Pharmaceutical Chemistry Journal
Vol. 35, No. 12, 2001
SYNTHESIS AND STUDY OF ANTIMICROBIAL
AND ANTIINFLAMMATORY ACTIVITY
OF 2-SUBSTITUTED NICOTINIC ACID AMIDES
M. V. Pavlova,1 A. I. Mikhalev,1 M. E. Kon’shin,1 M. Yu. Vasil’eva,2 L. G. Mardanova,2
T. F. Odegova,1 and M. I. Vakhrin1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 12, pp. 21 – 22, December, 2001.
Original article submitted July 9, 2001.
Previously, we have synthesized alkyl(aryl)amides of
2-chloro-, 2-amino-, and 2-arylaminonicotinic acids possess-
ing anticonvulsant activity [1, 2]; 2-chloro-, 2-methoxy-, and
2-hydroxynicitinic acid amides, some of which exhibited
antiinflammatory activity [3, 4]; and 2-arylhydroxynicotino-
nitriles and unsubstituted amides of 2-arylhydroxynicotinic
acids producing antiinflammatory and hypoglycemic effects
[5].
In the search for new antiinflammatory and antibacterial
agents in the group of 2-substituted nicotinic acid amides, we
have synthesized a series of nicotinamides containing
pharmacophore 4-sulfamylanilino or aryloxy groups at C-2
atom of the pyridine ring.
IIId: R1 = 2,4-(CH3)2C6H3; R2 = OCH3;
IIIe: R1 = 4-CH3COC6H4, R2 = NHCOCH3;
IIIf: R1 = 4-antipyryl, R2 = NHCOCH3.
Compounds IIa – IIg were synthesized by heating
2-chloronicotinic acid amides with p-aminosulfanylamides
in 50% acetic acid (this medium seems to simultaneously
produce a catalytic action). The target 2-aryloxynicotinic
acid amides (IIIa – IIIf ) were obtained via interaction of
2-chloronicotinic acid amides with phenols in DMF in the
presence of anhydrous potassium carbonate.
The final products IIa – IIf and IIIa – IIIf (Table 1) ap-
pear as colorless or slightly tinted crystalline substances well
soluble in organic solvents and insoluble in water. The pro-
COR1
1
CONHR1
posed structures were confirmed by the results of H NMR
+ HOC6H4R2
measurements.
N
O
R2
N
Cl
EXPERIMENTAL CHEMICAL PART
I
IIIa IIIf
1
The H NMR spectra were measured on an RYa-2310
COR1
NH
+NH2C6H4SO2NHR2
spectrometer using DMSO-d6 as the solvent and HMDS as
the internal standard. The yields and some properties of the
synthesized compounds are listed in Table 1. The data of ele-
mental analyses agree with the results of analytical calcula-
tions using empirical formulas.
SO2NHR2
N
IIa IIg
IIa: R1 = 3-CH3C6H4NH, R2 = H;
N-(4-Acetylphenyl)-2-chloronicotinamide (I, R1
=
IIb: R1 = morpholino, R2 = 4,6-dimethylpyrimidinyl;
4-MeCOC6H4NH). To 1.57 g (0.01 mole) of 2-chloronicoti-
nic acid was added 20 ml of thionyl chloride and the mixture
was heated on a water bath for 3 h, after which the excess
thionyl chloride was distilled off in vacuum. The residue was
mixed with 20 ml of benzene, 1.31 g (0.01 mole) of
p-aminoacetophenone, and 3 ml of triethylamine and the
mixture was heated on a water bath for 1 h. The precipitated
triethylamine hydrochloride was separated by filtration; vol-
atile impurities (benzene, etc.) were distilled off with water
vapor. The residue was treated with a 10% sodium hydrocar-
IIc: R1 = n-C4H9NH, R2 = 4,6-dimethylpyrimidinyl;
IId: R1 = cyclo-C6H11NH, R2 = 4,6-dimethylpyrimidinyl;
IIe: R1 = 3-CH3C6H4NH, R2 = 4,6-dimethylpyrimidinyl;
IIf: R1 = C6H5CH2NH, R2 = 4,6-dimethylpyrimidinyl;
IIg: R1 = 4-CH3COC6H4NH, R2 = 4,6-dimethylpyrimidinyl;
IIIa: R1 = cyclo-C6H11, R2 = F;
IIIb: R1 = C6H5CH2, R2 = OCH3;
IIIc: R1 = 4-CH3COC6H4, R2 = OCH3;
1
State Pharmaceutical Academy, Perm, Russia.
2
Perm State University, Perm, Russia.
664
0091-150X/01/3512-0664$25.00 © 2001 Plenum Publishing Corporation