Pharmaceutical Chemistry Journal
Vol. 34, No. 11, 2000
THE SYNTHESIS AND PHARMACOLOGICAL ACTIVITIES
OF 1-ISOPROPYL-2-FORMYL-3-AMINOPYRAZOLIDINES
1
2
1
2
1
L. F. Mel’nikova, K. N. Zelenin, E. E. Lesiovskaya, I. P. Bezhan, and B. A. Chakchir
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 34, No. 11, pp. 12 – 14, November, 2000.
Original article submitted May 15, 2000.
With the aim of identifying safe, high-efficacy sub-
stances with anti-inflammatory activity, we have synthesized
aminopyrazolidines (compounds I – VIII) from 1-isopropyl-
10 ml of benzene was mixed with an equimolar quantity of
aniline; the mixture was heated for 1 h and cooled; the result-
ing precipitate was collected by filtration and recrystallized
from a mixture of ethyl acetate and petroleum ether. The
yield was 57% (Table 1). Compounds II – VIII were pre-
pared by the same method, from substituted anilines,
benzylamine, and morpholine. Some of the physicochemical
properties of the study compounds are presented in Table 1;
PMR spectral data are shown in Table 2.
2
-formyl-3-hydroxypyrazolidine (compound IX). Compound
IX was selected as the initial compound, as it has been shown
1] to have high anti-inflammatory activity combined with
[
low toxicity. Compound IX was synthesized by interaction of
acrolein with 1-formyl-2-isopropylhydrazine. The active
polyaminal hydroxyl group of compound IX reacts with
amines, forming the corresponding 1-isopropyl-2-formyl-3-
aminopyrazolidines (compounds I – VIII):
EXPERIMENTAL PHARMACOLOGICAL PART
OH
H C
1
HNR R
2
The acute toxicities of compounds on i.p. dosage was
measured as described in [2] in mongrel white mice weigh-
ing 18 – 20 g.
3
H C CH· CHO
2
N
O
NH
NH
O
H
N
H C
3
H
H C
CH3
3
Anti-inflammatory activities were studied in a model of
acute inflammation edema in the footpads of male rats
weighing 180 – 200 g, induced by subplantar administration
of 0.1 ml of 0.1% carrageenan 1 h after p.o. doses of study
compounds [5]. Oncometric measurements were made of
limb volume before and 4 h after experiments started (i.e., at
the time of maximum edema). The antiproliferative activities
of study compounds were studied in the cotton granuloma
model [6]; inflammation was induced by subcutaneous inser-
tion of sterilized cotton balls weighing 15 mg on the back
1
NR R
2
IX
N
O
N
H
CH3
H C
3
I VIII
EXPERIMENTAL CHEMICAL PART
(
the procedure was performed under light ether anesthesia).
Compounds were given for seven days; on experimental day
, implanted cotton balls with the surrounding newly formed
PMR spectra were recorded on a Tesla BS-497 (Czecho-
slovakia) spectrometer with a working frequency of 100
8
MHz at 25°C in DMSO-d solutions; the internal standard
6
granulation tissue were removed, dried to constant weight at
a temperature of 55 – 60°C, and the weight of newly formed
granulation tissue was determined from the difference be-
tween the weight of the dried granuloma and the weight of
the implanted cotton ball. Study compounds were given p.o.
at doses of 1/20 to 1/50 of the LD . The reference agent
was HMDS. Reaction courses and product purities were
monitored by TLC on Silufol UV-254 plates developed with
a benzene : acetone (4 : 1) system and detected with iodine
vapor.
1-Isopropyl-2-formyl-3-anilinopyrazolidine
(com-
5
0
pound I). Hydroxypyrazolidine IX (15.8 g, 0.1 mole) in
was butadione.
Analgesic activity was studied in mongrel white mice us-
ing an acetic acid spasm model [6], with measurement of the
number of spasms induced by i.p. doses of 3% acetic acid
1
State Chemicopharmaceutical Academy.
Military Medical Academy, St. Petersburg.
2
582
0
091-150X/00/3411-0582$25.00 © 2001 Plenum Publishing Corporation
Mel'nikova
