Synthesis and Neurotropic Activity of New Pyrimido[4′,5′:4,5]Thieno[2,3-b]Quinoline Derivatives

Article abstract of DOI:10.1007/s11094-015-1334-5

New methods for preparing pyrimido[4′,5′:4,5]thieno[2,3-b]quinoline derivatives based on 3-cyanohexahydro-2-quinoline were developed. The neurotropic activity of these compounds was studied.

Full text of DOI:10.1007/s11094-015-1334-5

DOI 10.1007/s11094-015-1334-5
Pharmaceutical Chemistry Journal, Vol. 49, No. 9, December, 2015 (Russian Original Vol. 49, No. 9, September, 2015)
SYNTHESIS AND NEUROTROPIC ACTIVITY OF NEW
PYRIMIDO[4¢,5¢:4,5]THIENO[2,3-b]QUINOLINE DERIVATIVES
V. V. Dabaeva,1 M. R. Bagdasaryan,1 A. S. Noravyan,1 I. A. Dzhagatspanyan,1
I. M. Nazaryan,1 and A. G. Akopyan1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 49, No. 9, pp. 17-21, September, 2014.
Original article submitted September 30, 2013.
New methods for preparing pyrimido[4¢,5¢:4,5]thieno[2,3-b]quinoline derivatives based on 3-cyanohexahyd-
ro-2-quinoline were developed. The neurotropic activity of these compounds was studied.
Keywords: synthesis, pyrimido[4¢,5¢:4,5]thieno[2,3-b]quinoline; neurotropic activity.
As derivatives of condensed thieno- and furopyridines
have valuable biological properties [1 – 3], there is interest in
studying the properties of analogous derivatives containing
the tetrahydroquinoline ring. With this aim we developed an
accessible synthesis method based on 3-cyanohexahydro-2-
quinoline (I) [4]. Boiling of this compound in phosphorus
oxychloride led to synthesis of 2-chloro derivative II, inter-
action of which with thioglycolic acid ethyl ester yielded the
amino ester of condensed thieno[2,3-b]pyridine III. Use of
the Niementowski reaction by heating with formamide led to
formation of a pyrimidine ring (compound IV). The effects
of the nature of the substituents in positions 3 and 4 on the
biological activity of the resulting compounds were assessed
by chlorodehydroxylation with phosphorus oxychloride fol-
lowed by substitution of the chlorine with various amines.
On the other hand, condensed pyrimidinones were alkylated,
with substitution in position 3, the resulting compounds lack-
ing the absorption band characteristic of the NH group but
retaining the band characteristic of the C=O group at
1670 cm–1.
EXPERIMENTAL CHEMICAL SECTION
IR spectra were taken on a UR-20 spectrometer in Vase-
line grease. PMR spectra were taken on a Mercury-300 spec-
trometer in DMSO-d . TLC was run on Silufol UV-254
6
plates run in systems consisting of ethyl acetate and petro-
leum ether (1:2) (II, III), pyridine and butanol (1:3) (IV, V,
VIII, IX); and chloroform and ether (1:3) (VI, VII); plates
were developed in iodine vapor. Found values for elemental
analyses corresponded to atomic formulas.
2-Chloro-3-cyano-5,6,7,8-tetrahydroquinoline (II). A
mixture of 1.74 g (0.01 mol) of compound I and 35 ml of
phosphorus oxychloride was heated in a boiling water bath
for 8 h. Excess phosphorus oxychloride was then evaporated
in vacuo and the residue was alkalinized with aqueous so-
dium hydroxide with cooling using iced water; the resulting
crystalline precipitate was collected by filtration, washed
with water, and dried. The yield was 1.6 g (85.6%) and the
melting temperature was 136 – 137°C (ethanol). R was 0.75.
f
The atomic formula was C H ClN . The IR spectrum, n
,
max
10
9
2
cm–1, was: 1580, 1620 (arom.), 2240 (CN). The PMR spec-
trum, ppm, was: 1.84 – 2.02 (m, 4H, CH CH ), 2.98-3.07 (m,
2
2
4H, 5-CH and 8-CH ), 7.73 (s, 1H, CH).
2
2
Hydrolysis of amino ester III with aqueous sodium hy-
droxide solution was used to synthesize the corresponding
amino acid VIII, boiling of which in acetic anhydride pro-
duced condensed oxazine IX.
Ethyl-3-amino-5,6,7,8-tetrahydrothieno-[2,3-b]quino-
line-2-carboxylate (III). Sodium ethylate prepared from
0.23 g (0.01 mol) of metallic sodium and 25 ml of absolute
ethanol was supplemented by dropwise addition of 1.2 ml of
thioglycolic acid ethyl ester and 1.92 g (0.01 mol) of com-
pound II with mixing. The reaction mix was boiled with mix-
ing for 6 h. Solvent was then evaporated, water was added,
and the crystalline precipitate was collected by filtration. The
1
Science and Technology Center for Organic and Pharmaceutical Chemis-
try, National Academy of Sciences of the Republic of Armenia,
A. L. Mndzhoyan Institute of Fine Organic Chemistry, 26 Azatutyan
Street, 0014 Erevan; e-mail Noravyhan@mail.ru.
587
0091-150X/15/4909-0587 © 2015 Springer Science+Business Media New York

588
V. V. Dabaeva et al.
NH
CN
O
CN
Cl
2
POCl
HSCH COOC H
3
2
2
5
C H ONa
2
5
N
H
N
N
COOC H
2 5
S
II
III
I
N
O
N
O
1 Cl
HCONH2
R
NH
N
R1
N
N
S
S
IV
Va-k
POCl3
C H N
2
5
N
N
N
HNR2R3
N
N
N
S
N
S
Cl
R3
R2
VI
VIIa-i
CH2
CH3
O
V, a: R1 = –C5H11i; b: R1 = –CH2COOCH3; c: R1 = –CH2–C
; d: R1 = –(CH2)2–OCH3;
O
e: R1 = –CH2–C
; f: R1 = –CH2–C6H5; g: R1 = –CH2–C
;
CH3
NH2
NH2
CH3
O
O
h: R1 = –CH2–C
; i: R1 = –CH2–C
OCH3
;
NH
NH
CH3O
O
O
j: R1 = –CH2–C
; k: R1 = –CH2–C
OCH3
Ph ;
NH
NH–CH
Ph
VII, a: R2 = H, R3 = –C4H9i; b: R2 = H, R3 = –C6H13; c: R2 = H, R3 = NH2;
C2H5
d: R2 = H, R3 = –(CH2)2–N
; e: R2 = H, R3 = –C6H13; f: NR2R3 = –N
;
C2H5
O; h: R2 = H, R3 = –(CH2)2–C6H5; i: R2 = H, R3 = –CH2C6H5.
NH
g: NR2R3 = –N
NH
2
2
NaOH
N
S
COOC H
N
S
COOH
2
5
VIII
III
(CH CO) O
3
2
N
CH
3
O
N
S
O
IX

Synthesis and Neurotropic Activity
589
yield was 1.6 g (59.5%) and the melting temperature was
(s, 3H, CH ), 2.97 – 3.07 (m, 4H, 7-CH and 10-CH ), 4.92
3
2
2
238 – 239°C (ethanol). R was 0.63. the atomic formula was
(s, 2H, NCH ), 7.03 – 7.09 and 7.45 – 7.50 (m, 2H-2H,
f
2
C H N O S. The IR spectrum, n , cm–1, was: 1540,
C H ), 8.23 (t, 1H, J 1.0 Hz, 11-CH), 8.49 (s, 1H, N=CH),
6
4
14 16
2
2
max
10.23 (broad, 1H, NH), Vh: 1.86 – 2.02 (m, 4H, CH CH ),
1580 (arom.); 1680 (C=O); 3180, 3280, 3410 (NH ). The
2
2
2
2.97 – 3.07 (m, 4H, 7-CH and 10-CH ), 3.77 (s, 3H,
PMR spectrum, ppm, was: 1.41 (t, 3H, J 7.1 Hz,
CH CH ),1.84 – 2.02 (m, 4H, CH CH ), 2.97 – 3.06 (m, 4H,
2
2
n-OCH ) and 3.90 (s, 3H, o-OCH ), 5.00 (s, 2H, NCH ), 6.41
3
3
2
2
3
2
2
(dd, 1H, J 8.8, J 2.6 Hz, =CH), 6.54 (d, 1H, J 2.6 Hz,
5-CH and 8-CH ), 4.28 (q, 2H, J 7.1 Hz, OCH CH ), 5.83
1
2
2
2
2
3
NHC=CHCH), 7.83 (d, 1H, J 8.8 Hz, NHC=CH), 8.23 (t, 1H,
J 1.0 Hz, 11-CH), 8.47 (broad s, 1H, N=CH), 9.43 (broad,
1H, NH), Vi: 1.87-2.03 (m, 4H, CH CH ), 2.33 (s, 3H, CH ),
(s, 2H, NH ), 7.98 (s, 1H, CH).
2
3,4,7,8,9,10-Hexahydropyrimido[4¢,5¢:4,5]thieno[2,3-b]-
quinolin-4-one (IV). A mixture of 2.76 g (0.01 mol) of com-
pound III and 20 ml of formamide was heated at 195-200°C
for 3 h. The reaction was then cooled, crystals were collected
by filtration, washed with water and ethanol, and dried. The
yield was 1.8 g (69.8%) and the melting temperature was
2
2
3
2.98-3.08 (m, 4H, 7-CH and 10-CH ), 4.93 (s, 2H, NCH ),
2
2
2
6.80 – 7.46 (m, 4H, C H ), 8.22 (t, 1H, J 1.0 Hz, 11-CH),
6
4
8.46 (s, 1H, N=CH), 10.19 (broad, 1H, NH), Vj: 1.87 – 2.03
(m, 4H, CH CH ), 2.98 – 3.08 (m, 4H, 7-CH and 10-CH ),
2
2
2
2
3.76 (s, 3H, OCH ), 4.91 (s, 2H, NCH ), 6.77 – 6.82 (m, 2H)
333-334°C (ethanol). R was 0.52. the atomic formula was
3
2
f
C H N OS. The IR spectrum, n , cm–1, was: 1550, 1600,
and 7.49 – 7.54 (m, 2H, C H ), 8.22 (t, 1H, J 1.0 Hz, 11-CH),
6
4
13 11
3
max
8.46 (s, 1H, N=CH), 10.15 (broad, 1H, NH), Vk: 1.87 – 2.03
(m, 4H, CH CH ), 2.97-3.08 (m, 4H, 7-CH and 10-CH ),
1620 (arom., C=C, C=N); 1680 (C=O); 3110 (NH). The
PMR spectrum, ppm, was: 1.84 – 2.01 (m, 4H, CH CH ),
2
2
2
2
2
2
4.86 (s, 2H, NCH ), 6.17 (d, 1H, J 8.5 Hz, NHCH),
2.94 – 3.04 (m, 4H, 7-CH and 10-CH ), 8.21 (t, 1H, J 1.0
2
2
2
7.21 – 7.36 (m, 10H, 2C H ), 8.21 (t, 1H, J 1.0 Hz, 11-CH),
Hz, 11-CH), 8.33 (s, 1H, N=CH), 12.90 (m, 1H, NH).
6
5
8.42 (s, 1H, N=CH), 9.19 (d, 1H, J 8.5 Hz, NH).
3-(3-Methylbutyl)-3,4,7,8,9,10-hexahydropyrimido-
[4¢,5¢:4,5]thieno[2,3-b]quinolin-4-one (Va). A mixture of
2.57 g (0.01 molecule) of compound IV, 1.7 g (0.012 mol) of
potash, and 10 ml of absolute DMF was boiled for 0.5 h. Af-
ter cooling, the mixture was supplemented by dropwise addi-
tion of 1.28 g (0.012 mol) of isopentyl chloride and boiled
for 1 h. After cooling, the mixture was supplemented with
iced water and the resulting crystalline precipitate was col-
lected by filtration, washed with water and ether, and dried.
The yield was 2.3 g (61.2%) and the melting temperature
4-Chloro-7,8,9,10-hexahydropyrimido[4¢,5¢:4,5]thieno-
[2,3-b]quinoline (VI). A mixture of 2.57 g (0.01 mol) of
compound IV, 2 ml of absolute pyridine, and 30 ml of phos-
phorus oxychloride was heated for 3 h at 95-100°C. Excess
phosphorus oxychloride was evaporated in vacuo and the
residue was supplemented by dropwise addition of 20 ml of
iced water with cooling. The mixture was then neutralized
was 151-152°C (ethanol). R was 0.57. The atomic formula
TABLE 1. Properties of Compounds Vb-k, VIIb-i
f
was C H N OS. The IR spectrum, n , cm–1, was: Va-k:
18 21
3
max
Compound
Vb
Yield, %
59.9
61.2
62.3
75.3
69.3
68.2
68.4
69.2
71.1
69.9
58.9
65.3
54.3
63.2
68.7
69.3
71.1
69.8
mp, °C
Rf
Atomic formula
C16H15N3O3S
C17H17N3OS
C16H17N3O2S
C15H14N4O2S
C20H17N3OS
C22H20N4O2S
C23H22N4O4S
C22H20N4O2S
C22H19N4O3S
C28H24N4O2S
C19H24N4S
1550, 1575, 1590 (arom., C=C, C=N conj.). The PMR spec-
199 – 200
146 – 147
162 – 163
333 – 334
158 – 159
319 – 320
283 – 284
223 – 224
304 – 305
242 – 243
156 – 157
191 – 192
210 – 211
241 – 242
161 – 162
148 – 149
218 – 219
271 – 272
0.56
0.58
0.61
0.55
0.59
0.57
0.55
0.59
0.58
0.54
0.63
0.52
0.54
0.61
0.63
0.64
0.62
0.61
trum, ppm, was: 1.02 (d, 6H, J 6.2 Hz, CH(CH ) ), 1.63-1.78
3 2
Vc
(m, 3H, CHCH ),1.86 – 2.02 (m, 4H, CH CH ), 2.96-3.08
2
2
2
(m, 7-CH and 10-CH ), 4.05 – 4.11 (m, 2H, NCH ), 8.16 (t,
Vd
2
2
2
1H, J 1.0 Hz, 11-CH), 8.43 (s, 1H, N=CH). Compounds Vb-k
were prepared by an analogous method (Table 1). PMR spec-
tra, ppm, were: Vb: 1.86-2.03 (m, 4H, CH CH ), 2.97-3.08
Ve
Vf
2
2
Vg
(m, 4H, 7-CH and 10-CH ), 3.79 (s, 3H, OCH ), 4.91 (s,
2
2
3
Vh
2H, NCH ), 8.20 (t, 2H, J 1.0 Hz, 11-CH), 8.48 (s, 1H,
2
N=CH), Vc: 1.83 (broad s, 3H, CH ), 1.86-2.03 (m, 4H,
Vi
3
CH CH ), 2.97 – 3.08 (m, 4H, 7-CH and 10-CH ), 4.65
Vj
2
2
2
2
(broad s, 2H, NCH ), 4.76 – 4.78 and 4.94 – 4.96 (m, 1H and
2
Vk
1H, =CH ), 8.17 (t, 1H, J 1.0 Hz, 11-CH), 8.34 (s, 1H,
2
VIIb
VIIc
VIId
VIIe
VIIf
VIIg
VIIh
VIIi
N=CH), Vd: 1.86 – 2.03 (m, 4H, CH CH ), 2.97 – 3.08 (m,
2
2
C13H13N5S
4H, 7-CH and 10-CH ), 3.32 (s, 3H, CH ), 3.68 (t, 2H, J 5.1
2
2
3
C19H25N5S
Hz, OCH ), 4.25 (t, 2H, J 5.1 Hz, N=CH ), 8.17 (t, 1H, J 1.0
2
2
Hz, 11-CH), 8.31 (s, 1H, N=CH), Ve: 1.86 – 2.03 (m, 4H,
CH CH ), 2.97 – 3.08 (m, 4H, 7-CH and 10-CH ), 4.71 (s,
C19H22N4S
2
2
2
2
C18H20N4S
2H, NCH ), 7.10 (broad, 1H) and 7.65 (broad, 1H, NH ),
2
2
C17H18N4OS
C21H20N4S
8.20 (t, 1H, J 1.0 Hz, 11-CH), 8.37 (s, 1H, N=CH), Vf:
1.86 – 2.02 (m, 4H, CH CH ), 2.96 – 3.07 (m, 4H, 7-CH
2
2
2
C20H18N3S
and 10-CH ), 5.29 (s, 2H, NCH ), 7.24 – 7.36 (m, 3H) and
2
2
7.42 – 7.47 (m, 2H, C H ), 8.16 (t, 1H, J 1.0 Hz, 11-CH),
6
5
* Recrystallized from ethanol
8.61 (s, 1H, N=CH), Vg: 1.85 – 2.02 (m, 4H, CH CH ), 2.30
2
2

590
V. V. Dabaeva et al.
with aqueous ammonia solution and the resulting crystalline
precipitate was collected by filtration, washed with water,
and dried. The yield was 1.8 g (65.7%) and the melting tem-
2.97 – 3.06 (m, 4H, 7-CH and 10-CH ), 4.09 – 4.21 (m, 1H,
2
2
NHCH), 7.12 (d, 1H, J 7.9 Hz, NH), 8.21 (broad s, 1H,
11-CH), 8.39 (s, 1H, N=CH), VIIf: 1.70 – 1.82 (m, 6H,
CH CH CH ), 1.86 – 2.03 (m, 4H, CH CH ), 2.98 – 3.07
perature was 132 – 133°C (ethanol). R was 0.63. The atomic
2
2
2
2
2
f
formula was C H ClN S. The IR spectrum, n , cm–1,
(m, 4H, 7-CH and 10-CH ), 3.92 – 3.97 (m, 4H,
2
2
13 10
3
max
CH -N-CH ), 8.25 (t, 1H, J 1.0 Hz, 11-CH), 8.47 (s, 1H,
was: 1520, 1560, 1600 (arom., C=C, C=N). The PMR spec-
2
2
N=CH), VIIg: 1.86 – 2.03 (m, 4H, CH CH ), 2.98 – 3.08 (m,
trum, ppm, was: 1.87-2.04 (m, 4H, CH CH ), 2.99-3.11 (m,
2
2
2
2
4H, 7-CH and 10-CH ), 3.78 – 3.82 (m, 4H) and 3.93-3.97
4H, 7-CH and 10-CH , 8.39 (t, 1H, J 1.0 Hz, 11-CH), 9.0 (s,
2
2
2
2
(m, 4H, C H NO), 8.27 (t, 1H, J 1.0 Hz, 11-CH), 8.53 (s, 1H,
1H, N=CH).
4
8
N=CH), VIIh: 1.86 – 2.02 (m, 4H, CH CH ), 2.95 – 3.07
2
2
N-4-Isobutyl(7,8,9,10-hexahydropyrimido[4¢,5¢:4,5]-
thieno[2,3-b]quinolin-4-yl)amine (VIIa). A mixture of
2.76 g (0.01 mol) of compound VI, 1.44 g (0.02 mol) of
isobutylamine, and 50 ml of absolute ethanol was boiled for
6 h. Solvent was then evaporated in vacuo and the residue
was supplemented with 20 ml of water and the resulting
crystalline precipitate was collected by filtration, washed
with water, and dried. The yield was 1.8 g (58.1%) and the
(m, 6H, CH CH and CH C H ), 3.72 – 3.81 (m, 2H,
2
2
2
6
5
NCH ),7.12 – 7.19 (m, 1H) and 7.22 – 7.28 (m, 4H, C H ),
2
6
5
7.60 (t, 1H, J 5.7 Hz, NH), 8.23 (t, 1H, J 1.0 Hz, 11-CH),
8.47 (s, 1H, N=CH), VIIi: 1.86 – 2.02 (m, 4H, CH CH ),
2
2
2.96 – 3.07 (m, 4H, 7-CH and 10-CH ), 5.31 (s, 2H, NCH ),
2
2
2
7.19 – 7.32 (m, 3H, H-3.4.5 C H ), 7.43 – 7.47 (m, 2H,
6
5
H-2,6 C H ), 8.22 (t, 1H, J 1.0 Hz, 11-CH), 8.47 (s, 1H,
6
5
N=CH).
melting temperature was 223 – 224°C (ethanol). R was 0.56.
f
3-Amino-5,6,7,8-tetrahydrothieno[2,3-b]quinolin-2-
carboxylic acid (VIII). A mixture of 2.76 g (0.01 mol) of
compound III and 50 ml of 5% aqueous sodium hydroxide
solution was boiled for 4 h. After cooling, the mixture was
supplemented with acetic acid to pH 6. The resulting crystal-
line precipitate was collected by filtration, washed with wa-
ter and ethanol, and dried. The yield was 1.5 g (61.4%) and
The atomic formula was C H N S. IR spectra, n , cm–1,
17 20
4
max
were: VIIa-i: 1520, 1560, 1600 (arom., C=C, C=N); 3220
(NH); VIIc: 3150, 3300 (NH-NH ). The PMR spectrum,
2
ppm, was: 0.98 (d, 6H, J 6.7 Hz,(CH ) ), 1.86 – 2.02 (m, 4H,
3 2
CH CH ), 1.98 – 2.12 (m, 1H, CH(CH ) ), 2.97 – 3.07 (m,
2
2
3 2
4H, 7-CH and 10-CH ), 3.36 (dd, 2H, J 7.0, 5.8 Hz, NCH ),
2
2
2
7.48 (t, 1H, J 5.8 Hz, NH), 8.22 (t, 1H, J 1.0 Hz, 11-CH),
8.40 (s, 1H, N=CH). Compounds IVb-i were prepared by an
analogous method (Table 1). PMR spectra, ppm, were: VIIb:
0.91 (t, 3H, J 6.8 Hz, CH ), 1.29 – 1.44 (m, 6H, (CH ) CH ),
the melting temperature was 162 – 163°C (ethanol). R was
f
0.50. The atomic formula was C H N O S. The IR spec-
12 12
2
2
trum, n , cm–1, was: 1560, 1590, 1610 (arom.), 1660 (C=O),
max
3200, 3340, 3430 (NH , OH). The PMR spectrum, ppm, was:
3
2 3
3
2
1.59 – 1.70 (m, 2H,NHCH CH ), 1.85 – 2.01 (m, 4H,
1.84-2.02 (m, 4H, CH CH ), 2.96 – 3.06 (m, 4H, 5-CH and
2
2
2
2
2
CH CH ), 2.96 – 3.05(m, 4H, 7-CH and 10-CH ), 3.47 –
8-CH ), 6.81 (broad, 2H, NH ), 11.22 (broad, 1H, OH).
2
2
2
2
2
2
3.54 (m, 2H, NCH ),7.42 (t, 1H, J 5.5 Hz, NH), 8.20 (t, 1H, J
2-Methyl-7,8,9,10-tetrahydrothieno-4H-[1,3]oxazino-
[4¢,5¢:4,5]thieno[2,3-b]quinolin-4-one (IX). A mixture of
2.48 g (0.01 mol) of compound VIII and 20 ml of acetic an-
hydride was boiled for 1 h. The reaction mix was cooled and
the resulting crystalline precipitate was collected by filtra-
tion, washed with ether and water, and dried. The yield was
1.5 g (59.4%) and the melting temperature was 190-191°C
2
1.0 Hz, 11-CH), 8.40 (s, 1H, N=CH), VIIc: 1.84 – 2.01 (m,
4H, CH CH ), 2.95 – 3.05 (m, 4H, 7-CH and 10-CH ), 4.72
2
2
2
2
(broad, 2H, NH ), 8.21 (t, 1H, J 1.0 Hz, 11-CH), 8.33 (s, 1H,
2
N=CH), 8.87 (broad, 1H, NH), VIId: 1.05 (t, 6H,
N(CH CH ) ), 1.86-2.02 (m, 4H, CH CH ), 2.60-3.06 (m,
2
3 2
2
2
10H, 7-CH , 10-CH , NCH and N(CH CH ) ), 3.62 (qu,
2
2
2
2
3 2
(ethanol).
R
was 0.62. The atomic formula was
2H, J 6.5 Hz, NHCH ),8.22 (t, 1H, J 1.0 Hz, 11-CH), 8.46 (s,
f
2
C H N O S. The IR spectrum n , cm–1, was: 1560, 1590,
1H, N=CH), VIIe: 1.16-1.29 (m, 1H, C H ), 1.32 – 1.51 (m,
6
11
14 12
2
2
max
4H, C H ), 1.67-2.03 (m, 9H, CH CH and C H ),
1620 (arom., C=C, C=N), 1750 (C=O, lactone). The PMR
6
11
2
2
6
11
TABLE 2. Comparative Anticorasol and Exploratory Activity of Compounds Vb, VIIa, and Diazepam
Number of
Corasol antagonism
Compound
(ED50, mg/kg)
horizontal movements
21 *(17.3 – 24.7)
vertical movements
5.3 (3.03 – 7.57)
cell sniffings
Control for compounds
(emulsifer)
4.2 (3.0 – 5.4)
Vb
36 *(24.0 – 54.0)
41 (22.5 – 74.6)
27 (19.4 – 34.6)
9.3 (3.4 – 15.2)
18.6 (13.7 – 23.5)
6.5 (2.2 – 10.08)
3.2 (2.8 – 3.6)
1.1 (0.7 – 1.5)
2.4 (1.1 – 3.7)
–
VIIa
Control for diazepam (emul-
sifier)
2.1 (1.0 – 3.2)
Diazepam
0.5 (0.4 – 0.7)
33.6 (29.4 – 37.8)
6.4 (5.4 – 7.4)
5.0 (3.7 – 6.3)
* Significance interval at a probability level of p = 0.05.

Synthesis and Neurotropic Activity
591
spectrum, ppm, was: 1.84 – 2.01 (m, 4H, CH CH ), 2.55 (s,
corasol convulsions (ED values were 36 mg/kg for Vb,
2
2
50
3H, CH ), 2.94 – 3.04 (m, 4H, 7-CH and 10-CH ), 8.21 (t,
41 mg/kg for VIIa, and 41 (22.5 – 74.6) mg for Va). Refer-
ence agent diazepam displayed 50% anticorasol activity in
mice at a dose of 0.5 mg/kg (Table 2).
3
2
2
1H, J 1.0 Hz, 11-CH), 8.32 (s, 1H, N=CH).
Undesirable side effects – impairments to motor coordi-
nation and myorelaxation – were not seen with study com-
pounds at a dose of 50 mg/kg.
EXPERIMENTAL BIOLOGICAL SECTION
Experiments were performed using 185 white mice
weighing 18 – 24 g and 40 rats weighing 120 – 130 g of both
genders. Studies of anticonvulsant activity were performed
for 17 compounds – VIIa-c, g, h, f and Va-h. The anticonvul-
sant activity of compounds was assessed in terms of the pre-
vention of the clonic component of convulsions elicited in
mice by s.c. administration of corasol (90 mg/kg), with re-
placement by clonic twitches or the complete absence of
convulsions. Undesirable side effects in these animals – a
central myorelaxant effect and impairment to motor coordi-
nation – were studied using a “rotating bar” method [5, 6].
These tests and the doses of each compound, monitoring, and
comparison with diazepam were performed in five experi-
ments.
In open field experiments, rats given emulsifier (control
for test compounds and diazepam) produced around 18.6 –
21.0 horizontal movements, 1.1 – 5.3 vertical movements,
and 2.1 – 4.2 cell sniffing reactions. Comparison of the ef-
fects of the most active compounds, Vb and VIIa, at a dose
of 50 mg/kg, with diazepam showed low levels of both hori-
zontal and vertical movement activity and cell sniffing inten-
sity. Thus, values for compound Vb were 27, 6.5, and 2.4 re-
spectively, and showed statistically minor differences from
control values, i.e., evidencing sedative and depressive ef-
fects.
Thus, a number of new condensed hexahydropyrimido-
quinolinones (VIIa and Va, b) were found to have neuro-
tropic properties. The new compounds, although less active
than diazepam, were able to prevent clonic corasol convul-
sions in animals although, in contrast to the tranquilizer diaz-
epam, sedative effects were seen in the complex open field
model. Analysis of these results indicates that the nature of
the radicals did not have any significant influence on the ac-
tivity of the compounds. It should be emphasized that like
the reference tranquilizer, the new substances did not elicit
central myorelaxation at the anticonvulsive doses used.
These data suggest that these agents have potential as hypno-
sedatives rather than activatory tranquilizers, emphasizing
the potential for further studies of the spectrum of
neurotropic activity in this new series of compounds.
The sedative, arousing, and anxiolytic actions of the
most active compounds, i.e., Vc and VIIa, as well as diaze-
pam, were assessed in terms of motor and exploratory behav-
ior in rats using a modified open field model. An apparatus
with a floor divided into squares with openings (“cells”) was
used. Experiments were performed in the daytime with natu-
ral illumination. Indicators of sedation and aroused behavior
were assessed during the 5 min of the test, i.e., the number of
horizontal movements (square crossings) and rearings onto
the hindlimbs (vertical displacements), along with measures
of anxiolytic behavior – sniffing of cells – in the experimen-
tal and control groups of animals [7 – 9]. Eight experiments
with this model were run with each compound, with controls
for compounds, and separate controls for diazepam. Open
field experiments were run on different days for study com-
pounds and diazepam. Results were compared with the cor-
responding controls.
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