Synthesis and antinociceptive profile of novel acidic sulphonylhydrazone derivatives from natural safrole

Article abstract of DOI:10.1211/146080899128734370

The synthesis and antinociceptive activity of new sulphonylhydrazone derivatives is described. The synthetic route started from safrole, an abundant Brazilian natural product which occurs in sassafras oil (Ocotea pretiosa). The active compounds were obtai

Full text of DOI:10.1211/146080899128734370

Pharm. Pharmacol. Commun. 1999, 5: 673±678
Received August 26, 1999
Accepted October 28, 1999
# 1999 Pharm. Pharmacol. Commun.
Synthesis and Antinociceptive Pro®le of Novel Acidic
Sulphonylhydrazone Derivatives From Natural Safrole
Â
LIDIA M. LIMA*{, EMANUEL G. AMARANTE*, ANA L. P. MIRANDA*, CARLOS A. M. FRAGA*{
AND ELIEZER J. BARREIRO*{
*
Laborat o rio de Avalia cË aÄ o e S Âõ ntese de Subst aà ncias Bioativas Faculdade de Farm a cia and
Departamento de Qu Âõ mica Org aà nica, Instituto de Qu Âõ mica, Universidade Federal do Rio de Janeiro,
{
Rio de Janeiro, RJ, Brazil
Abstract
The synthesis and antinociceptive activity of new sulphonylhydrazone derivatives is
described.
The synthetic route started from safrole, an abundant Brazilian natural product which
occurs in sassafras oil (Ocotea pretiosa). The active compounds were obtained by
introducing an acidic moiety in the phenyl ring of the sulphonylhydrazone framework.
The compounds were tested for analgesic and anti-in¯ammatory activity in the acetic acid-
induced abdominal constriction and carrageenan-induced rat paw oedema tests, respec-
0
tively. The most active analgesic was (4 -carboxybenzylidene) 6-methyl-3,4-methylene-
dioxyphenylsulphonylhydrazide which was approximately 1Á5-fold more potent than the
standard dipyrone (52Á4 vs 35Á9% inhibition, respectively). The most active anti-in¯am-
0
matory was the phenol compound (4 -hydroxy-3,5-ditert-butylbenzylidene) 6-methyl-3,4-
methylenedioxyphenylsulphonylhydrazide (30% inhibition).
The introduction of an acidic substituent in the phenyl ring of the sulphonylhydrazone
moiety led to new lead compounds from safrole with analgesic and anti-in¯ammatory
activity.
As part of a research programme aimed at identi-
fying new lead compounds with antinociceptive
activity, we previously reported the analgesic pro-
nociceptive pro®le of the active compounds 1 and 2
by introducing structural modi®cations. An acidic
substituent was introduced in the aza-benzylidene
moiety of the hydrazone function to give the new
sulphonylhydrazone derivatives (5a±e) (Figure 1).
®
le of a series of new acylhydrazone derivatives
(
1a±c) and sulphonylhydrazone isosteres (2a±c)
Figure 1; Lima et al 1999). Compound 1c was
(
equipotent to the standard indomethacin, at a con-
centration of 100 mM kg
�
1
in the acetic acid-
Material and Methods
induced abdominal constriction test in mice. The
sulphonyl bioisoster, 2c, at the same concentration,
had an inferior analgesic pro®le compared with
indomethacin. However, although they had pro-
nounced analgesic effects, compounds 1 and 2 had
no anti-in¯ammatory activity in the carrageenan-
induced rat paw oedema test. Considering that all
classical non-steroidal anti-in¯ammatory drugs, for
example indomethacin (3) and diclofenac (4), pre-
sent an acidic group important in the interaction
with bioreceptors, we aimed to improve the anti-
Chemistry
Melting points were determined on a Quimis 340
1
apparatus and are uncorrected. H NMR spectra
were determined in deuterated solvents, using tetra-
methylsilane as an internal standard on a Brucker
AC 200 spectrometer. Splitting patterns were as
follows: s, singlet; d, doublet; t, triplet; q, quartet.
13
C NMR spectra were determined on a Brucker
AC 200 spectrometer at 50 MHz, using deuterated
chloroform as internal standard. The mass spectra
were obtained on a GC=VG Micromass 12 at
Correspondence: E. J. Barreiro, Laborat o rio de Avalia cË aÄ o e
S Âõ ntese de Subst aà ncias Bioativas Faculdade de Farm a cia,
Universidade Federal do Rio de Janeiro, PO Box 68006,
21944-970, Rio de Janeiro, RJ, Brazil.
E-Mail: eliezer@pharma.ufrj.br
7
0 eV.
The progress of all reactions was monitored by
TLC on 2 6 5 cm aluminum sheets precoated with

Â
LIDIA M. LIMA ET AL
674
Figure 1. Structure of acylhydrazone derivatives, 1a±c, sulphonylhydrazone isosteres, 2a±c, and the standards indomethacin (3),
dicloferiac (4) and sulphonylhydrazones 5a±e.
silica gel 60 (HF-254, Merck) to a thickness of
61Á75 (ArOCH CO CH CH ), 14Á23 (ArOCH CO
2 3
2
2
2
3
2
2
0
Á25 mm. The developed chromatograms were
CH CH ) ppm.
visualized under UV light (254±265 nm). For col-
umn chromatography Merck silica gel (70±230
mesh) was used. The solvents used in reactions
were dried, re-distillated before use and stored over
General procedure for the preparation of the
6-methyl-3,4-methylenedioxybenzene-sulphonyl-
hydrazone derivatives (5a±d) (Lima et al 1999)
To a solution of 0Á2 g (0Á87 mmol) of 6-methyl-3,4-
methylenedioxyphenylsulphonylhydrazine (6) in
absolute ethanol (20 mL) containing two drops of
3
±4 A molecular sieves.
3
7% HCL, was added 0Á87 mmol of the corre-
Ethyl 2-(4-formylphenoxy)acetate (7d)
To a suspension of 4-hydroxybenzaldehyde (7b)
sponding benzaldehyde derivative. At the end of
the reaction cold water was added and the resulting
colored precipitate was collected by ®ltration and
dried, to give the desired sulphonylhydrazone
derivatives (5a±d) as described below.
(
1
2
0Á4 g; 1Á19 mmol) and potassium carbonate (0Á16 g;
Á19 mmol) in dry acetone (30 mL) was added ethyl
-bromoacetate (0Á13 mL; 1Á19 mmol). The reaction
mixture was stirred at room temperature, under
argon atmosphere, for 2 h and then the solvent was
evaporated at reduced pressure. The crude residue
was diluted with water (approx. 30 mL) and then
extracted with ethyl acetate (4 6 10 mL). The
organic layer was washed with brine, dried over
anhydrous Na SO and evaporated under reduced
0
dioxyphenylsulphonylhydrazide (5a)
(
4 -Carboxybenzylidene) 6-methyl-3,4-methylene-
This compound was obtained as a white solid in
80% yield, by condensation of 6 with 4-carboxy-
benzaldehyde (7a). H NMR (200 MHz, d6-
1
2
4
pressure and the obtained residue was puri®ed by
silica gel column chromatography using n-hexane±
AcOEt (10 : 0, 10 : 1 then 10 : 2) to give 0Á1 g (95%)
DMSO): d 11Á90 (s, 1H, SO NH±), 7Á98 (s, 1H,
2
0
0
±N ˆ CH±), 7Á92 (d, 2H, H-3 and H-5 ,
0
0
J ˆ 8Á37 Hz), 7Á63 (d, 2H, H-2 and H-6 ,
J ˆ 8Á40 Hz), 7Á34 (s, 1H, H-2), 6Á96 (s, 1H, H-5),
6Á01 (s, 2H, O±CH ±O), 2Á55 (s, 3H, Ar-CH )
1
of the ester (7d) as a yellow oil. H NMR
(
200 MHz, CDCl ): d 7Á83 (d, H-3 and H-5,
3
2
3
13
J ˆ 8Á58 Hz), 6Á99 (d, H-2 and H-6, J ˆ 8Á60 Hz),
Á69 (s, 2H, ArOCH CO CH CH ), 4Á26 (q, 2H,
ppm; C NMR (50 MHz, d -DMSO) d: (Table 2);
6
‡
4
MS (70 eV) m=z: 362 (M ).
2
2
2
3
ArOCH CO CH CH , J ˆ 7Á14 Hz), 1Á28 (t, 3H,
2
2
2
3
13
0
dioxyphenylsulphonylhydrazide (5b)
ArOCH CO CH CH , J ˆ 7Á14 Hz) ppm; C NMR
(4 -Hydroxybenzylidene) 6-methyl-3,4-methylene-
2
2
2
3
(
1
50 MHz, CDCl ): d 190Á80 (ArOCH CO CH CH ),
3
2
2
2
3
62Á75 (C-4), 132Á05 (C-2 and C-6), 130Á85 (C-1),
15Á02 (C-3 and C-5), 65Á33 (ArOCH CO CH CH ),
This compound was obtained as a white solid in
92% yield, by condensation of 6 with 4-hydroxy-
1
2
2
2
3

SYNTHESIS OF NOVEL ANTINOCICEPTIVE SULPHONYLHYDRAZONES
675
1
benzaldehyde (7b). H NMR (200 MHz, d -DMSO):
J ˆ 8Á52 Hz), 7Á28 (s, 1H, H-2), 6Á95 (s, 1H, H-5),
0 0
6
d 11Á45 (s, 1H, SO NH±), 9Á98 (s, 1H, ArOH±),
6Á88 (d, 2H, H-2 and H-6 , J ˆ 8Á52 Hz), 6Á05 (s,
2H, O±CH ±O), 4Á66 (s, 2H, ArOCH CO H), 2Á46
2
0
7
6
6
Á87 (s, 1H, ±N ˆ CH±), 7Á40 (d, 2H, H-2 and H-
2
2
2
0
13
(s, 3H, Ar±CH ) ppm; C NMR (50 MHz, d -
3 6
, J ˆ 8Á51 Hz), 7Á36 (s, 1H, H-2), 6Á99 (s, 1H, H-5),
0
0
‡
Á80 (d, 2H, H-3 and H-5 , J ˆ 8Á51 Hz), 6Á09 (s, 2H,
DMSO) d: (Table 2); MS (70 eV) m=z: 392 (M ).
1
3
O±C H ±O), 2Á59 (s, 3H, Ar±CH ) ppm; C NMR
2
3
(
3
50 MHz, d -DMSO) d: (Table 2); MS (70 eV) m=z:
6
‡
34 (M ).
Biology
Analgesic activity. Albino mice of both sexes (18±
23 g) were used (n ˆ 7±10). Analgesic activity was
determined in-vivo by the acetic acid-induced
0
,4-methylenedioxyphenylsulphonylhydrazide (5c)
(
4 -Hydroxy-3,5-ditert-butylbenzylidene) 6-methyl-
3
This compound was obtained in 94% yield, by
abdominal constriction test (0Á6% acetic acid;
condensation of 6 with 4-hydroxy-3,5-ditert-butyl-
benzaldehyde (7c), as a white solid. H NMR
0Á1 mL=10 g)
(Whittle
1964).
Compounds
1
� 1
(100 mmol kg ; 0Á1 mL=20 g) were administered
orally as a suspension in 5% arabic gum in saline
(vehicle). Control mice received an equal volume
(
200 MHz, d -DMSO): d 11Á21 (s, 1H, SO NH±),
6
2
7
1
Á83 (s, 1H, ±N ˆ CH), 7Á38 (s, 1H, H-2), 7Á33 (s,
0
0
� 1
H, H-2 ), 7Á34 (s, 1H, H-6 ), 6Á98 (s, 1H, H-5), 6Á15
of vehicle. Indomethacin (100 mmol kg ) and
�
1
(
(
s, 2H, O±CH ±O), 3Á41 (s, 9H, ±C(CH ) ) 2Á55
dipyrone (100 mmol kg ) were used as standard
drugs under the same conditions. The acetic acid
solution was administered intraperitoneally 1 h
after administration of acylhydrazone compounds
2
3 3
13
s, 3H, Ar±CH ) ppm; C NMR (50 MHz, d -
3
6
‡
DMSO) d: (Table 2); MS (70 eV) m=z : 446 (M ).
5
a±e. After 10 min, the number of constrictions
were recorded for 20 min. Analgesic activity was
expressed as percentage inhibition of constrictions
compared with the control group (Table 3).
0
-methyl-3,4-methylenedioxyphenylsulphonyl-
(
4 (Ethoxycarbonylmethyleneoxy)benzylidene)
6
hydrazide (5d)
This compound was obtained in 92% yield, by
condensation of (6) with ethyl 2-(4-formyl-
phenoxy)acetate 5d, as a yellow solid. H NMR
1
Anti-in¯ammatory activity
(
(
200 MHz, CDCl ): d 9Á90 (s, 1H, SO NH±), 7Á88
Anti-in¯ammatory activity was determined in-vivo
using the carrageenan-induced rat paw oedema test
(Ferreira 1979). Fasted albino rats of both sexes
(150±200 g) were used (n ˆ 6±15). Compounds
5a±e and standard compounds were administered
3
2
s, 1H, ±N ˆ CH±), 7Á46 (s, 1H, H-2), 7Á45 (d, 2H,
0
0
0
0
H-3 and H-5 , J ˆ 8Á65 Hz), 6Á83 (d, 2H, H-2 and
H-6 , J ˆ 8Á65 Hz), 6Á65 (s, 1H, H-5), 6Á01 (s, 2H,
O±CH ±O), 4Á63 (s, 2H, ArOCH R), 4Á26 (q, 2H,
2
2
�
1
RCO CH CH , J ˆ 7Á14 Hz), 2Á59 (s, 3H, Ar±CH ),
orally and intraperitoneally (100 mmol kg ;
0Á1 mL=20 g) as a suspension in 5% arabic gum in
saline (vehicle). Control rats received an equal
volume of vehicle. After 1 h, the rats were injected
with either 0Á1 mL of a 1% carrageenan solution in
saline (0Á1 mg=paw) or sterile saline (NaCl 0Á9%),
into the subplantar surface of the hind paw. The
volume of the paw was measured using a glass
plethysmometer coupled to a peristaltic pump,
every hour for 4 h. Oedema was calculated as the
difference in volume between carrageenan- and
2
2
3
3
1
3
1
Á26 (t, 3H, RCO CH CH , J ˆ 7Á14 Hz) ppm;
C
2
2
3
NMR (50 MHz, CDCl ) d: (Table 2); MS (70 eV)
m=z: 420 (M ).
3
‡
0
(
4 (Carboxymethyleneoxy)benzylidene) 6-methyl-
3
,4-methylenedioxyphenylsulphonylhydrazide (5e)
To a solution of the ethyl ester derivative 5d
0Á23 g; 0Á55 mmol) in methanol (10 mL) was added
(
1
M aqueous LiOH solution (1Á64 mL, 1Á64 mmol)
�
1
saline-treated paws. Indomethacin (100 mmol kg )
was used as a standard drug under the same con-
ditions. Anti-in¯ammatory activity was expressed
as percentage inhibition of oedema compared with
the control group (Table 3).
and the resulting emulsion was stirred at room
temperature for 20 min. The reaction mixture was
diluted with ethyl ether (20 mL) and carefully
acidi®ed with 2 M aqueous HCl. The organic layer
was washed with brine, dried over anhydrous
Na SO and evaporated under reduced pressure to
2
4
give the acid derivative 5e as a white solid in 91%
ꢀ
1
yield, mp 193±195 C. H NMR (200 MHz, d -
Statistics
Results are expressed as the meanÆ s.e.m. of n
6
DMSO): d 11Á39 (s, 1H, SO NH±), 7Á84 (s, 1H,
2
0
0
±
N ˆ CH±), 7Á46 (d, 2H, H-3 and H-5 ,
animals per group. The data were analysed using

Â
LIDIA M. LIMA ET AL
676
Student's t-test and *P < 0Á05 was considered
phenoxy)acetate (7d). Compound 7d (93% yield)
was easily prepared by O-alkylation of the 4-
hydroxybenzaldehyde 7b with ethyl 2-bromoace-
tate in acetone, using K CO as base (Figure 2).
signi®cant.
2
3
Results and Discussion
Finally, hydrolysis of the ethyl ester 5d using LiOH
monohydrate in CH OH, followed by acidi®cation
with 2 M aqueous HCl (Eh et al 1995) provided the
corresponding acid derivative 5e, in 83% yield
The synthesis of the title compounds, 5a±e, is
outlined in Figure 2. We used the 6-methyl-3,4-
methylenedioxy benzenesulphonylhydrazide 6, as
the key intermediate because it is easily obtained
3
(
Figure 2).
The next step was to determine the relative
(
approx. 35% yield) from natural safrole (8) using a
con®guration of the C ˆ N bond in sulphonyl-
simple synthetic sequence previously reported,
which explores the high yield regioselective func-
tionalization process at the C-6 position of the 1,3-
benzodioxole ring (Lima et al 1999). By sequential
classical functional group interconversion (i.e.
RSO NHNH ! RSO NHN ˆ CHAr), 5a±e were
1
hydrazone derivatives 5a±e. Analysis of the H
NMR spectra of 5a±e, showed the presence of a
single signal referring to an imino hydrogen (Table
1), attributed to the E-diastereomer in agreement
with the previous report (Lima et al 1999). All the
new sulphonylhydrazone derivatives were structu-
2
2
2
obtained from 6. For instance, treatment of 6 with
the appropriate functionalized benzaldehydes (7a±
c) in ethanol, using HCl as catalyst (Lima et al
1
13
rally characterized by H and C NMR (Table 2)
and supported by elemental analyses.
The analgesic pro®le of the sulphonylhydrazone
derivatives 5a±e, was determined by the acetic
acid-induced abdominal constriction test in mice
1
999), gave the corresponding sulphonylhydrazone
derivatives 5a±c in yields ranging from 80 to 94%
Figure 2; Table 1). To avoid the formation of N,O-
(
(
Whittle 1964), with dipyrone and indomethacin as
bis alkylated derivatives during treatment of 5b
with ethyl 2-bromoacetate in basic media, due to
the similar pK values of phenol and sulphonamide
a
standards. The results are given in Table 3. The
active compounds were obtained by the introduc-
tion of the acidic moiety at the phenyl ring of the
sulphonylhydrazone framework. The most active
groups, compound 5d (92% yield) was prepared by
condensation of
6
with ethyl 2-(4-formyl-
Table 1. Physical and spectroscopic data of the 6-methyl-3,4-methylenedioxybenzene-sulphonylhydrazone derivatives 5a±e.
Compound
Formula
MW
Elemental analysis
mp
C)
d (ppm)
N ˆ CH
ꢀ
(
Calculated
H
Found
H
C
N
C
N
a
b
5
5
5
5
5
a
b
c
C
16
H
14
N
C H N O S
5 14 2 5
2
O
6
S
362Á35
334Á34
446Á55
420Á43
392Á38
53Á04
53Á89
61Á86
54Á28
52Á04
3Á89
4Á22
6Á77
4Á79
4Á11
7Á73
8Á38
6Á27
6Á66
7Á14
52Á98
53Á95
61Á91
54Á33
51Á97
3Á93
4Á25
6Á82
4Á84
4Á15
7Á77
8Á43
6Á22
6Á71
7Á20
212±213
175±176
163±165
150±152
193±195
7Á98b
7Á87
b
1
C H N O S
7
7Á83
23 30 2 5
C H N O S
c
d
e
7Á88
19
20
2
b
C
17
H
16
N
2
O
7
S
7Á84
a
b
Recrystallized from ethanol±water. Recorded at 200 MHz, using d -DMSO as solvent. Recorded at 200 MHz, using CDCl as
c
6
3
solvent.
Figure 2. Synthesis of title compounds (5a±e).

SYNTHESIS OF NOVEL ANTINOCICEPTIVE SULPHONYLHYDRAZONES
677
13
Table 2.
C NMR spectra at 50 MHz of the 6-methyl-3,4-methylenedioxybenzene-sulphonylhydrazones 5a±e.
Chemical Shifts d (ppm)
a
a
a
5b
a
b
5d
a
5
5c
5e
C-1
C-2
C-3
C-4
C-5
C-6
137Á70
109Á05
145Á50
150Á97
111Á91
133Á20
131Á63
129Á79
126Á94
128Á20
144Á71
20Á06
102Á38
±
133Á26
109Á12
145Á44
150Á79
111Á83
130Á11
124Á83
128Á48
115Á71
159Á35
146Á60
20Á17
102Á32
±
±
±
±
±
±
±
±
133Á47
109Á03
145Á43
150Á73
111Á74
129Á97
125Á19
139Á13
123Á15
155Á94
147Á26
20Á29
102Á28
29Á90
±
134Á41
110Á64
146Á08
151Á77
112Á18
132Á17
127Á10
129Á20
114Á96
159Á73
147Á25
20Á98
102Á33
±
133Á76
109Á51
147Á57
151Á33
112Á32
130Á55
127Á36
128Á71
115Á32
159Á72
146Á39
20Á61
102Á83
±
0
C-1
0
0
0
C-2 ˆ C-6
0
C-3 ˆ C-5
0
C-4
N ˆ CH
OCH O
ArCH
2
3
tert-Butil
ArCOOH
ArOCH
ArOCH
ArOCH
160Á86
±
±
±
±
±
2
2
2
CO
CO
CO
2
2
2
CH
CH
CH
2
2
2
CH
CH
CH
3
3
3
3
±
±
±
±
±
±
±
65Á45
168Á73
61Á74
14Á31
±
±
±
±
±
ArOCH CO CH CH
±
2
ArOCH CO H
2
2
64Á98
2
ArOCH CO H
2
±
±
170Á42
2
2
a
b
Approximately 50 mg in 0Á7 mL d
6
-DMSO. Approximately 50 mg in 0Á7 mL CDCl
3
.
Table 3. Antinociceptive pro®le of substituted benzylidene sulphonylhydrazide derivatives 5a±e, and the standards indomethacin
and dypirone.
a
Compound
Analgesic activity
Constrictions
Anti-in¯ammatory activity
b
c
n
Inhibition (%)
n
Volume variation (mL)
Inhibition (%)
Vehicle control (5% arabic gum)
Dypirone
Indomethacin
10
9
7
10
8
10
7
93Á0Æ 6Á1
59Á5Æ 4Á4
41Á9Æ 4Á4
44Á3Æ 2Á5
58Á8Æ 3Á9
69Á0Æ 2Á1
71Á1Æ 5Á5
43Á9Æ 1Á6
±
15
±
7
6
6
8
6
7
478Á6Æ 28Á6
±
±
±
35Á9*
54Á9*
52Á4*
37Á2*
25Á8*
24Á1*
53Á2*
153Á2Æ 11Á9
318Á8Æ 36Á9
432Á6Æ 37Á1
335Æ 22Á1
440Á9Æ 33Á6
314Á7Æ 36Á3
67Á9*
33Á4*
9Á6
5
5
5
5
5
a
b
c
d
e
30Á0*
7Á8
8
34Á3*
a
� 1
b
All compounds were evaluated at a concentration of 100 mM kg . Percentage inhibition compared with vehicle control group.
c
Percentage inhibition compared with vehicle control group and expressed by the mean volume variationÆ s.e.m., 3 h after
carrageenan injection. *P < 0Á05 (Student's t-test).
compounds, 5a and 5e, at a concentration of
1
active than the unsubstituted phenol derivative 5b,
indicating that the presence of the bis-hydrophobic
alkyl group in the phenyl ring of the acidic phenol
may be deleterious to analgesic activity. The
introduction of the acidic function in compound 5a
improved the analgesic activity of this derivative
approximately 2Á5-fold compared with the non-
acidic lead-derivative 2a previously reported (Lima
et al 1999).
Compounds 5a and 5e had weak anti-in¯amma-
tory activity in the carrageenan-induced rat
paw oedema test (33Á4 and 34Á3% inhibition at the
same dose, respectively; Table 3). In contrast, the
�
1
00 mM kg , produced 52Á4 and 53Á2% inhibition
of the induced abdominal constrictions, respec-
tively, being approximately 1Á5-fold more potent
than the standard dipyrone. Compound 5e was
approximately 2Á2-fold more active than the cor-
responding ethyl ester 5d (53Á2 vs 24Á1%, respec-
tively), indicating the relevance of the acidic
function for the analgesic activity in these deriva-
tives. The less acidic phenols derivatives, 5b and
5c, had only modest analgesic activity, and were
the least active compounds in this bioassay. In fact,
the di-tert-butylphenol compound 5c was less

Â
LIDIA M. LIMA ET AL
678
less analgesic phenol compound 5c, had 30%
anti-in¯ammatory activity, possibly due to the
presence of the hydrophobic and redox-active
di-tert-butylphenol group increasing the analgesic
activity compared with the inactive phenol deriva-
tive 5b.
support of this work. We thank CNPq and CAPES
for fellowships to L. M. Lima, A. L. P. Miranda, C.
A. M. Fraga and E. J. Barreiro. The technical
assistance of Mr. Renato Moreira, is also gratefully
acknowledged.
In conclusion, we obtained a series of new
analgesic derivatives from the sulphonylhydrazone
class (5), synthesized from natural safrole (8). The
results represent an optimization of the previously
reported lead compound 2a by introduction of an
acidic functionality in the p-position of the phenyl
ring of the sulphonylhydrazone moiety. Compound
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5
a was the most analgesic agent with approximately
1Á5-fold the activity of the standard dipyrone.
Acknowledgements
We are grateful to the CNPq (Grant 52.0033=96-5),
FAPERJ (Grant 171.299=95) and FUJB (Grant
6
276-6, 6487-4 and 7675-9) for the ®nancial