН2), 2.95 (d, 3 H,
H3), 3.96 (s, 3 H, OC 3), 4.35 (br. s, 2 H,
ꢀСН2), 6.39 (q, 1 H, 4.4, CH2), 6.82–6.91 (m,
), 7.57 (br. s, 1 H, N ), 8.51–8.57 (m, 1 H,
H
H
NH
H
c
°
.
ν
Sedative, activating, and anxiolytic effects of the
selected most active compounds were studied in rats in
the open field test [18–20]. Experiments were carried
out during the daytime at natural lighting. Registration
of spontaneous behavior in each individual animal was
continued for 5 min. The presence of sedative and
activating effects was assessed by the number of horiꢀ
zontal (intersection of squares) and vertical (rising on
hind legs) movements; anxiolytic effect was evaluated
by the number of examined chambers in animals of
experimental and control groups.
Н
J
4.4, NH
C
H
1
J
NH
3 H, 3C
).
6ꢀ[(3ꢀMethoxyphenyl)amino]ꢀ3,3ꢀdimethylꢀ8ꢀ
methylaminoꢀ3,4ꢀdihydroꢀ1 ꢀpyrano[3,4ꢀ ]pyridineꢀ
5ꢀcarbonitrile (Vg). Yield 69%, mp 188–189 C.
Found, %: C 67.49, H 6.62, N 16.50. С19Н22N4O2
Calculated, %: C 67.44, H 6.55, N 16.56. IR (
, cm–1):
2204 (CN), 3372 (NH), 3395 (NH). H NMR: 1.27
(s, 6 H, C(С 3)2), 2.54 (br. s, 2 H, 4ꢀСН2), 2.93 (d, 3
H, 4.4, NHCH3), 3.76 (s, 3 H, OC 3), 4.32 (br. s, 2
H, 1ꢀСН2), 6.39 (q, 1 H, 4.4, CH3), 6.43 (dd, 1
H, ), 7.01–7.11 (m, 1 H, C
1 8.4, 2 2.1, C
(br. d, 1 H, 8.4, C ), 7.41–7.47 (m, 1 H, C
(br. s, 1 H, N ).
6ꢀ[(4ꢀMethoxyphenyl)amino]ꢀ3,3ꢀdimethylꢀ8ꢀ
methylaminoꢀ3,4ꢀdihydroꢀ1 ꢀpyrano[3,4ꢀ ]pyridineꢀ
5ꢀcarbonitrile (Vl). Yield 68%, mp 218–219 C.
Found, %: C 67.49, H 6.50, N 16.62. С19Н22N4O2
Calculated, %: C 67.44, H 6.55, N 16.56. IR (
, cm–1):
2208 (CN), 3337 (NH), 3360 (NH). 1H NMR: 1.26 (s,
6 H, C(С 3)2), 2.53 (br. s, 2 H, 4ꢀСН2), 2.85 (d, 3 H,
4.5, NHCH3), 3.76 (s, 3 H, OC
ꢀСН2), 6.27 (q, 1 H, 4.5, CH3), 6.72–6.78 (m,
), 7.51–7.56 (m, 2 H, 2C ), 7.69 (br. s, 1 H,
). C NMR: 25.8, 27.7, 37.4, 54.6, 58.3, 69.0,
H
H
CH
H
c
°
.
ν
1
Н
In this model, the number of animals was eight for
each tested compound, control, and diazepam. The
tested compounds were injected to rats in the most
effective dose of 50 mg/kg intraperitoneally in a susꢀ
pension of carboxymethyl cellulose and Tweenꢀ80.
The compounds were injected 45 min before the aniꢀ
mals were placed in the open field. Diazepam, the
known tranquilizer served as a reference drug; it was
injected intraperitoneally in a dose of 2 mg/kg. Only
an emulsifier was injected to control animals. Because
the experiments were carried out on different days, the
corresponding control data were obtained for the tested
J
H
J
NH
J
J
H
H
H
H
), 7.17
), 7.84
J
H
H
c
°
.
ν
Н
J
H3), 4.30 (br. s, 2 H, compounds and diazepam. The results were statistically
1
J
NH
processed at a probability level of = 0.05 [17].
P
2 H, 2C
H
H
13
NH
ACKNOWLEDGMENTS
77.2, 103.6, 112.8, 117.1, 121.8, 133.1, 143.6, 154.2,
154.5, 155.5.
The study was financially supported by the State
Committee of Science of the Ministry of Education and
Science of Armenia and the Russian Foundation for
Basic Research in the framework of joint scientific proꢀ
Biologic Tests
Anticonvulsant activity of the compounds was
assessed by the prevention of the seizure clonic comꢀ grams 15RFꢀ027 and 15ꢀ53ꢀ05064/15, respectively.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 42
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2016

222
PARONIKYAN et al.
CN
CN
CN
NH2
Ar
NH2
NH2
ArNH
–
C H ONa
2 5
2
O
N
O
S
O
S
*CH SO
S
3
4
NAr
SCH3
(I
)
(
IIа
–g
)
(IIIа–g)
( –IV)
II
), Ar = C6H5
), Аr = 4ꢀСН3С6Н4
), Ar = 2ꢀCH3OC6H4
), Аr = 3ꢀСН3С6Н4
), Аr = 4ꢀСН3ОС6Н4
), Аr = 2ꢀСН3С6Н4
CN
Ar
(
(
(
(
(
(
(
a
b
c
d
e
f
CN
NH
NH2
Ar
NH R
2
O
N
O
N
–
4
*CH SO
3
HN
SCH3
R
)
g
), Аr = 3ꢀСН3ОС6Н4
(
IVа
–g
)
(
Vа
–o
(V)
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
а
b
), Аr = С6Н5, R = (СН2)3ОСН3
), Аr = С6Н5, R = (CH2)3N(CH3)2
c
d
e
f
), Аr = С6Н5, R = СН2ꢀ2ꢀtetrahydrofuranyl
), Аr = 2ꢀСН3С6Н4, R = СН3
), Аr = 2ꢀСН3ОС6Н4, R = СН3
), Аr = 3ꢀСН3С6Н4, R = СН2ꢀ2ꢀfuranyl
g
h
), Аr = 3ꢀСН3ОС6Н4, R = СН3
), Аr = 3ꢀСН3ОС6Н4, R = СН2ꢀ3ꢀpyridinyl
i), Аr = 3ꢀСН3ОС6Н4, R = (СН2)2ꢀ4ꢀmorpholinyl
j
), Аr = 4ꢀСН3С6Н4, R = (СН2)3ОН
k
l
m
n
o
), Аr = 4ꢀСН3С6Н4, R = (СН2)2ОСН3
), Аr = 4ꢀСН3ОС6Н4, R = СН3
), Аr = 4ꢀСН3ОС6Н4, R = (СН2)2ОСН3
), Аr = 4ꢀСН3ОС6Н4, R = (CH2)2N(CH3)2
), Аr = 4ꢀСН3ОС6Н4, R =СН2ꢀ2ꢀtetrahydrofuranyl
Scheme 1.
6. Wei, Sh., Jiang, Zh., Tian, Sh., and Zhang, D., Tetraꢀ
hedron Lett., 2013, vol. 54, pp. 4515–4517.
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Translated by G. Levit
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 42
No. 2
2016