NO791221L - PROCEDURE FOR THE PREPARATION OF BENZYLIDE DERIVATIVES - Google Patents

Abstract

Process for the production of benzylidene derivatives.

Description

The present invention relates to a method for the production of pharmacologically active benzylidene derivatives with the general formula (I)

in which

X^, X£ and are the same or different and each represents a hydrogen atom or a hydrogen atom or methyl or methoxy,

n = an integer from 1 to 10, and

R stands for

. an alkyl radical with 1 to 16 carbon atoms. a radical O^COOR^ in which R^ is higher alkyl with 11 to 15 carbon atoms, . a radical (CH 2 ) 2 OR 2 in which R 2 is alkyl of 1 to 6 carbon atoms or

. a radical CH2C0

The peculiarity of the method according to the invention is that an acid of formula (II)

or a functional derivative thereof, in which X^, X2, X^ and n have the above meaning, is reacted with a compound of the general formula

RX or ROH or ROMe

in which R has the above meaning and Me stands for an alkali metal and X is halogen (optionally in the presence of carbonyldiimidazole or sulfonyldiimidazole), or

a benzophenone of the general formula (III)

in which X^, X2, and X^ have the above meaning, are traded with

a compound of the general formula (IV)

wherein n and R have the above meaning.

There are previously known benzylidene derivatives with formula

in which

X^, X2 and X^, the same or different, each independently represents hydrogen or halogen, especially chlorine or fluorine, or preferably methyl or methoxy,

n stands for an integer from 1 to 10, and

R stands for hydroxyl, OM, NH2, NH(CH2)3-C00H, -NH(CH2)3~C00M (where M stands for an alkali metal, especially sodium), NHtGE^Jg-COOC2H5,

NH-cycloalkyl, NH-phenyl, NH-benzyl (the benzyl radical can carry a substituent selected from halogen atoms and trifluoromethyl),

NH-alkyl, N-(alkyl)2, N-(alkyl)-(benzyl), the alkyl radicals being straight or branched with 1 to 4 carbon atoms,

cycloalkyl of 3 to 6 carbon atoms.

The compounds of formula (I) which can be prepared by the method according to the invention are therapeutically active with an effect on the central nervous system.

The first of the above reactions is carried out in a solvent such as dimethylsulfoxide (DMSO) at a temperature of 40 to 100°C, or in toluene at the boiling temperature of this solvent.

The second of the aforementioned reactions is carried out in a solvent such as ethanol at a temperature of 60 to 100°C in the presence of sodium bicarbonate.

The starting acids (II) and the benzophenones (III) are previously known compounds.

The compounds (IV) are obtained by reaction between an acid H2N-CnH2n~COOH, in which n has the above meaning, and a compound is OH, in which R has the above meaning, in the presence of e.g. thionyl chloride.

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

Example 1 n-butyl-N-[oc-(4-chloro-phenyl)-5-fluoro-2-hydroxy-benzylideneyl]-4-amino-butyrate.

</h=3, X1=5-F, X2=H, X3=4C1, R=nC4Hg7'

1. Preparation of n-butyl-Y-aminobutyrate hydrochloride

20.6 g (0.2 mol) of #-aminobutyric acid and 200 ml of n-butanol are introduced into a 500 ml flask.

It is heated to 60°C and 25 ml of thionyl chloride are introduced dropwise and the mixture is then brought to the reflux temperature for 2.5 hours. It is evaporated to dryness, evaporated twice with 100 ml of benzene and treated with cold ether. The hydrochloride crystallizes, this is filtered, filtered off, washed with ether, filtered off and dried in a desiccator in the presence of powdered NaOH.

The compound is recrystallized from a chloroform/ether mixture.

2. n-butyl-N/a-(4-chloro-phenyl)-5-fluoro-2-hydroxy-benzylideneyl/-

4-amino-butyrate

12.5 g (0.05 mol) 4-chloro-5-fluoro-2-hydroxy-benzophenone, 9.8 g (0.05 mol) n-butyl-y-amino-butyrate are introduced into a 100 ml flask hydrochloride, 350 ml of ethanol and 4.2 g of sodium bicarbonate. Ethanol is evaporated under atmospheric pressure (90°C), 300 ml of methanol and 5 ml of water are added and it is evaporated with repetition three times.

It is then evaporated to dryness, the product is taken up in ether, insoluble matter is filtered off, the product is washed with water, dried over MgSO^ and evaporated to dryness. An oil is obtained which is purified the first time in a silica drying column with chloroform as eluent and a further time over a normal silica column with a mixture of chloroform 90/ether 10

as eluent.

An oil is obtained.

Example 2 tetradecyloxycarbonylmethyl-N-/α-phenyl-5-fluoro-2-hydroxy-benzylideneyl/-4-amino-butyrate /X1=5-F, X2=X3=H, n=3, R=CH2CO0 (CH2 ) -^CHy7

10 g (0.0309 mol) sodium (α-phenyl-5-fluoro-2-hydroxy-benzylideneyl)-4-amino-butyrate and 8.99 g (0.0390 mol) tetradecyloxy- carbonyl methyl chloride, 100 ml D.M.S.O. and 2 drops of triethylamine. The mixture is heated at 90°C for 1 hour. The mixture is cooled and then evaporated to dryness. The residue is taken up in ether and insoluble matter is filtered off. The product is re-evaporated to dryness after being dried several times over MgSO^. A yellow oil is obtained which is purified by passing it through a silica column.

Example 3 2-ethoxy-ethyl-N/oc-(4-chloro-phenyl-5-fluoro-2-hydroxy-benzylideneyl/-4-amino-butyrate

/h=3, X1=5-F, X2=H, X3=4-C1, R=C2H50(CH2) J

To 11.19 g (1/30 mol) of α-(4-chloro-phenyl)-5-fluoro-2-hydroxy-benzylideneyl/-4-amino-butyric acid in solution in 1000 ml of tetrahydrofuran is added 5.7 g carbonyldiimidazole and the mixture is stirred for 2 hours at ambient temperature. It is evaporated to dryness, 200 ml of toluene and 3.6 g of ethoxyethanol are added. The mixture is refluxed for 3 hours and evaporated to dryness at 60°C. The residue is taken up in ether, the ether phase is washed with water, then with bicarbonate-containing water and dried over MgSO^.

Ether is evaporated and the oil obtained is purified by chromatography over a silica column with a mixture CHCl390/Et2O 10 as eluent. An oil is obtained.

Example 4 4-phenyl-phenacyl-N/a-(4-chloro-phenyl)-5-fluoro-2-hydroxy-benzylideneyl 7-4-amino-butyrate

/n=3, X1=5-F, X2=H, X3=4-C1, R= CO-CH2^7

1, 6 g of CH 3 O Na. It is evaporated to dryness under reduced pressure and the sodium salt of the acid is dried in a heated desiccator (140°C under lmm).

300 ml of DMSO and 8.2 g of 4-(£enyl-phenacyl)-methyl bromide are added to the residue and it is evaporated to dryness under reduced pressure (bath at 100°C). The remainder is dissolved in ether and treated with charcoal.

It is filtered and the filtrate is evaporated to dryness. The product is dissolved in a small amount of chloroform and chromatographed over a silica column (large capacity) and eluted with chloroform. The oil obtained crystallizes from petroleum ether. It is filtered off with suction and dried at 60°C in a heated desiccator.

Temp. = 80.5 - 81.5°C.

In the following table I, various compounds prepared by means of the method according to the invention are indicated. The compounds which can be produced by the method according to the invention were subjected to pharmacological tests which show their effect on the central nervous system.

The acute toxicity was determined in mice by intraperitoneal administration. LD50 (50% lethal doses) which resulted in the death of 50% of the animals are indicated in the following table II.

The activity of the compounds was shown by antagonism vis^:a-vis convulsions induced in the mice by means of bicuculline.

Bicuculline is a relatively selective blocker of the GABA-minergic post-synaptic receptors and lethal convulsions are antagonized by compounds that raise the content of cerebral GABA or that have a GABA-mimetic effect.

50% active doses (ED 50) have been determined as doses that protect 50% of the animals against the effects of bicuculline for the investigated substances. The results are reproduced in the following table II.

The compounds produced by the method according to the invention are active anticonvulsants and can be used within human and veterinary therapy for the treatment of various disorders in the nervous system, e.g. for the treatment of psychoses and certain neurological diseases.

The active compounds (I) can be used as such or in conjunction with common additives for different administration methods, especially oral (tablets, dragees, gels, capsules, solutions or drinkable suspensions) or parenteral administration.

The daily dose ranges from 5 to 400 mg.

Claims (1)

Process for the preparation of pharmacologically active benzylidene derivatives of the general formula (I) in which X^ , X2 , and X^ are the same or different and each represents hydrogen or halogen, methyl or methoxy, n is an integer from 1 to 10, and R stands for alkyl of 1 to 16 carbon atoms, a radical CH2 COOR1 in which R^^ is higher alkyl of 11 to 15 carbon atoms, a radical (CH2)2OR2 in which R2 is alkyl of 1 to 6 carbon atoms, or a CH2 CO radical characterized by one either reacts an acid of formula (II) in which X^ , X2 , X^ and n have the above meaning, or et functional derivative thereof, with a compound of formula RX or ROMe or ROH in which R has the above meaning and Me stands for an alkali metal and X is halogen (possibly in the presence of carbonyldiimidazole or sulfonyldiimidazole), or one reacts a benzophenone of formula (III) "where X^ , X2 and X^ have the above meaning, with a compound of formula (IV) wherein n and R have the above meaning.