Synthesis and study of the analgesic and antiinflammatory activity of α-acetoxyphenylacetic acid amides

Full text of DOI:10.1023/A:1010427928327

Pharmaceutical Chemistry Journal
Vol. 35, No. 4, 2001
SYNTHESIS AND STUDY OF THE ANALGESIC
AND ANTIINFLAMMATORY ACTIVITY
OF a-ACETOXYPHENYLACETIC ACID AMIDES
I. V. Mashevskaya,1 M. I. Vakhrin,1 V. A. Safin,1 I. A. D’yakova,2 M. A. Nikiforova,2
S. Yu. Solodnikov,2 and L. V. Anikina2
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 4, pp. 22 – 23, April, 2001.
Original article submitted February 17, 1990.
In order to study the effect of acetylation on the biologi-
cal activity of compounds, we have synthesized a series of
O-acetyl derivatives of phenylhydroxyacetic acid amides ac-
cording to the scheme
readily soluble in DMSO, DMF, acetone, and ethanol; com-
pounds IIa and IIb are moderately soluble in water.
The proposed structures of compounds IIa – IIj were
1
confirmed by the H NMR spectroscopic data. The spectra
O
C
display singlet signals due to protons of the CH groups (d =
6.00 – 6.20 ppm) and CH3 groups of the acetyl component
(d = 2.00 – 2.18 ppm). In the spectra of compounds IIb, IId,
and IIg, the signals from protons of the alkyl groups range
within d = 0.81 – 4.37 ppm. The spectra also contain signals
due to the protons of amide groups; the spectrum of
unsubstituted amide IIa displays two signals from protons of
the NH group, which is evidence of hindered rotation in the
amide group.
O
C
C6H5 CH
NHR
+ (CH3CO)2O
NHR
C6H5 CH
OH
OCOCH3
IIà – IIj
Ià – Ij
(for R see Table 1)
The initial compounds Ia – Ij were obtained using the
method described in [1]; the acetylation reaction with acetic
anhydride was performed on heating in benzene. The yields
and physicochemical characteristics of acetyl derivatives
IIa – IIj are presented in Table 1. The target products were
obtained with a yield of 50 – 67%. All compounds are
Compounds IIa – IId, IIh, and IIi were characterized with
respect to their antiinflammatory and analgesic properties.
The results of these tests are summarized in Table 2. It was
established that only compound IIi produced a reliable anal-
gesic action comparable with that of a reference drug
(analgin). At the same time, all compounds exhibited pro-
1
State Pharmaceutical Academy, Perm, Russia.
Institute of Natural Sciences, Perm State University, Perm, Russia.
2
TABLE 1. Yields and Physicochemical Characteristics of Compounds IIa – IIj
1H NMR chemical shift: d, ppm
Compound
R
Yield, %
M.p., °C*
Empirical formula
CH
CH3
Alkyl
Aryl
NH
IIa
H
62
65
67
62
60
53
50
63
57
110 – 112
92 – 93
C10H11NO3
C11H13NO3
C13H17NO3
C14H19NO3
C16H15NO3
C17H17NO3
C16H14ClNO3
C17H17NO3
C15H14N2O3
6.04
6.07
6.13
6.03
6.20
6.17
6.00
6.07
6.20
2.08
2.14
2.10
2.11
2.18
2.14
2.00
2.08
2.14
–
6.83 – 7.80 6.43, 6.73
IIb
IIc
IId
IIe
IIg
IIh
IIi
CH3
2.76
6.93 – 8.03
6.50
n-C3H7
165 – 166
94 – 95
2.30 – 3.30 7.00 – 7.80 7.60 – 8.30
n-C4H9
0.81 – 3.14 6.87 – 7.80
6.37
7.96
7.96
10.06
6.63
9.19
C6H5
115 – 116
147 – 148
142 – 143
78 – 79
–
2.24
–
7.03 – 7.63
6.70 – 7.63
7.03 – 8.06
6.93 – 7.56
6.33 – 8.50
C6H4–CH3-4
C6H4–Cl-4
C6H5CH2
C5H4N-2
4.37
–
IIj
89 – 90
*
Compounds IIb, IIc, IId, and IIh were recrystallized from aqueous ethanol and the other, from acetone.
199
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200
I. V. Mashevskaya et al.
TABLE 2. Antiinflammatory (I) and Analgesic (II) Activity of
Compounds II
a-Acetoxyphenylacetic acid methylamide (IIb). To a
solution of 1.65 g (0.01 mole) of a-acetoxyphenylacetic acid
methylamide Ib in 10 ml of benzene was added with stirring
2ml (0.02 mole) of acetic anhydride. The mixture was boiled
for 5 – 6 h, after which the solvent (benzene) was distilled
off. The residual mass was diluted with 5 ml of water and
neutralized. The precipitate was filtered, dried, and
recrystallized from aqueous ethanol. Yield of compound IIb,
1.34 g (65%); m.p., 92 – 93°C.
II
I
Edema vol- Latent period of defensive reflex (sec) after
Compound
ume growth,
% of initial
30 min
60 min
120 min
foot volume
IIa
IIb
IIc
IId
IIh
IIi
10.0 ± 4.3 9.4 ± 1.8
p < 0.001 p < 0.5
9.9 ± 1.9
p > 0.5
10.8 ± 1.7
p > 0.5
33.5 ± 5.9 12.4 ± 2.6 10.1 ± 1.6 10.2 ± 1.5
Compounds IIa and IIc – IIj were synthesized using anal-
ogous procedures.
p < 0.001
37.3 ± 9.9 5.8 ± 0.6
p < 0.002 p < 0.1
35.6 ± 5.6 7.0 ± 0.9
p < 0.001 p < 0.5
43.9 ± 6.9 8.9 ± 0.6
p < 0.01 p > 0.5
18.8 ± 1.8 11.5 ± 0.7
p < 0.1
p < 0.5
p < 0.5
5.7 ± 0.4
p < 0.02
9.2 ± 1.5
p < 0.5
EXPERIMENTAL PHARMACOLOGICAL PART
6.8 ± 1.4
p < 0.25
9.3 ± 0.8
p > 0.5
The analgesic activity was studied on a group of both
male and female white mongrel mice weighing 18 – 22 g
subjected to a hot plate test. The compounds were injected
1 h before test in a dose of 50 mg/kg (i.p.) with a 2% starch
jelly (0.1 ml per 100 g body weight) [2]. The reference drug
was analgin administered in a dose of ED50 = 93 mg/kg. The
drug activity was evaluated 30, 60, and 120 min after intro-
duction by measuring the increase in the latent time of the
defensive response (hind paw licking).
8.7 ± 1.2
p > 0.5
8.6 ± 0.5
p < 0.5
9.3 ± 1.4
p > 0.5
17.1 ± 1.4
p < 0.05
p < 0.001
p < 0.05
Ortophen
Analgin
–
–
–
27.9 ± 5.2
p < 0.001
–
13.1 ± 0.9 12.8 ± 1.9 16.3 ± 3.0
p < 0.1
p < 0.01
p < 0.05
Control (2%
starch jelly)
72.6 ± 8.9 8.5 ± 0.9
8.9 ± 0.8
10.8 ± 1.6
The antiinflammatory activity was studied on a group of
both male and female rats weighing 180 – 220 g using a
carrageenan-induced edema model [2]. An increase in the
foot edema volume was determined oncometrically before
and 4 h after carrageenan injection. The reference drug was
ortophen (10 mg/kg).
nounced antiinflammatory properties. The most active com-
pounds IIa and IIi were even more effective than ortophen.
EXPERIMENTAL CHEMICAL PART
REFERENCES
1
The H NMR spectra were measured at 25°C on an
1. M. S. Mashevskaya, V. S. Zalesov, and L. B. Falaleeva, USSR
Inventor’s Certificate No. 803358 (08.10.80).
2. B. A. Prozorovskii, Farmakol. Toksikol., No. 4, 497 – 502
(1978).
3. F. P. Trikus, N. L. Makhorod, and B. N. Kolebanov, Nonstan-
dard Antiinflammatory Agents [in Russian], Zdorov’e, Kiev
(1975).
RS-60 spectrometer (working frequency, 60 MHz) using
deuterated DMSO as the solvent and HMDS as the internal
standard. The data of elemental analyses for nitrogen agree
with the results of calculations based on the empirical formu-
las.