NO841486L - PROCEDURE FOR THE PREPARATION OF HYDROXYLATED DIFENYLAZOMETIN DERIVATIVES - Google Patents

Description

The present invention relates to the production of therapeutically active hydroxylated diphenylazomethine derivatives of formula (I)

where in

n is an integer from 1 to 4,

Xl'^2 °^ ^3 each independently represents a hydrogen atom, a halogen atom, methoxy or straight or branched C^_^alkyl,

R stands for NH2, OH or OM (M = alkali metal or alkaline earth metal) and

Z represents COOH; COOalkyl, CONH2, CONH alkyl,

CON (alkyl) 2 , Cr^OH, CH 2 alkyl, Oalkyl, NO 2 , NH 2>

NH alkyl or N(alkyl)2 in which the alkyl groups have 1 to 4 carbon atoms and the method is characterized in that a benzophenone of formula (II) in which X^, X2, X^ and Z have the above meaning is reacted with a compound of formula (III)

where R and n have the above meaning.

These features of the invention appear in the patent claim.

The preferred compounds are those corresponding to the formula

in which the radicals have the above meanings and more particularly those in which n is equal to 2 or 3,

X^ is a halogen atom or methyl,

X2 is a halogen atom or methyl,

R is NH2, OH or ONa, and

Z is a group CH 2 OCH 3 , OCH 3 , N(CH 3 ) 2 or

NH2.

The reaction between the benzophenone of formula (II) and a compound of formula (III), optionally in the form of a salt such as the hydrochloride, is advantageously carried out at a temperature of 20 to 80°C in a solvent such as e.g. methanol or ethanol.

The starting benzophenones of formula (II) are new and are prepared using methods described in the literature.

The following examples illustrate the invention. Analyzes and spectra IR and RMN confirm the structure of the compounds.

EXAMPLE 1

4-(4-chlorophenyl)(5-chloro-2-hydroxy-3-methoxy-phenyl) methylene amino-butanamide.

To a suspension of 0.37 g (2.69 m mol) of the hydrochloride of gabamide in 20 cm^ absolute ethanol is added 10.4 cm^

of an ethanolic solution of sodium ethylate, 0.27 N (ie 2.8 mmol) and 0.8 g (2.69 mmol) of 4',5-dichloro-2-hydroxy-3-methoxy-benzophenone.

The mixture is heated at the reflux temperature for 1 hour and then 20 cc of alcohol is distilled off. 200 cm 3 absolute alcohol is added and the same volume is then distilled off.

After evaporation to dryness, 20 cm 3 of water is added to the residue and this is extracted with methylene chloride.

The extract, washed with water and dried over MgSO 4 gives on evaporation a residue which is recrystallized from absolute ethanol. After washing with petroleum ether and drying for 8 hours at 100°C under vacuum, the product is obtained which melts at 209 to 210°C.

EXAMPLE 2

4 - (4-chloro-phenyl) (5-chloro-2-hydroxy-3-methoxymethylphenyl) methylene amino-butyric acid and its sodium salt.

_2

1. Into a 1 liter flask, introduce 5 g (1.61.10 mol)

(4-chlorophenyl) (5-chloro 2-hydroxy 3-methoxymethyl phenyl-

_2

methanone, 300 ml methanol, 3.1 g (3.10 mol) -aminobutyric acid and 1.6 g (3.10 mol) sodium methylate.

The reaction mixture is maintained at the reflux temperature

for 8 hours, evaporated to dryness, the residue taken up in 1.8 1 distilled water, acidified to pH 4.5 by adding citric acid. The mixture is extracted twice with 400 ml of dichloromethanone, the organic phases are combined, washed with 500 ml of water, dried over Na 2 SO 4 , filtered and evaporated to dryness.

The acid obtained is recrystallized from 25 ml of methanol.

Mp = 104 to 105°C

2. Into a 500 ml flask, introduce 4.7 g (1.19.IO"<2>mo1} of the acid obtained previously, 100 ml of methanol and 9.7 ml of sodium methylate in solution (1.22 N). The reaction mixture evaporated at 60°C, 200 ml of pentane are introduced and the mixture is stirred for 10 min.

After filtration, suction and drying in a desiccator at 60°C in the presence of P2°5, the sodium salt is obtained.

M.p. = 136°C

EXAMPLE 3

4 (4-chloro-phenyl) (5-chloro-2-hydroxy-3-dimethylamino-phenyl) methylene amino -butanamide.

2.35 g (0.017 mol) of gabamide hydrochloride, 500 ml of ethanol, 17 ml of a molar solution of sodium methylate and 5.3 g (0.017 mol) of (4-chloro-phenyl) (5-chloro -2-hydroxy-3-dimethylamino-phenyl-methanone).

The reaction mixture is heated at the reflux temperature and ethanol is evaporated.

Evaporate to dryness, the residue is taken up in water and chloroform, the organic phase is decanted, dried over magnesium sulphate and evaporated.

The residue is triturated on the filter with pentane, filtered and recrystallized from a mixture of ethyl acetate-isopropyl ether.

Mp = 144.5 - 145°C

The antidepressant activity of the compounds was shown

by antagonism to "head-twitches" produced with 1-5-hydroxy-tryptophan in mice.

The mice (male mice CD1, Charles River France; 18-22 g body weight) received the products to be studied in increasing doses or the solvent, simultaneously with L-5-HTP in a dose of 250 mg/kg by subcutaneous administration. 45 minutes after this injection of 5-HTP, the number of "head-twitches" was counted for each mouse for one minute.

For each treatment, the mean number of_"head-twitches" as well as the percentage variation in relation to

the sample group calculated.

From the effect/dosage curve, the AD 50 (50% active dose or the dose which reduces the mean number of "head-twitches") is determined with 50% determined using the graphic method of Miller and Tainter (1944).

AD 50 of the compounds that can be prepared by the invention

varies from 40 to 60 mg/kg by intraperitoneal administration.

The anticonvulsant activity of the compounds was measured by antagonism to mortality induced with bicuculline in mice.

Bicuculline is a relatively selective blocker of GABA-ergic postsynaptic receptors and its convulsive and lethal effects are antagonized by compounds that raise the cerebral GABA content and have a GABA-mimetic activity.

The 50% active dose (AD 50) is judged as the dose that protects 50% of the animals against the effects of bicuculline for the substances examined.

AD 50 for the compounds that can be prepared by the invention varies from 10 to 100 mg/kg when administered intraperitoneally.

The compounds that can be prepared by the invention are active as antidepressants and anticonvulsants and likewise have antiulcer, anxiolytic, analgesic and anti-inflammatory properties. They can be used within human and veterinary therapy for the treatment of various diseases of the central nervous system, e.g. for the treatment of depression, psychosis, certain neurological diseases such as epilepsy, spasticity, dyskinesia.

The compounds can be used in pharmaceutical preparations as active principles in association with all usual additives for their administration, especially for oral administration (tablets, dragees, gels, capsules, drinkable solutions or suspensions) or for parenteral administration.

The daily dose can amount to 100 to 3000 mg.

Claims (1)

Process for the preparation of therapeutically active hydroxylated diphenylazomethine derivatives of the general formula (I) where in n is an integer from 1 to 4, *2°^ ^3 each independently represents hydrogen, halogen, methoxy or a straight-chain or branched C^_4 alkyl radical, R represents Nr^, OH or OM (M = alkali metal or alkaline earth metal) and Z represents COOH, C00 alkyl, CONH2 , CONH alkyl, CON (alkyl)^ CH 0 H; CH^ alkyl f oalkyl, N02-NHalkyl or N(alkyl)2 , the alkyl groups having 1 to 4 carbon atoms, characterized in that a benzophenone with formula (II) in which X^ , X2 , X^ and Z have the above meaning, is reacted with a compound of formula (III) in which R and n have the above meaning.