FR2484410A2 - Alpha-phenyl benzylidenyl aminoacid derivs. - which are anticonvulsants and centrally active, prepd. from di:phenyl methanone and aminoacid - Google Patents

Alpha-phenyl benzylidenyl aminoacid derivs. - which are anticonvulsants and centrally active, prepd. from di:phenyl methanone and aminoacid Download PDF

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FR2484410A2
FR2484410A2 FR7903430A FR7903430A FR2484410A2 FR 2484410 A2 FR2484410 A2 FR 2484410A2 FR 7903430 A FR7903430 A FR 7903430A FR 7903430 A FR7903430 A FR 7903430A FR 2484410 A2 FR2484410 A2 FR 2484410A2
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sep
aminoacid
phenyl
ona
anticonvulsants
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FR2484410B2 (en
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Synthelabo SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group

Abstract

Benzylidene derivs. of formula (I) are new. In (I) X2 is H and X1 is 5-Br; X3 is 4-C1, H, 4-Br, or 2-C1; R is NH2, OH or ONa; n is 3; or X1 is 5-C1; X3 is 4-C1, 4-Br, H, 4-F, or 2-G1; R is NH2, OH, or ONa; or X1 is 5-F; X3 is 4-C1; n is 1, 2 or 4; R is NH2, OH, or ONa; or X1 is 5-F; X3 is 2-Cl or 4-CF3; n is 3; R is ONa or OH. (I) are anticonvulsants and active on central nervous system, esp. in treatment of psychoses and neurological disorders. The cpds. may be given orally or parenterally at a daily dosage of 100-1500 mg.

Description

Le présent certificat d'addition concerne des exemples particuliers de composés de formule (I)

Figure img00010001

dans laquelle
X1, X2 et X3, qui sont identiques ou différents, représentent chacun, indépendamment l'un de l'autre, un atome d'hydrogène ou d'halogène, notamment le chlore ou le fluor, ou bien un radical méthyle, méthoxyle ou CF3, n représente un nombre entier au moins égal à 1 et au plus égal
à 10 et,
R représente un radical hydroxyle, OM, NH2, NH(CH2 > 3- COOH,-NH
(CH2)3 - COOM, (M représentant un atome de métal alcalin, en
particulier le sodium), NH (CH2)3 - COOC2H5,
NH - cycloalkyle, NH - phényle, NH - benzyle (le radical benzy
le pouvant porter un substituant choisi parmi les atomes d'ha
logène et le radical trifluorométhyle)
NH - alkyle, N - (alkyl)2, N - (alkyl) - (benzyl),
les radicaux alkyles linéaires ou ramifiés ayant de 1 à 4 atomes
de carbone, les radicaux cycloalkyles ayant de 3 à 6 atomes de
carbone, à l'exception du composé pour lequel X1= X3 = H,X2 = 5-Cl,n = 1 et
R = OH.This certificate of addition relates to particular examples of compounds of formula (I)
Figure img00010001

in which
X1, X2 and X3, which are identical or different, each represent, independently of one another, a hydrogen or halogen atom, especially chlorine or fluorine, or a methyl, methoxyl or CF3 radical; , n represents an integer at least equal to 1 and at most equal
at 10 and,
R represents a hydroxyl radical, OM, NH2, NH (CH2> 3-COOH, -NH
(CH 2) 3 - COOM, (M representing an alkali metal atom, in
especially sodium), NH (CH2) 3 - COOC2H5,
NH - cycloalkyl, NH - phenyl, NH - benzyl (the benzyl radical
the can carry a substituent chosen from the atoms of ha
logene and the trifluoromethyl radical)
NH - alkyl, N - (alkyl) 2, N - (alkyl) - (benzyl),
linear or branched alkyl radicals having from 1 to 4 atoms
of carbon, cycloalkyl radicals having from 3 to 6 carbon atoms
carbon, with the exception of the compound for which X1 = X3 = H, X2 = 5-Cl, n = 1 and
R = OH.

Ces composés so.nt préparés1 Selon le procédé:du brevet principal c'est-a-dire par réaction entre une cétone de formule (II)

Figure img00010002

et le composé de formule (III) NH2 - C CnH2n - CO-R (III). sous forme de base ou de chlorhydrate.These compounds are prepared according to the process of the main patent, that is to say by reaction between a ketone of formula (II)
Figure img00010002

and the compound of formula (III) NH 2 -CnH 2n -CO-R (III). as a base or hydrochloride.

La réaction est effectuée dans un solvant alcoolique tel que le méthanol ou l'éthanol, à une température allant de 100C à la température d'ébullition du solvant, en présence d'un métal alcalin ou d'un alcoolate de métal alcalin.The reaction is carried out in an alcoholic solvent such as methanol or ethanol, at a temperature ranging from 100C to the boiling point of the solvent, in the presence of an alkali metal or an alkali metal alkoxide.

Les cétones (II) de départ sont préparées 1) soit à partir des composés

Figure img00020001

par réaction avec un composé
Figure img00020002

puis on déméthyle l'intermédiaire obtenu avec du chlorure d'aluminium ou du trichlorure de bore, 2) soit à partir des composés
Figure img00020003

que l'on fait réagir avec un composé
Figure img00020004

et on hydrolyse l'intermédiaire pour obtenir un composé
Figure img00020005

que l'on déméthyle en composé (II) à l'aide de chlorure d'aluminium ou de trichlorure de bore.The starting ketones (II) are prepared 1) either from the compounds
Figure img00020001

by reaction with a compound
Figure img00020002

the resulting intermediate is then demethylated with aluminum chloride or boron trichloride, or 2) from the compounds
Figure img00020003

that is reacted with a compound
Figure img00020004

and hydrolyzing the intermediate to obtain a compound
Figure img00020005

that is demethylated in compound (II) using aluminum chloride or boron trichloride.

L'exemple suivant illustre l'invention.The following example illustrates the invention.

Les analyses et les spectres IR et wXN ont confirmé la structure des composés.IR and wXN analyzes and spectra confirmed the structure of the compounds.

Exemple : N- [α-(choro-2' phényl) chloro-5 hydroxy-2 benzyîiaényîj
amino-4 butyramide.Example: N- [α- (2-chloro-phenyl) -5-chloro-2-hydroxybenzylidenyl)
4-amino-butyramide.

On introduit dans un ballon de 1 1 5,18 g de chlorhydrate de g-amino butyramide en solution dans 400 ml de méthanol. On ajoute 2 g de méthylate de sodium. On ajoute 10gde di-chloro-2'5 hydroxy-2 diphényl méthanone et 200 ml dléthanol. On évapore à sec. On reprend le résidu dans du chloroforme, lave la phase chloroformique à l'eau.5.18 g of g-amino butyramide hydrochloride dissolved in 400 ml of methanol are introduced into a flask of 1 l. 2 g of sodium methoxide are added. 10 g of 2-chloro-2-hydroxy-2-diphenylmethanone and 200 ml of ethanol are added. Evaporate to dryness. The residue is taken up in chloroform and the chloroform phase is washed with water.

On sèche sur MgSO4. On filtre, on évapore le chloroforme à sec, on reprend le résidu dans de l'acétate d'éthyle et on fait passer le produit sur une colonne de silice. Après élution, on filtre et évapore à sec. On reprend le résidu dans de l'éther, le traite au charbon végétal, filtre, concentre, et recristallise le solide dans un mélange éther/éther de pétrole.It is dried over MgSO4. The mixture is filtered, the chloroform is evaporated to dryness, the residue is taken up in ethyl acetate and the product is passed through a column of silica. After elution, filter and evaporate to dryness. The residue is taken up in ether, treated with charcoal, filtered and concentrated, and the solid is recrystallized from an ether / petroleum ether mixture.

Dans le tableau suivant sont représentés les autres composés qui sont préparés de la même manière.

Figure img00040001
In the following table are represented the other compounds which are prepared in the same way.
Figure img00040001

<tb> Composé <SEP> x1 <SEP> x2 <SEP> x3 <SEP> n <SEP> R <SEP> F <SEP> ( C)
<tb> <SEP> 1 <SEP> F-5 <SEP> H <SEP> Cl-1' <SEP> 3 <SEP> OH <SEP> 85,5-87
<tb> <SEP> 2 <SEP> Br-5 <SEP> H <SEP> E <SEP> 3 <SEP> ONa <SEP> 247-8
<tb> <SEP> 3 <SEP> Br-5 <SEP> H <SEP> Cl-4' <SEP> 3 <SEP> ONa <SEP> 230
<tb> <SEP> 4 <SEP> C1-5 <SEP> H <SEP> Cl-4' <SEP> 3 <SEP> ONa <SEP> > <SEP> 250
<tb> <SEP> 5 <SEP> Br-5 <SEP> H <SEP> Br-4' <SEP> 3 <SEP> ONa <SEP> > <SEP> 250
<tb> <SEP> 6 <SEP> Cl-5 <SEP> H <SEP> Br-4' <SEP> 3 <SEP> ONa <SEP> > <SEP> 235
<tb> <SEP> 7 <SEP> F-5 <SEP> H <SEP> Cl-4' <SEP> 2 <SEP> ONa <SEP> > <SEP> 240
<tb> <SEP> 8 <SEP> F-5 <SEP> H <SEP> Cl-4' <SEP> 2 <SEP> NH2 <SEP> 157-8
<tb> <SEP> 9 <SEP> C1-5 <SEP> H <SEP> H
<tb> 1o <SEP> H <SEP> H <SEP> CH3O-2' <SEP> 3 <SEP> NH2 <SEP> 119-20
<tb> 11 <SEP> F-5 <SEP> H <SEP> Cl-4' <SEP> 1 <SEP> OH <SEP> 192-3
<tb> 12 <SEP> F-5 <SEP> H <SEP> Cl-4' <SEP> 4 <SEP> ONa <SEP> ) <SEP> 300
<tb> 13 <SEP> F-5 <SEP> H <SEP> Cl-4' <SEP> 3 <SEP> OH <SEP> 98-9
<tb> 14 <SEP> F-5 <SEP> H <SEP> Cl-4' <SEP> 4 <SEP> NH2 <SEP> 140-1
<tb> 15 <SEP> Cl-5 <SEP> H <SEP> F-4' <SEP> 3 <SEP> NE2 <SEP> 140-1
<tb> 16 <SEP> C1-5 <SEP> H <SEP> F-4' <SEP> 3 <SEP> OH <SEP> 127-8
<tb> 17 <SEP> F-5 <SEP> H <SEP> CF34' <SEP> 3 <SEP> Osa <SEP> > <SEP> 250
<tb> 18 <SEP> Cl-5 <SEP> H <SEP> Cl-2' <SEP> 3 <SEP> OH <SEP> 102
<tb> 19 <SEP> C1-5 <SEP> H <SEP> - <SEP> Cl-2' <SEP> 3 <SEP> NH2 <SEP> 104
<tb> 20 <SEP> Br-5 <SEP> H <SEP> Hr-2' <SEP> 3 <SEP> NH2 <SEP> 133
<tb> 21 <SEP> Br-5 <SEP> H <SEP> Br-2' <SEP> 3 <SEP> OH <SEP> 138
<tb> 22 <SEP> Br-5 <SEP> H <SEP> Cl-2' <SEP> 3 <SEP> OH <SEP> 118-119
<tb> 23 <SEP> Br-5 <SEP> H <SEP> Ct-2' <SEP> 3 <SEP> NH2 <SEP> 131-132
<tb> 24 <SEP> Br-5 <SEP> H <SEP> Cl-2' <SEP> 3 <SEP> OH <SEP> 130-131
<tb> 25 <SEP> Br-5- <SEP> H <SEP> Cl-2' <SEP> 3 <SEP> NH2 <SEP> 125-126
<tb> 26 <SEP> C1-5 <SEP> H <SEP> Br-2' <SEP> 3 <SEP> NH2 <SEP> 118-119
<tb> 27 <SEP> Cl-2 <SEP> Cl-5 <SEP> Cl-2' <SEP> 3 <SEP> NH2 <SEP> 135-136
<tb> 28 <SEP> Cl-2 <SEP> Cl-5 <SEP> Cl-2' <SEP> 3 <SEP> OH <SEP> 149-150
<tb> <tb> Compound <SEP> x1 <SEP> x2 <SEP> x3 <SEP> n <SEP> R <SEP> F <SEP> (C)
<tb><SEP> 1 <SEP> F-5 <SEP> H <SEP> Cl-1 '<SEP> 3 <SEP> OH <SEP> 85.5-87
<tb><SEP> 2 <SEP> Br-5 <SEP> H <SEP> E <SEP> 3 <SEP> ONa <SEP> 247-8
<tb><SEP> 3 <SEP> Br-5 <SEP> H <SEP> Cl-4 '<SEP> 3 <SEP> ONa <SEP> 230
<tb><SEP> 4 <SEP> C1-5 <SEP> H <SEP> Cl-4 '<SEP> 3 <SEP> ONa <SEP>><SEP> 250
<tb><SEP> 5 <SEP> Br-5 <SEP> H <SEP> Br-4 '<SEP> 3 <SEP> ONa <SEP>><SEP> 250
<tb><SEP> 6 <SEP> Cl-5 <SEP> H <SEP> Br-4 '<SEP> 3 <SEP> ONa <SEP>><SEP> 235
<tb><SEP> 7 <SEP> F-5 <SEP> H <SEP> Cl-4 '<SEP> 2 <SEP> ONa <SEP>><SEP> 240
<tb><SEP> 8 <SEP> F-5 <SEP> H <SEP> Cl-4 '<SEP> 2 <SEP> NH2 <SEP> 157-8
<tb><SEP> 9 <SEP> C1-5 <SEP> H <SEP> H
<tb> 1o <SEP> H <SEP> H <SEP> CH3O-2 '<SEP> 3 <SEP> NH2 <SEP> 119-20
<tb> 11 <SEP> F-5 <SEP> H <SEP> Cl-4 '<SEP> 1 <SEP> OH <SEP> 192-3
<tb> 12 <SEP> F-5 <SEP> H <SEP> Cl-4 '<SEP> 4 <SEP> ONa <SEP>) <SEP> 300
<tb> 13 <SEP> F-5 <SEP> H <SEP> Cl-4 '<SEP> 3 <SEP> OH <SEP> 98-9
<tb> 14 <SEP> F-5 <SEP> H <SEP> Cl-4 '<SEP> 4 <SEP> NH2 <SEP> 140-1
<tb> 15 <SEP> Cl-5 <SEP> H <SEP> F-4 '<SEP> 3 <SEP> NE2 <SEP> 140-1
<tb> 16 <SEP> C1-5 <SEP> H <SEP> F-4 '<SEP> 3 <SEP> OH <SEP> 127-8
<tb> 17 <SEP> F-5 <SEP> H <SEP> CF34 '<SEP> 3 <SEP> Osa <SEP>><SEP> 250
<tb> 18 <SEP> Cl-5 <SEP> H <SEP> Cl-2 '<SEP> 3 <SEP> OH <SEP> 102
<tb> 19 <SEP> C1-5 <SEP> H <SEP> - <SEP> Cl-2 '<SEP> 3 <SEP> NH2 <SEP> 104
<tb> 20 <SEP> Br-5 <SEP> H <SEP> Hr-2 '<SEP> 3 <SEP> NH2 <SEP> 133
<tb> 21 <SEP> Br-5 <SEP> H <SEP> Br-2 '<SEP> 3 <SEP> OH <SEP> 138
<tb> 22 <SEP> Br-5 <SEP> H <SEP> Cl-2 '<SEP> 3 <SEP> OH <SEP> 118-119
<tb> 23 <SEP> Br-5 <SEP> H <SEP> Ct-2 '<SEP> 3 <SEP> NH2 <SEP> 131-132
<tb> 24 <SEP> Br-5 <SEP> H <SEP> Cl-2 '<SEP> 3 <SEP> OH <SEP> 130-131
<tb> 25 <SEP> Br-5- <SEP> H <SEP> Cl-2 '<SEP> 3 <SEP> NH2 <SEP> 125-126
<tb> 26 <SEP> C1-5 <SEP> H <SEP> Br-2 '<SEP> 3 <SEP> NH2 <SEP> 118-119
<tb> 27 <SEP> Cl-2 <SEP> Cl-5 <SEP> Cl-2 '<SEP> 3 <SEP> NH2 <SEP> 135-136
<tb> 28 <SEP> Cl-2 <SEP> Cl-5 <SEP> Cl-2 '<SEP> 3 <SEP> OH <SEP> 149-150
<Tb>

Les composés de l'invention ont été soumis à des essais pharmacolo giques montrant leur activité sur le système nerveux central.The compounds of the invention have been subjected to pharmacological tests showing their activity on the central nervous system.

La toxicité aiguë a été déterminée chez la souris par voie intrapéritonéale. La DL 50 (dose létale 50 %) induisant la mort chez 50% des animaux varie de 400 à > 1000 mg/kg par voie intrapéritonéale.Acute toxicity was determined in the mouse intraperitoneally. The LD 50 (50% lethal dose) inducing death in 50% of animals ranges from 400 to> 1000 mg / kg intraperitoneally.

L'activité des composés a été montrée par l'antagonisme vis-à-vis de la mortalité induite par la bicuculline chez la souris.The activity of the compounds was shown by antagonism to bicuculline-induced mortality in mice.

La bicuculline est un bloqueur relativement sélectif des récepteurs
GABA-ergiques post-synaptiques et ses effets convulsivants et létaux sont antagonisés par les composés élevant le taux de GABA cérébral ou possédant une activité GABA-mimétique. Bicuculline is a relatively selective receptor blocker
GABA-post-synaptic ergics and its convulsive and lethal effects are antagonized by compounds elevating the level of brain GABA or possessing GABA-mimetic activity.

On a évalué la dose active 50 % (DA 50), dose protégeant 50 % des animaux contre l'effet de la bicuculline, des substances étudiées.The active dose 50% (DA 50), a dose protecting 50% of animals against the effect of bicuculline, was evaluated for the substances studied.

Elle varie de 30 à 80 mg/kg par voie intrapéritonéale.It ranges from 30 to 80 mg / kg intraperitoneally.

Les composés de l'invention sont actifs comme anticonvulsivants.The compounds of the invention are active as anticonvulsants.

Ils sont utilisables en thérapeutique humaine et vétérinaire pour le traitement de diverses maladies du système nerveux central, par exemple pour le traitement des psychoses et de certaines maladies neurologiques.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.

L'invention comprend, par conséquent, toutes compositions pharmaceutiques renfermant les composés (I) comme principes actifs, en association avec tous excipients appropriés à leur administration, en particulier par voie orale (comprimés, dragées, gélules, capsules, cachets, solution ou suspensions buvables) ou parentérale.The invention therefore comprises any pharmaceutical compositions containing the compounds (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.

La posologie quotidienne peut aller de 100 à 1500 mg. The daily dosage can range from 100 to 1500 mg.

Claims (3)

Revendicationsclaims 1. Dérivés benzylidéniques répondant à la formule (I)1. Benzylidenic Derivatives of Formula (I)
Figure img00060001
Figure img00060001
 dans laquelle X2 est H, et - lorsque X1 est Br-5, X3 est Cl-4', H, Br-4 ou Cl-2' ' et R est wherein X2 is H, and when X1 is Br-5, X3 is Cl-4 ', H, Br-4 or Cl-2' 'and R is NH2, OH ou ONa et n est 3 - lorsque X1 est C1-5, X3 est Cl-4', Br-4', H, F-4' ou C1-2' et NH2, OH or ONa and n is 3 - when X1 is C1-5, X3 is Cl-4 ', Br-4', H, F-4 'or C1-2' and R est NH2, OH ou ONa, - lorsque X1 est F-5, X3 est Cl-4' et n est 1,2 ou 4 et R est OH, R is NH2, OH or ONa, when X1 is F-5, X3 is Cl-4 'and n is 1,2 or 4 and R is OH, ONa ou NH2' - lorsque X1 est F-5, X3 est C1-2' ou CF3-4', n est 3 et R est ONa ONa or NH2 '- when X1 is F-5, X3 is C1-2' or CF3-4 ', n is 3 and R is ONa ou OH. or OH. 2. Procédé de préparation des composés selon la revendication 1, procédé caractérisé en ce que l'on fait réagir une cétone (II)2. Process for the preparation of the compounds according to claim 1, characterized in that a ketone (II) is reacted
Figure img00060002
Figure img00060002
 avec un composé de formule (III) NH2- CnH2 n - COR sous forme de base ou de chlorhydrate. with a compound of formula (III) NH 2 -CnH 2 n-COR in base form or hydrochloride. 3. Médicament caractérisé en ce qu'il contient un composé tel que spécifié dans la revendication 1. 3. Medicinal product characterized in that it contains a compound as specified in claim 1.
FR7903430A 1979-02-12 1979-02-12 Alpha-phenyl benzylidenyl aminoacid derivs. - which are anticonvulsants and centrally active, prepd. from di:phenyl methanone and aminoacid Granted FR2484410A2 (en)

Priority Applications (1)

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FR7903430A FR2484410A2 (en) 1979-02-12 1979-02-12 Alpha-phenyl benzylidenyl aminoacid derivs. - which are anticonvulsants and centrally active, prepd. from di:phenyl methanone and aminoacid

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FR7903430A FR2484410A2 (en) 1979-02-12 1979-02-12 Alpha-phenyl benzylidenyl aminoacid derivs. - which are anticonvulsants and centrally active, prepd. from di:phenyl methanone and aminoacid

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FR2484410A2 true FR2484410A2 (en) 1981-12-18
FR2484410B2 FR2484410B2 (en) 1982-09-24

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2319338A1 (en) * 1975-08-01 1977-02-25 Synthelabo NEW A-PHENYL BENZYLIDENIC DERIVATIVES OF AMINO ACIDS, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2319338A1 (en) * 1975-08-01 1977-02-25 Synthelabo NEW A-PHENYL BENZYLIDENIC DERIVATIVES OF AMINO ACIDS, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM

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