FR2501201A2 - Anticonvulsant butenyl benzophenone ketimine(s) - prepd. from 2-hydroxy benzophenone and butenyl amine - Google Patents

Abstract

Benzylidene derivs. of formula (I) are new (where X1-X4-H, halogen, 1-4C alkyl, CF3, NO2 phenyl, CH3O, or NH2, tow of these substituents being other than H; R= alkenyl of 4C atoms.). Used as anticonvulsants, in the treatment of psychoses and neurological disorders.

Description

This certificate of addition relates to benzylidenic derivatives, their preparation and their therapeutic application.

X1, X2, X3 et X4 reorésentent, indépendamment l'un de l'autre, un atome d'hydrogène, un atome d'halogène, un radical alkyle droit ou ramifié de 1 à 4 atomes de carbone, le radical CF3, le radical NO2, le radical phényle, le radical méthoxy ou le radical amino, deux des substituants X1, X2, X3 et X4 étant différents d'un atome d'hydrogène,
R représente un radical alkyle droit ou ramifié de 1 à 16 atomes ou un radical alcényle de 2 à 8 atomes de carbone, en particulier les composés comportant un radical R = alkyle.In her patent, to which this certificate of addition is attached, the Applicant has described compounds corresponding to the formula in which

X1, X2, X3 and X4 represent, independently of each other, a hydrogen atom, a halogen atom, a straight or branched alkyl radical of 1 to 4 carbon atoms, the radical CF 3, the radical NO2, the phenyl radical, the methoxy radical or the amino radical, two of the substituents X1, X2, X3 and X4 being different from a hydrogen atom,
R represents a straight or branched alkyl radical of 1 to 16 atoms or an alkenyl radical of 2 to 8 carbon atoms, in particular compounds comprising an R = alkyl radical.

In this certificate of addition will be more specifically described the compounds (I) for which R is an alkenyl radical of 4 carbon atoms.

Among these compounds are preferred those for which the radicals X1, X2, X3 and X4 are, independently of one another, a hydrogen or halogen atom or the methyl radical and more particularly those for which X2 = H X1 is in position 4 and X3 and / or X4 are in position 2 'and / or 4'.

According to the invention, the compounds (I) can be prepared according to the following reaction scheme
Reaction scheme

The compounds (II) are described by the Applicant in his previous patents.

Compounds (III) are used in base form or hydrochloride and are described in the literature.

The reaction is carried out in an alcoholic solvent, such as methanol or ethanol, at a temperature ranging from 10 ° C. to the boiling point of the solvent, in the presence of an alkali metal or an alkali metal alcoholate.

The following example illustrates the invention. Analyzes and IR and NMR spectra confirmed the structure of the compounds.

EXAMPLE [(BUTENE -3 YL-IMINO) (CHLORO-2-PHENYL METHYL) -2
CHLORO-4 PHENOL.

3.5 g (5-chloro-2-hydroxyphenyl) (2-chlorophenyl) methanone dissolved in 50 ml of methanol are introduced into a 500 ml flask and 12 g are added. butene-3-yl amine.

It agitates until complete dispatirion of the ketone. Then it is evaporated to dryness, the residue is taken up in chloroform. The chloroform phase is washed with water (several times), decanted and dried over MgSO4; it is sintered and the filtrate is evaporated to dryness.

The product is crystallized from petroleum ether, the precipitate is sintered, drained, and dried in a desiccator.

The compound obtained melts at 67-680C.

In the following table are represented the compounds prepared as examples.

BOARD

<tb> Compound <SEP> X1 <SEP> X2 <SEP> X3 <SEP> X4 <SEP> R <SEP> F (OC)
<tb><SEP> or <SEP> nD
<tb><SEP> 1 <SEP> C1-5 <SEP> H <SEP> C1-4 <SEP> H <SEP> CH2-CH2-CH "CH2 <SEP> 67-68
<tb><SEP> 2 <SEP> C1-5 <SEP> H <SEP> C1-4 <SEP> H <SEP> CH2-CH = CH-CH3 <SEP> 19
<tb><SEP> nD <SEP> = 1.6140
<tb><SEP> 3 <SEP> Cl-S <SEP> H <SEP> Cl-4 <SEP> H <SEP> CH-F = CH2 <SEP> 47-48
<tb><SEP> CH3
<Tb>
The compounds of the invention have been subjected to pharmacological tests showing their activity on the central nervous system.

Acute toxicity was determined in the mouse intraperitoneally. The LD 50 (lethal dose 50 inducing death in 50% of the animals is greater than 3000 mg / kg.

The activity of the compounds was shown by antagonagonism with respect to bicuculline-induced mortality in mice.

Bicuculline is a relatively selective blocker of post-synaptic GABA-ergic receptors and convulsive and lethal effects are antagonized by compounds elevating the levels of cerebral GABA or possessing GABA-mimetic activity.

The active dose 50% (DA 50), a dose protecting 50% of animals against the effect of bicuculline, was evaluated for the substances studied.

The DA 50 of the compounds of the invention ranges from 20 to 80 mg / kg intraperitoneally.

The comnosés of the invention are active as anticonvulsants. They are useful in human and veterinary therapy for the treatment of various diseases of the central nervous system, for example for the treatment of psychoses and certain neurological diseases such as epilepsy.

The invention therefore includes any pharmaceutical compositions containing comoose (I) as active ingredients, in combination with any excipients suitable for their administration, in particular orally (tablets, dragees, capsules, capsules, cachets, solutions or suspensions drinkable) or parenteral.

The daily dosage can range from 100 to 1500 mg.

Claims (9)

claims 1. Compounds according to the formula

 in which X1, X2, X3 and X4 represent, independently of one another, a hydrogen atom, a halogen atom, a straight or branched alkyl radical of 1 to 4 carbon atoms, the radical CF3, the radical NO 2, the phenyl radical, the methoxy radical or the -amino radical, two of the substituents X 1, X 2, X 3 and X 4 being different from a hydrogen atom, and R represents an alkenyl radical of 4 carbon atoms. 2. Compounds according to claim 1, wherein X1, X2, X3 and X4 represent, independently of one another, a hydrogen or halogen atom or the methyl radical. 3. Compounds according to claim 2, wherein X2 is H, X1 is in position 4 and X3 and / or X4 are in position 2 'and / or 4'. 4. # (Butene-3-yl-imino) (2-chloro-phenyl) methyl-2-chloro-4-phenol. 5. [1- (2-Butenyl-imino) (2-chlorophenyl) methyl] -4-chlorophenol. 6. # (2-methyl-2-propenyl-imino) (2-chlorophenyl) methyl-2-chloro-4-phenol. 7. Process for the preparation of the compounds according to claim 1, characterized in that a ketone of formula (II) is reacted

 with a compound nNn2 v1ll). 8. Pharmaceutical composition characterized in that it contains a compound specified in any one of claims 1 to 6, in combination with any suitable excipient. 9. Medicament characterized in that it consists of a compound specified in any one of claims 1 to 6.