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L. Labanauskas et al. / IL FARMACO 59 (2004) 255–259
precipitate was filtered off and recrystallized from
2-propanol.
boxymethylcellulose solution. Right hind-paw volume was
measured with an electronic onkograph immediately before
and 1, 2, 3 and 5 h after the carrageenin injection. The
increase of results was matched with that of control rats.
Each experiment was made with five groups of rats, 10 ani-
mals each (the 1st one was control).
3.1.3. 5-Butylsulfanyl-3-(2-,3-, and 4-methoxyphenyl)-1H-
1,2,4-triazoles (5a–c)
A mixture of 0.01 mol 3-(2-,3- or 4-methoxyphenyl)-4,5-
dihydro-1H-1,2,4-triazole-5-thione (3a–c) and 0.4 g (0.0105
mol) NaOH was dissolved in 20 ml 50% aqueous 2-propanol,
then 2.0 g (0.011 mol) of 1-iodobutane was added. The
reaction mixture was refluxed 15 h, 2-propanol was evapo-
rated in vacuo. Product was extracted with trichloromethane
and recrystallized from hexane.
3.2.2. Bentonite test
Bentonite-induced hind-paw edema was studied analo-
gously [9]. Bentonite suspension (5% in sterile 0.9% NaCl
solution) in a volume of 0.1 ml was injected subcutaneously
into the subplantar region of the left hind paw 1 h after the
administration of the test compound. Control animals re-
ceived only 0.5% carboxymethylcellulose solution. Left
hind-paw volume was measured with an electronic onko-
graph immediately before and 1, 2, 3 and 5 h after the
carrageenin injection. The increase of results was matched
with that of control rats. Each experiment was made with five
groups of rats, 10 animals each (the 1st one was control).
3.1.4. 1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-[3-(2-,3-
and
ethanones (6a–c), 1-(1,3-Benzodioxol-5-yl)-, 1-(2,3-
dihydro-1,4-benzodioxin-6-yl)- and 1-(3,4-dihydro-
4-methoxyphenyl)-1H-1,2,4-triazol-5-ylsulfanyl]-1-
2H-1,5-benzodioxepin-7-yl)-2-[5-(2-,3- and 4-methoxy-
phenyl)-4-phenyl-4H-1,2,4-triazol-3-ylsulfanyl]-1-ethanones
(7a–c, 8a–c, 9a–c)
3.2.3. Acute toxicity
To a solution of 0.01 mol sodium salts of 3-(2-,3- and
4-methoxyphenyl)-4,5-dihydro-1H-1,2,4-triazole-5-thiones
(3a–c) or 3-(2-,3- and 4-methoxyphenyl)-4-phenyl-4,5-
dihydro-1H-1,2,4-triazole-5-thiones (4a–c) prepared from
0.01 mol 3a–c or 4a–c in the sodium methoxide solution
(0.23 g (0.01 mol) sodium in 20 ml methanol) was added
0.01 mol of 1-(1,3-benzodioxol-5-yl)-2-bromo-1-ethanone,
2-bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-ethanone
or 2-bromo-1-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-1-
ethanone and refluxed 20 h. Reaction mixture was poured
into 200 ml water, acidified with hydrochloric acid to pH
4 and extracted with trichloromethane. Extract was dried
over sodium sulfate and evaporated in vacuo. Obtained prod-
uct was recrystallized from ethanol.
The tests of acute toxicity of the compounds were done on
mice fasted for 24 h, water ad libitum. Groups of six mice
were treated perorally with the test compound at various dose
levels. The animals were watched for mortality and symp-
4. Results and discussion
Anti-inflammatory activity was studied using
carrageenin- and bentonite-induced paw edema in rats. The
inhibition of edema was evaluated by the comparison of paw
volume measured with an electronic onkograph immediately
before and 1, 2, 3 and 5 h after the injection of carrageenin or
bentonite. Obtained data are given as an arithmetical means
of measurements (Table 2). Acetylsalicylic acid and ibupro-
fen were used as a reference drugs. Only compound 9a
possess week anti-inflammatory activity. Compounds 4b, 6a,
7c, 8b and 9c possess the anti-inflammatory activity compa-
rable with that of acetylsalicylic acid or higher and the
compounds 4a,c, 5a, 6b possess the anti-inflammatory activ-
ity comparable with that of ibuprofen. Compounds 7a,b are
significantly more active than ibuprofen. The difference of
anti-inflammatory activity of synthesized compounds was
too small to make any founded conclusions about the influ-
ence of any substituent.
In spite of our previous results [3] and prognosis, the
S-alkylation of 3-(2-,3- and 4-methoxyphenyl)-1H-1,2,4-
triazole-5-thiones (4a–c) did not enhanced their activity. The
activity of 4a–c and their S-alkylderivatives 6a–c, 7a–c and
8a–c lies in the same range both by carrageenin and bentonite
tests.
The influence of phenyl group in 4th position of 1,2,4-
triazole ring can not be evaluated exactly as well. The anti-
inflammatory activity of 2- and 4-methoxyphenylderivatives
3.2. Pharmacology
Adult male Wistar strain rats weighing 180–220 g and
male BALB/C strain mice weighing 18–22 g were used. The
animals were allowed food and water ad libitum. They were
housed in rooms at 18–20 °C with a 12 h light/dark cycle and
relative humidity of 55–60%. The animals were randomly
allocated into groups at the beginning of all the experiments.
All test compounds and the reference drugs were adminis-
tered orally suspended in 0.5% carboxymethylcellulose solu-
tion. The data for activity and toxicity were evaluated statis-
tically using Student’s t-test. A level of P < 0.05 was adopted
for the test of significance.
3.2.1. Carrageenin test
Carrageenin-induced hind-paw edema in rats was pro-
duced by the method of Winter et al. [8]. Carrageenin solu-
tion (1.0% in sterile 0.9% NaCl solution) in a volume of
0.1 ml was injected subcutaneously into the subplantar re-
gion of the right hind paw 1 h after the administration of the
test compound. Control animals received only 0.5% car-
Labanauskas
