CA1266050A - Process for the preparation of novel indole carboxamide derivatives and their salts - Google Patents

Abstract

The invention relates to a process for preparing the derivatives of the indole carboxamide and their salts of formula: <IMG> I where R and R1 represents hydrogen, linear or branched alkyl, cycloalkyl, cycloalkylalkyl, aralkyl or R + R1 form a heterocycle which can include an oxygen and sulfur or nitrogen atom, 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, A represents <IMG> with m = 1,2 or 3, or or - (CH2) n- with n = 2, 3, 4 or 5 B represents -CO-NH- or - NH-CO-R3 represents hydrogen, alkyl, alkoxyl, chlorine, bromine, iodine, nitro, amino optionally substituted by aliphatic acyl or alkyl, R2 represents hydrogen, linear or branched alkyl. The products (I) are useful as medicaments, in particular antiarrhythmics.

Description

; O ~ (~

Process for the preparation; new derivatives of the indole carboxamide and of their salts.

______________________ ____ Said company: ROUSSEL-UCLAF
__ __________ ____________ The present invention relates to a process for preparing d ~ rivés of indole carboxamide, as well as their addition salts with ~
mineral or organic acids, corresponding to the general formula (I):

OAN ~
~ - R
B

~ ~ a \ R2 in which R and R1 represent, independently of one another, a 15 hydrogen atom ~ a linear alkyl radical containing 1 ~ 5 atoms of carbon, a branched alkyl radical ~ containing 3 to 5 atoms of carbon, a cycloalkyl radical containing 3 ~ 7 carbon atoms, a cycloalkylalkyl radical containing from 4 to 7 carbon atoms, or an aralkyl radical containing from 7 to 12 carbon atoms possibly 20 substituted ~ by 1, 2 or 3 radicals selected in the group const; killed by halogens and methyl radicals, ~ thyle, methoxy, ethoxy, trifluoro methyl, methylthio, amino and nitro, or R and R1 together form a 0 ~ (~
heterocycle satur ~ or; nsaturated which may contain a second hetero ~ roatom chosen from oxygen, sulfur and nitrogen atoms, this nitrogen ato ~ e possibly being subst; killed by an alkyl radical containing from 1 to 5 carbon atoms, by a phenyl, substituted ph ~ nyl or naphthyl radical 5 or by an aralkyl radical containing from 7 to 12 carbon atoms, R3 repr ~ feels a hydrogen atom, a rad; cal alkyl containing from 1 to 5 carbon atoms, an alkoxy radical containing from 1 to 3 atores of carbon, a chlorine, bromine or iodine atom, a rad; cal n; tro or a rad; cal am; no optionally substituted with an aliphatic acyl group 10 containing 2 to 5 carbon atoms or a rad; cal alkyl containing 1 has 5 carbon atoms, represents together with b an oxo function, or repr ~ feels together with c a carbon-carbon bond, b represents a hydrogen atom, or together with has an oxo function, c represents a atom of hydrogen ~ ne, or together with a represent ~ a carbon bond-15 carbon, A represents a chain - (CH2) n-in which n can take the values 2, 3, 4 or 5, or a chain ~ ne - ~ CH2) m-CH- ~ H2- in IH
which m can take the values 1, 2 or 3, B represents a chain -C0-NH- or -NH-C0-, R2 represents a hydrogen atom, a radical 20 linear alkyl containing 1 to 5 carbon atoms or an alkyl radical branched with 3 to 5 carbon atoms.
The invention particularly relates to a method of pr ~ preparation of derivatives of formula (I) as defined above, in which R3 represents a hydrogen atom.
In the general formula tI) and in what follows, the radical term linear alkyl containing from 1 to 5 carbon atoms denotes, from preferably a radical m ~ thyle, ~ thyle or propyl, the term radical branched alkyl containing 3 to 5 carbon atoms denotes, pref ~ rence, an isopropyl or tert-butyl radical, the term cycloalkyle 30 containing 3 to 7 carbon atoms preferably denotes a radical cyclopentyle; the term cycloalkylalkyl containing 4 to 7 atoms designe carbon, preferably ~ rence, a cyclopropylmethyl radical; the term aralkyl radical containing 7 to 1Z carbon atoms denotes, pr ~ ference, a benzyl or phenethyl radical, optionally substituted by 35 1,2 or 3 radicals chosen from the group of halogens, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, methylthio, amino and nitro; when R
and R1 together form, with the nitrogen atom, a heterocycle, it is, for example, from a pyrrolidino, pip ~ ridino, morpholino, piperazinyle ring, m ~ thylpiperazinyl, ethyl piperazinyl or propyl p; perazinyl; phenyl 40 substituted may carry the same substituents as the benzyl radicals and 3 the ~ O ~
ph ~ nethyl above.
The term alkoxy radical containing 1 to 3 carbon atoms denotes the methoxy, ethoxy or propoxy radical. The term acyl al; phatic containing 2 to 5 carbon atoms preferably denotes the radical 5 acetyl or propionyl.
Addition salts with mineral or organic acids can be, for example, the salts formed with hydrochloric acids, hydrobromic, nitric, sulfuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, 10 citric, oxalic, glyo ~ ylique, aspartic, alkane sulfonic such as methane and ethane sulfonic, arylsulfonic acids, such as benzene and paratolu acids ~ ne sulfonic and arylcarboxylic.
Among the derivatives obtained by the process which is the subject of the invention, there are may include in particular the drifts ~ answering ~ the formula tI) above, 15 as well as their addition salts with mineral or organic acids, characterized in that, in said formula (I), R2 represents an atom of hydrog ~ ne.
Among these, mention may be made more particularly of derivatives characterized in that in said formula (I), a and c form together 20 a lia; its carbon-carbon.
Among the derivatives obtained according to the invention, mention may also be made of derivatives meeting the formula (I) above as well as their salts addition with mineral or organic acids characterized in that in the formula ~ I) R3 represents a hydrogen atom.
Among the derivatives obtained by the process which is the subject of the invention, there are may also cite the derivatives corresponding to formula (I) above as well as their addition salts with mineral or organic acids characterized in that in formula (I) the side chain 30 formula (I) the side chain -0-AN \ is fixed in the ortho position.

Among the derivatives obtained according to the invention, mention may also be made of derivative corresponding to formula (I) above as well as their additive salts tion with mineral or organic acids characterized in that in the 35 formula (I) B represents a chain ~ -NH-C0, NH being on the side of the indole.
Among the products prefer ~ s above, we can cite any especially:
- 2- / Zt (1,1-dimethylethyl) amino / ethoxy / N- (1H-indo! -4-yl) ~ enzamide, - 2- ~ 3 - / (1,1-dim ~ thyl ~ thyl) amino / 2-hydroxy propoxy / N- ~ 1H-indol-4-yl) 40 benzamide, 4 1 ~ ti0 ~ 0 - 2- / 3- / tbis- (1-m ~ thylethyl) / amino / 2-hydroxypropoxy / N- (1 ~ -indol-4-yl) benzamide, - 2- / 3 - / (1,1-d; methylethyl) amino / propoxy / N- (1H-indol-4-yl) ben2amide, 5 as well as their addition salts with mineral or organic acids.
The proc ~ of the invention is characterized in that one makes r ~ act a drift of formula II:
~ 3 \ R2 in which 8, R2 and R3 have the meanings already indicated, with A halide of formula III:
Ha lG III
in which Hal represents a chlorine, bromine or iodine atom and G represents a group of formula - (CH2) nD, in which D
represents a chlorine, bromine, iodine atom, a hydroxy radical or a 20 sulfonate of this hydroxy radical, and has the meaning already indicated, or G represents a group - (CH2) m- ~ CH2, in which my la meaning already indicated, to obtain a derivative of formula IY:

B ~

~ IV
I

in which ~, R2 and R3 have the meaning already indicated, and G ' represents a group of formula - (CH2) n-Hal in which n and Hal have the meaning already indicated or a grouping of formula - (CH2 ~ m C \ -CH2 d ~ finished above, which is reacted with an amine VS
of formula V: / R
HN ~ V

in which R and R1 have the meaning already indicated, for 40 obtain a product of formula IA

0 ~ 0 ~ -OAN / Rl \ R IA

in which A, ~, R, R1, R2 and R3 have s; gn; fication d ~ j ~
ind; quee, let us isolate and, s; desire ~, salify, or if desire ~, submit 10 to an alkylating agent, am; ne seconda; re of the side chain ~ when R or R1 represents a hydrogen atom, so; t sou ~ and ~ The action of a halogenating agent to obtain; r a produ; t of formula VI:

oA- ~ 1 ~ ll VI

\ R2 in which Hal1 represents a bromine or chlorine atom, and ~, 8, R, R1, R2 and R3 have the meaning already indicated ~ e, which we submit ~ hydrolysis to obtain a product of ~ ule Ih:

~ ¢ ~ -AN ~ 1 in which A, ~, R, R1, R2 and R3 have the meaning of ~
indicated, that one; sole and, if desired, salif; e.
When ~ ue we want to obtain a chain of formula -tCH2) n- for A, if a halide ~ nure of formula III corresponding to the formula is used:
Hal- (CH2) nD
d ~ ms which D represents a chlorine, brore, or ode atom and Hal has the meaning already indicated, it is preferable that D and Hal represents two different halogens to avoid condensation of two ~ olecules of d ~ r; v ~ of formula IV. This is how, for example, for D
40 representing a chlorine atom, we will choose a halide for Hal 6 lZ ~ S ~

more r ~ act; f such as bromide.
When using a hydroxyl halide ~ formula III
responding to the formula:
HO (CH2) n ~ al 5 in which n and Hal have the meaning already indicated, we operate from preferably in the presence of triphenyl phosphine and azodicarboxylate ethyl in t ~ trahydrofuran.
Advantageously ~ a sulfonate of this hydroxylated derivative is used;
in this case, preferably, we use its tosylate of formula:
1G TsO- (CH2) n-Hal in which Ts represents a tosyle radical ~ 4-methylbenzene sulfonate) and n and Hal have the significance; we already indicated.
We then operate by phase transfer using as phase preferably an aqueous solution of an alkali hydroxide such as Potassium hydroxide; um or sodium hydroxide, and as an organic phase not miscible with water a solvent such as benzene, in the presence of a transfer such as an quaternary ammonium salt; tetrabutyl ammonium re, especially bromide or hydrogen sulfate ~
The reaction of the product of formula IV with the amine of formula V is 20 r ~ alis ~ e for example in an inert organic solvent such as dioxane, benzene, tolu ~ ne, dimethylformamide, or a alcohol, preferably ethanol, preferably in the presence of an agent condensation such as an alkali carbonate or bicarbonate such as carbonate potassium, an alkali hydroxide like soda or potash, or a 25 tertiary amine such as tri ~ thylamine. We can also operate in using com ~ e solvent directly the amine of formula V.
When we want to obtain a chain of formula - (CH2) m-1H-CH2 OH
for A, a halide of formula Hal - (CH2) mC \ - / H2 is used;

in this case, Hal preferably represents a chlorine atom. The reaction of the derivative of formula II with the halide of formula III is then preferably carried out in the presence of a base such as carbonate potassium or sodium, soda or potash.
The reaction of the derivative of formula IY in which G 'represents a chain - (CH2 ~ m-CH-fH2 with the amine of formula V is made either directly using amine as a solvent, either using a solvent such as an aliphatic alcohol such as methanol or ethanol.

-7 1'f ~) 50 In the product of formula IA the possible alkylation (e of the amine secondary of the side chain is carried out preferably by action of an alkyl halide in the presence of a condensing agent such as a alkaline carbonate like sodium or potassium carbonate within 5 of an organic solvent. One can operate e ~ alement by reductive alkylation.
This is how when we want to perform for example a methylation is used; preferably the formaldehyde in the presence of a reducing agent such as sodiun cyanoborohydride within a solvent such as an aliphatic alcohol such as methanol.
Methyl paratoluene sulfonate can also be reacted to presence of an alkaline carbonate such as potassium carbonate or sodium in an organic solvent such as xylene.
Halogenation of derivatives of formulas IA can be used for example using the brominated pyridine complex of formula:
~
I ~ N ~ J, Br2. HBr in the case of bromination. It is carried out advantageously with the aid a N-halo succinimide pr ~ preferably N-bromo or N-chloro 20 succini ~ ide: we operate in dioxane or preferably in acid ac ~ tick ~ The product of formula (VI) obtained is preferably a chlorinated product.
The hydrolysis of the product of formula (VI) is carried out; preferably using a mineral acid such as phosphori acid ~ ue ac;
25 sulfuric or preferably hydrochloric acid in aqueous solution.
This solution can be used concentrated but preferably diluted for example in normal solution. A solvent can also be used.
such as an aliphatic alcohol such as ~ thanol.
The derivatives of formula II can be prepared as follows:
30 To obtain a derivative of formula IIA

~ Oh o NH
~ ~ IIA
I

8 ~ 2 ~: ~ tj05 (~

in which R2 has the meaning already indicated, we react the corresponding methyl or ethyl ndole 4-carboxylate or the acid indol-4-carboxylic acid corresponding to an aminophenol derivative of formula VII: NH2 ~} OK VII

in which K represents a hydrogen atom or a protecting group for hydroxy radical to obtain a derivative of formula VIII:
~
~ OK
O NH VIII

in which K and R2 have the meaning already indicated, which we release if necessary, the hydroxy function to obtain the product of formula He searched.
The term “protective group K of the hydroxy radical” means for example the benzyl or tosyle radical but preferably the tosyle radical.
The reaction of methyl or ethyl indole 4-carboxylate with derivative of formula VII is preferably carried out in the presence of tri; sobutylaluminium. The solvent used is preferably chloroform.
The operation is advantageously carried out at reflux of the reaction mixture.
The reaction of indol-4-carboxylic acid with the derivative of formula VII is carried out in the presence of a dehydrating agent such as carbonyl-diimidazole or preferably dicyclohexyLcarbodiimide, within a solvent such as t ~ trahydrofuran.
The unlocking of the hydroxy function of the derivative of formula VII} is produced by hydrogenolysis when K represents a ben ~ yle radical or by saponification when K represents a tosyle radical in preference to using soda or potash, in a solvent such as a weak alkanol;
po; ds mol ~ culaire such as m ~ thanol or, preferably, ethanol.
To obtain a derivative of formula IIB:
~ Oh Hp ~ o IIB

l ~

9 1 ~ 0 ~

in which R2 has the sign; f; cat; one already; ndiquee, one makes reaair the 4-amino indole corresponding with a methyl or ethyl carboxylate of phenol or with hydroxy benzo acid; only to obtain; r the derivative of formula IIB searched.
When we use a carboxy ~ methyl or ethyl phenol ate, one operates under conditions identical to those indicated for the preparation of the IIA product from the indole 4-carboxylate of methyl or ethyl.
When using hydroxy benzo acid; when operating in 1û identical conditions ~ those; nd; quées pour la préoarat; on du produ; t IIA starting from indol-4-carboxylic acid.
In a variant of the process described above; for the preparation of derivatives of formula I, in which A represents a chain - (CH2) n-, a derivative of formula II is made to react with a derivative of formula IX:

Hal- (CH2) n ~~ IX
~ "*

in which Hal, n, R and R1 already have the meaning; indicated, 25 to obtain the desired derivative of formula IA which is transformed if desired ~ é a product of formula I ~ corresponding as indicated above. ûn reacts the derivative of formula IX in the form free amine or, preferably in the form of a salt such as a hydrochloride.
According to another variant of the method described above for the preparation of a derivative of formula (I), in which R3 represents a amino radical optionally substituted, we reduce the ~ er; vé in which R3 represents a nitro radical and if necessary, we react;
amino derivative with reactive derivative; f of the substance; killing as desired 35 get it. The corresponding operating conditions are known from the skilled person.
The derivatives of formula (I) have a basic character. We can advantageously prepare the additive salts; there are derivatives of formula (I), by reacting, in sense; clearly stoichiometric proportions, an acid 4û m; inorganic or organic with said derivative of formula (I). Salts can 10 l ~ V

be pr ~ prepared without isolating the corresponding bases.
The derivatives which are the subject of the present invention have very interesting pharmacological properties; They are gifted in particular with remarkable antiarrhythmic properties.
These properties are illustrated later in the section experimental.
These properties justify the use of indole derivatives carboxamide of formula ~, as well as their salts, as med; caments.
By ~; the medicaments according to the invention, it is preferred to retain drugs characterized in that they consist of new indole carboxamide derivatives corresponding to formula (I) in which R2 represents a hydrogen atom as well as their addition salts with pharmaceutically acceptable acids.
Among these, there are in particular those corresponding to formula (I), in which a and c together form a carbon-carbon bond as well as their addition salts with acids pharmaceutically acceptable.
Among the medicaments according to the invention, mention may also be made of those Z ~ caract ~ laughed in that they are constituted by the new rivets of formula ~ I3 in which R3 represents a hydrogen atom thus; than by their add; t; on salts with pharmaceutically acceptable acids;
Among the medicaments according to the invention, mention may also be made of those characterized in that they consist of new derivatives of formuLe (I) in which the side chain -0-AN \ is fixed in ortho position as well as their addition salts with acids pharmaceutically acceptable.
Among the medicaments according to the invention, there may also be mentioned those characterized in that they consist of new derivatives of formula (I) in which ~ represents a chain -N H-C0, NH being side of indole, a; ns; only by their addition salts with acids pharmaceutically acceptable.
Among the various drugs preferred above, we retain all particularly those consisting of derivatives whose names follow:
- 2- / 2 - / (1,1-dimethylethyl) amino / ethoxy / N- (1H-indol-4-yl) benzamide, - 2- / 3 ~ dimethylethyl) amino / 2-hydroxy propoxy / N- ~ 1H-indol-4-yl) benzamide, 4û - le 2- ~ 3 - // bis- (1-m ~ thylethyl) / amino / 2-hydroxypropoxy / N- (1H-indol-4-1; ~ i05 ~ D
yl) benzamide, - 2- / 3 - / (1,1-di ~ ethyl ~ thyl) amino / propoxy / tJ- (1H-indol-4-yl) benzamide, as well as their addition salts with acids pharmaceutically 5 acceptable.
~ Medicines according to the invention find their use, for example in the treatment of arrhythmias.
The usual dose, which varies according to the derivative used, the subject and the condition in question can be, for example, from 50 mg to 19 per day. By 1. Orally, in humans, the derivative of Example 5 can be administered to the daily dose of 200 mg to 800 mg, for example for the treatment of ventricular arrhythmias, supraventr; cular and junctional, i.e.
approximately 3 mg to 12 mg per kilogram of body weight.
The derivatives of formula (I), as well as their addition salts with the 15 pharmaceutically acceptable acids can be used to prepare pharmaceutical compositions containing them, as a principle act; f.
As medicaments, the derivatives corresponding to formula (I) and their addition salts with pharmaceutically acceptable acids;
20 can be incorporated into pharmaceutical compositions;
the digestive or parenteral route.
These pharmaceutical compositions can be, for example, solid or what and commonly come in pharmaceutical forms used in human medicine, such as tablets, tablets 25 or coated, capsules, granules, suppositories, pr ~ injectable preparations; they are prepared according to the methods usual. The principle (s) act; fs may be incorporated therein patients usually employed in these pharmaceutical compositions;
such as talc, gum arabic, lactose, starch, stearate 30 magnesium ~, cocoa butter, aqueous vehicles or not, fatty substances gold; animal or vegetable; paraffinic derivatives, glycols, various wetting, dispersing or foaming agents, preservatives.
The process of the invention makes it possible to prepare products new media, namely products meeting the formula 35 (II ~:

~ Oh B "~
II
SN

in which B and R2, have the meaning already indicated.
In addition to the products described in the examples, the following products 10 constitute new products which can be obtained within the framework of the present invention:
- 2- / 3 - / (1,1-dim ~ thylpropyl) amino / 2-hydroxy propoxy / N- ~ 1H-indol-4-yl) benzamide, - lr 2- / 3 - / (1,1-dimethylethyl) amino / 2-hydroxy propoxy / N- (1-m ~ thyl 1H-Indol-4-yl) benzamide, - 2- / 3- ~ 4-morpholinyl) Z-hydroxy propoxy / N- ~ 1H-indol-4-yl) benzamide.
The following examples illustrate the present invention, without however, miter it.
Exe ~ 41e 1: ~ propoxy /
20 Dh ~ nYl / 1H-indol-4-car ~ oxa ~ ide and its oxa ~ neutral ate.
. ~.,. _.
Stage A: N- / 2- / ~ 2-oxiranyl ~ m ~ thoxy / phenyl / 1H-; ndol-4-carboxamide.
It is heated under reflux for 24 hours, under an inert atmosphere, a solution of 3 9 of N- ~ 2-hydroxyphenyl) 1H-indol-4-carboxamide and 25 1.65 g of potassium carbonate in 100 cm3 of acetone with 4.7 cm3 of ~ pichLorhydrin, purified by chromatography on silica ~ glowing:
ethyl acetate-triethyla ~ ine: 9-1), brings ~ dry, emp3te in the pentane, filter, dry under pressure reduced to 60C and obtains 2.8 9 of the expected product F ~ 122C.
30 Stage B. N- / 2- / 3 - / (1,1-dimethylethyl) amino / 2-hydroxy propoxy ~ phenyl / 1H-indol-4-carboxamide and its neutral oxalate Heated to 8DC with stirring and inert atmosphere for 1 hour a solution of 2.8 9 of product of stage A in 40 cm3 of ~ thanol, with 7.6 cm3 of ter butylamine, purified by chromatography on silica 35 ~ eluents: ethyl acetate-triethylamine 9-1, then chloroform-methanol 5-5) and obtains 3 ~ 05 9 from the base of the expected product (amorphous powder beige ~.

Z, 9 9 of the above base is dissolved in 300 cm 3 of acetone, 40 add U 0 mg of oxalic acid, bring to reflux for 15 min, concentrate 13 ~ 0 ~

at about 200 cm3, ice, filter, dry under reduced pressure at ao ~ c and obtains 2.9 9 of the expected product; 2.35 9 after recr; stallization in methanol F ~ 2ûOC.
Preparation of N- ~ 2-h ~ phenyl) 1H-indol-4-carboxamide used ~ at 5 start from example 1:
STAGE A: N- / 2 - / (4-methylph ~ nyl) sulfonyloxy / phenyl / 1H-indol-4-carboxamide.
To a solution of 18 9 of 2-aminophenol 4-methylbenzenesulfonate in 300 cm3 of chloroform, added with stirring and inert atmosphere 10,140 cm3 of triisobutylaluminum in solution in toluene ~ 1.1 mole / l, stir for 15 min, add a solution of 12.15 9 indol-4-carboxylate of methyl in 120 cm3 of chloroform and brings to reflux for 20 hours. Cool ~ 10C and add 5ûO cm3 of aqueous solution N
hydrochloric acid, stirred for 15 minutes, purifies the phase 15 chloroform by chromatography on silica, teluant: chloride of methylene), and obtains 25 9 of the expected product F = 135 ~ C.
STAGE 8: Preparation of N- (2-hydroxyph ~ nyl) 1H-indol-4-carboxamide.
250 c ~ 3 of a solution are added with stirring and inert atmosphere.
of potash in ~ thanol at 10 9 per 100 cm3 ~ a suspension of 25 9 20 of N- / 2 - / (4-methylph ~ nyl) sulfonyloxy / phenyl / 1H -indol-4-carboxamide-in 50 c ~ 3 ethanol ~ 95C, leaves stirring for 21 hours, add 1 liter of ice water, acidify with an aqueous solution concentrated hydrochloric acid, stirred for another 15 min, filter, dry, pastes under reflux in 1.5 l of methylene chloride, concentrated to 300 cm3 25 approximately, filter, dries at 80C under reduced pressure and obtains 13 9 of the expected product F ~ 2û8C.
Spectrum W ~ Ethanol):
max. 230 nm E11 = 1,012 ~ = 25,500 infl. 265 nmE11 = 208 max. 304 nm E11 = 564 = 14 2DO

infl. 318 nmE1 ~ = 482 Exe ~ ple 2: N- / 2- / 2 ~ dio ~ thyl ~ thyl) a-ino! ~ thoxy ~ ph ~ nyl /
1 ~ -indol- ~ -carboxa ~ id ~ and its hydrochloride.
Stage A: N- ~ 2- (2-chloroethoxy) phenyl / 1H-indol-4-carboxamide.
Heating ~ bOC with stirring and inert atmosphere 2.5 9 d ~
40 N- (2-hydroxyphenyl ~ 1H-; ndol-4-carboxamide in 100 cm3 of benzene 05 (~
and 50 cm3 of acetonitrile with 850 mg of n-tetrabutyl hydrogen sulfate ammonium, 3.6 cm3 of 3-chloroethylparatoluene sulfonate and 50 cm3 of 5 N sodium hydroxide, cools, decant, extracts with ethyl acetate, purifies by chromatography on silica / ~ glow: dichloroethane, brings to dryness under 5 pressure reduced to 50nc and obtains 1.65 9 of the expected product F ~ 135C.
STAGE 9: N- ~ 2- / 2 - / (1,1-dimethylethyl) am; no / ~ thoxy / phenyl ~
1H-indol ~ 4-carboxamide and its hydrochloride.
Heated to 1Z0C with stirring and pressure of 2 bars 10 a solution of 2.3% of product from stage A in 40 cm3 of ethanol and 37.5 cm3 of ter butylamine for 24 hours, diluted with 400 cm3 of water and 4û ~ cm3 of ethyl acetate, basified with sodium hydroxide, saturated with potassium carbonate, extract 3 ethyl acetate, paste crystals obtained using ether and obtains 2.3 9 of the expected product 15 F ~ 148C.
Hydrochloride formation The above base is dissolved in 20 × cm 3 of ~ ethyl acetate, adds a hydrochloric ethyl acetate solution until acid pH, heated at reflux for 15 min, concentrated to approximately 100 cm3, ice, 2a filter, dry at 80C under pressure ~ pick, recrystallized in isopropanol and obtains 2.15 9 of the expected product F ~ ~ 260 ~ C ~
UV spectrum (ethanol) max 229 nm E11 = 724 ~ = 28 100 max 3û2 nm ~ 11 = 3û3 ~ = 11 750 Example 3: N- / 2- / 3 - / (1,1-di ~ thethylethyl) amino hydrochloride /
propoxy / ph ~ nyl / 1H-indoL-4 ~ carboxamide.
Stage A: N- / 2- (3-chloropropoxy) phenyl / 1H-; ndol-4-carboxamide.
A solution of

2 9 of N- (2-hydroxyph ~ nyl) 1H-indol-4-carboxamide, 150 cm3 of tetrahydrofuran, 0.65 cm3 of 3-chloropropanol and 2.1 9 of triphenyl-phosphine, slowly add 1.2 cm3 of ethyl azodicarboxylate, leaves 35 for 3 hours with stirring, add 2.1 9 of triphenylphosphine, 0.65 cm3 of 3-chloropropanol then slowly 1.2 cm3 of azodicarboxylate ethyl leaves again with stirring for 16 hours, brings to dryness, purifies by chromatography on silica (Eluent: chloride of m ~ thylene), brings to dry, isopropyl ether paste, filter, pressurized ~ 0 reduced and obtains 1.3 9 of the expected product F ~ 144 C.

1 ~ 66V ~

Stage ~: N- / 2- / 3 - / (1,1-dimethylethyl) amino / hydrochloride propoxy / phenyl / 1H-indol-4-carboxamide.
It is heated to 100C under a pressure of 2 bars and with stirring

3.1 9 of product from stage A above in 60 cm 3 of ~ thanol and 5 30 cm3 of ter butylamine, diluted with 200 ml of water, acidifies using a concentrated aqueous solution of hydrochloric acid, filter, wash ~ water, emp ~ te ~ ther, then hot using acetone for 15 min at reflux and obtains 2.9 9 of the expected product F ~ Z38C.
UV spectrum (ethanoL):
max. Z27 nm E11 = 709 ~ = 28,400 infl. 262 nm E11 = 130 max. 301 nm E11 = 327 ~ = 13 IO

infl. 32û nm E11 = 227 Exe ~ ple 4: 2-J3- / t1, t-di ~ thy ~ thyl) a ~ ino / 2-hydroxy propoxy /
~ 1 ~) benzao; de and its neutral oxalete.
By operating according to a process similar to that described above for example 1, but ~ from 3.5 9 of 2- / N- (1H-indol-4-yl) amido /
phenol, 3 9 of the sought oxalate F ~ '190C is obtained.
UV spectrum (Ethanol ~ Hcl 0.1 N):
infl. 216 nm E11 = 1,003 max. 296 nm E11 = 264 ~ = 11,300 infl. Z35, 274, 288, 309 nm.

Preparation of 2- / N- (1H-indol-4-yl) amido / phenol used ~ from example n ~ 4.
It is added slowly under agitation and inert atmosphere 35 92 cm3 of a solut; one of triisobutylaluminium in solution at 1.1 mol / l in toluene, ~ a solution of 6.6 9 of 4-amino indole in 250 cm3 chloroform ~ then adds 9.6 cm3 of methyl salicylate, refluxed for 20 hours, cooled to room temperature, add 300 cm3 of hydrochloric acid N and 300 cm3 of chloride of 40 methylene, wash ~ water, dry, bring to dry under reduced pressure at 50C, emp3te ether, filter, dry ~ 60C under reduced pressure and obtains 9.4 9 of the expected product. F ~ 232C.
UV- (Ethanol) spectrum:

infl. 216 nm E11 ~ 1,595 infl. 233 nm E11 = 680 ~ = 17,200 infl. 262 nm E11 = 187 1û
infl. 303 nm E11 = 482 = 12,200 infl. 314 nm E11 = 494 ~ = 12,500 Example 5: 2- / Z- hydrochloride / 1,1-dinethyl ~ thyl) amino /
~ thoxy / N- ~ 1H-indoL-4-yl) benzamide.
By operating according to a process analogous to that described above;
for example 2, but ~ from 27 9 on 2- / N- (1H-indol-4-yl ~ amido /
phenol benzamide, 4.4 9 of expected hydrochloride F ~ 248C is obtained.
20 UV spectrum (~ thanol or ~ thanol ~ HCl O ~ t N):

infl. 215 nm E11 = 1,099 = 42,600 max. 293 nm E11 = 285 ~ = 11 100 Exe ~ ple 6: 2- / 3 - / (1 ~ 1-di ~ thy_t ~ a-ino / propoxy / N- (1H-; ndol-

4-yl) benza ~ ide and sc ~ n acid oxalate.
By operating according to a process similar to that described above for example 3, but ~ from 5 9 of 2- / N- (1H-indol-4-yl) amido /
30 ph ~ nol benzamide, we get; ent 3.1 ~ of the expected base F ~ 146C, then 3.1 9 of its oxalate F ~ 180 C.
W spectrum of oxalate (EthanoL) -infl. 218 nm E11 = 879 max. 297 nm E11 = 246 = 11,200.

Example 7: acid fumarate of N- ~ 2- / Z ~ pip ~ ridinyl) ~ thoxy /
.
phenyl / 1H-indol-4-carboxamide.
It is heated to 60C for 3 hours with stirring and atmosphere 17 ~ o ~
inert 3 9 of N- (2-hydroxyphenyl) 1H-indol-4-carboxamide in 50 cm3 benzene, 25 cm3 acetonitrile, and 50 cm3 5N aqueous sodium hydroxide, with 0.4 9 N-tetrabutylammonium hydrogen sulfate and 2.2 9 hydrochloride of 2-p; peridino 1-chloro ~ thane, cools, d ~ cante, extract a ac ~ tate

5 of ethyl, purifies by chromatography on silica (Eluent: acetate ethylettriethylamine 9-1) and obtains 3.6 9 of the expected base.
Formation of fu ~ arate:
The above base is dissolved in 10 10 cm3 of isopropanol, added 1.15 9 fumaric acid, reflux door, ice, filter, am ~ ne ~ dry under 10 reduced pressure and obtains in 2 jets 3.80 9 of the expected product, F ~ 186C after recr; allalisation in ethanol.
W spectrum:

infl. 230 nm E1 ~ = 681 infl. 260 nm E11 = 141 ~ ax. 300 nm E11 = 271 = 13 ûoo infl. 320 nm E11 = 224 Example ~: / 2- / 2-CJi ~ thylamino) ~ thoxy / ~ h ~ nyl / tH-indol- ~ -carboxa-ide, and its acid tartrate.
By operating according to a process analogous to that described above 25 for Example 7, but ~ from chloride hydrochloride of dimethylaminoethyl, 3.6 9 of base F ~ 110C are obtained, then 4.49 tartrate (softening point ~ 11ûDC).
UV spectrum of tartrate (Ethanol):

max. 228 nm E11 = 559 = 26,500 infl. Z63 n ~ E11 = 123 max. 300 nm E11 = 261 ~ = 12,400.

Example 9: N- / 2- / 2- ~ bis ~ thyl ~ thyl) a ~ ino / ethoxy / phenyl /
1H-indol-4-car ~ oxa ~ ide and its hydrochloride.
By operating according to a procedure similar to that of cr above for Example 7, but from 3.5 9 chloride hydrochloride 4û of diisopropylaminoethyl, 4 9 of base F ~ 145 C is obtained, tiO ~ .O
pu; s 2, ~ 9 of hydrochloride F ~ 214C.
Example ln ~ - ~ 1H-indol-4- l) 2- ~ 2- (1-p; peridinyl) ethoxy / benzamide Y, _ and its phosphate.
The procedure is as in Example 7 ~ starting from 2.5 9 from 2- / N- (1H-indol-4-yl) 5 amido / phenol and 1.84 9 2-pip hydrochloride ~ r; d; no 1-chloroethane. We 3.0 3.0 of expected product is obtained in the form of the base. F = 154C after recrystallization from ethyl ether.
Phosphate formation.
2.7 9 of the above base are dissolved in SOO cm 3 of ethanol and added 10 10 cm3 of a 1M solution of phosphoric acid in ethanol. We heat at reflux, add 500 cm3 of methanol, filter 3 hot, concentrate partially the reaction medium, ice, filter and dry under press;
r ~ reduced to 80C the product obtained. After recrystallization, we mix ethanol-methanol (1-1), 2.4 9 of expected product is collected ~ F = 238C.
t5 Analysis: C22 ~ 25N32 ~ H3P4 Calculated: CX 57.26 H% 6.12 NX 9.11 P% 6.71 Found: 57.1 6.2 9.0 6.6 Exe ~ le 11: 2- / 2-tdim ~ thyla ~ inG) ~ thoxy / N- ~ 1H-; ndol-4-yl) benzamide and its phosphate.
The procedure is as in Example 7 starting from 2.5 g of Z- / N- (1H-indol-4-yl) amido / phenol and 1.44 9 dimethyl thloroaminoethyl hydrochloride maintaining the heating for 24 hours. 2.15 9 of product are obtained expected as a base. F = 138C after recrystallization; etheration ethyl.
25 Training of haste.
We qpere as indicated in example 10 from 3.3 9 base prepared as above and replacing the ethanol with isopropanol.
3.5 9 of expected product are obtained ~
Analysis: C1gH2 ~ N302, H3P04: 421.37 ~
30 Calculates: CX 54.15 HX 5.70 NX 9.97 PX 7.35 Found: 53.8 5.8 9.8 7.3 Exe ~ pLe 12: 2- / Z- ~ bis (1 qethyl ~ thyl) a-ino ~ ~ thoxy ~ N- (1H-indoL-4-Yl? benzamide.
We ~ father as ~ example 7 ~ from 3.5 9 of 2- / N- (1H-indol-4-yl) 35 amido / phenol and Z, 8 g diisopropylamino chloride hydrochloride ethyl. 5.7 g of crude product are obtained which are purified by chromatography on silica (~ glow: chloroform-acetone-triethylamine

6-3-1) and recrystallizes from chloroform, then from a mixture isopropanol-methanol (2 ~ 2.25 9 of expected product is collected.
40 F = 180C.

lZ {i ~ iO5 (~
Analysis: C23H2gN302: 379.48.
Calculated: C% 72.79 HX 7.70 N% 11.07 Found: 72.9 7.9 10.9 Example 13: 2- ~ Z-hydroxy 3- (propy (a ~ ino) Propox ~ (1H-indol-4-yl) 5 benza-ide and its arid oxalate.
Heated for 2 hours at reflux 3.1 9 of 2- / t2-oxiranyl) methoxy / N- ~ 1H-indol-4-yl) benzam; from prepar ~ as in Example 4 in 60 cm3 of ~ thanol and 8.5 cm3 of n-propylamine. Solvents are removed under reduced pressure at 50C, chromatography the residue on silica (eluent: chloroform-methanol 10 7-3) and collects 2.8 9 of the expected product in the form of the base.
Acid oxalate formation.
1.7 g of the above base are dissolved in 200 cm 3 of isopropanol and 100 cm3 of methanol at reflux and added 583 mg of oxalic acid. We partially concentrates the reaction place, ice, filter, and dry under press; the product obtained is reduced to 80C. We collect 1.7 9 of expected product. F ~ 110 C.
Analysis: C21H25N303 ~ C2H24 467 ~ 48 Calculated: C% 60 ~ 39 HX 5 ~ 95 NX 9r18 Found: 60.2 6.0 9.2 20 Exe ple 14 ~ indol-4-yl) Z- ~ Z-hydroxy 3 - / (1_ ~ thyLethyl) amino /
propoxy / benza ~; de and its neutral oxalate ~
Onop ~ re as in Example 13 by replacing, ant n-propylamine by 8.6 cm3 of isopropylam; ne. 2.8 9 of product are obtained, expected in the form basic.
25 Formation of neutral oxalate.
We qpere as in Example 13 from 2.8 9 of base prepared above above ~ t 960 mg of oxalic acid. 1.7 9 of expected product are collected.
F = 190'C
AnaLys-e: C2lH25N303 ~ 1/2 C2H24 30 Calculated: CZ 64.06 HZ 6.35 NX 10.19 Found: 63.8 6.5 10.0 Exe ~ pLe 15: 2-J3- / ~ b; s ~ 1 ~ thyl ~ thYl) / a-ino / Zh- ~ droxy propoxy / N-(1H-indo1- ~ -yl) benza ~ ide.
The procedure is as in Example 13, replacing the n-propylamine with 35 14 cc of diisopropylamine maintaining reflux for 5 hours. We 4 9 of crude product is obtained which is chromatographed on silica ~ eluent:
chloroform-ethyl acetate-triethylamine 6-3-1) and recrystallizes from ethyl acetate. 2.4% of expected product is obtained. F = 160C.
Analysis: C24H31N33 l ~; G ~ (3 CalcuL ~: CX 70.39 HX 7.63 N ~ 10.26 Found: 70.4 7.8 10.2 Example 16: 2- / 3- (di ~ thyla ~ ino) 2-hydroxy propoxy / N- (1H-indol-4-yl) benzamide and its ch ~.
We operate as ~ Example 13, replacing n-propylamine with 10 cm3 of diethylamine. 3 9 of expected product are obtained in the form of based.
Formation of chlor ~ ydrate.
2.5 q of the above base are dissolved in 65.6 cm3 of acid 10 hydrochloric acid,, 1N and add 10 c ~ 3 of methanol, flush methanol under reduced pressure and freeze-dried the solution. We recover 2.67 9 of product expected.
Ana ~ yse: Cz2H27 ~ 03, ~ Cl: 417,939-Calculation ~: CX 63.23 HX 6.75 NX 10.05 ClX 8.48 15 Found: 62.9 6.9 9.9 8.7 Example 17: 2- ~ 3- / ~ t 8enzoate, 1-diD ~ thylethyl) am; no / 2-hydroxy DroDoxy / N- (1H-indol-4-yl) benza ~ ide.
2 9 of the base obtained in Example 4 are dissolved in 2 × 10 cm 3 isopropanol at reflux, and adds 640 mg of benzolque acid. We filter at 20 hot solution, partially concentrated, ice, filter and dry ~
press; we reduce ~ e to 80C the product; t obtained. After recrystallization in isopropanol, 2.09 of expected product is collected. F = 190C.
Analysis: C22H27 ~ 3 ~ C7 ~ 6 ~ 503 ~ 60 -Calculated: CX 69 ~ 17 HX 6.61 NZ 8.34 25 Found: S9.4 6.7 8.3 Exe ~ ple 18: 2- / 3 ~ di- ~ thyl ~ thYl) a ~ ino / 2-hydroxy propoxy / N-2,3-d; hydro 2-oxo 1H-; ndoL-4-yl / benza ~ ide and its neutral oxalate.
Stage A: 2- / 3 - / (1,1 ~ d; methylethyl) amino / Z-hydroxy propoxyt N- (3-chloro 1H-; ndol-4-yl) benzamide.
The mixture is stirred for 1 hour 3 at ambient temperature and under an atmosphere inert, the mixture comprising 3.39 of the base prepared in Example 4, 40 cm3 of acetic acid and 1.3 9 of N-chloro succinimide. We read the reaction medium with water, alkalinizes using ammonia and extract with ethyl acetate. We remove the solvents under pressure 35 reduced, chromatography on the res; silica (eluent: ethyl acetate-triethylamine 9-1) and obtains 2rS g of the expected product.
Stage B: 2- / 3 - / (1,1 ~ d; methylethyl) am; no / 2-hydroxy propoxyt N-2,3-d; hydro 2-oxo 1H-indol-4-yl ~ benzamide and its neutral oxalate.
Heated for 1 hour at reflux 2.5 9 of the product obtained above in 40 35 cm3 of ethanol and 70 cm3 of 1N hydrochloric acid. We dilute with water the U ~

reaction medium, basified with sodium hydroxide and extracted with acetate ethyl. After removal of the solvent under reduced pressure, it is collected 2.5 9 of crude product which spontaneously crystallizes in a mixture of solvents: chloroform-acetate of ~ thyle-triethylamine (6-3-1). We obtain 5 1.9 g of expected product in base form. F = 160C.
Formation of neutral oxalateO
1.9 9 of the above base are dissolved in 300 c ~ 3 of isopropanol and 100 cm3 of methanol at reflux and added 600 mg of oxalic acid. We now reflux for 15 minutes, cools, partially concentrates 10 the reaction medium, ice, filter and dry under reduced pressure on expected gross product. After recrystallization from an isopropanol mixture methanol (1-3 ~, 1.8 9 of the expected oxalate are obtained. F = 234C.
Analysis: C22H27 ~ 04, 1/2 C2H24 442 ~ 4 Calculation ~: CX 62.43 H% 6.38 NZ 9.50 15 Found: 62.2 6.4 9.3 ExeMple l9: 2- / 3- (4- ~ thyl 1-pip ~ razinyl) 2-hydroxy propoxy / N- ~ 1H-indol-4-yL ~ benzaoide and its acid oxalate.
Is heated under reflux for 1 hour 1.8 9 of Z - / (2-oxiranyl) methoxy /
N- (1H-indol-4-yl) benzamide prepared as indicated in Example 4 in 20 3 $ cm3 of ethanol and b, 5 cm3 of N-methyl pip ~ razine. We eliminate solvents under reduced pressure, chromatography the residue on silica (eluent: chloroform-methanol -1) and obtain; ent 1.77 9 of the expected product in basic form.
Acid oxalate formation.
Dissolve 1.7 9 of the above base in 100 cm 3 of isopropanol, add 524 mg of oxalic acid, filters and dries under reduced pressure at 70C on product obtained. After recrystallization from isopropanol, it is collected 0.96 9 of oxalate ~ stretched. F ~ 130 C (decomposition).
Analysis: C23H28N ~ 3 ~ C2H24 498 ~ 54-30 Calculation ~: CX 60.23 H ~ 6.07 NX 11.24 Found: 60.3 6.3 11.2 Example 20: 2-! 3- / 4- (2- ~ thox ~ ph ~ nyl ~ 1-pip ~ razinyl / Z-hydroxy propoxy / N- (1H-indol- ~ -yl ~ benzamide.
Is heated under reflux for 4 hours 1.6 9 of 2 - / (2-oxiranyl) 35 methoxy / N- (1ff-indol-4-yl) benzamide in 36 cm3 of ethanol with 1.82 cm3 of (methoxy phenyl) piperazine. The solvent is removed under pressure reduced, purifies the residue by chromatography on silica (eluent:
chloroform-ethyl acetate-tri ~ thylamine 6-3-1) and collects 1.85 9 of expected product.
40 W spectrum (ethanol) infl, 235 nm E11 = 449 ~ = 22400 max. Z87 nm E11 = 222 ~ = 11 100 ; nfl. 294 n ~ E11 ~ 215 infl. 310 nm E11 = 179 ~ = 8900 ~ (chloroform) 10 OH free: 3600cm-1 = C-NH: 3481Cm-1-3373cm-1 ~ C = O: 1661 Cm-1 C = C ~ aromatic + amide II I 1623Cm 1ol600Cm-1-1587Cm 1_ 1 1538Cm ~ 1-15oocm-1-148scm-1 15 Exe ~ ple 21: 2- / 3 - /! 2- (3,4-dim ~ thoxy ~ l) ~ thyl / amino / 2-hydroxy propoxy / N- ~ tH-indol- ~ nzamide Heated for 1 hour at reflux 4 9 of 2- / t2-ox; ranyl) methoxy / N- (1H-; ndol-4-yl) benzamide in 48 cm3 of ~ thanol with 6.57 cm3 of dimethoxy phenyl ethylamine, ~ removes the solvent under reduced pressure and purifies the 20 residue by chromatography on silica ~ eluent: chloroform-nethanol 9-1).
4.60 9 of expected product are obtained.
UV spectrum (ethanol) infl. 218 nm E11 = 921 infl. 230 nm E11 = 528 ~ = 258ûO

max. 288 nm E11 = 222 = 1U900 ~ nax. 299 nm E11 ~ 211 = 10300 ; nfl. 310 nm E11 = 187 ~ = 9150 IR spectrum ~ chloroform) 35 secondary amide NH: 3360cm-1 c = o 16sgcm-1 amide II: 1,534 cm-1 aromatic: 16Z3Cm 1-16o15m ~ 1_1s87cm-1 ~ 0 aromati ~ eu C ~ O ~ CH2: 1516 /

CH30 ~
methoxy: 2g37cm-1 5 Exe ~ ple 22: 2- / 3- ~ cyxlohexylamino ~ 2-hydroxy propoxy / N- (~ H-indol-4-yl) ben2am; of.
Heated for 2 hours at reflux 2.5 9 of 2 - / (2-ox; ranyl) methoxy / N- (1H-indol-4-yl ~ benzamide in 20 cm3 of ~ thanol with 1.86 cm3 of cyclohexyl-amine. The solvent is removed under reduced pressure, chromatography 10 residue on teluant silica: chloroform-methanol 9-1 ~ and obtains 1.97 9 of expected product.
UV spectrum (ethanol) infl. 216 nm E11 = 832 infl. 234 nm E1 ~ = 320 ; nfl ~ 270 nm E11 = 113 ~ ax. 296 nm E11 = 212 = 8650 infl. 304 nm E11 = 199-IR spectrum (chloroform ~
25 NH indole: 3480 Amide: 1660C ~
Amide II: 1,536cm-1 Aromatics: 1624Cm-1-1600Cm-1-1588Cm ~ 1-1503Cm-1-1485Cm-1.
Exe ~ p ~ e 23: 4-r3 - / (~ 1-dim ~ thyl, ethYl) amino / 2-hydroxy propoxy / N-30 t ~ H-indbL-4-yl) benzamide ct its neutral fumarate.
Stage A: 4 - / (2-oxiranyl) m ~ thoxy / N- (1H-indol-4-yl) benzamide.
We ~ p ~ re as ~ Example 1 apart; r of 5.37 9 of 4 ~ - (1H-indol-4-yl) amido / phenol and 25.8 cm3 of ~ pichlorohydrin. After chromatography on sil; this (~ glow: ethyl chloroform-acetate-tri ~ thylamine 6-3-1 ~ and 35 th ~ pasting in ~ ther isopropyl; that, 2.9 g of product are collected expected. F = 170C.
Stage a :: 4- / 3 - / (1,1-dimethylethyl) amino / Z-hydroxy propoxy / N- (1H-indol-4-yl) benzamide and its neutral fumarate.
The procedure is carried out as in stage B of Example 1 ~ starting from Z, 9 9 of product 40 obtained in stage A and obtains 3.5 9 of the expected product in the form of the base.

F = 212C.
Formation of neutral fumarate.
2.9 9 of the base obtained above is dissolved in 300 cm3 of isopropanol at reflux, add 0.88 9 of fumaric acid then 200 cm 3 of 5 methanol and continue heating at reflux for 30 minutes. We partially concentrates the reaction medium; onnel, ice, filter, dries under reduced pressure ~ 80C and obtains 2.3 9 of crude product. After recr; stallization in the ethanol-methanol-water mixture (10-10-1), we collects 1.8 9 of neutral fumarate. F> 270 C.
10 Analysis: C2zH27N302 ~ 1/2 ~ 4H404 439 ~ 5 Calculates: CZ 65.5 ~ HX 6.65 NX 9.56 Found: 65.3 6.7 9.6 Preparation of 4-lN- ~ 1H-indol-4 ~ amido / phenol.
42 cm3 of tr; -isobutyl- are added slowly under an inert atmosphere.
15 aluminum in tolu solution ~ nique ~ 1.1M) ~ a solution of 3 9 of 4-amino indole in 100 cm3 of chloroform. Then added 3.5 9 of para-hydroxyethyl benzoate in 50 cm3 of chloroform and then heated to ref ~ ux for 24 hours. Cool, add 20 cm3 of acid hydrochloric 2N, stirred for 30 minutes, filters the precipitate ~, washes it 20 water and dry under reduced pressure ~ 80C. We get 4.9 9 of expected gross productO
W ~ ethanol spectrum) max. 212 nm E11 = 1455 ~ = 3670û
max. 256 nm E11 = 557 ~ = 140ûO

max. 277 nm E11 = 438 = 11 ooo max. 284 nm E11 ~ 444 = 11200 infl. 294 nm E11 = 432 ~

Example 24: 4-chloro 2- / 3 ~ di ~ thyl ~ thyl) amino / 2-hydroxy 35 DrODoxY / N- ~ 1H-indol 4-yl) benzaoid and its neutral oxalate , Stage A: 4-chloro 2- / ~ 2-oxiranyl ~ methoxy ~ N- (1H-indol-4-yl ~
benzamide ~
The mixture is refluxed for 24 hours under an inert atmosphere 4.5 g of 5-chloro 2 - / (2-oxiranyl) methoxy / N- (1H-indol-4-yl) benzamide in 150 cm3 40 ac ~ tone with 2 ~ 2 g of potassium carbonate and 12.5 cm3 of epichlorhy-2s l ~

drine. The product crystallizes in the reaction medium; el; mine the solvent under press; reduced to 50C, resumes the residue ~ water, filter, dries it under pressure reduced to 80C. We get 5 9 of product expected. F = 19 ~ C.
5 Stage ~: 4-chloro 2- ~ 3 - / (1,1-dimethylethyl) amino / 2-hydroxy propoxy /
N- (1H-indol-4-yl) benzam; de and its neutral oxalate.
Heated for 2 hours at reflux 5 9 of the above product in 100 cm3 ethanol and 7.6 cm3 of terbutylam; do not then remove the solvent under pressure reduced to 50C. After chromatography on silica (glue: chloroform-10 m ~ thanol-triethylamine 8-1-1), 5 9 of the expected product are collected under basic form.
Oxalate formation.
5 9 of the above base are dissolved in 300 cm 3 of isopropanol and 300 cm3 of methanol at reflux, then add 1.5 9 of oxalic acid and 15 maintains the heating for 15 minutes. We partially concentrate, ice, filter and dry under reduced pressure ~ 80 ~ C the product crystallizes. 4.49 of expected product is obtained. F ~ 254C.
Analysis: C22H26 ~ C ~ ~ 1/2 C2H24 46 ~
Calcube: C% 59.93 HX 5.90 NX 9.12 ClX 7.69 20 Found: 59.9 6.1 8.9 7.6 Preparation of 5-chloro 2-N- (1H-indol ~ 4-yl) amido / ph ~ nol.
The mixture is heated at reflux for 2 hours under an inert atmosphere under inert atmosphere the solution comprising 5.28 9 of 4-amino indole, 10û cm3 tetrahydrofuran, 6.9 9 ac; 4-chlorosalicylic acid and 9.06 9 ac DicyclohexylcarbodiiMide. Filter the dicyclohexylurea formed and flush the solvent under pressure r ~ reduced to 50C. After chromatography on silica teluant: chloroform-ethyl acetate (9-1), the r ~ sidu is pasted ether ~ dries and obtains 5.55 9 of the expected product. F = 245C.
Analysis: C15H11N2ClO2: 286.720.
30 Calculated: CX 62.84 H% 3.87 NZ 9.77 CLX 12.3 Found: 62.5 4.0 9.7 12.3 Example 25: 2- ~ 3 ~ dimethyl ~ thyl) a0ino / 2-hydroxy propoxy / N-t1H-indoL-4-yl) 5- ~ benzoxy ethoxy and its neutral oxalate.
Stage A ~ 5-m ~ thoxy 2- / t2 ~ oxiranyl) m ~ thoxy / ~ J- (1H-indol-4-yl) 35 benzamide.
The mixture is heated at reflux for 20 hours under an inert atmosphere 4.5% of 4 ~ m ~ thoxy 2- / N-t1H-indol-4-yl) amido / phenol in 150 cm3 of acetone with 2.2 9 of potassium carbonate and 12.5 cm 3 of epichlorohydrin. We filter potassium carbonate, removes the solvent under reduced pressure at 50C
4tl and chromatography the residue on silica (eluent: chloroform-acetate Z6 ~ t ~

ethyl 9-1). 5.49 of product is collected which is placed in ether, filter and dry under reduced pressure. 5 9 of expected product are obtained.
~ = 122C.
Stage 8: 2- / 3- / ~ 1,1-dimethylethyl) amino / 2-hydroxy propoxy / N- ~ tH-5 indol-4-yl) 5-methoxy benzamide and its neutral oxalate.
The operation is carried out as in stage B of example 24 using at the start 5 9 of the product of stage A above and obtains 4.99 of the expected product under basic form.
Formation of the neutral o ~ late.
The procedure is carried out as in stage 9 of Example 24 starting from 4.9 9 from the base.
obtained above and obtains 3.2 9 of expected product. F = 254C.
Analy ~: C23H2gN304, 1/2 C2H24 456 ~ 523-Calculated: C ~ 63.14 HZ 6.62 NX 9.20 Found: 62.9 6.7 9.0 Preparation of 4-methoxy 2- / N- (1H-indol-4-yl) amido / phenol.
Heated for 6 hours under reflux under an inert atmosphere 3.96 9 of 4-amino indole in 70 cm3 of tetrahydrofuran with 5 9 of 5-methoxy acid salicylic acid and 6.18 9 of dicyclohexylcarbodiimide. We add again 618 mg of dicyclohexylcarbodiimide and continues stirring at temperature 2D ambient for 20 hours. Filter, remove the solvent under pressure reduced to 50C, takes up the residue with 300 cm3 of ethyl acetate, wash the organic phase with 2N hydrochloric acid, then with a solution saturated aqueous ~ e in sodium chloride, dries and removes the solvent under reduced pressure ~ 50 ~ C. 9.4 9 of crude product are obtained which is purified 25 by chromatography on silica (eluent: chloroform-ethyl acetate 9-1). The product collected is pasted in isopropyl ether, filter, dry and obtain 4.7 g of the expected product. F = 225 C.
Example 26: 2- / 30 (cyclohexyl ~ ethyl) a ~; no / 2-hydroxy propoxy / N- (1H-indol-4-yl) benzamide.
Dissolved by heating at reflux 2.5 9 of 2 - / (2-oxiranyl) m ~ thoxy / N-(1H-indol-4-yl) benzamide prepared as in e ~ example 4 in 50 cm3 of ~ thanol in the presence of 1,147 9 of cyclohexane methylamine and continues the heating for 2 hours and 15 minutes. The solvent is removed under reduced pressure, chromatography the residue on silica (eluent: chloride 35 of methyl ~ ne-methanol 9-1) and obtains 1.97 9 of the expected product.
UV spectrum (ethanol) infl. 215 nm E11 = 385 4û infl. Z34 nm E11 = 365 27 ~ 0 ~ 0 infl. 269 nm E11 = 128 infl. 292 nm E11 = 229 max. 297 nm E1 ~ = 237 ~ = 10,000 infl. 310 nm E11 = 211.

EXAMPLE 27: 2- / 3 - // 2- ~ 3,4-dim ~ thoxy ~ h ~ nyl) ~ thyl / ~ thyla ~ ino ~ 2-10 hYdroxY DroDoxY / N- (1h-; ndol-4-Yl) ben ~ a ~ ide _ _ It is dissolved at ambient temperature under an inert atmosphere 0.2 9 of 2-/ 3 - // 2- (3 ~ 4-dimethoxyphenyl) ethyl / amino / 2-hydroxy propoxy / N- (1H-indoL-4-yl) benzamide pr ~ prepared as in Example 21 in S cm3 of methanol in presence of 0.1 cm3 of formaldehyde at 40% water. We add a solution 15 comprising 26 mg of sodium cyanoborohydride and 27.2 mg of sodium chloride zinc in 5 cm3 of m ~ thanol and leaves for 2 hours at room temperature.
S cm3 of 1N sodium hydroxide is added, extracted with ethyl acetate, the phase is washed organic ~ water, dry and remove solvents under press; reduced.
0.230 9 of crude product is collected which is purified by chromatography 20 on silica ~ eluent: chloroform-ac ~ tate of ~ thyle-triethylamine 6-3-1). We 0.150 9 of expected product is obtained.
UV spectrum (ethanol) infl. 218 n ~ E11 = 794 infl. Z30 nm E11 = 429 max. 286 nm E11 = 181 max. 298 nm E11 = 176 ~ ~ 8850 infl. 310 nm E11 = 158 infl. 318 nm E11 = 147.
Pharmacologic study;
1) Antiarrhythmic action in rats Male rats weighing 300-350 9 anaesthetized with tracheotomy intraperitoneal route ~ ale ~ using 1.20 g / kg of ur ~ thane and submits them to 40 artificial respiration (40-50 breaths of 3 ml / minute).

28 ~ O ~ ~

Needles are implanted under the skin to record the electrocardiogram of the rats on the signal below; DII.
The products to be tested are administered intravenously or by orally.
C; nq m; nutes after administration of the product intravenously or 1 hour after oral administration, the vein is perfused jugula; re rats with 10 Jug / min of an aconitine solution and the time of onset of heart rhythm disturbance (10 ~ 9 aconitine corresponding to the infusion of 0 ~ 2 ml of solution.) The results are expressed as a percentage of time extension Apparently there are heart rhythm disturbances compared to the controls and in dark; one of the dose of the tested product. The results shown on the table below show that the products of this application are endowed with remarkable antiarrhythmic properties.
¦ Example product ¦ Dose ¦ Elongation percentage vo; e ¦ in mg / kg ¦ of the time ¦ 1 IV ¦ 0.25 1 + 31 20 1 1 0.5 1 + 41 1 1 1 + 110 2 IV ¦ 1 ¦ + 6 1 2.5 1 + 57 3 IV ¦ 2.5 1 + 68 4 IV ¦ 0.5 1 + 17 + 38 30 1 1 2.5 1 + lZ4 P0 1 5 1 + 7 ¦ 10 1 + 46.
1 25 1 + 81 IV ¦ 0 ~ 25 ¦ + 9 0.5 1 + 36 I 1 1 + 33 ¦ 2.5 1 + 61 40 1. I. .

29l ~ ifiO ~

¦ Example product ¦ Dose ¦ Elongation percentage ¦ route ¦ in mg / kg ¦ time . 1.. I. I
5 I PO I 2.5 1+ 22 1+ 32 I 1 10 1+ 59 1 6 IV ¦ 1 1+ 23 10 1 1 2.5 1+ 41 PO I 25 1+ 29 1 15 IV ¦ 2.5 ¦ + 25.5 15 1 1 5 1+ 56 2) Study of acute toxicity We have ~ Yalu ~ lethal doses DLo of the different compounds 20 tested after oral administration in mice.
DLo is called the maximum dose; male causing no mortality in 8 days.
The results obtained are as follows:

. _ Z5 I Product of example ¦DLo in mgJkg -. ._ I

1 4 1 ~ 400 12! > 400 1 5 1> ~ 400 ~ _ ._. .I. ._ _ I

o ~

ADDITIONAL DISCLOSURE

This additional disclosure and the related claims relate to a very special group of N- derivatives (1H-indol-4-yl) benzamide, which derivatives fall within the definition of the general formula (I) given in the disclosure main.
More specifically, this disclosure additional subject is new derivatives falling in the general formula given in the disclosure main, which new derivatives are endowed with anti-arrhythmic properties in particular interesting and meet the formula (I ' Y ~ CH3 ~ Y ~ N ~ CH3 \ N / OH H 3 (I ') ~ `N ~.
H

in which either of the substituents X or Y
represents an alkyl radical containing from 1 to 5 atoms of carbon, an alkoxy radical containing from 1 to 3 atoms of carbon, a chlorine, bromine or iodine atom, a radical nitro or an amino radical optionally substituted by a aliphatic acyl group containing 2 to 5 atoms of carbon or one or two alkyl radicals containing from 1 to 5 carbon atoms and the other substituent represents an atom of hydrogen, it being understood that Y does not represent the - 31 - lZ ~ 050 methoxy group and X a chlorine atom as well as their addition salts with acids.
When X or Y represents an alkyl radical, it it is preferably a methyl or ethyl radical, but they can also represent an n-propyl radical, isopropyl, n butyl, isobutyl, tert-butyl or n-pentyl.
When X or Y represents an alkoxy radical, it it is preferably a methoxy, ethoxy, n- radical propoxy or isopropoxy.
When X or Y represents an amino radical substituted by an aliphatic acyl group containing from 2 to 5 carbon atoms, it is preferably a radical amino preferably substituted by an acetyl radical or propionyle.
When X or Y represents an amino radical substituted by one or two alkyl radicals, these are preferably methyl or ethyl radicals.
Addition salts with mineral acids or organic can be, for example, the salts formed with hydrochloric, hydrobromic, nitric acids, sulfuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkane sulfonic such as methane and ethane sulfonic, arylsulfonic, such as benzene acids and sulfonic and arylcarboxylic paratoluene.
Particularly preferred are the compounds of formula (I ') characterized in that X represents a radical methoxy, nitro, amino or acetylamino and Y represents a hydrogen atom or Y represents a chlorine atom, a nitro, amino or acetylamino radical and X represents a hydrogen atom, as well as their addition salts with acids and especially 2-¦3- ~ (1,1-dimethylethyl) amino ~ 2-hydroxy propoxy ~ N- (1H-indol-4-yl) 5-nitro ~, l ~ titiO ~

benzamide and its addition salts with acids.
The compounds of formula (I ') as defined above can be prepared by a process similar to the one described in the main disclosure.
The process for preparing the products of the this request is characterized in that one reacts a compound of formula (II '):

/

/

X

Y_ ~
--OH
O - (II) HN

in which X and Y have the above meanings, with a halide of formula (III):

15 Hal-CH2 ~ -CH2 (III) to obtain a compound of formula (IV):

y `~
~ \ O-CH2-C ~ H - C ~ 2 IV
~ 0 25 H- ~

H
that we react with ter-butylamine to get a compound of Formula (I) which, if desired, is subjected to the action of a mineral acid or organiq ~ e to obtain a salt.
When X or Y represents an alkyl ~ alkoxy group or an atom of chlorine, bromine or iodine in the compound of formula (II), Hal is preferably a chlorine atom in the compound of formula (III ~.
The reaction of the compound of formula (II5 with the compound of formula (III) is then preferably carried out in the presence of a base such as potassium or sodium carbonate, soda or potash.
When X or Y represents a nitro group in the compound of formula (II), Hal is preferably a bromine atom in the compound of 40 formula (IIIS. The reaction is then carried out by heating at reflux the . t -t; O ~

compound of formula (IV ').
The reaction of the derivative of formula (IV ') with the terbutylamine is produced using a solvent such as aliphatic alcohol such as methanol or ethanol.
When you want to prepare a compound of formula (I ') in which X GU Y represents an amino radical optionally substituted, the compound can be reduced formula (I ') in which X or Y represents a radical nitro and if necessary, the amino derivative is reacted with a derivative of the substituent which it is desired to obtain.
The corresponding operating conditions are known to those skilled in the art.
The starting material of formula (II ′) can be prepared by reaction of 4-amino indole with hydroxy acid benzoic substituted by`X or Y.
The derivatives of formula (I ') have very interesting pharmacological properties; they are gifted notably remarkable antiarrhythmic properties and some products have anti-lime properties.
These properties are illustrated later in the Experimental part.
These properties justify the use of derivatives of N ~ 1H-indol-4-yl) benzamide of formula (I '), thus as their salts, as medicaments.
Among these drugs, it is preferable to retain drugs made up of new derivatives of N- (1H-indol-4-yl) benzamide corresponding to formula (I '), characterized in that X represents a methoxy radical, nitro, amino or acetylamino and Y represents an atom hydrogen or Y represents a chlorine atom, a nitro, amino or acetylamino radical and X represents an atom of hydrogen as well as their addition salts with acids.

, ~ t; o ~, o - 34a -Among these, we particularly note 2-L3 - [(1,1-dimethylethyl) amino ~ 2-hydroxy propoxy ~ N- (1H-indol-4-yl) 5-nitro benzamide and its addition salts with acids.
These drugs find their use, for example in the treatment of arrhythmias.
The usual dose, which varies depending on the derivative used, the subject and the affection in question can be, for example, /

`- 3 ~ 050 oral route, in humans ~ the derivative of Example 1 can be administered to the daily dose of 200 mg to 800 mg, for example for treatment ventricular, supraventricular and junctional arrhythmias, i.e.
about 3 mg to 1Z mg per kilogram of body weight.
The invention also relates to pharmaceutical compositions which contain at least one aforementioned derivative or one of its addition salts with pharmaceutically acceptable acids, as active ingredient.
As medicaments, the derivatives corresponding to formula (I) and their addition salts with pharmaceutically acceptable acids can 10 to be incorporated into pharmaceutical compositions for the track digestive or parenteral.
These pharmaceutical compositions can be, for example, solid or fluids and come in pharmaceutical forms commonly used in human medicine, such as tablets, simple or 15 sugar-coated pills, capsules, granules, suppositories, preparations injectables; they are prepared according to the usual methods. The active ingredients can be incorporated into exicpients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, butter 20 cocoa, vehicles with or without x, fatty substances of animal origin or vegetable, paraffinic derivatives, glycols, various agents wetting agents, dispersants or emulsifiers, preservatives.
The following examples illustrate the present invention without however, limit it.
25 Example 28: 2- B ~ dimethyleth ~ l? amino] 2-h ~ droxy propoxy] N- ~ 1H-indol 4-yl) 5-nitro b nza de and its hydrochloride.
Is heated under reflux for 1 hour 9.8 9 of 2-hydroxy 5-nitro N- (1H-indol-4-yl) benzamide with 40 cm3 of epibromhydrin. Remove under pressure reduced 3 60 ~ C the excess of ~ pibromhydrin, takes up the resin obtained by 30 100 cm3 of ethanol and 40 cm3 of terbutylamine and heated at reflux for 2 hours. The excess solvent and reagent are removed under reduced pressure at 60 ~ C and obtains 78 9 of crude product. The purification is carried out by two successive chromatographies on silica (1st: eluent: chloroform 8-methanol 1-triethylamine 1, 2nd: eluent: chloroform S-acetone 4-Triethylamine 1). 4 ~ 4 9 of product is recovered in the form of base F = 208 ~ C ~
Hydrochloride formation 3.5 9 of the base prepared above are dissolved in one liter isopropanol and 250 cm3 of methanol at reflux, add a saturated solution 40 hydrochloric acid in ethyl acetate to acidic pH. We heat - 36 ~ 050 30 minutes at reflux, concentrate up to around 500 cm3, ice, filter-and-. . . ~
dry under reduced pressure at 50 ~ C. 2.85 9 of expected product are obtained.
F 260 ~ C.
Analysis: i 5 Calculated: CX 57.08 H% 5.88 N% 12.1U Cl% 7.66 Found: 56.8 6.1 12.0 7.4 Preparation of Z-hydroxy 5-nitro N- (1H-indol 4-yl) benzamide The mixture is refluxed for 3 hours, t 3 hours, 6 g of 4-am; no indole, 150 cm3 of tetrahydrofuran, 8.4 9 of 5-nitro sal; cylic acid and 12.5 9 of 10 dicyclohexylcar ~ odiimide. Cool, filter, add 200 cm3 of acetate ethyl, removes excess unreacted 4-amino indole by washing with 1N hydrochloric acid, dry, filter, evaporate to dryness under pressure reduced to 50 ~ C. 20 9 are obtained from a resin which is impasted by a mixture chloroform methanol t50 / 50), filter, dry under reduced pressure and obtain 15 7.5 9 of expected product F> 260 ~ C.
Example 29 5-amino 2- ~ 3- ~ (1,1-dimethyl ~ th ~ l) amino ~ 2-hydroxy propoxy] N-(1H-indol 4-Yl? Benzam; de.
Is heated for 1 hour at reflux, 142 mg of product of example 28.5 cm3 methanol, a pinch of Raney nickel and 0.2 cm3 of hydrate 20 of hydrazine. Filter, remove the methanol under reduced pressure at 50 ~ C and obtains 128 mg of expected product.
UV spectrum:
ethanol:
Max. 219 nm E11 _ 443 Max. 31U nm E11 = 230 in ethanol, HCl N
1 ~) Max. 299 nm E11 = Z08 ~ = 8,200 Infl. : 275 and 332 nm Example 30: 5-ac ~ tylamino Z- [3-C (1c1-dimethylethyl) amino ~ 2-hydroxy propoxy] N- (1H-indol-4-yl) benzamide and its neutral oxalate.
Stage A: 5-amino 2-hydroxy N- (1H-indol-4-yl) benzamide.
A suspension comprising 6 g is heated at reflux for 2 hours.
35 of 5-nitro 2-hydroxy N- (1H-indol-4-yl) benzamide prepared ~ Example 28 600 cm3 of methanol and 15 cm3 of 64% dthydrazine hydrate in the presence of 6 9 of Roney's Nickel. The solution obtained is filtered, the solvent is removed under reduced pressure at 50UC, takes up the residue with a chloroform mixture-methanol (1-1), filters the crystallized product, dries and collects 4 g of 40 expected product. F ~ 260 ~ C.

- 37 ~
Stade_B: 5-acetylamino 2-acetoxy N- (1H-indol-4-yl) benz3mide. ~ ~
Ao / + snc ~ 2.6 9 of product prepared in the preceding stage is cooled, suspended in 70 cm3 of tetrahydrofuran and then adds 4.7 cm3 of acetic anhydride then maintains 3 hours at room temperature. We 5 removes the solvent under reduced pressure at 50 ~ C, takes up the residue in a chloroform-methanol mixture (1-1), filters and obtains after drying at 80 ~ C, 2.7 9 of expected product. F = 263 ~ C.
Stage C: 5-acetylamino 2-hydroxy N- (1H-indol-4-yl) benzamide.
1.5% of boron and sodium hydride are added at room temperature 10 in a suspension comprising 1.5 9 of product obtained in the previous stage and 150 cm3 of methanol, then heats for 2 hours at reflux. We elect; mine partially methanol under reduced pressure at 50 ~ C, diluted by 200 cm3 water and 2 ~ 0 cm3 of ethyl acetate then extracted with ethyl acetate. We dry, removes solvents under pressure reduced to 50 ~ C and collected;
1.35 9 of the expected product used as it is for the next stage.
Stage D: 5-acetylamino 2-C ~ 2-oxjranyl) methoxy ~ N- (1H-indol-4-yl) benzamide.
3.5% of product prepared as reflux is heated for 2 hours in stage C, 150 cm3 of acetone, 1.6 9 of potassium carbonate and 9 cm3 20 epibromhydr; ne. 9 cm3 of epibromhydrin are again added and continue;
reflux for 2 hours. Filter, wash with acetone, remove the solvent under reduced pressure at 50 ~ C, takes up the residue in ether, filter ~ dry at 80 ~ C and collects 3.4% of the expected product. F = 230 ~ C.
Stage E: 5-acetylamino 2-C3-C (1,1-dimethylethyl) am; no] 2-hydroxy .5 propoxy] N- (1H-indol-4-yl) benzamide and its neutral oxalate.
3.4% of the product obtained is heated at reflux for 1 hour.
above in 200 cm3 of ethanol and 20 cm3 of terbutylamine. We eliminate solvents under reduced pressure at 50 ~ C, chromatograph the residue on silica (eluent: chloroform-methanol-triethylamine 8-1-1) and collects 3.9 g of 30 base expected.
Preparation_of_oxalate.
2.7 9 of base are dissolved in 200 cm3 of ethanol and 330 mg are added.
oxalic acid. Filter, dry at 80 ~ C under reduced pressure and obtain 2.2 9 of the expected oxalate ~ F> 260 ~ C.
35 Analysis: c24H3oN4o4 ~ 1/2 C2HZ04 Calculated: C% 62.10 H% 6.46 N% 11.59 Found: 61.9 6.2 11.5 Example 31: 2- ~ 3- ~ (1,1-dim ~ thylethyl) amino] 2-hydroxy propoxy] N- (1H-indol-4-yl) 4-m ~ thoKy benzamide and its benzoate.
40 Stage A: 4-methoxy 2 - [(2-oxiranyl) methoxy] N- (1H-indol-4-yl) - 38 - 1 ~ ~ ~ '~
benzamide.
The procedure is carried out as in stage D of example 30 starting from 5 9 of 4-methoxy 2-hydroxy N- (1H-indol-4-yl) benzamide, 150 cm3 of acetone, 2.45 9 of potassium carbonate and 14 cm3 of epichlorohydrin. We get 7.3 9 of S expected product. F = 157 ~ C.
Stage B: 2- [3-C (1,1-dimethylethyl) amino] 2-hydroxy propoxy ~ N- (1H-indol-4-yl) 4-methoxy benzamide and its benzoate.
We operate as in Stage E of Example 30 from 6 9 of the product prepared in stage A above, 100 cm3 of ethanol, 9.2 cm3 of terbutylamine, 10 maintaining reflux for 3 hours. We obtain 6.1 9 of expected base which is dissolved in 300 cm3 of isopropanol at reflux and then added 1.8 9 benzolque acid. We concentrate together; ice, filter, dry under reduced pressure and obtains 5.1 9 of expected benzoate. F = 195 ~ C after ~
recrystallization in ~ thanol.
15 Analysis: C23H29N34r C7H62 533 ~ 629 Calculation: CX 67.53 H ~ 6.61 N ~. 7.87 Found: 67.5 6.7 8.0 Preparation of 4-methoxy 2-hydroxy N-t1H-indol-4-yl) benzamide used in starting from example 4.
Is heated under reflux for 24 hours 3.96 9 of 4-amino 1H-indole, 70 cm3 of tetrahydrofuran, 5 9 of 2-hydroxy 4-methoxybenzo acid; and 6.2 9 of dicyclohexylcarbodiimide. The solvent is removed under pressure reduced to SOnC, take up the residue in ethyl acetate and remove; do not 4-amino indole unreacted by washing with 2N hydrochloric acid. We 25 eliminates ethyl acetate under reduced pressure, takes up the residue at ether and dry at 50 ~ C. 7.1 g of expected product are obtained. F = 190 ~ C.
Example 32: 5-ch ~ oro Z- ~ 3- ~ (1,1-dimethylethyl) amino] 2-hydroxy propoxy]
N- ~ 1H-indol-4y 1) benzamide and its neutral oxalate.
Stage A: S-chloro 1-C (2-oxiranyl) methoxy] N- (1H-indol-4-yl) 30 benzamide.
The procedure is carried out as in stage D of Example 30 from 3 9 of S-chloro 2-hydroxy N- (1H-indol-4-yl) benzamide, 100 cm3 of acetone, 1.47 9 potassium carbonate and 8.3 cm3 of epichlorohydrin. We get 3.35 9 of expected product. F = 175 ~ C.
35 Stage B: S-chloro 2- [3 - [(1,1-dimethylethyl) amino] 2-hydroxy propoxy]
N- (1H-indol-4-yl) benzamide and its neutral oxalate.
We operate as in stage E of the example 30j starting from 3 9 of the product obtained in stage A, 60 cm3 of ethanol and 4.6 cm3 of terbutylamine. We obtain 2.6 9 of base expected then 2.4 9 of oxalate. F ~ 260 ~ C.

39 - 1A ~
Analysis: CZ2H26clN303, 1/2 C2 ~ 124 460 ~ 941 Calculated: C% 59.93 H% 5.90 N% 9.12 Cl% 7.69 Found: 60.2 5.8 9.1 7.9 Preparation of 5-chloro 2-hydroxy N- (1H-indol-4-yl) _b_nzamide used in 5 start from example 32.
Is heated to reflux 3.96 9 of 4-amino 1H-indole in 75 cm3 of tetrahydrofuran with 5.16 9 of 5-chloro salicylic acid and 6.2 g of dicyclohexylcarbodiimide, for Z hours, 0.6Z g is added again dicyclohexylcarbodiimide, still heats for 1 hour at reflux, 10 cools, filters, removes the solvent under reduced pressure at 50uc ~ On takes up the residue in ethyl acetate, washed with acid 2N hydrochloric acid, dries and eliminates ethyl acetate under reduced pressure at 50uC After chromatography of the residue on silica (eluent: chloroform-ethyl acetate 9-1 ~, 3.9 g of expected product is recovered. F = 248 ~ C ~
15 Example 33:
We prepared tablets ~ corresponding to the formula:
- product of Example 28 ............................ 50 mg - excipient qs for one tablet finished at .......... 100 mg (details of the excipient: lactose, starch, talc, magnesium stearate).
20 Pharmacological study 1 /. Anti-arrhythmic action in rats:
Male rats weighing 300-350 9 anaesthetized with tracheotomy intraperitoneally using 1.20 g / kg of urethane and subjecting them to artificial respiration (40-50 breaths of 3 ml / minute).
Needles are implanted subcutaneously to record the electrocardiogram of rats on the DII bypass signal.
The products to be tested are administered intravenously or by orally.
Five minutes after administration of the product by intravenous route, 30 infuse the jugular vein of rats with 10 ~ g / min of a solution of aconitine and note the time of onset of rhythm disturbances cardiac (10 ug of aconitine corresponding to the infusion of 0.2 ml of solution).
The results are expressed as a percentage of time extension 35 onset of heart rhythm disturbances compared to evidence; ns and depending on the dose of the product tested. The results shown on the table below show that the products of this application are endowed with remarkable antiarrhythmic properties.

- 40 - 12 ~ 0 ~ 0 ¦ Product of Example I Dose ¦ Percentage of elongation I channel IV channel I in mg / kg I of time 28 1 2.5 1 + 77%
ll 1 1 +39 X
¦ 1 0.5 ¦ + 17%

31 1 2.5 1 +38 ~ 1 OX
, 15 2 /. In vitro anti-scale activity test.
Spiral rat tail caudal arteries are connected to voltage sensors and are kept in 25 ml vats of buffer Krebs-sodium bicarbonate (NaCl: 120.8 mM, KCl: 5.9 mM, MgCL2:
1.2 mM, NaH2PO4: 1 ~ 2 mM, NaHC ~: 15 ~ 5 mM, glucose 12.6 mM) at 37 ~ C
2 ~ gassed with a mixture 2: 95% ~ C2 5 X-The preparations are depolarized by a buffer solution with a concentration of 100 mM in K + ions (NaCl: 26.7 mM, KC ~: 100 mM, MgCl2:
1.2 mM, NaH2po4: 1.2 mM, NaHC03: 15.5 mM, glucose: 12.6 mM).
Adding, in a volume of 250 μl, calcium chloride, 25 so as to obtain a range of increasing concentrations of Ca2 + ions ranging from 0.1 to 3.0 mM; we record the contractions of the arteries and thus establishes a control range. We repeat the operation with the ion range Ca2 + every 15 minutes; the preparation is washed four times, after each range.
When we get a stable response, we perform the operation with ranges of Ca2 + ons in the presence of different concentrations of product to be tested, until a stable response is obtained.
Artery contractions depend on the entry of Ca ions in smooth muscle cells and are caused by the 35 depolarization of the smooth uscle by ions + and by the action of noradrenaline released at the presynaptic level. By restarting the operation with arteries denervated by the action of 6-OH dopamine, the action is suppressed clean due to norepinephrine.
The results are expressed in IC 50 (inhibitory concentration 50) 4U concentration of the tested product which inhibits by 50 ~ the contraction due to J ~.

- 41 - 1 ~ 50 K + ions.
We can see from the results shown in the table below that the products of the present application have a strong activity anticalcic.
s .
¦ Product of the example! CI 50 in ~ M ¦
¦!
31! 8 ¦!
32! 5.4 l!
3 / ~ Study of the aiclue toxicity:
Was evaluated the dose ~ DLo spread of the compound of Example 28 tested after oral administration in mice.
The maximum dose causing no mortality is called DLo ~
2û in 7 days.
The DLU found is 200 mg / Kg.

Claims (28)

1.- Process for the preparation of indole carboxamide derivatives, as well as of their addition salts with mineral or organic pharmaceutical acids tically acceptable, corresponding to the general formula (I):

I

in which R and R1 represent, independently of one another, a hydrogen atom, a linear alkyl radical containing 1 to 5 atoms carbon, a branched alkyl radical containing 3 to 5 atoms of carbon, a cycloalkyl radical containing 3 to 7 carbon atoms, a cycloalkylalkyl radical containing from 4 to 7 carbon atoms, or an aralkyl radical containing from 7 to 12 carbon atoms which can be substituted by 1, 2 or 3 radicals chosen from the group made up by halogens and methyl, ethyl, methoxy, ethoxy radicals, trifluoromethyl, methylthio, amino and nitro, or R and R1 form together a saturated or unsaturated heterocycle which may contain a second heteroatom chosen from oxygen, sulfur and nitrogen atoms, this nitrogen atom which can be substituted by an alkyl radical containing from 1 to 5 carbon atoms, by a phenyl, phenyl radical substituted or naphthyl or by an aralkyl radical containing from 7 to 12 carbon atoms, R3 represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, an alkoxy radical containing from 1 to 3 carbon atoms, a chlorine, bromine or iodine atom, a radical nitro or an amino radical which can be substituted by an acyl group aliphatic containing 2 to 5 carbon atoms or by an alkyl radical containing from 1 to 5 carbon atoms, a represents together with b a 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 bond carbon-carbon, A represents a chain - (CH2) n- in which n can take the values 2, 3, 4 or 5, or a chain in which m can take the values 1, 2 or 3, B represents a chain -CO-NH- or -NH-CO-, R2 represents an atom of hydrogen, a linear alkyl radical containing from 1 to 5 atoms of carbon or a branched alkyl radical containing 3 to 5 atoms of carbon, characterized in that a derivative of formula II is reacted:

II

in which B, R2 and R3 have the meanings already indicated, with or a halide of formula III:
Hal-G III
in which Hal represents a chlorine, bromine or iodine atom and G represents a group of formula - (CH2) nD, in which D
represents a chlorine, bromine, iodine atom, a hydroxy radical or a sulfonate of this hydroxy radical, and has the meaning already indicated, or G represents a group , in which my meaning already indicated, to obtain a derivative of formula IV:

IV
in which B, R2 and R3 have the meaning already indicated, and G ' represents a group of formula - (CH2) n-Hal in which n and Hal have the meaning already indicated or a grouping of formula in which my the meaning already indicated, which one reacts with an amide of formula V:

V

in which R and R1 have the meanings already indicated, to obtain a product of formula IA:

IA

in which A, B, R, R1, R2 and R3 have the meaning already indicated, or a derivative of formula IX:
IX

in which Hal, n, R and R1 have the meaning already indicated, to obtain the derivative of formula IA such as defined above in which A represents a chain - (CH2) n, product of formula IA that either isolate and, if desired, salify or submit to an agent side chain amine alkylation when R or R1 represents a hydrogen atom, or, if desired, when R3 represents a radicalnitro, reduced to obtain the corresponding amino derivative which can be reacted with a reactive derivative of the substituent, either subject to the action of a halogenating agent to obtain a product of formula VI:

VI
in which Hal1 represents a bromine atom or chlorine, and A, B, R, R1, R2 and R3 have the meaning already indicated, which is subjected to hydrolysis to obtain a product of formula IB:

IB

in which A, B, R, R1, R2 and R3 Gnt the meaning already indicated, which is isolated and, if desired, salified or again, if desired, when R3 represents a nitro radical, reduced to obtain the corresponding amino derivative which is can react with a reactive derivative of the substituent. 2. Method according to claim 1, characterized in that the reaction of the derivative of formula II with the halide of formula III is produced:
- in the presence of a base when G represents a chain - with the sulfonate of formula Ts-O- (CH2) nhal in which Ts represents a tosyle radical and Hal has the meaning already indicated when G represents a chain - (CH2) nD. 3. Method according to claim 1 for the pre-paration of the derivatives of formula I as defined in claim 1 wherein A represents a chain - (CH2) n-, characterized in that a derivative is reacted of formula II with a derivative of formula IX:

IX

in which Hal, n, R and R1 have the meaning already indicated, to obtain the corresponding derivative of formula IA
while transforming, if desired, into a product of formula Corresponding IB. 4. Method according to claim 1 for the pre-paration of a derivative of formula I as defined in claim 1, in which R3 represents a radical amino which can be substituted, characterized in that reduces a derivative of formula I as defined in the claim 1 in which R3 represents a nitro radical, if desired, the amino derivative is reacted with a derivative reagent of the substituent which it is desired to obtain. 5. Method according to claim 1, characterized in that a derivative of formula (II) is used at the start in which R3 represents a hydrogen atom. 6. Method according to claim 1, characterized in that a derivative of formula (II) is used at the start in which R2 represents a hydrogen atom. 7. Method according to claim 1, characterized in that a derivative of formula (II) is used at the start in which the hydroxy radical is in the ortho position. 8. Method according to claim 1, characterized in that a derivative of formula (II) is used at the start in which B represents a -NH-CO chain, NH being side of indole. 9. Method according to claim 1, characterized in that derivatives of formula (I) are prepared in which a and c together form a carbon-carbon. 10. The method of claim 5 of preparation of 2- / 3 - / (1,1-dimethylethyl) amino / 2-hydroxy pro-poxy / N- (1H-indol-4-yl) benzamide and its neutral oxalate, characterized in that the 2- / N- (1H-indol-4-yl) amido / phenol with epichlorohydrin and reacts the product thus obtained with terbutylamine to obtain the benzamide derivative desired to be salified, if desired, with oxalic acid. 11. The derivatives of formula (I) as defined in claim 1, as well as their addition salts with pharmaceutically acceptable mineral or organic acids wheat. 12. The derivatives of formula (I) as defined in claim 1, as well as their addition salts with pharmaceutically acceptable mineral or organic acids bles, characterized in that R and R1 form together with the nitrogen atom to which they are linked a piperidinyl radical or substituted or unsubstituted piperazinyl. 13. The derivatives of formula (I) as defined in claim 11 or 12 and their addition salts with mineral or organic acids pharmaceutically acceptable, characterized in that R3 represents a radical substituted or unsubstituted amino. 14. The derivatives of formula (I) as defined in claim 11 or 12 and their addition salts with mineral or organic acids pharmaceutically acceptable, characterized in that R3 is an atom hydrogen. 15. The derivatives of formula (I) as defined to claim 11 or 12, and their addition salts with mineral or organic acids pharmaceutically acceptable, characterized in that R2 is an atom hydrogen. 16. The derivatives of formula (I) as defined to claim 11 or 12, and their addition salts with mineral or organic acids pharmaceutically acceptable, characterized in that A is a chain - (CH2) n. 17. The derivatives of formula (I) as defined to claim 11 or 12, and their addition salts with mineral or organic acids pharmaceutically acceptable, characterized in that the hydroxy radical is in ortho position. 18. The derivatives of formula (I) as defined to claim 11 or 12, and their addition salts with mineral or organic acids pharmaceutically acceptable, characterized in that B is a chain -NH-CO-, NH being on the indole side. 19. The derivatives of formula (I) as defined to claim 11 or 12, and their addition salts with mineral or organic acids pharmaceutically acceptable, characterized in that a and c form together a carbon-carbon bond. 20. 2- / 3 - / (1,1-dimethylethyl) amino / 2-hydroxy propoxy / N- (1H-indol-4-yl) benzamide and its neutral oxalate. 21. The derivatives of formula (I), as defined to claim 1, as well as their addition salts with mineral or organic acids pharmaceutically acceptable, characterized in that they are chosen from the group formed by the derivatives whose names follow:
- 2- / 2 - / (1,1-dimethylethyl) amino / ethoxy / N- (1-indol-4-yl) benzamide, - 2- / 3 - / (1,1-dimethylethyl) amino / 2-hydroxy propoxy / N-(1H-indol-4-yl) benzamide, - 2- / 3 - // bis- (1-methylethyl) / amino / 2-hydroxypropoxy / N-(1H-indol-4-yl) benzamide, and - 2- / 3 - / (1,1-dimethylethyl) amino / propoxy / N- (1H-indol-4-yl) benzamide. 22. Pharmaceutical compositions, characterized by what they contain at least one derivative of formula (I) as defined in claim 11 or 12, or one of its addition salts with mineral or organic acids pharmaceutically acceptable, mixed with at least one pharmaceutically acceptable excipient. 23. Pharmaceutical compositions, characterized in that they contain at least one derivative as defined to claim 20 or 21 in admixture with at least one pharmaceutically acceptable excipient.

CLAIMS SUPPORTED BY ADDITIONAL DISCLOSURE 24. Derivatives of formula (I '):

(I ') in which either of the substituents X or Y
represents an alkyl radical containing from 1 to 5 atoms of carbon, an alkoxy radical containing from 1 to 3 atoms of carbon, a chlorine, bromine or iodine atom, a radical nitro or an amino radical unsubstituted or substituted by a aliphatic acyl group containing 2 to 5 atoms carbon or one or two alkyl radicals containing from 1 to 5 carbon atoms, and the other substituent represents a hydrogen atom, it being understood that Y does not represent the methoxy group and X a chlorine atom, as well as their addition salts with acids pharmaceutically acceptable. 25. Derivatives of formula (I '), as defined in claim 24, characterized in that X represents a methoxy, nitro, amino or acetylamino radical and Y represents a hydrogen atom or else Y represents a chlorine atom, a nitro, amino or acetylamino radical and X represents a hydrogen atom, as well as their addition salts with pharmaceutically acceptable acids. 26. 2- [3-C (1,1-dimethylethyl) amino] 2-hydroxy propoxy] N- (1H-indol 4-yl) 5-nitro benzamide and its addition salts with acids pharmaceutically acceptable. 27. Process for the preparation of the derivatives of formula (I '), as defined in claim 24, characterized in what is reacted with a compound of formula (II '):

(II ') in which X and Y have the meanings given in the claim 21, with a halide of formula (III '):

(III ') to obtain a compound of formula (IV '):

(IV ') that we react with terbutylamine to get a compound of formula (I ') which, if desired, is subjected to the action of a mineral or organic acid to obtain a salt. 28 Pharmaceutical compositions, characterized by what they contain as an active ingredient, one at minus the derivatives defined in claim 24, 25 or 26 in mixture with at least one pharmaceutically acceptable excipient table.