Pharmaceutical Chemistry Journal Vol. 33, No.

4, 1999

SYNTHESIS AND ANTIINFLAMMATORY ACTIVITY

OF 4-AMINOANTIPYRINE DERIVATIVES OF SUCCINAMIDES

D. B u r d u l e n e , ~ A . P a l a i m a , i Z . S t u m b r y a v i c h y u t e , I a n d Z. T a l a i k i t e ~

Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 33, No. 4, pp. 2 0 - 2 2 , April, 1999.

Original article submitted June 13, 1998.

It was reported that there are active antiinflammatory

substances among the derivatives of 4-aminoantipyrine [ 1 - H3C'c:c/NHSO~
4]. In the search for new antiinflammatory agents, we have [ t 5' 6'
synthesized and characterized a series of substituted succi- N C..~
H3C/ "N ~ O
namides (I - XIV). Ph
XII XIV
H3C",C :. C/NHCOCH2CH2COR
I I
H3C"N "~ / C,,~O XII NHCOCH3
XIII NH2
Ph
1 - XI XIV NHCOCH2CH2COOH
R

1 OCH3
I1 OH Substituted 4-(N-antipyryl)succinediamides I I I - V were
--N O obtained by aminolysis of [3-carbomethoxypropionamide (I)
Ill
with ethanol solutions of amines or amino alcohols as de-
IV N(CH3)CH2CH2OH scribed in [5, 6]. Diamides VI - XI were synthesized by inter-
V N(CH2CH2OH)2 action of the corresponding N-[p-(sulfamoyl)phenyl]succi-
namic acids [5, 7] with aminoantipyrine using a procedure
VI HN~SO2NH2 proposed in [5]. Compound II was obtained from I under the
action of an alkali solution in ethanol.
CH 3
The interaction of p-acetaminobenzene sulfochloride
with aminoantipyrine in acetonitrile led to compound XII.
VII
N =--~, This product was converted into compound XIII under the ac-
CH 3 tion of an alkali solution in ethanol as described in [7]. Fi-
nally, succinamide XIV was synthesized by condensation of
VIII compound XIII with succinic anhydride in acetone [9].
The synthesized compounds appeared as white crystal-
line substances stable at room temperature. The compound
IX are soluble in water and DMSO. The proposed structures of
the synthesized compounds were confirmed by data of IR and
HN - ~ - ~ S O 2 N H _ T C - - ,C"CH3 IH NMR spectroscopy (see Table 1 and the experimental
chemical part). Interpretation of the IH NMR spectra was
I based on the chemical shifts, multiplicities, ad integral inten-
Ph sities of the signals.

XI EXPERIMENTAL CHEMICAL PART

The IR spectra were measured on a Specord IR-75 spec-

I Institute o f B i o c h e m i s t r y , Vilnius, Lithuania. trophotometer (Germany) using samples prepared as nujol

191
0091- 150X/99/3304-0191$22.009 1999Kluwer Academic/Plenum Publishers
192 D. Burdulene et al.

mulls. The IH NMR spectra were recorded on a Bruker AC-
300 spectrometer (Germany) operating at a working fre-
quency of 300.15 MHz, using DMSO-d6 as the solvent and
TMS as the internal standard.
The data of elemental analyses coincide with the results
of analytical calculations according to empirical formulas.
The completion of reactions was checked and the purity
of the reaction products was established by TLC on Silufol
UV-254 plates eluted with a chloroform-methanol (8:2)
mixture. The spots were visualized with the aid of an ultra-
chemiscope.
The yields and physicochemical characteristics of pre-
viously unreported compounds (III-XIV) are presented in
Table 1.
Substituted suceinediamides I I I - V . To a solution of
0.01 mole of N-(1-phenyl-2,3-dimethyl-4-pyrazolon-5-
yl)succinamic acid methyl ester (I) in propyl alcohol was
added 0.02 mole of the corresponding secondary amine and
the reaction mixture was boiled for 3 - 9 h. Then the solvent
was distilled off in vacuum and the residue mixed with a
small amount of ether. The precipitate was filtered, dissolved
in a minimum amount of chloroform, and passed through a

TABLE i. Physicochemical Characteristics of Compounds 111-X1V

M.p., ~ IR spectrum
Corn- Yield, % (solvent for Empirical (Vmax,c m -I) ]H NMR spectrum: chemical shift 8, ppm
pound crystalliza}ion)* formula
CO NH, OH

Ill 91 203.5 - 204.5 (A) CIgH24N404 1645,1670 3200 2.10 (s, CH3C), 2.50-2.66 (m, CHzCH2), 3.04 (s, CH3N), 3.38 -
3.64 (m, morpholino), 7.29-7.52 (m, C6H5), 8.94 (s, NH)
IV 98 107-172 (B) C18H24N404 1650,1680 3200, 2.10 (s, CH3C), 2.50 - 2.68 (m, COCH2CH2), 2.84 and 3.04 (s,
3340 2CH3N), 3.32 - 3.60 (m, CH2CH20) , 4.54 and 4.76 (bs, OH),
7.29-7.55 (m, C6H5), 8.96 (s, NH)
95 161 - 162 (C) CIgH26N405 1645, 1660 3t85, 2.10 (s, CH3C), 2.47 - 2.70 (m, CH2CH2), 3.04 (s, CH3N), 3.30 -
3380 3.60 (m, 2NCH2CH20), 4.57 and 4.78 (bs, 2OH), 7.29 - 7.56 (m,
C6H5), 8.96 (s, NH)
VI 93 225 - 2 2 7 (D) C21H23N505S 1645,1690 3160, 2.1.1 (s, CH3C), 2.66 (m, CHzCH2), 3,03 (s, CH3N), 7.09 (s,
3240, NH2),7.29 - 7.56 (m, C6H5), 7,78 - 7.84 (m, C6H4), 8.94 (s, N H),
3300 10.15(s, NHC6H 4)
Vll 89 228 - 2 2 9 (C) C27H29N7OsS 1650, 1695 3170, 2.10 (s, CH3C-antipyryl), 2.26 (s, 2CH3C*=*), 2.64 (m,
3255, CH2CH2),3.03 (s, CH3N), 6.76 (s, CH), 7.29- 7.56 (m, C6H5),
3295, 7.73 - 7.93 (m, C6H4), 8.94 (s, NH-antipyryl), 10.15 (s,
3350 NHC6H4), 11.25 (s, NHS)
VIII 87 226 - 229 (E) C25H27N705S2 1650,1695 3165, 1.23 (t, CH3CH2), 2.11 (s, CH3C-antipyryl), 2.66 (m, CH2CH2),
3250, 2.83 (q, CH~CH3), 3.05 (s, CH3N), 7.27- 7.57 (m, C6H5), 7.75 -
3295 7.71 (m, C6H4), 8.94 (s, NH-antipyryl), 10.18 (s, NHC6H4), 13.70
(s, NHS)
1X 81 222 - 224 (E) C24H24N605G2 1650,1690 3160, 2.11 (s, CH3C), 2.66 (m, CH2CH2), 3.04 (s, CH3N), 6.79 (d,
3230, SCH), 7.18 (d, NCH), 7.27 - 7.56 (m, C6H5), 7.72 (m, C6H4),
3280, 8.94 (s, NH-antipyryl), 10.15 (s, NHC6H4)
3390
X 92 173 - 175 (E) C32H32N706G 1645, 1690 3160, 2.09 (s, 2CH3C), 2.66 (m, CH2CH2), 3.04 (s, CH3N), 7.21 - 7.56
3230, (m, 2C6H5), 7.68 - 7.78 (m, C6H4), 8.92 and 9.08 (s, NH-
3290, antipyryl), 10.20 (s, NHC6H4)
3460
XI 85 259 - 2 6 1 (E) CLsHIoNsO3S 1650,1680, 3160, 2.11 (s, CH3C), 2.60-2.73 (m, CH2CH2), 3.04 (s, CH3N),
1700 3210, 7.15 (d, CHS), 7.27 - 7.55 (m, C6H5) , 7.46 (d, CHN), 8.98
3405 (s, NH-antipyryl), 11.93 (s, Nil)
Xll 98 261 - 264 (D) CIgH20N404S t640 3155, 2.07 (s, 2CH3C), 3.06 (s, CH3N), 7.23 - 7.50 (m, C6Hs),
3220, 7.69-7.76 (m, C6H4), 8.98 (s, NHS), 10.19 (s, NHCO)
3260
Xlll 93 2 6 5 - 268(D) CITHIgN403S 1630 3190, 2.06 (s, CH3C), 3.04 (s, CH3N), 5.73 (s, NH~), 6,58 (m, H2', H6'),
3310, 7.26-7.50 (m, C6H5, H3', H5'), 8.49 (s, NHS)
3440
XIV 95 205 - 209 (D) C21H22N406S 1700,1735 3160, 2.11 (s, CH3C), 2.54- 2.66 (m, CH2CH2), 3.06 (s, CH3N),
3210, 7.22 - 7.52 (m, C6H5), 7.69 - 7.78 (m, C6H4), 8.93 (s, NHS),
3240, 10.18 (s, NHCO)
3295
A = acetone; B = 2-propanot; C = 60% aqueous 2-propanol; D = methanol - DMF; E = 2-propanol - D M F .
Synthesis and Antiinflammatory Activity of 4-aminoantipyrine Derivatives of Succinamides 193

layer of aluminum oxide. Finally, the solvent was distilled off TABLE2. Antiinflammatory Activity of Substituted N-(4-Antipyryl)suc-
cinic Acid Diamides with Respectto Adjuvant Arthritis in Rats
and the residue washed with ether and dried.
General method for the synthesis of diamides V I - XI. Daily Percentagechange ofjoint volume (left hind paw)
Compoun dose, on the day of treatment indicated
To a solution o f 0.01 mole o f the corresponding N-[p-(sul- d nag/ kg
famoyl)phenyl]succinamic acid in 16 ml pyridine cooled t o - (p.o,) 3-4 5-8 9- II 12- 15 17- 18
2~ was added 2.03 g (0.01 mole) o f 4-aminoantipyrine and 111 500 -6.57 - 13.85 - 1.75 + 11.68 - 19.18
2.3 g (0.011 mole) o f N,N'-dicyclohexylcarbodiimide and the IV 500 - 12.41 -0.87 + 0.58 + 2.54 -31.05"
reaction mixture was allowed to stand for 24 h in a refrigera- V 500 -6.29 -4.51 -6.96 - I 1.40 - 11.30
tor. The precipitated N,N'-dicyclohexylurea was separated by Butadion 80 -31.82" -31.75" -11.27 -38.74* -53.09*
filtration and the residual pyridine evaporated at a reduced * p < 0.05 against control.
pressure. The residue was washed with cold water, 1 N hy-
drochloric acid, and water aga!n. The precipitate was filtrated
and dried.
l-Phenyl-2,3-dimethyl-4-(4'-aeetylaminophenyl)sulf perorally at a single daily therapeutic dose o f 500 m g / k g
onylamino-5-pyrazolone (XII). To a solution o f 2.33 g (LDs0 in mice is 5000 r a g / k g ) over a period o f 17 - 18 days
(0.01 mole) o f N-acetylsulfanyl acid chloroanhydride in (except weekends). The daily dose o f the reference drug bu-
30 ml of acetonitrile was added 1.45 ml o f triethylamine and tadion was 80 m g / kg.
2.03 g (0.01 mole) o f 4-aminoantipyrine. The reaction mix- The experimental data were statistically processed by
ture was stirred for 1 h at room temperature and poured into conventional techniques [10]. The data were considered as re-
50 ml of water. The precipitate was filtrated, washed with liable f o r p < 0.05.
cold water, and dried in a vacuum desiccator. It was found that compound IV is the only one possessing
l-Phenyl-2,3-dimethyl-4-(4'-aminophenyl)sulfonylam antiinflammatory activity among the series o f substances
ino-5-pyrazolone (XIII). To a solution of 1.68 g (0.03 mole) studied (Table 2).
o f KOH in 30 ml o f methanol was added 4 g (0.01 mole) of
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