Condensed thienopyrimidine derivatives. Part 20: Synthesis and neurotropic activity of a series of new pyrano[4′,3′:4,5]thieno[3,2-e]imidazolidino-[2,1-b]pyrimidines

Full text of DOI:10.1023/A:1015384228176

Pharmaceutical Chemistry Journal
Vol. 35, No. 12, 2001
SEARCH FOR NEW DRUGS
CONDENSED THIENOPYRIMIDINE DERIVATIVES. PART 20:
SYNTHESIS AND NEUROTROPIC ACTIVITY OF A SERIES
OF NEW PYRANO[4¢,3¢:4,5]THIENO[3,2-e]IMIDAZOLIDINO-
[2,1-b]PYRIMIDINES
A. Sh. Oganisyan,1 A. S. Noravyan,1 I. A. Dzhagatspanyan,1 and A. G. Akopyan1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 12, pp. 8 – 9, December, 2001.
Original article submitted May 15, 2001
Previously we reported on the neurotropic properties of
condensed thieno[2,3-d]pyrimidine derivatives [1 – 3]. To
our knowledge, the synthesis and pharmacological activity of
pyranothienoimidazolidino[2,1-b]pyrimidines have not been
described so far. To fill the gap, we have developed a method
for the synthesis of new pyranothienoimidazopyrimidines
that are condensed and studied their neurotropic and
antiamnesic properties.
The interaction of 2-aminothiophene I [4] with
allylisothiocyanate led to the corresponding thioureido deriv-
ative II. Under the action of potassium hydroxide solution in
aqueous ethanol, this compound converted into
2-thio-4-oxothieno[2,3-d]pyrimidine III. By alkylating com-
pound III with methyl iodide, we obtained the corresponding
S-methyl derivative IV. Finally, the condensation of com-
pound IV with primary amines led to the target
imidazo[2,1-b]pyrimidines V and VI.
COOC2H5
H2C CHNCS
O
S
NH2
EXPERIMENTAL CHEMICAL PART
I
COOC2H5
The IR absorption spectra were measured on an UR-20
spectrophotometer (Germany) using samples suspended in
Vaseline oil. The IR spectra of the synthesized compounds
exhibit characteristic absorption bands in the regions of
1665 – 1675 cm – 1 (amide C=O bonds) and 3100 – 3300
(NH). The 1H NMR spectra were recorded on a Varian T-60
spectrometer using TMS as the internal standard. TLC was
performed on Silufol UV-254 plates; the spots were visual-
ized by exposure to iodine vapors. The data of elemental
analyses agree with the results of calculations using the pro-
posed empirical formulas.
KOH
NHCH2 CH CH2
O
NH
C
S
S
II
O
CH2
CH3I
N
CH2CH
S
O
N
H
S
III
O
CH2
NCH2CH
SCH3
O
N
S
IV
2-(N¢-Allylthioureido)-5,5-dimethyl-3-ethoxycarbonyl
-4,5-dihydro-7H-thieno[2,3-c]pyran (II). A mixture of
2.55 g (0.01 mole) of compound I [4] and 0.99 g (0.01 mole)
of allylisothiocyanate in 40 ml of methanol was boiled for
12 h and allowed to stand overnight. The precipitate crystals
were separated by filtration and washed with diethyl ether to
obtain 1.6 g (45.2%) of compound II; m.p., 151 – 152°C; Rf ,
0.62 (acetone – hexane, 1 : 1); C16H22N2O3S2; 1H NMR
spectrum in CDCl3 (d, ppm): 11.90 (s, 1H, NH), 6.93 (t, 1H,
NH–CH2–), 6.23 – 4.96 (m, 3H, CH=CH2), 4.0 (t, 2H,
O
N
RNH2
O
N
N
R
CH3
S
V, VI
V: R = CH3; VI: R = CH2CH2OH.
1
Mndzhoyan Institute of Fine Organic Chemistry, National Academy of
Sciences of Armenia, Yerevan, Armenia.
650
0091-150X/01/3512-0650$25.00 © 2001 Plenum Publishing Corporation

Condensed Thienopyrimidine Derivatives
651
TABLE 1. Anticonvulsant Properties, Tranquilizer Activity, and Acute Toxicity of Compounds V and VI
Anxiolytic activity
(number of water
takes)
Anticorazole activity
Myorelaxant
(TD50), mg/kg
TD50/ED50
LD50, mg/kg
Compound
(ED50), mg/kg
> 1000
> 1000
20
12
3
Compound V (100 mg/kg)
Compound VI (100 mg/kg)
Phenobarbital
12.1 (9.1 ¸ 15.1) 50 (34.5 ¸ 72.5)
1300 (1083 ¸ 1560)
1500 (1181 ¸ 1905)
92 (51.2 ¸ 147.2)
9.5 (8.4 ¸ 10.6)
86 (49.1 ¸ 110.5)
12.5 (8.3 ¸ 18.5) 46 (29.5 ¸ 71.8)
5
Diazepam (2 mg/kg)
Control
16 (7.7 ¸ 24.3)
1.6 (1.1 ¸ 2.1)
0.5 (0.4 ¸ 0.7)
2.7 (1.4 ¸ 5.5)
–
–
–
–
7-CH2), 4.23 (q, 2H, OCH2CH3), 4.03 (t, 2H, NH–CH2–),
2.67 (t, 2H, 4-CH2), 1.28 (t, 3H, OCH2–CH3), 1.23 (s, 6H,
(CH3)2).
Hydrochloride (V × HCl): m.p., 218 – 220°C (anhydr.
ethanol); C15H19N3O2S × HCl.
2,7,7-Trimethyl-5-oxo-1-(b-hydroxy)-ethyl-6,7-dihydro-
3-Allyl-6,6-dimethyl-4-oxo-2-thio-5,6-dihydro-8H-py
9H-pyrano[4¢,3¢:4,5]thieno[2,3-e]imidazolidino[2,1-b]pyri
dine (VI). A mixture of 3.22 g (0.01 mole) of compound IV
and 20 ml of monoethanolamine was heated in a metal bomb
at 150°C for 20 h. Upon cooling, the mixture was diluted
with water. The precipitated crystals were separated by filtra-
tion, washed with water and ether, and dried to obtain 1.3 g
(38.7%) of compound VI; m.p., 219 – 220°C (ethanol);
rano[4¢,3¢:4,5]thieno[2,3-d]pyrimidine (III). A mixture of
3.54 g (0.01 mole) of compound II and 1.12 g (0.02 mole) of
potassium hydroxide in 40 ml of 50% aqueous ethanol was
boiled for 2 h. Upon cooling, the reaction mixture was acidi-
fied with a 10% aqueous hydrochloric acid solution to obtain
a weak acid reaction. The precipitated crystals were sepa-
rated by filtration, washed with water, and dried to obtain
3.0 g (97.8%) of compound III; m.p., 213 – 215°C (ethanol);
Rf , 0.55 (chloroform – benzene – acetonitrile, 6 : 2 : 1);
Rf , 0.50
(chloroform – benzene – acetone,
2 : 1 : 3);
C16H21N3O3S; 1H NMR spectrum in CDCl3 (d, ppm): 4.69 (t,
2H, 9-CH2), 4.31 – 3.27 (m, 7H, CH2–CH2, 2-CH, 3-CH2),
2.92 (t, 2H, 6-CH2), 1.40 (d, 3H, –CH–CH3), 1.09 (s, 6H,
(CH3)2).
1
C14H16N2O2S2; H NMR spectrum in CDCl3 (d, ppm): 9.50
(s, 1H, NH), 6.35 – 5.15 (m, 3H, CH=CH2), 5.05 (d, 2H,
N–CH2), 4.63 (t, 2H, 8-CH2), 2.83 (t, 2H, 5-CH2), 1.23 (s,
6H, (CH3)2).
Hydrochloride (VI × HCl): m.p., 228 – 230°C (anhydr.
ethanol); C16H21N3O3S × HCl.
3-Allyl-6,6-dimethyl-2-methylhtio-4-oxo-5,6-dihydro-
8H-pyrano[4¢,3¢:4,5]thieno[2,3-d]pyrimidine (IV). To a
solution of 3.1 g (0.01 mole) of compound III and 0.56 g
(0.01 mole) of potassium hydroxide in 20 ml of 90% aque-
ous ethanol at room temperature was added, with stirring,
1.4 g (0.01 mole) of methyl iodide. The precipitated crystals
were separated by filtration, washed with water, and dried to
obtain 2.5 g (78.4%) of compound IV; m.p., 145 – 146°C
(ethanol); Rf , 0.64 (chloroform – benzene – acetonitrile,
EXPERIMENTAL PHARMACOLOGICAL PART
The substances to be tested were introduced by
intraperitoneal injections in the form of suspensions with
Tween-80 in a dose of 25, 50, 100, 500, 1000, or
2000 mg/kg. The injections were made 45 min before the
administration of convulsant (corazole) or the test for tran-
quilizer, myorelaxant, or neurotoxicity.
1
6 : 2 : 1); C15H18N2O2S2; H NMR spectrum in CDCl3 (d,
The effect of compounds V – VI on the clonic convul-
sion component was studied using 340 white mongrel mice
weighing 18 – 24 g and 60 rats weighing 180 – 220 g (each
test was performed in a group of eight animals). The model
convulsions were induced by corazole (90 mg/kg, s.c.),
arecoline (15 mg/kg, s.c.), or nicotine (8 mg/kg, i.p.), or by
the maximum electroshock technique. The tranquilizer effect
was studied using the “conflict situation” test. In addition,
we monitored the side effects (disturbed coordination of
movements) and determined the acute toxicity. The methods
used in the investigation of anticonvulsant, tranquilizer, and
myorelaxant properties, as well as the method of statistical
data processing and determining the effective dose (ED50),
acute toxicity (LD50), and neurotoxicity (TD50) values, were
described elsewhere [5, 6]. In addition, we calculated the
ppm): 6.10 – 5.0 (m, 3H, CH=CH2), 4.77 (d, 2H, N–CH2),
4.62 (t, 2H, 8-CH2), 2.90 (t, 2H, 5-CH2), 2.57 (s, 3H, SCH3),
1.27 (s, 6H, (CH3)2).
1,2,7,7-Tetramethyl-5-oxo-6,7-dihydro-9H-pyrano[4¢,
3¢:4,5]thieno[2,3-e]imidazolidino[2,1-b]pyridine (V).
A
mixture of 3.22 g (0.01 mole) of compound IV and 40 ml of
a 30% aqueous methylamine solution was heated in a metal
bomb at 150°C for 18 h. Upon cooling, the precipitated crys-
tals were separated by filtration, washed with water and
ether, and dried to obtain 1.2 g (41.2%) of compound V;
m.p., 209 – 211°C (ethanol); Rf , 0.50 (chloroform – ben-
1
zene – acetone, 2 : 2 : 1); C15H19N3O2S; H NMR spectrum
in CDCl3 (d, ppm): 4.63 (t, 2H, 9-CH2), 4.30 – 3.30 (m, 3H,
2-CH, 3-CH2), 2.90 (s, 3H, N–CH3), 2.76 (t, 2H, 5-CH2),
1.48 (d, 3H, –CH–CH3), 1.20 (s, 6H, (CH3)2).

652
A. Sh. Oganisyan et al.
protection index, defined as the ratio of TD50 and ED50. The
reference drugs were phenobarbital and diazepam [6].
It was found that compounds V and VI in the dose range
studied do not prevent convulsions induced by nicotine,
arecoline, or maximum electroshock. However, beginning
barbital show more pronounced anticorazole activity and the
former drug produces a tranquilizer effect as well, the signif-
icantly greater protection ratios of compounds V and VI may
be evidence of higher selectivity and lower toxicity of the
newly synthesized imidazolidinopyrimidine derivatives.
with a dose of 25 mg/kg, both compounds decreased or pre-
vented corazole-induced convulsions (Table 1). In a dose
corresponding to ED50, these substances produced a weak
myorelaxant effect; only a very significant increase in the
dose dose level (almost 20-fold for compound V) led to
myorelaxation and loss of animals.
Beginning with a dose of 25 and 50 mg/kg, compounds
V and VI led to an increase in the number of water takes in
the conflict situation test, but the tranquilizer activity of both
drugs was significantly lower as compared to that of diaze-
pam. The protection indices (determined as the ratio of
anticonvulsant and myorelaxant doses) of compounds V and
VI amount to 20 and 12 (against 5 and 3 for diazepam and
phenobarbital), respectively. Although diazepam and pheno-
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