Synthesis and antiinflammatory activity of isonicotinic and cinchoninic acid derivatives

Full text of DOI:10.1023/A:1021258510259

Pharmaceutical Chemistry Journal
Vol. 36, No. 8, 2002
SYNTHESIS AND ANTIINFLAMMATORY ACTIVITY
OF ISONICOTINIC AND CINCHONINIC ACID DERIVATIVES
M. V. Pavlova,1 A. I. Mikhalev,1 M. E. Kon’shin,1 M. V. Vasilyuk,1 and V. P. Kotegov1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 36, No. 8, pp. 27 – 28, August, 2002.
Original article submitted May 16, 2002.
It was reported that amides of isonicotinic [1, 2],
2-chloroisonicotinic [3], 2-chlorocinchoninic [5, 6], and
2-oxocinchoninic [7, 8] acids possess antiinflammatory
properties. In continuation of the previous investigations
aimed at finding new effective antiinflammatory agents, we
have synthesized a series of previously unreported substi-
tuted amides and esters of 2-chloroisonicotinic acid (Ia – Ij,
Table 1) and aryl esters of 2-chloro-(IIa – IIg) and
2-oxocinchoninic (IIIa – IIIe) acids (Table 2).
tion of chloroanhydrides of the corresponding acids with
amines or phenols.
The 2-oxocinchoninic acid esters IIIa – IIIe were ob-
tained on heating aryl esters of 2-chlorocinchoninic acid with
concentrated acetic acid in the presence of sodium acetate.
The smooth character of this reaction is apparently related to
the high nucleophilicity of the acetate ion, the considerable
mobility of the chlorine atom, and the solvating action of
acetic acid.
Compounds Ia – Ij and IIa – IIg appear as colorless crys-
talline substances insoluble in water and well soluble in most
organic solvents. Esters IIIa – IIIe appear as yellowish crys-
talline substances insoluble in water and soluble in organic
solvents such as dioxane, DMF, and DMSO. The proposed
COXR
COCl
RNH2 or ROH
N
Ià – Ij
Cl
N
Cl
1
structures were confirmed by the data of H NMR spectros-
copy.
I: X = NH (a – d), O (e – j); R = iso-C3H7 (a), tert-C4H9 (b), 3-ClC6H4 (c);
4-ClC6H4 (d); 4-BrC6H4 (e); 4-CH3C6H4 (f); 4-CH3OC6H4 (g);
4-CH3COC6H4 (h); 2-CH3OCOC6H4 (i); 4-CH3CONHC6H4 (j)
EXPERIMENTAL CHEMICAL PART
COCl
COOC6H4R
1
The H NMR spectra were measured at 20°C on an
CH3COONa,
HOC6H4R
CH3COOH
RYa-2310 (working frequency, 60 MHz) and Bruker WD-80
(80 MHz) spectrometers using HMDS at the internal stan-
dard. The samples were prepared as 5% solutions in
DMSO-d6 (for compounds Ia – Ij and IIa – IIf) and CDCl3
(for IIg and IIIa – IIIe). The yields and some physico-
chemical characteristics of the synthesized compounds are
given in Tables 1 and 2. The data of elemental analyses agree
with the results of analytical calculations using empirical for-
mulas.
N
Cl
N
Cl
IIà – IIg
COOC6H4R
N
H
O
IIIà – IIIe
2-Chloroisonicotinic acid amides (Ia – Id). To 1.57 g
(0.01 mole) of 2-chloroisonicotinic acid was added 30 ml of
thionyl chloride and the mixture was boiled for 1 h, after
which the excess thionyl chloride was distilled off at reduced
pressure. The residue was dissolved in 20 ml of benzene. To
this solution was added 0.01 mole of the corresponding
amine in 50 ml of the same solvent and 0.01 mole of
triethylamine and the mixture was heated for 1 h on a water
bath. Then benzene was distilled off and the residue was
treated with a 10% sodium hydrocarbonate solution. The pre-
II: R = 4-Br (a); 4-F (b); 4-CH3 (c); 4-CH3O (d); 4-CH3CO (e); 2-CH3OCO
(f); 4-CH3CONH (g);
III: R = 4-Br (a); 4-CH3 (b); 4-CH3O (c); 4-CH3CO (d); 2-CH3OCO (e).
It was established that amides Ia – Id and aryl esters
Ie – Ij and IIa – IIg are obtained with a high yield via interac-
1
State Pharmaceutical Academy, Perm, Russia.
State Medical Academy, Perm, Russia.
2
425
0091-150X/02/3608-0425$27.00 © 2002 Plenum Publishing Corporation

426
M. V. Pavlova et al.
cipitated product was separated by filtration and recry-
stallized from ethanol; 1H NMR spectrum (d, ppm):
6.08 – 6.31 (d, 1H, NH-alkylamide) or 10.22 – 10.36 (s, 1H,
NH-arylamide), 7.02 – 8.46 (m, ArH).
EXPERIMENTAL BIOLOGICAL PART
The antiinflammatory activity of the synthesized com-
pounds (Ia – Ij, IIa – IIg, IIIa – IIIe), 2-chloroisonicotinic
acid, and 2-chlorocinchoninic acid was studied on white
mongrel rats weighing 150 – 220 g bearing a foot edema
model [8] induced by subplantar injections of 0.1 ml of a 1%
carrageenan solution into the hind paws of the test animals.
The compounds to be tested (in a dose of 50 mg/kg) and the
reference drug ortophen (10 or 25 mg/kg) were intraperito-
neally injected 1 h prior to carrageenan. The edema growth
was evaluated oncometrically, by measuring the inflamed
foot volume 3 and 5 h after carrageenan injection [8], and ex-
pressed as percentage edema growth inhibition relative to
control. The experimental data were statistically processed in
terms of the Student t-criterion [9].
2-Chloroisonicotinic acid aryl esters (Ie – Ij). To
1.57 g (0.01 mole) of 2-chloroisonicotinic acid was added
30 ml of thionyl chloride and the mixture was boiled for 1 h,
after which the excess thionyl chloride was distilled off at re-
duced pressure. The residue was dissolved in 20 ml of ben-
zene. To this solution was added 0.01 mole of the corre-
sponding phenol in 50 ml of the same solvent and 0.01 mole
of triethylamine and the mixture was heated for 1 h on a wa-
ter bath. Then the benzene was distilled off and the residue
was treated with a 10% sodium hydrocarbonate solution. The
precipitated product was separated by filtration and
1
recrystallized from ethanol; H NMR spectrum (d, ppm):
6.75 – 8.58 (m, ArH).
It was found that 2-chloroisonicotinic acid administered
in a dose of 50 mg/kg inhibits the carrageenan edema
growth: by 61.2% after 3 h and by 59.4% after 5 h. Among
the 2-chloroisonicotinic acid aryl esters and amides (Ia – Ij),
a reliable antiinflammatory effect was observed only for
compound Ih which, in the same dose of 50 mg/kg, inhibited
the edema growth by 57.3 and 52.3% after 3 and 5 h, respec-
tively (thus being inferior to ortophen).
2-Chlorocinchoninic acid aryl esters (IIa – IIg). To
2.07 g (0.01 mole) of 2-chlorocinchoninic acid was added
30 ml of thionyl chloride and the mixture was boiled for 1 h,
after which the excess thionyl chloride was distilled off at re-
duced pressure. The residue was dissolved in 20 ml of ben-
zene. To this solution was added 0.01 mole of the corre-
sponding phenol in 50 ml of the same solvent and 0.01 mole
of triethylamine and the mixture was heated for 1 h on a wa-
ter bath. Then benzene was distilled off and the residue was
treated with a 10% sodium hydrocarbonate solution. The pre-
cipitated product was separated by filtration and recry-
stallized from isopropyl alcohol; 1H NMR spectrum (d,
ppm): 6.83 – 8.95 (m, ArH).
2-Chlorocinchoninic acid in a dose of 50 mg/kg inhibits
the carrageenan edema growth by 45.3 and 41.6% after 3 and
5 h, respectively. Among the aryl esters of 2-chloro- and
2-oxocinchoninic acids, a reliable antiinflammatory effect
was observed only for compounds IIa, IIb, IIIa, IIIb, and IIIe
(Table 2).
2-Oxo-1,2-dihydrocinchoninic acid esters (IIIa – IIIe).
A mixture of 0.01 mole of 2-chlorocinchoninic acid ester and
1.2 g (0.015 mole) sodium acetate in 10 ml of concentrated
acetic acid was boiled for 1 h, cooled, and diluted with water.
The precipitated product was separated by filtration and
TABLE 2. Yields, Physicochemical Characteristics, and Antiinf-
lammatory Activity of Compounds IIa – IIg and IIIa – IIIe
1
recrystallized from dioxane; H NMR spectrum (d, ppm):
12.21 – 12.42 (bs, 1H, NH rings), 6.95 – 8.48 (m, ArH).
Edema growth
inhibition,
Com- Yield,
pound
M.p.,
°C
Empirical
formula
Dose,
% of control
%
mg/kg
3 h 5 h
IIa
83 160 – 161 C16H9BrClNO2 50
20.3* 26.2*
IIb
81 124 – 125 C16H9ClFNO2
79 125 – 126 C17H12ClNO2
81 125 – 127 C17H12ClNO3
72 120 – 122 C18H12ClNO3
75 129 – 131 C18H12ClNO4
64 194 – 196 C18H13ClN2O3
91 260 – 262 C16H10BrNO3
83 228 – 229 C17H13NO3
78 238 – 240 C17H13NO4
85 243 – 244 C18H13NO4
87 228 – 230 C18H13NO5
50
50
…
…
50
50
27.6** 34.0***
IIc
–
…
…
–
–
…
…
–
TABLE 1. Yields and Physicochemical Characteristics of Com-
pounds Ia – Ij
IId
IIe
Compound
Yield, %
M.p., °C
Empirical formula
IIf
Ia
Ib
Ic
Id
Ie
If
73
76
79
77
85
83
79
77
81
76
104 – 105
105 – 106
131 – 132
144 – 145
80 – 81
80 – 81
79 – 80
C9H11ClN2O
C10H13ClN2O
C12H8Cl2N2O
C12H8Cl2N2O
C12H7BrClNO2
C13H10ClNO2
C13H10ClNO3
C14H10ClNO3
C14H10ClNO4
C14H11ClN2O3
IIg
–
–
IIIa
IIIb
IIIc
IIId
IIIe
Ortophen
50 43.6** 39.5***
50
…
…
22.0*
22.3*
…
…
…
…
50 49.0*** 44.4***
25 69.4*** 72.2***
Ig
Ih
Ii
63
10 55.4**
…
80 – 81
Ij
166 – 167
Notes: * p > 0.05, ** p < 0.05, *** p < 0.001 relative to control.

Synthesis and Antiinflammatory Activity of Isonicotinic and Cinchoninic Acid Derivatives
427
4. O. A. Yanborisova, V. E. Kolla, S. A. Vikhareva, et al., Dep.
VINITI (07.06.90), No. 3119-B90.
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Thus, aryl eaters of 2-chloroisonicotinic acid and
2-chloro- and 2-oxocinchoninic acids are characterized by
lower antiinflammatory activity as compared to the acids
proper and their amides.
7. A. I. Mikhalev, M. E. Kon’shin, T. M. Konydina, et al.,
Khim.-Farm. Zh., 31(3), 37 – 38 (1997).
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