CH635081A5 - Imidazoline derivatives - Google Patents

Description

The present invention relates to new imidazoline derivatives, their addition salts with pharmaceutically acceptable acids, their preparation process and the pharmaceutical compositions containing them.

Imidazoline derivatives have already been described by the licensee in its French patents N ° 1312410 and N ° 71.25858.

The compounds according to the invention correspond to the formula:

H

CH

in which R represents a cyclobutyl, cyclopentyl or cyclohexyl radical.

According to the invention, the compounds of formula (I) are prepared by reaction of a substituted phenoxyacetonitrile of formula:

with ethylenediamine monotosylate, so as to obtain the phenoxymethyl-2-imidazoline tosylate of formula (I) and release of the compound (I) from the tosylate by alkalization.

The reaction is preferably carried out in a solvent such as orthodichlorobenzene, under nitrogen, at elevated temperature (about 180 ° C).

The tosylate obtained is made alkaline with dilute ammonium hydroxide.

The compounds of the invention are vasoconstrictors. The following examples illustrate the invention. The analyzes and the IR and NMR spectra confirmed the structure of the compounds.

Example 1:

(2-Cyclobutylphenoxy) 2-methylimidazoline and its hydrochloride

3 g (0.016 M) of orthocyclobutylphenoxyacetonitrile, 3.71 g (0.016 M) of ethylenediamine monotosylate and 20 ml of o-dichlorobenzene are introduced into a 50 ml three-necked flask.

This mixture is brought to a boil by passing a stream of nitrogen so as to remove the ammonia released. The reaction mixture is allowed to cool and diluted with 60 ml of ether. The precipitate formed is drained and washed with ether. The tosylate is decomposed by NH4OH, extracted with 100 ml of chloroform, washed with water, dried and evaporated.

The hydrochloride is formed by passing hydrochloric gas, the precipitate is drained and washed with ether. The compound is recrystallized from a 15/85 ethyl acetate / ethanol mixture. Mp 205 ° C.

Example 2:

(2-Cyclopentyl phenoxy) 2-methylimidazoline and its hydrochloride

The oily base is crystallized from hexane; colorless crystals are obtained. Mp 112-113 ° C.

The hydrochloride is obtained by adding hydrochloric ether. The colorless microcrystals melt at 167 ° C.

Example 3:

(2-Cyclobutylphenoxy) 2-methylimidazoline and its hydrochloride The hydrochloride (colorless microcrystals) melts at 204 ° C.

The base melts at 126 ° C.

Example 4:

(2-Cyclohexylphenoxy) 2-methylimidazoline and its hydrochloride The hydrochloride melts at 252-254 ° C.

The compounds of the invention have been subjected to pharmacological tests in order to determine their vasoconstrictor activity.

1. Effects on the isolated rabbit aorta

The contracting effects of the compounds are studied on the isolated rabbit aorta (Furchgott and Bhadrakom, 1953, "J. Pharmacol. Exp. Ther.", 108,129), in cumulative doses (10 ~ 11 Ml-1 at 10-5 Ml -1) and the respective pD2 are calculated as well as the average pD2 (n = 4) for each compound.

The compounds of the invention contract the isolated rabbit aorta.

2. Effects on the aortic pressure of the amyélé rat

Changes in aortic pressure and heart rate of amyele rats are studied after intravenous administration of increasing doses of the compounds (0.25 to 16 (ig / kg-1); mean curves (n = 5) dose / effect are constructed and the activity reports calculated.

The compounds cause an increase in aortic pressure unaccompanied by an increase in heart rate;

this hypertension, a reflection of vasoconstriction, shows that the compounds are vasoconstrictive.

The results are collated in Table II. The compounds were compared with naphazoline or (1-naphthyl methyl) -2-imidazoline.

5

10

15

20

25

30

35

40

45

50

55

60

65

3

Table II

635,081

Compound

Isolated rabbit aorta contraction

Increased aortic pressure in amylated rats

pD2

Activity versus Naphazoline

Activity versus Naphazoline

1

6.7

0.4

0.5

2

7.7

4

4

3

7.1

1

1

The above results show that the compounds are vasoconstrictors. They are useful in the treatment of rhinological affections accompanied by nasal congestion and in particular coriza, 20 rhinitis, sinusitis, etc.

The present invention also includes pharmaceutical compositions containing one of the compounds (I) as active ingredient. The compounds can be administered in solutions, either by instillation of drops, or by nebulization. The concentration of solutions generally ranges from 1% to 5%. The number of doses can be two to four per day.

R

Claims (3)

635081 1. Imidazoline derivatives corresponding to the formula: HN- in which R represents a cyclobutyl, cyclopentyl or cyclohexyl radical. 2. Process for the preparation of the compounds according to claim 1, characterized in that a substituted phenoxyacetonitrile is reacted 0CH „CN with ethylenediamine monotosylate so as to obtain the 2-phenoxymethylimidazoline to-sylate of formula (I) and the compound (I) is released from the tosylate by alkalization. 2 3. Pharmaceutical composition usable in the treatment of rhinological affections accompanied by nasal congestion, characterized in that it contains as active ingredient one of the compounds according to claim 1.