G. Turan-Zitouni et al. / Il Farmaco 54 (1999) 218–223
221
3.2.5. (5,6,7,8-Tetrahydronaphthalen-2-yl)oxyacetic
acid hydrazide (6)
thalene), 2.6 (4H, br s, C5 and C8 protons of tetrahy-
dronaphthalene), 4.85 (2H, s, OCH2), 6.45 (1H, d
(J=2.38 Hz), C1 proton of tetrahydronaphthalene),
6.5 (1H, dd (J=8.29 and 2.58 Hz) C3 proton of
tetrahydronaphthalene) 6.85 (1H, d (J=8.30) C4 pro-
ton of tetrahydronaphthalene) 7.3–7.6 (5H, m, aro-
matic protons), 14 (1H, br, NH); MS(FAB+): M+1:
m/z 338.
To prepare ethyl, (5,6,7,8-tetrahydronaphthalen-2-
yl)oxyacetate, a mixture of acid 1 (0.3 mol) and 6 ml
of concentrated sulfuric acid in 300 ml of anhydrous
ethanol was refluxed for 6 h. The reaction mixture
was concentrated under reduced pressure and upon
cooling, extracted with ether. A solution of this ester
(0.25 mol) and hydrazine hydrate (99%, 0.40 mol) in
100 ml of ethanol was refluxed for 2 h. The excess of
ethanol was removed under reduced pressure. The
concentrated solution, on cooling, gave a solid mass
of 6 which was filtered, dried and recrystallized from
ethanol, m.p. 132°C.
3.2.8. 3-[(5,6,7,8-Tetrahydronaphthalen-2-yl)oxy-
methyl]-4-phenyl-5-phenacyl (or p-chlorophenacyl)
thio-1,2,4-triazole (9a–b)
A mixture of phenacyl chloride (0.015 mol), triazole
8 (0.015 mol) and anhydrous potassium carbonate
(0.018 mol) in acetone (60 ml) was refluxed for 4–5
h. The reaction mixture was filtered and an excess of
acetone was removed under reduced pressure to give
9a–b. Finally the crude products were recrystallized
from ethanol.
IR (KBr, cm−1): 3340 (NH2), 3200 (NH), 1660
(CꢀO), 1225–1000 (C–O–C); 1H NMR (250 MHz),
(DMSO-d6, l (ppm)): 1.6 (4H, br s, C6 and C7 pro-
tons of tetrahydronaphthalene), 2.6 (4H, br s, C5 and
C8 protons of tetrahydronaphthalene), 5.1 (2H, s,
OCH2), 6.3 (1H, br, NH), 6.45–6.60 (2H, m, C1, C3
protons of tetrahydronaphthalene), 6.85 (1H, d (J=
8.28 Hz) C4 proton of tetrahydronaphthalene) 7.4–8.0
(5H, m, aromatic protons).
9a: IR (KBr, cm−1): 1620 (CꢀN), 1225–1000 (C–
O–C); 1H NMR (250 MHz), (DMSO-d6, l (ppm)):
1.60 (4H, br s, C6 and C7 protons of tetrahydronaph-
thalene), 2.6 (4H, br s, C5 and C8 protons of tetrahy-
dronaphthalene), 4.93 (2H, s, SCH2), 4.98 (2H, s,
OCH2), 6.45–6.60 (2H, m, C1, C3 protons of tetrahy-
dronaphthalene), 6.85 (1H, d (J=8.18 Hz) C4 proton
of tetrahydronaphthalene), 7.40–8.05 (10H, m, aro-
matic protons); MS(FAB+): M+1: m/z 456.
9b: IR (KBr, cm−1): 1610 (CꢀN), 1225–1009 (C–
O–C); 1H NMR (250 MHz), (DMSO-d6, l (ppm)):
1.65 (4H, br s, C6 and C7 protons of tetrahydronaph-
thalene), 2.6–2.7 (4H, br s, C5 and C8 protons of
tetrahydronaphthalene), 4.85 (2H, s, SCH2), 5.00 (2H,
s, OCH2), 6.4–6.6 (2H, m, C1 and C3 protons of
tetrahydronaphthalene), 6.80 (1H, d (J=8.19 Hz) C4
proton of tetrahydronaphthalene) 7.35–7.50 (5H, m,
aromatic protons), 7.55 (2H, d (J=8.62 Hz), C3 and
C5 phenacyl protons), 8.00 (2H, d (J=9.02 Hz) C2
and C6 phenacyl protons); MS(FAB+): M+1: m/z
491.
3.2.6. 1-[(5,6,7,8-Tetrahydronaphthalen-2-yl)oxy-
acetyl]-4-phenyl-3-thiosemicarbazide (7)
To a solution of the acid hydrazide 6 (0.01 mol) in
hot ethanol (40 ml) was added an equivalent amount
of the phenylisothiocyanate in ethanol (10 ml) and
the mixture was refluxed for 1 h. The solid separated
upon cooling was filtered, washed with ethanol, dried
and recrystallized from ethanol, m.p. 148°C.
IR (KBr, cm−1): 3330, 3180 (NH), 1640 (CꢀO),
1
1225–1000 (C–O–C); H NMR (250 MHz), (DMSO-
d6, l (ppm)): 1.55 (4H, br s, C6 and C7 protons of
tetrahydronaphthalene), 2.5 (4H, br s, C5 and C8 pro-
tons of tetrahydronaphthalene), 5.2 (2H, s, OCH2),
6.45–6.65 (2H, m, C1, C3 protons of tetrahydronaph-
thalene), 6.85 (1H, d (J=8.18 Hz) C4 proton of te-
trahydronaphthalene) 7.2–7.6 (5H, m, aromatic
protons), 7.9 (1H, br, CSNH), 9.40 and 10.65 (1H
and 1H, br, NHCS and CONH, respectively).
3.3. Biological acti6ity
Compounds 5a–e were screened for analgesic activ-
ity. To test for analgesic activity, the acetic acid test
(Modified Koster Test) [16] was performed in male
albino mice (25–30 g). Aspirin was used as the refer-
ence analgesic agent. The substances were dissolved in
DMSO and water (1:1) (dose: 50 mg/kg) and were
given orally at a 0.3 ml volume to the animals using
a stomach tube. Each group (control, aspirin and
substances (5a–e)) included five mice. Some 60 min
after drug administration, 0.6% acetic acid solution
was injected i.p. (60 mg/kg). Then, each control
group of mice was given the same amount of DMSO/
water orally. Mean stretching numbers were recorded
5 min after the injection of acetic acid solution. Per-
3.2.7. 3-[(5,6,7,8-Tetrahydronaphthalen-2-yl)oxy-
methyl]-4-phenyl-5-mercapto-1,2,4-triazole (8)
Substituted thiosemicarbazide 7 (0.0175 mol) was
dissolved in 2 N NaOH (50 ml) and the resulting
solution was refluxed for 2–3 h. After cooling, the
reaction mixture was filtered and the filtrate was aci-
dified with dilute hydrochloric acid until complete
precipitation occurred. The solid mass which precipi-
tated out was filtered, washed with water, dried and
recrystallized from ethanol, m.p. 173°C.
IR (KBr, cm−1): 1620 (CꢀN), 1225–1000 (C–O–
1
C); H NMR (250 MHz), (DMSO-d6, l (ppm)): 1.60
(4H, br s, C6 and C7 protons of tetrahydronaph-