CA1094566A

CA1094566A - Imidazoline derivatives

Info

Publication number: CA1094566A
Application number: CA305,122A
Authority: CA
Inventors: Icilio A.G. Cavero; Henry Najer; Braham Shroot
Original assignee: Synthelabo SA
Current assignee: Synthelabo SA
Priority date: 1977-06-13
Filing date: 1978-06-09
Publication date: 1981-01-27
Also published as: SE7806740L; NL7806269A; ZA783327B; NO782027L; IT7824416A0; LU79794A1; FR2394532B1; IE781169L; DK258778A; DE2825388A1; GB1572689A; AU515492B2; JPS545975A; BE867984A; AU3699478A; CH635081A5; NZ187507A; IE46988B1; FR2394532A1; IT1095286B

Abstract

A B S T R A C T

Imidazoline derivatives having the general formula

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.

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.

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.

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 ~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.
- . - ~-- . .

.

Claims

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) 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 (II) with 2-chloromethylimidazoline hydrochloride, or (2) reacting a substituted phenoxyacetonitrile (IV) (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 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) 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.