Synthesis and Local Anesthetic Activity of Enamides
637
TABLE 4. Activity in Surface Anesthesia in Rabbits and Acute
Toxicity in Mice for Compounds IIa – IVf and IVa – IVf
2.5 g (0.016 mole) 3,4-dimethoxyaniline was added to
11.4 g (0.08 mole) tropinone in 100 ml toluene. The reaction
mixture was boiled for 3 days. After distillation, we obtained
3.45 g product, yield 15.3%, b.p. 190 – 194°C/2 mm.
The remaining tropanone Schiff’s bases were obtained
earlier in [2].
LD50 (mg/kg
intraperitoneally)
Compound
Regnier index
IIa
1185.5 ± 29.5
16.0 ± 2.9
70.0 ± 2.6
140.0 ± 6.6
85.6 ± 4.4
280.0 ± 10.1
90.0 ± 2.7
200.7 ± 2.6
246.0 ± 3.0
375.0 ± 11.4
80.7 ± 3.2
180.0 ± 8.2
120.7 ± 2.6
180.9 ± 3.5
26.0 ± 2.2
190.0 ± 8.4
80.0 ± 5.3
IVa
IIb
The calculated elemental analysis data correspond to the
found values for all the compounds obtained.
426.5 ± 13.1
511.0 ± 9.1
1024.3 ± 4.8
407.5 ± 10.1
13.0 ± 0.0
IVb
IIc
IVc
IId
EXPERIMENTAL PHARMACOLOGICAL PART
We determined the capacity of the compounds to induce
surface anesthesia by the Regnier method on the cornea of
rabbits’ eyes (1% solution), and we determined their capacity
to induce infiltration and conduction anesthesia on mice us-
ing the “tailflick” test (2% solution) [6]. The compounds
were injected in a volume of 0.05 ml subcutaneously into the
tail of the mice using a microinjector. We recorded the
tailflick latency period upon thermal stimulation directly at
the site of injection of the compounds (to assess the level of
infiltration anesthesia) or at a site below injection of the
compounds, at the tip of the tail (to assess the level of con-
duction anesthesia).
IVd
IIe
13.0 ± 0.0
415.5 ± 14.5
13.0 ± 0.0
IVe
IIf
598.5 ± 2.2
13.0 ± 0.0
IVf
Dicain
1300.0 ± 0.0
1300.0 ± 0.0
590.0 ± 16.0
Pyromecaine
Cocaine
Note: averaged data for 8 trials with standard error of the mean for
1% solutions.
We studied the analgesic action on mice (in a dose that
was 1/10 of LD50) using the following tests: tailflick test on
the Analgesia Test device (Kern, FRG); hot-plate test (55°C)
[7] and tail pressure test (Randell Selitto) on an Ugo Basile
(Italy) analgesimeter [8].
The acute toxicity was determined in mice by Behren’s
method; the local irritant effect was determined on rabbits by
the Setnicar method (1% and 2% solutions) [6].
As the reference drugs, we used cocaine, Dicain, and
Pyromecaine for surface anesthesia; Novocain and Trime-
caine for conduction and infiltration anesthesia; and mor-
phine for studying the analgesic activity.
In experiments on mice, we established that compounds
IIa-m and IVa – IVf display weak analgesic activity com-
pared with the action of morphine (3 mg/kg subcutane-
ously). They are able to temporarily increase the pain sensi-
tivity threshold of the animals by only 20 – 60%.
Thus the results obtained allow us to conclude that com-
pounds IIa – IIm and IVa-f have local anesthetic activity.
Compounds IIa – IIm, containing a double bond in the
tropane ring, have higher activity than analogs with a single
bond (compounds IVa – IVf) and also previously synthesized
acetomesidides [1] and tropane 3-N-butyleneamides [3].
EXPERIMENTAL CHEMICAL PART
REFERENCES
The PMR spectra were taken on a Bruker A-250 spec-
trometer, solvent CD3OD, internal standard HMDS. The IR
spectra of the compounds were recorded on a Perkin-Elmer
580 in KBr. GLC analysis of all the products was performed
on a Tsvet-152 chromatograph (column of length 0.7 m, di-
ameter 3 mm, liquid phase SE-30/5% on Chromaton N-AW
0.16 – 0.20 mm), carrier gas nitrogen, temperature program-
ming 75 – 300°C/20°C per minute. The melting point was
determined on a Boetius hot stage.
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1.5 g PtO2 was added to a solution of 25 g
phenylethyliminotropane in 100 ml ethanol and this was hy-
drogenated at atmospheric pressure. After distillation, we ob-
tained 21.5 g III, yield 85.3%, b.p. 142 – 143°C/1 mm.
3-(3,4-Dimethoxyphenylimino)tropane [I, R = 3,4-
(MeO)2C6H3].
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