CA1093582A

CA1093582A - Process for the preparation of propylenediamines

Info

Publication number: CA1093582A
Application number: CA271,653A
Authority: CA
Inventors: Michel Vincent; Georges Remond; Michel Laubie
Original assignee: Science Union et Cie
Current assignee: Science Union et Cie
Priority date: 1976-02-13
Filing date: 1977-02-11
Publication date: 1981-01-13
Also published as: PT66182A; JPS52105156A; GB1574046A; AU2222277A; FR2340724A2; BE851372A; PT66182B; ES455870A1; DE2705639A1; FR2340724B2; NL7701509A; CH620906A5; IL51425A0

Abstract

L'invention concerne des composés 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 un radical alcoyle inférieur, A et B représentent, simultanément ou distinctement, un halogène, un alcoyle inférieur ou un radical alcoxy inférieur, et dans ce cas X1, X2, X3 et X4 peuvent être en outre de l'hydrogène et n et n' sont des nombres entiers de 1 à 3, ou bien lorsque X1, X2, X3 et X4 sont autres que de l'hydrogène, n et n' peuvent prendre la valeur zéro, un, deux ou trois, R1 représente de l'hydrogène ou un radical alcoyle inférieur, R3 représente un radical alcoyle inférieur, un radical alcényle inférieur, un radical aralcoyle inférieur ou un radical alcoyle substitue par un hétérocycle ayant de 3 à 7 atones de carbone éventuellement substitué, ainsi que de leurs sels d'addition avec un acide minéral ou organique, notamment un acide thérapeutiquement compatible. Les composes de l'invention sont utiles en thérapeutique, en particulier dans les tachycardies ou les troubles du rythme cardiaque consécutifs à une intoxication du type digitalique.The invention relates to 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 a radical lower alkyl, A and B represent, simultaneously or distinctly, a halogen, a lower alkyl or a lower alkoxy radical, and in this case X1, X2, X3 and X4 may also be hydrogen and n and n 'are whole numbers from 1 to 3, or when X1, X2, X3 and X4 are other than hydrogen, n and n 'can take the value zero, one, two or three, R1 represents hydrogen or a radical lower alkyl, R3 represents a lower alkyl radical, a lower alkenyl radical, a lower aralkyl radical or an alkyl radical substituted by a heterocycle having from 3 to 7 carbon atoms optionally substituted, as well as their addition salts with a mineral acid al or organic, in particular a therapeutically compatible acid. The compounds of the invention are useful in therapy, in particular in tachycardias or disorders of the cardiac rhythm consecutive to poisoning of the digitalis type.

Description

10~3582 La presente demande a pour objet de nouvelles propylènediamines et leur procede d'obtent;on. Elle a plus particulierement pour objet des propylenediamines substituees 3 l'azote par un acide diarylacetique.
L'invention concerne des composes de formule generale I:

(B)n ~ CH ~ (h)nl (I) x2 co 7 -4CH2 - CH2 - CH2 NH - R3 dans laquelle:
Xl et X3 representent, simultanement ou distinctement un radical alcoyle inferieur, un radical alcoxy inferieur ou un radical alcoylthio inferieur, X2 et X4 representent un radical alcoyle inferieur semblable ou different, A et B representent, simultanement ou distinctement, un halogène, un alcoyle inferieur ou un radical alcoxy infe-rieur, et dans ce cas Xl, X2, X3 et X4 peuvent être en outre de l'hydrogene et n et n' sont des nombres entiers variant de 1 a 3, ou bien lorsque Xl, X2, X3 et X4 sont autre que de l'hydro-gène n et n' peuvent prendre la valeur zero, un, deux ou trois, Rl est de l'hydrogène ou un radical alcoyle infe-rieur, R3 represente un radical alcoyle inferieur, un radical alcenyle inferieur, un radical aralcoyle inferieur, ou bien un radical alcoyle substitue par un heterocycle sature ayant de 3 a 7 cha~nons, lui-mê~e substitue eventuellement par un ou plusieurs alcoyles inferieurs, un acyloxyalcoyl infe-rieur, un (alcoxyalcoyl) inferieur, ou un (hydroxy alcoyle) lQ~3582 inf~rieur.
Les composes de la présente invention sont obtenus par la condensation d'un acide diary~acêtique de formule genérale II: ~

~/ \ CH ~(A)n l ( I I ) X2 COOH x4 dans laque11e les substituants A, B, Xl, X2, X3, X4, n et n' gardent les significations fournies precedemment ou un de ses derives fonctionnels, avec une propane diamine de formule génerale III:
R HN - CH - CH - CH N - R
1 2 2 2 1 3 (III) dans laquelle les substituants Rl et R3 sont definis comme precedemment et R2 represente de l'hydrogene ou un radical benzyle pour obtenir un diarylacetamide de formule genérale:
f X2 CO - N - CH2 - CH2 - CH2 N\ 2 dans laquelle les substituants Xl, X2, X3, X4, A, B, Rl, R2, R3, n et n' sont definis comme precedemment.
L'invention concerne encore l'obtention des composes de formule generale I', actuellement preferes, 3 C H~

CH3 ¦ CH3 CO - l - CH2 - CH2 - CH2 NH - R3 R~
dans laquelle Rl et R3 possedent les mêmes signifi-cations que celles fournies ci-dessus qui consiste en ce que l'on condense un acide t~tram~thyldiphenylacetique ou un de ses derives fonctionnels avec une propylenediamine de formule generale III:

R~ - NH - CH2 - CH2 ~ CH2 N\ 3 ( I I I ) dans laquelle les substituants Rl et R3 sont definis comme precedemment et R2 est de l'hydrog@ne ou un radical benzyle pour former un compos~ de formule generale I'.
L'invention s'~tend aussi a l'obtention des composes suivants suivant le procede de l'invention - la N- ~2,6-2',6'-tetramethyl diphenyl) acety ~ 3-N'-ethylamino propylamine, - la N- ~2,6-2',6'-tetramethyl diphenyl) acety ~ 3 N'-terbutylamino propylamine et son methanesulfonate, - la N- ~2,6-2',6'-tetramethyl diph~nyl) acety ~ 3-N-(2-phenyl propyl) amino propylamine et son chlorhydrate, - la N- ~2,6-2',6'-tetramethyl diph~nyl) acety ~ 3-N'-isopropylamino propylamine.
Le procede selon l'invention inclut encore le stade ulterieur de salification des composes de formule generale I

~Q~35#Z

par addition d'un acide mineral ou organique et notamment un acide therapeutiquement compatible.
Le procede selon l'invention inclut aussi le stade eventuel de debenzylation dans lequel lorsque R2 represente un radical benzyle, on hydro-g~nolyse ou hydrolyse en milieu acide un compose benzyle pour obtenir un compose de formule generale I pour lequel R2 est de l'hydrogène.
L'invention concerne egalement un procede d'obtention des composes de formule generale I caracterise en ce que l'on condense un acide diarylacetique de formule generale II ou un de ses derives fonctionnels avec une propane amine ~-substituee de formule IV:
Rl NH - CH2 - CH2 - CH2 Z (IV) dans laquelle Z est un radical aisement clivable choisi dans le groupe des halogenes, des radicaux aryl sul-fonyloxy, alcoyl sulfonyloxy, trialcoyl silyloxy et hydroxy pour obtenir un diarylacetamide de formule generale V:

CH ~ (V) Rl dans laquelle la signification des substituants A, B, Xl, X2, X3, X4, Rl et Z demeure celle fournie anterieurement, que l'on fait reagir avec un derive amine de formule generale VI:
R3 NH2 (VI) dans laquelle R3 a les significations fournies ante-rieurement et l'on obtient le compose de formule generale I
desire.

1~9 3 5 8 2 Les proc~d~s selon l'invention peuvent encore se définir par les modes operatoires suivants, actuellement preferes:
- le derive fonctionnel de l'acide diarylacetique est un halogenure comme le chlorure ou le bromure; ou l'anhydride ou un anhydride mixte comme un anhydride avec l'acide formique ou l'acide acetique; ou les anhydrides mixtes formes "in situ"
par reaction avec un dialcoyl carbodiimide ou dicyclohexyl carbodiimide, l'acetoxyacetylene ou le carbonyldiimidazole.
- le derive fonctionnel de l'acide diarylacetique de formule II peut etre un ester d'alcoyle ou d'aryle comme par exemple un ester methylique, ethylique, phenylique ou nitro-phenylique.
- la condensation est effectuee dans un solvant inerte polaire ou non polaire commè un ether, la pyridine, le diméthylformamide, la 4-diméthylaminopyridine ou l'hexam~thyl-phosphorotriamide.
- l'hydrogenolyse est effectuee en presence d'un catalyseur de la famille du platine comme par exemple le platine ou le palladium.
- le propane amine ~-substituee de formule generale IV est de preference un derive p.toluene sulfonyloxy, benzene sulfonyloxy, un derive chlore, un derive brom~ ou un dêrive methyl sulfonyloxy.
- la reaction entre le diarylacetamide de formule generale V et l'amine de formule generale VI s'effectue en milieu basique comme par exemple une trialcoylamine, une base pyridique, le dimethylformamide ou le dimêthylacetamide.
- l'amine de formule generale VI est de preference la pyrrolidylmethylamine, la N-ethylpyrrolidylmethylamine~ la N-methylpiperazinylethylamine, la N-hydroxyethylpiperazinylethyl-lOg35~Z

amine, la N-methylpiperidinylethylamine ou la morpholylethyl-amine.
L'invent;on a encore pour objet les propylenediamines substituees a l'azote de formule g~n~rale I:
~X ~ X~( A ) n l ( I ) X2 x4 Rl dans laquelle Xl et X3 representent, simultanement ou distinctement un radical alcoyle inferieur, un radical alcoxy inferieur ou un radical alcoylthio inferieur, X2 et X4, simultanément ou distinctement, repré-sentent un radical alcoyle inferieur, A et B representent, simultanement ou distinctement, ; un halog~ne, un alcoyle inferieur ou un radical alcoxy infe-rieur, et dans ce cas Xl, X2, X3 et X4 peuvent être en outre de l'hydrogene et n et n' sont des nombres entiers de 1 à 3, ou bien lorsque Xl, X2, X3 et X4 sont autres que de l'hydrogene, n et n' peuvent prendre la valeur zero, un, deux ou trois, Rl represente de l'hydrogene ou un radical alcoyle inferieur, R3 represente un radical alcoyle inferieur, un radical alcenyle inferieur, un radical aralcoyle inferieur ou un radical alcoyle substitue par un heterocycle ayant de 3 a 7 atomes de carbone eventuellement substitue, chaque fois qu'ils sont obtenus par l'un ou l'autre procede selon l'invention ainsi que leurs sels d'addition avec un acide mineral ou organique.

. :, - .. . .

~0935~

L'invention comprend aussi les composes de formule generale I':
CH3 CH ~ (I') CH3 ¦ CH3 co 7 - CH2 - CH2 - CH2 NH - R3 Rl dans laquelle Rl et R3 possèdent les memes signifi-cations que celles fournies ci-dessus et plus particulierement - la N- ~2,6-2',6'-tetramethyl diphenyl) acety ~ 3-N'-éthylamino propylamine, - la N- ~2,6-2',6'-tetramethyl diph~nyl) acety ~ 3-N'-terbutylamino propylamine et son methanesulfonate~
- la N- ~2,6-2',6'-tetramethyl diphenyl) acety ~ 3 N-(2-phenyl propyl) amino propylamine et son chlorhydrate, - la N- ~2,6-2',6'-tetramethyl d;phenyl) acéty ~ 3-N'-isopropylamino propylamine, chaque fois qu'ils sont obtenus par l'un ou l'autre procedê selon l'invention.
Les composes de formule generale I selon l'invention sont doues de proprietes pharmacologiques interessantes, notam-ment anti-arrythmiques. Ils ne possedent pas d'effet neuro depresseur. Ils n'ont pas d'effet anti-convulsivant. Ils n'abaissent pas la pression arterielle.
Ils peuvent donc trouver un emploi en therapeutique, en particulier dans les tachycardies ou les troubles du rythme cardiaque consecutifs a une intoxication du type digitalique.
Ils sont employes à cette fin sous forme de compositions phar-maceutiques, adaptees pour l'usage parenteral, buccal, sublin-gual, ou rectal, renfermant au moins un compose de formule generale I ou un de ses sels avec un acide mineral ou organique ~(39358Z

en association avec un excipient inerte non toxique pharmaceu-tiquement acceptable.
Les compositions pharmaceutiques, selon l'invention, peuvent contenir en outre un ou plusieurs autres principes actifs d'action similaire, complementaire ou synergistique.
La posologie utile peut varier selon l'âge et le poids du sujet et la gravite de l'indication therapeutique.
Elle s'echelonne notamment entre 50 et 200 mg par prise et 100 et 600 mg par jour chez l'adulte, principalement par voie buccale.
Les composes de formule generale I ou de formule I' sont des composes basiques qui peuvent être salifies. Les sels de ces composes résultent de l'addition d'un acide minéral ou organique, carboxylique, sulfonique ou phosphorique, de prefe-rence un acide thérapeutiquement compatible.
Le terme "alcoyle inf~rieur" désigne ic; et dans ce qui suit un radical hydrocarbone eventuellement substitue par un hydroxy ou un alcoxy inferieur ou un dialcoylamino, ayant de 1 a 6 atomes de carbone, lineaire ou ramifie, comme par exem-ple, un methyle, un ethyle, un isopropyle, un sec-butyle, un neopentyle, un terbutyle, un hexyle, un ~,-hydroxyethyle ou un diethylaminoéthyle.
Le terme "alcoxy inférieur" designe un radical alcoyloxy ou le radical alcoyle est defini comme ci-dessus, comme ethoxy ou isopropoxy.
Le terme "alcenyle inferieur" designe un radical hydrocarbone mono- ou poly-insature ayant de 2 ~ 10 atomes de carbone en cha~ne droite ou ramifiee comme par exemple, allyle, méthallyle, isopentenyle, dimethylallyle, butenyle ou triallyl-methyle.
Le terme "aryl" (alcoyle inferieur) designe un radical phenyle eventuellement mono- ou poly-substitue sur le noyau par un halog~ne, un alcoxy inferieur ou un trifluoro-methyle porteur d'une chafne hydrocarbonee ayant de 1 a 4 atomes de carbone en chafne droite ou ramifiee comme par exem-ple, benzyle, dimethoxy benzyle, trifluoromethylbenzyle, ~-methylbenzyle, p-chloro benzyle, phenylethyle, phenylpropyle ou ~-methyl phenylethyle.
L'héterocycle ayant de 3 a 7 chaSnons peut être un heterocycle azote comme la pyrrolidine, la piperidine ou l'hexamethylene imine. Il peut inclure en outre, un autre heteroatome comme un atome d'azote, d'oxygene ou de soufre.
Des exemples de telles structures cycliques sont notamment l'oxazolidine, la morpholine, la thiazolidine, la thiamorpho-line, la piperazine ou l'homomorpholine. Ces heterocycles peuvent comporter en outre un ou des substituants alcoyles.
Parmi ces heterocycles on pourra mentionner notamment la N-hydroxyethylpiperazine, la N-acétoxyethylpiperazine, la N-ethylpipérazine ou la ~-ethoxy ~-ethoxyethylpiperazine, la 3-methylpip@ridine et la 3,5-dimethylpiperidine.
La salification des composes de formule generale I
est effectuee par addition d'un acide mineral tel que l'acide chlorhydrique, bromhydrique, sulfurique, phosphorique, nitri-que, ou par addition d'un acide organique, tel que l'acide acetique, propionique, laurique, benzo~que, salicylique, cinna-mique, lactique, maleique, fumarique, pyruvique, glutamique, oxalique, methane sulfonique, isethionique, benzene sulfonique, glucose-l phosphorique ou pamoïque.
Les exemples suivants illustrent l'invention, sans toutefois la limiter.

~093582 3-N- ~2,6-2',6'-tetramethyl diphenyl) acety~7 l-terbutylamino ~roDvlamine .
On introduit dans un ballon ~ trois tubulures 3g9 de N-terbutyl propane diamine en solution dans 20 ml d'ether et 4ml2 de triethylamine et on refroidit le melange en dessous de 10. On aioute alors sous agitation et en maintenant la tempe-rature a + 10 par refroidissement externe, une solution de 3g6 de chlorure d'acide (2,6-2',6'-tetramethyl diphenyl) acetique dans 90 ml d'ether. On poursuit l'agitation pendant 5h. envi-ron. On ajoute alors 37ml5 d'une solution 2N de soude et laisse en contact sous agitation pendant 2 heures. On separe un l~ger precipite puis decante la phase etheree. On la lave a l'eau puis a la soude 2N puis deux fois a l'eau, la seche sur sulfate de magnesium, la filtre et l'evapore a sec. On obtient ainsi un residu sec pesant 9g6 que l'on reprend a l'ether isopropylique. Par concentration le produit cristallise de l'ether isopropylique. On essore le precipite, le lave avec un peu d'ether isopropylique glac~ puis seche a poids constant, le rendement est de 6gl.
Le produit est purifie par passage sous forme de méthane sulfonate puis alcalinisation.
La 3-N- ~2,6-2',6'-tetramethyl diphenyl) acety ~ 1-terbutylamino propylamine precipite. On separe par filtration, l'essore, la lave a l'eau et la seche à poids constant.
Le rendement en produit pur est de 5g6.
La 3-N-~r2,6-2',6'-tetramethyl diphenyl) acety ~ 1-terbutylamino propylamine fond a 144.
EXEMPLE II
3-N- ~2,6-2',6'-tetramethyl diphenyl) acety ~ l-isopropylamino propylamine et son chlorhydrate En operant comme a 1 ~exemple I au depart de 398 de ~0~3358~:

N-isopropyl propylenediamine et de 8g6 de chlorure d'acide 10 ~ 3582 The subject of this request is new propylenediamines and their process of obtaining; She has more particularly for the subject of substituted propylenediamines 3 nitrogen with a diarylacetic acid.
The invention relates to compounds of formula general I:

(B) n ~ CH ~ (h) nl (I) x2 co 7 -4CH2 - CH2 - CH2 NH - R3 in which:
Xl and X3 represent, simultaneously or distinctly a lower alkyl radical, a lower alkoxy radical or a lower alkyl radical, X2 and X4 represent a lower alkyl radical similar or different, A and B represent, simultaneously or distinctly, halogen, lower alkyl or lower alkoxy radical laughing, and in this case Xl, X2, X3 and X4 can also be hydrogen and n and n 'are whole numbers varying from 1 to 3, or when Xl, X2, X3 and X4 are other than hydro-gene n and n 'can take the value zero, one, two or three, Rl is hydrogen or a lower alkyl radical laughing, R3 represents a lower alkyl radical, a lower alkenyl radical, lower aralkyl radical, or well an alkyl radical substituted by a saturated heterocycle having from 3 to 7 cha ~ nons, itself ~ e possibly substituted by one or more lower alkyls, a lower acyloxyalkyl-lower, lower (alkoxyalkyl), or lower (hydroxyalkyl) lQ ~ 3582 lower.
The compounds of the present invention are obtained by the condensation of a diary ~ acetic acid of formula general II: ~

~ / \ CH ~ (A) nl (II) X2 COOH x4 in which the substituents A, B, Xl, X2, X3, X4, n and n keep the meanings provided previously or one of its functional derivatives, with propane diamine of general formula III:
R HN - CH - CH - CH N - R
1 2 2 2 1 3 (III) in which the substituents Rl and R3 are defined as before and R2 represents hydrogen or a benzyl radical to obtain a diarylacetamide of general formula:
f X2 CO - N - CH2 - CH2 - CH2 N \ 2 in which the substituents Xl, X2, X3, X4, A, B, R1, R2, R3, n and n 'are defined as above.
The invention also relates to obtaining the compounds of general formula I ', currently preferred, 3 CH ~

CH3 ¦ CH3 CO - l - CH2 - CH2 - CH2 NH - R3 R ~
in which Rl and R3 have the same meanings cations than those provided above which is that a t ~ tram ~ thyldiphenylacetic acid or one of its functional derivatives with a propylenediamine of formula General III:

R ~ - NH - CH2 - CH2 ~ CH2 N \ 3 (III) in which the substituents Rl and R3 are defined as before and R2 is hydrogen @ or a radical benzyl to form a compound ~ of general formula I '.
The invention also extends to obtaining the compounds following according to the process of the invention - N- ~ 2,6-2 ', 6'-tetramethyl diphenyl) acety ~ 3-N'-ethylamino propylamine, - N- ~ 2,6-2 ', 6'-tetramethyl diphenyl) acety ~ 3 N'-terbutylamino propylamine and its methanesulfonate, - N- ~ 2,6-2 ', 6'-tetramethyl diph ~ nyl) acety ~ 3-N- (2-phenyl propyl) amino propylamine and its hydrochloride, - N- ~ 2,6-2 ', 6'-tetramethyl diph ~ nyl) acety ~ 3-N'-isopropylamino propylamine.
The process according to the invention also includes the stage subsequent salification of the compounds of general formula I

~ Q ~ 35 # Z

by addition of a mineral or organic acid and in particular a therapeutically compatible acid.
The method according to the invention also includes the stage possible debenzylation in which when R2 represents a benzyl radical, hydro-g ~ nolysis or hydrolysis in an acid medium a benzyl compound for obtain a compound of general formula I for which R2 is hydrogen.
The invention also relates to a method for obtaining compounds of general formula I characterized in that one condenses a diarylacetic acid of general formula II or a of its functional derivatives with an amine propane ~ -substituted of formula IV:
Rl NH - CH2 - CH2 - CH2 Z (IV) in which Z is an easily cleavable radical chosen from the group of halogens, aryl sul- radicals fonyloxy, alkyl sulfonyloxy, trialcoyl silyloxy and hydroxy to obtain a diarylacetamide of general formula V:

CH ~ (V) Rl in which the meaning of the substituents A, B, Xl, X2, X3, X4, Rl and Z remains that supplied previously, that we react with an amine derivative of formula general VI:
R3 NH2 (VI) in which R3 has the meanings provided ante-laughingly and we get the compound of general formula I
longed for.

1 ~ 9 3 5 8 2 Proc ~ d ~ s according to the invention can also be define by the following operating modes, currently favorite:
- the functional derivative of diarylacetic acid is a halide such as chloride or bromide; or anhydride or a mixed anhydride such as an anhydride with formic acid or acetic acid; or mixed anhydrides "in situ" forms by reaction with a dialkoyl carbodiimide or dicyclohexyl carbodiimide, acetoxyacetylene or carbonyldiimidazole.
- the functional derivative of diarylacetic acid formula II can be an alkyl or aryl ester such as by example a methyl, ethyl, phenyl or nitro- ester phenyl.
- the condensation is carried out in a solvent polar or non-polar inert such as an ether, pyridine, dimethylformamide, 4-dimethylaminopyridine or hexam ~ thyl-phosphorotriamide.
- hydrogenolysis is carried out in the presence of a platinum family catalyst like for example the platinum or palladium.
- propane amine ~ -substituted of general formula IV is preferably a p.toluene sulfonyloxy, benzene derivative sulfonyloxy, a chlorine derivative, a bromine derivative or a derivative methyl sulfonyloxy.
- the reaction between the diarylacetamide of formula general V and the amine of general formula VI is carried out in basic medium such as a trialcoylamine, a base pyridic, dimethylformamide or dimethylacetamide.
the amine of general formula VI is preferably the pyrrolidylmethylamine, N-ethylpyrrolidylmethylamine ~ N-methylpiperazinylethylamine, N-hydroxyethylpiperazinylethyl-lOg35 ~ Z

amine, N-methylpiperidinylethylamine or morpholylethyl-amine.
The invention; we still have propylenediamines substituted for nitrogen of general formula I:
~ X ~ X ~ (A) nl (I) X2 x4 Rl in which Xl and X3 represent, simultaneously or distinctly a lower alkyl radical, an alkoxy radical lower or a lower alkylthio radical, X2 and X4, simultaneously or distinctly, represent feel a lower alkyl radical, A and B represent, simultaneously or distinctly, ; a halogen, a lower alkyl or a lower alkoxy radical laughing, and in this case Xl, X2, X3 and X4 can also be hydrogen and n and n 'are whole numbers from 1 to 3, or when Xl, X2, X3 and X4 are other than hydrogen, n and n 'can be zero, one, two or three, Rl represents hydrogen or an alkyl radical inferior, R3 represents a lower alkyl radical, a lower alkenyl radical, a lower aralkyl radical or an alkyl radical substituted by a heterocycle having from 3 to 7 carbon atoms possibly substituted, whenever they are obtained by one or the other process according to the invention as well as their addition salts with a mineral acid or organic.

. :, - ... .

~ 0935 ~

The invention also includes the compounds of formula General I ':
CH3 CH ~ (I ') CH3 ¦ CH3 co 7 - CH2 - CH2 - CH2 NH - R3 Rl in which Rl and R3 have the same signifi-cations than those provided above and more particularly - N- ~ 2,6-2 ', 6'-tetramethyl diphenyl) acety ~ 3-N'-ethylamino propylamine, - N- ~ 2,6-2 ', 6'-tetramethyl diph ~ nyl) acety ~ 3-N'-terbutylamino propylamine and its methanesulfonate ~
- N- ~ 2,6-2 ', 6'-tetramethyl diphenyl) acety ~ 3 N- (2-phenyl propyl) amino propylamine and its hydrochloride, - N- ~ 2,6-2 ', 6'-tetramethyl d; phenyl) acety ~ 3-N'-isopropylamino propylamine, whenever they are obtained by one or the other process according to the invention.
The compounds of general formula I according to the invention are endowed with interesting pharmacological properties, notably anti-arrhythmic. They have no neuro effect depressant. They have no anti-convulsant effect. They do not lower blood pressure.
So they can find a job in therapy, especially in tachycardia or arrhythmia following a digital type intoxication.
They are used for this purpose in the form of pharmaceutical compositions.
maceutical, suitable for parenteral, buccal, sublin-gual, or rectal, containing at least one compound of formula general I or one of its salts with a mineral or organic acid ~ (39358Z

in combination with an inert non-toxic pharmaceutical excipient politically acceptable.
The pharmaceutical compositions according to the invention, may also contain one or more other principles active ingredients of similar, complementary or synergistic action.
The useful dosage may vary according to age and weight of the subject and the severity of the therapeutic indication.
It ranges in particular between 50 and 200 mg per dose and 100 and 600 mg per day in adults, mainly by the buccal.
Compounds of general formula I or of formula I ' are basic compounds that can be salified. The salts of these compounds result from the addition of a mineral acid or organic, carboxylic, sulfonic or phosphoric, preferably ment a therapeutically compatible acid.
The term "lower alkyl" denotes ic; and in this which follows a hydrocarbon radical possibly substituted by hydroxy or lower alkoxy or dialkoylamino, having 1 to 6 carbon atoms, linear or branched, as for example-ple, methyl, ethyl, isopropyl, sec-butyl, neopentyle, terbutyle, hexyle, ~, -hydroxyethyl or diethylaminoethyl.
The term "lower alkoxy" denotes a radical alkyloxy or the alkyl radical is defined as above, like ethoxy or isopropoxy.
The term "lower alkenyl" denotes a radical mono- or poly-unsaturated hydrocarbon having 2 ~ 10 atoms of carbon in straight or branched chain such as, for example, allyl, methallyl, isopentenyle, dimethylallyl, butenyle or triallyl-methyl.
The term "aryl" (lower alkyl) means a phenyl radical possibly mono- or poly-substituted on the nucleus by halogen, lower alkoxy or trifluoro-methyl carrying a hydrocarbon chain having from 1 to 4 carbon atoms in a straight or branched chain as for example-ple, benzyle, dimethoxy benzyle, trifluoromethylbenzyle, ~ -methylbenzyle, p-chloro benzyle, phenylethyle, phenylpropyle or ~ -methyl phenylethyle.
The heterocycle having 3 to 7 chaSnons can be a nitrogen heterocycle like pyrrolidine, piperidine or hexamethylene imine. It can also include, another heteroatom like a nitrogen, oxygen or sulfur atom.
Examples of such cyclic structures are in particular oxazolidine, morpholine, thiazolidine, thiamorpho-line, piperazine or homomorpholine. These heterocycles may also contain one or more alkyl substituents.
Among these heterocycles we can mention in particular N-hydroxyethylpiperazine, N-acetoxyethylpiperazine, N-ethylpiperazine or ~ -ethoxy ~ -ethoxyethylpiperazine, 3-methylpip @ ridine and 3,5-dimethylpiperidine.
Salification of compounds of general formula I
is carried out by adding a mineral acid such as acid hydrochloric, hydrobromic, sulfuric, phosphoric, nitri-that, or by adding an organic acid, such as acid acetic, propionic, lauric, benzo ~ que, salicylic, cinna-mique, lactic, maleique, fumarique, pyruvique, glutamic, oxalic, methane sulfonic, isethionic, benzene sulfonic, phosphoric or pamoic glucose-l.
The following examples illustrate the invention, without however limit it.

~ 093582 3-N- ~ 2,6-2 ', 6'-tetramethyl diphenyl) acety ~ 7 l-terbutylamino ~ roDvlamine .
We introduce into a balloon ~ three 3g9 tubes of N-terbutyl propane diamine in solution in 20 ml of ether and 4ml2 of triethylamine and the mixture is cooled below 10. Then add with stirring and maintain the temperature strikes a + 10 by external cooling, a solution of 3g6 acid chloride (2,6-2 ', 6'-tetramethyl diphenyl) acetic in 90 ml of ether. The agitation is continued for 5 hours. envi-Ron. 37ml5 of a 2N sodium hydroxide solution are then added and leaves in contact with stirring for 2 hours. We separate a slight precipitate then decanted the ethereal phase. We wash it water then with 2N soda then twice with water, dry on magnesium sulfate, filter and evaporate to dryness. We obtain thus a dry residue weighing 9g6 which is taken up with ether isopropyl. By concentration the product crystallizes from isopropyl ether. The precipitate is drained, washed with a little glacial isopropyl ether then dry to constant weight, yield is 6gl.
The product is purified by passage in the form of methane sulfonate then alkalization.
La 3-N- ~ 2,6-2 ', 6'-tetramethyl diphenyl) acety ~ 1-precipitated terbutylamino propylamine. We separate by filtration, wring it out, wash it in water and dry it to constant weight.
The yield of pure product is 5g6.
La 3-N- ~ r2,6-2 ', 6'-tetramethyl diphenyl) acety ~ 1-terbutylamino propylamine melts at 144.
EXAMPLE II
3-N- ~ 2,6-2 ', 6'-tetramethyl diphenyl) acety ~ l-isopropylamino propylamine and its hydrochloride By operating as in 1 ~ example I from 398 of ~ 0 ~ 3358 ~:

N-isopropyl propylenediamine and 8g6 acid chloride

2,6-2',6'-tétram~thyl diphenylacetique, on obtient 797 de N-~2,6-2',6'-tetramethyl diphenyl) acety~7 3-isopropylamino propylamine que l'on purifie par conversion en chlorhydrate.
Par recristallisation de l'ac~tonitrile on obtient~5g5 de chlorhydrate de N- ~,6-2',6'-tetramethyl diphenyl) acety ~ 3-isopropylamino propylamine fondant a 220-222.
EXEMPLE III 2.6-2 ', 6'-tetram ~ thyl diphenylacetic, we obtain 797 of N-~ 2.6-2 ', 6'-tetramethyl diphenyl) acety ~ 7 3-isopropylamino propylamine which is purified by conversion to the hydrochloride.
By recrystallization of ac ~ tonitrile we obtain ~ 5g5 of N- ~ hydrochloride, 6-2 ', 6'-tetramethyl diphenyl) acety ~ 3-isopropylamino propylamine melting at 220-222.
EXAMPLE III

3-N- ~2,6-2',6'-tetram~thyl diphenyl) acety ~ 1-(2-ph~nyl-propylamino) propylamine et son chlorhydrate En operant comme a l'exemple I, au depart de 896 de chlorure d'acide 2,6-2',6'-tetramethyl diphenylacetique et 5975 de N(2-phenylpropyl) propylènediamine on obtient 13g9 de N-~2,6-2',6'-tetramethyl diphenyl) acety ~ 1-(2-phenylpropyl-amino) propylamine que l'on transforme en son chlorhydrate après cristallisation de l'ether. Celui-ci fond a 220.
EXEMPLE IV
3-N- ~2,6-2',6'-tetramethyl diphenyl) acety ~ l-ethylamino propylamine En operant comme a l'exemple I au depart de 8g6 de chlorure d'acide 2,6-2',6'-tetramethyl diphenylacetique et de 3g9 de 3-ethylamino propylamine on obtient 7g7 de 3-N- ~2,6-2',6'-tetram~thyl diphenyl) acety ~ l-ethylamino propylamine qui fond a 116 apres recristallisation du cyclohexane.
EXEMPLE V
De la même maniere au depart de l'acide bis (2,4-diterbutyl 6-isopropylphenyl) acetique et de la N-isopropyl propylenediamine on obtient la 3-N- ~is (2,4-diterbutyl 6-isopropylphenyl) acety ~ 3-isopropylamino propylamine.
De la même maniere au depart du 4,4-difluorodiphenyl-acetate d'ethyle et de la N-isopropyl propylenediamine on obtient la 3-N- ~ ,4'-difluorodiphenylacety ~ 3-isopropylamino-propylamine.
De la même maniere au depart de l'acide (3',5'-dichloro 2,2',6',4-tetramethoxy 4',6-dimethyldiphenyl) acetique obtenu a partir de la 3',5'-dichloro 2,2',6'-trihydroxy 4-methoxy 4',6-dimethylbenzophenone decrite par M. Afzal et coll.
J. chem. Soc. 1969 (section C) 1721 - et de la N-terbutyl propylenediamine on obtient la 3-N-~3',5'-dichloro 2,2',6',4-tetramethoxy 4',6-dimethyldiphenyl~ acety ~ l-terbutyl propyl~nediamine.
Etude eha_macologique des composes de l'invention 1) etude toxicologique La toxicite aiguë des composes de l'invention a ete determinee sur des lots de souris de souche Rockland pesant environ 20 9 auxquels on administre le compose a tester a doses croissantes par voie intraperitoneale ou par voie buccale en suspension dans un solvant aqueux. Apres 8 jours d'observation pendant lesquels les morts sont denombrees, la dose lethale moyenne est calculee graphiquement.
Selon les produits la dose l~thale moyenne s'eche-lonne entre 50 et 100 mg par voie intraperitoneale et entre 500 mg et lg/kg par voie buccale.
2) recherche d'une activite neurologique Des doses de 25 mg/kg par voie intraperitoneale chez la souris entra~nent une legere diminution de la motricite.
Des doses de 50 mg/kg entra~nent une baisse de la motricite puis une mortalite retardee. Ces symptômes sont faibles et ne se manifestent qu'aux doses sub-lethales.
Les composes de l'invention n'ont aucun effet protec-teur sur les convulsions provoquees par l'electrochoc ou le cardiazol.

3) action cardio-regulatrice . . .
L'experimentation de l'activite cardio-regulatrice a ete effectuee sur des lots de chiens anesthesies par 30 mg/kg de pentobarbital administres par voie intraveineuse. On enre-gistre l'~lectrocardiogramme en derivation D2. On injecte ensuite l'ouabaine par voie intraveineuse a la dose de 0.05 mg/kg. On injecte toutes les quinze minutes une nouvelle dose de O.O10 mg/kg jusqu'a apparition d'une tachycardie ventricu-1aire stable pendant au moins quinze minutes. La dose totale moyenne necessaire a l'apparition de cette tachycardie est en genera1 de l'ordre de 0.070 mg/kg.
Les substances a tester sont injectees par voie intraveineuse a des doses variables selon les lots de chiens allant de 0.5 mg/kg a 5 mg/kg.
On peut ainsi determiner la dose de produit etudie qui provoque un retour definitif a un rythme sinusal normal.
Cette dose est en general de 2 mg/kg. Pour certains produits, elle est même de lmg/kg. La persistance de l'effet varie selon les produits et selon les doses de 10 minutes à 90 minutes et plus.
Aux doses experimentees les composes de l'invention n'ont pas d'effet sur la pression arterielle. 3-N- ~ 2,6-2 ', 6'-tetram ~ thyl diphenyl) acety ~ 1- (2-ph ~ nyl-propylamino) propylamine and its hydrochloride By operating as in example I, starting from 896 2,6-2 'acid chloride, 6'-tetramethyl diphenylacetic acid and 5975 of N (2-phenylpropyl) propylenediamine we obtain 13g9 of N-~ 2.6-2 ', 6'-tetramethyl diphenyl) acety ~ 1- (2-phenylpropyl-amino) propylamine which is transformed into its hydrochloride after crystallization of ether. This melts at 220.
EXAMPLE IV
3-N- ~ 2,6-2 ', 6'-tetramethyl diphenyl) acety ~ l-ethylamino propylamine By operating as in example I from 8g6 of 2,6-2 ', 6'-tetramethyl diphenylacetic acid chloride and 3g9 of 3-ethylamino propylamine we obtain 7g7 of 3-N- ~ 2,6-2 ', 6'-tetram ~ thyl diphenyl) acety ~ l-ethylamino propylamine which melts at 116 after recrystallization from cyclohexane.
EXAMPLE V
In the same way at the start of bis acid (2,4-diterbutyl 6-isopropylphenyl) acetate and N-isopropyl propylenediamine is obtained 3-N- ~ is (2,4-diterbutyl 6-isopropylphenyl) acety ~ 3-isopropylamino propylamine.
In the same way at the start of 4,4-difluorodiphenyl-ethyl acetate and N-isopropyl propylenediamine on obtains 3-N- ~, 4'-difluorodiphenylacety ~ 3-isopropylamino-propylamine.
In the same way at the start of the acid (3 ', 5'-dichloro 2,2 ', 6', 4-tetramethoxy 4 ', 6-dimethyldiphenyl) acetic obtained from 3 ', 5'-dichloro 2,2', 6'-trihydroxy 4-methoxy 4 ', 6-dimethylbenzophenone described by M. Afzal et al.
J. chem. Soc. 1969 (section C) 1721 - and N-terbutyl propylenediamine we get 3-N- ~ 3 ', 5'-dichloro 2,2', 6 ', 4-tetramethoxy 4 ', 6-dimethyldiphenyl ~ acety ~ l-terbutyl propyl ~ nediamine.
Eha_macological study of the compounds of the invention 1) toxicological study The acute toxicity of the compounds of the invention was determined on lots of Rockland strain mice weighing approximately 20 to which the test compound is administered in doses growing intraperitoneally or orally suspension in an aqueous solvent. After 8 days of observation during which the dead are counted, the lethal dose average is calculated graphically.
Depending on the products, the average l ~ thale dose dries up.
lonne between 50 and 100 mg intraperitoneally and between 500 mg and lg / kg by mouth.
2) search for neurological activity Doses of 25 mg / kg intraperitoneally in the mouse causes a slight decrease in motor skills.
Doses of 50 mg / kg lead to a drop in motor skills then delayed mortality. These symptoms are weak and appear only at sub-lethal doses.
The compounds of the invention have no protective effect on convulsions caused by electroshock or cardiazol.

3) cardio-regulating action . . .
Experimentation with cardio-regulatory activity has was performed on lots of dogs anesthetized with 30 mg / kg of intravenous pentobarbital. We are records the D2 bypass electrocardiogram. We inject then the ouabaine intravenously at a dose of 0.05 mg / kg. A new dose is injected every fifteen minutes of O. 10 mg / kg until the onset of ventricular tachycardia 1st stable for at least fifteen minutes. The total dose mean necessary for the appearance of this tachycardia is in genera1 of the order of 0.070 mg / kg.
The test substances are injected by intravenous at variable doses according to the batches of dogs ranging from 0.5 mg / kg to 5 mg / kg.
We can thus determine the dose of product studied which causes a definitive return to a normal sinus rhythm.
This dose is generally 2 mg / kg. For some people products, it is even lmg / kg. The persistence of the effect varies by product and dose from 10 minutes to 90 minutes and more.
At tested doses, the compounds of the invention have no effect on blood pressure.

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 the preparation of the compounds of general formula I:

(I) in which:
X1 and X3 represent a lower alkyl radical, X2 and X4 represent a lower alkyl radical similar or different, R1 is hydrogen or a lower alkyl radical laughing, and R3 represents a lower alkyl radical, or else a lower aralkyl radical, characterized in that A) condensing a diarylacetic acid of general formula II:
(II) in which the substituents X1, X2, X3 and X4 keep the meanings provided previously or one of its functional derivatives, with propane diamine of general formula III:

R1 HN - CH2 - CH2 - CH2 NH - R3 (III) in which the substituents R1 and R3 are defined like before to obtain a diarylacetamide of general formula:

in which the substituents X1, X2, X3, X4, R1 and R3 are defined as above, or B) condensing a diarylacetic acid of general formula II or one of its functional derivatives with propane .omega.-substituted amine of formula IV:
R1 NH - CH2 - CH2 - CH2 Z (IV) in which Z is an easily cleavable radical chosen from the group of halogens, aryl radicals sulfonyloxy, trialcoyl silyloxy, alkyl sulfonyloxy and hydroxy to obtain a diarylacetamide of general formula V:
(V) in which the meaning of the substituents X1, X2, X3, X4, R1 and Z remains that previously supplied, that we react with a derivative of formula general VI:

R3 NH2 (VI) in which R3 has the meanings provided previously and the compound of general formula is obtained I desired.

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

(I ') in which R1 and R3 have the same meanings cations than those provided above, characterized in that a diarylacetic acid of general formula II is condensed:

(II) in which the substituents X1, X2, X3 and X4 keep the meanings provided previously or one of its functional derivatives, with propane diamine of general formula III:
R1 HN - CH2 - CH2 - CH2 NH - R3 (III) in which the substituents R1 and R3 are defined like before to obtain a diarylacetamide of general formula:

in which the substituents X1, X2, X3, X4, R1 and R3 are defined as above.

3. The method according to claim 1 which comprises the later stage of salification of the compounds of formula general I by addition of a mineral or organic acid for form a therapeutically acceptable salt.

4. The process according to claim 1 for obtaining the compounds of formula general I characterized in that an acid is condensed diarylacetic acid of general formula II or one of its derivatives functional with an .omega.-substituted propane amine of formula IV:
R1 NH - CH2 - CH2 CH2 (IV) in which Z is an easily cleavable radical chosen from the group of halogens, aryl radicals sulfonyloxy, trialcoyl silyloxy, alkyl sulfonyloxy and hydroxy to obtain a diarylacetamide of general formula V:

(V) in which the meaning of the substituents X1, X2, X3, X4, R1 and Z remains that previously supplied, that we react with a derivative of formula general VI:

R3 NH2 (VI) in which R3 has the meanings provided previously laughingly and we obtain the compound of general formula I
longed for.

5. A method according to claim 1 for producing N - [(2,6-2 ', 6'-tetramethyl diphenyl) acetyl] 3-N'-ethylamino propylamine, which consists of condensing the chloride of the acid (2,6-2 ', 6'-tetramethyl diphenyl) acetic with N-ethyl propylenediamine and isolating the desired compound.

6. A method according to claim 1 for producing N - [(2,6-2 ', 6'-tetramethyl diphenyl) acetyl] 3-N'-tertbutyl-amino propylamine and its methanesulfonate, which consists of densify the acid chloride (2,6-2 ', 6'-tetramethyl diphenyl) acetic acid with N-terbutyl propylenediamine and to isolate the desired compound which can be salified by adding acid methane sulfonic, to its methanesulfonate.

7. A method according to claim 1 for producing N - [(2,6-2 ', 6'-tetramethyl diphenyl) acetyl] 3-N- (2-phenyl propyl) amino propylamine and its hydrochloride, which consists of which one condenses the acid chloride (2.6-2 ', 6'-tetra-methyl diphenyl) acetic with N (2-phenylpropyl) propylene-diamine and obtains the desired compound which can be salified in its hydrochloride by addition of hydrochloric acid.

8. A method according to claim 1 for obtaining tion of N - [(2,6-2 ', 6'-tetramethyl diphenyl) acetyl] 3-N'-isopropylamino propylamine, which consists of dense acid chloride (2,6-2 ', 6'-tetramethyl diphenyl) acetic with N-isopropyl propylenediamine and obtains the desired compound.

9. A method according to one of claims 1 or 4 in which, the functional derivative of diarylacetic acid is a halide, anhydride or mixed anhydride, or a mixed anhydride formed "in situ" by reaction with a dialkyl carbodiimide.

10. A method according to one of claims 1 or 4 in which the condensation is carried out in a solvent inert polar or non-polar.

11. A method according to claim 4 in which, .omega.-substituted propane amine of general formula IV is a p.toluene sulfonyloxy derivative, benzene sulfonyloxy, a derivative chlorine, a bromine derivative or a methyl sulfonyloxy derivative.

12. A method according to claim 4 in which, the reaction between the diarylacetamide of general formula V and the amine of general formula VI is carried out in basic medium.

13. Nitrogen-substituted propylanediamines general formula I:

(I) in which:
X1 and X3 represent a lower alkyl radical, X2 and X4 represent a lower alkyl radical similar or different, R1 represents hydrogen or an alkyl radical lower, and R3 represents a lower alkyl radical, or else a lower aralkyl radical, each time they are obtained by the process of the claim 1 or one of its obvious chemical equivalents.

14. The compounds of general formula I ', each time that they are obtained by the process of claim 2 or a of its obvious chemical equivalents.

15. Nitrogen-substituted propylenediamines general formula I, each time they are obtained according to the process of claim 4 or one of its equivalents obvious chemicals.

16. N - [(2,6-2 ', 6'-tetramethyl diphenyl) acetyl]
3-N'-ethylamino propylamine, each time it is obtained according to the method of claim 5 or one of its equivalents slow chemical obvious.

17. N - [(2,6-2 ', 6'-tetramethyl diphenyl) acetyl] 3-N'-terbutylamino propylamine and its methanesulfonate, each once they are obtained according to the method of claim 6 or one of its obvious chemical equivalents.

18. N - [(2,6-2 ', 6'-tetramethyl diphenyl) acetyl] 3-N '- (2-phenyl propyl) amino propylamine and its hydrochloride, each time they are obtained according to the process of the claim cation 7 or one of its obvious chemical equivalents.

19. N - [(2,6-2 ', 6'-tetramethyl diphenyl) acetyl] 3-N'-isopropylamino propylamine, each time it is obtained according to the method of claim 8 or one of its equivalents obvious chemicals.