434 Santagati et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 429–435
IR (cm–1): 3320 and 3270 (NH2), 1735 (C=O), 1675 (C=O); 1H
NMR (DMSO-d6): δ 3.70 (s, 3 H, OCH3), 5.55 (s, 1 H, CH), 6.05
(s, 2 H, NH2) 7.35–8.20 (m, 9 H, aromatic).
IR (cm–1): 3275 and 3190 (NH2); 1675 (br C=O); 1H NMR (DM-
SO-d6): δ 4.75 (s, 2 H, CH2), 6.05 (s, 2 H, NH2), 7.10–8.20 (m,
9 H, aromatic).
Anal. Calcd. for C19H15N3O3S2: C, 57.43; H, 3.78; N, 10.58; S
16.12. Found: C, 57.70; H, 3.50; N, 10.75; S, 16.30.
Anal. Calcd. for C18H13N3O2S2 : C, 58.85; H, 3.55; N, 11.45; S
17.45. Found: C, 59.05; H, 3.70; N, 11.65; S, 17.30.
( )-2-Methyl-2H,6H-[1]benzothieno[3Ј,2Ј:4,5]pyrimido[2,1-b]-
[1,3,4]thiadiazin-3,6-(4H)-dione 7 a
3-Phenyl-2H,6H-[1]benzothieno[3Ј,2Ј:4,5]pyrimido[2,1-
b][1,3,4]thiadiazin-6-one 10
A suspension of methyl ester 6 a (0.39 g, 1.2 mmol) in a solution
of NaOH (50 mg, 1.2 mmol) in methanol (10 mL) and water
(2 mL) was stirred at room temperature for 24 h; the mixture
was poured into water (100 mL) and filtered: by acidification of
the resulting solution with conc.HCl to pH 4–5 a white solid sep-
arated; this solid was collected, washed with water, dried, and
recrystallized from dioxane/water to give the dione 7 a as a
white amorphous powder (0.29 g, 0.96 mmol, 80 %); m.p. 263–
265 °C dec.
To a refluxing suspension of derivative 9 (0.30 g, 0.85 mmol) in
ethanol (25 mL) p-toluenesulfonic acid monohydrate (p-TSA)
(50 mg) was added.The mixture was refluxed for 1.5 h and then
cooled to room temperature.The resulting solid was collected,
washed with warm ethanol, dried, and recrystallized from diox-
ane/ethanol to give the phenyl derivative 10 as yellow micro-
crystals (0.22 g, 0.64 mmol, 75 %); m.p. 248–250 °C dec.;
1
IR (cm–1): 1680 (C=O); H NMR (DMSO-d6): δ 4.40 (s, 2 H,
CH2), 7.55–8.20 (m, 9 H, aromatic).
IR (cm–1):3180 (br.NH), 1690 (br.C=O); 1H NMR (DMSO-d6):δ
1.45 (d, J = 7.2 Hz, 3 H, CH3), 4.30 (q, J = 7.2 Hz, 1 H, CH),
7.55–8.25 (m, 4 H, aromatic), 12.05 (br s, 1 H, NH).
Anal. Calcd. for C18H11N3OS2 : C, 61.90; H, 3.15; N, 12.00; S
18.30. Found: C, 61.80; H, 3.00; N, 11.90; S, 18.45.
( )-2-[(3-Amino-3,4-dihydro-4-oxo-[1]benzothieno[3,2-d]pyrimi-
din-2-yl)thio]-propionic acid 11 a
Anal. Calcd. for C13H9N3O2S2: C, 51.48; H, 2.75; N, 13.85; S
21.10 Found: C, 51.70; H, 2.65; N, 13.70; S, 21.30.
A mixture of amino-thioxo derivative 4 (0.25 g, 1.0 mmol), 2-
bromopropionic acid (0.1 mL, 99.0 %, d = 1.7), triethylamine
(0.3 mL) in tetrahydrofuran (THF) (20 mL) was stirred at room
temperature for 48 h.The resulting mixture was treated with 5 %
NaHCO3 solution and after filtration, the resulting solution was
acidified with conc. HCl to pH 5–6; a white solid separated it
was collected, washed with water, and dried to give the acid de-
rivative 11 a as an amorphous solid (0.16 g, 5 mmol, 50 %); tlc
pure; m.p. 260–263 °C dec.
( )-2-Phenyl-2H,6H-[1]benzothieno[3Ј,2Ј:4,5]pyrimido[2,1-b]-
[1,3,4]thiadiazin-3,6-(4H)-dione 7 b
A suspension of methyl ester 6 b (0.47 g, 1.2 mmol) in a solu-
tion of NaOH (50 mg, 1.2 mmol) in methanol (10 mL) and water
(2 mL) was stirred at room temperature for 24 h; the mixture
was poured into water (100 mL) and then filtered; by acidifica-
tion of the resulting solution with conc. HCl to pH 4–5 a white
solid separated; this solid was collected, washed with water,
dried, and recrystallized from dioxane/water to yield the dione
7 b as a white amorphous powder (0.32 g, 0.88 mmol, 73 %);
m.p. 285–88 °C dec.
IR (cm–1): 3305 and 3190 (NH2); 1680 and 1660 (C=O); ); 1H
NMR (DMSO-d6): δ 1.60 (d, J = 7.6, 3 H, CH3), 4.33 (q, J = 7.6,
1 H, CH), 6.00 (s, 2 H, NH2) 7.54–8.23 (m, 4 H, aromatic).
IR (cm–1): 3200 (br NH), 1685 (br C=O); 1H NMR (DMSO-d6): δ
5.60, (s, 1 H, CH), 7.30–8.20 (m, 9 H, aromatic), 12.50 (s, 1 H,
NH).
Anal. Calcd. for C13H11N3O3S2: C, 48.60; H, 3.45; N, 13.10; S
19.95. Found: C, 48.55; H, 3.70; N, 12.90; S, 19.75.
( )-α-[(3-Amino-3,4-dihydro-4-oxo-[1]benzothieno[3,2-d]pyrimi-
din-2-yl)thio]-phenylacetic acid 11 b
Anal. Calcd. for C18H11N3O2S2: C, 59.17; H, 3.10; N, 11.50; S
17.55. Found: C, 59.45; H, 3.35; N, 11.70; S, 17.50.
A mixture of amino-thioxo 4 (0.37 g, 1.5 mmol), α-bromo-phe-
nylacetic acid (0.32 g, 1.5 mmol), triethylamine (0.2 mL) in tet-
rahydrofuran (THF) (20 mL) was stirred at room temperature for
2 days;the mixture was treated with 5 % NaHCO3 (50 mL);after
filtration the resulting solution was acidified with conc. HCl to
pH 5–6.The separating solid was collected, washed with water,
and dried to give the acid derivative 11 a as a white amorphous
powder (0.17 g, 4.5 mmol, 30 %); tlc pure; m.p. >235 °C dec.
3-Methyl-2H,6H-[1]benzothieno[3Ј,2Ј:4,5]pyrimido[2,1-b]-
[1,3,4]thiadiazin-6-one 8
A mixture of potassium salt 3 (0.37 g, 1.3 mmol) and chloroace-
tone (0.15 mL, 96 %, d = 1.16) in ethanol (20 mL) was refluxed
for 2 h and then cooled to room temperature; the resulting pre-
cipitate was collected, washed with water, dried, and crystal-
lized from ethanol to give the methyl derivative 8 as pale yellow
needles (0.19 g, 0.65 mmol, 50 %); m.p. 258–261 °C dec.
IR (cm–1): 3310 and 3190 (NH2); 1710 and 1675 (C=O); ); 1H
NMR (DMSO-d6): δ 5.45 (s, 1 H, CH), 6.05 (s, 2 H, NH2) 7.30–
8.30 (m, 9 H, aromatic).
1
IR (cm–1): 1685 (C=O); H NMR (DMSO-d6): δ 2.40 (s, 3 H,
CH3), 3.85 (s, 2 H, CH2), 7.55–8.20 (m, 4 H, aromatic).
Anal. Calcd. for C13H9N3OS2 : C, 54.35; H, 3.15; N, 14.65; S
22.30 Found: C, 54.45; H, 3.05; N, 14.45; S, 22.30.
Anal. Calcd. for C18H13N3O3S2 : C, 56.40; H, 3.40; N, 10.95; S
16.70. Found: C, 56.55; H, 3.70; N, 10.90; S, 16.45.
3-Amino-2-[(2-phenyl-2-oxo-ethyl)thio][1]benzothieno[3,2-d]-
pyrimidin-4(1H)-one 9
Pharmacology
Subjects
A mixture of potassium salt 3 (0.37 g, 1.3 mmol) and of 2-bro-
moacetophenone (0.26 g, 1.3 mmol) in ethanol (30 mL) was
stirred at room temperature for 2 h. The resulting mixture was
poured into water (300 mL); the solid separated was collected
after 24 h, dried,and crystallized from ethanol/water to give
compound 9 as pale yellow powder (0.37 g, 1.04 mmol, 80 %);
m.p. 232–235 °C dec.
Healthy volunteers (aged 27–32) were asked to consent to the
drawing of blood from their peripheral veins and to take aspirin.
The study protocol was in a accordance with the Italian laws
(D.L.116/92, art. 5).
Peripheral venous blood samples were drawn at 10 am, before
and 48 h after the oral administration of 300 mg of aspirin.The
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim