New substituted 2-(pyrazol-1-yl) o-, m-, p-methylacetanilides with potential local anaesthetic and antiarrhythmic action. Part I

Article abstract of DOI:10.1016/S0014-827X(00)00052-5

Fifteen substituted 2-(pyrazol-1-yl)acetanilides were synthesized by N- alkylation of pyrazole and some of its derivatives with several 2- iodoacetanilides. The new compounds exhibited local anaesthetic and antiarrhythmic actions. The new compounds have been characterized by elemental chemical analysis, UV-Vis, IR, ¹H, ¹³C NMR spectra and pharmacology research. (C) 2000 Elsevier Science S.A.

Full text of DOI:10.1016/S0014-827X(00)00052-5

www.elsevier.nl/locate/farmac
Il Farmaco 55 (2000) 362–368
New substituted 2-(pyrazol-1-yl) o-, m-, p-methylacetanilides with
potential local anaesthetic and antiarrhythmic action. Part I
Mircea Iovu a,*, Christina Zalaru b, Florea Dumitrascu c, Constantin Draghici c,
Elena Cristea d
a Uni6ersity of Medicine and Pharmaceutics ‘Carol Da6ila’, Department of Organic Chemistry, 6 Traian Vuia St., Bucharest, Romania
b Uni6ersity of Bucharest, Faculty of Chemistry, Department of Organic Chemistry, Bucharest, Romania
c Organic Chemistry Centre, Bucharest, Romania
d Uni6ersity of Medicine and Pharmaceutics ‘Carol Da6ila’, Clinical and Sanitary Chemistry Laboratories, Bucharest, Romania
Received 25 March 1999; accepted 12 April 2000
Abstract
Fifteen substituted 2-(pyrazol-1-yl)acetanilides were synthesized by N-alkylation of pyrazole and some of its derivatives with
several 2-iodoacetanilides. The new compounds exhibited local anaesthetic and antiarrhythmic actions. The new compounds have
been characterized by elemental chemical analysis, UV–Vis, IR, 1H, 13C NMR spectra and pharmacology research. © 2000
Elsevier Science S.A. All rights reserved.
Keywords: Pyrazolyl-acetanilides; Local anesthetics; Antiarrhythmics
1. Introduction
amines were also used for getting aminoacetanilides [4].
Some other compounds having lidocaine-like molecular
structure were also tested for the local anesthetic action
[5,6]. 2-Aminoacetanilides were found to have an-
tiarrhythmic properties besides their anesthetic ones
[7–9]. Several researchers insisted on changing the
amino group with heterocyclic amines [10] or on replac-
ing them with ether groups [8–11].
To obtain a good local anesthetic is still a very
topical issue. The present paper therefore reports the
synthesis and characterization of some new compounds
analogous to lidocaine, where the amino-group is re-
placed by less basic pyrazole derivatives and the ben-
zene ring is substituted by a methyl radical in the ortho,
meta and para positions.
The first amides used as local anesthetics were dis-
covered during the investigations made in the ac-
etanilide series for getting antipyretics. In 1946, Lo¨fgren
[1] investigated 30 new substituted acetanilides and
found out that a local anesthetic should contain both a
lipophylic aromatic structure and a hydrophylic one
having a tertiary amino-group, such as lidocaine, the
drug used even nowadays (Scheme 1).
For better activity, the two parts should contain not
only ester, ether, amino and carbonyl groups, but
mainly amides.
In the aminoacetanilides synthesis, Lo¨fgren used the
acylation reaction of the aromatic amines with
chloroacetyl chloride in the presence of sodium acetate;
the acetanilides obtained were treated with cyclic or
acyclic secondary amines [1–3]. Later on, primary
* Corresponding author. Tel.: +40-21-07 558; fax: +40-21-12
730.
Scheme 1.
E-mail address: iovu@gg.unibuc.ro (M. Iovu).
0014-827X/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(00)00052-5

M. Io6u et al. / Il Farmaco 55 (2000) 362–368
363
transformed into the more reactive iodoacetanilides, by
reaction with sodium iodide in anhydrous acetone [14].
Treatment of pyrazole and its derivatives II with
substituted 2-iodoacetanilides I in DMSO and in the
presence of sodium carbonate gave 15 new compounds,
substituted 2-(pyrazol-1-yl)acetanilides III according to
the reaction (Scheme 2, Table 1):
The new synthesized compounds were characterized
by elemental analyses (C, H, N), determinations of
molecular weights by mass spectrometry, purity deter-
1
minations, UV–Vis, IR, H and 13C NMR spectra.
3. Experimental
All the compounds used in the present paper: 2-
chloroacetanilides, 2-iodoacetanilides and the substi-
tuted pyrazoles were prepared according to literature
[12–17].
Carbon, hydrogen and nitrogen analyses were carried
out by microcombustion.
Thin layer chromatography (TLC) was carried out
on silica gel E. Merck plates, in a one-dimensional
technique; for the development solution of 7.5:1:2:1
petroleum ether–ethyl ether–methylene chloride–ethyl
acetate was used. The visualization was made with a
UV lamp, u=254 nm.
Scheme 2.
2. Chemistry
Molecular weight was obtained with a GC–MS 8000
MD 800 Fission’s spectrometer at 70 eV with source
temperature 200°C, carrier gas He at 2 ml/min.
The melting points were determined with a Boetius
apparatus and are not corrected.
Electronic spectra within 200–800 nm range were
obtained with Unicam UV–Vis spectrometer in ethanol
solution. The concentration was 10−4 M.
Both lidocaine and its analogous compounds are
known to be obtained by reaction of some chloroac-
etanilides with amines [1,12]. We have chosen another
synthesis route since the 2-chloroacetanilides we got
obtained by the Lo¨fgren [1] and Bu¨chi [13] methods did
not react with pyrazole or its derivatives. Therefore, all
2-chloroacetanilides initially prepared by us have been
Table 1
Analytical data and some properties
No.
Comp.
R
Molecular mass
C (%)
Calc.
H (%)
Calc.
N (%)
Calc.
I (%)
Calc.
-
R1
R2
R3
Found
Found
Found
Found
34.68
1
2
3
4
5
6
7
8
2%-Me
2%-Me
2%-Me
2%-Me
2%-Me
3%-Me
3%-Me
3%-Me
3%-Me
3%-Me
4%-Me
4%-Me
4%-Me
4%-Me
4%-Me
H
H
H
I
NO2
H
H
H
I
NO2
H
H
H
I
H
215.26
243.31
369.21
288.31
305.38
215.26
243.31
369.21
288.31
305.38
215.26
243.31
369.21
288.31
305.38
66.96
69.11
45.54
58.33
74.73
66.96
69.11
45.54
58.33
74.73
66.96
69.11
45.54
58.33
74.73
67.10
69.52
45.84
58.71
75.09
67.30
69.43
45.91
58.81
75.08
67.25
69.40
45.83
58.67
75.04
6.09
7.04
4.37
5.59
6.27
6.09
7.04
4.37
5.59
6.27
6.09
7.04
4.37
5.59
6.27
6.50
7.33
4.68
5.89
6.52
6.42
7.28
4.58
5.79
6.59
6.41
7.29
4.67
5.84
6.58
19.52
17.27
11.38
19.43
13.76
19.52
17.27
11.38
19.43
13.76
19.52
17.27
11.38
19.43
13.76
19.88
17.54
11.40
19.61
13.90
19.80
17.60
11.41
19.63
14.09
19.72
17.58
11.39
19.71
14.08
Me
Me
Me
Ph
H
Me
Me
Me
Ph
H
Me
Me
Me
Me
H
Me
Me
Me
Me
H
34.37
34.37
34.37
34.78
34.79
9
10
11
12
13
14
15
Me
Me
Me
Ph
Me
Me
Me
Me
NO2
H

364
M. Io6u et al. / Il Farmaco 55 (2000) 362–368
Table 2
Some properties of the prepared compounds III
a
No.
Comp.
R
Formula
Molecular mass
M.p. (°C)
Yield (%)
RF
R1
R2
R3
Calc.
Exp. (SM)
1
2
3
4
5
6
7
8
2%-Me
2%-Me
2%-Me
2%-Me
2%-Me
3%-Me
3%-Me
3%-Me
3%-Me
3%-Me
4%-Me
4%-Me
4%-Me
4%-Me
4%-Me
H
H
H
I
NO2
H
H
H
I
NO2
H
H
H
I
H
C12H13N3O
C14H17N3O
C14H16N3OI
C14H16N4O3
C19H19N3O
C12H13N3O
C14H17N3O
C14H16N3OI
C14H16N4O3
C19H19N3O
C12H13N3O
C14H17N3O
C14H16N3OI
C14H16N4O3
C19H19N3O
215.26
243.31
369.21
288.31
305.38
215.26
243.31
369.21
288.31
305.38
215.26
243.31
369.21
288.31
305.38
215
243
369
288
305
215
243
369
288
305
215
243
369
288
305
144–146
151–152
193–194
217–218
135–137
80–82
136–138
155–156
189–191
145–147
161–163
145–147
212–214
246–248
180–182
54.5
36.2
53
0.11
0.17
0.27
0.19
0.31
0.11
0.13
0.19
0.13
0.24
0.13
0.20
0.23
0.14
0.33
Me
Me
Me
Ph
H
Me
Me
Me
Ph
H
Me
Me
Me
Me
H
Me
Me
Me
Me
H
46.35
56.8
46.5
79.5
54.5
38.5
23.4
40.1
52.5
65.6
43.9
20.2
9
10
11
12
13
14
15
Me
Me
Me
Ph
Me
Me
Me
Me
NO2
H
a Analytical results for C, H, I, N were within 90.4% of calculated values.
IR spectra were recorded in the 4000–400 cm−1
range using a BIO-RAD FTS-135 spectrometer and
KBr pellets.
NMR spectra were recorded on a Varian Gemini 300
spectrometer operating at 300 MHz (1H NMR) and 75
MHz (13C NMR), respectively, in CDCl3 or DMSO-d6
in 5 mm NOREL-57 PP grade sample tubes. The
chemical shifts were referred to TMS as internal
standard.
The 15 new compounds were synthesized according
to the following example. Several changes of the reac-
tion conditions were made as a function of the sub-
stituents nature in the heterocycle.
in doses ranging between 250 and 750 mg/kg of body
weight, per os. The graphic method [18] was used.
Infiltration local anesthetic action was determined by
Bianchi’s method [19]. The mice were injected subcuta-
neousely 1 cm from the tails bases with 1% lidocaine
hydrochloride and 1% suspension of the compounds to
be tested at a dose corresponding to 1/10 of LD50. The
time of enduring pain without the reflex movement of
the tail was registered. The mean enduring time versus
the effect of lidocaine considered to be equal to 100 was
expressed.
To test the surface local anesthetic action the corneal
reflex of rabbits by mechanical stimulation before and
after the application of the new compounds to be tested
was used comparatively with lidocaine as a reference
substance. The number of touches without of the rabbit
blinking their eyes, was registered [18].
3.1. 2-(Pyrazol-1-yl) 2%-methylacetanilide
A total of 2 g (7.3 mmols) 2%-methyl-2-iodoac-
etanilide and 0.5 g (7.3 mmols) pyrazole were dissolved
in 4 ml of DMSO to which an equimolecular amount of
sodium carbonate was then added. The mixture was
heated at 60°C for 5 h. The resulting solution was
treated with 10% Na2CO3 solution. The solid raw
product was recrystallized from ethanol.
4.2. Antiarrhythmic action
A total of 13 batches, each of five white male mice
weighting 2092 g were used as follows: to 10 batches
were administered the studied compounds per os in an
equal dose of 1/10 LD50, and to two batches were given
50 mg/kg of body weight lidocaine hydrochloride and
75 mg/kg of body weight quinidine sulfate. The remain-
ing batch was used as the control. Heart fibrillation,
artificially created by chloroform atmosphere, appeared
after 30 min. The latent time of the appearance of heart
fibrillation was measured using Hackenberger’s tech-
nique [20] for the new compounds were compared to
lidocaine and quinidine sulfate.
4. Pharmacology
4.1. Acute toxicity (LD50)
White mice weighting 2092 g each were used in
batches of six; the new compounds were administered

M. Io6u et al. / Il Farmaco 55 (2000) 362–368
365
5. Results and discussion
1500–1354 cm−1 range. The different positions of these
bands could be explained by the influence of the sub-
stituents in the aromatic ring. The broad multiplet band
(2759–3200 cm−1) present in the IR spectrum of pyra-
zole and of substituted pyrazoles due to intermolecular
hydrogen bonds characteristic of pyrazole [22] cannot
be found in the IR spectrum of the new compounds.
1H and 13C NMR spectra recorded at 300 and at 75
MHz, respectively, in the CDCl3 and DMSO-d6 solu-
tion support the structure formulas assigned to these
compounds, deduced from the equation of the synthesis
reaction and from the data of the UV–Vis and IR
spectra. Tables 3 and 4 give the chemical shifts, l (ppm)
and the coupling constants of representative com-
pounds. Chemical shifts occur within the range charac-
teristic of different kinds of protons in the molecules.
The positions of the protons and of the substituents
in the ring can be found out using HETCOR and
COSY. Our results of the increments of the chemical
shifts in the 13C NMR spectra for the compounds 5, 10,
15 are in agreement with the literature data [23] The
tautomeric 3(5)-phenyl-methylpyrazole by reaction with
2-iodoacetanilides could lead to a mixture of two iso-
mers but in fact only the formation of one isomer (5,
10, 15) was observed by 1H NMR spectroscopy
(Scheme 3). This can be plausibly explained by steric
5.1. Chemical and spectral results
Some of the properties are given in Table 2. The
purity of the new compounds and of the intermediary
ones was checked through thin layer chromatography
using silica gel G chromoplates (Rf given in Table 2).
The compounds electronic spectra recorded in
ethanolic solution show the umax values exist in the
characteristic ranges (222–246 nm and 254–280 nm) of
the chromophores present in the molecule (benzene,
pyrazole ring, carbonyl group), but with different
bathochromic shifts for each compound. These bands
are assigned to the p–p* transitions.
IR spectra recorded in the 4000–400 cm−1 range in
KBr pellets reflect the molecular structure of the new
compounds. The bands characteristic of the secondary
amides [21] and also the bands characteristic of pyra-
zole [22] and benzene ring [21] can be visualized. The
amide band I (very strong), due to the stretching fre-
quency, wCO appears within the 1660–1690 cm−1 range
as a function of each compound; the amide band II,
due to the lNH and wCN coupling is present within the
1500–1570 cm−1 range and the bands due to the
stretching of the pyrazole ring can be found within the
Table 3
1H resonance data for representative compounds, l (ppm), J (Hz) a
Comp.
R1
R2
R3
R1
R3
CH2
NH
H-3
H-4
H-5
CH3 (3)
CH3 (5)
1
2
3
4
5
10
15
7.72 d, 2.1
6.40 dd, 2.1, 2.3
5.92 s
7.55 d, 2.3
4.98 s
4.78 s
4.86 s
5.13 s
4.90 s
4.87 s
4.86 s
8.25 bs
8.28 bs
8.18 bs
9.72 bs
8.38 bs
8.50 bs
8.42 bs
2.16 s
2.28 s
241 s
2.27 s
2.34 s
2.57 s
2.36 s
2.34 s
2.36 s
6.46 s
6.46 s
6.45 s
7.30–7.81 b
7.32–7.81 b
7.40–7.82 b
a s=singlet; bs=broad singlet; d=doublet; dd=double doublet.
b Ph protons. Solvent: CDCl3, DMSO-d6.
Table 4
13C resonance data for representative compounds, l (ppm)
Comp.
R1
R2
R3
R1
R3
CO
CH2
C-3
C-4
C-5
CH3 (3)
CH3 (5)
1
2
3
4
5
10
15
141.72
149.98
151.87
144.91
152.39
152.33
152.31
107.09
106.46
64.39
131.60
103.77
103.90
103.83
131.50
140.91
142.52
142.38
141.54
141.65
141.57
165.17
165.55
164.79
164.33
165.13
165.25
165.06
55.66
52.51
53.61
52.29
52.75
52.85
52.74
13.43
14.06
13.43
10.99
12.03
11.47
11.14
11.28
11.23
128.61–132.55 a
128.19–132.88 a
125.35–132.80 a
a Ph carbon. Solvent: CDCl3, DMSO-d6.

366
M. Io6u et al. / Il Farmaco 55 (2000) 362–368
group resulted in the enhancement of the 5-Me group
signal. No equilibrium between the s-cis and s-trans
possible conformations could be observed. It is worth
mentioning the strong shielding of the 4-C atom bound
to iodine in compounds 3, 8 and 13 in the 13C NMR
spectra. To assign the chemical shifts of the methyl
groups 2D experiments (COSY 13CꢀH) were necessary.
5.2. Pharmacological results
Scheme 3.
The acute ;toxicity (LD50) of the compounds ranges
within 470–602 mg/kg body weight, per os. Com-
pounds 1, 6 and 11 are the least toxic (Table 5).
The anesthetic and antiarrhythmic actions were
tested using 1/10 of the LD50 value of the compounds
as a working dose [24].
The anesthetic action was tested using Bianchi’s
[19,25] experiment on mice (Table 6) and the corneal
reflex test on rabbits (Table 7) using lidocaine as a
reference substance.
At first, the animals responded to the mechanical
stimuli after 1.60–2 s. When the compound solutions
were injected in mouse tail, the mean response time
ranged between 2.5090.14 and 5.5090.41 s.
Compared to lidocaine, the most active compounds
were in the order 1, 11, 3, 7, 12, 6 and 8 that showed an
activity between 71 and 52% of the reference substance
effect.
Table 5
Acute toxicity (LD50) in mice
Comp.
LD50
Body weight per os
(mg/kg)
Body weight
(mmol/kg)
1
2
3
4
6
7
8
11
593 (425–604)
489 (415–530)
565 (420–600)
470 (414–518)
589 (466–615)
538 (485–620)
508 (461–584)
602 (543–631)
519 (484–563)
543 (470–600)
292 a
2.76
2.01
1.53
1.63
2.74
2.21
1.38
2.80
2.14
1.47
1.01
12
13
Lidocaine
hydrochloride
a See Ref. [24].
Structurally, the most active compounds were char-
acterized by the presence of the methyl group in the
ortho or para position on the benzene ring: compounds
1 and 11 had 71 and 66%, respectively of the lidocaine
action. Compound 4 with a nitro group in position 4 of
the pyrazole ring was the least active one, although its
molecule had a methyl group in the ortho position of
the benzene ring, similar to compound 1.
Table 7 shows that the surface local anesthetic effect
of the studied compounds appears 12–15 min following
their contact with the cornea of the rabbit’s eye. When
compounds 1, 7 and 11 were used the action appeared
9 min, after the treatment. The mean number of stimuli
endured without blinking ranges within 2.0090.17 and
3.2590.23 when touching the cornea. The most active
compounds were: 1, 3, 7, 11 and 12 with a local
anesthetic action between 40 and 32.10% of the effect of
lidocaine tested under the same conditions (Table 7).
The influence of the studied compounds was deter-
mined on the experimental fibrillation induced in mice
by an atmosphere of chloroform [20]. The reference
substances were quinidine sulfate and lidocaine
hydrochloride.
Table 6
Infiltration local anesthetic action
Comp.
Mean response time (s) 4
Effect vs.
lidocaine
(7.75=100)
tests (x¯ 9s.e.) a
1
2
3
4
6
7
8
11
5.5090.41
3.2590.20
4.8690.22
2.5090.14
4.0890.38
4.5090.4
4.0590.43
5.1390.44
4.2590.28
3.1590.31
7.7590.54
70.97
41.94
62.71
32.26
52.65
58.06
52.26
66.19
54.84
40.65
100
12
13
Lidocaine
hydrochloride
a x¯ 9e.s.=mean value9standard error.
factors and resonance energy. A noncoplanar phenyl
group in the 5-position would lose its resonance energy
of conjugation to the pyrazole ring which would not be
the case in the 3-position. The structures were ascer-
tained by using the Overhauser effect (NOE). The
irradiation of the resonance frequency of methylene
All tested compounds delayed the appearance of the
toxic fibrillating effect of chloroform, with compounds
2, 7, 6 and 11 being the most active. The observed

M. Io6u et al. / Il Farmaco 55 (2000) 362–368
367
Table 7
Surface local anesthetic action (corneal reflex test)
Comp.
No. of impulses generating the oculo-palpebral reflex
Effect of lidocaine
At starting time
3%
2.2
2
2
2
2
2.2
2
2
6%
2.3
9%
12%
15%
18%
21%
24%
27%
30%
Mean (x¯ 9s.e.) a
8.10=100
P
1
2
3
4
6
7
8
11
12
13
L
1.5
2
2.2
2
2
1.8
2
2
2
2
2
3
2
2
2
2
3
2
3
2
2
3
5
3
4
3
3
5
4
4
3
6
4
5
2
4
3
4
3
4
4
3
3
2
3
2
2
3
4
2
9
3
2
2
2
2
2
2
2
3
2
8
2
2
2
2
2
2
2
2
2
2
3
2
2
2
2
2
2
2
2
2
2
2
3.2590.23
2.4090.19
2.7090.20
2.2090.17
2.5090.20
2.7290.22
2.5090.21
2.7090.21
2.3090.19
2.2090.17
8.1090.54
40.12
29.63
33.33
27.16
30.86
33.58
30.86
33.33
28.40
27.16
100
B0.01
B0.1
B0.01
B0.2
B0.1
B0.1
B0.1
B0.01
B0.01
B0.1
2
2
2
2
2
2
2
2
2
7
2
3
3
3
4
3
5
2
2
2
2
2
3
14
3
12
10 14
a x¯ 9e.s.=mean value9standard error.
Table 8
The action of 2-(pyrazol-1-yl)acetanilides, lidocaine and quinidine on the experimental fibrillation in mice
Comp.
Dose body weight per os
Time of fibrillation appearance (s) (x¯ 9s.e.) a Activity of substances with the
(mg/kg)
standard taken as 100
Lidocaine
Quinidine
Control mice
1
2
3
4
6
7
8
5.2090.46
14.0091.20
17.4091.50
14.6091.20
10.9090.89
16.2091.41
16.6091.40
12.6091.02
15.8091.40
15.0091.28
13.5091.22
18.60 91.64
60
50
55
50
60
53
50
60
52
55
50
65.76
91.07
70.22
42.68
82.14
85.09
55.36
79.15
73.21
62.05
100
20.92
28.98
22.34
13.58
26.14
27.07
17.61
25.18
23.30
19.74
31.82
11
12
13
Lidocaine
hydrochloride
Quinidine sulfate
75
47.4093.90
314.29
100
a x¯ 9e.s=mean value9standard error.
.
delays ranged from 13 to 29% of that produced by
quinidine, but ranged from 42 to 91% of that produced
by lidocaine (Table 8).
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