Synthesis and neurotropic activity of the derivatives of fused triazolo[4,3-c]- and triazolo[1,5-c]pyrimidines

Article abstract of DOI:10.1134/S1068162017040070

The methods for preparation of fused triazolo[4,3-c]- and triazolo[1,5-c]pyrimidines were developed. The Dimroth rearrangement of these systems was studied. Pharmacological investigation of the synthesized compounds was conducted in known tests, such as a

Full text of DOI:10.1134/S1068162017040070

ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2017, Vol. 43, No. 5, pp. 595–603. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © E.G. Paronikyan, Sh.Sh. Dashyan, R.G. Paronikyan, I.A. Dzhagatspanyan, I.M. Nazaryan, A.G. Akopyan, N.S. Minasyan, 2017, published in Bioorganicheskaya
Khimiya, 2017, Vol. 43, No. 5, pp. 563–571.
Synthesis and Neurotropic Activity of the Derivatives of Fused
Triazolo[4,3-с]- and Triazolo[1,5-с]pyrimidines
E. G. Paronikyana, Sh. Sh. Dashyana, 1, R. G. Paronikyana, I. A. Dzhagatspanyana, I. M. Nazaryana,
A. G. Akopyana, and N. S. Minasyanb
aMndzhoyan Institute of Fine Organic Chemistry, Scientific and Technological Center for Organic and Pharmaceutical
Chemistry, National Academy of Sciences of Armenia, Yerevan, 0014 Armenia
bMolecular Structure Research Center, Scientific and Technological Center for Organic and Pharmaceutical Chemistry,
National Academy of Sciences of Armenia, Yerevan, 0014 Armenia
Received January 9, 2017; in final form, January 19, 2017
Abstract⎯The methods for preparation of fused triazolo[4,3-c]- and triazolo[1,5-c]pyrimidines were devel-
oped. The Dimroth rearrangement of these systems was studied. Pharmacological investigation of the syn-
thesized compounds was conducted in known tests, such as antagonism with subcutaneous administration of
corazole and the open-field test. The rotating rod method was used to assess the neurotoxicity. Neurotropic
properties were found in many derivatives of triazolopyrimidine. They, like diazepam, prevent the occurrence
of clonic twitching and corazole-induced clonic convulsions in animals. All selected compounds as well as
diazepam exhibit an anxiolytic effect.
Keywords: triazolo[4,3-c]- and triazolo[1,5-c]pyrimidines, Dimroth rearrangement, neurotropic activity,
anticonvulsant effect
DOI: 10.1134/S1068162017040070
INTRODUCTION
Many fused compounds with a pyrimidine frag-
ment possess biological activities [3–5]. Derivatives of
triazolopyrimidines exhibit a diverse biological effect:
antitumor [5, 6], antimicrobial [7–9], anti-inflamma-
tory [10], and anticonvulsant [11, 12].
Epilepsy is one of the most common diseases of the
human brain, which affects more than 60 million peo-
ple worldwide [1, 2]. Today, in the arsenal of neurolo-
gists there are a great number of antiepileptic drugs.
The correct choice of drug can control seizures in 70–
80% of patients, thereby ensuring an improvement in
their quality of life. With the correct selection of anti-
convulsants, most patients can be relieved of epileptic
fits. However, do not forget that epilepsy is multifac-
eted, and each form requires special correction. Char-
acterizing the current trend of creating a new genera-
tion of antiepileptic drugs, it should be noted that such
drugs should have a wide spectrum of action, be effec-
tive both in generalized and localized seizures, not to
cause unwanted side effects such as drowsiness, and
reduced concentration of attention; in clinical condi-
tions, to ensure a transition from polytherapy to
monotherapy accompanied by fewer adverse effects.
In addition, an antiepileptic drug should possess a
general nonspecific balanced sedative-activating
effect, prevent focal neurological symptoms, alleviate
emotional stress, and prevent mood swings in bipolar
disorders of manic-depressive states.
As a continuation of studies on the synthesis and
biological activity of triazolopyrimidines [13, 14], in
the present work we synthesized the functionally sub-
stituted triazolo[4,3-c]- and triazolo[1,5-c]pyrimi-
dines, studied the Dimroth rearrangement in these
systems, and examined their neurotropic properties.
RESULTS AND DISCUSSION
10-Thioxo-thieno[3,2-d]pyrimidin-8-ones (Ia–g)
(we described their synthesis earlier [15, 16]) were
used as starting compounds for the synthesis of triazo-
lopyrimidines (V)–(VII). The 10-thioalkyl derivatives
(IIa–j) were obtained by the reaction of compounds (I)
with methyl iodide and benzyl chloride (see Scheme 1)
and then converted to 10-thioalkyl-8-chloroth-
ieno[3,2-d]pyrimidines (IIIa–j) in the reaction with
phosphorus oxychloride. Further, 8-hydrazino deriv-
atives (IVa–j) were obtained by the reaction of com-
pounds (IIIa–j) with hydrazine hydrate.
1
Corresponding author: phone: +374 (10) 287789; e-mail:
shdashyan@gmail.com.
595

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PARONIKYAN et al.
R
R
R
X
R
SR2
NH
O
SH
NH
O
( )n
X
( )
n
N
N
R1
N
R1
N
S
S
(Ia −g
)
(IIa−j)
R
R
R
R
R
R
SR2
SR2
SR2
( )n
X
( )n
( )n
X
X
N
N
N
NH2NH2
HC(OEt)3
N
N
N
N
N
R1
N
Cl
NHNH2
R1
N
R1
N
S
S
S
(Va−j)
(IVa−j)
(IIIa−j)
NH2NH2
H3C CH3
8
R
X
R
R
R
5 OEt
OEt
NHNH2
6
N
7
9 O
4
( )n
X
( )n
N3
N
N
S
N
10
11
N
N
N
N
2
N
N
N
S
R1
N
R1
N
1
N
N
S
13
12
(VIa−g)
(VIIa−g)
(VIa)*
(II−V)
(I, VI, VII)
(a) X = O, n = 1, R = CH3, R1 = pyrrolidin-1-yl, R2 = CH3
(b) X = O, n = 1, R = CH3, R1 = piperidin-1-yl, R2 = CH3
(c) X = O, n = 1, R = CH3, R1 = morpholin-4-yl, R2 = CH3
(a) X = O, n = 1, R = CH3, R1 = pyrrolidin-1-yl
(b) X = O, n = 1, R = CH3, R1 = piperidin-1-yl
(c) X = O, n = 1, R = CH3, R1 = morpholin-4-yl
(d) X = CH2, n = 1, R = H, R1 = pyrrolidin-1-yl
(e) X = CH2, n = 1, R = H, R1 = piperidin-1-yl
(f ) X = CH2, n = 1, R = H, R1 = morpholin-4-yl
(g ) X = CH2, n = 0, R = H, R1 = morpholin-4-yl
= pyrrolidin-1-yl, R2 = CH3
= piperidin-1-yl, R2 = CH3
= morpholin-4-yl, R2 = CH3
= morpholin-4-yl, R2 = CH3
= morpholin-4-yl, R2 = CH2C6H5
= morpholin-4-yl, R2 = CH2C6H5
(d) X = CH2, n = 1, R = H, R1
(e) X = CH2, n = 1, R = H, R1
(f ) X = CH2, n = 1, R = H, R1
(g ) X = CH2, n = 0, R = H, R1
(h) X = O, n = 1, R = CH3, R1
(i ) X = CH2, n = 1, R = H, R1
(j ) X = O, n = 1, R = CH3, R1 = piperidin-1-yl, R 2 = CH2C6H5
* Numbering of the atoms in compound (VIa).
Scheme 1.
We have previously shown that treatment of the
Triazolo[1,5-c]pyrimidines (VI) and (VII) were
synthesized using the Dimroth rearrangement under
conditions of basic catalysis. We chose sodium ethox-
ide and hydrazine hydrate as bases. Triazolo[1,5-
c]pyrimidines (VIa–g) and (VIIa–g) were obtained by
the reaction of triazolo[4,3-c]pyrimidines (Va–j) with
sodium ethoxide and hydrazine hydrate. In the
1H NMR spectra, the singlet signals of CH-groups in
the triazole ring were at δ 8.28–8.58 ppm. In addition,
the substitution of S-alkyl groups with ethoxy and
hydrazino derivatives that do not contain substituents
at position 5 with orthoformic ester leads to tri-
azolo[4,3-c]pyrimidines; and with formic acid, to tri-
azolo[1,5-c]pyrimidines [13, 14]. In this work, where
the S-methyl and S-benzyl substituents are located at
position 5, triazolo[4,3-c]pyrimidines (Va–j) were
isolated in both reactions. This is indicated by the sin-
glets of the triazole protons at δ 9.07–9.47 ppm, which
is characteristic of triazolo[4,3-c]pyrimidines [13, 14]. hydrazino groups proceeds under the reaction condi-
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SYNTHESIS AND NEUROTROPIC ACTIVITY
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Table 1. Comparative anticorazole activity of compounds
(Vc), (VIa–d, g), (VIIa, b, d, f), and diazepam
panied by prevention of corazole seizures in mice, and
ED50 in these animals varied from 30 to 56 mg/kg
(Table 1). At these doses, coordination of movements
in mice was not violated, the muscle relaxation phe-
nomena were not observed. The most efficient com-
pounds (VIc, d) and (VIIb, f) were investigated in the
open-field model. The diazepam effective dose (ED50)
by anticorazole action in mice was 0.5 mg/kg (Table 1).
However, diazepam already at a dose of 2 mg/kg
caused central miorelaxation in mice.
In the open-field behavioral model, the number of
horizontal movements was 22.8; vertical movements,
5.4; and the number of examined chambers, 1.8 in rats
of the control group (Table 2). Compounds under
investigation caused some changes of the behavior
indicators compared to the control: a tendency to
inhibition of horizontal movements (up to 14.4) of
animals was observed when compound (VId) was
injected; and other compounds did not lead to any
changes in the number of both horizontal and vertical
movements. However, all selected compounds
increased the number of examined cells, which may be
due to the manifestation of some anxiolytic activity of
the compounds (Table 2). Diazepam (2 mg/kg)
caused a significant increase in all the studied indica-
tors as compared to the control, i.e., it exhibited an
activating and antianxiety effect.
Antagonism to corazole*
Compound
(ED50, mg/kg)
(Vc)
(VIa)
55.0 (39.2–77.0)
56.0 (43–72.8)
(VIb)
(VIc)
(VId)
(VIg)
38.0 (29.2–49.4)
35.0 (28.0–43.75)
40.0 (26.7–60.0)
50.0 (39.0–64.0)
44.3 (35.44–55.38)
34.0 (27.86–41.48)
53.0 (36.6–76.85)
30.0 (21.4–42.0)
0.51 (0.39–0.69)
(VIIa)
(VIIb)
(VIId)
(VIIf)
Diazepam
* Confidence intervals at a probability level P = 0.05.
tions, respectively. The mechanism of the Dimroth
rearrangement was described in [17]; however, in our
case, the S-alkyl groups instead of the base residues
were leaving groups.
Neurotropic Activity
CONCLUSION
Neurotropic activity of the novel synthesized tri-
azolopyrimidine derivatives was studied by indicators
characterizing the anticonvulsant, sedative, anti-anxi-
ety activities, and side effects. A study of 24 com-
pounds (V)–(VII) and a reference drug diazepam was
carried out in 325 white mice weighing 18–24 g and
50 male Wistar rats weighing 120–140 g.
Thus, novel derivatives of fused triazolo[4,3-c]-
and triazolo[1,5-c]pyrimidines were synthesized. The
study of the Dimroth rearrangement in these systems
in a basic medium showed that recyclization is accom-
panied by nucleophilic substitution in the pyrimidine
ring. While studying the neurotropic properties of tri-
In the study of anticonvulsant action, it was found azolopyrimidine derivatives it was found that many
that not all synthesized derivatives have the same anti- representatives of this series possess an anticonvulsant
corazole activity. Thus, compounds (Vf, g), (VIe, f), anticorazole effect that was not previously described.
and (VIIc, g) at a dose of 50 mg/kg prevented convulsions In contrast to the tranquilizer diazepam, the compounds
only in 20–40% of animals, whereas compounds (Vc), at anticonvulsant doses did not exhibit central myorelax-
(VIa–d, g), and (VIIa, b, d, f) exhibited a pronounced ant activity. With the exception of compound (VId)
anticonvulsant effect: administration of these com- exhibiting some sedative effect, other compounds did
pounds starting from a dose of 25 mg/kg was accom- not cause any sedative-activating effects. The behav-
Table 2. The effect of compounds (VIc, d), (VIIb, f), and diazepam in the open-field test
Number of (in absolute values for 5 min)*
Compound
horizontal movements
vertical movements
examined chambers
Control (emulsifier)
(VIc)
(VId)
(VIIb)
(VIIf)
22.8 3.1
20.8 4.7
14.4 4.5
22.5 4.5
26.8 4.9
33.6 3.2
5.4 1.9
4.2 1.2
5.0 2.2
5.1 2.1
5.6 1.5
8.3 1.1
1.8 0.3
3.2 0.8
3.5 1.1
4.0 2.1
3.8 1.2
5.0 1.3
Diazepam
* P ≤ 0.05.
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PARONIKYAN et al.
1Н NMR: 1.26 (s, 6 H, C(СН3)2), 1.66–1.77 (m, 6 H,
5-(СН2)3), 3.25–3.30 (m, 4 H, 5-N(СН2)2), 3.32 (s, 2 H,
1-СН2), 4.49 (s, 2 H, SСН2), 4.61 (s, 2 H, 4-СН2),
7.18–7.30 (m, 3 H, 3СН), 7.41–7.45 (m, 2 H, 2СН).
13C NMR: 23.9, 25.4, 26.5, 34.7, 37.1, 39.0, 50.3, 59.1,
69.0, 117.3, 118.8, 122.7, 126.5, 127.8, 128.0, 136.7,
143.6, 152.4, 158.2, 160.6, 160.8, 166.7.
Compounds (IVa–j). General procedure. Hydrazine
monohydrate (5 mL) was added to a solution of com-
pound (IIIa–j) (0.01 mol) in dry isopropanol
(40 mL). The reaction mixture was refluxed for 5 h.
After cooling, the precipitate was filtered off, washed
subsequently with water and ethanol, and recrystal-
lized from a CHCl3–EtOH mixture (3 : 1). IR (ν, cm–1):
3260–3410 (NHNH2).
ior-activating effect was detected in diazepam at a
dose of 2 mg/kg in the open-field model. All selected
compounds, like diazepam, possessed anxiolytic
activity in the open-field test.
EXPERIMENTAL
In this work, we used the commercially available
reagents purchased from Fluka (Germany) and
Sigma-Aldrich (United States). The solvents were
purified according to standard procedures. The melt-
ing points were determined on a Boetius microheater.
Elemental analysis was performed on a Euro EA 3000
Elemental Analyzer (Germany). The IR spectra were
recorded on a Nicolet Avatar 330 FT-IR spectrometer
13
(United States) in mineral oil. The 1H and C NMR
spectra (δ, ppm; J, Hz) were measured on a Mercury
Vx 300 instrument (United States) at an operating fre-
quency of 300 and 75.462 MHz, respectively, in
DMSO-d6 with tetramethylsilane as internal standard.
The mass spectra were recorded on a MX-1320 instru-
ment with a system of direct input of the sample in the
ion source.
8-Hydrazino-2,2-dimethyl-10-methylthio-5-pyrro-
lidin-1-yl-1,4-dihydro-2H-pyrano-[4'',3'':4',5']pyrido-
[3',2':4,5]thieno[3,2-d]pyrimidine (IVa). Yield 82%,
mp 266–267°C. Found, %: С 54.82, Н 5.78, N 20.11,
S 15.46. С19Н24N6OS2. Calculated, %: С 54.78, Н
5.81, N 20.17, S 15.40. 1H NMR: 1.34 (s, 6 H,
C(СН3)2), 1.93–2.01 (m, 4 H, 5-(СН2)2), 2.52 (s, 3 H,
SСН3), 3.47 (s, 2 H, 1-СН2), 3.57–3.64 (m, 4 H,
5-N(СН2)2), 4.48 (br, 2 H, NH2), 4.76 (s, 2 H, 4-СН2),
8.48 (br, 1 H, NH).
Synthesis of compounds (Ia–g), (IIa–i), and (IIIa–i)
and their properties were described earlier [15, 16].
10-Benzylthio-2,2-dimethyl-5-piperidin-1-yl-1,4-
dihydro-2H-pyrano[4'',3'':4',5']-pyrido[3',2':4,5]-
thieno[3,2-d]pyrimidin-8(9H)-on (IIj). DMF (50 mL)
and compound (Ib) (4.03 g, 0.01 mol) were added to a
solution of potassium hydroxide (0.56 g, 0.01 mol) in
water (5 mL). A solution of benzyl chloride (1.27 g,
0.01 mol) in ethanol (30 mL) was gradually added to
the reaction mixture at 10°C. The reaction mixture
was stirred at room temperature for 5 h. Then water
(50 mL) and ethanol (50 mL) were added to the reac-
tion mixture. The precipitate was filtered off and
recrystallized from an EtOH–DMF mixture (2 : 1).
Yield 91%, mp 281–282°C. Found, %: С 66.45, Н
5.82, N 11.32, S 12.95. С26Н28N4O2S2. Calculated, %:
8-Hydrazino-2,2-dimethyl-10-methylthio-5-piper-
idin-1-yl-1,4-dihydro-2H-pyrano-[4'',3'':4',5']pyrido-
[3',2':4,5]thieno[3,2-d]pyrimidine (IVb). Yield 90%,
mp 275–277°C. Found, %: С 55.85, Н 6.13, N 19.45,
S 14.81. С20Н26N6OS2. Calculated, %: С 55.79, Н
1
6.09, N 19.52, S 14.89. H NMR: 1.33 (s, 6 H,
C(СН3)2), 1.62–1.80 (m, 6 H, 5-(СН2)2), 2.53 (s, 3 H,
SСН3), 3.12–3.19 (m, 4 H, 5-N(СН2)2), 3.51 (s, 2 H,
1-СН2), 4.51 (br, 2 H, NH2), 4.65 (s, 2 H, 4-СН2),
8.65 (br, 1 H, NH).
8-Hydrazino-2,2-dimethyl-10-methylthio-5-mor-
pholin-4-yl-1,4-dihydro-2H-pyrano-[4'',3'':4',5']pyr-
ido[3',2':4,5]thieno[3,2-d]pyrimidine (IVc). Yield
88%, mp 261–262°C. Found, %: C 51.81, Н 5.62, N
19.37, S 14.76. С19Н24N6O2S2. Calculated, %: С 52.76,
С 63.39, Н 5.79, N 11.37, S 13.02. IR (ν, cm–1): 1658
1
(CO), 3408 (NH). Н NMR: 1.19 (s, 6 H, C(СН3)2),
1.63–1.77 (m, 6 H, 5-(СН2)3), 3.13–3.19 (m, 4 H,
5-N(СН2)2), 3.34 (s, 2 H, 1-СН2), 4.52 (s, 2 H, SСН2),
4.61 (s, 2 H, 4-СН2), 7.19–7.32 (m, 3 H, 3СН), 7.39–7.43
(m, 2 H, 2СН), 12.84 (br, 1 H, NH).
1
Н 5.59, N 19.43, S 14.83. H NMR: 1.34 (s, 6 H,
C(СН3)2), 2.53 (s, 3 H, SСН3), 3.15–3.22 (m, 4 H,
5-N(СН2)2), 3.74–3.82 (m, 4 H, 5-O(СН2)2), 3.52 (s,
2 H, 1-СН2), 4.68 (s, 2 H, 4-СН2), 4.45 (br, 2 H,
NH2), 8.70 (br, 1 H, NH).
10-Benzylthio-8-chloro-2,2-dimethyl-5-piperidin-
1-yl-1,4-dihydro-2H-pyrano-[4'',3'':4',5']pyrido[3',2':4,5]-
thieno[3,2-d]pyrimidine (IIIj). A mixture of com-
pound (IIj) (4.93 g, 0.01 mol), phosphorus oxychlo-
ride (50 mL), and pyridine (2.5 mL) was refluxed for 2 h.
An excess of phosphorus oxychloride was distilled off;
ice water (100 mL) was added to the residue; and the
reaction mixture was neutralized with aqueous ammo-
nia. The precipitate was filtered off, washed with
water, and recrystallized from a CHCl3–EtOH mix-
ture (4 : 1). Yield 76%, mp 203–204°C. Found, %: С
61.15, Н 5.36, N 10.89, S 12.51. С26Н27ClN4OS2. Cal-
culated, %: С 61.10, Н 5.32, N 10.96, S 12.55.
8-Hydrazino-10-methylthio-5-pyrrolidin-1-yl-
1,2,3,4-tetrahydropyrimido[4',5':4,5]-thieno[2,3-c]-
isoquinoline (IVd). Yield 82%, mp 253–255°C. Found,
%: С 55.98, Н 5.80, N 21.67, S 16.52. С18Н22N6S2.
Calculated, %: С 55.93, Н 5.74, N 21.74, S 16.59.
1H NMR: 1.70–1.79 (m, 2 H, 3-СН2), 1.83–1.93 (m,
2 H, 2-СН2), 1.91–2.00 (m, 4 H, 5-(СН2)2), 2.53 (s,
3 H, SСН3), 2.70 (br. t, 2 H, J 5.1, 4-CH2), 3.56 (br. t,
2 H, J 6.3, 1-CH2), 3.56–3.62 (m, 4 H, 5-N(СН2)2),
4.41 (br, 2 H, NH2), 8.41 (br, 1 H, NH). MS, m/z (Irel,
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SYNTHESIS AND NEUROTROPIC ACTIVITY
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%): 386 [M]+ (100), 366 (16), 358 (49), 356 (78), 344
(34), 335 (55).
10-Benzylthio-8-hydrazino-2,2-dimethyl-5-piperi-
din-1-yl-1,4-dihydro-2H-pyrano-[4'',3'':4',5']pyrido-
[3',2':4,5]thieno[3,2-d]pyrimidine (IVj). Yield 64%,
mp 271–272°C. Found, %: С 61.71, Н 5.92, N 16.67,
S 12.59. С26Н30N6OS2. Calculated, %: С 61.63, Н
8-Hydrazino-10-methylthio-5-piperidin-1-yl–1,2,3,4-
tetrahydropyrimido[4',5':4,5]-thieno[2,3-c]isoquino-
line (IVe). Yield 85%, mp 269–270°C. Found, %: С
57.03, Н 6.08, N 20.91, S 15.95. С19Н24N6S2. Calcu-
1
5.97, N 16.59, S 12.66. Н NMR: 1.21 (s, 6 H,
C(СН3)2), 1.63–1.77 (m, 6 H, 5-(СН2)3), 3.11–3.17
(m, 4 H, 5-N(СН2)2), 3.41 (s, 2 H, 1-СН2), 4.44 (s,
2 H, SСН2), 4.57 (br, 2 H, NH2), 4.62 (s, 2 H, 4-СН2),
7.14–7.28 (m, 3 H, 3СН), 7.39–7.43 (m, 2 H, 2СН),
8.80 (br, 1 H, NH).
lated, %: С 56.97, Н 6.04, N 20.98, S 16.01. 1H NMR:
1.56–1.74 (m, 8 H, 3-СН2, 5-(СН2)3), 1.81–1.91 (m,
2 H, 2-СН2), 2.52 (s, 3 H, SСН3), 2.68 (br. t, 2 H,
J 5.8, 4-CH2), 3.10–3.18 (m, 4 H, 5-N(СН2)2), 3.54
(br. t, 2 H, J 6.4, 1-CH2), 4.79 (br, 2 H, NH2), 8.89
(br, 1 H, NH).
Compounds (Va–j). General procedure. A mixture
of compound (IVa–j) (0.01 mol) and triethyl orthofor-
mate (50 ML) was refluxed for 15 h. The reaction mix-
ture was cooled; the precipitate was filtered off,
washed with water and recrystallized from a CHCl3–
8-Hydrazino-10-methylthio-5-morpholin-4-yl-
1,2,3,4-tetrahydropyrimido[4',5':4,5]-thieno[2,3-c]-
isoquinoline (IVf). Yield 83%, mp 270–272°C. Found,
%: C 53.75, Н 5.58, N 20.72, S 15.84. С18Н22N6OS2.
Calculated, %: C 53.71, Н 5.51, N 20.88, S 15.93.
1H NMR: 1.74–1.81 (m, 2 H, 3-СН2), 1.86–1.95 (m,
2 H, 2-СН2), 2.53 (s, 3 H, SСН3), 2.67–2.74 (m, 2 H,
4-CH2), 3.16–3.24 (m, 4 H, 5-N(СН2)2), 3.57–3.63
(m, 2 H, 1-CH2), 3.74–3.80 (m, 4 H, 5-O(СН2)2),
4.60 (br, 2 H, NH2), 8.68 (br, 1 H, NH).
EtOH mixture (2 : 1). IR (ν, cm–1): 1610–1615
(C=N).
8,8-Dimethyl-5-methylthio-11-pyrrolidin-1-yl-7,10-
dihydro-8H-pyrano[4'',3'':4',5']-pyrido[3',2':4,5]-
thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine (Va).
Yield 92%, mp 269–270°C. Found, %: С 56.39, Н
5.24, N 19.58, S 14.95. С20Н22N6OS2. Calculated, %:
1
С 56.31, Н 5.20, N 19.70, S 15.03. Н NMR: 1.35 (s,
7-Hydrazino-9-methylthio-4-morpholin-4-yl-2,3-
dihydro-1H-cyclopenta[4',5']pyrido-[3',2':4,5]thieno[3,2-
d]-pyrimidine (IVg). Yield 86%, mp 271–272°C.
Found, %: C 52.64, Н 5.25, N 21.55, S 16.42.
С17Н20N6OS2. Calculated, %: С 52.55, Н 5.19, N
6 H, C(СН3)2), 1.96–2.04 (m, 4 H, 11-(СН2)2), 2.84
(s, 3 H, SСН3), 3.34 (s, 2 H, 7-СН2), 3.58–3.68 (m, 4 H,
11-N(СН2)2), 4.79 (s, 2 H, 10-СН2), 9.07 (s, 1 H, 3-CH).
8,8-Dimethyl-5-methylthio-11-piperidin-1-yl-7,10-
dihydro-8H-pyrano[4'',3'':4',5']-pyrido[3',2':4,5]-
thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine (Vb).
Yield 81%, mp 312–314°C. Found, %: C 57.31, Н
5.56, N 19.16, S 14.47. С21Н24N6OS2. Calculated, %:
21.63, S 16.51. 1H NMR: 1.90–1.98 (m, 2 H, 2-СН2),
2.57 (s, 3 H, SСН3), 2.87–2.98 (m, 2 H, 3-СН2),
3.51–3.57 (m, 2 H, 1-СН2), 3.56–3.61 (m, 4 H, 4-
N(СН2)2), 3.74–3.83 (m, 4 H, 4-O(СН2)2), 4.51 (s,
2 H, NH2), 8.29 (s, 1 H, NH).
С 57.25, Н 5.49, N 19.07, S 14.56. 1Н NMR: 0.69 (s,
6 H, C(СН3)2), 1.52–1.64 (m, 6 H, 11-(СН2)3), 2.86
(s, 3 H, SСН3), 3.02–3.08 (m, 6 H, 7-СН2, 11-N(СН2)2),
4.45 (s, 2 H, 10-СН2), 8.58 (s, 1 H, 3-CH).
10-Benzylthio-8-hydrazino-2,2-dimethyl-5-mor-
pholin-4-yl-1,4-dihydro-2H-pyrano-[4'',3'':4',5']pyr-
ido[3',2':4,5]thieno[3,2-d]pyrimidine (IVh). Yield
85%, mp 247–248°C. Found, %: С 59.10, Н 5.63, N
16.44, S 12.55. С25Н28N6O2S2. Calculated, %: С
8,8-Dimethyl-5-methylthio-11-morpholin-4-yl-7,10-
dihydro-8H-pyrano[4',3'':4',5']-pyrido[3',2':4,5]-
thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine (Vc).
Yield 85%, mp 294–295°C. Found, %: C 54.35, Н
5.06, N 18.87, S 14.40. С20Н22N6O2S2. Calculated, %:
59.03, Н 5.55, N 16.52, S 12.61. 1Н NMR: 1.21 (s, 6 H,
C(СН3)2), 2.96 (br, 2 H, NH2), 3.16–3.22 (m, 4 H,
5-N(СН2)2), 3.74–3.81 (m, 4 H, 5-O(СН2)2), 3.43 (s,
2 H, 1-СН2), 4.44 (s, 2 H, SСН2), 4.65 (s, 2 H,
4-СН2), 7.14–7.28 (m, 3 H, 3СН), 7.38–7.44 (m, 2 H,
2СН), 8.82 (br, 1 H, NH).
С 54.28, Н 5.01, N 18.99, S 14.49. 1Н NMR: 1.37 (s, 6
H, C(СН3)2), 3.01 (s, 3 H, SСН3), 3.21 (t, 4 H, J 5.1,
11-N(СН2)2), 3.50 (s, 2 H, 7-СН2), 3.80 (t, 4 H, J 4.6,
11-O(СН2)2), 4.71 (s, 2 H, 10-СН2), 8.61 (s, 1 H, 3-CH).
10-Benzylthio-8-hydrazino-5-morpholin-4-yl-1,2,3,4-
tetrahydropyrimido-[4',5':4,5]-thieno[2,3-c]isoquino-
5-Methylthio-11-pyrrolidin-1-yl-7,8,9,10-tetrahy-
line (IVi). Yield 87%, mp 272–273°C. Found, %: С dro[1,2,4]triazolo[4'',3'':1',6']-pyrimido[4',5':4,5]-
60.28, Н 5.56, N 17.47, S 13.28. С24Н26N6OS2. Calcu- thieno[2,3-c]isoquinoline (Vd). Yield 89%, mp 318–
lated, %: C 60.22, Н 5.48, N 17.56, S 13.40. 1Н NMR:
1.72–1.80 (m, 2 H, 3-СН2), 1.87–1.98 (m, 2 H,
2-СН2), 2.68–2.74 (m, 2 H, 4-CH2), 3.21–3.35 (m,
4 H, 5-N(СН2)2), 3.48–3.56 (m, 2 H, 1-CH2), 3.75–
3.81 (m, 4 H, 5-O(СН2)2), 4.51 (s, 2 H, NH2), 4.55 (s,
2 H, SСН2), 7.18–7.27 (m, 3 H, 3СН), 7.36–7.45 (m,
2 H, 2СН), 8.72 (s, 1 H, NH).
320°C. Found, %: С 57.63, Н 5.04, N 21.27, S 16.06.
С19Н20N6S2. Calculated, %: С 57.55, Н 5.08, N 21.19,
S 16.17. 1Н NMR: 1.73–1.82 (m, 2 H, 9-СН2), 1.90–
1.98 (m, 2 H, 8-СН2), 2.12–2.24 (m, 4 H, 11-(СН2)2),
2.68–2.77 (m, 2 H, 10-СН2), 2.85 (s, 3 H, SСН3),
3.18–3.25 (m, 4 H, 5-N(СН2)2), 3.52–3.60 (m, 2 H,
7-СН2), 9.28 (s, 1 H, 3-CH). MS, m/z (Irel, %): 396
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600
PARONIKYAN et al.
[M]+ (24), 381 (28), 355 (48), 254 (43), 212 (34), 185
(28), 184 (100).
5-Benzylthio-8,8-dimethyl-11-piperidin-1-yl-7,10-
dihydro-8H-pyrano[4'',3'':4',5']-pyrido[3',2':4,5]-
thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine (Vj).
Yield 83%, mp 239–240°C. Found, %: С 62.84, Н
5.51, N 16.19, S 12.28. С27Н28N6OS2. Calculated, %: С
5-Methylthio-11-piperidin-1-yl-7,8,9,10-tetrahydro-
[1,2,4]triazolo[4'',3'':1',6']-pyrimido[4',5':4,5]thieno-
[2,3-c]isoquinoline (Ve). Yield 90%, mp 300–302°C.
Found, %: С 58.57, Н 5.46, N 20.38, S 15.51.
С20Н22N6S2. Calculated, %: С 58.51, Н 5.40, N 20.47,
62.76, Н 5.46, N 16.27, S 12.41. 1Н NMR: 1.23 (s, 6 H,
C(СН3)2), 1.64–1.78 (m, 6 H, 11-(СН2)3), 3.16–3.21
(m, 4 H, 11-N(СН2)2), 3.39 (s, 2 H, 7-СН2), 4.66 (s,
2 H, 10-СН2), 4.81 (s, 2 H, SСН2), 7.24–7.36 (m, 3 H,
3СН), 7.47–7.51 (m, 2 H, 2СН), 9.20 (s, 1 H, 3-CH).
13C NMR: 23.9, 25.5, 26.4, 34.7, 37.1, 38.7, 50.7, 59.1,
68.9, 110.8, 119.1, 119.5, 127.2, 128.0, 128.1, 128.2,
133.6, 134.8, 135.2, 137.6, 141.1, 141.9, 144.7, 145.4,
157.6, 159.2.
S 15.62. 1Н NMR: 1.71–1.86 (m, 8 H, 9-СН2,
11-(СН2)3), 1.90–1.97 (m, 2 H, 8-СН2), 2.72–2.79
(m, 2 H, 10-СН2), 2.86 (s, 3 H, SСН3), 3.20–3.28 (m,
4 H, 11-N(СН2)2), 3.55–3.64 (m, 2 H, 7-СН2), 9.23
(s, 1 H, 3-CH).
5-Methylthio-11-morpholin-4-yl-7,8,9,10-tetra-
hydro[1,2,4]triazolo[4'',3'':1',6']-pyrimido[4',5':4,5]-
thieno[2,3-c]isoquinoline (Vf). Yield 81%, mp 286–
288°C. Found, %: С 55.37, Н 4.82, N 20.26, S 15.48.
С19Н20N6OS2. Calculated, %: C 55.32, Н 4.89, N
Compounds (VIa–g). General procedure. Com-
pound (Va–j) (0.01 mol) was added to a solution of
sodium ethylate obtained from sodium (0.23 g,
0.01 mol) and absolute ethanol. The reaction mixture
was refluxed for 0.5 h and kept at room temperature for
12 h. The precipitate was filtered off, washed with
water, dried, and recrystallized from EtOH. IR
(ν, cm–1): 1623–1628 (C=N).
20.37, S 15.55. 1Н NMR: 1.74–1.84 (m, 2 H, 9-СН2),
1.91–2.00 (m, 2 H, 8-СН2), 2.71–2.78 (m, 2 H, 10-CH2),
2.88 (s, 3 H, SСН3), 3.22–3.27 (m, 4 H, 11-N(СН2)2),
3.55–3.62 (m, 2 H, 7-CH2), 3.77–3.83 (m, 4 H,
11-O(СН2)2), 9.30 (s, 1 H, 3-CH).
5-Ethoxy-8,8-dimethyl-11-pyrrolidin-1-yl-7,10-
dihydro-8H-pyrano[4'',3'':4',5']pyrido-[3',2':4,5]thieno-
[2,3-e] [1, 2, 4]triazolo[1,5-c]pyrimidine (VIa). Yield
68%, mp 218–219°C. Found, %: С 59.48, Н 5.75, N
19.71, S 7.46. С21Н24N6O2S. Calculated, %: С 59.41, Н
5-Methylthio-10-morpholin-4-yl-8,9-dihydro-7H-
cyclopenta[4',5']pyrido[3',2':4,5]-thieno[2,3-e] [1, 2,
4]triazolo[4,3-c]pyrimidine (Vg). Yield 90%, mp 304–
306°C. Found, %: С 54.32, Н 4.58, N 20.98, S 16.01.
С18Н18N6OS2. Calculated, %: С 54.25, Н 4.55, N
5.70, N 19.80, S 7.55. 1Н NMR: 1.37 (s, 6 H,
C(СН3)2), 1.65 (t, 3 H, J 7.0, 5-СН3), 1.95–2.03 (m,
4 H, 11-(СН2)2), 3.43 (s, 2 H, 7-СН2), 3.60–3.68 (m,
4 H, 11-N(СН2)2), 4.79 (q, 2 H, J 7.0, 5-OСН2), 4.80
(s, 2 H, 10-СН2), 8.29 (s, 1 H, 2-CH).
21.09, S 16.09. 1Н NMR: 2.12–2.23 (m, 2 H, 8-СН2),
2.86 (s, 3 H, SСН3), 2.98 (t, 2 H, J 7.2, 9-СН2), 3.42
(t, 2 H, J 7.7, 7-СН2), 3.48–3.55 (m, 4 H,
10-N(СН2)2), 3.72–3.80 (m, 2 H, 10-CH2), 9.47 (s,
1 H, 3-CH).
5-Ethoxy-8,8-dimethyl-11-piperidin-1-yl-7,10-
dihydro-8H-pyrano[4'',3'':4',5']pyrido-[3',2':4,5]thieno-
[2,3-e] [1, 2, 4]triazolo[1,5-c]pyrimidine (VIb). Yield
70%, mp 213–214°C. Found, %: С 60.32, Н 6.02, N
19.25, S 7.24. С22Н26N6O2S. Calculated, %: С 60.25,
5-Benzylthio-8,8-dimethyl-11-morpholin-4-yl-7,10-
dihydro-8H-pyrano[4'',3'':4',5']-pyrido[3',2':4,5]thieno-
[2,3-e] [1, 2, 4]triazolo[4,3-c]pyrimidine (Vh). Yiled,
83%, mp 236–237°C. Found, %: C 60.27, Н 5.09, N
16.12, S 12.31. С26Н26N6O2S2. Calculated, %: C 60.21,
1
Н 5.98, N 19.16, S 7.31. Н NMR: 1.37 (s, 6 H,
1
Н 5.05, N 16.20, S 12.37. Н NMR: 1.23 (s, 6 H,
C(СН3)2), 1.66 (t, 3 H, J 7.1, 5-СН3), 1.69–1.80 (m,
46 H, 11-(СН2)3), 3.18–3.23 (m, 4 H, 11-N(СН2)2),
3.48 (s, 2 H, 7-СН2), 4.68 (s, 2 H, 10-СН2), 4.81 (q,
C(СН3)2), 3.20–3.25 (m, 4 H, 11-N(СН2)2), 3.40 (s,
2 H, 7-СН2), 3.77–3.82 (m, 4 H, 11-O(СН2)2), 4.69
(s, 2 H, 10-СН2), 4.80 (s, 2 H, SСН2), 7.24–7.36 (m,
3 H, 3СН), 7.47–7.52 (m, 2 H, 2СН), 9.23 (s, 1 H, 3-CH).
2 H, J 7.1, 5-OСН2), 8.35 (s, 1 H, 2-CH). 13C NMR:
13.7, 24.0, 25.5, 26.6, 36.8, 50.7, 59.2, 65.0, 69.0,
109.5, 119.0, 119.2, 141.4, 143.7, 146.9, 149.6, 153.6,
158.6, 159.3.
5-Benzylthio-11-morpholin-4-yl-7,8,9,10-tetrahydro-
[1,2,4]triazolo[4'',3'':1',6']-pyrimido[4',5':4,5]thieno-
[2,3-c]isoquinoline (Vi). Yield 93%, mp 274–275°C.
Found, %: С 61.52, Н 4.98, N 17.28, S 12.04.
5-Ethoxy-8,8-dimethyl-11-morpholin-4-yl-7,10-
С25Н24N6OS2. Calculated, %: С 61.45, Н 4.95, N dihydro-8H-pyrano[4'',3'':4',5']pyrido-[3',2':4,5]thieno-
1
[2,3-e] [1, 2, 4]triazolo[1,5-c]pyrimidine (VIc). Yield
64%, mp 245–246°C. Found, %: C 57.34, Н 5.52, N
18.96, S 7.17. С21Н24N6O3S. Calculated, %: С 57.26, Н
17.20, S 13.12. Н NMR: 1.73–1.93 (m, 4 H, 9-СН2,
8-СН2), 2.71–2.75 (m, 2 H, 10-СН2), 3.22–3.27 (m,
4 H, 11-N(СН2)2), 3.77–3.81 (m, 4 H, 11-O(СН2)2),
3.46–3.52 (m, 2 H, 7-СН2), 4.82 (s, 2 H, SСН2),
7.25–7.37 (m, 3 H, 3СН), 7.46–7.52 (m, 2 H, 2СН),
9.20 (s, 1 H, 3-CH). 13C NMR: 21.3, 21.7, 25.7, 26.8,
34.9, 49.7, 65.9, 122.6, 127.4, 128.3, 128.4, 134.4,
125.3, 142.1, 144.6, 144.9, 145.5, 156.1, 160.7.
5.49, N 19.08, S 7.28. 1Н NMR: 1.37 (s, 6 H,
C(СН3)2), 1.65 (t, 3 H, J 7.0, 5-СН3), 3.20–3.28 (m, 4
H, 11-N(СН2)2), 3.48 (s, 2 H, 7-СН2), 3.77–3.84 (m,
4 H, 11-O(СН2)2), 4.70 (s, 2 H, 10-СН2), 4.80 (q, 2 H,
J 7.0, 5-OСН2), 8.37 (s, 1 H, 2-CH). 13C NMR: 13.7,
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Vol. 43
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SYNTHESIS AND NEUROTROPIC ACTIVITY
601
1
26.6, 36.9, 49.9, 59.1, 65.1, 65.9, 69.0, 109.8, 119.2,
119.5, 141.8, 143.6, 147.0, 149.6, 153.7, 158.2, 158.4.
3270 (NHNH2). Н NMR: 1.37 (s, 6 H, C(СН3)2),
1.91–2.01 (m, 4 H, 11-(СН2)2), 3.58 (s, 2 H, 7-СН2),
5-Ethoxy-11-pyrrolidin-1-yl-7,8,9,10-tetrahydro- 3.57–3.65 (m, 4 H, 11-N(СН2)2), 4.62 (br, 2 H, NH2),
[1,2,4]triazolo[1'',5'':1',6']pyrimido-[4',5':4,5]thieno-
[2,3-c]isoquinoline (VId). Yield 71%, mp 239–240°C.
Found, %: С 60.97, Н 5.68, N 21.18, S 8.04.
С20Н20N6OS. Calculated, %: С 60.89, Н 5.62, N
4.79 (s, 2 H, 10-СН2), 8.36 (s, 1 H, 2-CH), 8.99 (br,
1 H, NH).
5-Hydrazino-8,8-dimethyl-11-piperidin-1-yl-7,10-
dihydro-8H-pyrano[4'',3'':4',5']-pyrido[3',2':4,5]thieno-
[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (VIIb). Yield
85%, mp 321–323°C. Found, %: С 56.65, Н 5.76, N
26.31, S 7.47. С20Н24N8OS. Calculated, %: С 56.58, Н
1
21.30, S 8.13. Н NMR: 1.65 (t, 3 H, J 7.0, 5-СН3),
1.72–1.82 (m, 2 H, 11-СН2), 1.86–1.96 (m, 2 H,
11-СН2), 1.96–2.04 (m, 4 H, 9-СН2, 8-СН2), 2.72 (br.
t, 2 H, J 5.6, 10-СН2), 3.49 (br. t, 2 H, J 6.2, 7-СН2),
3.60–3.68 (m, 4 H, 11-N(СН2)2), 4.78 (q, 2 H, J 7.1,
5-OСН2), 8.28 (s, 1 H, 2-CH).
5.70, N 26.40, S 7.55. IR (ν, cm–1): 1623 (C=N), 3315,
1
3268 (NHNH2). Н NMR: 1.34 (s, 6 H, C(СН3)2),
1.57–1.72 (m, 6 H, 11-(СН2)3), 3.11–3.16 (m, 4 H,
11-N(СН2)2), 3.63 (s, 2 H, 7-СН2), 4.67 (s, 2 H,
5-Ethoxy-11-piperidin-1-ил-7,8,9,10-tetrahydro-
[1,2,4]triazolo[1'',5'':1',6']pyrimido-[4',5':4,5]thieno- 10-СН2), 4.71 (br, 2 H, NH2), 8.57 (s, 1 H, 2-CH),
[2,3-c]isoquinoline (VIe). Yield 85%, mp 239–240°C.
Found, %: С 61.79, Н 5.88, N 20.48, S 7.76.
С21Н24N6OS. Calculated, %: С 61.74, Н 5.92, N
9.34 (br, 1 H, NH).
5-Hydrazino-8,8-dimethyl-11-morpholin-4-yl-7,10-
dihydro-8H-pyrano[4'',3'':4',5']-pyrido[3',2':4,5]thieno-
[2,3-e] [1, 2, 4]triazolo[1,5-c]pyrimidine (VIIc).
Yield 78%, mp 299–300°C. Found, %: С 53.58, Н
1
20.57, S 7.85. Н NMR: 1.65 (t, 3 H, J 7.1, 5-СН3),
1.62–1.84 (m, 8 H, 11-(СН2)3, 9-СН2), 1.91–2.01 (m,
2 H, 8-СН2), 2.73 (br. t, 2 H, J 5.8, 10-СН2), 3.17–3.25 5.24, N 26.18, S 7.44. С19Н22N8O2S. Calculated, %: С
53.51, Н 5.20, N 26.27, S 7.52. IR (ν, cm–1): 1626
(C=N), 3316, 3273 (NHNH2). 1Н NMR: 1.35 (s, 6 H,
C(СН3)2), 3.15–3.21 (m, 4 H, 11-N(СН2)2), 3.66 (s,
2 H, 7-СН2), 3.74–3.79 (m, 4 H, 11-O(СН2)2), 4.72
(m, 4 H, 11-N(СН2)2), 3.57 (br. t, 2 H, J 6.5, 7-СН2),
4.80 (q, 2 H, J 7.1, 5-OСН2), 8.32 (s, 1 H, 2-CH).
5-Ethoxy-11-morpholin-4-yl-7,8,9,10-tetrahydro-
[1,2,4]triazolo[1'',5'':1',6']pyrimido-[4',5':4,5]thieno-
[2,3-c]isoquinoline (VIf). Yield 71%, mp 271–272°C. (s, 2 H, 10-СН2), 4.74 (br, 2 H, NH2), 8.58 (s, 1 H, 2-
Found, %: С 58.59, Н 5.46, N 20.35, S 7.74.
С20Н22N6O2S. Calculated, %: С 58.52, Н 5.40, N
CH), 9.35 (br, 1 H, NH).
5-Hydrazino-11-pyrrolidin-1-yl-7,8,9,10-tetrahy-
dro[1,2,4]triazolo[1'',5'':1',6']-pyrimido[4',5':4,5]-
thieno[2,3-c]isoquinoline (VIId). Yield 79%, mp 280–
1
20.47, S 7.81. Н NMR: 1.65 (t, 3 H, J 7.0, 5-СН3),
1.76–1.82 (m, 2 H, 9-СН2), 1.92–2.02 (m, 2 H,
8-СН2), 2.69–2.77 (m, 2 H, 10-СН2), 3.20–3.30 (m, 282°C. Found, %: С 56.86, Н 5.27, N 29.34, S 8.36.
С18Н20N8S. Calculated, %: С 56.82, Н 5.30, N 29.45,
4 H, 11-N(СН2)2), 3.53–3.61 (m, 2 H, 7-СН2), 3.75–
3.85 (m, 4 H, 11-O(СН2)2), 4.80 (q, 2 H, J 7.0, 5- S 8.43. IR (ν, cm–1): 1622 (C=N), 3314, 3271
1
OСН2), 8.35 (s, 1 H, 2-CH).
(NHNH2). Н NMR: 1.71–1.81 (m, 2 H, 9-СН2),
1.87–2.01 (m, 6 H, 11-(СН2)2, 8-СН2), 2.74 (br. t,
2 H, J 5.7, 7-СН2), 3.56–3.63 (m, 4 H, 11-N(СН2)2),
3.67 (br. t, 2 H, J 6.4, 10-СН2), 4.50 (br, 2 H, NH2),
5-Ethoxy-10-morpholin-4-yl-8,9-dihydro-7H-
cyclopenta[4',5']pyrido[3',2':4,5]thieno-[2,3-e][1, 2,
4]triazolo[1,5-c]pyrimidine (VIg). Yield 65%, mp
273–274°C. Found, %: С 57.62, Н 5.05, N 21.13, S 8.34 (s, 1 H, 2-CH), 8.90 (br, 1 H, NH).
7.98. С19Н20N6O2S. Calculated, %: С 57.56, Н 5.08, N
5-Hydrazino-11-piperidin-1-yl-7,8,9,10-tetrahydro-
1
21.20, S 8.09. Н NMR: 1.61 (t, 3 H, J 7.0, 5-СН3),
[1,2,4]triazolo[1'',5'':1',6']-pyrimido[4',5':4,5]thieno-
2.15–2.26 (m, 2 H, 8-СН2), 2.96 (t, 2 H, J 7.0, [2,3-c]isoquinoline (VIIe). Yield 92%, mp 298–
300°C. Found, %: С 57.91, Н 5.66, N 28.31, S 8.04.
9-СН2), 3.42 (t, 2 H, J 7.4, 8-СН2), 3.49–3.58 (m,
4 H, 10-N(СН2)2), 3.73–3.83 (m, 4 H, 10-O(СН2)2),
4.79 (q, 2 H, J 7.0, 5-OСН2), 8.41 (s, 1 H, 2-CH).
Compounds (VIIa–j). General procedure. A mix-
ture of compound (Va–j) (0.01 mol), hydrazine
monohydrate (20 mL), and DMSO (40 mL) was
refluxed for 6 h. The precipitate was filtered off,
washed with water, and recrystallized form DMSO.
С19Н22N8S. Calculated, %: С 57.85, Н 5.62, N 28.40,
S 8.13. IR (ν, cm–1): 1625 (C=N), 3310, 3267
1
(NHNH2). Н NMR: 1.63–1.83 (m, 8 H, 9-СН2,
11-(СН2)3), 1.92–2.00 (m, 2 H, 8-СН2), 2.73 (t, 2 H,
J 5.9, 10-СН2), 3.15–3.23 (m, 4 H, 11-N(СН2)2), 3.69
(t, 2 H, J 6.5, 7-СН2), 4.48 (br, 2 H, NH2), 8.31 (s, 1
H, 2-CH), 8.75 (br, 1 H, NH).
5-Hydrazino-8,8-dimethyl-11-pyrrolidin-1-yl-7,10-
5-Hydrazino-11-morpholin-4-yl-7,8,9,10-tetrahy-
dihydro-8H-pyrano[4'',3'':4',5']-pyrido[3',2':4,5]thieno- dro[1,2,4]triazolo[1'',5'':1',6']-pyrimido[4',5':4,5]-
[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (VIIa). Yield thieno[2,3-c]isoquinoline (VIIf). Yield 84%, mp 287–
72%, mp 285–287°C. Found, %: С 55.65, Н 5.47, N 288°C. Found, %: С 54.58, Н 5.12, N 28.19, S 7.98.
21.19, S 7.75. С19Н22N8OS. Calculated, %: С 55.59, Н С18Н20N8OS. Calculated, %: С 54.53, Н 5.08, N
5.40, N 27.30, S 7.81. IR (ν, cm–1): 1620 (C=N), 3312, 28.26, S 8.09. IR (ν, cm–1): 1623 (C=N), 3316, 3272
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PARONIKYAN et al.
1
was injected intraperitoneally in a dose of 2 mg/kg. An
emulsifier was injected to control animals. The results
were statistically processed at a probability level of Р ≤
0.05 [25].
(NHNH2). Н NMR: 1.69–1.78 (m, 2 H, 9-СН2),
2.85–2.94 (m, 2 H, 8-СН2), 2.70–2.75 (m, 2 H,
10-СН2), 3.17–3.22 (m, 4 H, 11-N(СН2)2), 3.74–3.80
(m, 4 H, 11-O(СН2)2), 3.67–3.73 (m, 2 H, 7-СН2),
4.69 (br, 2 H, NH2), 8.58 (s, 1 H, 2-CH), 9.29 (br, 1
H, NH).
REFERENCES
5-Hydrazino-10-morpholin-4-yl-8,9-dihydro-7H-
cyclopenta[4',5']pyrido[3',2':4,5]-thieno[2,3-e] [1, 2,
4]triazolo[1,5-c]pyrimidine (VIIg). Yield 79%, mp
289–290°C. Found, %: С 53.45, Н 4.78, N 29.21, S
8.29. С17Н18N8OS. Calculated, %: С 53.39, Н 4.74, N
1. Scheurer, M.L. and Pedley, T.A., N. Engl. J. Med.,
1990, vol. 323, pp. 1468–1474.
2. Löscher, W., Klitgaard, H., Twyman, R.E., and
Schmidt, D., Nat. Rev. Drug Discov., 2013, vol. 12,
pp. 757–776.
3. Jiang, N., Deng, Xian-Qing, Li Fu-Nan, and Quan
Zhe-Shan, Iran. J. Pharm. Res., 2012, vol. 11, no. 3,
pp. 799–806.
4. Loidreau, Y., Marchand, P., Dubouilh-Benard, C.,
Nourrisson, M.-R., Duflos, M., Lozach, O., Loaec, N.,
Meijer, L., and Besson, T., Eur. J. Med. Chem., 2012,
vol. 58, pp. 171–183.
29.30, S 8.38. IR (ν, cm–1): 1623 (C=N), 3328, 3279
1
(NHNH2). Н NMR: 2.10–2.20 (m, 2 H, 8-СН2),
2.97 (t, 2 H, J 7.2, 9-СН2), 3.46–3.51 (m, 4 H,
10-N(СН2)2), 3.72–3.78 (m, 4 H, 10-O(СН2)2), 3.53
(t, 2 H, J 7.7, 7-СН2), 4.67 (br, 2 H, NH2), 8.54 (s,
1 H, 2-CH), 9.27 (br, 1 H, NH).
5. Guetzoyan, L.J., Spooner, R.A., Michael, LordJ.,
Roberts, L.M., and Clarkson, G.J., Eur. J. Med. Chem.,
2010, vol. 45, pp. 275–283.
6. Zhao Xiang-Lin, Zhao Yan-Fang, Guo Shu-Chun,
Song Hai-Sheng Wang, D., and Gong, P., Molecules,
2007, vol. 12, pp. 1136–1146.
7. Holla, B.Sh., Mahalinga, M., Karthikeyan, M.S., Poo-
jary, B., Akberali, P.M., and Kumari, N.S., Eur. J.
Med. Chem., 2005, vol. 40, pp. 1173–1178.
8. Eid, F.A., Abd El-Wahab, A.H.F., El-Hag
Ali, G.A.M., and Khafagy, M.M., Acta Pharm., 2004,
vol. 54, pp. 13–26.
9. Gami, S.P., Vilapara, K.V., Khunt, H.R., Babariya, J.S.,
and Naliapara, Y.T., Int. Lett. Chem. Phys. Astron.,
2014, vol. 30, pp. 127–134.
10. Rashad, A.E., Heikal, O.A., El-Nezhawy, A.O., and
Abdel-Megeid, F.M.E., Heteroatom Chem., 2005,
vol. 16, pp. 226–234.
11. Paronikyan, E.G., Akopyan, Sh.F., Noravyan, A.S.,
Dzhagatspanyan, I.A., Paronikyan, R.G., Nazaryan, I.M.,
and Akobyan, A.G., Pharm. Chem. J., 2012, vol. 46,
pp. 154–156.
Biological Tests
Anticonvulsant activity of the compounds was
assessed by the prevention of the seizure clonic com-
ponent induced by subcutaneous injection of corazole
(90 mg/kg) to mice [18–22]. Unwanted side effects in
these animals, namely the central myorelaxant effect
and impaired motor coordination were examined by
the rotating rod method [18, 23, 24]. The compounds
under investigation were injected in a dose range of 12.5,
25, 50, and 100 mg/kg; reference drug diazepam (Polfa,
Poland), at doses of 0.1–0.3, 1.0, and 2.0 mg/kg intra-
peritoneally 45 min before injection of corazole (Acros
Organics, United States) in the form of a suspension
with carboxymethyl cellulose (Viadi-Ingredienti, Rus-
sia) and Tween 80 (Ferak Berlin, Germany). An emulsi-
fier was administered to control animals. A 50% effective
dose (ED50) of the tested compounds was determined by
the Litchfield and Wilcoxon method [25].
Sedative, activating, and anxiolytic effects of the
selected most active compounds were examined in rats
in the open field test while studying the motor and ori-
enting-exploratory activity [26–28]. Experiments
were carried out during the daytime under natural
lighting. Recording of spontaneous behavior in each
individual animal was continued for 5 min. The pres-
ence of sedative and activating effects was assessed by
the number of horizontal (intersection of squares) and
vertical (rising on hind legs) movements; the anxio-
lytic effect was evaluated by the number of chambers
examined by animals of experimental and control
groups. 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
suspension of carboxymethyl cellulose and Tween 80.
The compounds were injected to mice 45 min before
the animals were placed in the open field. Diazepam,
the known tranquilizer, served as a reference drug; it
12. Wang, S.B., Piao, G.C., Zhang, H.J., and Quan, Z.S.,
Molecules, 2015, vol. 20, pp. 6827–6843.
13. Paronikyan, E.G., Dashyan, Sh.Sh., Noravyan, A.S.,
and Minasyan, N.S., Chem. J. Arm., 2013, vol. 66,
pp. 611–617.
14. Paronikyan, E.G., Dashyan, Sh.Sh., Noravyan, A.S.,
and Minasyan, N.S., Russ. J. Org. Chem., 2014, vol. 50,
pp. 1829–1834.
15. Paronikyan, E.G., Dashyan, Sh.Sh., Noravyan, A.S.,
Dzhagatspanyan, I.A., Paronikyan, R.G., Nazaryan, I.M.,
and Akopyan, A.G., Russ. J. Bioorg. Chem., 2015,
vol. 41, pp. 663–669.
16. Paronikyan, E.G., Dashyan, Sh.Sh., Minasyan, N.S.,
Stepanyan, H.M., and Babaev, E.V., Chem. Heterocycl.
Compd., 2016, vol. 52, no. 5, pp. 337–345.
17. Vorob’ev, E.V., Extended Abstract of Cand. Sci. (Chem.)
Dissertation, Rostov-on-Don, 2006.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
Vol. 43
No. 5
2017

SYNTHESIS AND NEUROTROPIC ACTIVITY
603
18. Vogel, H.G. and Vogel, W.H., Psychotropic and neuro- 24. Jones, B.J. and Roberts, D.J., J. Pharm. Pharmacol.,
tropic activity, in Drug Discovery and Evaluation. Phar-
macological Assays Springer, Vogel, H.E., Ed., Berlin&
NY, 2008, pp. 569–874.
1968, vol. 20, no. 4, pp. 302–304.
25. Belen’kii, M.L., Elementy kolichestvennoi otsenki far-
makologicheskogo effekta (Elements of Quantitative
Evaluation of the Pharmacological Effect), Leningrad:
Meditsina, 1961.
19. Loscher, W. and Schmidt, D., Epilepsy Res., 1988,
pp. 145–181.
20. Swinyard, E.A., in Experimental Models of Epilepsy,
26. File, S.E., Behav. Brain. Res., 2001, vol. 125, pp. 151–
New York: Raven Press, 1992, pp. 433–458.
157.
21. Gevorkyan, K.A., Papayan, G.L., Chshmarityan, S.G.,
and Paronikyan, R.G., Pharm. Chem. J., 1987, vol. 21,
pp. 95–98.
27. Stanford, S.C., J. Psycopharmac., 2007, vol. 21,
pp. 134–135.
22. Drugs Used in Generalized Seizures. Basic and Clinical
Pharmacology, 9th ed., Katzung, B., Ed., Large Medi-
cal Books/McGraw-Hill, 2003.
28. Prut, C.B., Eur. J. Pharmacol., 2003, vol. 463, nos. 1–
3, pp. 3–33.
23. Dunham, N.W. and Miya, T.S., J. Am. Pharm. Ass. Sci.
Ed., 1957, vol. 46, no. 3, pp. 208–209.
Translated by G. Levit
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 43 No. 5 2017