Condensed thienopyrimidine derivatives: Synthesis and anticonvulsant activity of a series of new pyrano(thiopyrano)[4′,3′:4,5]thieno[2,3-d]pyrimidines

Full text of DOI:10.1023/A:1010445510155

Pharmaceutical Chemistry Journal
Vol. 35, No. 3, 2001
CONDENSED THIENOPYRIMIDINE DERIVATIVES: SYNTHESIS
AND ANTICONVULSANT ACTIVITY OF A SERIES OF NEW
PYRANO(THIOPYRANO)[4¢,3¢:4,5]THIENO[2,3-d]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. 3, pp. 9 – 10, March, 2001.
Original article submitted June 21, 1999.
Previous pharmacological investigations of a series of
condensed derivatives of pyrano(thiopyrano)[4¢,3¢:4,5]thie-
no[2,3-d]pyrimidines showed that some of these compounds
possess pronounced anticonvulsant and tranquilizer activity
[1 – 4]. We have synthesized new derivatives of pyrano-
(thiopyrano)[2,3-d]pyrimidine (V – X) condensed with vari-
ous heterocycles.
isothiocyanate in methanol at 30 – 40°C gave the corre-
sponding ureido derivatives III (IV) with a high yield.
Treating the products III, IV with an aqueous-alcohol solu-
tion of potassium hydroxide and then with hydrochloric acid
led to the formation of 2-thio-4-oxo-3,4,5,6-tetrahydro-6,6-
dimethyl-8H-pyrano(thiopyrano)[4¢,3¢:4,5]thieno[2,3-d]pyri-
midines (V, VI). Finally, we synthesized new condensed
tetracyclic compounds (VII – X) containing thienopy-
rimidine fragments by heterocyclization of compounds V, VI
through reaction with 1,3-dibromopropane or 1,4-dibromo-
butane.
COOC2H5
+ PhCONCS
X
S
NH2
I, II
EXPERIMENTAL CHEMICAL PART
COOC2H5
1) KOH
2) HCl
The IR absorption spectra were measured on a 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 – 1670 cm – 1 (amide C=O bonds), 1720 cm – 1 (C=O),
and 3100 – 3300 cm – 1 (NH).
X
S
NH
C
S
NHC Ph
O
III, IV
O
NH
1
The H NMR spectra were recorded on a Varian T-60
X
S
N
H
S
spectrometer using TMS as the internal standard. The mass
spectra were obtained with an MX-1303 spectrometer with
an electron-impact ionization source operating at 70 eV. TLC
was performed on Silufol UV-254 plates; the spots were vi-
sualized by exposure to iodine vapor. The data of elemental
analyses agree with the results of calculations using the em-
pirical formulas.
Br(CH2)3Br
V, VI
Br(CH2)4Br
O
O
4
5
7
8
4
8
6
7
5
9
3
2
N
3
2
N
X
9
X
10
S
N
S1
S
N
10
S
VII, VIII
IX, X
2-(N¢-Benzoylthioureido)-3-ethoxycarbonyl-5,5-dimet
hyl-4,5-dihydro-7H-thieno[2,3-c]pyran (III). To a solution
of 2.55 g (0.01 mole) of compound I [4] in 20 ml of metha-
nol at 35°C was added with stirring 1.63 g (0.01 mole) of
benzoylisothiocyanate. The mixture was stirred for 3 h. The
precipitated crystals were separated by filtration and washed
with diethyl ether to obtain 3.5 g (83.8%) of compound III;
m.p., 208 – 210°C (ethanol); Rf, 0.65 (acetone – hexane,
1 : 2); C20H22N2O4S2.
I, II, V, VII, IX: X = O;
II, IV, VI, VIII, X: X = O.
The interaction of 2-amino-5,5-dimethyl-3-ethoxycarbo-
nylthieno[2,3-c]pyran(thiopyran) I (II) [4] with benzoyl-
1
Mndzhoyan Institute of Fine Organic Chemistry, National Academy of
Sciences of Armenia, Yerevan, Armenia.
127
0091-150X/01/3503-0127$25.00 © 2001 Plenum Publishing Corporation

128
A. Sh. Oganisyan et al.
1H NMR spectrum in C5D5N (d, ppm): 9.15 (s, 1H,
6-Oxo-8,8-dimethyl-2,3,4,7,8,10-hexahydropyrano[4¢,
NH–CO–), 7.35 – 8.20 (m, 6H, C6H5NH), 4.76 (t, 2H,
7-CH2), 4.50 (q, OCH2CH3), 2.96 (t, 2H, 4-CH2), 1.36 (t, 3H,
OCH2CH3), 1.30 (s, 6H, 5-CH3).
3¢:4,5]thieno[2,3-d]thiazino[3,2-a]pyrimidine (VII). To a
solution of 2.68 g (0.01 mole) of compound V and 1.12 g
(0.02 mole) of potassium hydroxide in 90 ml of 90% aque-
ous ethanol was added dropwise 2.02 g (0.01 mole) of
1,3-dibromopropane and the mixture was boiled for 8 h.
Upon cooling, the reaction mixture was diluted with 50 ml of
water. The precipitated crystals were separated by filtration,
washed with water, and dried to obtain 2.1 g (68.2%) of com-
pound VII; m.p., 221 – 222°C (ethanol); Rf, 0.51 (ethyl ace-
tate – chloroform, 1 : 1); C14H16N2O2S2.
1H NMR spectrum in DMSO-d6 (d, ppm): 4.66 (t, 2H,
10-CH2), 4.01 (t, 2H, 4-CH2), 3.25 (t, 2H, 2-CH2), 2.83 (t,
2H, 7-CH2), 2.25 (m, 2H, 3-CH2), 1.23 (s, 6H, 8-CH3).
6-Oxo-8,8-dimethyl-2,3,4,7,8,10-hexahydrothiopyrano-
2-(N¢-Benzoylthioureido)-3-ethoxycarbonyl-5,5-dimet
hyl-4,5-dihydro-7H-thieno[2,3-c]thiopyran (IV). Com-
pound IV was obtained by a procedure analogous to that de-
scribed above, proceeding from 2.71 g (0.01 mole) of com-
pound II [5]; yield, 3.7 g (84.6%); m.p., 193 – 195°C (etha-
nol); Rf, 0.62 (acetone – hexane, 1 : 2); C20H22N2O3S3.
1H NMR spectrum in CDCl3 (d, ppm): 9.10 (s, 1H,
NH–CO–), 7.38 – 8.0 (m, 6H, C6H5, NH), 4.52 (q, 2H
OCH2CH3), 3.78 (t, 2H, 7-CH2), 3.02 (t, 2H, 4-CH2), 1.35 (t,
3H, OCH2CH3), 1.28 (s, 6H, 5-CH3).
2-Thio-4-oxo-3,4,5,6-tetrahydro-6,6-dimethyl-8H-py-
rano[4¢,3¢:4,5]thieno[2,3-d]pyrimidine (V). A mixture of
9.18 g (0.01 mole) of compound III and 1.12 g (0.02 mole)
of potassium hydroxide in 50 ml of 50% aqueous ethanol
was boiled for 2 h. Upon cooling, the reaction mixture was
acidified with a 10% aqueous hydrochloric acid solution to
obtain a weak acid reaction. The precipitated crystals were
separated by filtration, washed with water, and dried to ob-
tain 2.6 g (96.5%) of compound V; m.p., 305 – 307°C
(butanol); Rf, 0.47 (chloroform – carbon tetrachloride, 2 : 1);
C11H12N2O2S2.
[4¢,3¢:4,5]thieno[2,3-d]thiazino[3,2-a]pyrimidine (VIII).
Compound VIII was obtained by a procedure analogous to
that described above, proceeding from 2.84 g (0.01 mole) of
compound VI; yield, 2.2 g (67.9%); m.p., 232 – 234°C (etha-
nol); Rf, 0.53 (acetone – chloroform, 1 : 2); C14H16N2OS3.
1H NMR spectrum in CDCl3 (d, ppm): 4.08 (t, 2H,
4-CH2), 3.80 (t, 2H, 10-CH2), 3.16 (t, 2H, 2-CH2), 2.90 (t,
2H, 7-CH2), 2.26 (m, 2H, 3-CH2), 1.30 (s, 6H, 8-CH3).
7-Oxo-9,9-dimethyl-2,3,4,5,8,9-hexahydro-11H-pyran
1H NMR spectrum in C5D5N (d, ppm): 13.20 (s, 1H,
NH), 12.0 (s, 3-NH), 4.65 (t, 2H, 8-CH2), 2.84 (s, 2H,
5-CH2), 1.25 (s, 6H, 6-CH3).
o[4¢,3¢:4,5]thieno[2,3-d][1,3]thiazepino[3,2-a]pyrimidine
(IX). To a solution of 2.68 g (0.01 mole) of compound V and
0.56 g (0.01 mole) of potassium hydroxide in 90 ml of 90%
aqueous ethanol were added dropwise 2.16 g (0.01 mole) of
1,4-dibromobutane and the mixture was boiled for 8 h. Upon
cooling, the reaction mixture was diluted with 50 ml of wa-
ter. The precipitated crystals were separated by filtration,
washed with water, and dried. Then the crystals were boiled
in 6 ml of DMSO for 3 h and the resulting solution was al-
lowed to stand overnight. The precipitated crystals were fil-
tered and washed with water to obtain 1.7 g (52.8%) of com-
pound IX; m.p., 340 – 342°C (ethanol); Rf, 0.52 (metha-
nol – ethyl acetate, 1 : 1); C5H18N2O2S2.
2-Thio-4-oxo-3,4,5,6-tetrahydro-6,6-dimethyl-8H-thio-
pyrano[4¢,3¢:4,5]thieno[2,3-d]pyrimidine (VI). Compound
VI was obtained by a procedure analogous to that described
above, proceeding from 4.34 g (0.01 mole) of compound IV;
yield, 2.7 g (95.0%); m.p., 312 – 314°C (ethanol); Rf, 0.50
(chloroform – carbon tetrachloride, 2 : 1); C11H12N2OS3.
1H NMR spectrum in C5D5N (d, ppm): 13.19 (s, 1H,
NH), 12.0 (s, 3-NH), 3.75 (t, 2H, 8-CH2), 2.80 (s, 2H,
5-CH2), 1.23 (s, 6H, 6-CH3).
1H NMR spectrum in CF3COOD (d, ppm): 5.10 (t, 2H,
11-CH2), 3.62 (m, 4H, 2-CH2, 5-CH2), 3.16 (t, 2H, 8-CH2),
2.16 (m, 4H, 3-CH2, 4-CH2), 1.50 (s, 6H, 9-CH3).
TABLE 1. Anticonvulsant Activity, Neurotoxicity, and Acute Tox-
icity of Compounds IX and X
7-Oxo-9,9-dimethyl-2,3,4,5,8,9-hexahydro-11H-thiop
yrano[4¢,3¢:4,5]thieno[2,3-d][1,3]thiazepino[3,2-a]pyrimi-
dine (X). Compound X was obtained by a procedure analo-
gous to that described above, proceeding from 2.84 g
(0.01 mole) of compound VI; yield, 1.7 g (50.3%); m.p.,
324 – 325°C (ethanol); Rf, 0.58 (methanol – ethyl acetate,
1 : 1); C5H18N2OS3.
1H NMR spectrum in CF3COOD (d, ppm): 3.74 (t, 2H,
11-CH2), 3.33 (m, 4H, 2-CH2, 5-CH2), 3.0 (t, 2H, 8-CH2),
1.94 (m, 4H, 3-CH2, 4-CH2), 1.35 (s, 6H, 9-CH3).
Violated
Anticora-
coordina-
tion of
Acute
Index of
protection:
TD50/ED50
Therapeutic
index:
zole activity
toxicity
Compound
movements
LD50/ED50
ED50,
TD50,
LD50,
mg/kg
mg/kg
mg/kg
IX
X
74
2150
29
93
~ 4000
2130
54.5
100
21.5
» 2000
Phenobar-
bital
12.5
46
3.7
92
7.4
Mass spectrum, m/z (Irel, %): M+ 338(56), 305(50),
295(40), 284(100), 264(20), 252(40), 251(50), 241(35),
238(10), 210(44), 192(26), 189(18), 88(40), 60(56).
Note: ED50, TD50, LD50 are the 50% effective, 50% neurotoxicity,
and 50% lethal doses, respectively.

Condensed Thienopyrimidine Derivatives: Synthesis and Anticonvulsant Activity
129
EXPERIMENTAL PHARMACOLOGICAL PART
nicotine, arecoline, or maximum electroshock; at the same
time, all the compounds showed a more or less pronounced
effect with respect to corazole-induced convulsions. The
most active substances (compounds IX and X) were inferior
to phenobarbital in anticonvulsant effect, but exceeded the
reference drug in therapeutic breadth.
The effect of compounds III – X on the clonic convul-
sion component was studied on a group of 434 white mon-
grel mice weighing 18 – 24 g. 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 electro-
shock method. In addition, we monitored the side effects
(disturbed coordination of movements) and determined the
acute daily toxicity.
REFERENCES
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The substances to be tested were introduced by
intraperitoneal injections as suspensions with Tween-80. The
injections were made 45 min before the administration of
convulsants or the electroshock induction. The reference
drug was phenobarbital. The effective dose (ED50),
neurotoxicity (TD50), and acute toxicity (LD50) values were
determined as described elsewhere [4].
2. A. P. Mkrtchyan, S. G. Kazaryan, A. S. Noravyan, et al.,
Khim.-Farm. Zh., 19(5), 557 – 560 (1985).
3. A. S. Noravyan, A. P. Mkrtchyan, I. A. Dzhagatspanyan, et al.,
Khim.-Farm. Zh., 11(8), 20 – 24 (1977).
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S. G. Kazaryan,
A. S. Noravyan,
and
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It was found that none of the tested compounds produce
a protective action with respect to convulsions induced by