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V. A. Glushkov et al.
tion of crystals precipitated from the toluene layer washed
with 200 ml of water and allowed to stand for 1 – 2 h. The
third portion was obtained from the aqueous layer washed
with 40 ml of toluene and alkalized with dry NaHCO3 to
pH ~ 7. The three portions were combined, dried, and recrys-
tallized from dichloroethane to obtain 15.6 g (58%) of com-
pound IVc; m.p., 141 – 142°C.
A similar procedure was used to obtain amide IVd proce-
eding from carbinol Ib and benzonitrile; the final product
was recrystallized from aqueous ethanol (Table 1).
N-[(1- p-Hydroxyphenyl-2-methyl)-2-propyl]carbamic
acid thiobenzyl ester (IVe). To 15 ml of a 96% sulfuric acid
was added dropwise with stirring at a temperature within
10 – 20°C (cooling on a water bath) a solution of 9.0 g
(50 mmole) of carbinol Ia and 5.96 g (40 mmole) of benzyl
rhodan in 110 ml of toluene. When all the solution was ad-
ded, the reaction mass was stirred for 0.5 h and the thicke-
ning mass was poured into 300 ml of cold water. The aqueo-
N-[(1- p-Hydroxyphenyl-2-methyl)-2-propyl]malona-
mic acid p-fluorobenzylidenehydrazide (VIa). A mixture
of 0.5 g (1.79 mmole) of hydrazide Va and 0.24 g
(1.97 mmole) of p-fluorobenzaldehyde in 5 ml of ethanol
was boiled for 5 min. The precipitate was separated by filtra-
tion, washed with hot ethanol, and recrystallized to obtain
0.4 g (72%) of compound VIa. Similar procedures were used
to obtain hydrazides VIb – VIe.
N-[(1- p-Hydroxyphenyl-2-methyl)-2-propyl]malona-
mic acid furfurylidenehydrazide (VIf). A mixture of 0.5 g
(1.79 mmole) of hydrazide Va and 0.19 mg (1.79 mmole) of
freshly distilled furfural in 3 ml of ethanol was boiled for
0.5 h. Then 1 ml of water was added and the mixture was al-
lowed to stand for 12 h. The precipitate was separated by filt-
ration and recrystallized from aqueous ethanol to obtain
0.39 g (71%) of hydrazide VIf.
EXPERIMENTAL PHARMACOLOGICAL PART
us layer was washed with toluene (2 ´ 40 ml) and neutralized
with dry NaHCO3 to pH ~ 8. The precipitate was separated
by filtration and dried. The toluene layer was allowed to
stand in the cold and the precipitate product was also separa-
ted and dried. Finally, the combined precipitates were recrys-
tallized from aqueous ethanol to obtain 9.2 g (81%) of com-
pound IVe.
The antiinflammatory activity was studied on a group of
both male and female rats weighing 180 – 220 g. A model
edema was induced by subplantar injections of 0.1 ml of a
1% aqueous carrageenan solution [7]. The test compounds
were intraperitoneally injected (1 h before carrageenan) with
a 2% starch jelly in a dose of 50 mg/kg. The reference drug
was ortophen (10 mg/kg). The increase in the foot edema
volume was determined oncometrically before test and 4 h
after carrageenan injection. The antiinflammatory effect was
evaluated by the percentage inhibition of the model edema
growth relative to that in the control group (injected with a
pure 2% starch jelly).
The analgesic activity was studied on a group of both
male and female white mongrel mice weighing 18 – 20 g
subjected to a hot plate test [8]. The compounds were injec-
ted 1 h before test in a dose of 50 mg/kg (i.p.) with a 2%
starch jelly The reference drug was analgin administered in a
dose of ED50 = 93 mg/kg [9]. The drug activity was evalua-
ted by determining the onset time of the defensive response
(hind paw licking).
Each compound was tested in a group of six animals; the
control groups contained ten animals. The acute toxicity was
determined by intraperitoneal injection to white mice and
evaluated by LD50 [10]. The experimental data were statisti-
cally processed in terms of the Student t-criterion [11]. The
effects were considered as reliable for p £ 0.05.
It was established that intermediate spiropyrrolines (IIIa,
IIIb) do not exhibit antiinflammatory action, although com-
pound IIIb produced an analgesic effect [(Table 3).
N-[2-( p-Hydroxyphenyl)-1,1-dialkylethyl]malonamic acid
ethyl esters IVa, IVb, and IVg also produced a reliable ana-
lgesic effect, this activity being weakly pronounced in substi-
tuted N-( p-hydroxyphenylethyl)amides of benzoic (IVc,
IVd), benzylthiocarboxylic (IVe), and phenylacetic (IVf)
acids. In view of the similar structure of these compounds,
we may suggest that the analgesic activity of the former es-
A similar procedure was used to obtain amide IVf proce-
eding from carbinol Ib and benzyl cyanide.
N-[(1- p-Hydroxy-m-methoxyphenyl-2-methyl)-2-pro-
pyl]malonamic acid ethyl ester (IVg). To 60 ml of a 96%
sulfuric acid was added dropwise with stirring a mixture of
13.1 ml (13.8 g, 0.1 mole) 1,3-dimethoxybenzene, 9.1 ml
(7.2 g, 0.1 mole) of freshly distilled isobutyric aldehyde, and
10.6 ml (11.3 g, 0.1 mole) of cyanoacetic ester, and 30 ml to-
luene. The reaction mass was stirred for 1 h and poured into
300 ml of water. The aqueous layer was separated, washed
with 30 ml of toluene, and neutralized with dry NaHCO3 to
pH ~ 7. The product was extracted with CH2Cl2 (2 ´ 70 ml),
the extract was dried over MgSO4, and the solvent was distil-
led off. This yielded 19.3 g of a viscous gummy product. Af-
ter chromatography of a 1-g portion on 70 g of silica gel elu-
ted with a hexane – ethyl acetate (2 : 1) mixture, the fraction
with Rf = 0.35 was collected, the solvent was distilled off,
and the residue was crystallized from acetone (with water ad-
ded on cooling to –20°C). This yielded 0.44 g of compound
IVg with m.p. = 103 – 106°C; total yield, 45% (calculated
for the initial charge of reagents).
N-[(1- p-Hydroxyphenyl-2-methyl)-2-propyl]malona-
mic acid hydrazide (Va). A solution of 1.0 g (3.57 mmole)
of ester IVa and 0.5 ml (8.5 mmole) of 85% hydrazine hydra-
te in 10 ml of ethanol was boiled for 2 h, poured into 10 ml
of water, and allowed to stand for 12 h. The precipitate was
separated by filtration and recrystallized to obtain 0.32 g
(64%) of compound Va. A similar procedure was used to ob-
tain hydrazide Vb proceeding from ester IVb.
Glushkov
