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4.1.7. N-(4-Phenyl-2-thioxothiazol-3-yl)-
N0-thiazol-2-yl-malonamide (12)
(2s, 2H, 2 NH, exchangeable with D2O); EIMS: m/z (%) 468
(Mþ, 8) and at 299 (100, base peak).
A mixture of potassium salt of compound 11 (0.63 g,
2 mmol) and phenacyl bromide (0.4 g, 2 mmol) in ethanol
(20 mL) was heated under reflux for 3 h. The formed solid
was collected by filtration, washed with ethanol, dried and
crystallized from methanol to give the corresponding thiazole
derivative 12. IR (KBr, n, cmꢀ1): 1043 (C]S), 1688 (C]O,
amide), 3188 (NH); 1H NMR (DMSO-d6, 270 MHz)
d (ppm): 3.34 (s, 2H, CH2), 6.98 (d, 1H, J4,5 ¼ 7.78 Hz, thia-
zole-H), 7.08 (d, 1H, J4,5 ¼ 7.76 Hz, thiazole-H), 7.26e7.44
(m, 5H, Ar-H), 8.18 (s, 1H, CH), 10.12 (s, 1H, NH, exchange-
able with D2O), 11.28 (s, 1H, NH, exchangeable with D2O);
EIMS: m/z (%) 378 (Mþ, 10) and at 341 (100, base peak).
4.1.11. Synthesis of bis-imide derivatives 16 and 17
A mixture of compound 10 (0.4 g, 2 mmol) and dianhy-
drides, namely, 1,2,4,5-benzenetetracarboxylic acid dianhy-
dride and 1,4,5,8-naphthalenetetracarboxylic acid dianhydride
(1 mmol) in glacial acetic acid (50 mL) was heated under reflux
for 6 h. The obtained solid was filtered off and crystallized to
yield the corresponding bis-imide derivatives 16 and 17.
4.1.11.1. N-{1,3,5,7-Tetraoxo-6-[2-(thiazol-2-ylcarbamoyl)a-
cetylamino]-3,5,6,7-tetrahydro-1H-pyrrolo[3,4-f]isoindol-2-
yl}-N0-thiazol-2-yl-malonamide (16). IR (KBr, n, cmꢀ1),
1678 (C]O, amide), 1739 (C]O, ring), 3163 (NH); 1H
NMR (DMSO-d6, 270 MHz) d (ppm): 3.78 (s, 2H, CH2),
7.08 (d, 1H, J4,5 ¼ 7.78 Hz, thiazole-H), 7.16 (d, 1H,
J5,4 ¼ 7.80 Hz, thiazole-H), 7.86 (s, 2H, Ar-H), 10.90,
11.15 (2s, 4NH, exchangeable with D2O); EIMS: m/z (%)
582 (Mþ, 22) and at 386 (100, base peak).
4.1.8.
4-(4-Bromophenyl)-5-{[2-(thiazol-2-ylcarbamoyl)-
acetyl]-hydrazono}-4,5-dihydro[1,3,4]-thiadiazole-2-
carboxylic acid ethyl ester (13)
To a solution of potassium salt of compound 11 (0.63 g,
2 mmol) in ethanol (20 mL), ethyl 2-[2-(4-bromo-phenyl)hydra-
zono]-2-chloroacetate (0.61 g, 2 mmol) was added. The reaction
mixturewas heated under reflux for4 h; after cooling, theprecip-
itated solid was collected by filtration, washed with ethanol and
crystallized from ethanol to afford compound 13. IR (KBr, n,
4.1.11.2. N-{1,3,6,8-Tetraoxo-7-[2-(thiazol-2-ylcarbamoyl)-
acetylamino]-3,6,7,8-tetrahydro-1H-benzo[lmn][3,8]phenan-
throlin-2-yl}-N0-thiazol-2-yl-malonamide (17). IR (KBr, n,
cmꢀ1): 1686 (C]O, amide), 1732 (C]O, ring), 3279
(NH); 1H NMR (DMSO-d6, 270 MHz) d (ppm): 3.78 (s,
2H, CH2), 7.08 (d, 1H, J4,5 ¼ 7.76 Hz, thiazole-H), 7.16 (d,
1H, J5,4 ¼ 7.75 Hz, thiazole-H), 7.46e7.88 (m, 4H, Ar-H),
10.94, 11.10 (2s, 4NH, exchangeable with D2O); EIMS: m/
z (%) 632 (Mþ, 14) and at 186 (100, base peak).
1
cmꢀ1): 1634 (C]O, amide), 1678 (C]O), 3168 (NH); H
NMR (DMSO-d6, 270 MHz) d (ppm): 1.20 (t, 3H, CH3), 3.37
(s, 2H, CH2), 4.18 (q, 2H, CH2), 3.37 (s, 2H, CH2), 7.18 (d,
1H, J4,5 ¼ 7.76 Hz, thiazole-H), 7.25 (d, 1H, J4,5 ¼ 7.75 Hz, thi-
azole-H), 7.38 (d, 2H, J ¼ 7.78 Hz, Ar-H), 7.54 (d, 2H,
J ¼ 7.79 Hz, Ar-H), 10.94, 11.31 (2s, 2H, 2NH, exchangeable
with D2O); EIMS: m/z (%) 511 (Mþ, 14) and at 386 (100, base
peak).
4.2. Pharmacological activity
4.1.9. 2-[5-Acetyl-3-(4-sulfamoyl-phenyl)-
4.2.1. Antiarrhythmic activity [29e34]
3H-[1,3,4]thiadiazol-2-ylidenehydrazinocarbonyl]-
N-thiazol-2-yl-acetamide (14)
4.2.1.1. Purpose and rational. The plant alkaloid aconitine
persistently activates sodium channel. Infusion of aconitine
into the anesthetized rat causes ventricular arrhythmias. Drugs
that are considered to have antiarrhythmic properties can be
tested in aconitine-intoxicated rats.
A mixture of potassium salt of compound 11 (0.63 g, 2 mmol)
and 1-[(2-p-sulfonamido-phenyl)-hydrazono]-1-chloropropan-2-
one (0.55 g, 2 mmol) in ethanol (20 mL) was refluxed for 1 h.
The formed solid was filtered off, dried and crystallized from meth-
anol to afford compound 14. IR(KBr, n, cmꢀ1): 1330 (S]O), 1667
(C]O, amide), 1685 (C]O), 3232, 3208 (NH2); 1H NMR
(DMSO-d6, 270 MHz) d (ppm): 2.61 (s, 3H, CH3), 3.70 (s, 2H,
CH2), 7.10 (d, 1H, J4,5 ¼ 8.21 Hz, thiazole-H), 7.21 (d, 1H,
J4,5 ¼ 8.18 Hz, thiazole-H), 7.62 (d, 2H, J ¼ 7.84 Hz, Ar-H),
7.86 (d, 2H, J ¼ 7.82 Hz, Ar-H), 10.90 (s, 1H, NH, exchangeable
with D2O), 11.18 (s, 1H, NH), 12.29 (s, 2H, NH2, exchangeable
with D2O); EIMS: m/z(%)481(Mþ, 4) andat 236 (100, base peak).
4.2.1.2. Procedure. Male Ivanovas rats weighing 300e350 g
are used. The animals are anesthetized by intraperitoneal injec-
tion of 1.25 g/kg urethane: 5 mg/kg aconitine dissolved in 0.1 N
HNO3 is administered by continuous infusion into the saphe-
nous vein (0.1 mL/min) and the electrocardiogram (ECG) in
lead II is recorded every 30 s. The test compound is injected
i.v. at a screening dose of 3 mg/kg, 5 min before the start of
the aconitine infusion; 24 animals are used per compound.
4.1.10. N-(4,5,6,7-Tetrachloro-1,3-dioxo-1,3-dihydro-isoin
dol-2-yl)-N0-thiazol-2-yl-malonamide (15)
4.2.1.3. Evaluation. The antiarrhythmic effect of a test com-
pound is measured by the amount of aconitine/100 g of ani-
mal. (Duration of infusion) which induces.
Compound 15 was synthesized by using the same proce-
dure of synthesis of derivative 9 but using compound 10 as
a starting material. IR (KBr, n, cmꢀ1): 1671 (C]O), 1742
1
(C]O, ring), 3230 (NH); H NMR (DMSO-d6, 270 MHz)
d (ppm): 3.84 (s, 2H, CH2), 7.22 (d, 1H, J4,5 ¼ 7.54 Hz, thia-
e Ventricular extra systoles.
e Ventricular tachycardia.
e Ventricular fibrillation.
zole-H), 7.26 (d, 1H, J5,4 ¼ 7.55 Hz, thiazole-H), 10.38, 11.15