Synthesis and Neurotropic Activity of Novel Condensed Cyclopentanopyrido[3',2':4,5]-Thieno[3,2-D]Pyrimidine Derivatives

Article abstract of DOI:10.1007/s11094-020-02259-y

2-Oxo-2,5,6,7-tetrahydro-3-cyano-1H-cyclopenta[b]pyridine was used as the starting point to develop an accessible synthesis of condensed cyclopentanopyrido[3',2':4,5]thieno[3,2-d]pyrimidine derivatives. The neurotropic activity of these compounds was studied, and a number of them showed anticonvulsant activity as antagonism to corasol. Compound II, like diazepam, had anti-anxiety and activating effects, while the other compounds had sedative activity.

Full text of DOI:10.1007/s11094-020-02259-y

DOI 10.1007/s11094-020-02259-y
Pharmaceutical Chemistry Journal, Vol. 54, No. 7, October, 2020 (Russian Original Vol. 54, No. 7, July, 2020)
SYNTHESIS AND NEUROTROPIC ACTIVITY
OF NOVEL CONDENSED CYCLOPENTANOPYRIDO[3¢,2¢:4,5]-
THIENO[3,2-d]PYRIMIDINE DERIVATIVES
V. V. Dabaeva,1,* M. R. Bagdasaryan,1 E. G. Paronikyan,1
Sh. Sh. Dashyan,1 R. G. Paronikyan,1 I. M. Nazaryan,1
and A. G. Akopyan1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 54, No. 7, pp. 27 – 32, July, 2020.
Original article submitted August 18, 2019.
2-Oxo-2,5,6,7-tetrahydro-3-cyano-1H-cyclopenta[b]pyridine was used as the starting point to develop an ac-
cessible synthesis of condensed cyclopentanopyrido[3¢,2¢:4,5]thieno[3,2-d]pyrimidine derivatives. The
neurotropic activity of these compounds was studied, and a number of them showed anticonvulsant activity as
antagonism to corasol. Compound II, like diazepam, had anti-anxiety and activating effects, while the other
compounds had sedative activity.
Keywords: synthesis, cyclopentanopyrido[3¢,2¢:4,5]thieno[3,2-d]pyrimidine, neurotropic activity.
Thieno[3,2-d]pyrimidines are of undoubted interest in
the search for novel biologically active compounds, as evi-
denced by the extensive literature [1 – 3]. Studies of the bio-
logical properties of thieno- and furopyridines previously
synthesized in our work and condensed with the tetrahydro-
pyrane ring showed these compounds to have valuable bio-
logical properties [4 – 6], so there is interest in studying the
properties of analogous derivatives containing a cyclopen-
tane ring.
The starting compound for synthesis of these latter sub-
stances was 2-oxo-2,5,6,7-tetrahydro-3-cyano-1H-cyclopen-
ta[b]pyridine-3-carbonitrile (I) [7]. Boiling of I with phos-
phorus oxychloride was used to synthesize the 2-chloro de-
rivative II, interaction of which with the ethyl ester of
thioglycolic acid yielded the amino ester of condensed
thieno[2,3-b]pyridine III (Scheme 1). The Nimentovsky re-
1
Science and Technology Center for Organic and Pharmaceutical Chemis-
try, National Academy of Sciences of the Republic of Armenia, 26
Azatutyan Prospekt, 0014 Erevan, Armenia.
*
e-mail: valya.dabayeva@mail.ru
Scheme 1
NH
CN
Cl
2
CN
O
POCl
, 8 h
HSCH COOC H
3
2
2
5
C H ONa,
, 6 h
2
5
N
COOC H
N
S
N
H
2
5
I
II
III
N
O
N
POCl
H NCSNH
HCONH
3
2
2
2
, 2 h
C H N,
, 2 h
NH
N
C H OH,
5
5
, 2 h
2
5
N
S
N
S
Cl
V
IV
N
S
N
NH
N
N
S
N
S
SH
VI
707
0091-150X/20/5407-0707 © 2020 Springer Science+Business Media, LLC

708
V. V. Dabaeva et al.
action, run by heating amino ester III in formamide, led to
cyclization to form a pyrimidine ring (compound IV). The
influences of the type of substituent in this compound on its
biological activity were investigated by running the
chlorodehydroxylation reaction with phosphorus oxychloride
followed by substitution of the chlorine atom with thiourea
to form thiol VI.
Analyzer (Germany). Melting temperatures were measured
using a Boetius microheating platform. Found values for ele-
mental analysis were consistent with atomic formulas.
2-Chloro-6,7-dihydro-5H-cyclepenta[b]pyridine-3-car-
bonitrile (II). A mixture of 1.6 g (10 mmol) of compound I
and 30 ml of phosphorus oxychloride was heated at
115 – 120°C for 8 h. Excess phosphorus oxychloride was
then evaporated in vacuo and the residue, on cooling with
water, was made alkaline with sodium hydroxide solution;
the precipitating crystals were collected by filtration, washed
with water, and recrystallized from ethanol. The yield was
1.5 g (83.9%). T was 133 – 134°C. R was 0.59 (ethyl ace-
This latter can exist in the thiolactam and thiolactime
forms. The NH group signal at 3120 cm-1 in the IR spectrum
indicates a preference for the thione form. However, substi-
tution reactions with various halogenides involve displace-
ment of the equilibrium towards the thiolactime form and the
valent bond is formed with the more nucleophilic sulfur at-
oms, so the milder conditions in which alkylation is carried
out yields exclusively the S derivatives VIIa – d (Scheme 2).
Scheme 2
m
f
tate-petroleum ether, 3:5). C H ClN . The IR spectrum, n,
1
9
7
2
cm-1, was: 1560, 1590 (arom.), 2240 (C = N). The H NMR
spectrum (DMSO-d ), d, ppm, was: 2.20 (tt, 2H, J 7.7,
6
7.5 Hz, CH ), 2.99 (t, 2H, J 7.5 Hz, CH ), 3.04 (t, 2H, J
2
2
7.7 Hz, CH ), 8.04 (s, 1H, =CH). The 13C NMR spectrum
N
N
2
RCl, KOH
1 h
(DMSO-d ), d , ppm, was: 22.3 (CH ), 29.1 (CH ), 33.7
N
N
6
C
2
2
C H OH,
2
5
N
S
N
S
(CH ), 106.7 (CCN), 114.6 (CCN), 136.0 (C ), 137.7 (CH),
2
Ar
SR
SH
VI
VII: a) R = C4H9; b) R = C6H13; c) R = (CH2)2C6H5; d) R = CH2CONH2.
VIIa–d
149.7 (C ), 170.3 (C ).
Ar
Ar
3-Amino-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]py-
ridine-2-carboxylic acid ethyl ester (III). Thioglycolic acid
ethyl ester (1.2 ml) and 1.8 g (10 mmol) of compound II
were added dropwise with mixing to sodium ethylate pre-
pared from 0.23 g (10 mmol) of sodium metal and 25 ml of
absolute ethanol. The reaction mix was boiled with mixing
for 6 h. Solvent was then evaporated, water was added, and
the precipitating crystals were collected by filtration, washed
with water and ether, and recrystallized from ethanol. The
yield was 1.9 g (72.4%). T was 222 – 223°C. R was 0.66
At the same time, it is quite difficult to confirm this un-
ambiguously using only the IR and PMR spectra. For final
determination of the structure of thio derivatives, we synthe-
sized hydrazine VIII by boiling compound VIIa with hydra-
zine hydrate in absolute ethanol (Scheme 3).
Scheme 3
N
N
NH NH
2
2
m
f
D, 6 h
N
N
N
S
N
S
(ethyl acetate-hexane, 1:1). C H N O S. The IR spectrum,
13 14
2
2
SC H
NHNH
2
n
, cm-1, was: 1542, 1585 (arom.), 1680 (C = O), 3180,
4
9
max
VIII
VIIa
1
3280, 3410 (NH ). The H NMR spectrum (DMSO-d ), d,
2
6
In contrast to the thione, as suggested, alkylation of
pyrimidinone IV leads to N-substitution products IXa – e
(scheme 4). This is evidenced by the lack of the absorption
band typical of the NH group and presence of the band corre-
sponding to the C = O group at 1670 cm-1.
ppm, was: 1.38 (t, 3H, J 7.1 Hz, CH ), 2.19 (qn, 2H, J 7.6 Hz,
3
CH ), 3.03 (t, 4H, J 7.6 Hz, 2 ´ CH ), 4.28 (q, 2H, J 7.1 Hz,
2
2
OCH ), 6.93 (broad s, 2H, NH ), 8.18 (s, 1H, =CH). The 13
C
2
2
NMR spectrum (DMSO-d ), d , ppm, was: 14.2 (CH ), 23.1
6
C
3
(CH ), 29.5 (CH ), 33.4 (CH ), 58, 9 (CH ), 93.5 (C ),
2
2
2
2
Ar
Scheme 4
123.4 (C ), 125.9 (CH), 131.9 (C ), 147.7 (C ), 158.7
Ar
Ar
Ar
N
N
RCl
(C ), 164.3 (C ), 167.1 (CO).
Ar
Ar
NH
N
C H ONa,
8,9-Dihydro-3H-cyclopenta[5¢,6¢]pyrido[3¢,2¢:4,5]-thi-
eno[3,2-d]pyrimidin-4-(7H)-one (IV). A mixture of 2.6 g
(10 mmol) of compound III and 20 ml of formamide was
heated for 2 h at 190 – 200°C. The mixture was then cooled,
20 ml of water was added, the precipitating crystals were
collected by filtration, washed with water and ether, and
2
5
N
S
N
S
R
, 1 h
O
IXa–e
IX: a) R = C5H11i; b) R = (CH2)2OCH3; c) R = CH2CONH2;
O
IV
d) R = CH2C(CH3)CH2; e) R = CH2CH(OCH3)2.
recrystallized from ethanol. The yield was 2.2 g (90.4%). T
EXPERIMENTAL CHEMICAL SECTION
m
was 230 – 231°C. R was 0.51 (pyridine-butanol, 1:2).
f
C H N OS. The IR spectrum, n , cm-1, was: 1550, 1600,
IR spectra were recorded on a Nicolet Avatar 330 FT-IR
1
12
9
3
max
spectrometer (USA) in Vaseline grease. H and 13C NMR
1620 (arom., C = C, C = N ), 1680 (C = O), 3110 (NH).
conj
1
The H NMR spectrum (DMSO-d ), d, ppm, was: 2.17 (tt,
spectra were recorded on a Mercury Vx instrument (USA) in
6
2H, J 7.7, 7.5 Hz, CH ), 3.06 (t, 2H, J 7.5 Hz, CH ), 3.07 (t,
DMSO-d solution with working frequencies of 300 and
2
2
6
75.462 MHz respectively; the internal standard was TMS.
Elemental analysis was run on a EuroEA 3000 Elemental
2H, J 7.7 Hz, CH ), 8.32 (s, 2H, 2´ =CH), 12.79 (broad s,
2
NH). The 13C NMR spectrum (DMSO-d ), d , ppm, was:
6
C

Synthesis and Neurotropic Activity
709
23.1 (CH ), 29.6 (CH ), 33.7 (CH ), 95.4 (C ), 126.1 (C ),
1.8 g (15 mmol) of 1-chlorohexane. The yield was 2.9 g
2
2
2
Ar
Ar
126, 7 (CH), 134.8 (C ), 147.4 (CH), 150.9 (C ), 157.3
(84.4%). T was 208 – 209°C. R was 0.53 (pyridine-buta-
Ar
Ar
m
f
1
nol, 1:1). C H N S . The H NMR spectrum (DMSO-d ),
(C ), 159.9 (C ), 168.8 (CO).
Ar
Ar
18 21 3 2 6
4-Chloro-8,9-dihydro-7H-cyclopenta[5¢,6¢]pyrido[3¢,2¢:
4,5]thieno[3, 2-d]pyrimidine (V). A mixture of 2.4 g
(10 mmol) of compound IV, 2 ml of absolute pyridine, and
30 ml of phosphorus oxychloride was heated to 105°C for
4 h. Excess phosphorus oxychloride was then evaporated in
vacuo and the residue, on cooling with water, was supple-
mented with 20 ml of iced water. The mixture was then neu-
tralized with 25% aqueous ammonia solution and the precip-
itating crystals were collected by filtration, washed with wa-
ter, and recrystallized from ethanol. The yield was 1.8 g
(68.8%). T was 203 – 204°C. R was 0.65 (pyridine-buta-
d, ppm, was: 0.93 (m, 3H, CH CH ), 1.29 – 1.39 (m, 4H,
2
3
CH CH CH ), 1.50 (m, 2H, SCH CH CH ), 1.80 (m, 2H,
2
2
3
2
2
2
SCH CH ), 2.22 (tt, 2H, J 7.6, 7.4 Hz, CH ), 3.12 (td, 2H, J
2
2
2
7.4, 1.1 Hz, CH ), 3.13 (t, 2H, J 7.6 Hz, CH ), 3.40 (t, 2H, J
2
2
7.2 Hz, SCH CH ), 8.27 (s, 1H, N=CH), 8.33 (t, 1H, J
2
2
1.1 Hz, =CH).
4-(2-Phenylethylthio)-8,9-dihydro-7H-cyclopenta[5¢,6¢]-
pyrido[3¢,2¢:4,5]thieno[3,2-d]pyrimidine (VIIc) was pre-
pared by the same method from 2.6 g (10 mmol) compound
VI and 2.1 g (15 mmol) of phenylethylchloride. The yield
was 2.8 g (77.0%). T was 215 – 216°C. R was 0.56
m
f
m
f
nol, 1:1). C H ClN S. The IR spectrum, n , cm-1, was:
(pyridine-butanol, 1:2). C H N S . The 1H NMR spectrum
12
8
3
max
20 17
3 2
1
1520, 1560, 1600, (arom., C = C, C = N ). The H NMR
(DMSO-d ), d, ppm, was: 2.25 (tt, 2H, J 7.6, 7.4 Hz, CH ),
conj
6
2
spectrum (DMSO-d ), d, ppm, was: 2.29 (tt, 2H, J 7.6 Hz,
3.11 (td, 2H, J 7.4, 1.1 Hz, CH ), 3.08 (m, 2H, CH C H ),
6
2
2
6
5
CH ), 3.15 (td, 2H, J 7.4,0.9 Hz, CH ), 3.17 (t, 2H, J 7.6 Hz,
3.13 (t, 2H, J 7.6 Hz, CH ), 3.63 (m, 2H, SCH ), 7.15 – 7.32
2
2
2
2
CH ), 8.50 (t, 1H, J 0.9 Hz, =CH), 9.00 (s, 1H, N=CHN).
(m, 5H, C H ), 8.27 (s, 1H, N=CH), 8.33 (t, 1H, J 1.1 Hz,
2
6
5
8,9-Dihydro-7H-cyclopenta[5¢,6¢]pyrido[3¢,2¢:4,5]thi-
eno[3,2-d]pyrimidine-4-thiol (VI). A mixture of 2.6 g
(10 mmol) of compound V, 1.0 g (13 mmol) of thiourea, and
60 ml of absolute ethanol was boiled with mixing for 3 h. Af-
ter cooling, the resulting crystalline precipitate was collected
by filtration, dissolved in 20 ml of 2 N sodium hydroxide so-
lution, and neutralized with acetic acid. The precipitating
crystals were collected by filtration, washed with water and
ether, and recrystallized from ethanol. The yield was 2.3 g
(87.9%). T was >350°C. R was 0.65 (pyridine—butanol,
=CH).
2-(8,9-Dihydro-7H-cyclopenta[5¢,6¢]pyrido[3¢,2¢:4,5]-
thieno[3,2-d]pyrimidin-4-yl)acetamide (VIId) was pre-
pared by the same method from 2.6 g (10 mmol) compound
VI and 1.4 g (15 mmol) of chloroacetamide. The yield was
2.8 g (88.5%).
1
(pyridine-butanol, 1:2). C H N OS . The H NMR spec-
T
was 254 – 255°C.
R
was 0.53
m
f
14 12
4
2
trum (DMSO-d ), d, ppm, was: 2.28 (tt, 2H, J 7.7, 7.4 Hz,
6
CH ), 3.14 (td, 2H, J 7.4, 1.0 Hz, CH ), 3.16 (t, 2H, J 7.7 Hz,
2
2
CH ), 4.11 (s, 2H, SCH ), 7.01 (broad s, 1H)-7.41 (broad s,
m
f
2
2
1:1). C H N S . The IR spectrum, n , cm-1, was: 1545,
1H, NH ), 8.47 (t, 1H, J 1.0 Hz, =CH), 8.98 (s, 1H, N=CH).
12
9
3
2
max
2
1
1575, 1595 (arom., C = C, C = N ), 3120 (NH). The H
4-Hydrazino-8,9-dihydro-7H-cyclopenta[5¢,6¢]-pyrido-
[3¢,2¢:4,5]thieno[3,2-d]pyrimidine (VIII). A mixture of
2.8 g (10 mmol) compound VIIa in 10 ml of concentrated
hydrazine hydrate was boiled for 6 h. After removal of ex-
cess hydrazine hydrate, the residue was supplemented with
20 ml of water. The precipitating crystals were collected by
filtration, washed with water and ether, and recrystallized
conj
NMR spectrum (DMSO-d ), d, ppm, was: 2.25 (tt, 2H, J 7.6,
6
7.4 Hz, CH ), 3.11 (td, 2H, J 7.4, 1.1 Hz, CH ), 3.13 (t, 2H, J
2
2
7.6 Hz, CH ), 8.27 (s, 1H, N=CH), 9.00 (s, 1H, N=CH), 8.33
2
(t, 1H, J 1.1 Hz, =CH), 14.10 (broad s, 1H, SH).
4-(Butylthio)-8,9-dihydro-7H-cyclopenta[5¢,6¢]pyrido-
[3¢,2¢:4,5]thieno[3,2-d]pyrimidine (VIIa). 1-Chlorobutane
(1.4 g, 15 mmol) was added dropwise with mixing to a mix-
ture of 2.6 g (10 mmol) of compound VI, 0.6 g (10 mmol)
potassium hydroxide, and 60 ml of 90% ethanol. Mixing was
continued for 1 h, after which crystals were collected by fil-
tration, washed with water and ether, and recrystallized from
from ethanol. The yield was 1.7 g (66.1%). T was 264 –
m
265°C. R was 0.52 (pyridine-butanol, 1:2). C H N S. The
f
12 11
5
IR spectrum, n , cm-1, was: 1580, 1600 (arom., C = C),
3260, 3320 (NH, NH ). The 1H NMR spectrum (DMSO-d ),
max
2
6
d, ppm, was: 2.23 (qn, 2H, J 7.6, 7.4 Hz, CH ), 3.09 (t, 4H, J
2
ethanol. The yield was 2.8 g (88.8%). T was 231 – 232°C.
7.6 Hz, 2 x CH ), 4.78 (broad s, 2H, NH ) 8.33 (s, 1H, =CH),
m
2
2
R was 0.56 (pyridine-butanol, 1:1). C H N S . The IR
8.34 (s, 1H, =CH), 8.88 (broad s, 1H, NH).
f
16 17
3 2
spectra, n , cm-1, of compounds VIIa – d, were: 1540,
3-(3-Methylbutyl)-8,9-dihydro-3H-cyclopenta[5¢,6¢]py-
rido[3¢,2¢:4,5]thieno[3,2-d]pyrimidin-4-(7H)-one (IXa).
Compound IV (2.4 g, 10 mmol) was added to a solution of
sodium ethylate prepared from 0.46 g (20 mmol) of sodium
and 25 ml of absolute ethanol and the mixture was boiled for
1 h. After cooling, the mixture was supplemented with 2.1 g
(20 mmol) of isoamylchloride and boiled for 8 h. After cool-
ing, precipitated crystals were collected by filtration, washed
with water and ether, and recrystallized from ethanol. The
yield was 2.0 g (63.6%). T was 176 – 177°C. R was 0.52
max
1570, 1600 (arom., C = C, C = N ). The 1H NMR spectrum
conj
(DMSO-d ), d, ppm, was: 1.01 (t, 3H, J 7.3 Hz, CH CH ),
6
2
3
1.54 (m, 2H, CH CH ), 1.79 (m, 2H, SCH CH ), 2.20 (tt,
2
3
2
2
2H, J 7.6, 7.4 Hz, CH ), 3.10 (td, 2H, J 7.4, 1.1 Hz, CH ),
2
2
3.12 (t, 2H, J 7.6 Hz, CH ), 3.41 (t, 2H, J 7.2 Hz, SCH ),
2
2
8.26 (s, 1H, N=CH), 8.32 (t, 1H, J 1.1 Hz, =CH).
4-(Hexylthio)-8,9-dihydro-7H-cyclopenta[5¢,6¢]pyrido-
[3¢,2¢:4,5]thieno[3,2-d]pyrimidine (VIIb) was prepared by
the same method from 2.6 g (10 mmol) of compound VI and
m
f

710
V. V. Dabaeva et al.
3-chloro-2-methylpropene-1. The yield was 1.8 g (60.5%).
(pyridine-butanol, 1:3). C H N OS. The IR spectrum, n ,
max
17 19
3
cm-1, was: compound IXa – e, 1600 (arom.), 1630 (C = N),
T
was 156 – 157°C. R was 0.60 (pyridine—butanol, 2:3).
f
m
1
1680 (C = O). The H NMR spectrum (DMSO-d ), d, ppm,
1
C H N OS. The H NMR spectrum (DMSO-d ), d, ppm,
6
16 15 3 6
was: 1.83 (broad s, 3H, CH ), 2.25 (qn, 2H, J 7.6 Hz, CH ),
was: 1.02 (d, 6H, J 6.2 Hz, 2 ´ CH ), 1.64 – 1.78 [m, 3H,
3
2
3
CH CH (CH ) ], 2.25 (tt, 2H, J 7.7, 7.5 Hz, CH ), 3.11 (td,
3.11 (t, 2H, J 7.4 Hz, CH ), 3.12 (t, 2H, J 7.6 Hz, CH ), 4.65
2 2
2
3 2
2
2H, J 7.5, 1.0 Hz, CH ), 3.12 (t, 2H, J 7.7 Hz, CH ),
(s, 2H, NCH ), 4.77 (broad s, 1H) and 4.95 (broad s, 1H,
2
2
2
=CH ), 8.27 (broad s, 1H, =CH), 8.34 (s, 1H, =CH). The 13
C
4.04 – 4.19 (m, 2H, NCH ), 8.27 (t, 1H, J 1.0 Hz, =CH), 8.43
2
2
(s, 1H, =CH).
NMR spectrum (DMSO-d ), d , ppm, was: 19.8 (CH ), 23.1
6
C
3
3-(2-Methoxyethyl)-8,9-dihydro-3H-cyclopenta[5¢,6¢]-
pyrido[3¢,2¢:4,5]thieno[3,2-d]pyrimidin-4-(7H)-one (IXb)
was prepared by the same method from 2.4 g (10 mmol) of
compound IV and 1.9 g (20 mmol) of 1-chloro-2-methoxy-
ethane. The yield was 1.9 g (63.0%). T was 220 – 221°C. R
(CH ), 29.6 (CH ), 33.6 (CH ), 49.9 (NCH ), 112.4 (=CH ),
2
2
2
2
2
121.0 (C ), 125.9 (C ), 126.1 (CH), 134.0 (C ), 139.8
Ar
Ar
Ar
(C ), 148.8 (CH), 149.8 (C ), 156.0 (C ), 160.6 (C ),
Ar
Ar
Ar
Ar
168.1 (CO).
3-(2,2-Dimethoxyethyl)-8,9-dihydro-3H-cyclopenta-
[5¢,6¢]pyrido[3¢,2¢:4,5]thieno[3,2-d]pyrimidin-4-(7H)-one
(IXe) was prepared by the same method from 2.4 g
(10 mmol) of compound IV and 2.5 g (20 mmol) of 1-chlo-
m
f
was 0.55 (pyridine-butanol, 1:3). C H N O S. The 1H
15 15
3
2
NMR spectrum (DMSO-d ), d, ppm, was: 2.25 (tt, 2H, J 7.6,
6
7.4 Hz, CH ), 3.10 (td, 2H, J 7.4, 1.1 Hz, CH ), 3.11 (t, 2H, J
2
2
7.6 Hz, CH ), 3.34 (s, 3H, OCH ), 3.67 (t, 2H, J 5.1 Hz,
2
3
ro-2-dimethoxyethane. The yield was 2.1 g (63.4%). T was
m
NCH ), 4.25 (t, 2H, J 5.1 Hz, NCH ), 8.27 (t, 1H, J 1.1 Hz,
2
2
186 – 187°C.
R
was 0.54 (pyridine-butanol, 2:3).
f
=CH), 8.30 (s, 1H, N=CH).
1
C H N O S. The H NMR spectrum (DMSO-d ), d, ppm,
16 17
3
3
6
2-(4-Oxo-4,7,8,9-tetrahydro-3H-cyclopenta[5¢,6¢]pyri-
do[3¢,2¢:4,5]thieno[3,2-d]pyrimidin-3-yl)acetamide (IXc)
was prepared by the same method from 2.4 g (10 mmol) of
compound IV and 1.6 g (20 mmol) of a-chloroacetamide.
The yield was 1.9 g (63.2%). T was >310°C. R was 0.54
was: 2.24 (tt, 2H, J 7.7, 7.4 Hz, CH ), 3.10 (td, 2H, J 7.4,
2
1.0 Hz, CH ), 3.11 (t, 2H, J 7.7 Hz, CH ), 3.40 (s, 6H,
2
2
2 ´ OCH ), 4.15 (d, 2H, J 5.2 Hz, NCH ), 4.64 (t, 1H, J
3
2
5.2 Hz, CH), 8.26 (t, 1H, J 1.0 Hz, =CH), 8.30 (s, 1H,
=CHN).
m
f
1
(pyridine—butanol, 2:3). C H N O S. The H NMR spec-
14 12
4
2
trum (DMSO-d ), d, ppm, was: 2.25 (qn, 2H, J 7.6 Hz, CH ),
6
2
EXPERIMENTAL PHARMACOLOGICAL SECTION
3.11 (t, 4H, J 7.6 Hz, 2 x CH ), 4.71 (s, 2H, NCH ), 7.11
2
2
(broad s, 1H) and 7.66 (broad s, 1H, NH ), 8.30 (s, 1H,
2
=CH), 8.37 (s, 1H, =CH). The 13C NMR spectrum
Biological experiments were carried in full compliance
with the European Convention for the Protection of Verte-
brates Used for Experimental and Other Scientific Purposes
(European Treaty Series No. 123), Strasbourg, 18.03.1986).
Studies of the anticonvulsant activity of eight cyclopen-
(DMSO-d ), d , ppm, was: 23.1 (CH ), 29.6 (CH ), 33.7
6
C
2
2
(CH ), 47.5 (CH ), 120.3 (C ), 126.0 (C ), 126.5 (CH),
2
2
Ar
Ar
134.6 (C ), 150.3 (C ), 150.4 (CH), 156.5 (C ), 160.3
Ar
Ar
Ar
(C ), 167.7 (CO), 168.6 (CO).
Ar
tapyrido[3¢,2¢:4,5]-thieno[3,2-d]pyrimidine derivatives (II,
III, V, VId, IXa – d) were run on 300 white mice weighing
18 – 24 g and 30 white rats weighing 130 – 150 g of both
sexes.
3-(2-Methylprop-2-en-1-yl)-8,9-dihydro-3H-cyclopenta-
[5¢,6¢]pyrido[3¢,2¢:4,5]thieno[3,2-d]pyrimidin-4-(7H)-one
(IXd) was prepared by the same method from 2.4 g
(10 mmol) of compound IV and 1.6 g (20 mmol) of
TABLE 1. Comparative Anticonvulsant and Exploratory Activity of Compounds II, V, and IXe and Reference Agents
Number of
Corasol antagonism
Compound
(ED50, mg/kg)*
horizontal movements*
18.8 (15.9 – 22.2)
vertical movements*
2.6 (1.4 – 3.8)
hole sniffs*
Control for compounds
and diazepam
-
1.4 (1.18 – 1.65)
II (50 mg/kg)
37.5 (20.8 – 67.5)
36.0 (23.8 – 48.2)
23.0 (15.9 – 35.1)
155 (117.5 – 204.5)
0.5 (0.4 – 0.7)
28.0 (23.3 – 33.6)**
15.8 (12.9 – 18.7)
10.0 (9.1 – 10.9)**
16.8 (14 – 20.16)
33.6 (9.4 – 11.87)**
4.8 (4.0 – 5.8)**
2.2 (1.2 – 3.2)
1.0 (0.7 – 1.3)**
8 (2.24 – 3.5)
3.4 (2.8 – 4.08)**
0.6 (0.2 – 1.0)**
0.8 (0.68 – 0.9)**
1.6 (1.28 – 2.0)
5.6 (4.66 – 6.7)**
V (50 mg/kg)
IXe (50 mg/kg)
Ethosuximide (200 mg/kg)
Diazepam (2 mg/kg)
6.4 (5.4 – 7.4)**
*
p £ 0.05
Significant differences compared with controls
**

Synthesis and Neurotropic Activity
711
Anticonvulsant and tranquilizing activities were studied
in terms of the influences of compounds on clonic twitches
and convulsions induced by s.c. administration of corasol
(pentylenetetrazole, PTZ, Acros Organics, New Jersey, USA,
90 mg) to mice [8 – 12]. Control animals received emulsifier
(suspension of tween-80 with carboxymethycellulose). Each
dose of compounds in each test was studied in six animals.
Analogs for comparison were the succinimide anticonvulsant
ethosuximide (Neuraxpharm Arzneimittel GmbH, Germany)
and the tranquilizer diazepam (Polfa, Poland). This latter as
used for comparison on the grounds that some thienopyrimi-
dine derivatives have anti-anxiety actions [13].
duration of active swimming, and the total duration of immo-
bility were recorded in the 6-min test. Experiments were run
in conditions of natural illumination.
Neurotoxic (myorelaxant) side effects of compounds
were also studied in mice at doses from 50 to 100 mg/kg
given i.p., as well as analogs at effective anticonvulsant
doses. Myorelaxation in mice was assessed in the rotating
bar test [8, 19]. The mouse was placed on a metal bar with a
corrugated plastic coating, rotating at a speed of 5 rpm. The
number of animals unable to stay on the bar for 2 min was
determined. The 50% effective dose (ED
) was the dose giv
-
50
ing an anticonvulsant effect in 50% of the animals and was
determined using the statistical method of Litchfield and
Wilcoxon probit analysis [20].
Exploratory activity was also studied for selected com-
pounds, with recording of spontaneous movement/explor-
atory behavior in a modified open field test in rats (each
group consisting of eight animals). The apparatus was di-
vided into squares and had openings (holes). Experiments
were performed in the daytime with natural illumination.
Rats received study compounds at the most effective dose of
50 mg/kg i.p. The number of horizontal movements (square
crossings), hole sniffs, and rearing on the hindpaws (vertical
movements) were measured in experimental and control ani-
mals during the 5-min test [14 – 16].
Analysis of data on the anticorasol effect showed that
study compounds at a dose of 50 mg/kg, with the exception
of compound IXa, had some level of anticorasol activity. Ta-
ble 1 shows ED values for compounds II, V, and IXd. The
50
others showed only weak anticonvulsant activity - 20 – 40%
efficacy. Active compounds, like ethosuximide and diaze-
pam, prevented clonic twitches and clonic convulsions and
had several-fold greater anticorasol activity than ethosuxi-
mide. However, in contrast to diazepam, this activity was ap-
parent at higher doses - from 23 to 38 mg/kg. Reference
agent diazepam (a tranquillizer) had anticorasol activity in
50% of mice at a dose of 0.5 mg/kg. At the doses studied,
neither any of the test compounds nor ethosuximide induced
myorelaxation in mice, while diazepam induced myorelax-
ation from doses of 2 – 3 mg/kg.
Anti-anxiety, sedative, and antidepressant actions were
studied in an elevated plus maze (EPM) test in mice, as de-
veloped in 1986 [17]. The plus maze elevated above the floor
had pairs of open and closed arms orthogonal to each other.
Normal animals prefer to spend most of the time in the
closed (dark) arms of the maze. The time spent in the closed
arms, the numbers of attempts to enter the closed arms, and
the time spent in the center of the maze were measured. Test
compounds and reference substances were given i.p. before
experiments. Control animals received emulsifier. Results
were analyzed statistically (p £ 0.05).
In the behavioral model, the open field test, the number
of horizontal movements in rats of the control group was
18.8, the number of vertical movements was 2.6, and the
number of holes investigated was 1.4 (Table 1). Test com-
pounds induced some changes in behavioral parameters as
compared with controls.
“Despair and depression” were studied using the forced
swimming model [18]. Experimental animals were forced to
swim in a glass container (height 22 cm, diameter 14 cm)
one third filled with water. Intact mice generally swim very
actively, though with time they have to become immobile.
The latent period of the first period of immobility, the total
Administration of compound II produced statistically
significant increases in all measures from values seen in con-
trols (it had an activatory action). Compounds V and IXe,
conversely, decreased all values of exploratory activity (sig-
nificantly compared with controls in the case of compound
TABLE. 2. Effects of Compounds II, V, and IXe and Reference Agents in the EPM Model (5 min)
Compound (dose)
Time spent in open arms, sec*
Number of entries into closed arms*
7 (5.8 – 8.4)
Time spent in center, sec*
21.8 (11.0 – 32.6)
Control
278.2 (262 – 294.0)
II (50 mg/kg)
243 (216.8 – 260.6)**
196 (162.3 – 229.7)**
241.8 (197 – 286.5)**
245.2 (212.9 – 277.5)
257.5 (226.2 – 288.8)
5.8 (3.4 – 8.2)
57 (47.3 – 66.3)**
V (50 mg/kg)
6.2 (4 – 8.3)
104 (70.3 – 137.7)**
51.0 (41.5 – 62.7)**
52.8 (19.7 – 85.9)
IXe (50 mg/kg)
6.6 (3.4 – 9.8)
Ethosuximide (200 mg/kg)
Diazepam (2 mg/kg)
8.1 (5.6 – 10.6)
5.5 (4.58 – 6.6)
42.5 (34.8 – 51.85)**
* p £ 0.05
** Significant differences compared with controls

712
V. V. Dabaeva et al.
TABLE 3. Activities of Compounds II, V, and IXe and Diazepam in the Forced Swimming Test (6 min).
Total duration of
Duration of active swimming,
Compound (dose)
latent period of first period of immobility
immobility, sec
75.3 (58.5 – 92.1)
151 (136.9 – 165)**
142 (108 – 176)**
124 (97.5 – 150.5)**
98 (75.3 – 127.4)
24 (13.9 – 34.1)**
active swimming, sec
284.6 (242.2 – 328)
209 (194.9 – 223.1)**
210 (182.6 – 241.5)**
205 (173.7 – 241.9)**
262 (199.9 – 324.1)
336 (282.6 – 389.4)
Control
109.3 (74.1 – 144.5)
76.0 (56.6 – 95.4)**
63.0 (51.5 – 74.5)**
83 (59.9 – 106.1)**
105 (87.5 – 104.4)
174 (144 – 204)**
II (50 mg/kg)
V (50 mg/kg)
IXe (50 mg/kg)
Ethosuximide (200 mg/kg)
Diazepam (2 mg/kg)
*p £ 0.05
**Significant differences compared with controls
IXe) and produced significant reductions in hole-sniffing.
Ethosuximide (200 mg/kg) had no effect on any parameter of
exploratory activity, while diazepam produced statistically
significant increases in exploratory activity (horizontal and
vertical movements) and the number of hole sniffs. Diaze-
pam (2 mg/kg), as compared with controls, induced a signifi-
cant increase in the number of holes explored, i.e., it had
anti-anxiety (like compound II) and activatory effects. The
other compounds had some degree of sedative action.
obtained in the EPM model suggest protective reactions with
both compounds and diazepam (2 mg/kg). Studies in the
forced swimming model showed that all selected compounds
at a dose of 50 mg/kg had sedative activity. Studies of the re-
lationship between chemical structure and the biological ac-
tivity of the compounds synthesized here showed that the
most marked anticonvulsant properties were obtained with
compounds containing a chlorine atom in the pyridine or py-
rimidine ring, as well as derivatives with an acetamide
substituent.
In the EPM model, control animals mostly remained in
the closed arms (Table 2). Administration of study com-
pounds was followed by an interesting effect. Compounds
decreased the time spent in the closed arms and the number
of entries into the closed arms as compared with controls.
Animals spent large amounts of time in the center, unlike
controls but like diazepam, which may be evidence that the
compounds produced protective reactions.
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