Synthesis and antiinflammatory and analgesic activity of some arylamides of N-substituted anthranilic acids

Full text of DOI:10.1023/A:1010423827419

Pharmaceutical Chemistry Journal
Vol. 35, No. 4, 2001
SYNTHESIS AND ANTIINFLAMMATORY AND ANALGESIC ACTIVITY
OF SOME ARYLAMIDES OF N-SUBSTITUTED ANTHRANILIC ACIDS
A. B. Shakirova,1 A. V. Podchezertseva,1 L. M. Korkodinova,1 M. Yu. Vasil’eva,1 V. É. Kolla,1
L. G. Mardanova,1 N. I. Vakhrina,1 and Yu. L. Danilov1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 4, pp. 17 – 19, April, 2001.
Original article submitted July 18, 2000
Our previous analysis [1] of the structure – antiinflam-
matory activity – toxicity relationship in a series of
1-(3¢-chlorobuten-2¢-yl)-2-methyl-3-aryl-4(3H)-quinazolino-
nium perchlorates obtained from N-acetyl-N-(3¢-chlorobu-
ten-2¢-yl)anthranilic acid arylamides was not complemented
by a study of the antiinflammatory properties of the latter
compounds. To fill the gap, we have synthesized and charac-
terized a series of N-alkenylanthranilic acid arylamides with
the general formula
in the presence of concentrated sulfuric acid [1], was treated
with a mixture of ethylmagnesium bromide and arylamine to
obtain compounds I. Compounds II were obtained by
acetylation of the corresponding N-(3¢-chlorobuten-2¢-yl)an-
thranilic acid arylamides. Compound III was synthesized by
acylating bromoanilide Ic with adamantanecarboxylic acid
anhydride.
The synthesized compounds are white, sometimes with a
yellowish tint, crystalline substances insoluble in water and
soluble in ethanol, DMSO, and DMF.
CONHR'
N
R
CH2CH CClCH3
I – III
EXPERIMENTAL CHEMICAL PART
The IR spectra were recorded on a UR-20 spectrophoto-
meter (Germany) using samples prepared as nujol mulls. The
1H NMR spectra were measured on an RYa-2310 spectrome-
ter operated at a working frequency of 60 Hz. The chemical
shifts were calculated relative to HMDS internal standard
and expressed on the d (ppm) scale.
Compounds I – III were synthesized according to the
scheme
CONHR"
COOCH3
NH CH2CH CClCH3
Ia – Id
NH CH2CH CClCH3
N-(3¢-chlorobuten-2¢-yl)anthranilic acid 4-bromoani-
lide (Ic). To a solution of ethylmagnesium bromide, obtained
from 16.3 g (150 mmole) of ethyl bromide and 3.6 g
(150 mmole) Mg in 50 ml of anhydrous diethyl ether, were
added 9.6 g (75 mmole) of 4-bromoaniline in 20 ml of anhy-
drous ether and the mixture was heated for 30 min on a water
bath. Then a solution of 12 g (50 mmole) of N-(3¢-chlorobu-
ten-2¢-yl)anthranilic acid methyl ester was added dropwise
and the mixture was heated for another 30 min. Upon termi-
nation of the reaction, the organomagnesium compound was
decomposed by treatment with a 10% CH3COOH. The ether
layer was decanted and the aqueous layer was extracted with
CONHR"
COCH3
CONHR"
CO
N
CH2CH CClCH3
N
CH2CH CClCH3
IIa – IIg
III
I: R¢ = C6H4CH3-4 (a); C6H4OCH3-4 (b); C6H4Br-4 (c); 2-PyBr-5 (d);
II: R¢ = C6H4CH3-4 (a); C6H4OCH3-4 (b); C6H4Br-4 (c); 2-PyBr-5 (d);
C6H4CH3-3 (e); C6H4CH3-2 (f); C6H5 (g);
III: R¢ = C6H4Br-4.
ether (3 ´ 40 ml). Finally, solvent was distilled off from the
ether extracts with aqueous vapor. Yield of compound Ic,
75%.
The methyl ether of N-(3¢-chlorobuten-2¢-yl)anthranilic
acid, synthesized by esterification of this acid with methanol
Analogous procedures were used to obtain compounds
Ia, Ib, and Id.
1
State Pharmaceutical Academy, Perm, Russia.
193
0091-150X/01/3504-0193$25.00 © 2001 Plenum Publishing Corporation

194
A. B. Shakirova et al.
TABLE 1. Yields, Physicochemical Characteristics, and Parameters of the IR and 1H NMR Spectra of the Synthesized Compounds
Compound Empirical formula Yield, %
M.p., °C
IR spectrum: nmax, cm – 1
1H NMR spectrum (solvent): d, ppm
Ia
Ib
C18H19ClN2O
C18H19ClN2O2
77
62
113 – 115
1320, 1370, 1390, 1460,
1510, 1590, 1640, 3120,
3150, 3320, 3380
CDCl3, 2.1 (d, 6H, 2CH3), 3.76 (m, 2H, CH2), 5.4 (m,
H, CH=), 6.26 – 7.50 (m, arom. H), 7.6 (s, 2H, NH,
CONH)
120 – 121
1310, 1450, 1570, 1640,
3200, 3350
(CD3)2SO, 2.03 (s, 3H, CH3), 3.57 (s, 3H, OCH3), 3.87
(d, 2H, CH2), 5.57 (t, H, CH=), 6.07 – 7.87 (m, arom. H,
NH, 9H), 9.1 (s, H, CONH)
Ic
Id
C17H16BrClN2O
C15H15BrClN3O
75
45
122 – 124
71 – 73
1340, 1450, 1520, 1590,
1630, 3220
CDCl3, 1.96 (s, 3H, CH3), 3.8 (d, 2H, CH2), 5.43 (m, H,
CH=), 6.7 – 7.5 (m, arom. H), 7.7 (s, 2H, NH, CONH)
1370, 1460, 1520, 1560,
1580, 1650, 3340
CF3COOH, 2.0 (s, 3H, CH3), 3.73 (s, 2H, CH2), 5.53 (d,
H, CH=), 6.5 (d, 3H, Py), 6.8 – 8.47 (m, arom. H), 10.3
(s, 2H, NH, CONH)
IIa
IIb
IIc
IId
IIe
IIf
C20H21ClN2O2
C20H21ClN2O3
C19H18BrClN2O2
C17H17BrClN3O2
C20H21ClN2O2
C20H21ClN2O2
77
67
69
51
52
57
129 – 130
113 – 115
179 – 181
159 – 161
152 – 154
129 – 131
…
CDCl3, 1.78 (d, 6H, 2CH3), 2.23 (d, 3H, COCH3), 4.26
(m, 2H, CH2), 5.53 (m, H, CH=), 6.63 – 8.1 (m, arom.
H), 8.5 (s, H, CONH)
1310, 1410, 1450, 1640,
1680, 3200
CDCl3, 1.7 (s, 3H, CH3), 2.06 (d, 3H, COCH3), 3.72 (s,
3H, OCH3), 4.25 (t, 2H, CH2), 5.56 (m, H, CH=),
6.3 – 7.8 (m, arom. H), 8.03 (s, H, CONH)
1320, 1400, 1440, 1510,
1570, 1610
CF3COOH, 2.1 (s, 3H, CH3), 2.93 (d, 3H, COCH3), 5.38
(d, 2H, CH2), 5.78 (m, H, CH=), 7.1 – 8.3 (m, arom. H),
8.96 (s, H, CONH)
1300, 1380, 1400, 1450,
1470, 1490, 1520, 1580,
1590, 1680, 3080, 3230
CF3COOH, 1.87 (s, 3H3, CH3), 3.60 (d, 3H, COCH3),
4.03 (d, 2H, CH2), 5.53 (m, H, CH=), 6.93 – 8.43 (m,
arom. H), 10.7 (s, H, CONH)
1320, 1380, 1470, 1610, 3250 CDCl3, 2.0 (d, 9H, 2CH3, COCH3), 4.03 (m, 2H, CH2),
5.4 (m, H, CH=), 6.4 – 7.73 (m, arom. H), 7.8 (s, H,
CONH)
1330, 1460, 1510, 1560,
1610, 3200
CDCl3, 1.87 (s, 6H, 2CH3), 2.1 (d, 3H, COCH3), 4.31
(m, 2H, CH2), 5.58 (m, H, CH=), 6.9 – 8.1 (m, arom. H,
CONH, 9H)
IIg
III
C19H19ClN2O2
79
49
154 – 155
187 – 188
1300, 1310, 1380, 1410,
1450, 1490, 1640, 1680, 3210
…
C28H30BrClN2O2
1390, 1460, 1530, 1590,
1610, 1670, 3250
CF3COOH, 1.7 (s, 3H, CH3), 1.9 – 2.6 (d, 15H
1-adamantyl), 4.27 (d, 2H, CH2), 5.7 (m, H, CH=),
7.1 – 8.2 (m, arom. H), 9.3 (s, H, CONH)
EXPERIMENTAL PHARMACOLOGICAL PART
N-(3¢-chlorobuten-2¢-yl)-N-acetylanthranilic acid 4-ani-
sidide (IIb). A solution of 3.31 g (10 mmole) of compound
Ib in 6 ml of acetic anhydride was heated for 35 min on a wa-
ter bath and allowed to cool. Then the reaction mass was di-
luted with 50 ml of water and neutralized with sodium car-
bonate. The precipitate was separated by filtration and
recrystallized from ethanol; yield of compound IIb, 67%.
Analogous procedures were used to obtain compounds
IIa and IIc – IIg.
The antiinflammatory activity of the synthesized com-
pounds was studied on white mongrel rats weighing
180 – 220 g, bearing a carrageenan-induced foot edema
model. The compounds to be tested (in a dose of 50 mg/kg)
and the reference drug ortophen (10 mg/kg) were
intraperitoneally injected with a 2% starch jelly 1 h before
inducing inflammation. The degree of edema development
was evaluated oncometrically, by measuring the inflamed
foot volume 4 h after carrageenan injection (0.1 ml of an 1%
N-(3¢-chlorobuten-2¢-yl)-N-(adamant-1²-yl)anthranilic
acid 4-bromoanilide (III). To a solution of 3.79 g
(10 mmole) of N-(3¢-chlorobuten-2¢-yl)anthranilic acid
4-bromoanilide (Ic) in 10 ml of benzene was added 1.98 g
(10 mmole) of adamantane-1-carboxylic acid anhydride and
the mixture was heated for 30 min at 80°C. Then benzene
was distilled off and the reaction mass was diluted with
20 ml of methanol and neutralized by sodium carbonate. The
precipitate was recrystallized from a methanol – DMF mix-
ture (1 : 1); yield of compound III, 49%.
aqueous solution) [2].
The analgesic activity was studied by the “hot plate” test
on white mongrel mice weighing 18 – 23 g [3]. Here, the
compounds studied were introduced in a dose of 50 mg/kg
perorally 30 min before placing the animal onto a metal plate
heated to 53.5°C. The change in the pain reaction was evalu-
ated by measuring the time of animal staying on the hot plate

Synthesis and Antiinflammatory and Analgesic Activity of Some Arylamides
195
TABLE 2. Antiinflammatory and Analgesic Activity and Acute
Toxicity of Compounds Ia – Id, IIa – IIg, and III
The acute toxicity of the synthesized compounds upon
single intraperitoneal injection was studied on white mice
weighing 17 – 22 g. The LD50 values were determined taking
into account the loss of animals within 24 h after injection
[4]. All experimental data were statistically processed by
Carrageenan
Latent period
Dose, foot edema
for defensive
reflex in mice,
sec
LD50,
Compound mg/kg growth inhi-
(i.p.) bition in rats,
% of control
mg/kg
conventional methods [5].
It was established that most of the synthesized com-
Ia
50
50
50
50
50
50
50
50
50
50
50
50
40.5*
38.8*
18.3
> 2000
> 2000
> 1500
…
14.6 ± 1.2
Ib
10.8 ± 0.8
pounds possess antiinflammatory and analgesic properties
(Table 2). The most pronounced antiinflammatory effect was
observed for compounds IIg and IIf and the analgesic action,
for compounds Id, IIb, IId – IIf, and III, which were compa-
Ic
15.3 ± 1.3
Id
17.5
21.0 ± 2.4**
15.2 ± 1.7
IIa
IIb
IIc
IId
IIe
IIf
IIg
III
45.4*
42.4*
35.4*
40.4*
49.7*
50.1*
57.3*
15.9
> 1500
> 1500
> 1500
…
18.8 ± 1.6**
14.1 ± 0.9
rable in activity with the reference drug (ortophen).
Thus, N-substituted anthranilic acid amides represent a
21.0 ± 2.2**
22.0 ± 2.6**
19.8 ± 1.8**
15.2 ± 1.5
promising group of compounds in the search for new
antiinflammatory and analgesic substances.
> 1500
> 1500
> 3000
REFERENCES
1000
(840 – 1190)
19.0 ± 1.7**
1. L. M. Korkodinova, M. I. Vakhrin, Yu. V. Kozhevnikov, et al.,
Khim.-Farm. Zh., 20(5), 553 – 556 (1986).
Ortophen
10
61.3*
74.0
(48.8 – 124.8)
17.4 ± 0.7**
2. R. S. Salyamon, Drug Control of the Inflammation Process [in
Russian], Medgiz, Leningrad (1958), pp. 11 – 43.
3. N. B. Eddy and D. J. Leimbach, J. Pharmacol. Exp. Ther., 107,
385 – 393 (1953).
Control
(2% starch
jelly)
–
–
…
11.0 ± 0.5
p < 0.05, ** p < 0.001 relative to control.
*
4. V. B. Prozorovskii, Practical Guide to Accelerated Determina-
tion of Mean Effective Doses and Concentrations of Biologically
Active Substances [in Russian], NPP-Nauka, St. Petersburg
(1992).
before the onset of a protective reaction (hind paw licking).
Each compound was tested in a group of ten animals.
5. M. L. Belen’kii, Elements of Quantitative Assessment of the
Pharmacological Effect [in Russian], Medgiz, Leningrad (1963).