NO850920L - PROCEDURE FOR THE PREPARATION OF PHENYL-ALKAN CARBOXYLIC ACID DERIVATIVES - Google Patents

Description

The present invention relates to a method for the production of therapeutically active CU - 2-hydroxyphenyl) methylene-amino^]-phenyl-alkanecarboxylic acid derivatives of formula (I)

in

in which

and R- each independently represents a hydrogen atom, a halogen atom or (C1-4)alkyl,

R, represents (C^_g)alkyl or phenyl which may bear a halogen atom or (C^_^)alkyl,

R^ represents a hydrogen atom or halogen atom or (C1-4 alkyl,

R,, represents hydroxy, O-alkali metal or O-alkaline earth metal, (C^_^)alkyl or amino, and

n and m each represent an integer 0, 1 or 2, and the characteristic of the invention is that a compound of formula (II)

in which

R^, R2 and R^ have the above meaning, are converted to

a compound of formula (III)

The compounds that can be prepared by the invention can exist in the form of racemates or optical isomers.

Schematic presentation of the reaction in the following reaction scheme

IN

In the above structural formulas, the definitions for the compounds (II) and (III)' are as previously stated.

The reaction between the compound (II) and (III) is carried out in a solvent such as methanol, at the reflux temperature of the solvent, in the presence of an alkali metal alcoholate.

The compounds (II) are described in the literature, or described in French patent documents 75 24065, 81 21559 and 82 19981.

The compounds (III) are described in the literature.

From the acids (I) corresponding amides (I) can be prepared in which

Ri- is NH 2 , esters (I) in which R 5 is (C 1_4 ) alkoxy and

the salts (I) in which R5 is O-alkali metal or O-alkaline earth metal, using classical methods.

The following examples illustrate the preparation of the compounds and analyzes and IR and NMR spectra confirm the structure of the compounds.

Example 1

4-£[(5-Chloro-2-hydroxy-phenyl)methyl-methyl-aminoj-3-(4-chloro-phenyl)-butanoic acid.

A mixture of is evaporated to dryness under reduced pressure

10 g (0.0586 mol) 4-chloro-2-hydroxy-acetophenone, 12.5 g (0.0585

mol) of 4-amino-3-(4-chloro-phenyl)-butanoic acid and 3.2 g (0.0592 mol) of sodium methylate in 600 ml of methanol.

It is cooled, the residue is dissolved in 1 liter of water and then acidified to pH 4 with citric acid.

The product is precipitated and stirred for a short time, after which it is filtered on a glass filter, suction is applied to the filter and the product is washed several times with water. Suction is applied to the filter and dried in a desiccator in the presence of P2O5"

The product is dissolved hot in 1 liter of CH2Cl2 and 400 ml of MeOH, the mixture is treated with active carbon, filtered through paper, evaporated to 200 ml. The precipitated product is filtered, filtered off with suction and washed several times with ether. The product is redissolved in 700 ml CH2Cl2 and 400 ml MeOH (hot solution).

It is evaporated to approximately 150 ml. The product is precipitated and filtered, filtered off with suction and washed twice with 30 ml of ether. It is filtered off with suction and dried in a desiccator at 80°C

in the presence of P^ 0^-

The obtained compound melts at 220-221°C.

Example 2

4-[(5-chloro-2-hydroxy-3-propyl-phenyl)(4-methyl-phenyl)-methyl-enylamino]-3-(4-chloro-phenyl)-butanoic acid.

A mixture of 5 g (0.0173 mol) (5-chloro-2-hydroxy-3-n-propyl-phenyl)(4-methyl-phenyl)methanone, 3.69 g (0.0173 mol) 4-amino -3-(4-chloro-phenyl)-butanoic acid, 1 g (0.0185 mol) of sodium methylate and 600 ml of methanol are evaporated to dryness under reduced pressure.

The mixture dissolved in 500 ml methanol is evaporated 6 times, the residue is dissolved in 1.2 1 water and 0.200 1 CH2Cl2 and then acidified to pH 4 with citric acid. It is then extracted with 3 times 500 ml of CH2Cl2, the organic phase is washed with water, deposited, dried over MgSO4, filtered and evaporated to dryness. The precipitated product is transferred onto a glass filter with 100 ml of petroleum ether and filtered off with suction. The product is dissolved in 300 ml of ether and evaporated to 100 ml. The product is crystallized, filtered, filtered and dried in a desiccator. The obtained compound melts at 195-196°C.

The compounds were subjected to pharmacological tests showing their activity on the central nervous system.

The acute toxicity of the compounds was determined in mice by oral administration. Lethal dose 50 is must more than 1000 mg/kg.

The activity of the compounds on the flexion reflex was studied in spinally anesthetized male Spraque-Dawley rats (Charles River, France) weighing 200 to 240 g. 24 h before the test, the rats were anesthetized with chloral hydrate (400 mg/kg i.p.) and their spinal cords were severed at the height of the 6th - 8th thoracic vertebra.

For the test, the spinally anesthetized rats were fixed on a small table with the left paw resting on a support. The Achilles tendon in

this paw is connected by a wire (under 5 g stretch) to a strain gauge which is connected to a writing device.

A stainless steel electrode is inserted subcutaneously into the arch of the foot. The reflex is produced with series of electrical stimulations with an intensity of 7 mA with a duration of 200 ms, with a frequency of 50 Hz every 5 seconds, for one minute using an electrical stimulator GRASS S-48.

The products under study are injected intravenously in the form of a suspension prepared in physiological serum to which 0.1% "Tween 80" has been added. ED 50, corresponding to the dose which reduces the reflex power by 50% in relation to the control period, varies from 1 to 10 mg/kg i.v.

The myorelaxant and sedative effect was also assessed by the pulling wire test. In this test, a control rat or control mouse is suspended by a wire in the front paws, returned to at least one of the hind paws on the wire for at least 10 seconds.

If the treatment with a compound affects the animal's ability to keep its hind paws on the wire for less than 10 seconds, the effect is considered to be myorelaxant-sedative.

Groups of 6 rats are injected intravenously with variable doses of compounds prepared in accordance with the invention, in suspension in "Tween 80" (0.1%) and their muscle relaxant effect is noted every 10 minutes for 2 hours. The percentage of animals unable to climb is calculated for each dose and each time period.

For compounds produced in accordance with the invention, the ED 50 (the dose that prevents 50% of the animals from climbing the wire) is over 10 mg/kg, which shows that the compounds produced in accordance with the invention do not have a sedative-rnyorelaxant effect.

The compounds produced according to the invention can be used for the treatment of spastic conditions and movement problems.

The compounds produced in accordance with the invention can be administered in usual forms suitable for oral or parenteral administration and the daily dose can be from 10 to 200 mg.

Claims (1)

Analogous process for the preparation of therapeutically active CJ-Q 2-hydroxy-phenyl)methylene-amino]l-phenyl-alkanecarboxyl- acid derivatives of formula (I) in which R^ and R_ independently represent a . hydrogen atom, a halogen atom or (C^ _4 )alkyl, R-. represents (C^ g)alkyl or a phenyl radical which can carry a halogen atom or (C^ _4 )alkyl, R^ represents a hydrogen atom or halogen atom or (C1_4 )-alkyl, R,, represents hydroxy, O-alkali metal or O-alkaline earth metal, (C^ _4 ) alkoxy or amino, and n and m each represent an integer 0, 1 or 2, characterized in that a compound with for- flour (II) in which R^ , R 2 and R^ have the above meaning, are reacted with a compound of formula (III) where n, m and Rj. has the above-mentioned meaning, and if desired, the amides "(I) in which R,- is NH2 , the esters (I) in which R,- is (C 1 -4 ) alkoxy are prepared from an obtained acid (I) in a manner known per se and the salts (I) in which R 1 is O-alkali metal or O-alkaline earth metal.