CA1271197A

CA1271197A - Process for preparing 4-phenylpropylindole derivatives

Info

Publication number: CA1271197A
Application number: CA000510849A
Authority: CA
Inventors: Francois Clemence; Gilles Hamon; Jacques Guillaume
Original assignee: Roussel Uclaf SA
Current assignee: Sanofi Aventis France
Priority date: 1985-06-05
Filing date: 1986-06-04
Publication date: 1990-07-03
Anticipated expiration: 2007-07-03
Also published as: FR2583047B1; ATA151786A; FI862376A; HUT42066A; FI862376A0; AT386823B; FR2583047A1; FI85465B; FI85465C; HU196751B

Abstract

L'invention concerne un procédé pour préparer les dérivés de formule (I): <IMG> (I) et leurs sels pharmaceutiquement acceptables, où R et R1 représentent hydrogène, alkyle linéaire ou ramifié, cycloalkyle, cycloalkylalkyle ou aralkyle, ou R + R1 forment un hetérocycle pouvant comporter un atome d'oxygène, de soufre ou d'azote éventuellement substitué par alkyle, phényle, naphtyle ou aralkyle, a + b forment une fonction oxo ou a + c forment une liaison carbone-carbone, b est un hydrogène ou b + a forment une fonction oxo, c est un hydrogène ou c + a forment une liaison carbone-carbone, le pointillé représente une liaison optionnelle, A est (-CH2-)n avec n = 2,3,4 ou 5, R2 est hydrogène, alkyle linéaire ou ramifié, X est OH, hydrogène ou x + y forment une fonction oxo, y est hydrogène ou y + x forment une fonction oxo. Les dérivés I sont utiles comme médicaments, en raison notamment de remarquables propriétés anti-arythmiques et bloquantes des canaux calcicosodiques lents.The invention relates to a process for preparing the derivatives of formula (I): <IMG> (I) and their pharmaceutically acceptable salts, where R and R1 represent hydrogen, linear or branched alkyl, cycloalkyl, cycloalkylalkyl or aralkyl, or R + R1 form a heterocycle which may contain an oxygen, sulfur or nitrogen atom optionally substituted by alkyl, phenyl, naphthyl or aralkyl, a + b form an oxo function or a + c form a carbon-carbon bond, b is a hydrogen or b + a form an oxo function, c is a hydrogen or c + a form a carbon-carbon bond, the dotted line represents an optional bond, A is (-CH2-) n with n = 2,3,4 or 5, R2 is hydrogen, linear or branched alkyl, X is OH, hydrogen or x + y form an oxo function, y is hydrogen or y + x form an oxo function. The derivatives I are useful as medicaments, in particular because of remarkable antiarrhythmic and blocking properties of the slow calcium calcium channels.

Description

~ ''7~197 La présente invention concerne un procéde de préparation de dérivés du 4-phénylpropyl indole ainsi que de leurs sels.
L'invention a pour objet un procédé de préparation de dérivés du 4-phénylpropyl indole,ainsi que de leurs sels pharmaceutiquement acceptables répondant à la formule (I):

~ ~ O A-N / 1 R
~, / a ~' ~ N~

dans laquelle R et R1 representent, indépendam!nent l'un de l'autre, un atome d'hydrogène, un radical alkyle linéaire renfermant de 1 à 5 atomes de carbone, un radical alkyle ramifié renfermant de 3 à 5 atomes de carbone, un radical cycloalkyle renfermant de 3 à 7 atomes de carbone, un radical cycloalkylalkyle renfermant de 4 à 7 atomes de carbone, ou un radical aralkyle renfermant de 7 à 12 atomes de carbone éventuellement substitué par 1, 2 ou 3 radicaux choisis dans le groupe constitué par les halogènes et les radicaux méthyle, éthyle, méthoxy, éthoxy, trifluoromethyle, méthylthio, amino et nitro, ou R et R1 forment ensemble un hétérocycle saturé ou insaturé pouvant renfermer un second hetéroatome choisi parmi les atomes d'oxygène, de soufre et d'azote, cet atome d'azote étant éventuellement substitué
par un radical alkyle linéaire renfermant de 1 à 5 atomes de carbone, par un radical phényle ou naphtyle, ou par un radical aralkyle renfermant de 7 à 12 atomes de carbone, a représente 3'~

ensemble avec b une fonction oxo, ou repr~sente ensemble avec c une liaison carbone carbone, b représente un atome d'hydrogène, ou ensemble avec a une fonction oxo, c représente un atome d'hydrogène, ou ensemble avec a represente une liaison carbone-carbone, le pointillé represente S la presence éventuelle d'une liaison carbone-carbone, A représente une cha~ne -~CH2)-n dans laquelle n peut prendre les valeurs 2, 3~
4 ou 5, R2 represente un atome d'hydrog~ne, un radical alkyle linéaire renfermant de 1 a S atomes de carbone ou un rad;cal alkyle ramif;~
renfermant de 3 a 5 atomes de carbone, x repr~sente un atome d'hydrogene 10 ou un groupement hydroxy, ou ensemble avec y, unle fonction o~o, et y représente un atome d'hydrog~ne ou, ensemble avec x, une fonction oxo, caracterise en ce que A) l'on fait rea~ir un produit de formule II:

~ ~ 0-A-Hal ~ (II) dans laquelle Hal représente un atome de chlore, de brome, ou d'iode, et R2 et A ont la signification dejà indiquée, avec un dérivé de formule III o / R'1 H-N \ R' (III) dans laquelle R' et R'1 ont la signification d~jà indiqu~e pour l? et 3û R1, ou R' représente un atome d'hydrogène et R'~ représente un radical trifluoro acétyle, pour obtenir un produit de formule IA :

O-A-N /
~ ~ \ R' ~ A
,~

R~

3 ~ ~d ~ 7 dans laquelle A, 2',R'1 et R2 ont la s;gn;f;cat;on d~ja ;nd;quée~
que~ dans le cas où R'1 représente un rad;cal tr;fluoro ac~tyle, l'on soumet à l'act;on d'un agent de clivage pour obtenir l'amine pr;maire correspondante, et produits de formule IA que soit l'on féduit par 5 act;on d'hydrogène gazeux en pr~sence d'un catalyseur a base de plat;ne ou de palladium dans un solvant tel qu'un alcanol renfermant de 1 a 5 atomes de carbone, ou par action d'hydrogene gazeux en présence de N;ckel de Raney dans un solvant tel que l'acétate d'~thyle, ou encore par action pendant mo;ns de 3 heures de sod;um dans l'ammoniac au seir, d'un solvant 10 pour obten;r un produ;t de formule IB :

~ O-A-N /
C~ (IB) // ~
R

dans laquelle A, R, R1 et R2 ont la sign;ficat;on déja ;ndiquée, que ou b;en l'on ;sole et, si d~sir~, salif;e, ou h;en l'on réduit par act;on d'un borohydrure ou cyanoborohydrure alcalin pour obtenir un produit de ~ formule IC : ~ / R
~ O-A-N

( Ic) ~

35 dans laquelle A, R~ R1 et R2 ont la s;gnification déjà indiquée9 que ou b;en l'on isole et, s; dés;ré, sal;f;e, ou b;en l'on réduit par action de sod;um dans l'anmon;ac pour obtenir un produ;t de formule ID :

f~

~30-A-N \

( ID) '~5 dans laquelle A, R, R1 et R2 ont la signification déj~ ind;quee, 10 que l'on isole et, si desiré~ salifie~
soit l'on fa;t réagir ledit produit de formule 1~ avec le complexe formé entre un borohydrure alcalin et la pyridine, pour obten;r ~n produit de formule IE :

O A ~R
HO ~J~ N\

( IE ) W~N~J

dans laquelle A, R, R1, et R2 ont la signif;cation déjà indiquée, que ou bien l'on isole, ou b; n l'on réduit a l'aide de sodium dans 25 l'a~moniac pour obtenir un produit de formule ID que l'on isole et, si désiré, salifie, soit l'on réduit led;t produit de formule IA à l'aide de sodium dans l'ammoniac pour obtenir un produit de formule ID que l'on isole et, si d~sir~, salifie, 30 puis soumet~ si désir~, lesdits produits de formule IA, IB, Ic, ID et IE à l'action d'un agent d'halogénation pour obtenir un produit de formule IV : ~ R1 X~ O-A-N/
( IV ) ~_~ Ha l I

~ N~
v ~7~ 3'7 dans laquelle Hallrepresente un atome de brome ou de chlore, et x, y, A, R, R1, R2 et le pointillé ont la signification déjà indiquee, que l'on soumet à une hydrolyse pour obtenir un produit de formule IF:

j,~O-A-N/

0 ~ ( IF) O

dans laquelle x, y, A, R, Rl, R2 et le pointillé ont la signification déjà indiquée, que l'on isole et, si désiré, salifie;
B) (i)-soit l'on soumet un produit de formule (II):

~ ~ O-A-N~l ¦ (II) ~3 ~2 dans laquelle A, R2 et Hal ont la signification déjà
indiquee, à une réduction par l'action d'hydrogène gazeux en présence d'un catalyseur à base de platine ou de palladium 7'~ 1~37 - 5a -dans un solvant, ou par act.ion d'hydrogène gaze~x en presence de Nickel de Raney dans un solvant, ou encore par action pendant moins de trois heures, de sodium dans l'ammoniac au sein d'un solvant, pour obtenir un produit de formule (IIB) ~
~ ~ 0-A-N~l ~ ( I IB ) dans laquelle A, R2 et Hal ont la signification dejà
indiquee, que ou bien l'on isole, ou bien l'on réduit par action d'un borohydrure ou cyanoborohydrure alcalin pour obtenir un produit de formule (IIC):

H0 ~ 0-~-H81 ¦ (IIC) ~D

dans laquelle A, R2 et Hal ont la signification dejà
indiquée, que ou bien l'on isole, ou bien l'on reduit par action de sodium dans l'ammoniac pour obtenir un produit de formule (IID) ~,.

- 5b -O-A-Hal ( I I D ) ~Z

dans laquelle A, R2 et Hal ont la signification déj~
indiquée, que l'on isole, - soit l'on fait réagir ledit produit de formule (II) précedemment défini~ avec un complexe formé entre un borohydrure alcalin et la pyr.idine pour obtenir un pxoduit de formule (IIE):

~ ~ O-A-H~

~ ( IIE) ~2 dans laquelle A, R2 et Hal ont la signification déjà
indiquée, que ou bien l'on isole, ou bien l'on réduit à
l'aide de sodium dans l'ammoniac pour obtenir un produit de formule (IID) tel que précédemment défini, que l'on isole, - soit l'on réduit ledit produit de formule (II) precedemment défini, à l'aide de sodium dans l'ammoniac pour "

1~'7~

- 5c -obtenir un produit de formule tIID) tel que precédemment defini, que l'on isole, puis soumet, si desiré, lesdits produits de formu'e (II), (IIB), (IIC), ~IID) et (IIE) à l'action d'un agent d'halogénation pour obtenir un produit de formule (IV'):

/~
x ~ O-A-Hal Y~
~ (IV') ~ ~ ~a11 dans laquelle x, y, A, R2, Hal et le trait pointillé ont la signification déjà indiquee, et Hall représente un ato~e de brome ou de chlore, que l'on soumet à une hydrolyse pour obtenir un produit de formule (IIF):

~ - O-A-Hal ~' ( IIF) ~ O

dans laquelle x, y, A, R2, Hal et le trait pointille ont la signification déjà indiquée, que l'on isole; et -: . . .

7~ 3~

- 5d -(ii) l'on fait réagir lesdits produits de formule (II), (IIB), (IIC), (II~), (IIE) et (IIF) précédemment définis, soit avec un dérivé de formule (III):

/ R'l - ~ (III) R' dans laquelle R~ et R'l ont la signification déjà indiquée pour R et Rl, et obtient le dérivé cherché que l'on isole et, si désiré, salifie avec un acide pharmaceutiquement acceptable, soit avec un dérivé de foxmule (III):

\ (III) R' dans laquelle R' représente un atome d'hydrogène et R'1 représente un radical trifluoroacétyle, puis soumet le produit obtenu à l'action d'un agent de clivage pour obtenir l'amine primaire correspondante que l'on isole et, si désiré, salifie avec un acide pharmaceutiquement acceptable; ou C) (i) -solt l'on soumet un dérive de formule (VII):

~ OH
0~

(VII) : [~ ~3 N
I

7~

- 5e -dans laquelle R2 a la signification déjà indiquée, à une réduction par action d'hydrogène gazeux en présence d'un catalyseur à base de platine ou de palladium dans un solvant, ou par action d'hydrogène gazeux en présence de Nickel de Raney dans un solvant, ou encore par action pendant moins de trois heures,de sodium dans l'ammoniac au sein d'un solvant, pour obtenir un produit de formule IVIIB) ~ ~H
0~

3 (VIIB, I

dans laquelle R2 a la signification déjà indiquée, que ou bien l'on isole, ou bien l'on réduit par action d'un borohydrure ou cyanoborohydrure alcalin pour obtenir un produit de formule (VIIC):

~ ~H
HO ~

( VI I C ) ~3 I

dans laquelle R2 a la signification déjà indiquée, que ou - 5f -bien l'on isole, ou bien l'on réduit par action de sodium dans l'ammoniac pour obtenir un produit de formule (VIID):

: ¦¦ + ~H
~

a2 dans laquelle R2 a la signification déjà indiquée, que l'on isole, - soit l'on fait réagir le dérivé de formule (VII) précédemment defini, avec un complexe formé entre un borohydrure alcalin et la pyridine, pour obtenir un produit de formule (VIIE):

:~ H

; 25 ~3 ( VI IE ) . 12 dans laquelle R2 a la signification déjà indiquée, que ou i bien l'on isole, ou bien l'on réduit à l'aide de scdium dans l'ammoniac pour ~btenir un produit de formule ~VIID) tel : -1~7~L~L i-3~7 5~

que précedemment défini, que l'on isole, - soit l'on réduit ledit produit de formule (VII) precédemment défini, à l'aide de sodium dans l'ammoniac pour obtenir un produit de formule (VIID) tel ~ue précedemment défini, que l'on isole, puis soumet, si desiré, lesdits produi-ts de :Eormule (VII), (VIIB), (VIIc), (VIID) et (VIIE) à l'action d'un agent d'halogenation pour obtenir un produit de formule (IV"):

~ ~ -J OH

~ (IV") ~ ~ Hall dans laquelle x, y, R2 et le trait pointillé ont la signification déjà indiquée, et Hall représente un atome de brome ou de chlore, que l'on soumet a une hydrolyse pour obtenir un produit de formule (VIIF):

~
~ OH

f~' ~VIIF) <3 - 5h -dans laquelle x, y, R2 et le trait pointillé ont la signification déjà indiquée, que l'on isole;
(ii) l'on fait réagir lesdits produits de formule (VII), (VIIB), (VIIc), (VIID), (VIIE) et (VIIF) avec un derive halogéné, un dérivé hydroxyle, ou un sulfonate dudit dérivé hydroxylé d'un halogénure d'alkylène de Eormule ~VIII):

- A - Hal (VIII) dans laquelle A et Hal ont la signification déjà indiquée, pour obtenir un produit de formule (II'):
x ~
~ ~ O-A-Hal ~ c (II') dans laquelle a, b, c, x, y, A, R2, Hal et le trait pointillé ont la signification déjà indiquée, que l'on fait réagir soit avec un dérivé de formule (III):

H-N (III) \ R' dans la~uelle R'1 et R ont la signification déjà indiquée pour R et Rl, et obtient le derivé cherché que l'on isole et, si désiré, salifie avec un acide pharmaceutiquement . .

acceptable, soit avec un dérivé de formule (III~

, ~ 1 H-N (III) \ R' dans laguelle R' représente un atome d'hydrogène et R'1 représen-te un radical trifluoroacétyle, puis soumet le produit obtenu à un agent de clivage pour obtenir l'amine - 10 primaire correspondante que l'on isole et, si désiré, salifie avec un ~cide pharmaceutiquement acceptable.
Les dérivés de formule I sont décrits dans la demande canadienne No. 507,303 déposée le ~2 avril 1986 et ayant pour obje-t de nouve.aux dérivés du ~-phénylpropyl indoles, leurs sels, procédé de préparation, application ~`
; titre de médicaments, et compositions les renEermant.
La réaction du produit de Eormule II avec le dérivé de formule III est réalisée par exemp:Le au sein d'un solvant organique inerte tel que le dioxanne, le ~enzène, le toluène ou, notamrnent, le dimethylformamide, de préEérence en présence d'un agen-t de condensation tel gu'un carbonate ou bicarbonate alcalin comme le carbonate de potassium, un hydroxyde alcalin comme la soude ou la potasse, ou une amine tertiaire comme la triéthylamine. On peut opérer également ~ '' 7 ~ 197 The present invention relates to a method of preparation of derivatives of 4-phenylpropyl indole as well as their salts.
The subject of the invention is a method of preparation derivatives of 4-phenylpropyl indole, and their salts pharmaceutically acceptable corresponding to formula (I):

~ ~ O AN / 1 R
~, / at ~ '~ N ~

in which R and R1 represent, independently one of the other, a hydrogen atom, a linear alkyl radical containing from 1 to 5 carbon atoms, an alkyl radical branched containing 3 to 5 carbon atoms, a radical cycloalkyl containing 3 to 7 carbon atoms, one cycloalkylalkyl radical containing from 4 to 7 atoms of carbon, or an aralkyl radical containing from 7 to 12 atoms of carbon optionally substituted with 1, 2 or 3 radicals chosen from the group consisting of halogens and methyl, ethyl, methoxy, ethoxy, trifluoromethyl radicals, methylthio, amino and nitro, or R and R1 together form a saturated or unsaturated heterocycle which may contain a second heteroatom chosen from oxygen, sulfur and of nitrogen, this nitrogen atom being optionally substituted by a linear alkyl radical containing from 1 to 5 atoms of carbon, by a phenyl or naphthyl radical, or by a aralkyl radical containing 7 to 12 carbon atoms, a represented 3 '~

together with b an oxo function, or represents together with c a carbon carbon bond, b represents a hydrogen atom, or together with has an oxo function, c represents a hydrogen atom, or together with a carbon-carbon bond, the dotted line represents S the possible presence of a carbon-carbon bond, A represents a chain ~ ne - ~ CH2) -n in which n can take the values 2, 3 ~
4 or 5, R2 represents a hydrogen atom, a linear alkyl radical containing 1 to S carbon atoms or a rad; cal branched alkyl; ~
containing 3 to 5 carbon atoms, x represents a hydrogen atom 10 or a hydroxy group, or together with y, a function o ~ o, and y represents a hydrogen atom or, together with x, an oxo function, characterized in that A) a product of formula II is reacted:

~ ~ 0-A-Hal ~ (II) in which Hal represents a chlorine, bromine or iodine atom, and R2 and A have the meaning already indicated, with a derivative of formula III o / R'1 HN \ R '(III) in which R 'and R'1 have the meaning already indicated for l? and 3û R1, or R 'represents a hydrogen atom and R' ~ represents a radical trifluoro acetyl, to obtain a product of formula IA:

OAN /
~ ~ \ R ' ~ A
, ~

R ~

3 ~ ~ d ~ 7 in which A, 2 ', R'1 and R2 have the s; gn; f; cat; on d ~ ja; nd; quée ~
that ~ in the case where R'1 represents a rad; cal tr; fluoro ac ~ tyle, we subject to the act; on of a cleavage agent to obtain the primary amine corresponding, and products of formula IA that either one federates by 5 act; hydrogen gas is present in the presence of a dish-based catalyst;
of palladium in a solvent such as an alkanol containing from 1 to 5 atoms carbon, or by the action of gaseous hydrogen in the presence of N;
Raney in a solvent such as ~ ethyl acetate, or by action for less than 3 hours of sodium in ammonia, a solvent 10 to obtain a product of formula IB:

~ OAN /
C ~ (IB) // ~
R

in which A, R, R1 and R2 have the sign; ficat; it is already indicated, that or b; in one; sole and, if desired, salif; e, or h; in one reduced by act;
of an alkali borohydride or cyanoborohydride to obtain a product of ~ IC formula: ~ / R
~ OAN

(Ic) ~

35 in which A, R ~ R1 and R2 have the meaning already indicated9 that or b; we isolate and, s; dice; re, sal; f; e, or b; by reducing it by action of sod; um in the anmon; ac to obtain a product of formula ID:

f ~

~ 30-YEAR \

(ID) '~ 5 in which A, R, R1 and R2 have the meaning already ~ ind; quee, 10 that we isolate and, if desired ~ salify ~
either we react; said product of formula 1 ~ with the complex formed between an alkaline borohydride and pyridine, to obtain; r ~ n product of formula IE:

OA ~ R
HO ~ J ~ N \

( IE ) W ~ N ~ J

in which A, R, R1, and R2 have the meaning; cation already indicated, that either we isolate, or b; n reduced with sodium in 25 a ~ moniac to obtain a product of formula ID which is isolated and, if desired, salify, either reduce the led; t product of formula IA using sodium in ammonia to obtain a product of formula ID which is isolated and, if desired, salify, 30 then submit ~ if desired ~, said products of formula IA, IB, Ic, ID and IE to the action of a halogenating agent to obtain a product of formula IV: ~ R1 X ~ OAN /
(IV) ~ _ ~ Ha l I

~ N ~
v ~ 7 ~ 3'7 in which Hallrepresents a bromine or chlorine atom, and x, y, A, R, R1, R2 and the dotted line have the meaning already indicated, which is subjected to hydrolysis to obtain a product of formula IF:

j, ~ OAN /

0 ~ (IF) O

in which x, y, A, R, Rl, R2 and the dotted line have the meaning already indicated, which is isolated and, if desired, salifies;
B) (i) - or a product of formula (II) is submitted:

~ ~ OAN ~ l ¦ (II) ~ 3 ~ 2 in which A, R2 and Hal have the meaning already indicated, to a reduction by the action of hydrogen gas in presence of a platinum or palladium catalyst 7 '~ 1 ~ 37 - 5a -in a solvent, or by act.ion of hydrogen gauze ~ x in presence of Raney Nickel in a solvent, or by action for less than three hours, sodium in ammonia in a solvent, to obtain a product of formula (IIB) ~
~ ~ 0-YEAR ~ l ~ (I IB) in which A, R2 and Hal have the meaning already indicated, that either we isolate, or we reduce by action of an alkaline borohydride or cyanoborohydride for obtain a product of formula (IIC):

H0 ~ 0- ~ -H81 ¦ (IIC) ~ D

in which A, R2 and Hal have the meaning already indicated, that either one isolates, or one reduces by action of sodium in ammonia to obtain a product of formula (IID) ~ ,.

- 5b -OA-Hal (IID) ~ Z

in which A, R2 and Hal have the meaning already ~
indicated, which we isolate, - either reacting said product of formula (II) previously defined ~ with a complex formed between a alkaline borohydride and pyr.idine to obtain a pxoduct of formula (IIE):

~ ~ OAH ~

~ (IIE) ~ 2 in which A, R2 and Hal have the meaning already indicated, that either we isolate, or we reduce to using sodium in ammonia to get a product of formula (IID) as defined above, which is isolated, - either reduce said product of formula (II) previously defined, using sodium in ammonia to "

1 ~ '7 ~

- 5c -obtain a product of formula tIID) as previously defined, that we isolate, then submit, if desired, said formu'e products (II), (IIB), (IIC), ~ IID) and (IIE) to the action of an agent halogenation to obtain a product of formula (IV '):

/ ~
x ~ OA-Hal Y ~
~ (IV ') ~ ~ ~ a11 in which x, y, A, R2, Hal and the dotted line have the meaning already indicated, and Hall represents an ato ~ e of bromine or chlorine, which is subjected to hydrolysis to obtain a product of formula (IIF):

~ - OA-Hal ~ ' (IIF) ~ O

in which x, y, A, R2, Hal and the dotted line have the meaning already indicated, which is isolated; and -:. . .

7 ~ 3 ~

- 5d -(ii) reacting said products of formula (II), (IIB), (IIC), (II ~), (IIE) and (IIF) previously defined, either with a derivative of formula (III):

/ R'l - ~ (III) R ' in which R ~ and R'l have the meaning already indicated for R and Rl, and obtains the sought derivative which we isolate and, if desired, salifies with a pharmaceutically acid acceptable, either with a foxmule derivative (III):

\ (III) R ' in which R 'represents a hydrogen atom and R'1 represents a trifluoroacetyl radical, then submits the product obtained by the action of a cleavage agent to obtain the corresponding primary amine that is isolated and, if desired, salifies with a pharmaceutically acid acceptable; or C) (i) -solt we submit a drift of formula (VII):

~ Oh 0 ~

(VII) : [~ ~ 3 NOT
I

7 ~

- 5th -in which R2 has the meaning already indicated, at a reduction by the action of hydrogen gas in the presence of a catalyst based on platinum or palladium in a solvent, or by the action of hydrogen gas in the presence of Raney nickel in a solvent, or by action for less than three hours, sodium in ammonia at within a solvent, to obtain a product of formula IVIIB) ~ ~ H
0 ~

3 (VIIB, I

in which R2 has the meaning already indicated, that or either we isolate, or we reduce by the action of a alkali borohydride or cyanoborohydride to obtain a product of formula (VIIC):

~ ~ H
HO ~

(VI IC) ~ 3 I

in which R2 has the meaning already indicated, that or - 5f -either it is isolated, or it is reduced by the action of sodium in ammonia to obtain a product of formula (VIID):

: ¦¦ + ~ H
~

a2 in which R2 has the meaning already indicated, which one isolated, - either react the derivative of formula (VII) previously defined, with a complex formed between a alkaline borohydride and pyridine, to obtain a product of formula (VIIE):

: ~ H

; 25 ~ 3 (VI IE) . 12 in which R2 has the meaning already indicated, that or i either isolate, or reduce with scdium in ammonia to ~ get a product of formula ~ VIID) such : -1 ~ 7 ~ L ~ L i-3 ~ 7 5 ~

that previously defined, that we isolate, - either reduce said product of formula (VII) previously defined, using sodium in ammonia to obtain a product of formula (VIID) such ~ ue previously defined, that we isolate, then submit, if desired, the said products of: Eormule (VII), (VIIB), (VIIc), (VIID) and (VIIE) to the action of an agent halogenation to obtain a product of formula (IV "):

~ ~ -J OH

~ (IV ") ~ ~ Hall in which x, y, R2 and the dotted line have the meaning already indicated, and Hall represents an atom of bromine or chlorine, which is subjected to hydrolysis to obtain a product of formula (VIIF):

~
~ Oh f ~ '~ VIIF) <3 - 5h -in which x, y, R2 and the dotted line have the meaning already indicated, which is isolated;
(ii) reacting said products of formula (VII), (VIIB), (VIIc), (VIID), (VIIE) and (VIIF) with a halogenated derivative, a hydroxyl derivative, or a sulfonate of said hydroxylated derivative of an alkylene halide from Eormule ~ VIII):

- A - Hal (VIII) in which A and Hal have the meanings already indicated, to obtain a product of formula (II '):
x ~
~ ~ OA-Hal ~ c (II ') where a, b, c, x, y, A, R2, Hal and the line dotted have the meaning already indicated, which we do react either with a derivative of formula (III):

HN (III) \ R ' in the ~ uelle R'1 and R have the meaning already indicated for R and Rl, and obtains the sought derivative which we isolate and, if desired, salifies with a pharmaceutically acid . .

acceptable, either with a derivative of formula (III ~

, ~ 1 HN (III) \ R ' in laguelle R 'represents a hydrogen atom and R'1 represents a trifluoroacetyl radical, then submits the product obtained with a cleavage agent to obtain the amine - 10 corresponding primary which is isolated and, if desired, salifies with a pharmaceutically acceptable acid.
The derivatives of formula I are described in Canadian Application No. 507,303 filed April 2, 1986 and having for object new to derivatives of ~ -phenylpropyl indoles, their salts, preparation process, application ~ `
; titer of medicaments, and compositions containing them.
The reaction of the product of Eormule II with the derivative of formula III is produced for example: The within a inert organic solvent such as dioxane, ~ enzyme, toluene or, in particular, dimethylformamide, preferably in presence of a condensing agent such as a carbonate or alkaline bicarbonate such as potassium carbonate, a alkali hydroxide like soda or potash, or an amine tertiary like triethylamine. We can also operate

2~ en utilisant comme solvant l'amine de formule III elle-même~
Lorsque l'on veut préparer un produit de Formule `; IB à partir d'un produit de formule IA par action de sodium dans l'ammoniac, le temps de contact est de préférence d'environ 1 heure; lorsque l'on veut préparer un produit de formule ID, le temps de contact est de préférence d'environ ` 6 heures. On opère de préférence dans un solvant tel que le tétrahydrofuranne.
Le borohydrure ou cyanoborhydrure alcalin utilisé
pour la réduction du produit de formule IB est par exemple i ~;, . .

~L~; f~

le cyanoborohydrure de potassium ou de sodium, ou de preference le borohydrure de sodium.
Le borohydrure alcalin utilisé en complexe avec la pyridine est de preférence le borohydrure de sodium. On utilise comme milieu réactionnel de preference un alcanol renfermant au plus 5 atomes de carbone, tel que l'~thanol.
,!

f 19~
L'halog~nation des produits de formules (IA~ ), (Ic)~
(ID) ee tIE~ peut être realisée, par exemple, ~ lla;de du complexe bromé de la pyridine de formule :

~N~!J , Br2 ~ H~3r dans le cas de la bromation. Elle est realisée avantageusement à l'aide d'un N-halo succ;nimide~ de préf~rence le N-bromo ou le N-chloro succ;nimide ~ on opere dans le dioxanne ou de préférence dans l'ac;de acet;que. Le produ;t de formule (IY) obtenu est de pr~ference un 15 produit chloré.
L'hydrolyse du produit de formule (IV) est real;s~e, de préférence ~ lla;de d'un acide minéral tel que l'acide phosphorique, l'acide sulfurique, ou de preférence l'ac;de chlorhydrique en solut;on aqueuse. Cette solut;on peut être utilis~e concentrée~ mais de 20 préférence diluée par exemple en solut;on 1N. On peut utiliser~ en outre, un solvant tel qu'un alcool aliphat;que comme l'~thanol.
La présente invention a également pour objet une var;ante du procedé ci-dessus d~crit~ caractérisée en ce que l'on effectue sur le deriv~ de ~ormule II les d;ff~rentes opérations prévues pour 25 transformer le derivé de fDrmule IA en der;v~s de formules I
Ic, ID, IE et IF, puis fait reag;r les produ;t ainsi obtenus avec le d~rivé de formule III.
Dans des conditions préférent;elles de mise en oeuvre, le proc~d~ ~i-dessus d~cr;t est caractér;sé en ce que le d~rive de 30 formule II est prépare par reaction d'un indole de formule ~ :

H~C~
(V) dans laquelle R2 a la signfication déjà indiquee, avec un dérive de 40 formule VI :

~L~'7~

CH~ G

~ H (VI) pour obten;r un dérivé de formule VII :

~ OH
10 ~ ~
(VII) f~

; dans laquelle R2 a la sign;f;cat;on déj~ ind;quée, que l'on fait reagir avec un dér;v~ halog~n~ un d~rivé hydroxylé, ou un sulfonate dudit dérivé hydroxylé d'un halogénure d'alkylène de formule VIII:
-A-Hal VIII

dans laquelle A et Hal ont la signification dej3 indiquee, pour obten;r le dériv~ de formule II desir~.
La réaction entre l'indole de for~ule V et le dérivé de formule VI est realisée de preférence en nilieu alcanol;que, notamment ~thanoliqueO en présence dlun agent alcal;n, tel que la soude ou de préférence la potasse. On opère avantageusement en présence d'un sel d'ammon;um quaternaire tel que le chlorure de tri~thylben2yl ammonium.
La reaction entre l'indole de formule V et le dérivé de formule VI peut être auss; réalisée par transfert de phase en utilisant comme phase aqueuse de préférence une solution aqueuse d'un hydroxyde alcalin tel que l'hydroxyde de potassium ou de sodium~ et comme phase organique non misc;ble à l'eau un solvant tel que le benzène, en présence 35 d'un agent de transfert tel qu'un sel d'ammonium quaternaire de tétrabutyl ammonium, notamment le bromure ou l'hydrogénosulfate.
Lorsque l'on utilise un dérivé halogéné d'un halogénure d'aLkylène de formule VIlI, il est préférable d'utiliser deux halogènes différents pour éviter la condensation de deux molécules de produit de for~ule 40 VII. C'est ainsi que, par exemple~ pour Hal representant un atome ~L~7~

de chlore~ on choisira comme dérive halog~ne un derive plus reactif tel que Le bro~ure.
On peut aussi ueiliser un dér;v~ hydroxyl~ d'un halogenure d'alkylène de formule VIII répondant a la formule VIII':

H0-A-Hal VIII' dans laquelle A et ~al ont la signification déjà indiqu~e, pour le faire reagir avec le dér;ve de formule VII. On opere alors de 1O préference en présence de triph~nyl phosphine et dlazodicarboxylate d'éthyle dans le tétrahydrofuranne.
Avantageusement, on utilise un sulfonate du dériv~ de formule VIII'; dans ce cas~ de préferenre, on utilise comme sulfonate du dér;v~ hydroxylé de l'halo~énure d'alkylène de formule 15 VIII' son tosyiate de formule VIII":

TsO-A-Ha l VI I I "

dans laquelle TS représente un radical tosyle et A et Hal ont 20 la signification d~j~ indiquée.
On opere alors par transfert de phase, dans les cond;tions decrites ci-dessus.
La présente invention a en outre pour objet une variante du proc~de c;-dessus décrit~ caractér;sée en ce que l'on effectue sur le 25 dér;vé de formule VII les différentes opérations prevues pour transformer le dériv~ de formule IA en dérivés de formule IB, Ic, ID, IE et IF, puis fait réagir les différents produits ainsi obtenus avec le derivé de formule VIII.
Dans d'autres condit;ons préférentie~les, le procéde de préparation 30 des dérivés de formule I ci-dessus d~crit est caractérisé en ce que le dériv~ de formule II est préparé par reaction d'un indole de formule V :
H o ~c~

~ I (v) I

dans laquelle R2 a la signification déja indiquée, avec un derive de ~~ 40 formule IX :

H~

~3~0-A-Ha 1 ( IX ) dans laquelle Hal a la s;gnification déjà indiqu~e, pour obten;r le d~rivé de formule II desire.
La reaction de l'indole de formule V avec le d~riv~ de formule IX
10 est réalisee de preférence en présence dlune base telle que la soude ou la potasse.
Les deriv~s de ~ormule I presentent un caract~re bas;que. On peut ; avantageusement préparer les sels d'addition des dériv~s de formule I, en fa;sant réagir, en proportions sensiblement stoechiométriques, un 15 acide mineral ou organ;que avec ledit dérivé de formule I~ Les sels peuvent être préparés sans isoler les bases correspondantes.
Les sels d'addition avec les acides minéraux ou organiques peuvent être, par exemp(e " es sels formés avec les ac;des chlorhydrique, bromhydrique, nitrique, sulfurique~ phosphorique, 20 acétique, formique, propionique, benzo;que, mal~ique, fuMarique, succinique, tartrique, c;trique, oxal;que, glyoxylique, aspartique, alcane sulfoniques tels que les ac;des m~thane et éthane sulfon;ques, arylsulfoniques, tels que les ac;des benz~ne et paratoluène sulfoniques et arylcarboxyliques.
Les dériv~s de formule I possèdent de très interessantes propriét~s pharmacologiques ; ils sont doués notamment de remarquables proprietes antiarythmiques et bloquantes de canaux calcicosodiques lents. Ces propriét~s sont illustrées plus loin dans la part;e experimentale.
Les dérivés de formule I trouvent leur emploi, par exemple dans le traitement de l'insuffisance card;aque, de l~angor sous toutes ses formes et dans le traitement des arythmies.
La dose usuelle, variable selon le dér;vé util;sé, le sujet et l'affection en cause peut être par exemple, de 5û mg à 1 9 par jour.
35 Par voie orale, chez l'homme, le dér;vé de l'exemple 8 Peut être administre à la dose quotid;enne de 20û mg à 80û mg~ par exemple pour le traitement des arythmies ventriculaires~ supraventiculaires et jonctionnelles, soit env;ron de 3 mg à 12 mg par kiJogramme de poids corporel.
4û A t;tre de médicaments, les der;ves répondant à la formule I

1 0 ~ .9';i~

et leurs sels d'addition avec les acides pharmaceutiquement acceptables peuvent ~tre ;ncorpor~s dans des compositions pharmaceutiques destin~es la voie digestive ou parent~rale.
Ces compositions pharmaceutiques peuvent être, par exemple, 5 solides ou liquides et se présenter sous les formes pharmaceutiques couramment utilis~es en médecine hu~a;ne, comme par exemple, les compr;mes, simples ou dra~eifi~s, les ~elules, les granules~ les suppositoires, les pr~parations injectables ; elles sont pr~par~es selon les m~thodes usuelles. Le ou les principes actifs peuvent y être 10 incorporés à des excipients habituellement employes dans ces compositions pharmaceutiques, tels que le talc, la gomme arabique " e lactose, l'amidon, le stéarate de magn~sium " e beurre de cacao, les v~hicules aqueux ou non, les corps gras d'origine animale ou végétale, les d~riv~s paraffiniques, les glycols, les d;Yers agents mou;llants, 15 dispersants ou ~mulsifiants, les conservateurs.
~ e proc~dé de l'invention permet de préparer des intermédiaires nouveaux, à savoir les dérivés de formule II':
x ¦ l _~ O-A-Hal Y~l~
~J (II') N ~
a dans laquelle Hal représente un atome de chlore, de brome ou d'iode, et 30 A, R2, a, b, c~ x, y et le pointille ont la signification déjà
indiquée, et de formule VII':
x~ OH

~' ~ C
¦ a ~2 dans laquelle R2t a, b, c, x~ y, et le po;ntill~ ont la signification d~jà indiqu~e.
Les exemples qu; su;vent illustrent la présente invention, sans toutefois la limiter.
5 Exemple n~ /?-/2~ di~thyl~thyl? a~ino~ ~thoxy/ph~nyl/ 2 ~ using as solvent the amine of formula III itself ~
When you want to prepare a Formula product `; IB from a product of formula IA per sodium action in ammonia, the contact time is preferably about 1 hour; when you want to prepare a product of formula ID, the contact time is preferably approximately `6 hours. It is preferably carried out in a solvent such as tetrahydrofuran.
The alkali borohydride or cyanoborhydride used for reduction of the product of formula IB is for example i ~ ;,. .

~ L ~; f ~

potassium or sodium cyanoborohydride, or preferably sodium borohydride.
The alkaline borohydride used in complex with the pyridine is preferably sodium borohydride. We preferably uses an alkanol as reaction medium containing at most 5 carbon atoms, such as ~ thanol.
,!

f 19 ~
The halogenation of the products of formulas (IA ~), (Ic) ~
(ID) ee tIE ~ can be realized, for example, ~ lla; de of the complex pyridine bromine of formula:

~ N ~! J, Br2 ~ H ~ 3r in the case of bromination. It is advantageously carried out using a N-halo succ; nimide ~ preferably ~ N-bromo or N-chloro succ; nimide ~ one operates in dioxane or preferably in ac;
acet; as. The product of formula (IY) obtained is preferably a 15 chlorine product.
The hydrolysis of the product of formula (IV) is real; s ~ e, of preferably ~ lla; of a mineral acid such as phosphoric acid, sulfuric acid, or preferably ac, hydrochloric acid in solution;
aqueous. This solut; we can be used ~ e concentrated ~ but of 20 preferably diluted, for example in solution; 1N. We can use ~ en addition, a solvent such as an aliphat alcohol; as like ~ thanol.
The present invention also relates to a var; ante of above process d ~ crit ~ characterized in that one performs on the deriv ~ de ~ ormule II les d; ff ~ rentes operations planned for 25 transform the derivative of fDrmule IA into der; v ~ s of formulas I
Ic, ID, IE and IF, then reacts the products thus obtained with the d ~ rivé of formula III.
In preferred conditions, they of implementation, the proc ~ d ~ ~ above d ~ cr; t is characterized; sé in that the d ~ bank of 30 formula II is prepared by reaction of an indole of formula ~:

H ~ C ~
(V) in which R2 has the meaning already indicated, with a derivative of 40 formula VI:

~ L ~ '7 ~

CH ~ G

~ H (VI) to obtain; r a derivative of formula VII:

~ Oh 10 ~ ~
(VII) f ~

; in which R2 has the sign; f; cat; we already indicated; that we do react with a der; v ~ halog ~ n ~ a d ~ rivé hydroxylé, or a sulfonate of said hydroxylated derivative of an alkylene halide of formula VIII:
-A-Hal VIII

in which A and Hal have the meaning of j3 indicated, for get; r the derivative ~ of formula II desire ~.
The reaction between indole for ~ ule V and the derivative of formula VI is carried out preferably in nilieu alkanol; that, in particular ~ thanolicO in the presence of an alkaline agent; n, such as sodium hydroxide or preferably potash. It is advantageous to operate in the presence of a salt ammonium; quaternary um such as tri chloride ~ thylben2yl ammonium.
The reaction between the indole of formula V and the derivative of formula VI can also be; performed by phase transfer using as aqueous phase preferably an aqueous solution of an alkali hydroxide such as potassium or sodium hydroxide ~ and as an organic phase immiscible; ble in water a solvent such as benzene, in the presence 35 of a transfer agent such as a quaternary ammonium salt of tetrabutyl ammonium, especially bromide or hydrogen sulfate.
When using a halogenated derivative of an alkylene halide of formula VIlI, it is preferable to use two different halogens to avoid condensation of two molecules of for ~ ule product 40 VII. This is how, for example ~ for Hal representing an atom ~ L ~ 7 ~

of chlorine ~ we will choose as halog drift ~ do a more reactive drift such as Le bro ~ ure.
We can also use a der; v ~ hydroxyl ~ of a halide of alkylene of formula VIII corresponding to formula VIII ':

H0-A-Hal VIII ' in which A and ~ al have the meaning already indicated, for the react with the der; ve of formula VII. We then operate from 1O preference in the presence of triph ~ nyl phosphine and dlazodicarboxylate ethyl in tetrahydrofuran.
Advantageously, a sulfonate of the derivative of formula VIII '; in this case ~ of preference, we use as sulfonate of der; v ~ hydroxylated halo ~ alkylene enure of formula 15 VIII 'his tosyiate of formula VIII ":

TsO-A-Ha l VI II "

in which TS represents a tosyle radical and A and Hal have 20 the meaning already indicated.
We then operate by phase transfer, under the conditions;
described above.
The present invention further relates to a variant of the proc ~ of c; above described ~ characterized; sée in that one performs on the 25 der; vé of formula VII the different operations planned for transform the derivative of formula IA into derivatives of formula IB, Ic, ID, IE and IF, then reacts the different products thus obtained with the derivative of formula VIII.
In other condit; we prefer ~ les, the preparation process 30 derivatives of formula I above d ~ crit is characterized in that the derivative of formula II is prepared by reaction of an indole of formula V:
H o ~ c ~

~ I (v) I

in which R2 has the meaning already indicated, with a derivative of ~~ 40 formula IX:

H ~

~ 3 ~ 0-A-Ha 1 (IX) in which Hal has the meaning already indicated, to obtain the d ~ rivé of formula II desire.
The reaction of the indole of formula V with the d ~ riv ~ of formula IX
10 is preferably carried out in the presence of a base such as soda or potash.
The derivatives of ~ ormule I have a low character; We can ; advantageously prepare the addition salts of derivatives of formula I, by reacting, in substantially stoichiometric proportions, a 15 mineral or organ acid; only with said derivative of formula I ~ The salts can be prepared without isolating the corresponding bases.
Addition salts with mineral or organic acids can be, for example (e "es salts formed with ac; des hydrochloric, hydrobromic, nitric, sulfuric ~ phosphoric, 20 acetic, formic, propionic, benzo; that, mal ~ ique, fuMarique, succinic, tartaric, cric, oxal; que, glyoxylic, aspartic, sulfonic alkane such as ac; m ~ thane and ethane sulfon; ques, arylsulfonic, such as ac; benz ~ ne and paratoluene sulfonic and arylcarboxylic.
The derivatives of formula I have very interesting pharmacological properties; they are gifted with remarkable antiarrhythmic and blocking properties of calcium calcium channels slow. These properties are illustrated further in the part; e experimental.
The derivatives of formula I find their use, for example in the treatment of heart failure; aque, angina in all its forms and in the treatment of arrhythmias.
The usual dose, which varies according to the dose used, the subject and the condition in question can be, for example, from 5 mg to 19 mg per day.
35 Orally, in humans, the derivative of Example 8 Can be administered at the daily dose; as of 20 mg to 80 mg ~ for example for treatment of ventricular arrhythmias ~ supraventicular and junctional, about 3 mg to 12 mg per kg of weight bodily.
4û At t of drugs, the derivatives corresponding to formula I

1 0 ~ .9 '; i ~

and their addition salts with pharmaceutically acceptable acids can be incorporated in pharmaceutical compositions intended the digestive or parenteral route.
These pharmaceutical compositions can be, for example, 5 solid or liquid and come in pharmaceutical forms commonly used in hu ~ a medicine; do, for example, compr; mes, simple or dra ~ eifi ~ s, ~ elules, granules ~
suppositories, injectable preparations; they are ready according to the usual methods. The active ingredient (s) can be there 10 incorporated into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic "e lactose, starch, magnesium stearate, cocoa butter, v ~ hicules aqueous or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, dyers, soft agents, 15 dispersants or ~ emulsifiers, preservatives.
~ e proc ~ die of the invention allows to prepare intermediaries new, namely the derivatives of formula II ':
x ¦ l _ ~ OA-Hal Y ~ l ~
~ J (II ') N ~
at in which Hal represents a chlorine, bromine or iodine atom, and 30 A, R2, a, b, c ~ x, y and the dotted line have the meaning already indicated, and of formula VII ':
x ~ OH

~ ' ~ C
¦ a ~ 2 in which R2t a, b, c, x ~ y, and po; ntill ~ have the meaning already indicated.
The examples that; su; vent illustrate the present invention, without however limit it.
5 Example n ~ /? - / 2 ~ di ~ thyl ~ thyl? a ~ ino ~ ~ thoxy / ph ~ nyl /

3-/1H- ~ !3-d~hydroxy butane dioate acide ~ n chauffe ~ t20nc pendant 17 heures un melange de 71 mg de 1-/2-(2-chloroéthoxy) phènyl/ 3-/1H-indol-4-yl/ 2-propèn-1-one, de 10 30 mg de carbonate de potassium, et de 0,23 cm3 de terbutylamine dans 1~5 cm3 de N,N-dimèthylformamide, dilue à l'eau, extrait ~ l'acétate d'éthyle, lave à l'eau, sèche, amène ~ sec, purif;e par chromatograph;e sur silice (~luant acétate d'éthyle-triéthylamine 9-1) et obtient 40 mg du produ;t attendu.
15 Formation du ~) 2,3-dihydroxy butane-dioate acide.
On ajoute a 800C sous ag;tation 1,24 g d'acide DL tartrique à une solution de 3 g de base ci-dessus dans 159 cm3 dlisopropanol et 50 cm3 de méthanol, maint;ent à 80~C pendant 20 mn, ~vapore le solvant, reprend par un mélange de 45 cm3 de methanol et SO cm3 d'isopropanol en 20 présence d'un peu de pentane et laisse cristalliser~
On f;ltre et sèche à 80~C sous press;on r~duite les cristaux obtenus, et obtient en 2 jets 2,83 9 du produ;t attendu.
F~ ~ 172UC
Analyse (1er jet) pour C23H~6N20~C4H66 512,564 25 Calculé CX 63,27 HX 6,29 ~ 5,46 Trouv~ b3,3 6,6 5,5 Exem~le nn 2 . 1-/2-(3-chloropropoxy) ph~nyl/ 3-~1H-indol-4-yl/
~e~e~
Stade A : 3-(1H-indol-4 yl) 1-(2-hydroxyphényl) 2-propèn-1-one 3û On ajoute à 30~C sous agitation et atmosphère inerte 0,5 cm3 de potasse à 38 X à un mélange de 0,132 9 d'indole 4-carboxaldehyde, de 0,1 cm3 de 2-hydroxyacétophenone et de 0,189 9 de chlorure de triéthylbenzyl ammonium dans 2 cm3 d'ethanol. Après 23 h d'agitation à 3~oc, on dilue à l'eau, extrait à l'acetate d'èthyle~ lave à l'eau, 35 sèche,amène à sec, purifie par chromatographie sur silice (éluant :
chlorure de m~thylène) et obtient 159 mg du produit attendu.
F~ ~ 164~C
Stade B : 1-/2-(3-chloropropoxy) phényl/ 3-/1H-indol-4-yl/2-propèn-1-one On ajoute 2 cm3 de soude ~ sa x à un melange de 100 mg de produit du stade A, 94 mg de 3-chloropropyl paratoluène sulfonate et 54 mg de sulfate de tretabutylammon;um dans 2 cm3 de benzène et 2 cm3 d'acétonitrile.
S Après 6 heures d'agitation a 80~C, on decante, extrait a l'acétate d'éthyle, lave à l'eau, sèche, am~ne ~ secr purifie par chromatographie sur sil;ce ~luant chlorure de methylène~ et obtient b8 mg du produ;t attendu.
Spectre UV : (~thanol) max 218 nm E 1 951 = 32 300 " 266 nm E11 390 ~ = 13 300 15infl 342 n~ E11 269 max 389 nm E11 424 ~ = 14 40û

Exemple n~ 3 1-/2-(2-chloro~thoxy) ~he~ 3-/1H-indol~
2-prop~n-1-one On ajoute sous atomosphère ;nerte 0,4 cm3 de soude a 50 %
à une solut;on de 278 mg de 1-/2-(2-chloro~thoxy) phényl/ éthanone dans 3 cm3 d'éthanol, puis ajoute 200 mg d'indole-4-carboxaldehyde.
Après 30 h d'ag;tat;on, on d;lue ~ l'eau, extrait 3 l'acétate 25 d'~thyle, lave à l'eau~ sèche, amène à sec, purifie par chromatographie sur silice (Eluant chlorure de m~thylène) et obt;ent 142 mg du produ;t attendu.
Spectre UV : (éthanol~

30 max 215 nm E11 925 ~ = 30 100 max 268 nm E11 397 = 12 ~00 infl 340 nm E11 255 max 390 nm E11 434 ~ = 14 100 Exemple n~ 4 : 1-/2-!2~ dim~thyl~thyl? amino/ ethoxy/ ph~nyl/
3-!1H-indol-4-yl/ 1-propanone et son chlorhydrate On hydrogène 3,218 g de base de l'exemple 1 en presence de 13 ~L~v7~

1,1 9 charbon palladi~ ~ 10 X dans 3~0 cm3 de rethanol, filtre, amène à sec sous pression ~duiter lave avec 7 cm3 d'isopropanol, filtre, sèche sous pression reduite et obtient en 2 jets 2,35 g du produit attendu.
5 F~ ~ 112~C
Formation du chlorhydrate :
On ajoute 4 cm3 d'une solution d'acetate d'éthyle chlorhydrique à
une suspens;on de 2,25 9 de base c;-dessus dans 70 cm3 d'isopropanol, agite, filtre, sèche a 80~C et obt;ent 2,38 9 du produit attendu.
10 F~ ~ 250~C
Analyse pour C23H2gN202, HCl = 400,952 Calculé C% 68,9 HX 7,29 NX 6,99 Cl% 8~84 Trouv~ 68,9 7,5 6,9 8,7 Exemple n~ 5 : ~ -/2-/2-/(1,1-di~thylethyl) amino/ ~thoxy/
15 Dhem l/-1H-indole-4-DroDanol et son ~E) but~ne dioate neutre On ajoute 0,934 9 de borhydrure de sodium à une solution de 3 9 de base de l'exemple 4 dans 90 cm3 de methanol, agite 20 mn sous atmosphère inerte, ajoute de l'eau glac~e, extrait à l'ac~tate d'ethyle~ lave à l'eau, sèche, amène à sec, et obtient 2,79 9 d~l produit 20 attendu.
Formation du ~E) but~ne dioate n~utre :
On ajoute sous agitation 0,8b2 9 d'acide fumarique à une solution de 2,73 9 de base ci-dessus dans 70 cm3 d'isopropanol, ajoute 3 nouveau 20 cm3 d';sopropanol et amorce la cristallisation. Apres 16 h Z5 à ~4~C on filtre, s~che à 80~C sous press;on r~du;te, et obtient 2,5 9 du produ;t attendu~
F~ ~ 190nC
AnalYse pour tC23*3~N202)2~ C4H404 849~089 Calculé C% 70,73 H% 7,60 NX 6,60 30 Trouve 70,5 7,8 6,5 Exemple nn 6 : N - /2-/2-/3-(1H-indol-b-yl? propy l / eh~noxy /
ethyl~ 2-m~thyl-2~propanamine On ajoute une solution de 31 mg de base de l'exemple 5 dans 2 cm3 de tetrahydrofuranne à 3 cm3 d'ammoniac à -78nc, ajoute 35 100 mg de sodium à -40~C sous atmosphère inerte. Après 1 h d'agitation, on ajoute 800 mg de chlorure d'ammonium à -40nc, laisse évaporer a temperature ambiante, dilue à l'eau, extrait à l'acétate d'ethyle, lave à l'eau, sèche, filtre, évapore le solvant, ajoute un peu de pentane, filtre, sèche, et obtient 22 mg du produit attendu.
~0 F~ ^~ 112~C

; 14 Exemple n~ 7 : 1-/2-t2-~(1,?-dimethyl~
3-/1H-indol-4-yL~2~pro~n-1-ol On ajoute 1,t cm3 de pyridine et 624 mg de borohydrure de sodium sous ato~osphère inerte, à une solution de 1,5 g de base de produit de 5 l'exemple 1 dans 35 cm3 d'éthanol, agite pendant 15 mn à 70nc, ajoute de l'eau, refroidit, extra;t à l'acétate d'~thyle, lave à l'eau, sèche sur d~shydratant, amène à sec, purifie par chromatographie sur silice ~éluant ac~tate d'èthyle-triéthylam;ne 9 1) et obtient 1,32 9 du produit attendu.
10 Spectre UV (éthanol) max : 221 nm E11 685 c = 24 968 infl : Z33 nm E11 533 infl : 276 nm E11 151 ; infl : 285 nm E11 186 20 infl : 292 nm E11 219 max : 308 nm E11 267 ~ = 9 732 Exeme~e n~ 8 : N-/2~2-/3-(1H-indol-4-yl~ pnopyl/ ph~noxy/ ~thyl/
25 2-m~thyl-2-propana~ine et son (E) butène dioate neutre A 3a cm3 d'ammoniac à -78DC, on ajoute une solution de 3,94 9 de produit de l'exemple 7 dans 25 cm3 de tétrahydrofuranne, porte le mélange à -40~C, aioute 4,2 9 de sodium , poursuit l'agitation pendant 2 h sous atmosphère inerte, ajoute 36 9 de chlorure d'ammonium à -40UC, laisse 3û évaporer, dilue a l'eau en refroidissant, extrait à l'acètate d'éthyle, lave à l'eau, sèche, filtre, amène à sec, lave à l'isopropanol, sèche sous pression réduite et obtient 2,43 9 du produit attendu.
F~ ~ 114~C
Formation du ~E) but~ne dioate neutre A une solution de 2~4 9 de base ci-dessus, dans 90 cm3 d'éthanol on ajoute sous agitation 0,795 9 d'acide fumarique, concentre, amorce la cristallisation, abandonne 16 h ~ +4nc, filtre, sèche sous pression réduite, et obtient 1,67 9 du produit attendu.
F~ ~ 190~C

1;~ 7~ 7 Analyse pour C23H30~20 ~ C4H40~) = 408~545 Calculé C X n~so HX 7089 NX 6,86 Trouvé 73,3 7,9 7,2 5 Exemple n~ 9 : 1-/2-hydroxy~hen~l/3-/1H-indol-~-yl/ l-propanone On hydrogene jusqu'3 fin d'absorption 200 mg de produit du stade A
de l'exemple 2 dans 10 cm3 de méthanol en présence de charbon palladi~, filtre, évapore le m~thanol, purif;e par chromatographie sur s;lice ~Eluant : cyclohexane-dichloromethane-tr;éthylamine 6-3-1), et obtient 10 143 mg du produit attendu.
F~ ~ 143rlC
Spectre W (ethanol) max 214 nm E112 080 _ = 55 200 max 254 nm E115~5 ~ = 14 700 ;nfl 275 nm E1~2~5 20 ;nfl 28~ nm E1l220 max 323 nm E11117 ~= 4 700 Exemple nn 10 :
On a préparé des compr;més r~pondant a la formule :
- (E) buténe dioate neutre de la N-/2-/2-/3-(1H-;ndol-4-yl) propyl/ phénoxy/ ~thyl/
2-méthyl-2-propanam;ne ~ 100 mg ;
- Excipient q.s. pour un comprimé term;né ~ ............ 150 mg.
30 (Détail de l'excipient : lactose, am;don, talc~ stéarate de magnés;um).
Exemple n~
On a prépare des comprimes repondant à la formule :
- chlorhydrate de la 1-/2 /2-/(1,1-diméthyléthyl) amino/
éthoxy/ phényl/ 3-/1H-indol-4-yl/1-propanone ..... 0. 100 mg ;
35 - Excipient q.s. pour un comprime terminé a .~.......... 150 mg.
(Détail de l'excipient : lactose, amidon, talc, stéarate de magnésium).
Etude pharmacolo~ique 1) Action antiarythmique chez le rat On trachéotomise des rats mâles pesant 300-350 9 anesthesies par . 40 vo;e intrapéritoneale a l'aide de 1~ZO g/kg d'uréthane et les soumet à

711~

une respiration artific;elle (40-50 insufflations de 3 ml/minute).
On implante des a;gu;lles en sous cutan~ de man;~re à enreg;strer l'électr~card;ogramme des rats sur le signal en derivation DII.
On administre les produits 3 tester par voie intraveineuse ou par 5 voie orale.
Cinq minutes après l'adm;nistration du produ;t, on perfuse la veine jugulaire des rats avec 10 ~ g/mn d'une solut;on d'aconit;ne et on note le temps d'appar;t;on des troubles du rythme cardiaque ~10 Jus d'acon;tine correspondant à la perfus;on d'un volume de 0,2 ml de 10 solut;on).
Les r~sultats sont expr;més en pourcentage d3allongement du temps d'apparition des troubles du rythme card;aque par rapport au~ témoins et en fonction de la dose du produit test~.
Les r~sultats f;gurant sur le tableau ci-après montrent que les 15 produits de la presente demande sont doués de remarquables propri~tés ant;arythmiques.

¦ Produit de l'exemple ¦ Dose ¦ Pourcentage d'allongement I _ _ voie ~ du temps _ ¦ 1IV ¦ 0,5 mg/kg¦ 26 ¦ PO l10 mg/kgl 41 ¦ 4IV ¦ 2,5 m~/k~¦ 40 25 I PO l25 mg/kgl 32 ¦ 5IV I 0,05 mg/kg¦ 36 I PO I 5 mg/kgl 38 30 ¦ 8IV ¦ 2,5 ~g/kg¦ 49 I PO l25 mg/kgl 40 2) Test d'act;vité ant;calcique ;n vitro Des artères caudales de rat découpées en spirale sont reliees à des capteurs de tens;on et sont maintenues dans des cuves de 25 ml de tampon Krebs-b;carbonate de sodium (NaCl : 120,8 mM, KCl : 5,9 mM, MgCl2 :
1,2 mM, NaH2P04 : 1,2 mM, ~aHC03 : 15~5 mM, glucose : 12,6 mM) à
37~C gazees avec un mélange 2 : 95X - C02 : 5~.

1~ 7~ 1~3 7 Les pr~parations sont d~polaris~es par une solution tampon à
concentration 100 mM en ions K+ ~NaCl : 26,7 mM, KCl : 100 mM, MgCl2 1~2 mM, NaH2P04 : 1,2 mM~ NaHC~ : 15,5 mM, glucose : 12~6 mM).
On ajoute, de 250JuL de solutions de chlorure de calcium, de maniere 5 obtenir une gamme de concentrations croissantes en ions Ca2~ allant de 0~1 ~ 3,0 mM ; on enregistre les contractions des artères et établit ainsi une gamme temoin. On rep~te l'op~ration avec la gamme d'ions Ca2~ toutes les ~5 minutes et la pr~paration est lavée quatre fois apr~s chaque gamme.
Lorsque l'on obtîent une réponse stable, l'on effectue l'opération avec les gammes d'ions Ca2~ en pr~sence de d;fférentes concentrations du prod~it à tester, jusqu'a ce qu'une réponse stable soit obtenue.
~ es contract;ons des artères dépendent de l'entr~e des ions Ca2+
dans les cellules des muscles lisses et sont provoquées par la 15 dépolar;sat;on du muscle lisse par les ions K~ et par l'action de la noradrénaline l;bérée au niveau pr~synaptique. En recommenSant L'op~rat;on avec des art~res dénervées par action de 6-OH dopamine, on supprime l'action propre due ~ la noradr~naline.
Les resultats sont exprimés en CI 50 ~concentrat;on ;nh;bitr;ce 50) 20 concentration du produit testé qui inhibe de 50 % la contract;on due aux ions K~.
On constate d'apres les résultats f;gurant sur le tableau c;-apr~s que les produits de la pr~sente demande possedent une forte act;vité
anticalcique.

¦ Produit de l'exemple ¦ CI 50 en ~M

1 1 ¦ 1,9 3û 1 4 1 0,8 ¦ 5 ¦ 1,9 1 8 1 û,8 1, , I

3) Etude de la toxicit~ a;gue On a evalué les doses létales DLo des différents composés testés après admin;stration par voie orale chez la souris.
On appelle DLo la dose max;male ne provoquant aucune mortalite - 40 en 8 jours.

~a l~t~

Les r~sultats obtenus sont les suiv~nts:

Produ;t de l'exemple ¦ DLo en mg~kg 1 1 1 > 400 3- / 1H- ~! 3-d ~ hydroxy butane acid dioate ~ n heats ~ t20nc for 17 hours a mixture of 71 mg of 1- / 2- (2-chloroethoxy) phenyl / 3- / 1H-indol-4-yl / 2-propen-1-one, from 10 30 mg potassium carbonate, and 0.23 cm3 terbutylamine in 1 ~ 5 cm3 of N, N-dimethylformamide, diluted with water, extract ~ acetate ethyl, wash with water, dry, bring ~ dry, purifying; e by chromatography; e on silica (~ glowing ethyl acetate-triethylamine 9-1) and obtains 40 mg of expected product.
15 Formation of ~) 2,3-dihydroxy butane-dioate acid.
1.24 g of DL tartaric acid is added at 800 ° C. with agitation to a solution of 3 g of base above in 159 cm 3 of isopropanol and 50 cm3 of methanol, now; ent at 80 ~ C for 20 min, ~ vaporizes the solvent, taken up in a mixture of 45 cm3 of methanol and SO cm3 of isopropanol in 20 presence of a little pentane and leaves to crystallize ~
We filter and dry at 80 ~ C under press; we reduce the crystals obtained, and obtains in 2 jets 2.83 9 of the expected product.
F ~ ~ 172UC
Analysis (1st draft) for C23H ~ 6N20 ~ C4H66 512,564 25 Calculated CX 63.27 HX 6.29 ~ 5.46 Found ~ b3.3 6.6 5.5 Example ~ nn 2. 1- / 2- (3-chloropropoxy) ph ~ nyl / 3- ~ 1H-indol-4-yl /
~ e ~ e ~
Stage A: 3- (1H-indol-4 yl) 1- (2-hydroxyphenyl) 2-propen-1-one 3. Add 0.5 cm 3 of agitation and an inert atmosphere at 30 ° C.
potash at 38 X to a mixture of 0.132 9 of indole 4-carboxaldehyde, 0.1 cm3 of 2-hydroxyacetophenone and 0.189 9 chloride triethylbenzyl ammonium in 2 cm3 of ethanol. After 23 h of agitation at 3 ~ oc, diluted with water, extracted with ethyl acetate ~ washed with water, 35 dry, bring to dry, purify by chromatography on silica (eluent:
chloride of m ~ thylene) and obtains 159 mg of the expected product.
F ~ ~ 164 ~ C
Stage B: 1- / 2- (3-chloropropoxy) phenyl / 3- / 1H-indol-4-yl / 2-propen-1-one 2 cm3 of sodium hydroxide ~ sa x are added to a mixture of 100 mg of product from stage A, 94 mg of 3-chloropropyl paratoluene sulfonate and 54 mg of tretabutylammon sulfate; um in 2 cm3 of benzene and 2 cm3 acetonitrile.
S After 6 hours of stirring at 80 ~ C, decant, extract at ethyl acetate, washed with water, dried, am ~ ne ~ secr purifies by chromatography on sil; this ~ gleam methylene chloride ~ and obtains b8 mg expected product.
UV spectrum: (~ thanol) max 218 nm E 1,951 = 32,300 "266 nm E11 390 ~ = 13,300 15infl 342 n ~ E11 269 max 389 nm E11 424 ~ = 14 40û

Example n ~ 3 1- / 2- (2-chloro ~ thoxy) ~ he ~ 3- / 1H-indol ~
2-prop ~ n-1-one 0.4 cc of 50% sodium hydroxide is added under an atomosphere; inert to a solut; one of 278 mg of 1- / 2- (2-chloro ~ thoxy) phenyl / ethanone in 3 cm3 of ethanol, then add 200 mg of indole-4-carboxaldehyde.
After 30 h of agatat; on, we read ~ water, extract 3 acetate 25 of ~ thyle, wash with water ~ dry, bring to dry, purify by chromatography on silica (eluent chloride of m ~ thylene) and obtain; ent 142 mg of the product;
expected.
UV spectrum: (ethanol ~

30 max 215 nm E11 925 ~ = 30 100 max 268 nm E11 397 = 12 ~ 00 infl 340 nm E11 255 max 390 nm E11 434 ~ = 14 100 Example n ~ 4: 1- / 2-! 2 ~ dim ~ thyl ~ thyl? amino / ethoxy / ph ~ nyl /
3-! 1H-indol-4-yl / 1-propanone and its hydrochloride 3.218 g of base of Example 1 are hydrogenated in the presence of 13 ~ L ~ v7 ~

1.1 9 carbon palladi ~ ~ 10 X in 3 ~ 0 cm3 of rethanol, filter, brings to dry under pressure ~ duiter washing with 7 cm3 of isopropanol, filter, dries under reduced pressure and obtains 2.35 g of the product in 2 jets expected.
5 F ~ ~ 112 ~ C
Formation of hydrochloride:
4 cm 3 of a hydrochloric ethyl acetate solution are added to a suspension; of 2.25 9 of base c; above in 70 cm3 of isopropanol, stir, filter, dry at 80 ~ C and obtain; ent 2.38 9 of the expected product.
10 F ~ ~ 250 ~ C
Analysis for C23H2gN202, HCl = 400.952 Calculated C% 68.9 HX 7.29 NX 6.99 Cl% 8 ~ 84 Found ~ 68.9 7.5 6.9 8.7 Example n ~ 5: ~ - / 2- / 2 - / (1,1-di ~ thylethyl) amino / ~ thoxy /
15 Dhem l / -1H-indole-4-DroDanol and its ~ E) but ~ ne neutral dioate 0.934 9 of sodium borhydride is added to a solution of 3 base 9 of Example 4 in 90 cm3 of methanol, stir 20 min under an inert atmosphere, add ice water ~ e, extract with ac ~ tate of ethyl ~ washes with water, dries, brings to dryness, and obtains 2.79 9 d ~ l product 20 expected.
Formation of ~ E) goal ~ ne dioate n ~ utre:
0.8b2 9 of fumaric acid are added with stirring to a solution 2.73 9 base above in 70 cm3 of isopropanol, add 3 new 20 cm3 of sopropanol and initiates crystallization. After 4 p.m.
Z5 at ~ 4 ~ C we filter, s ~ che at 80 ~ C under press; we r ~ du; te, and obtains 2.5 9 of the product; t expected ~
F ~ ~ 190nC
Analysis for tC23 * 3 ~ N202) 2 ~ C4H404 849 ~ 089 Calculated C% 70.73 H% 7.60 NX 6.60 30 Found 70.5 7.8 6.5 Example nn 6: N - / 2- / 2- / 3- (1H-indol-b-yl? Propy l / eh ~ noxy /
ethyl ~ 2-m ~ thyl-2 ~ propanamine A solution of 31 mg of base from Example 5 is added to 2 cm3 of tetrahydrofuran to 3 cm3 of ammonia at -78nc, add 35 100 mg of sodium at -40 ~ C under an inert atmosphere. After 1 hour of agitation, 800 mg of ammonium chloride are added at -40nc, allowed to evaporate at room temperature, dilute with water, extract with ethyl acetate, wash with water, dry, filter, evaporate the solvent, add a little pentane, filter, dry, and obtains 22 mg of the expected product.
~ 0 F ~ ^ ~ 112 ~ C

; 14 Example n ~ 7: 1- / 2-t2- ~ (1,? - dimethyl ~
3- / 1H-indol-4-yL ~ 2 ~ pro ~ n-1-ol 1, t cm 3 of pyridine and 624 mg of sodium borohydride are added.
under inert ato ~ osphere, to a solution of 1.5 g of product base 5 Example 1 in 35 cm3 of ethanol, stirred for 15 min at 70 nm, added water, cools, extra; t with ethyl acetate, washing with water, drying on hydrating agent, brings to dryness, purifies by chromatography on silica ~ eluent ac ~ ethyl triethylam tate; ne 9 1) and obtains 1.32 9 of the product expected.
10 UV spectrum (ethanol) max: 221 nm E11 685 c = 24 968 infl: Z33 nm E11 533 infl: 276 nm E11 151 ; infl: 285 nm E11 186 20 infl: 292 nm E11 219 max: 308 nm E11 267 ~ = 9,732 Exeme ~ in ~ 8: N- / 2 ~ 2- / 3- (1H-indol-4-yl ~ pnopyl / ph ~ noxy / ~ thyl /
25 2-m ~ thyl-2-propana ~ ine and its (E) butene dioate neutral To 3a cm3 of ammonia at -78DC, a solution of 3.94 9 of product of Example 7 in 25 cm3 of tetrahydrofuran, bears the mixture at -40 ~ C, aioute 4.2 9 sodium, continue stirring for 2 h under an inert atmosphere, add 36 9 of ammonium chloride to -40UC, leave 3û evaporate, dilute with water while cooling, extract with ethyl acetate, wash with water, dry, filter, bring to dry, wash with isopropanol, dry under reduced pressure and obtains 2.43 9 of the expected product.
F ~ ~ 114 ~ C
Formation of ~ E) but ~ ne neutral dioate To a solution of 2 ~ 4 9 of base above, in 90 cm3 of ethanol 0.795 9 fumaric acid, concentrate, primer are added with stirring crystallization, leaves 16 h ~ + 4nc, filter, dries under pressure reduced, and obtains 1.67 9 of the expected product.
F ~ ~ 190 ~ C

1; ~ 7 ~ 7 Analysis for C23H30 ~ 20 ~ C4H40 ~) = 408 ~ 545 Calculated CX n ~ n / a HX 7089 NX 6.86 Found 73.3 7.9 7.2 5 Example n ~ 9: 1- / 2-hydroxy ~ hen ~ l / 3- / 1H-indol- ~ -yl / l-propanone 200 mg of product of stage A are hydrogenated until the end of absorption.
of Example 2 in 10 cm3 of methanol in the presence of carbon palladi ~, filter, evaporate the m ~ thanol, purified by chromatography on lice ~ Eluent: cyclohexane-dichloromethane-tr; ethylamine 6-3-1), and obtains 10 143 mg of the expected product.
F ~ ~ 143rlC
W spectrum (ethanol) max 214 nm E112 080 _ = 55 200 max 254 nm E115 ~ 5 ~ = 14,700 ; nfl 275 nm E1 ~ 2 ~ 5 20; nfl 28 ~ nm E1l220 max 323 nm E11117 ~ = 4,700 Example # 10:
We prepared tablets; answering the formula:
- (E) neutral dioate of N- / 2- / 2- / 3-(1H-; ndol-4-yl) propyl / phenoxy / ~ thyl /
2-methyl-2-propanam; ne ~ 100 mg;
- Excipient qs for a term tablet; born ~ ............ 150 mg.
30 (Detail of excipient: lactose, am; don, talc ~ magnes stearate; um).
Example n ~
We prepared tablets corresponding to the formula:
- 1- / 2/2 hydrochloride - / (1,1-dimethylethyl) amino /
ethoxy / phenyl / 3- / 1H-indol-4-yl / 1-propanone ..... 0.100 mg;
35 - Excipient qs for a finished tablet a. ~ .......... 150 mg.
(Details of excipient: lactose, starch, talc, magnesium stearate).
Pharmacological study 1) Antiarrhythmic action in rats Male rats weighing 300-350 9 anesthesia are tracheotomized . 40 vo; e intraperitoneal using 1 ~ ZO g / kg of urethane and subjected to 711 ~

an artificial respiration; it (40-50 breaths of 3 ml / minute).
We implant a; gu; lles in subcutan ~ so; ~ re to record; strer the electr card, ogram of the rats on the signal in derivation DII.
Administer the products 3 test intravenously or by 5 oral.
Five minutes after the administration of the product, the jugular vein of rats with 10 ~ g / min of a solution;
note the time of onset; heart rhythm disturbances ~ 10 Juices acon; tine corresponding to the perfus; on a volume of 0.2 ml of 10 solut; on).
The results are expressed as a percentage of time extension onset of cardiac arrhythmia; aque compared to ~ controls and depending on the dose of the test product ~.
The results shown in the table below show that the 15 products of this application are endowed with remarkable properties ant; arrhythmics.

¦ Example product ¦ Dose ¦ Elongation percentage I _ _ track ~ of time _ ¦ 1IV ¦ 0.5 mg / kg¦ 26 ¦ PO l10 mg / kgl 41 ¦ 4IV ¦ 2.5 m ~ / k ~ ¦ 40 25 I PO l25 mg / kgl 32 ¦ 5IV I 0.05 mg / kg¦ 36 I PO I 5 mg / kgl 38 30 ¦ 8IV ¦ 2.5 ~ g / kg¦ 49 I PO l25 mg / kgl 40 2) Activity test; antiquity; calcium; n vitro Spiral-cut rat caudal arteries are connected to blood pressure sensors and are kept in 25 ml vats of buffer Krebs-b; sodium carbonate (NaCl: 120.8 mM, KCl: 5.9 mM, MgCl2:
1.2 mM, NaH2PO4: 1.2 mM, ~ aHC03: 15 ~ 5 mM, glucose: 12.6 mM) at 37 ~ C gased with a mixture 2: 95X - C02: 5 ~.

1 ~ 7 ~ 1 ~ 3 7 The preparations are polarized by a buffer solution at concentration 100 mM in K + ions ~ NaCl: 26.7 mM, KCl: 100 mM, MgCl2 1 ~ 2 mM, NaH2PO4: 1.2 mM ~ NaHC ~: 15.5 mM, glucose: 12 ~ 6 mM).
250 JuL of calcium chloride solutions are added in a manner 5 obtain a range of increasing concentrations of Ca2 ~ ions ranging from 0 ~ 1 ~ 3.0 mM; the contractions of the arteries are recorded and thus established a witness range. We repeat the operation with the range of Ca2 ions all ~ 5 minutes and the preparation is washed four times after each range.
When we get a stable response, we perform the operation with Ca2 ~ ion ranges in the presence of different concentrations of the product to be tested, until a stable response is obtained.
~ es contract; arteries depend on the entry of Ca2 + ions in smooth muscle cells and are caused by the 15 depolar; sat; on of smooth muscle by K ~ ions and by the action of noradrenaline l; béré at the pr ~ synaptic level. Recommencing The op ~ rat; we with art ~ res denervated by the action of 6-OH dopamine, we suppresses the proper action due to norepine.
The results are expressed in CI 50 ~ concentrate; on; nh; bitr; ce 50) 20 concentration of the tested product which inhibits contract 50%;
to K ~ ions.
We can see from the results f; shown in table c; -apr ~ s that the products of the present demand have a strong activity;
anticalcic.

¦ Product of the example ¦ CI 50 in ~ M

1 1 ¦ 1.9 3û 1 4 1 0.8 ¦ 5 ¦ 1.9 1 8 1 û, 8 1,, I

3) Study of toxicity The lethal doses DLo of the various compounds were evaluated tested after admin; oral station in mice.
DLo is called the maximum dose; male causing no mortality - 40 in 8 days.

~ al ~ t ~

The results obtained are as follows:

Product of example ¦ DLo in mg ~ kg 1 1 1> 400

4 1 200 .. . ~ 4 1,200 ... ~

Claims

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

1. Process for the preparation of 4- derivatives phenylpropyl indole, and their salts pharmaceutically acceptable, corresponding to formula (I):
(I) in which R and R1 independently represent one of the other, a hydrogen atom, a linear alkyl radical containing from 1 to 5 carbon atoms, an alkyl radical branched containing 3 to 5 carbon atoms, a radical cycloalkyl containing 3 to 7 carbon atoms, one cycloalkylalkyl radical containing from 4 to 7 atoms of carbon, or an aralkyl radical containing from 7 to 12 atoms of carbon unsubstituted or substituted by 1, 2 or 3 radicals chosen from the group consisting of halogens and ra-methyl, ethyl, methoxy, ethoxy, trifluoromethyl dicals, methylthio, amino and nitro, or R and R1 together form a saturated or unsaturated heterocycle which may contain a second heteroatom selected from the group consisting of atoms of oxygen, sulfur and nitrogen, this nitrogen atom being non substituted or substituted by a linear alkyl radical containing-mant of 1 to 5 carbon atoms, with a phenyl radical or naphthyl, or by an aralkyl radical containing from 7 to 12 carbon atoms, a represents together with b an oxo function, or re-present together with c a carbon-carbon bond, b represents an atom of hydrogen, or together with has an oxo function, c represents a hydrogen atom, or together with a represents a carbon-carbon bond, the dotted line represents the presence or absence of a carbon-carbon, A represents a chain - (CH2) n- in which n can take the values 2,3,4 or 5, R2 represents an atom of hydrogen, a linear alkyl radical containing from 1 to 5 carbon atoms or a branched alkyl radical containing 3 to 5 carbon atoms, x represents a hydrogen atom or a hydroxy group, or together with y, a function oxo, and y represents a hydrogen atom or, together with x, an oxo function; characterized in that:
A) reacting a product of formula (II):
(II) in which Hal represents a chlorine, bromine atom, or iodine, and R2 and A have the meanings already indicated, with a derivative of formula (III):
(III) in which R 'and R'1 have the meaning already indicated for R and R1, where R 'represents a hydrogen atom and R'1 represents a trifluoro acetyl radical, to obtain a product of formula (IA):

(IA) in which A, R ', R'1 and R2 have the meaning already indicated, that in the case where R'1 represents a radical trifluoro acetyl, it is subjected to the action of an agent of cleavage to obtain the corresponding primary amine, and products of formula (IA) that is isolated and if desired, salifies with a pharmaceutically acceptable acid, either it is reduced by the action of hydrogen gas in the presence of a catalyst based on platinum or palladium in a solvent, or by the action of hydrogen gas in the presence of Raney nickel in a solvent, or by action for less than 3 hours, sodium in ammonia within of a solvent, to obtain a product of formula (IB):
(IB) in which A, R, R1 and R2 already have the meaning indicated, that either it is isolated and, if desired, salified with a pharmaceutically acceptable acid, or it is reduced by the action of an alkaline borohydride or cyanoborohydride to obtain a product of formula (IC):

(IC) in which A, R, R1 and R2 already have the meaning indicated, that either it is isolated and, if desired, salified with a pharmaceutically acceptable acid, or it is reduced by action of sodium in ammonia to obtain a product of formula (ID):
(ID) in which A, R, R1 and R2 already have the meaning indicated, which is isolated and, if desired, salified with a pharmaceutically acceptable acid, either reacting said product of formula (IA) with the complex formed between an alkaline borohydride and pyridine, to obtain a product of formula (IE):

(IE) in which A, R, R1 and R2 already have the meaning indicated, that either we isolate, or we reduce to using sodium in ammonia to get a product of formula (ID) which is isolated and, if desired, salified with a pharmaceutically acceptable acid, either reducing said product of formula (IA) using sodium in ammonia to obtain a product of formula (ID) which is isolated and, if desired, salified with an acid pharmaceutically acceptable, then submits, if desired, said products of formula (IA), (IB), (IC), (ID) and (IE) to the action of an agent halogenation to obtain a product of formula (IV):

(IV) in which Hal1 represents a bromine or chlorine atom, and x, y, A, R, R1, R2 and the dotted line have the meaning already indicated, which is subjected to hydrolysis to obtain a product of formula (IF):

(IF) in which x, y, A, R, R1, R2 and the dotted line have the meaning already indicated, which is isolated and, if desired, salifies with a pharmaceutically acceptable acid;
B) (i) - or a product of formula (II) is submitted:

(II) in which A, R2 and Hal have the meaning already indicated, to a reduction by the action of hydrogen gas in presence of a platinum or palladium catalyst in a solvent, or by the action of hydrogen gas in presence of Raney Nickel in a solvent, or by action for less than three hours, sodium in ammonia in a solvent, to obtain a product of formula (IIB) (IIB) in which A, R2 and Hal have the meaning already indicated, that either we isolate, or we reduce by action of an alkaline borohydride or cyanoborohydride for obtain a product of formula (IIC):
(IIC) in which A, R2 and Hal have the meaning already indicated, that either one isolates, or one reduces by action of sodium in ammonia to obtain a product of formula (IID):
(IID) in which A, R2 and Hal have the meaning already indicated, which we isolate, - either reacting said product of formula (II) previously defined, with a complex formed between a alkaline borohydride and pyridine to obtain a product of formula (IIE):

(IIE) in which A, R2 and Hal have the meaning already indicated, that either we isolate, or we reduce to using sodium in ammonia to get a product of formula (IID) as defined above, which is isolated, - either reduce said product of formula (II) previously defined, using sodium in ammonia to obtain a product of formula (IID) as above defined, that we isolate, then submit, if desired, said products of formula III), (IIB), (IIC), (IID) and (IIE) to the action of an agent halogenation to obtain a product of formula (IV '):

(IV ') in which x, y, A, R2, Hal and the dotted line have the meaning already indicated, and Hal1 represents an atom of bromine or chlorine, which is subjected to hydrolysis to obtain a product of formula (IIF):

(IIF) in which x, y, A, R2, Hal and the dotted line have the meaning already indicated, which is isolated; and (ii) reacting said products of formula (II), (IIB), (IIC), (IID), (IIE) and (IIF) previously defined, either with a derivative of formula (III):

(III) in which R 'and R'1 have the meaning already indicated for R and R1, and obtains the sought derivative which we isolate and, if desired, salifies with a pharmaceutically acid acceptable, either with a derivative of formula (III):

(III) in which R 'represents a hydrogen atom and R'1 represents a trifluoroacetyl radical, then submits the product obtained by the action of a cleavage agent to obtain the corresponding primary amine that is isolated and, if desired, salifies with a pharmaceutically acid acceptable; or C) (i) - or a derivative of formula (VII) is submitted:

(VII) in which R2 has the meaning already indicated, at a reduction by the action of hydrogen gas in the presence of a catalyst based on platinum or palladium in a solvent, or by the action of hydrogen gas in the presence of Raney nickel in a solvent, or by action for less than three hours, sodium in ammonia at within a solvent, to obtain a product of formula (VIIB) (VIIB) in which R2 has the meaning already indicated, that or either we isolate, or we reduce by the action of a alkali borohydride or cyanoborohydride to obtain a product of formula (VIIC):

(VIIC) in which R2 has the meaning already indicated, that or either it is isolated, or it is reduced by the action of sodium in ammonia to obtain a product of formula (VIID):

(VIID) in which R2 has the meaning already indicated, which one isolated, - either react the derivative of formula (VII) previously defined, with a complex formed between a alkaline borohydride and pyridine, to obtain a product of formula (VIIE):
(VIIE) in which R2 has the meaning already indicated, that or either isolate or reduce with sodium in ammonia to obtain a product of formula (VIID) such that previously defined, that we isolate, - either reduce said product of formula (VII) previously defined, using sodium in ammonia to obtain a product of formula (VIID) as previously defined, that we isolate, then submits, if desired, said products of formula (VII), (VIIB), (VIIC), (VIID) and (VIIE) to the action of an agent halogenation to obtain a product of formula (IV "):

(IV ") in which x, y, R2 and the dotted line have the meaning already indicated, and Hal1 represents an atom of bromine or chlorine, which is subjected to hydrolysis to obtain a product of formula (VIIF):
(VIIF) in which x, y, R2 and the dotted line have the meaning already indicated, which we isolate (ii) reacting said products of formula (VII), (VIIB), (VIIC), (VIID), (VIIE) and (VIIF) with a halogenated derivative, a hydroxylated derivative, or a sulfonate of said hydroxylated derivative of an alkylene halide of formula (VIII):

- A - Hal (VIII) in which A and Hal have the meanings already indicated, to obtain a product of formula (II '):

(II ') where a, b, c, x, y, A, R2, Hal and the line dotted have the meaning already indicated, which we do react either with a derivative of formula (III):

(III) in which R 'and R'1 have the meaning already indicated for R and R1, and obtains the sought derivative which we isolate and, if desired, salifies with a pharmaceutically acid acceptable, either with a derivative of formula (III) (III) in which R 'represents a hydrogen atom and R'1 represents a tritluoroacetyl radical, then submits the product obtained with a cleavage agent to obtain the amine corresponding primary which is isolated and, if desired, salifies with a pharmaceutically acceptable acid.

2. Process for the preparation of 4- derivatives phenylpropyl indole, and their salts pharmaceutically acceptable, corresponding to formula (I):

(I) in which R and R1 independently represent one of the other, a hydrogen atom, a linear alkyl radical containing from 1 to 5 carbon atoms, an alkyl radical branched containing 3 to 5 carbon atoms, a radical cycloalkyl containing 3 to 7 carbon atoms, one cycloalkylalkyl radical containing from 4 to 7 atoms of carbon, or an aralkyl radical containing from 7 to 12 atoms of carbon unsubstituted or substituted by 1, 2 or 3 selected radicals in the group consisting of halogens and methyl, ethyl, methoxy, ethoxy, trifluoromethyl, methylthio, amino and nitro, or R and R1 together form a saturated or unsaturated heterocycle which may contain a second heteroatom chosen from the group consisting of oxygen, sulfur and nitrogen atoms, this atom of nitrogen being unsubstituted or substituted by a radical linear alkyl containing 1 to 5 carbon atoms, by a phenyl or naphthyl radical, or by an aralkyl radical containing from 7 to 12 carbon atoms, a represents together with b an oxo function, or represents together with c a carbon-carbon bond, b represents an atom of hydrogen, or together with has an oxo function, c represents a hydrogen atom, or together with a represents a carbon-carbon bond, the dotted line represents the presence or absence of a carbon-carbon, A represents a chain - (CH2) n- in which n can take the values 2,3,4 or 5, R2 represents an atom of hydrogen, a linear alkyl radical containing from 1 to 5 carbon atoms or a branched alkyl radical containing 3 to 5 carbon atoms, x represents a hydrogen atom or a hydroxy group, or together with y, a function oxo, and y represents a hydrogen atom or, together with x, an oxo function; characterized in that:
A) reacting a product of formula (II):

(II) in which Hal represents a chlorine, bromine atom, or iodine, and R2 and A have the meanings already indicated, with a derivative of formula (III):

(III) in which R 'and R'1 have the meaning already indicated for R and R1, where R 'represents a hydrogen atom and R'1 represents a trifluoro acetyl radical, to obtain a product of formula (IA):
(IA) in which A, R ', R'1 and R2 have the meaning already indicated, that in the case where R'1 represents a radical trifluoro acetyl, it is subjected to the action of an agent of cleavage to obtain the corresponding primary amine, and products of formula (IA) that is isolated and, if desired, salifies with a pharmaceutically acceptable acid, either it is reduced by the action of hydrogen gas in the presence of a catalyst based on platinum or palladium in a solvent, or by the action of hydrogen gas in the presence of Raney nickel in a solvent, or by action for less than 3 hours of sodium in the ammonia in the breast of a solvent, to obtain a product of formula (IB):

(IB) in which A, R, R1 and R2 already have the meaning indicated, that either it is isolated and, if desired, salified with a pharmaceutically acceptable acid, or it is reduced by the action of an alkaline borohydride or cyanoborohydride to obtain a product of formula (IC):
(IC) in which A, R, R1 and R2 already have the meaning indicated, that either it is isolated and, if desired, salified with a pharmaceutically acceptable acid, or it is reduced by action of sodium in ammonia to obtain a product of formula (ID):

(ID) in which A, R, R1 and R2 already have the meaning indicated, which is isolated and, if desired, salified with a pharmaceutically acceptable acid, either reacting said product of formula (IA) with the complex formed between an alkaline borohydride and pyridine, to obtain a product of formula (IE):
(IE) in which A, R, R1 and R2 already have the meaning indicated, that either we isolate, or we reduce to using sodium in ammonia to get a product of formula (ID) which is isolated and, if desired, salified with a pharmaceutically acceptable acid, either reducing said product of formula (IA) using sodium in ammonia to obtain a product of formula (ID) which is isolated and, if desired, salified with an acid pharmaceutically acceptable, then submits, if desired, said products of formula (IA), (IB), (IC), (ID) and (IE) to the action of an agent halogenation to obtain a product of formula (IV):
(IV) in which Hal represents a bromine or chlorine atom, and x, y, A, R, R1, R2 and the dotted line have the meaning already indicated, which is subjected to hydrolysis to obtain a product of formula (IF):
(IF) in which x, y, A, R, R1, R2 and the dotted line have the meaning already indicated, which is isolated and, if desired, salifies with a pharmaceutically acceptable acid.

3. Process for the preparation of 4-phenyl- derivatives propyl indole, and their pharmaceutically salts acceptable, corresponding to formula (I):

(I) in which R and R1 independently represent one of the other, a hydrogen atom, a linear alkyl radical containing from 1 to 5 carbon atoms, an alkyl radical branched containing 3 to 5 carbon atoms, a radical cycloalkyl containing 3 to 7 carbon atoms, one cycloalkylalkyl radical containing from 4 to 7 atoms of carbon, or an aralkyl radical containing from 7 to 12 atoms of carbon unsubstituted or substituted by 1, 2 or 3 radicals chosen from the group consisting of halogens and methyl radicals, ethyl, methoxy, ethoxy, trifluoromethyl, methylthio, amino and nitro, or R and R1 together form a saturated heterocycle or unsaturated which may contain a second heteroatom chosen from the group consisting of oxygen, sulfur and nitrogen atoms, this nitrogen atom being unsubstituted or substituted by a radical linear alkyl containing 1 to 5 carbon atoms, by a phenyl or naphthyl radical, or by an aralkyl radical containing from 7 to 12 carbon atoms, a represents together with b an oxo function, or represents together with c a carbon-carbon bond, b represents an atom of hydrogen, or together with has an oxo function, c represents a hydrogen atom, or together with a represents a carbon-carbon bond, the dotted line represents the presence or absence of a carbon-carbon, A represents a chain - (CH2) n- in which n can take the values 2,3,4 or 5, R2 represents an atom of hydrogen, a linear alkyl radical containing from 1 to 5 carbon atoms or a branched alkyl radical containing 3 to 5 carbon atoms, x represents a hydrogen atom or a hydroxy group, or together with y, a function oxo, and y represents a hydrogen atom or, together with x, an oxo function, characterized in that:
(i) - either submit a product of formula (II):

(II) in which A and R2 have the meanings already indicated and Hal represents a chlorine, bromine, or iodine atom with reduction by the action of hydrogen gas in the presence of a catalyst based on platinum or palladium in a solvent, or by the action of hydrogen gas in the presence of Raney nickel in a solvent, or by action for less than three hours, from sodium in ammonia to within a solvent, to obtain a product of formula (IIB) (IIB) in which A, R2 and Hal have the meaning already indicated, that either we isolate, or we reduce by action of an alkaline borohydride or cyanoborohydride for obtain a product of formula (IIC):
(IIC) in which A, R2 and Hal have the meaning already indicated, that either one isolates, or one reduces by action of sodium in ammonia to obtain a product of formula (IID):

(IID) in which A, R2 and Hal have the meaning already indicated, which we isolate, - either reacting said product of formula (II) previously defined, with a complex formed between a alkaline borohydride and pyridine to obtain a product of formula (IIE):
(IIE) in which A, R2 and Hal have the meaning already indicated, that either we isolate, or we reduce to using sodium in ammonia to get a product of formula (IID) as defined above, which is isolated, - either reduce said product of formula (II) previously defined, using sodium in ammonia to obtain a product of formula (IID) as above defined, that we isolate, then submits, if desired, said products of formula (II), (IIB), (IIC), (IID) and (IIE) to the action of an agent halogenation to obtain a product of formula (IV '):
(IV ') in which x, y, A, R2, Hal and the dotted line have the meaning already indicated, and Hal1 represents an atom of bromine or chlorine, which is subjected to hydrolysis to obtain a product of formula (IIF):
(IIF) in which x, y, A, R2, Hal and the dotted line have the meaning already indicated, which is isolated; and (ii) reacting said products of formula (II), (IIB), (IIC), (IID), (IIE) and (IIF) previously defined, either with a derivative of formula (III):

(III) in which R 'and R'1 have the meaning already indicated for R and R1, and obtains the sought derivative which we isolate and, if desired, salifies with a pharmaceutically acid acceptable, either with a derivative of formula (III):

(III) in which R 'represents a hydrogen atom and R'1 represents a trifluoroacetyl radical, then submits the product obtained by the action of a cleavage agent to obtain the corresponding primary amine that is isolated and, if desired, salifies with a pharmaceutically acid acceptable.

4. Process for the preparation of 4-phenyl- derivatives propyl indole, and their pharmaceutically salts acceptable, corresponding to formula (I):
(I) in which R and R1 independently represent one of the other, a hydrogen atom, a linear alkyl radical containing from 1 to 5 carbon atoms, an alkyl radical mified containing 3 to 5 carbon atoms, a cyclo radical alkyl containing from 3 to 7 carbon atoms, a cy- radical cloalkylalkyl containing 4 to 7 carbon atoms, or a aralkyl radical containing 7 to 12 non-carbon atoms substituted or substituted by 1, 2 or 3 radicals chosen from the group consisting of halogens and methyl radicals, ethyl, methoxy, ethoxy, trifluoromethyl, methylthio, amino and nitro, or R and R1 together form a saturated heterocycle or unsaturated which may contain a second chosen heteroatom in the group consisting of oxygen, sulfur atoms and nitrogen, this nitrogen atom being unsubstituted or substituted killed by a linear alkyl radical containing 1 to 5 atoms carbon, by a phenyl or naphthyl radical, or by a ra-arical dical containing 7 to 12 carbon atoms, has presents together with b an oxo function, or represents together with c a carbon-carbon bond, b represents a hydrogen atom, or together with has an oxo function, c represents a hydrogen atom, or together with a represents a carbon-carbon bond, the dotted line represents the pre-sence or absence of a carbon-carbon bond, A represents feels a chain - (CH2) n- in which n can take the values 2, 3, 4 or 5, R2 represents a hydrogen atom, a linear alkyl radical containing from 1 to 5 carbon atoms or a branched alkyl radical containing 3 to 5 atoms of carbon, x represents a hydrogen atom or a group hydroxy, or together with y, an oxo function, and y represents a hydrogen atom or, together with x, an oxo function;
characterized in that:
(i) - or a derivative of formula (VII) is submitted:

(VII) in which R2 has the meaning already indicated, at a reduction by the action of hydrogen gas in the presence of a catalyst based on platinum or palladium in a solvent, or by the action of hydrogen gas in the presence of Raney nickel in a solvent, or by action for less than three hours of sodium in ammonia at within a solvent, to obtain a product of formula (VIIB):
(VIIB) in which R2 has the meaning already indicated, that or either we isolate, or we reduce by the action of a alkali borohydride or cyanoborohydride to obtain a product of formula (VIIC):

(VIIC) in which R2 has the meaning already indicated, that or either it is isolated, or it is reduced by the action of sodium in ammonia to obtain a product of formula (VIID):

(VIID) in which R2 has the meaning already indicated, which one isolated, - either react the derivative of formula (VII) previously defined, with a complex formed between a alkaline borohydride and pyridine, to obtain a product of formula (VIIE):

(VIIE) in which R2 has the meaning already indicated, that or either isolate or reduce with sodium in ammonia to obtain a product of formula (VIID)) such that previously defined, that we isolate, - either reduce said product of formula (VII) previously defined, using sodium in ammonia to obtain a product of formula (VIID) as previously defined, that we isolate, then submits, if desired, said products of formula (VII), (VIIB), (VIIC), (VIID) and (VIIE) to the action of an agent halogenation to obtain a product of formula (IV "):
(IV ") in which x, y, R2 and the dotted line have the meaning already indicated, and Hal1 represents an atom of bromine or chlorine, which is subjected to hydrolysis to obtain a product of formula (VIIF):
(VIIF) in which x, y, R2 and the dotted line have the meaning already indicated, which is isolated;
(ii) reacting said products of formula (VII) (VIIB), (VIIC), (VIID), (VIIE) and (VIIF) with a halogenated derivative, a hydroxylated derivative, or a sulfonate of said hydroxylated derivative of an alkylene halide of formula (VIII):

- A - Hal (VIII) in which A has the meaning already indicated, and Hal represents a chlorine, bromine, or iodine atom, for obtain a product of formula (II ') (II ') where a, b, c, x, y, A, R2, Hal and the line dotted have the meaning already indicated, which we do react either with a derivative of formula (III):

(III) in which R 'and R'1 have the meaning already indicated for R and R1, and obtains the sought derivative which we isolate and, if desired, salifies with a pharmaceutically acid acceptable, either with a derivative of formula (III):

(III) in which R 'represents a hydrogen atom and R'1 represents a trifluoroacetyl radical, then submits the product obtained with a cleavage agent to obtain the amine corresponding primary which is isolated and, if desired, salifies with a pharmaceutically acceptable acid.

5. Method according to claim 2, 3 or 4, characterized in that the reduction by the action of hydrogen gaseous in the presence of a platinum-based catalyst or palladium is carried out in an alkanol containing from 1 to 5 carbon atoms, or that reduction by action hydrogen gas in the presence of Raney Nickel takes place in ethyl acetate.

6. Method according to claim 1, characterized in that the derivative of formula (II) is prepared by reaction an indole of formula (V):

(V) in which R2 has the meaning already indicated in the claim 1, with a derivative of formula (VI):
(VI):

to obtain a derivative of formula (VII):

(VII) in which R2 has the meaning already indicated, which one reacts with a halogenated derivative, a hydroxylated derivative, or a sulfonate of said hydroxylated derivative of a halide of alkylene of formula (VIII):

-A-Hal (VIII) in which A and Hal have the meanings already indicated in claim 1, to obtain the derivative of formula (II) desired.

7. Method according to claim 3 or 6, characterized in that the derivative used is sulfonate hydroxylated alkylene halide of formula (VIII) son tosylate of formula (VIII "):

TSO-A-Hal (VIII ") in which TS represents a tosyle radical and A and Hal have the meaning already indicated in claim 3 or 6.

8. Method according to claim 1, 2 or 3, characterized in that the derivative of formula (II) is prepared by reaction of an indole of formula (V):

(V) in which R2 has the meaning already indicated in the claim 1, 2 or 3, with a derivative of formula (IX):
in which A and Hal have the meanings already indicated in the claim 1, 2 or 3, to obtain the derivative of desired formula (II).

9. Process for the preparation of a derivative of formula (II '):
(II ') in which Hal represents a chlorine, bromine atom, or iodine, a represents together with b an oxo function, or represents together with c a carbon-carbon bond, b represents a hydrogen atom, or together with has a oxo function, c represents a hydrogen atom, or together with a represents a carbon-carbon bond, the dotted line represents the presence or absence of a carbon-carbon, A represents a chain - (CH2) n- in which n can take the values 2,3,4 or 5, R2 represents an atom of hydrogen, a linear alkyl radical containing from 1 to 5 carbon atoms or a branched alkyl radical containing 3 to 5 carbon atoms, x represents a hydrogen atom or a hydroxy group, or together with y, a function oxo, and y represents a hydrogen atom or, together with x, an oxo function; characterized in that:
(i) - or a derivative of formula (VII) is submitted:

(VII) in which R2 has the meaning already indicated, at a reduction by the action of hydrogen gas in the presence of a catalyst based on platinum or palladium in a solvent, or by the action of hydrogen gas in the presence of Raney nickel in a solvent, or by action for less than three hours, sodium in ammonia at within a solvent, to obtain a product of formula (VIIB):

(VIIB) in which R2 has the meaning already indicated, that or either we isolate, or we reduce by the action of a alkali borohydride or cyanoborohydride to obtain a product of formula (VIIC):

(VIIC) in which R2 has the meaning already indicated, that or either it is isolated, or it is reduced by the action of sodium in ammonia to obtain a product of formula (VIID):

(VIID) in which R2 has the meaning already indicated, which one isolated, - either react the derivative of formula (VII) previously defined, with a complex formed between a alkaline borohydride and pyridine, to obtain a product of formula (VIIE):
(VIIE) in which R2 has the meaning already indicated, that or either isolate or reduce with sodium in ammonia to obtain a product of formula (VIID) such that previously defined, that we isolate, - either reduce said product of formula (VII) previously defined, using sodium in ammonia to obtain a product of formula (VIID) as previously defined, that we isolate, then submits, if desired, said products of formula (VII), (VIIB), (VIIC), (VIID) and (VIIE) to the action of an agent halogenation to obtain a product of formula (IV "):
(IV ") in which x, y, R2 and the dotted line have the meaning already indicated, and Hal represents an atom of bromine or chlorine, which is subjected to hydrolysis to obtain a product of formula (VIIF):
(VIIF) in which x, y, R2 and the dotted line have the meaning already indicated, which is isolated; and (ii) reacting said products of formula (VII), (VIIB), (VIIC), (VIID), (VIIE) and (VIIF) with a halogenated derivative, a hydroxylated derivative, or a sulfonate of said hydroxylated derivative of an alkylene halide of formula (VIII):

- A - Hal (VIII) in which A and Hal have the meanings already indicated, to obtain a product of formula (II ′) sought, being understood that when said product of formula (II ′) meets formula (II):
(II) in which A, R2 and Hal have the meaning already indicated, we can, if desired, either submit this product formula (II) to a reduction by action of hydrogen gaseous in the presence of a platinum-based catalyst or palladium in a solvent, or by the action of hydrogen gas in the presence of Raney Nickel in a solvent, or per action for less than three hours, sodium in ammonia in a solvent, to obtain a product of formula (IIB):

(IIB) in which A, R2 and Hal have the meaning already indicated, either to be isolated, or, if desired, reduced by the action of an alkali borohydride or cyanoborohydride to obtain a product of formula (IIC):
(IIC) in which A, R2 and Hal have the meaning already indicated, either to be isolated, or, if desired, reduced by action of sodium in ammonia to obtain a product of formula (IID):

(IID) in which A, R2 and Hal have the meaning already indicated, which we isolate, - either react said product of formula (II) previously defined, with a complex formed between a alkaline borohydride and pyridine to obtain a product of formula (IIE):

(IIE) in which A, R2 and Hal have the meaning already indicated, either to be isolated, or, if desired, reduced using sodium in ammonia to get a product of formula (IID) as defined above, which is isolated, - either reduce said product of formula (II) previously defined, using sodium in ammonia to get a product of formula (IID) as previously defined, that the said products are isolated and then submitted, if desired, formula (II), (IIB), (IIC), (IID) and (IIE) to the action of a halogenating agent to obtain a product of formula (IV '):
(IV ') in which x, y, A, R2, Hal and the dotted line have the meaning already indicated, and Hal1 represents an atom of bromine or chlorine, which is subjected to hydrolysis to obtain a product of formula (IIF):
(IIF) in which x, y, A, R2, Hal and the dotted line have the meaning already indicated, which we isolate.

10. Process for the preparation of a derivative of formula (VII '):
(VII ') in which a represents together with b an oxo function, or represents together with c a carbon-carbon bond, b represents a hydrogen atom, or together with has a oxo function, c represents a hydrogen atom, or together with a represents a carbon-carbon bond, the dotted line represents the presence or absence of a carbon-carbon, R2 represents a hydrogen atom, a radical linear alkyl containing 1 to 5 carbon atoms or one branched alkyl radical containing 3 to 5 atoms carbon, x represents a hydrogen atom or a group hydroxy, or together with y, an oxo function, and y represents a hydrogen atom or, together with x, a oxo function; characterized in that one reacts a indole of formula (V):
(V) in which R2 has the meaning already indicated, with a derivative of formula (VI):

(VI) to obtain a derivative of formula (VII):

(VII) in which R2 has the meaning already indicated, that or either we isolate, or, if desired, either we submit to a reduction by the action of hydrogen gas in the presence of a catalyst based on platinum or palladium in a solvent, or by the action of hydrogen gas in the presence of Raney nickel in a solvent, or by action for less than three hours, sodium in ammonia at within a solvent, to obtain a product of formula (VIIB):

(VIIB) in which R2 has the meaning already indicated, that or well one isolates, or else, if desired, reduced by the action of a alkali borohydride or cyanoborohydride to obtain a product of formula (VIIC):
(VIIC) in which R2 has the meaning already indicated that or well one isolates, or else, if desired, reduced by the action of sodium in ammonia to obtain a product of formula (VIID):

(VIID) in which R2 has the meaning already indicated, which one isolated, - either react the derivative of formula (VII) previously defined with a complex formed between a alkaline borohydride and pyridine, to obtain a product of formula (VIIE):
(VIIE) in which R2 has the meaning already indicated, that or well it is isolated, or, if desired, reduced using sodium in ammonia to obtain a product of formula (VIID) as previously defined, which is isolated, - either reduce said product of formula (VII) previously defined, using sodium in ammonia to obtain a product of formula (VIID) as previously defined that we isolate, then submits, if desired, said products of formula (VII), (VIIB), (VIIC), (VIID) and (VIIE) to the action of an agent halogenation to obtain a product of formula (IV "):
(IV ") in which x, y, R2 and the dotted line have the meaning already indicated, and Hal1 represents an atom of bromine or chlorine, which is subjected to hydrolysis to obtain a product of formula (VIIF):

(VIIF) in which x, y, R2 and the dotted line have the meaning already indicated, which we isolate.

11. Derivative of formula (VII '):
(VII ') in which a represents together with b an oxo function, or represents together with c a carbon-carbon bond, b represents a hydrogen atom, or together with has a oxo function, c represents a hydrogen atom, or together with a represents a carbon-carbon bond, the dotted line represents the presence or absence of a carbon-carbon, R2 represents a hydrogen atom, a radical linear alkyl containing 1 to 5 carbon atoms or one branched alkyl radical containing 3 to 5 atoms carbon, x represents a hydrogen atom or a group hydroxy, or together with y, an oxo function, and y represents a hydrogen atom or, together with x, a oxo function.

12. Method according to claim 1, characterized in that when the symbols R1 and R in formula (I), independently of one another, represent an atom of hy-drogen, a linear alkyl radical containing 1 to 5 atoms carbon, a branched alkyl radical containing from 3 to 5 carbon atoms, a cycloalkyl radical containing 3 to 7 carbon atoms, a cycloalkylalkyl radical containing 4 to 7 carbon atoms or an aralkyl radical containing 7 to 12 unsubstituted carbon atoms, the symbols R'1 and R 'of formulas (III) and (IA) correspond to the values of symbols R1 and R given above, and the symbols R1 and R
formulas (IB), (IC), (ID), (IE), (IV) and (IF) correspond to the values of the symbols R1 and R given above above.

13. Method according to claim 2, characterized when the symbols R1 and R in formula (I), independently represent each other, an atom of hydrogen, a linear alkyl radical containing from 1 to 5 carbon atoms, a branched alkyl radical containing 3 with 5 carbon atoms, a cycloalkyl radical containing 3 to 7 carbon atoms, a cycloalkylalkyl radical contains-mant of 4 to 7 carbon atoms or an aralkyl radical containing from 7 to 12 unsubstituted carbon atoms, the symbols R'1 and R 'of formulas (III) and (IA) correspond to the values of the symbols R1 and R given above and the symbols R1 and R of the formulas (IB), (IC), (ID), (IE), (IV) and (IF) correspond to the values of the symbols R1 and R
data above.

14. Method according to claim 3, characterized when the symbols R1 and R in formula (I), independently represent each other, an atom of hydrogen, a linear alkyl radical containing from 1 to 5 carbon atoms, a branched alkyl radical containing 3 with 5 carbon atoms, a cycloalkyl radical containing 3 to 7 carbon atoms, a cycloalkylalkyl radical contains-mant of 4 to 7 carbon atoms or an aralkyl radical containing from 7 to 12 unsubstituted carbon atoms, the symbols R'1 and R 'of the formulas (III) correspond to the values of the symbols R1 and R given above.

15. Method according to claim 4, characterized when the symbols R1 and R in formula (I), independently represent each other, an atom of hydrogen, a linear alkyl radical containing from 1 to 5 carbon atoms, a branched alkyl radical containing 3 with 5 carbon atoms, a cycloalkyl radical containing 3 to 7 carbon atoms, a cycloalkylalkyl radical contains-mant of 4 to 7 carbon atoms or an aralkyl radical containing from 7 to 12 unsubstituted carbon atoms, the symbols R'1 and R 'of the formulas (III) correspond to the values of the symbols R1 and R given above.

16. The method of claim 12 or 13, characterized in that the reduction by the action of hydrogen gaseous in the presence of a platinum-based catalyst or palladium is carried out in an alkanol containing from 1 to 5 carbon atoms, or that reduction by action hydrogen gas in the presence of Raney Nickel takes place in ethyl acetate.

17. Method according to claim 14 or 15, characterized in that the reduction by the action of hydrogen gaseous in the presence of a platinum-based catalyst or palladium is carried out in an alkanol containing from 1 to 5 carbon atoms, or that reduction by action hydrogen gas in the presence of Raney Nickel takes place in ethyl acetate.

18. The method of claim 12 or 15, characterized in that the derivative used is sulfonate hydroxylated alkylene halide of formula (VIII) son toxylate of formula (VIII "):

TSO-A-Hal (VIII ") in which TS represents a tosyle radical and A
represents a chain? CH2 in which n can take the values 2, 3, 4 or 5 and Hal represents an atom of chlorine, bromine or iodine.

19. Method according to claim 1, characterized in that when the symbols R1 and R in the formula (I) together form with the nitrogen atom to which they are linked, a radical chosen from the group consisting of radicals pyrrolidino, pipéridino, morpholino, pipérazinyle, methyl-piperazinyl, ethylpiperazinyl and propylpiperazinyl, the symbols R'1 and R 'of formulas (III) and (IA) correspond to the values of the symbols R1 and R given above and the symbols R1 and R of the formulas (IB), (IC), (ID), (IE), (IV) and (IF) correspond to the values of the symbols R1 and R
data above.

20. Method according to claim 2, characterized in that when the symbols R1 and R in the formula (I) together form with the nitrogen atom to which they are linked, a radical chosen from the group consisting of radicals pyrrolidino, pipéridino, morpholino, pipérazinyle, methyl-piperazinyl, ethylpiperazinyl and propylpiperazinyl, the symbols R'1 and R 'of formulas (III) and (IA) correspond to the values of the symbols R1 and R given above and the symbols R1 and R of the formulas (IB), (IC), (ID), (IE), (IV) and (IF) correspond to the values of the symbols R1 and R
data above.

21. Method according to claim 3, characterized in that when the symbols R1 and R in the formula (I) together form with the nitrogen atom to which they are linked, a radical chosen from the group consisting of radicals pyrrolidino, pipéridino, morpholino, pipérazinyle, methyl-piperazinyl, ethylpiperazinyl and propylpiperazinyl, the symbols R'1 and R 'of formula (III) correspond to values of symbols R1 and R given above.

22. Method according to claim 4, characterized in that when the symbols R1 and R in the formula (I) together form with the nitrogen atom to which they are linked, a radical chosen from the group consisting of radicals pyrrolidino, pipéridino, morpholino, pipérazinyle, methyl-piperazinyl, ethylpiperazinyl and propylpiperazinyl, the symbols R'1 and R 'of formula (III) correspond to values of symbols R1 and R given above.

23. Method according to claim 19 or 20, characterized in that the reduction by the action of hydrogen gaseous in the presence of a platinum-based catalyst or palladium is carried out in an alkanol containing from 1 to 5 carbon atoms, or that reduction by action hydrogen gas in the presence of Raney Nickel takes place in ethyl acetate.

24. Method according to claim 21 or 22, characterized in that the reduction by the action of hydrogen gaseous in the presence of a platinum-based catalyst or palladium is carried out in an alkanol containing from 1 to 5 carbon atoms, or that reduction by action hydrogen gas in the presence of Raney Nickel takes place in ethyl acetate.

25. The method of claim 19 or 22, characterized in that the derivative used is sulfonate hydroxylated alkylene halide of formula (VIII) son toxylate of formula (VIII "):

TSO-A-Hal (VIII ") in which TS represents a tosyle radical and A
represents a chain? CH2 in which n can take the values 2, 3, 4 or 5 and Hal represents an atom of chlorine, bromine or iodine.