TRADUCTION NON-DISPONIBLE

IMIDAZOLINE DERIVATIVES

Abrégé anglais

A B S T R A C T
Imidazoline derivatives having the general formula
<IMG> (I)
in which R represents a cyclobutyl, cyclopentyl or
cyclohexyl radical, and their pharmaceutically acceptable
acid addition salts are described. These derivatives and
salts are useful as vaso-constrictors, e.g. for nasal
drops and sprays, and are produced by reacting a phenol
with 2-chloromethylimidazoline hydrochloride or reacting
a substituted phenoxyacetonitrile with ethylenediamine
monotosylate.

Revendications

The embodiments of the invention, in which an
exclusive privilege or property is claimed, are defined as
follows:
1, A process for the preparation of an imidazoline
derivative having the general formula
(I)
<IMG>
wherein R is a cyclobutyl, cyclopentyl, or cyclohexyl
radical, or its non-toxic acid addition salts, comprising
either (1) reacting a phenol (II) or its sodium salt
<IMG> (II)
with 2-chloromethylimidazoline hydrochloride, or (2)
reacting a substituted phenoxyacetonitrile (IV)
<IMG> (IV)
with ethylenediamine monotosylate, so as to obtain the
tosylate of the 2-phenoxymethylimidazoline derivative of
the formula (I), and liberating the compound (I) from the
tosylate by alkalisation, and when required converting said
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derivative to a non-toxic acid addition salt thereof.
2. The process (1) according to claim 1, wherein R is
a cyclobutyl radical.
3. The process (2) according to claim 1, wherein R is
a cyclobutyl radical.
4. The process (1) according to claim 1, wherein R is
a cyclopentyl radical.
5. The process (2) according to claim 1, wherein R is
a cyclopentyl radical.
6. The process (1) according to claim 1, wherein R is
a cyclohexyl radical.
7. The process (2) according to claim 1, wherein R is
a cyclohexyl radical.
8. An imidazoline derivative having the general
formula
(I)
<IMG>
wherein R is a cyclobutyl, cyclopentyl or cyclohexyl
radical, or its non-toxic acid addition salts whenever
produced by the process according to claim 1 or an obvious
chemical equivalent.
9. An imidazoline derivative as defined in claim 8
wherein R is a cyclobutyl radical, whenever produced by the
process according to claim 2 or 3 or an obvious chemical
equivalent.

10. An imidazoline derivative as defined in claim 8
wherein R is a cyclopentyl radical, whenever produced by the
process according to claim 4 or 5 or an obvious chemical
equivalent.
11. An imidazoline derivative as defined in claim 8
wherein R is a cyclohexyl radical, whenever produced by the
process according to claim 6 or 7 or an obvious chemical
equivalent.

Description

10945~.6
The present invention relates to new imidazoline
derivatives, their addition salts with pharmaceuticallv
acceptable acids, their preparation and their application
in therapy.
S Imidazoline derivatives have already been described
by the Applicant Company in its French Patents No. 1,312,410
and No. 71/25,858.
The compounds of the invention correspond to the
formula (I~
H2C Cl H2
~ C ~ R (I)
2 ~
in which R represents a cyclobutyl, cyclopentyl or
cyclohexyl radical.
According to the invention, the compounds (I) are
prepared either (1) by reacting a phenol (II) or its sodium
salt with 2-chloromethylimidazoline hydrochloride (III) in
- accordance with the equation
O ~ a
~ ~ R
W H ~
~ C~ . HCl (I)
(~I) CH2Cl
(III)
or (2) by reacting a substituted phenoxyacetonitrile (IV)
~ 2 - ~

10~ S~;6
with ethylenediamine monotosylate, so as to obtain the
tosylate of the 2-phenoxymethylimidazoline of the formula (I),
and liberating the compound from the tosylate by alkalisation.
Reaction 1 is carried out in a polar solvent such
as an alcohol, initially at ambient temperature and then
at the reflux temperature of the solvent.
Reaction 2 is carried out in a solvent such as
orthodichlorobenzene, under nitrogen and at a high temperature
(about 180~C). The tosylate obtained is rendered alkaline,
e.g. using dilute ammonium hydroxide.
The compounds of the invention are vasoconstrictors.
The following examples illustrate the invention.
The usual analyses and IR and NMR spectra confirmed the
structure of the compounds.
EXAMPLE 1
2-(2-Cyclcpentylphenoxy)-methylimidazoline and its
hydrochloride.
8.1 g t0.0506 mol) of ortho-cyclopentylphenol are
added gradually to a soll1tion of sodium ethylate (100 ml of
absolute ethanol and 2.3 g of sodium). The mixture is
stirred for 30 minutes. 7.5 g (0.05 mol) of
2-chloromethylimidazoline hydrochloride are then added in
small portions. The reaction is allowed to proceed at

lO~S66
ambient temperature for 2 hours and the mixture is then
heated under reflux for 1 hour. After standing over
night, the sa~t which has formed is filtered off and washed
with hot ethanol, and the solution is evaporated, the
remaining oil is washed with water and extracted with
chloroform, and the extract is dried and evaporated. An
oil is obtained which crystallises. It is recrystallised
from hexane. Colourless crystals are obtainedO
Yield: 28%. Melting point = 112-113C.
The hydrochloride is obtained by adding a solution
of hydrogen chloride in ether. The colourless microcrystals
melt at 167C.
EXAMPLE 2
2-~2-Cyclobutylphenoxy)-methylimidazoline and its
hydrochloride.
The reaction is carried out in the same manner as
in Example 1, using o-cyclobutylphenol as the starting
material.
The hydrochloride (colourless microcrystals) melts
at 204C.
The base melts at 126C.
EXAMPLE 3
2-(2-Cyclohexylphenoxy)-methylimidazoline and its
hydro~hloride.
2-(2-Cyclohexylphenoxy)-methylimidazoline, which
melts at 252-254C, is obtained in the same manner as in
- 4 -

~09~S~6
Example 1, using o-cyclohexylphenol as the starting material.
The compounds of the invention were subjected
to pharmacological experiments in order to determine their
vasoconstrictive activity.
1. Effects on isolated rabbit aorta
The contraction-inducing effects of the compounds
were studied on an isolated rabbit aorta (Furchgott and
Bhadrakom, J. Pharmacol. Exp. Ther., 108, 129, lg53) at
cumulative doses (10-11Ml-1 t 10-5Ml-l) d h
respective PD2 values (~D2 = -log of the molar dose causing
50% of the maximum conbaction obtainable with a given compound)
as well as the mean PD2 values (n = 4) were calculated for
each compound.
The compounds of the invention caused contraction
of the isolated rabbit aorta.
2. Effects on the aortic pressure in pithed rats
The changes in aortic pressure and pulse rate in
rats deprived of their spinal marrow and all nervous centres
were studied after intravenous administration of increasing doses
of the compounds (0.25 to 16 ~g.kg 1), the mean dose/effect
curves (n = 5) were constructed and the activity ratios were
calculated.
The compounds caused an increase in aortic pressure
which was not accompanied by an increase in pulse rate' this
hypertension, which reflects vasoconstriction, shows that the
compounds are vasoconstrictive.
The re~ults are summarised in Table.l~ The compounds
were compared with naphazoline or 2-(naphth-1-yl-methyl)-
- imidazoline.
~ 5 --

l~g~
TABLE I
. ._
Contraction of isolated Increase in aortic
Compound rabb it aorta _ rats _
pD~ activity relative activity relative
to naphazoline to naphazoline
3 : ~ ~ O .
The above results show that the compounds are
vasoconstrictors~ They are useful in the treatment of
rhinological complaints accompanied by~nasal congestion,
especially coryza, rhinitis and sinusitis.
The present invention includes all the pharmaceutical
compositions containing one of~the compounds (I) as the active
principle. The compounds can be administered in solutions,
either by instillation of drops or by spraying at
concentrations of 1/oo to 5/oo, two to four times per day.
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.