1006
A.C. Cunha et al. / Il Farmaco 57 (2002) 999ꢁ1007
/
patterns are as follows: s, singlet; d, doublet; dd, double
doublet; br, broad; m, multiplet. 13C NMR was
determined using the same spectrometer described above
at 50 MHz, using deuterated Me2SO as internal
standard. IR spectra were obtained using a Bruker
IFS66 spectrophotometer by using KBr plates. Micro-
vacuum. The imidazolylhydrazone derivates 3aꢁ
purified in column flash chromatography using 50% n-
C6H14ꢁEtOAc as eluent (Tables 3 and 4).
/
o were
/
4.2. Pharmacology
analysis data was obtained using a Perkinꢁ
analyzer, using a PerkinꢁElmer AD-4 balance.
The progress of all reactions was monitored by TLC
performed on 2.0ꢄ
6.0 cm2 aluminum sheets precoated
/
Elmer 240
4.2.1. Analgesic activity
The analgesic activity was determined in vivo by using
abdominal constriction test induced by acetic acid 0.6%
/
/
(0.1 ml/10g) in mice [11]. Albino mice of both sexes (18ꢁ
/
with silica gel 60 (HF-254, E. Merck) to a thickness of
0.25 mm. The developed chromatograms were viewed
under ultraviolet light at 254 nm. For column chroma-
23 g) were used. Compounds were administered orally
(100 mmol/kg; 0.1 ml/20 g) as a suspension in 5% arabic
gum in saline (vehicle). Dipyrone (100 mmol/kg) was
used as the standard drug under same conditions. Acetic
acid solution was administered i.p. One hour after
tography E. Merck silica gel (60ꢁ
The N-substituted 5-chloro-2-(dimethylamino)imida-
zole-4-carboxaldehydes 5aꢁe were prepared by known
/200 mesh) was used.
/
administration of the NAH compounds 3aꢁo. Ten
/
procedure in the literature [9].
minutes after i.p. injection of the acetic acid solution,
the number of constrictions per animal was recorded for
20 min. Control animals received on equal volume of
vehicle. Analgesic activity was expressed as percentage
of inhibition of constrictions when compared with the
vehicle control group. Results are expressed as the
4.1.1. General procedure for the preparation of methyl N-
substituted 5-chloro-2-(dimethylamino)imidazole-4-
carboxylate (6aꢁ
To a mixture of 1.45 mmol of N-substituted 5-chloro-
2-(dimethylamino)imidazole-4-carboxaldehydes 5aꢁe in
/
e)
/
mean9
statistically analyzed by Student’s t-test for significance
level of ꢀr B0.05.
/
SEM of n animals per group. The data were
methanol (18 ml), and 0.35 g (7.14 mmol) of NaCN,
activated MnO2 1.60g (18.4 mmol) was added. The
reaction was stirred at room temperature for 12 h and
then the suspension was filtered through Celite† and
/
4.2.2. Antiinflammatory activity
treated with CH2Cl2 (3ꢄ
were joined, dried over anhydrous Na2SO4, filtered and
evaporated under reduced pressure to furnish crude
/
20 ml). The organic layers
The antiinflammatory activity was determined in vivo
using the carrageenan induced rat paw edema test
according to Pereira and coworkers [12]. Albino rats
methyl esters 6aꢁ
chromatography using 80% n-C6H14ꢁ
(see Table 1).
/
e, which were purified by flash column
of both sexes (150ꢁ200 g) were used. Compounds were
/
/EtOAc as eluent
administered orally 100 mmol/kg (0.1 ml/20g) as a
suspension in 5% arabic gum in saline (vehicle). Control
animals received on equal volume of the vehicle. One
hour after, the animals were then injected with either 0.1
ml of 1% carrageenan solution in saline (0.1 mg/paw)
and sterile saline (NaCl 0.9%), into the subplantar
surface of one of the hind paws, respectively. The paw
volumes were measured using a glass plethysmometer
coupled to a peristaltic pump, 3 h after the subplantar
injection. The edema was calculated as the volume
variation between the carrageenan and saline-treated
paw. Indomethacin (100 mmol/kg) and was used as
standard in the same conditions. Antiinflammatory
activity was expressed as percentage of inhibition of
the edema when compared with vehicle control group.
4.1.2. General procedure for preparation of the N-
substituted-phenylimidazolyl-4-carbohydrazide
derivatives (7aꢁ
A solution the appropriate methyl ester derivates 6aꢁ
e (3.41 mmol) and 3.2 ml of 80% hydrazine monohy-
drate in 16 ml of EtOH, was stirred at reflux for 8ꢁ10 h.
/
e)
/
/
After this time, the reaction mixture was concentrated
under reduced pressure and the colored solid formed
was collected by filtration, washed with cold water and
dried under vacuum to give the desired imidazolyl
hydrazides 7aꢁe, as showed in Table 1.
/
4.1.3. General procedure for the preparation of the N-
substituted-phenylimidazolyl-4-acylhydrazone derivatives
Results are expressed as the mean9
per group. The data were statistically analyzed by
Student’s t-test for significance level of ꢀr B0.05.
/
SEM of n animals
(3aꢁ
/
o)
/
To a solution of hydrazide derivatives 7aꢁ
/
e (0.50
mmol) in 15 ml of EtOH, was added an equimolar
amount of the appropriates aromatic aldehydes in the
presence catalytic amount of 37% aqueous HCl. The
reaction was stirred for 2 h, at reflux. Then, solvent was
evaporated and the colored precipitate was collected by
filtration, washed with cold water and dried under
Acknowledgements
Thanks are due to CNPq (grant 52.0033/96-5, BR.),
FAPERJ (BR.), UJB (BR.) for financial support and
fellowships (ACC, EJB and CAMF). We also thank the
Cunha, Anna C
