Synthesis and Anticonvulsant Properties of Polyfluorinated Aliphatic Acid Amides
241
The yields and physicochemical characteristics of the
synthesized polyfluorinated aliphatic acid amides are sum-
marized in Table 1.
compounds IV, V, VI, and VIII according to scheme (1). The
results of the pharmacological tests showed that compounds
IV and VI did not prevent the loss of animals from corazole
convulsions, although compound IV in a dose of 300 mg/kg
increased the latent period before the onset of tonic convul-
sions with lethal outcome. Compounds V and VIII produced
a significant anticonvulsant effect (Table 2). The former
compound was characterized by a markedly longer latent pe-
riod before the onset of tonic extension and the loss of test
animals as compared to the value for compound VIII. On the
other hand, the percentage survival in the group of mice
treated with compound V was lower as compared to that for
compound VIII (Table 2).
The absence of anticonvulsant properties in
N-[2-(2,2,3,3-tetrafluoropropoxy)acyl]-g-aminobutyric acid
(compound VI) can be related to insufficient basicity of the
amino group in this compound as compared to the basicity of
NH2 group in GABA. However, additional fluorine satura-
tion of the acyl fragment in compound VI (on passage to
compound XVI) or shortening of the carbon chain (com-
pound XV) affected neither the latent period before the onset
of convulsions nor the degree of loss prevention. Apparently,
the absence of the desired physiological activity in com-
pounds VI, XV, and XVI is not related to the acidity of the
acylating carboxylic acid.
EXPERIMENTAL PHARMACOLOGICAL PART
The anticonvulsant activity was evaluated by antagonism
with respect to the corazole-induced convulsion model [12].
The tests were performed on male white mongrel mice
weighing 18 – 23 g. The convulsant (corazole) subcutane-
ously injected in a dose of 130 mg/kg leads to tonic exten-
sion and a 95% loss of the control mice. The synthesized
compounds were intraperitoneally injected (30 min before
corazole) in a dose of 100 – 300 mg/kg with a Tween-80
suspension. The drug effect was assessed by determining the
latent period before the onset of clonic convulsions, tonic ex-
tension, and the loss of test animals. The single dose effect
was studied in a group of 10 – 12 mice. The experimental
data were statistically processed using the Student and Fisher
methods.
The reference drug was the well-known anticonvulsant
chloracon, containing an amide fragment and a halogen
substituent in the aliphatic chain [13]. The results of the
pharmacological tests are summarized in Table 2.
It was found that substituting fluorine for hydrogen in the
acyl fragment of chloracon decreases the anticonvulsant ac-
tivity (compound XI). This is manifested by a twice shorter
delay before the onset of tonic convulsions and by a greater
proportion of lost animals. On the other hand, there is some
increase in the latent period before the onset of clonic con-
vulsions (table 2). At the same time, substituting a
2-(2,2,3,3-tetrafluoropropoxy)acyl (TFA) fragment for the
acyl fragment of chloracon (compound I) preserves the pro-
tective effect (percentage survival), although the latent pe-
riod before the onset of convulsions becomes shorter. Intro-
duction of a methyl unit into the alkyl radical at the nitrogen
atom of compound I (on passage to compound II) leads to an
increase in the anticonvulsant activity (manifested by a 32%
survival). These results are consistent with the published data
[13]; note, however, that the latent period before the onset of
convulsions for compound II is somewhat shorter than for I.
The increase in lipophilicity (apparently due to the fluo-
rination) in compounds I, II, and XI as compared to
chloracon leads to increasing positive charge on the carbon
atom of the carbonyl group, which may account for the low
anticonvulsant activity of the former fluorine-substituted
compounds.
TABLE 2. Anticonvulsant Properties of Some Polyfluorinated
Aliphatic Acid Amides (Convulsant: Corazole, 130 mg/kg)*
Latent period before onset
of convulsions, sec
Dose,
mg/kg
Percentage
survival **
Compound
clonic
tonic expansion
and loss
convulsions
Control (phy-
siological
solution)
–
5
128.0 ± 24.3
450 ± 71.2
467 ± 68.4
I
100
100
100
100
300
100
100
150
100
100
100
100
16
32
20
0
100 ± 16
118 ± 39
212 ± 62
76 ± 14
419 ± 114
353 ± 79
II
III
IV
421 ± 79
274 ± 53
1657 ± 309***
1339 ± 237***
496 ± 190
232 ± 86
0
262 ± 35
148 ± 65
172 ± 16
206 ± 82
269 ± 37***
207 ± 89
144 ± 36
201 ± 46
V
20
0
VI
VIII
XI
32
0
776 ± 96***
XV
0
446 ± 49
Since TFA does not significantly change the anticorazole
effect of chloracon, it was expedient to study the influence of
this fragment upon the anticonvulsant properties of amino
acids (proline, glycine, GABA, glutamine) N-acylated by
2-(2,2,3,3-tetrafluoropropoxy)acetic acid. As is known, the
N-acylation of these amino acids by fluorine-free carboxylic
acids does not always impart to them the desired pharmaco-
logical activity. We have synthesized the TFA-substituted
XVI
Chloracon
0
398 ± 53
16
1502 ± 411***
*
Experiments performed with participation of S. L. Rozenke-
vich.
**
Data processed by the Fisher method revealed no reliable differ-
ence in percentage survival between test and control groups.
***
p < 0.05 (Student’s method).