NO122975B - - Google Patents

Description

Analogy process for the preparation of therapeutically active derivatives of α-piperazino-phenylacetonitrile.

It has been found that arriving at pharmacological value-

full derivatives of a-piperazino-phenylacetonitrile with the general

formula

in which Rls R2 and R^ mean hydrogen, halogen and alkoxy, A means a linear or branched alkylene residue with 2-4 C atoms when one reacts in a manner known per se ot-piperazino-phenylacetonitriles with the general formula in which X means the hydroxyl group or a halogen atom, with an alkoxy-benzoic acid of the formula <0>

respectively a functional derivative or an alkali salt of this acid, possibly in the presence of an acid-binding agent.

As carboxylic acid residues R^, FU and R^, those with 1-4 C atoms come into consideration in particular.

The derivatives of cx-piperazino-phenylacetonitrile which can be prepared according to the invention are valuable pharmaceuticals; they have e.g. a specific, coronary dilating effect, associated with a positive inotropic effect, and is in this respect superior to known substances of this type.

Their salts are colourless, crystalline substances that are easily soluble in water.

The pharmacological investigations of the coronary artery widening effect were carried out by means of changes in the oxygen pressure in coronary venous blood according to that of W.K.A. Schaper and co-workers discussed methods on dogs. (See W.K.A. Schaper, R. Xhonneux and J.M. Bogaard "Uber die continuous Messung des Sauerstoffdruckes im venosen Coronarblut" (Naunyn-Schmiederberg's Arch. exp. Path.u.Pharmak. 245, 383-389 (1963)). The narcotized, spontaneously breathing animals had the test preparations applied intravenously.

With this test device, an expansion of the coronary arteries produced by the test substance and the associated increase in coronary flow lead to an increase in the oxygen pressure in coronary venous blood. The oxygen pressure was measured polarographically with a platinum electrode according to Gleichmann-Lubbers (see U., Gleichmann and D.W. Lubbers "Die Messung des Sauerstoffdruckes in Gasen und Pliissigkeiten mit der Platin-Elektrode unter besonderer Beriicksichtigung der Messung im Blut" Pfliiger's archive 271, 431 -455

(1960)). The heart rate was determined continuously electronically from the systolic maxima of the arterial blood pressure. The arterial blood pressure was measured in a known manner with a Statham strain gauge electromanometer in the Arteria femoralis.

The following table summarizes the results of the conducted pharmacological investigations. The preparations were each time examined in the form of their dihydrochlorides.

Example 1.

28 g (= 0.1 mol) α-(4'-B-hydroxyethyl-piperazino/-1^7)-4-chlorophenylacetonitrile are dissolved in 200 ml of anhydrous benzene with the addition of 10.6 g (= 0.1 moles) of soda. A solution of 23 g (= 0.1 mol) of 3,4,5-trimethoxybenzoyl chloride in 100 ml of benzene is now added dropwise at room temperature with stirring. It is then stirred for 2 hours under reflux. After cooling, the reaction mixture is washed several times with water. After drying over calcium chloride, chlorine hydrogen gas is introduced into the benzoic solution for a Congolese reaction. The dihydrochloride of α-(4'-3-3", 4", 5"-trimethoxybenzoxyethyl-piperazino£— 1_]7)-4-chloro-phenylacetonitrile is thus obtained in the form of colorless crystals with a melting point of 160°C .Yield: 45 g = 82.5$ of the theoretical.

The a-(4'-$-hydroxyethyl-piperazino/~1J_7)-4-chloro-phenylacetonitrile used as starting product can be prepared in the following way: 14 g (= .0.1 mol) of 4-chlorobenzaldehyde is introduced under stirring and cooling with ice water in 30 g of a 40# sodium bisulfite solution. After 2 hours, 13 g (= 0.1 mol) of N-hydroxyethyl piperazine are then added dropwise, the reaction temperature not to rise above 30°C. It is then heated to 60°C and a solution of 7.4 g (= 0.15 mol) NaCN in 20 ml of water is then allowed to drip in. Stirring is continued for 4 hours and the separated reaction product is taken up in vinegar. After drying over pot ash, this solution is evaporated to dryness in a vacuum. For further purification, the reaction product is recrystallized from petrol. One thus obtains ot-(4»-3-hydroxyethyl-piperazino[1_]_7)-4-chloro-phenylacetonitrile with a melting point of 98°C. Yield: 23 g = 82$ of the theoretical.

Analogous to the above-mentioned method, the following intermediate products can be produced:

General formula:

Example 2.

42.2 g (= 0.1 mol) α-(4'-8-hydroxypropylpiperazino-/-1^7)-2,3,4-trimethoxyphenylacetonitrile is dissolved in 300 ml anhydrous. chloroform and 10.1 g (= 0.1 mol) of triethylamine are added. Now add 23 g (= 0.1 mol) dropwise while stirring. 3,4,5-trimethoxybenzoyl chloride, dissolved in 100 ml of anhydrous chloroform over the course of 1 hour. After completion of the exothermic reaction, stirring is continued for 2 hours at 50°C. The reaction solution is then washed with water, then with aqueous 5/5g sodium bicarbonate solution and finally again with water. After drying over dewatered sodium sulphate, the solvent is distilled off in a vacuum at 50°C. The residue thus formed is dissolved

in a little acetic acid and mix with ethereal hydrochloric acid to form a Congo acid reaction. The dihydrochloride of α-(4'-6-3",4",5"-trimethoxy-benzoxypropylpiperazino/<->lj_70-2,3,4-trimethoxyphenylacetonitrile with a cleavage point of 144°C is thus obtained.

Yield: 50 g = 815? of the theoretical.

In an analogous way as in examples 1 and 2, according to the invention, the following compounds can be produced:

General formula:

Claims (1)

Analogous process for the preparation of therapeutically active derivatives of o-piperazinophenylacetonitrile with the general formula in which R-j^ R2 and R^ mean hydrogen, halogen, alkoxy, A means a linear or branched alkylene residue with 2-4 carbon atoms, characterized by reacting the a-piperazino-phenylacetonitrile with the general formula wherein X means the hydroxyl group or a halogen atom, with an alkoxy-benzoic acid of the formula respectively a functional derivative or an alkali salt of this acid, possibly in the presence of an acid-binding agent.