CA1092136A

CA1092136A - Process for the preparation of novel acetamids and products thus prepared

Info

Publication number: CA1092136A
Application number: CA267,006A
Authority: CA
Inventors: Michel Vincent; Georges Remond; Michel Laubie; Jean-Claude Poignant
Original assignee: Science Union et Cie
Current assignee: Science Union et Cie
Priority date: 1976-12-02
Filing date: 1976-12-02
Publication date: 1980-12-23

Abstract

La présente invention se rapporte à un procédé d'obtention des composes de formule générale I: I dans laquelle X1 et X3 représentent simultanément ou distinctement, un radical alcoyle inférieur, un radical alcoxy inférieur ou un radical alcoylthio inférieur; X2 et X4 simultanément ou distinctement représentent de l'hydrogène ou un radical alcoyle inférieur; A et B représentent, simultanément ou distinctement, un halogène, un alcoyle inférieur ou un radical alcoxy inférieur; n et n' sont des nombres entiers variant de 0 à 3; Y et Z, simultanément ou distinctement, sont de l'hydrogène, un radical alcoyle inférieur en chaîne droite ou ramifiée, ou forment une chaîne alcoylène avec R4 ayant de 4 à 6 atomes de carbone; R4 représente de l'hydrogène, un radical alcoyle inferieur, un radical alcényle inférieur ou un radical benzyle; R5 représente un radical alcoyle inférieur, alcényle inférieur, aralcoyle inférieur; ou bien R4 et R5 forment ensemble une chaîne alcoylène ayant 4 ou 5 chaînons, dans laquelle un groupe méthylène peut être remplace par un groupe imino dans lequel R est de l'hydrogène, un alcoyle inférieur, un acyloxy alcoyle inférieur ou un alcoxy alcoyle inférieur ou un hydroxy alcoyle inférieur, caractérisé en ce que l'on condense un acide di-aryl acétique de formule générale II: II dans laquelle la définition des substituants A, B, X1, X2, X4, n et n' demeure inchangée, ou un derivé fonctionnel de celui-ci, avec une éthylène diamine de formule générale III: III dans laquelle les substituants Y, Z, R4 et R5 sont définis comme précédemment, pour obtenir un diarylacétamide de formule générale I. Les composés obtenus selon le procédé de l'invention peuvent se présenter sous forme de base ou sous forme de sels. Lorsque la molécule comporte un atome de carbone asymétrique, ils peuvent être dédoublés en leurs isomères optiques. Les composes obtenus selon le procédé de l'invention sont des médicaments précieux, notamment comme agents anticonvulsivants dans le traitement de l'epilepsie.The present invention relates to a process for obtaining the compounds of general formula I: I in which X1 and X3 represent simultaneously or distinctly, a lower alkyl radical, a lower alkoxy radical or a lower alkylthio radical; X2 and X4 simultaneously or distinctly represent hydrogen or a lower alkyl radical; A and B represent, simultaneously or distinctly, a halogen, a lower alkyl or a lower alkoxy radical; n and n 'are whole numbers varying from 0 to 3; Y and Z, simultaneously or distinctly, are hydrogen, a lower alkyl straight or branched chain, or form an alkylene chain with R4 having from 4 to 6 carbon atoms; R4 represents hydrogen, a lower alkyl radical, a lower alkenyl radical or a benzyl radical; R5 represents a lower alkyl, lower alkenyl, lower aralkyl radical; or R4 and R5 together form an alkylene chain having 4 or 5 members, in which a methylene group can be replaced by an imino group in which R is hydrogen, a lower alkyl, an acyloxy lower alkyl or a lower alkoxy or a hydroxy lower alkyl, characterized in that a di-aryl acetic acid of general formula II: II is condensed in which the definition of the substituents A, B, X1, X2, X4, n and n 'remains unchanged, or a functional derivative thereof, with an ethylene diamine of general formula III: III in which the substituents Y, Z, R4 and R5 are defined as above, to obtain a diarylacetamide of general formula I. The compounds obtained according to the process of the invention may be in the form of the base or in the form of salts. When the molecule has an asymmetric carbon atom, they can be split into their optical isomers. The compounds obtained according to the method of the invention are precious drugs, in particular as anticonvulsant agents in the treatment of epilepsy.

Description

~0'9Z136 La presente demande de brevet a pour objet de nouveaux diphenylacetamides.
Elle a plus particulierement pour objet de nouveaux diphenylacetamides substitues a l'azote amidique par une chaSne aminoalcoylene.
La presente demande concerne specifiquement un procede d'obtention des composes de formule generale I:

(B~n ~ CH ~ (A)nl I
X2 ~ X4 ~ R4 ONH - CH - CH - ~
y z R5 dans laquelle:
- Xl et X3 representent simultanement ou distincte-ment, un radical alcoyle inferieur, un radical alcoxy inferieur ou un radical alcoylthio inferieur;
- X2 et X4 simultanement ou distinctement represen-tent de l'hydrogene ou un radical alcoyle inferieur;
- A et B representent, simultanement ou distincte-ment, un halogene, un alcoyle inferieur ou un radical alcoxy inferieur;
- n et n' sont des nombres entiers variant de O a 3;
- Y et Z, simultanement ou distinctement, sont de l'hydrogene, un radical alcoyle inferieur en chaSne droite ou ramifiee, ou forment une chaîne alcoylene avec R4 ayant de 4 a 6 atomes de carbone;
- R4 represente de l'hydrogene, un radical alcoyle inferieur, un radical alcenyle inferieur ou un radical benzyle;
- R5 represente un radical alcoyle inferieur, alcenyle inferieur, aralcoyle inferieur;
- ou bien R4 et R5 forment ensemble une chaSne iO~Z136 alcoylene ayant 4 ou 5 cha~nons, dans laquelle un groupe methylene peut être remplace par un groupe imino ,N - R dans lequel R est de l'hydrogene, un alcoyle inferieur, un acyloxy alcoyle inferieur ou un alcoxy alcoyle inferieur ou un hydroxy alcoyle inferieur, caracterise en ce que l'on condense un acide di-aryl acetique de formule generale II:

(B) ~ CH ~ (A)nl II

COOH
dans laquelle la definition des substituants A, B, Xl, X2, X4, n et n' demeure inchangee, ou un derive fonctionnel de celui-ci, avec une ethylene diamine de formule gen~rale III:
, R4 Y Z
dans laquelle les substituants Y, Z, R4 et R5 sont definis comme precedemment, pour obtenir un diarylacetamide de formule generale I que l'on peut, le cas echeant, salifier par addition d'un acide mineral ou organique, ou lorsque la molecule comporte un atome de carbone asymetrique, dedoubler en ses isomeres optiques par salification a l'aide d'un acide optiquement actif, soit lorsque R4 represente un radical benzyle, le soumettre a une debenzylation par hydrogenolyse ou acidolyse pour obtenir un compose de formule generale I dans laquelle R4 represente de l'hydrogene.
Le procede d'obtention des composes de formule gene-rale I peut encore être caracterise par les modes d'execution suivants:

1()9Z136 1. La condensation entre l'acide diaryl acetique de formule gênerale II et l'ethylenediamine de formule III est effectuee en presence d'un agent activant le carboxyle, comme par exemple, un carbodiimide, l'êthoxyacetylene ou un alcoyl isonitrile. ~ 0'9Z136 The object of this patent application is to new diphenylacetamides.
More specifically, it relates to new diphenylacetamides substituted for nitrogen amide by a chain aminoalkylene.
This request specifically concerns a process for obtaining the compounds of general formula I:

(B ~ n ~ CH ~ (A) nl I
X2 ~ X4 ~ R4 ONH - CH - CH - ~
yz R5 in which:
- Xl and X3 represent simultaneously or distinctly -ment, a lower alkyl radical, a lower alkoxy radical or a lower alkylthio radical;
- X2 and X4 simultaneously or distinctly represented try hydrogen or a lower alkyl radical;
- A and B represent, simultaneously or separately-a halogen, a lower alkyl or an alkoxy radical inferior;
- n and n 'are whole numbers varying from O to 3;
- Y and Z, simultaneously or distinctly, are of hydrogen, a lower alkyl radical in the right chain or branched, or form an alkylene chain with R4 having from 4 to 6 carbon atoms;
- R4 represents hydrogen, an alkyl radical lower, lower alkenyl radical or benzyl radical;
- R5 represents a lower alkyl radical, lower alkenyl, lower aralkyl;
- or else R4 and R5 together form a chain iO ~ Z136 alkylene having 4 or 5 chains, in which a group methylene can be replaced by an imino group, N - R in which R is hydrogen, lower alkyl, acyloxy lower alkyl or lower alkoxy or hydroxy lower alkyl, characterized in that an acid is condensed di-aryl acetic of general formula II:

(B) ~ CH ~ (A) nl II

COOH
in which the definition of the substituents A, B, Xl, X2, X4, n and n 'remains unchanged, or a functional derivative thereof, with an ethylene diamine of general formula III:
, R4 YZ
in which the substituents Y, Z, R4 and R5 are defined as above, to obtain a diarylacetamide of general formula I which is can, if necessary, salify by adding a mineral acid or organic, or when the molecule contains an atom of asymmetric carbon, split into its optical isomers by salification using an optically active acid, i.e.
when R4 represents a benzyl radical, subject it to a debenzylation by hydrogenolysis or acidolysis to obtain a composed of general formula I in which R4 represents hydrogen.
The process for obtaining compounds of the gene formula rale I can still be characterized by the execution modes following:

1 () 9Z136 1. The condensation between diaryl acetic acid general formula II and the ethylenediamine of formula III is performed in the presence of a carboxyl activating agent, such as for example, a carbodiimide, ethoxyacetylene or an alkyl isonitrile.

2. Le derive fonctionnel de l'acide diaryl acetique de formule generale II est de preference un ester d'alcoyle ou d'aryle, un halogenure, un anhydride symetrique ou mixte ou un azide. 2. The functional derivative of diaryl acetic acid of general formula II is preferably an alkyl ester or aryl, a halide, a symmetrical or mixed anhydride or a azide.

3. La condensation de l'ethylene diamine de formule generale III avec le derive fonctionnel de l'acide diaryl acetique II s'effectue en presence ou en l'absence d'une base pyridique ou d'une amine tertiaire comme par exemple, une tri-alcoylamine ou une aryldialcoylamine. 3. Condensation of the ethylene diamine of formula general III with the functional derivative of diaryl acid acetic II is carried out in the presence or absence of a base pyridic or a tertiary amine such as, for example, a tri-alkylamine or aryldialcoylamine.

4. L'hydrogenolyse des composes de formule generale I pour lesquels R4 est un radical benzyle, est effectuee en presence d'un catalyseur de la famille du platine comme par exemple, le palladium ou le platine. 4. Hydrogenolysis of the compounds of general formula I for which R4 is a benzyl radical, is carried out in presence of a platinum family catalyst such as for example, palladium or platinum.

5. Lorsque les substituants R4 et R5 forment ensem-ble une cha~ne alcoylene interrompue par un groupe imino `N - R
dans lequel R est de l'hydrogene, le groupe imino peut être hydroxyalcoyle par action d'une halohydrine ou d'un haloepoxyde comme l'epichlorhydrine puis ouverture du cycle oxirane ou par action d'un epoxyde comme par exemple l'oxyde d'ethylene ou l'oxyde de propylène. 5. When the substituents R4 and R5 together form ble an alkylene chain interrupted by an imino group `N - R
in which R is hydrogen, the imino group can be hydroxyalkyl by the action of a halohydrin or a haloepoxide like epichlorohydrin then opening of the oxirane cycle or by action of an epoxide such as ethylene oxide or propylene oxide.

6. Lorsque les substituants R4 et R5 forment ensem-ble une cha~ne alcoylene interrompue par un groupe imino `N - R
dans lequel R est un radical hydroxy alcoyle inferieur, le compose correspondant peut être acyle au moyen d'un derive fonctionnel d'un acide organique de bas poids moleculaire, ou alcoyle par action d'un agent d'alcoylation tel qu'un halo-~09Z136 gênure ou un sulfate d'alcoyle inferieur en presence d'un agentbasique.
Parmi les acides optiquement actifs utilises pour le dedoublement, on peut citer comme acides carboxyliques, l'acide dibenzoyl tartrique ou l'acide d-camphorique, comme acide sul-fonique l'acide d-camphosulfonique et comme acide phosphorique, l'acide glucose l-phosphorique ou l'acide glucose l,~-di-phosphorique.
Il est egalement possible d'utiliser comme produit de depart une ethylene diamine de formule III prealablement dedou-blee de telle sorte que le compos~ de formule generale I est obtenu sous une forme optiquement active.
Parmi les acides utilises pour salifier les composes de formule generale I, on pourra citer comme acide mineral, l'acide chlorhydrique ou l'acide sulfuriquei comme acide orga-nique, l'acide acetique, l'acide benzoïque, l'acide salicyli-que, l'acide 5-thiazole carboxylique, l'acide 5-pyrrolidinone carboxylique, l'acide tartrique, l'acide pyruvique, l'acide benzene sulfonique ou l'acide pamoïque.
Les compos~s de l'invention possedent des proprietes pharmacologiques interessantes. Ils manifestent, en particu-lier, une action anti-convulsivante et une action anti-agressi-vite. Ils sont peu toxiques et aux doses non-toxiques, ils sont tres peu neuro-depresseurs.
Ils trouvent de ce fait un emploi en therapeutique notamment comme medicament anti-epileptique dans le traitement du petit Mal.
A cet effet, ils sont utilises sous forme de compo-sitions pharmaceutiques contenant comme principe actif au moins un compose de formule generale I en association avec un exci-pient inerte, non-toxique, pharmaceutiquement acceptable. En i~092136 outre, les compositions pharmaceutiques peuvent renfermer un autre principe actif d'action similaire ou synergistique ou complementaire, comme par exemple, le phenobarbital, la tri-methadione ou la phenacetyluree.
Parmi les compositions pharmaceutiques, on pourra citer plus particulierement celles qui conviennent pour l'admi-nistra~ion par voie parenterale, buccale, sublinguale ou rectale, comme par exemple les comprimes nus ou enrobes, les dragees, les gelules, les suspensions buvables, les sirops ou les granules; les solutes injectables presentes en ampoules, flacons multidoses, seringues auto-injectables ou capsules; les comprimes sublinguaux; les suppositoires.
La posologie peut varier largement en fonction de l'age et du poids du patient, de la voie d'administratibn et de l'indication therapeutique. Elle s'echelonne notamment de 100 à 500 mg par unite de prise et de 200 mg a 1500 mg par jour.
Les formes pharmaceutiques utilisees peuvent etre aisement preparees selon les techniques usuelles de la pharma-cotechnie.
En vue de la realisation de compositions pharmaceuti-ques, les composes de formule generale I ou un de leurs sels seront additionnes d'un ou plusieurs excipients inertes comme le talc, le stearate de magnesie, le lactose, le mannitol, le carbonate de calcium, la silice colloidale, l'oxyde de titane pour les formes solides, l'eau ou une solution saline pour les formes liquides, le beurre de cacao ou les stearates de poly-ethylene glycol pour les suppositoires.
On pourra egalement ajouter des diluants, des emul-sionnants comme les Tween~et les Span~, des agents liants comme la methyl cellulose, l'ethyl cellulose, la carboxymethyl cellu-lose ou l'hydroxypropyl cellulose, des agents epaississants ou 1~ - 5 -D~

lOS~Z136 gêlifiants comme un polyacrylamide ou un alginate de metal alcalin.
Selon les besoins therapeutiques et la forme d'admi-nistration, la concentration en principe actif sera comprise entre 10 et 90% de l'unite de prise.
Parmi les composes de formule g~nerale I obtenus par le procede de l'invention, on pourra distinguer plus particu-lierement:
- les composes de formule gen~rale IA:

(B) ~ CH ~ (A)n, IA

X2 C0 - NH - CH - CH - N ~ R4 R' Z ~ R5 dans laquelle A, B, Xl, X2, X3, X4, n et n sont definis comme precedemment, R' est un radical alcoyle inferieur, Z represente de l'hydrogene, un radical alcoyle inferieur ou forme avec R4 une chafne alcoylene ayant de 4 a 6 atomes de carbone, R4 et R5 representent un radical alcoyle inferieur ou forment ensemble une chatne alcoylene ayant 4 ou 5 chafnons;
- les composes de formule IB:

(B) ~ CH ~ (A)n~ IB

X2 ¦ X4 ~ (CH2~ ~

dans laquelle A~ B~ Xl~ X2, XB~ X4, n et n sont definis comme precedemment, ~09Z136 p et p', identiques ou differents, representent un total de 3 ou 4, et R represente de l'hydrogene, un radical alcoyle inferieur, un radical hydroxyalcoyle inferieur, un radical acyloxy alcoyle inferieur ou un radical alcoxy alcoyle infe-rieur;
- les composes de formule Ic:

(B)n ~ CH ~ (A)n, IC
X2 CONH - CH2-CH2 - N~ 4 dans laquelle A, B, Xl, X2, X3, X4, n et n sont definis comme precedemment, R4 et R5 sont des radicaux alcoyle inferieur identi-ques ou differents.
A titre de composes actuellement preferes obtenus par le procede de l'invention, on peut citer:
- le dl N-(2-dimethylamino propyl) ~-(2,6-2',6'-tetramethyl diphenyl) acetamide et son methane sulfonate.
- le N- ~-(l-piperidino) ethy ~ ~-(2,6-2',6'-tetramethyl diphenyl) acetamide et son methane sulfonate.
- le N- ~-(4-methyl piperazinyl-l) ethy ~ ~-(2,6-2',6'-tetra-methyl diphanyl) acetamide et son methane sulfonate.
- le N- ~4-~-hydroxy ethyl piperazinyl-l) ethy ~ ~-(2,6-2',6'-tetramethyl diphenyl) acetamide et son methane sulfonate.
- le N-(2-diethylamino ethyl) ~-(2,6-2',6'-tetramethyl diphenyl) acetamide et son methane sulfonate.
Pour autant que l'invention soit concernee, le terme alcoyle inferieur designe un radical hydrocarbone sature ayant de 1 a 6 atomes de carbone en chaîne droite ou ramifiee. De llO9Zi36 tels radicaux sont par exemple, le radical methyle, ethyle, isopropyle, ter-butyle, sec-butyle, néo-pentyle et n-hexyle.
Le terme alcenyle inferieur designe un radical hydro-carbone ayant une ou plusieurs doubles liaisons, comportant de 2 à 10 atomes de carbone comme par exemple allyle, methyl-allyle, dimethylallyle, isopentenyle, butenyle, buta-1,4-dienyle et triallylmethyle.
Lorsque R4 et R5 representent ensemble un reste alcoylene, ils forment avec l'atome d'azote un heterocycle azote ayant 5 ou 6 maillons comme par exemple, la pyrrolidine ou piperidine. Lorsqu'ils incluent, en outre, un groupe imino, ils peuvent former un cycle pyrazoline ou piperazine. Ces heterocycles peuvent, en outre, être substitues par un ou plusieurs radicaux alcoyle inferieur.
Le terme aryle designe un noyau benzenique non substitue ou substitue par un ou plusieurs substituants choisis dans le groupe constitue par les halogenes, un radical alcoxy inferieur, trifluoromethyle, alcoylthio, alcoylene dioxy, hydroxy ou alcoyle inferieur, comme par exemple, 3,4-dimethoxy phenyl 2,4-dichlorophenyl, m.trifluoromethyl phenyl, 3,4,5-trimethoxy phenyl, 2,6-dimethyl phenyl, 3,5-(dimethoxy 4-hydroxy) phenyl.
Le terme aryl (alcoyle inferieur) est defini de la même façon. Il inclut par exemple, les radicaux 3,4-dimethoxy benzyle, m.trifluoromethyl benzyle, ~-methyl benzyle, phenyl ethyle, phenyl propyle, ~-methyl phenylethyle, p.chlorobenzyle, methylene dioxy benzyle, et benzyle.
Parmi les acides utilises pour esterifier les compo-ses de formule generale I, lorsque R4 et R5 representent ensem-ble une cha~ne alcoylene interrompue par un groupe imino ~N - R
dans lequel R est un radical hydroxy alcoyle, on pourra citer ~05~2136 l'acide acetique, l'acide butyrique, l'acide di-(n.propyl) acetique, l'acide benzo9que, l'acide 3,4,5-trimethoxy benzoi-que, l'acide o.carbethoxysyringoique, l'acide nicotin;que, l'acide stearoylglycolique, l'acide naphtalene sulfonique, l'acide embonique ou l'acide n.propyl thiazole 5-carboxylique.
Les acides diaryl acetiques de formule generale II
sont obtenus selon le procede du brevet français 2,221,144.
Les ethylene diamines de formule generale III sont des produits deja decrits dans la litterature. Elles peuvent être obtenues commod~ment par condensation de la N-(~-bromoethyl) phtalimide avec une amine secondaire ou primaire, lineaire ou cyclique puis hydrazinolyse de la N-(~-aminoethyl) phtalimide formee.
Les exemples suivants illustrent l'invention. Ils ne la limitent en aucune façon.

N- ~N'-ethyl pyrrolidinyl-2) methy ~ ~-(2,6-2',6'-tetramethyl diphenyl) acetamide Dans un ballon ~ trois tubulures surmonte d'un agi-tateur mecanique, on coule 3g8 de l-ethyl 2-aminomethyl pyrroli-dine puis 4.2 ml de triethylamine et 25 ml d'ether. On refroi-dit le melange a 10 environ et ajoute progressivement une solution de 8g6 de chlorure de (2,6-2',6'-tetramethyl diphenyl) acetyle dans 25 ml d'ether tout en maintenant la temperature du milieu a 10-15 et en poursuivant l'agitation.
Une fois l'addition terminee, on laisse revenir a temperature ordinaire et on poursuit l'agitation pendant deux heures.
On reprend ensuite la suspension formee pendant la reaction par 100 ml d'une solution 2 N de soude. Apres agita-tion~ on separe la phase etheree et on epuise a deux reprisesla phase aqueuse par de l'ether. On reunit les phases ethe-rees, les lave a l'eau, les s~che sur sulfate de magnesium, les ~IO~Z~36 filtre puis evapore â sec sous vide. On recueille ainsi un residu sec, cristallise, pesant lOg4. Le produit brut est purifie par recristallisation du cyclohexane. Le N- ~N'-ethyl pyrrolidinyl-2) methy ~ a-(2,6-2',6'-tetramethyl diphenyl) acetamide fond a 118. Il est soluble dans un exces d'acide chlorhydrique dilue. Par evaporation, on obtient le chlorhy-drate.

C H N %
calcule 79.32 9.05 7.40 trouve79.09 9.11 7.43 dl N- ~-(dimethylamino) propy ~ ~-(2,6-2',6'-tetramethyl diphenyl) acetamide En operant de la même maniere qu'a l'exemple 1, au depart de 3905 de dl 2-dimethylamino propylamine, on obtient apres recristallisation de l'ether de petrole 696 de produit pur fondant a 100. Le rendement est donc de 70%.
Le produit est soluble dans l'acide methane sulfo-nique aqueux donnant naissance au methane sulfonate.
ANALYSE C23 H32 N20 ~ 352-51 C H N %
calcul~ 78.37 9.15 7.95 trouve78.40 8.90 7.95 N-(2-diethylamino ethyl) a-(2,6-2',6'-tetramethyl diphenyl) acetamide En op~rant selon le mode op~ratoire de l'exemple 1, au depart de 3g48 de diethyl ethylene diamine, on obtient 992 de produit brut fondant a 100 environ.
Apres recristallisation du pentane, on isole 8990 de N-(2-diethylaminoethyl) ~-(2,6-2',6'-tetramethyl diphenyl) acetamide fondant a 103. Le rendement est donc de 82%.

ANALYSEC24 H34 N20 ~ 366-55 C H N %
calcule78.64 9.35 7.64 trouve78.25 9.26 7.63 Le N-(2-diethylamino ethyl) ~-(2,6-2',6'-tetramethyl diphenyl) acetamide est soluble dans la quantite stoechio-métrique d'acide methane sulfonique en solution aqueuse. Par evaporation a sec, on isole le methane sulfonate.

N- ~-(piperidino-l) ethy ~ ~-(2,6-2',6'-tetramethyl diphenyl) ac~tamide En operant selon le procede de l'exemple 1, au depart de 293 de N-(2-aminoéthyl) piperidine, on obtient 696 de pro-duit brut micro-cristallin. Par recristallisation de l'ether de petrole par chaud et froid, on obtient 396 de produit pur fondant a 107.

C H N %
calcule 79.32 9.05 7.40 trouve79.36 9.04 7.37 Le produit est soluble dans une solution aqueuse d'acide methane sulfonique. Par evaporation, on obtient le methane sulfonate.

N- ~-(4-methyl piperazinyl-l) ethy ~ ~-(2,6-2',6'-tetramethyl diphenyl) acetamide En operant comme a l'exemple 1, au depart de 7945 de chlorure d'acide ~-(2,6-2',6'-tetramethyl diphenyl) acetyle et de 397 de N-methyl N'-~-amino ethyl piperazine, on obtient apres recristallisation du cyclohexane 391 de produit pur fon-dant a 114. Le rendement est donc de 30%.

lOgZ136 ANALYSE C2s H3s N3 04 C H N %
calcule 76.29 8.96 10.68 trouve 76.05 9.14 10.54 Le produit est soluble dans une solution aqueuse d'acide methane sulfonique donnant naissance au methane sulfo-nate.

N- ~ -(2-hydroxy ethyl) piperazinyl-l ethy ~ a-(2,6-2',6'-tetrameth 1 dinhenvl) acetamide Y r ~
En operant comme a l'exemple 1, au depart de 6915 de chlorure d'acide a-(2,6-2',6'-tetramethyl diphenyl) acetyle et de 394 de 4-(~-hydroxy ethyl) l-(~-amino ethyl) piperazine, on obtient après recristallisation de l'acetate d'isopropyle 497 de produit pur fondant a 138-139 soit un rendement de 51.5%.
ANALYSE C26 H37 N3 2 ~ 4 C H N %
calcule 73.72 8.81 9.92 trouve 73.55 8.61 9.72 Le produit est soluble dans l'acide methane sulfo-nique dilue. On isole apres evaporaiion le methane sulfonate correspondant.
- Par action de l'iodure de methyle en presence d'oxyde d'argent sur la N- ~-(2-hydroxy ethyl) piperazinyl- ~ ethyl a-(2,6-2',6'-tetramethyl diphenyl) acetamide, on obtient le N-~-(2-methoxyethyl~ piperazinyl- ~ ethyl a-(2,6-2',6'-tetra-methyl diphenyl~ acetamide.
Par action de l'anhydride acetique en presence de pyridine sur la N- ~-(2-hydroxyethyl) piperazinyl- ~ ethyl a-(2,6-2',6'-tetramethyl diphenyl) acetamide, on obtient le N-~-(2-acetoxy ethyl) piperazinyl- ~ ethyl a-(2,6-2',6'-tetra-methyl diphenyl) acetamide.

~09Z~36 De la même maniere, au depart de l'acide bis-(2,4-diterbutyl 6-methyl) diphenyl acetique decrit par 0. Akkerman, Rev. Trav. Chi~. Pays Bas 86 1018 (1967) et de la 4-(~-hydroxy ethyl) l-(~-amino ethyl) piperazine, on obtient le N- ~-(2-hydroxy ethyl) piperazinyl- ~ ethyl ~-(2,4-2',4'-tetra-terbutyl 6,6'-dimethyl) diphenyl acetamide.

Etude pharmacologique des composes selon l'invention a) Toxicite aiguë
La dose lethale moyenne des compos~s de formule gene-rale I a ete determinee sur des lots de 10 souris mâles, de souche CD, par administration intraperitoneale de doses crois-santes. Les animaux sont gardes en observation pendant 8 jours et les morts sont denombrees. La dose lethale moyenne est determinee graphiquement.
Selon les produits, la dose lethale moyenne s'eche-lonne entre 100 et 150 mg/kg par cette voie. Aux doses suble-thales, les animaux presentent une diminution de la motricite et du tonus musculaire. A doses toxiques, les animaux meurent en convulsions.
b) Protection contre les convulsions provoquees par l'electro-choc Des lots de souris sont soumis a l'action convulsi-vante d'un choc electrique cause par un courant de 100 V/300 Hz, pendant 110 ms. Une heure avant le test tous les lots, sauf un, reçoivent le compose a tester par voie intraperito-neale en suspension dans une solution aqueuse de gomme ara-bique.
Un lot temoin reçoit seulement la solution de gomme arabique sous un volume de 0.5 ml.
Les doses administrees s'echelonnent de 12 mg5 à 70 mg/kg et une protection a 50% est obtenue selon les produits 109Z~36 entre 30 et 50 mg/kg.
c) Protection contre les convulsions causees par le penta-methylene tetrazole L'injection de pentamethylene tetrazole provoque un spasme par extension dont l'inhibition constitue un mode de mesure de l'effet anticonvulsivant des composes de l'invention.
Les composes de l'invention sont administr~s par voie intra-peritoneale a des doses s'echelonnant entre 25 et 75 mg/kg. Le pentamethylene tetrazole a la dose de 100 mg/kg est injecte par la même voie une heure apres. On determine l'augmentation du temps de latence et la diminution du pourcentage de convulsions cloniques par rapport aux animaux temoins.
L'augmentation du temps de latence s'echelonne entre 25 et 175%.
d) Effet inhibiteur sur l'agressivite Ce test a ete effectue sur des souris isolees ou des rats mâles isoles ayant prealablement subi l'ablation des bulbes olfactifs selon la methode decrite par L. Valzelli, Aggressive Behaviour 1969 p. 70-76, Excerpta Medica Foundation (Amsterdam), et celle decrite par P. Karli, M. Vergnes et F.
Didier-georges, Aggressive Behaviour 1969, p. 47-55.
Aux doses de 10 ~ 50 mg/kg chez la souris, par voie intraperitoneale, les composes de l'invention diminuent de 20 a 100% le nombre des attaques entre animaux et le score d'agres-sivite.
Chez le rat, les doses de 25 mg/kg et 50 mg/kg, par voie intraperitoneale, reduisent le nombre des animaux muri-cides de 100% environ (lots temoins) a 40% environ. 6. When the substituents R4 and R5 together form ble an alkylene chain interrupted by an imino group `N - R
in which R is a lower alkyl hydroxy radical, the corresponding compound can be acylated by means of a derivative functional of a low molecular weight organic acid, or alkyl by the action of an alkylating agent such as a halo-~ 09Z136 genus or lower alkyl sulfate in the presence of a basic agent.
Among the optically active acids used for duplication, mention may be made, as carboxylic acids, of the acid tartaric dibenzoyl or d-camphoric acid, as sul-fonique d-camphosulfonic acid and as phosphoric acid, glucose l-phosphoric acid or glucose acid l, ~ -di-phosphoric.
It is also possible to use as a starting with an ethylene diamine of formula III beforehand wheat so that the compound of general formula I is obtained in an optically active form.
Among the acids used to salify compounds of general formula I, mention may be made as mineral acid, hydrochloric acid or sulfuric acidi as organic acid nique, acetic acid, benzoic acid, salicylic acid that, 5-thiazole carboxylic acid, 5-pyrrolidinone acid carboxylic, tartaric acid, pyruvic acid, acid benzene sulfonic or pamoic acid.
The compounds of the invention have properties interesting pharmacologicals. They demonstrate, in particular binding, an anti-convulsant action and an anti-aggressive action quickly. They are not very toxic and in non-toxic doses, they are very little neuro-depressants.
They therefore find a job in therapy especially as an anti-epileptic drug in the treatment of little Evil.
For this purpose, they are used in the form of a compound.
pharmaceutical compositions containing at least as active ingredient a compound of general formula I in combination with an excipient pient inert, non-toxic, pharmaceutically acceptable. In i ~ 092136 in addition, the pharmaceutical compositions may contain a other active ingredient of similar or synergistic action or complementary, such as, for example, phenobarbital, tri-methadione or phenacetyluree.
Among the pharmaceutical compositions, we can more particularly, cite those which are suitable for the administration nistra ~ ion parenterally, buccally, sublingually or rectal, such as for example naked or coated tablets, dragees, capsules, oral suspensions, syrups or granules; injectable solutions in ampoules, multidose vials, auto-injectable syringes or capsules; the sublingual tablets; suppositories.
The dosage can vary widely depending on the age and weight of the patient, the route of administration and the therapeutic indication. It ranges in particular from 100 at 500 mg per intake unit and from 200 mg to 1500 mg per day.
The pharmaceutical forms used can be easily prepared according to the usual pharmaceutical techniques cotechny.
For the production of pharmaceutical compositions that the compounds of general formula I or a salt thereof will be added with one or more inert excipients such as talc, magnesium stearate, lactose, mannitol, calcium carbonate, colloidal silica, titanium oxide for solid forms, water or saline solution for liquid forms, cocoa butter or poly stearates ethylene glycol for suppositories.
We can also add diluents, emul-striking like Tween ~ and Span ~, binding agents like methyl cellulose, ethyl cellulose, carboxymethyl cellu-lose or hydroxypropyl cellulose, thickening agents or 1 ~ - 5 -D ~

lOS ~ Z136 gelling agents such as polyacrylamide or metal alginate alkaline.
Depending on the therapeutic needs and the form of administration nistration, the concentration of active ingredient will be understood between 10 and 90% of the outlet unit.
Among the compounds of general formula I obtained by the process of the invention, we can distinguish more particularly together:
- the compounds of general formula IA:

(B) ~ CH ~ (A) n, IA

X2 C0 - NH - CH - CH - N ~ R4 R 'Z ~ R5 in which A, B, Xl, X2, X3, X4, n and n are defined as above, R 'is a lower alkyl radical, Z represents hydrogen, an alkyl radical lower or forms with R4 an alkyl chain having from 4 to 6 carbon atoms, R4 and R5 represent a lower alkyl radical or together form an alkylene cat having 4 or 5 chafnons;
- the compounds of formula IB:

(B) ~ CH ~ (A) n ~ IB

X2 ¦ X4 ~ (CH2 ~ ~

in which A ~ B ~ Xl ~ X2, XB ~ X4, n and n are defined as above, ~ 09Z136 p and p ', identical or different, represent a total of 3 or 4, and R represents hydrogen, an alkyl radical lower, a lower hydroxyalkyl radical, a lower lower alkyl acyloxy or a lower alkyl alkoxy radical laughing;
- the compounds of formula Ic:

(B) n ~ CH ~ (A) n, IC
X2 CONH - CH2-CH2 - N ~ 4 in which A, B, Xl, X2, X3, X4, n and n are defined as above, R4 and R5 are lower alkyl radicals identi-ques or different.
As currently preferred compounds obtained by the process of the invention, we can cite:
- dl N- (2-dimethylamino propyl) ~ - (2,6-2 ', 6'-tetramethyl diphenyl) acetamide and its methane sulfonate.
- N- ~ - (l-piperidino) ethy ~ ~ - (2,6-2 ', 6'-tetramethyl diphenyl) acetamide and its methane sulfonate.
- N- ~ - (4-methyl piperazinyl-l) ethy ~ ~ - (2,6-2 ', 6'-tetra-methyl diphanyl) acetamide and its methane sulfonate.
- N- ~ 4- ~ -hydroxy ethyl piperazinyl-l) ethy ~ ~ - (2,6-2 ', 6'-tetramethyl diphenyl) acetamide and its methane sulfonate.
- N- (2-diethylamino ethyl) ~ - (2,6-2 ', 6'-tetramethyl diphenyl) acetamide and its methane sulfonate.
As far as the invention is concerned, the term lower alkyl denotes a saturated hydrocarbon radical having from 1 to 6 carbon atoms in a straight or branched chain. Of llO9Zi36 such radicals are, for example, the methyl, ethyl radical, isopropyl, ter-butyl, sec-butyl, neo-pentyl and n-hexyl.
The term lower alkenyl designates a hydro-carbon having one or more double bonds, comprising 2 to 10 carbon atoms such as allyle, methyl-allyle, dimethylallyle, isopentenyle, butenyle, buta-1,4-dienyle and triallylmethyle.
When R4 and R5 together represent a remainder alcoylene, they form with the nitrogen atom a heterocycle nitrogen with 5 or 6 links such as, for example, pyrrolidine or piperidine. When they also include an imino group, they can form a pyrazoline or piperazine cycle. These heterocycles can, in addition, be substituted by one or several lower alkyl radicals.
The term aryle denotes a non-benzenic nucleus substitutes or substitutes with one or more selected substituents in the group consisting of halogens, an alkoxy radical lower, trifluoromethyl, alcoylthio, alcoylene dioxy, hydroxy or lower alkyl, such as 3,4-dimethoxy phenyl 2,4-dichlorophenyl, m.trifluoromethyl phenyl, 3,4,5-trimethoxy phenyl, 2,6-dimethyl phenyl, 3,5- (dimethoxy 4-hydroxy) phenyl.
The term aryl (lower alkyl) is defined from the same way. It includes, for example, 3,4-dimethoxy radicals benzyle, m.trifluoromethyl benzyle, ~ -methyl benzyle, phenyl ethyl, phenyl propyl, ~ -methyl phenylethyle, p.chlorobenzyle, methylene dioxy benzyl, and benzyl.
Among the acids used to esterify the compounds ses of general formula I, when R4 and R5 represent together ble an alkylene chain interrupted by an imino group ~ N - R
in which R is an alkyl hydroxy radical, mention may be made of ~ 05 ~ 2136 acetic acid, butyric acid, di- (n.propyl) acid acetic, benzoic acid, 3,4,5-trimethoxy benzoi-that, o.carbethoxysyringoic acid, nicotinic acid; that, stearoylglycolic acid, naphthalene sulfonic acid, embonic acid or n.propyl thiazole 5-carboxylic acid.
Diaryl acetic acids of general formula II
are obtained according to the method of French patent 2,221,144.
The ethylene diamines of general formula III are products already described in the literature. They can be obtained conveniently by condensation of N- (~ -bromoethyl) phthalimide with a secondary or primary, linear or cyclic amine then hydrazinolysis of the N- (~ -aminoethyl) phthalimide formed.
The following examples illustrate the invention. They don't limit it in any way.

N- ~ N'-ethyl pyrrolidinyl-2) methy ~ ~ - (2,6-2 ', 6'-tetramethyl diphenyl) acetamide In a balloon ~ three tubes surmounted by an agi-3 g8 of l-ethyl 2-aminomethyl pyrroli-dine then 4.2 ml of triethylamine and 25 ml of ether. We cool says the mixture to about 10 and gradually add a 8g6 chloride solution (2.6-2 ', 6'-tetramethyl diphenyl) acetyl in 25 ml of ether while maintaining the temperature of the middle at 10-15 and continuing agitation.
Once the addition is complete, we let return to ordinary temperature and stirring is continued for two hours.
The suspension formed during the reaction with 100 ml of a 2 N sodium hydroxide solution. After shaking tion ~ the ethereal phase is separated and the aqueous phase is exhausted twice with ether. We combine the phases ethe-rees, wash them with water, dry them with magnesium sulphate, ~ IO ~ Z ~ 36 filter then evaporate to dryness under vacuum. We thus collect a dry residue, crystallized, weighing lOg4. The gross product is purifies by recrystallization from cyclohexane. N- ~ N'-ethyl pyrrolidinyl-2) methy ~ a- (2,6-2 ', 6'-tetramethyl diphenyl) acetamide melts at 118. It is soluble in an excess of acid dilute hydrochloric. By evaporation, chlorhy- is obtained drate.

CHN%
calculate 79.32 9.05 7.40 found79.09 9.11 7.43 dl N- ~ - (dimethylamino) propy ~ ~ - (2,6-2 ', 6'-tetramethyl diphenyl) acetamide By operating in the same way as in Example 1, at departure from 3905 of dl 2-dimethylamino propylamine, we obtain after recrystallization of petroleum ether 696 from product pure fondant at 100. The yield is therefore 70%.
The product is soluble in methane sulfo- acid aqueous pic giving rise to methane sulfonate.
ANALYSIS C23 H32 N20 ~ 352-51 CHN%
calculation ~ 78.37 9.15 7.95 find78.40 8.90 7.95 N- (2-diethylamino ethyl) a- (2,6-2 ', 6'-tetramethyl diphenyl) acetamide By operating according to the operating mode of Example 1, from 3g48 of diethyl ethylene diamine, we obtain 992 of crude product melting at about 100.
After recrystallization of the pentane, 8990 of N- (2-diethylaminoethyl) ~ - (2.6-2 ', 6'-tetramethyl diphenyl) acetamide melting at 103. The yield is therefore 82%.

ANALYSEC24 H34 N20 ~ 366-55 CHN%
calculate78.64 9.35 7.64 finds78.25 9.26 7.63 N- (2-diethylamino ethyl) ~ - (2,6-2 ', 6'-tetramethyl diphenyl) acetamide is soluble in the amount stoechio-metric methane sulfonic acid in aqueous solution. By dry evaporation, the methane sulfonate is isolated.

N- ~ - (piperidino-l) ethy ~ ~ - (2,6-2 ', 6'-tetramethyl diphenyl) ac ~ tamide By operating according to the method of Example 1, initially of 293 of N- (2-aminoethyl) piperidine, 696 of pro-gross microcrystalline product. By recrystallization of ether of oil by hot and cold, we obtain 396 of pure product fondant at 107.

CHN%
calculate 79.32 9.05 7.40 found79.36 9.04 7.37 The product is soluble in an aqueous solution methane sulfonic acid. By evaporation, the methane sulfonate.

N- ~ - (4-methyl piperazinyl-l) ethy ~ ~ - (2,6-2 ', 6'-tetramethyl diphenyl) acetamide By operating as in Example 1, starting from 7945 from acid chloride ~ - (2,6-2 ', 6'-tetramethyl diphenyl) acetyl and of 397 of N-methyl N'- ~ -amino ethyl piperazine, we obtain after recrystallization of cyclohexane 391 from a pure dark product at 114. The yield is therefore 30%.

lOgZ136 ANALYSIS C2s H3s N3 04 CHN%
calculate 76.29 8.96 10.68 found 76.05 9.14 10.54 The product is soluble in an aqueous solution methane sulfonic acid giving rise to methane sulfo-nate.

N- ~ - (2-hydroxy ethyl) piperazinyl-l ethy ~ a- (2,6-2 ', 6'-tetrameth 1 dinhenvl) acetamide Y r ~
By operating as in Example 1, starting from 6915 from a- (2,6-2 ', 6'-tetramethyl diphenyl) acetyl acid chloride and of 394 of 4- (~ -hydroxy ethyl) l- (~ -amino ethyl) piperazine, obtained after recrystallization of isopropyl acetate 497 of pure product melting at 138-139, ie a yield of 51.5%.
ANALYSIS C26 H37 N3 2 ~ 4 CHN%
calculate 73.72 8.81 9.92 finds 73.55 8.61 9.72 The product is soluble in methane sulfo- acid diluted picnic. We isolate after evaporating the methane sulfonate corresponding.
- By the action of methyl iodide in the presence of oxide silver on N- ~ - (2-hydroxy ethyl) piperazinyl- ~ ethyl a-(2,6-2 ', 6'-tetramethyl diphenyl) acetamide, we obtain the N-~ - (2-methoxyethyl ~ piperazinyl- ~ ethyl a- (2,6-2 ', 6'-tetra-methyl diphenyl ~ acetamide.
By action of acetic anhydride in the presence of pyridine on N- ~ - (2-hydroxyethyl) piperazinyl- ~ ethyl a-(2,6-2 ', 6'-tetramethyl diphenyl) acetamide, we obtain the N-~ - (2-acetoxy ethyl) piperazinyl- ~ ethyl a- (2,6-2 ', 6'-tetra-methyl diphenyl) acetamide.

~ 09Z ~ 36 Similarly, starting from bis- (2,4-diterbutyl 6-methyl) diphenyl acetique described by 0. Akkerman, Rev. Trav. Chi ~. Netherlands 86 1018 (1967) and 4- (~ -hydroxy ethyl) l- (~ -amino ethyl) piperazine, we obtain N- ~ -(2-hydroxy ethyl) piperazinyl- ~ ethyl ~ - (2,4-2 ', 4'-tetra-terbutyl 6,6'-dimethyl) diphenyl acetamide.

Pharmacological study of the compounds according to the invention a) Acute toxicity The average lethal dose of the compounds of the gene formula rale I was determined on lots of 10 male mice, strain CD, by intraperitoneal administration of increasing doses health. Animals are kept under observation for 8 days and the dead are counted. The average lethal dose is determined graphically.
Depending on the product, the average lethal dose dries up.
lonne between 100 and 150 mg / kg by this route. In suble-thales, animals show reduced motor skills and muscle tone. In toxic doses, animals die in convulsions.
b) Protection against convulsions caused by electro-shock Batches of mice are subjected to convulsive action.
boasts of an electric shock caused by a current of 100 V / 300 Hz, for 110 ms. One hour before the test all batches, except one, receive the compound to be tested intraperitoneally neale suspended in an aqueous solution of macaw gum bique.
A witness batch receives only the gum solution Arabic in a volume of 0.5 ml.
The doses administered range from 12 mg5 to 70 mg / kg and 50% protection is obtained depending on the product 109Z ~ 36 between 30 and 50 mg / kg.
c) Protection against convulsions caused by penta-methylene tetrazole The injection of pentamethylene tetrazole causes a spasm by extension, the inhibition of which constitutes a mode of measurement of the anticonvulsant effect of the compounds of the invention.
The compounds of the invention are administered ~ s intra-peritoneal at doses ranging from 25 to 75 mg / kg. The pentamethylene tetrazole at a dose of 100 mg / kg is injected by the same route an hour later. We determine the increase in lag time and decreased percentage of seizures clonic compared to control animals.
The increase in latency is staggered between 25 and 175%.
d) Inhibitory effect on aggressiveness This test was carried out on isolated mice or isolated male rats previously removed olfactory bulbs according to the method described by L. Valzelli, Aggressive Behavior 1969 p. 70-76, Excerpta Medica Foundation (Amsterdam), and that described by P. Karli, M. Vergnes and F.
Didier-georges, Aggressive Behavior 1969, p. 47-55.
At doses of 10 ~ 50 mg / kg in mice, via intraperitoneally, the compounds of the invention decrease by 20 to 100% the number of attacks between animals and the score of agents-so fast.
In rats, the doses of 25 mg / kg and 50 mg / kg, per intraperitoneally, reduce the number of muri cides from around 100% (witness batches) to around 40%.

Claims

The embodiments of the invention about which an exclusive right of property or privilege is claimed, are defined as follows:

1. A process for obtaining the compounds of formula general I:

in which:
- X1 and X3 represent simultaneously or distinctly -a lower alkyl radical;
- X2 and X4 simultaneously or separately, represented feel a lower alkyl radical;
- A and B represent simultaneously or separately-halogen, lower alkyl or alkoxy radical inferior;

- Y and Z, simultaneously or distinctly, are of hydrogen, a lower straight chain alkyl radical or branched, or form with a cycle chosen from piperidine, piperazine or pyrrolidine;
- and R4 and R5 are a lower alkyl radical or together form a pyrrolidinyl radical, characterized in that a diaryl acetic acid is condensed of general formula II:

II

in which the definition of the substituents A, B, X1, X2, X3, X4, remains unchanged, or a functional derivative thereof, with an ethylene diamine of general formula III:

III
in which the substituents Y, Z, R4 and R5 are defined as above, to obtain a diarylacetamide of general formula I which is can salify by adding a mineral or organic acid, or when the molecule has an asymmetric carbon atom, split into its optical isomers by salification using an optically active acid.

2. A process for obtaining the compounds according to the claim 1, corresponding to the general formula IA:

IA
in which A, B, X1, X2, X3, 4, like before, - R 'is a lower alkyl radical, - Z represents hydrogen, an alkyl radical lower or forms with R4 a cycle chosen from piperi-dine, piperazine or pyrrolidine, - R4 and R5 represent a lower alkyl radical or together form a pyrrolidinyl radical, characterized in that a diarylacetic acid of general formula II or one of its functional derivatives with a ethylene diamine of general formula IIIA:

II IA

in which the substituents R ', Z, R4 and R5 have the meanings provided above, and obtains the compound of general formula IA desired.

3. A process for obtaining the compounds according to the claim 1, corresponding to the general formula IB:

in which the substituents A, B, X1, X2, X3 and X4 are defined as above, - p and p ', identical or different, represent a total of 3 or 4, - and R represents hydrogen, an alkyl radical lower, a lower hydroxyalkyl radical or a radical hydroxy lower alkyl, characterized in that a diarylacetic acid of general formula II or one of its functional derivatives, with an ethylene diamine of general formula IIIB:

IIIB

in which the substituents p, p 'and R are defined as above, to obtain the compound of formula general IB desired.

4. A method according to claim 1 for the preparation of compounds corresponding to the general formula IC:
IC
where A, B, X1, X2, X3, X4, are defined like before, and R4 and R5 are lower alkyl radicals identical or different, characterized in that a diarylacetic acid of general formula II or one of its functional derivatives, with an ethylene diamine of general formula IIIC:
IIIC

in which R4 and R5 are alkyl radicals identical or different, to obtain the compound of general formula IC desired.

5. A method according to claim 3, wherein the N- (2-aminomethyl) piperidine is condensed with the chloride of (2,6-2 ', 6'-tetramethyl diphenyl) acetyl to obtain the N- [2- (1-piperidino) ethyl] .alpha .- (2,6-2 ', 6'-tetramethyl diphenyl) acetamide which is reacted with methane sulfonic acid to obtain the corresponding methane sulfonate.

6. A method according to claim 3, wherein condensing the acid chloride .alpha .- (2,6-2 ', 6'-tetramethyl diphenyl) acetyl with N-methyl N '-. beta.-aminoethyl piperazine to obtain N- [2- (4-methyl piperazinyl-1) ethyl] .alpha .- (2,6-2 ', 6'-tetramethyl diphenyl) acetamide which is reacted with methane sulfonic acid to get methane corresponding sulfonate.

7. A method according to claim 3, wherein condensing the acid chloride .alpha .- (2,6-2 ', 6'-tetramethyl diphenyl) acetyl with 4 - (. beta.-hydroxy ethyl) -1 - (. beta.-amino ethyl) piperazine to obtain N - [(4-.beta.-hydroxyethyl piperazinyl-1) ethyl] .alpha .- (2,6-2 ', 6'-tetramethyl diphenyl) acetamide which is reacted with methane sulfonic acid to obtain the corresponding methane sulfonate.

8. A method according to claim 4, wherein the diethyl ethylene diamine is condensed with the chloride of (2,6-2 ', 6'-tetramethyl diphenyl) acetyl to obtain N-(2-diethylaminoethyl) .alpha .- (2,6-2 ', 6'-tetramethyl diphenyl) acetamide which is reacted with methane sulfonic acid to obtain the corresponding methane sulfonate.

9. A method according to claim 2, wherein the dl 2-dimethylamino propylamine is condensed with the chloride of (2,6-2 ', 6'-tetramethyl diphenyl) acetyl to obtain the dl N- (2-dimethylaminopropyl) .alpha .- (2,6-2 ', 6'-tetramethyl diphenyl) acetamide which is reacted with methane sulfonic acid to obtain the corresponding methane sulfonate.

10. The compounds of general formula I:
I
in which:
- X1 and X3 represent simultaneously or distinctly -a lower alkyl radical;
- X2 and X4 simultaneously or separately, represented feel a lower alkyl radical;
- A and B represent simultaneously or separately-halogen, lower alkyl or alkoxy radical inferior;
- Y and Z, simultaneously or distinctly, are of hydrogen, a lower straight chain alkyl radical or branched, or form with a cycle chosen from piperidine, piperazine or pyrrolidine;
- and R4 and R5 are a lower alkyl radical or together form a pyrrolidinyl radical, each time they are obtained by the process of claim 1, 2 or 3 or one of its obvious chemical equivalents.

11. The dl N- (2-dimethylaminopropyl) .alpha .- (2,6-2 ', 6'-tetramethyl diphenyl) acetamide and its methane sulfonate, each time it is obtained by the process of the claim tion 9 or one of its obvious chemical equivalents.

12. N- [2- (1-piperidino) ethyl] .alpha .- (2,6-2 ', 6'-tetramethyl diphenyl) acetamide and its methane sulfonate, each time it is obtained by the process of the claim tion 5 or one of its obvious chemical equivalents.

13. N- [2- (4-methyl piperazinyl-1) ethyl] .alpha .- (2,6-2 ', 6'-tetramethyl diphenyl) acetamide and its methane sulfo-nate, each time it is obtained by the method of claim 6 or one of its obvious chemical equivalents.

14. N - [(4-.beta.-hydroxyethyl piperazinyl-1) ethyl]
.alpha .- (2,6-2 ', 6'-tetramethyl diphenyl) acetamide and its methane sulfonate, each time it is obtained by the process of claim 7 or one of its obvious chemical equivalents.

15. N- (2-diethylaminoethyl) .alpha .- (2,6-2 ', 6'-tetramethyl diphenyl) acetamide and its methane sulfonate, each time it is obtained according to the process of the claim cation 8 or one of its obvious chemical equivalents.