NO143459B - ANALOGUE PROCEDURE FOR PREPARATION OF PHYSIOLOGICALLY ACTIVE 2-PHENYLIMINO-IMIDAZOLIDINE DERIVATIVES - Google Patents

Description

Due to their very good pharmacological and therapeutic properties, 2-phenylimino-imidazolidines have for a long time been the subject of strong interest. Connections of this type are therefore described in many places in the literature and are e.g. subject of Belgian Patent Nos. 623,305, 653,933, 687,656, 687,657 and 7o5,944. In these literature sources, the essential methods for the production of 2-phenylimino-imidazolidines are also described.

On the basis of recent investigations, it has now been established that among the structural features of 2-phenylimino-imidazolidines which are necessary for a central α-adrenergic stimulation, the conformation has a decisive importance. On the basis of structure-effect considerations, it has been found that only such derivatives whose phenyl and imidazole-idine ring have an aplanar conformation to each other show a good blood pressure-lowering effect.

In this case, the free rotation of the phenyl ring about the C-N single bond is prevented, and the two rings are perpendicular or nearly perpendicular to each other.

Aplanarity in 2-phenyliminoimidazolidines is achieved by at

one substitutes the ortho positions in the aromatic molecular part:

Blocking atoms or groups of atoms in these positions prevent the free rotatability of the phenyl ring about the C-N single bond and thus the possibility of a coupling arrangement of the two rings to each other.

Clonidine [2-(2,6-dichlorophenylimino)-imidazolidine] is a representative of this class of compounds and possesses a very strong antihypertensive effect. However, it is fraught with a number of unwanted side effects. The purpose of the present invention is to produce new compounds of this type, which, in addition to a strong hypotensive effect, also have an improved effect profile.

According to the invention, the therapeutically active compound 2-(2-fluoro-6-trifluoromethylphenylimino)-imidazolidine and physiologically compatible acid addition salts thereof are prepared. The method is characterized by reacting 2-fluoro-6-trifluoromethyl-phenylisocyanide dichloride with ethylenediamine, and possibly transferring the resulting compound to an acid addition salt.

The turnover is carried out at temperatures between 0 and 200°C.

Polar protic, polar aprotic or non-polar solvents can be used as solvents. However, the reaction can also be carried out without the use of solvents at a higher temperature. It is recommended to use an acid-binding agent during turnover. The reaction time depends on the reactivity of the reaction components used and varies between a few minutes and several hours.

The production of the new 2-fluoro-6-trifluoromethylaniline used as starting material usually takes place by the reaction path schematically described below:

By this synthetic route, in addition to the benzoic acids, their isomers are usually formed, which can best be separated by column chromatography (silica gel).

The isocyanide dichloride can be prepared from the aniline as follows:

The new compound I can be converted in the usual way to its physiologically compatible acid addition salts. Acids that are suitable for salt formation are e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, valeric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-hydroxy-benzoic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid, ethanephosphoric acid and 8-chlorotheophylline.

The new compound and its acid addition salts have valuable therapeutic and particularly blood pressure-lowering properties and can therefore be used in the treatment of various forms of hypertension. The compound can be used enterally or also parenterally. The dosage is 0.1 to 80 mg, preferably 0.5 to 30 mg.

The new connection or its acid addition salts can also be used together with active substances of other types. Suitable galenic preparations are e.g. tablets, capsules, suppositories, solutions or powders, and for the production of these the commonly used aids, carriers, explosives or lubricants or substances which have a depot effect can be used.

The new compound and clonidine were investigated for their antihypertensive properties in rabbits under urethane-nembutal anesthesia. Blood pressure was measured directly on the carotid artery. ED^q is the dose that results in a sustained lowering of blood pressure of 20 mm Hg.

Both compounds were examined for their effect on gastric secretion in rats by the device of Shay. ED5Q refers to a dose that causes a reduction in the volume of gastric juice and acidity in the gastric juice of 50%.

Both compounds show an anesthetic-enhancing effect in mice. The sleep time induced by hexobarbital sodium is prolonged compared to a control group. d^q0 is a dose that causes a doubling of sleep time.

The following values indicate inhibition of movement and exploration in mice in the hole board test.

The following example shall serve to further illustrate the invention.

Example

2~(2-fluoro-6-trifluoromethylphenylimino)-imidazolidine hydrochloride

9 g of N-(2-fluoro-6-trifluoromethylphenyl)-isocyanide dichloride [prepared from 3-fluoro-benzotrifluoride over the steps: 2-fluoro-6-trifluoromethyl-benzoic acid (m.p. 81-84°C), 2-fluoro -6-trifluoromethyl-aniline (oily) and 2-fluoro-6-trifluoromethyl-formanilide (m.p. 116-118°C)] are reacted with 21.6 ml of ethylenediamine (10-fold excess) at 10°C with stirring in 100 ml of absolute ether. After a reaction time of 30 minutes, the reaction mixture is evaporated to dryness in a vacuum, and the remaining oil is dissolved in dilute hydrochloric acid. After 2 ether extractions, the aqueous phase is separated and treated with activated charcoal. It is then extracted fractionally with ether at increasing pH values (alkalization with caustic soda). The thin-layer chromatographically pure ether fractions are collected, dried and ethereal hydrochloric acid is added to the Congo acid reaction to precipitate the imidazolidine hydrochloride. The yield of clean

2-(2-fluoro-6-trifluoromethylphenylimino)-imidazolidine hydrochloride = 4.35 g corresponding to 44.9% of the theoretical.

Melting point: 262-264°C. The white, crystalline compound dissolves in water and lower alcohols.

Claims (1)

Analogous process for the preparation of the therapeutically active compound 2-(2-fluoro-6-trifluoromethylphenyl-imino)-imidazolidine and physiologically compatible acid addition salts thereof, characterized in that 2-fluoro-6-trifluoromethyl-phenylisocyanide dichloride is reacted with ethylenediamine, and optionally transferred obtained compound to an acid addition salt.