FR2501208A1 - 4-Morpholinyl-indole and di:hydro-indole derivs. - useful as dopaminergic agonists - Google Patents

Abstract

Indole derivs. of formula (I) and their acid addn. salts are new: (where R is H, 1-5C alkyl or 7-12C aralkyl. R1 is H, 1-5C alkyl, 2-5C hydroxy- or halo-alkyl, 4-7C cycloalkylalkyl, 3-5C alkenyl or alkynyl, or opt. substd. 7-12C aralkyl). Also new are intermediates of formulae (II) and (VI): (I) are dopaminergic agonists useful in treatment of e.g. Parkinson's disease, prolactin hypersecretion, cerebral senescence or cerebral hypoxia. The usual oral dose is 0.1-50 mg per day.

Description

 The present invention relates to novel morpholinylindole derivatives and their salts, processes and preparation intermediates, the application as medicaments of these novel derivatives and the compositions containing them.

dans laquelle R représente un atome d'hydrogène, un radical alcoyle renfermant de 1 à 5 atomes de carbone ou un radical aralcoyle renfermant de 7 à 12 atomes de carbone, R1 représente un atome d'hydrogène, un radical alcoyle renfermant de I à 5 atomes de carbone, hydroxyalcoyle ou halogénoalcoyle renfermant de 2 à 5 atomes de carbone, un radical cycloalcoylalcoyle renfermant de 4 à 7 atomes de carbone, un radical alcényle ou alcynyle renfermant de 3 à 5 atomes de carbone, ou un radical aralcoyle renfermant de 7 à 12 atomes de carbone , éventuellement substitué, et le pcintillé représente la présence éven tuelle d'une liaison carbone-carbone.The invention relates to novel morpholinyl derivatives
indole, and their addition salts with mineral or organic acids, characterized in that they correspond to the general formula (I):

in which R represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms or an aralkyl radical containing from 7 to 12 carbon atoms, R 1 represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, carbon atoms, hydroxyalkyl or haloalkyl containing from 2 to 5 carbon atoms, a cycloalkylalkyl radical containing from 4 to 7 carbon atoms, an alkenyl or alkynyl radical containing from 3 to 5 carbon atoms, or an aralkyl radical containing from 7 to 12 carbon atoms, optionally substituted, and the pcintillé represents the possible presence of a carbon-carbon bond.

 In the general formula (I) and in the following, the term "alkyl radical" containing from 1 to 5 carbon atoms preferably denotes an ethyl, propyl, isopropyl, butyl, isobutyl or pentyl radical, whether or not substituted by an atom. chlorine or bromine,. or by a hydroxyl radical, or designated a methyl radical, the term aralkyl radical containing from 7 to 12 carbon atoms, preferably denotes a benzyl or phenethyl radical when it is substituted, the substituents may be, for example, chloro radicals; , bromo, methyl, ethyl, methoxy, trifluoromethyl or methylthio, the term cycloalkoylacoyl radical containing from 4 to 7 carbon atoms preferably denotes a cyclopropyl methyl radical, the term alkenyl radical containing from 3 to 7 carbon atoms designates preferably, an allyl radical, the term alkynyl radical containing from 3 to 7 carbon atoms preferably denotes a propargyl radical.

 The addition salts with inorganic or organic acids may be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, formic, propionic, maleic benzoic, fumaric, succinic, tartaric acids. citric, oxalic, glyoxylic, aspartic, alkanesulfonic, such as methane or ethanesulfonic, arylsulfonic acids such as benzene or para-toluenesulphonic and arylcarboxylic acids.

Among the products which are the subject of the invention, mention may be made especially of the derivatives corresponding to formula (I) above, and also their addition salts with mineral or organic acids, characterized in that, in said formula (I ), R represents a hydrogen atom or a methyl or benzyl radical and
R1 represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms.

 Among these, there may be mentioned more particularly derivatives characterized in that, in said formula (I), R represents a hydrogen atom and very particularly the products mentioned in the examples, as well as their addition salts with acids. minerals or organic.

Mention may also be made in particular of 4- (4-methyl-2-morpholinyl) -1H-indole-4- (4-propyl-2-morpholinyl) indole and -2,3-dihydro-4- (4-propyl-2-morpholinyl) ) indole, as well as their addition salts with mineral or organic acids.

ian5 -laquey'e R a la signification déjà indiquée,pour obtenir un produit de formule(IA).

The subject of the invention is also a process for preparing the derivatives, as defined by formula (I) above, and their salts, characterized in that a product of formula (II) is reduced:

ian5 -laquey'e R has the meaning already indicated, to obtain a product of formula (IA).

dans laquelle R a la signification déjà indiquée, que ou bien l'on isole etsalifie,-si désiré, ou bien, dans le cas ou R représente un radical benzyle,soumet, si désiré, à une hydro génolyse pour obtenir le produit de formule(k)::

que, ou bien l'on isole et, si désiré, salifie, ou bien l'on soumet ledit produit de formule(Ic#à une déshydrogénation pour obtenir le produit de formule (ID)

que l'on isole et, si désiré, salifie, et si désiré, soit l'on soumet lesdits produits de formules(IA),et()à une méthylation pour obtenir un produit de formule

dans laquelle R et le trait pointillé ont la signification déjà indiquée, étant entendu que R ne représente pas 1 atome d'hydrogène lorsque le pointillé ne représente pas une liaison carbone-carbone produit de formulef i) que l'on isole et salifie si désiré, soit l'on fait réagir lesdits produits de formules(IA),(IB),et avec un halogénure de formule(III)
Hal - R'1 (III) dans laquelle Hal représente un atome de chlore, de brome ou d'iode, et R'1 a la signification de R1 déjà indiquée,à l'exception de 11 hydrogène et du radical méthyle, pour obtenir un produit de formule( IF)::

dans laquelle R,R1 et le pointillé ont la signification déjà indiquée, étant entendu que lorsque R représente 1 atome d'hydrogène, le pointillé ne représente pas une liaison carbonecarbone que l'on. isole et salifie si désiré, puis si désiré, hydrogénolyse les produits de formules (I & et (IF) dans lesquelles R représente un radical benzyle et le pointillé ne représente pas une liaison carbone-carbone pour obtenir un produit de formule

dans laquelle R"1 a la valeur de R1 déjà indiquée, à l'exception de l'hydrogène, que l'on isole et, si désiré, salifie.wherein R has the meaning already indicated, regardless of whether it is isolated and, if desired, salified, or is subjected to the action of a reducing agent to obtain a product of formula (IB)

wherein R has the meaning already indicated, whether or not it is isolated and if desired, or, in the case where R represents a benzyl radical, subject, if desired, to a hydro-genolysis to obtain the product of formula (k) ::

or either isolating and, if desired, salifying, or subjecting said product of formula (Ic # to dehydrogenation to obtain the product of formula (ID)

that is isolated and, if desired, salified, and if desired, either subjecting said products of formulas (IA), and () to a methylation to obtain a product of formula

in which R and the dotted line have the meaning already indicated, it being understood that R does not represent 1 hydrogen atom when the dotted line does not represent a carbon-carbon bond produced of formula (i) which is isolated and salified if desired either the said products of formulas (IA), (IB) and with a halide of formula (III) are reacted
Hal - R'1 (III) in which Hal represents a chlorine, bromine or iodine atom, and R'1 has the meaning of R1 already indicated, with the exception of 11 hydrogen and the methyl radical, to obtain a product of formula (IF) ::

in which R, R 1 and the dotted line have the meaning already indicated, it being understood that when R represents 1 hydrogen atom, the dotted line does not represent a carbon carbon bond that one. isolates and salifies if desired, then if desired, hydrogenolyses the products of formulas (I) and (IF) in which R represents a benzyl radical and the dotted line does not represent a carbon-carbon bond to obtain a product of formula

in which R "1 has the value of R1 already indicated, with the exception of hydrogen, which is isolated and, if desired, salified.

The reduction of the product of formula (II) is preferably carried out using aluminum lithium hydride in a solvent such as tetrahydrofuran, but it is also possible to use, for example, diborane.
The reduction of the product of formula (I) is preferably carried out using the trimethylamine-borane complex in the presence of hydrochloric acid, in a solvent such as dioxane.

It is also possible to use sodium cyanoborohydride in acetic acid, or other hydrogenated boron complexes.

The hydrogenolysis of the product of formula (1B> in which R represents a benzyl radical is preferably carried out by the action of hydrogen in the presence of a catalyst such as
Raney nickel, palladium strontium carbonate, or palladium hydroxide, but more particularly in the presence of palladium on coal or talc.

The dehydrogenation of the product of formula (k) is carried out, for example, using a catalyst such as nickel
Raney or palladium in a boiling solvent such as xylene with a hydrogen acceptor such as cinnamic acid or maleic acid. It is also possible to use chloranil in xylene or, preferably, manganese dioxide in methylene chloride.

The methylation of the products of formulas (IA) and and (can be carried out using a mixture of formaldehyde and formic acid, but preferably formic hadehyde is used in the presence of a reducing agent such as sodium borohydride The solvent used is, for example, methanol.

 The halide of formula (III) may be a chloride or a bromide, but preferably an iodide. It reacts favorably with secondary amines of formulas (IA) '! And (T) in the presence of an acid-fixing agent, such as, for example, an alkaline carbonate such as potassium carbonate, in a solvent such as dimethylformamide. Other acid scavengers such as tertiary atones, or alkali hydroxides or alkoxides such as sodium hydroxide or sodium tert-butoxide can also be used.

dans laquelle R a la signification déjà indiquée, que l'on transforme en magnésien correspondant, sur lequel on fait réagir un agent d'acétylation pour obtenir un produit de formule (VI)

dans laquelle R a la signification déjà indiquée, dont l'on prépare l'oxime en de la cétone, puis réduit le produit obtenu pour obtenir un produit de formule(VII ) ::

dans laquelle R a la signification déjà indiquée, que l'on fait réagir avec le-chlorure de chloracétyle, pour obtenir un produit de formule(VIII)

dans laquelle R a la signification déjà indiquée, que l'on cyclise pour obtenir le produit de formule( 11) cherche. Under preferred conditions of implementation of the invention, the process of preparation described above is characterized in that the product of formula (II) is prepared by reaction of 4-chloroindole with a halide of formula IV:
Hal R in which Bal and R have the meaning already indicated, to obtain a product of formula:

in which R has the meaning already indicated, which is converted into the corresponding magnesium, on which an acetylating agent is reacted to obtain a product of formula (VI)

in which R has the meaning already indicated, the oxime of which is prepared in ketone, then reduces the product obtained to obtain a product of formula (VII) ::

in which R has the meaning already indicated, which is reacted with chloroacetyl chloride, to obtain a product of formula (VIII)

wherein R has the meaning already indicated, which is cyclized to obtain the product of formula (11) seeks.

 The halide of formula (IV) is preferably a chloride.

It is advantageously reacted with 4-chloroindole in the presence of an acid-fixing agent such as an alkali metal carbonate or hydroxide, for example, sodium carbonate or potassium hydroxide, and preferably sodium hydroxide.

 The formation of the magnesium product of formula (V) is preferably carried out by reacting the product of formula (VI) with magnesium in a suitable solvent such as tetrahydrofuran in the presence of a small amount of dibromoethane.

 The acetylating agent may be, for example, an acetyl halide, a mixed anhydride such as pivaloyl acetic mixed anhydride, 2-pyridyl thiolacetate, but preferably acetic anhydride.

 It is advantageously carried out cold between -20 and -400C, and preferably the magnesium is added to the acetylation reagent already present in the reaction medium, in a solvent such as tetrahydrofuran.

 The formation of the oxime of the product of formula (VI) is preferably carried out in a basic medium; the nitrite mixture of terbutyl terbutylate of potassium terbutanol is advantageously used in a solvent such as tetrahydrofuran. It operates around OOC, preferably between OBC and 50C.

 Since the oxime is not very stable, its reduction preferably takes place in situ, immediately after its formation. This reduction can be carried out in two operations, by reduction of the oxime function, for example by catalytic hydrogenation, preferably using palladium as a catalyst and then reducing the ketone function, preferably using sodium borohydride.

It is preferably carried out in a single operation, for example by reduction using aluminum-lithium hydride.

 The condensation of the product of formula (VII) with chloroacetyl chloride is advantageously carried out in the presence of an acid-fixing agent, preferably sodium hydroxide, in an organic solvent such as dioxane or tetrahydrofuran, but preferably in chloroform.

 The cyclization of the product of formula (VIII) is carried out for example with the aid of a strong base such as an alkaline hydroxide, such as sodium or potassium hydroxide, an alkaline alkoxide such as ethoxide or tert-butylate. sodium, but preferably using sodium hydride; it is advantageously carried out in an ether such as dioxane or tetrahydrofuran, in dimethoxyethane, but preferably in benzene.

 The derivatives of formula (I) have a basic character. It is advantageous to prepare the addition salts of the derivatives of formula (I) by reacting, in substantially stoichiometric proportions, an inorganic or organic acid with the said derivative of formula (I). Salts can be prepared without isolating the corresponding bases.

 The derivatives, object of the present invention, have very interesting pharmacological properties; they are endowed notably with remarkable agonist properties of minergic.

 These properties are illustrated further in the experimental section.

 These properties justify the use of morpholinylindole derivatives, as well as their salts, as medicaments.

 The present application also also relates to the application, as medicaments, morpholinylindole derivatives, as defined by formula (I), and their addition salts with pharmaceutically acceptable acids.

 Among the medicaments which are the subject of the invention, the medicaments characterized in that they consist of the new morpholinylindole derivatives corresponding to the formula (I), in which R represents a hydrogen atom, are preferably retained. or a methyl or benzyl radical and R1 represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms, as well as by their addition salts with pharmaceutically acceptable acids.

 Among these, particular mention is made of those corresponding to formula (I), in which R represents a hydrogen atom, and in particular 2,3-dihydro 4- (2-morpholinyl) 1Hindole, and 4- ( 2-morpholinyl) 1H-indole, as well as their addition salts with pharmaceutically acceptable acids.

 The medicaments according to the invention find their use, for example in the treatment of neurological syndromes of extrapyramidal origin, for example in the treatment of Parkinson's disease and in the treatment of Parkinson's post encephalitic syndromes; they can also be used in the treatment of hypersecretion of prolactin by the anterior pituitary, for example in the treatment of hypogonadism of women or men. They can also be used in the treatment of cerebral senescence or manifestations related to cerebral hypoxia.

The usual dose, variable according to the derivative used, the subject treated and the affection in question may be, for example, from 0.1 mg to 50 mg per day, orally in humans of the derivative of Example 4 to the treatment of the patient from
Parkinson.

 The invention finally 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 may be incorporated into pharmaceutical compositions intended for the digestive or parenteral route.

 These pharmaceutical compositions can be, for example, solid or liquid and be in the pharmaceutical forms commonly used in human medicine, such as, for example, tablets, single or coated tablets, capsules, granules, suppositories, injectable preparations; they are prepared according to the usual methods. The active ingredient (s) can be incorporated into excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non aqueous vehicles. fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

dans lesquelles R' a la signification déjà indiquée. The invention also extends to novel industrial products which are particularly useful for the preparation of the derivatives corresponding to formula (I), namely the products of formula (11) and (VI):

in which R 'has the meaning already indicated.

The examples which follow illustrate the present application, without however limiting it to Example No. 1: 4- 4- (2-morpholinyl) -1- (phenylmethyl) -1H-indole.

 16.5 g of 6- [1- (phenylmethyl) -1β-indol-4-yl] -morpholinone are stirred under an inert atmosphere in 300 cm 3 of tetrahydrofuran, 8.2 g of lithium aluminum hydride are added and the mixture is heated. at reflux for 15 minutes. It is cooled to 00-50C, the excess hydride is destroyed, diluted with water, filtered, extracted with ethyl acetate, dried and concentrated to dryness. The residue obtained is purified by chromatography on silica (eluent: chloroform-methanol 9-1) and 12.85 g of expected product are obtained. M.p .: 1180C.

UV spectrum in HCl -HCl
Max.

Max. : 221 nm E 1cm = 1227 t 35900
1% Max. : 287 nm E cm = 287 t = 8400 Infl.

Infl. : 295 nm E1cm = 255
Example 2: 2,3-dihydro 4- (2-morpholinyl) -1- (phenylmethyl) -1H-indole.

 18.9 g of product as obtained in Example 1, 200 cm 3 of dioxane, with 23.7 g of trimethylamine-borane complex, are stirred under an inert atmosphere, 22 cm 3 of 12 N hydrochloric acid are added without exceeding 250 ° C. After 24 hours at room temperature, the dioxane is removed at 500 ° C. under reduced pressure, diluted with water, washed with ether, rendered alkaline with sodium hydroxide, saturated with potassium carbonate, extracted with ether, dried and concentrated. dry the organic phase. The resulting resin is impasted with ether, filtered and dried under reduced pressure to obtain 10.5 g of expected product. M.p .: 1200C.

UV spectrum in ethanol
Max.

Max. : 258 nm E1cm = 372 t 11000
1%
Max. : 304 nm E 1cm = 82 t = 2400
Example 3: 2,3-Dihydro 4- (2-morpholinyl) 1H-indole.

11 g of product as obtained in Example 2 are dissolved in 200 cm 3 of methanol, 5.5 g of 10% palladium on active charcoal are added, hydrogen is stirred for 2 hours at 400 ° C. Cool to room temperature, filter and remove at 500C under
reduced pressure methanol and toluene formed. Purify
the residue obtained by chromatography on silica (eluent: chloroform-acetone-triethylamine 6-3-1), recrystallized from isopropyl ether and gave 6.2 g of the expected product.

M.p .: 840C.

Analysis: C12H16N2O = 204.274
Calculated: C 70.56 H% 7.90 N% 13.71
Found: 70.5 7.8 13.6
Example n04: 4- (2-Morpholinyl) 1H-indole Hydrochloride.

 1.2 g of product of Example 3 are dissolved in 25 cm 3 of methylene chloride, 4.8 g of activated manganese oxide are added, left for 24 hours at room temperature, filtered, the insoluble material is washed with a mixture chloroform-methanol 1-1. The solvents are removed from the filtrate at 500 ° C. under reduced pressure, the residue obtained is purified by chromatography on silica (eluent: chloroform-acetone-triethylamine 6-3-tf and 405 mg of 4- (2-morpholinyl) 1H-indole are obtained. : 175 C.

Hydrochloride formation
1.1 g of the product obtained above are suspended in ether (50 cc), a saturated hydrochloric acid ether solution is added, the filtrate is filtered and dried under reduced pressure, recrystallized from ethyl acetate to 20.degree. % of methanol and obtains 900 mg of expected product. PF: 2130C.

Analysis: C12H15ClN2 = 238.719
Calculated: C% 60.38 H% 6.33 N% 11.73 Cl% 14.85
Found: 60.4 6.4 11.6 14.6
The starting 6- [1- (phinylmethyl) 1H-indol-4-yl] -3-morpholinone of example n01 can be prepared as follows: a) 1 - [1- (phenylmethyl) 1H-indol-4-yl] ethanone.

 The magnesium solution prepared from 150 g of 4-chloro-1-phenylmethyl-1H-indole (described in US Pat. French patent application 2458 549) and stirred for 1 hour at -200C to + 100C; a saturated solution of ammonium chloride is added, diluted with water and extracted with ethyl acetate. The organic phases are washed with salt water, dried, the solvents under pressure are eliminated at 500 ° C. and the residue obtained is purified by chromatography on silica (eluent: cyclohexane-ethyl acetate 9-1). crude in refluxing isopropyl ether, and 70 g of the desired product are obtained.PF: 930C.

 b) - (aminomethyl) 1- (phenylmethyl) 1H-indole 4-methanol.

 A solution of 5.5 g of the above product, 60 cm 3 of tetrahydrofuran and 66 cm 3 of an N solution of potassium tert-butoxide in terbutanol is cooled to 0 ° -50 ° C., 13.1 cm 3 of terbutyl nitrite are added with stirring and atmosphere. inert for 1 hour. It is diluted with water, concentrated acetic acid to pH 4.5, stirred for 15 minutes and then neutralized with a saturated aqueous solution of sodium bicarbonate. Extracted with ethyl acetate and obtained 6.6 g of oxime.

 A suspension of 9 g of lithium aluminum hydride in 120 cm 3 of tetrahydrofuran is cooled to 0 ° -5 ° C., the above product is added in solution in 120 cm 3 of tetrahydrofuran and left stirring for 20 hours at 20 ° -250 ° C. . It is cooled to 0-SOC, the excess hydride is destroyed, the mixture is taken up with water and with ethyl acetate, filtered, extracted with ethyl acetate, dried and concentrated to dryness. The residue obtained is purified by chromatography on silica (eluent: chloroform-methanol 1-1), recrystallized from refluxing benzene, and 1.8 g of the expected product are obtained. M.p .: 920C.

c) 2-chloro-N- [2-hydroxy-2 - [(phenylmethyl) -1H-indol-4-yl] ethyl] acetamide.

 The product, as obtained above, is stirred under an inert atmosphere in 1 liter of chloroform and 300 cm 3 of water, with 27 g of sodium hydroxide. Chloroacetyl chloride (16 cc) is added, the mixture is stirred for 15 minutes, diluted with water, decanted, extracted with chloroform, the combined chloroform phases are dried, and the filtrate is dried to obtain 37.7 g of product used as is for the next stage. .

d) 6- [1- (phenylmethyl) -1H-indol-4-yl] -3-morpholinone,
34.7 g of the above product are dissolved at 55 ° -60 ° C. in 1.5 liters of benzene, with stirring and inert atmosphere, introduced in 2 hours, 20.2 g of sodium hydride at 60% in The paraffin oil, washed with petroleum ether (eb.60-800C), stirred for 1 minute at 50 ° C. It was cooled to 100 ° C. and 1 liter of water was added without exceeding 200 ° C. and then taken up with 1 liter of water. chloroform at 10% methanol, extracted with chloroform-methanol, dried, concentrated to dryness. The residue obtained is hot-concentrated in a benzene-ethyl acetate mixture 1-1, ice-cream, filter, dry in
oven under reduced pressure, and obtains 16.5 g of the product
expected. PF: 1400C.

Example 5
Tablets having the formula
2,3-dihydro 4- (2-morpholinyl) 1H-indole 5 mg
-Excellent qs for a tablet finished at 100 mg.

(Details of the excipient: lactose, starch, talc, stearate
magnesium).

Example 6
Tablets having the formula
4- (2-morpholinyl) hydrochloride H -indole 5 mg
Excipient qs for a tablet finished at. 100 mg.

(Detail of ltexcipient: lactose, starch, talc, magnesium stearate.

Pharmacological study 1) Rotational circumstance after unilateral lesion of the nigrostriatal tract by 6-hydroxydopamine
Technical
The lesion is performed in approximately 220% male rats by unilateral injection into the nigrostriatal dopaminergic beam, 8 g of 6-hydroxydopamine in a 2 g / l solution (U. Ingerstedt, Acta Physiol., Scand., 971.82). 367, 69-93).

 In such animals, direct dopaminergic agonists, such as apomorphine, administered systemically, lead to rotational behavior in the contralateral direction of the injured side.

 The test compound is administered at least 5 weeks after the lesion. The animals are placed in an automated rotometer that allows counting the number of rotations performed by each animal in both directions.

 The product of Example 4 administered intraperitoneally caused contraletaral rotations at a dose of 2 mg / kg.

2) Etude toxicity study.

 DLo lethal doses of the various compounds tested after oral administration were evaluated in mice.

 DLo is the maximum dose causing no mortality in 8 days.

The results obtained are as follows

<tb> Product <SEP> of <SEP> Example <SEP> DLo <SEP>
<tb><SEP> in <SEP> mg / kg
<tb><SEP> 3 <SEP> 400
<tb><SEP> 4 <SEP> 200 <SEP>
<Tb>

Claims (10)

 1) novel morpholinylindole derivatives, as well as their addition salts with mineral or organic acids, characterized in that they correspond to the general formula (i) in which:

 -R represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms or an aralkyl radical containing from 7 to 12 carbon atoms, -R1 represents a hydrogen atom, an alkyl radical containing 1 to 5 atoms of carbon, hydroxyalkyl or haloalkyl containing from 2 to 5 carbon atoms, a cycloalkylalkyl radical containing from 4 to 7 carbon atoms, an alkenyl or alkynyl radical containing from 3 to 5 carbon atoms, or an aralkyl radical containing from 7 to 12 carbon atoms. carbon atoms, optionally substituted, and the dotted line represents the possible presence of a carbon-carbon bond.  2) novel morpholinylindole derivatives as defined in formula (I) of claim 1, as well as their addition salts with mineral or organic acids, characterized in that R represents a hydrogen atom or a radical; methyl or benzyl and R1 represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms  3) novel morpholinylindole derivatives according to claim 2, as well as their addition salts with mineral or organic acids, characterized in that R represents a ylrogen atom.  4) The following derivatives, as well as their addition salts with mineral or organic acids-2,3-dihydro 4- (2-morpholinyl) 1H-indole, and 4- (2-morpholinyl) 1indole.  5) Process for the preparation of morpholinylindole derivatives as defined by the formula (I) of claim 1, as well as their salts, characterized in that a product of formula (II) is reduced

 in which R has the meaning already indicated, to obtain a product of formula (I):

 wherein R has the meaning already indicated, regardless of whether it is isolated and, if desired, salified, or is subjected to the action of a reducing agent to obtain a product of formula (B):

 in which R has the meaning already indicated, whether or not it is isolated and salified, if desired, or, in the case where R represents a benzyl radical, subjected, if desired, to a hydrogenolysis to obtain the product of formula ( tic)

  or either isolating and, if desired, salifying, or subjecting said product of formula (I) to dehydrogenation to obtain the product of formula (ID):

 that is isolated and, if desired, salified, and if desired, is subjecting said products of Formulas (IA), (IB) and (ID) to a methylation to obtain a product of formula (Ip)

 in which R and the dotted line have the meaning already indicated, it being understood that R does not represent 1 hydrogen atom when the dotted line does not represent a carbon-carbon bond, product of formula (IE), which is isolated and altered if desired, either said products of formulas (IA), (IB) and (ID) are reacted with a halide of formula (III) ::  Bal - R'1 (III) in which Bal represents a chlorine, bromine or iodine atom, and R'1 has the meaning of R1 already indicated, with the exception of hydrogen and the methyl radical, for obtain a product of formula (IF)

  in which R, R'1) and the dotted line have the meaning already indicated, it being understood that when R represents a hydrogen atom, the dotted line does not represent a carhone-oarbone bond which is isolated and salified if desired, then if desired, hydrogenolysis the products of formulas (i) and (i) in which R represents a benzyl radical and the dotted line does not represent a carbene-carbon bond to obtain a product of formula (IG):

 in which R "1 has the value of R1 already indicated, with the exception of hydrogen, which is isolated and, if desired, salified.  6) Process according to claim 5, characterized in that the product of formula (II) is prepared by reaction of 4-chloroindole with a halide of formula (fiv)  Hal R (IV) (IV) in which Hal e-t R have the meaning already indicated, to obtain a product of formula (V)

 in which R has the meaning already indicated, which is converted into the corresponding magnesium, on which an acetylating agent is reacted to obtain a product of formula (VI)

  in which R has the meaning already indicated, the oxime of which is prepared in ketone, then reduces the product obtained to obtain a product of formula (VII)

 in which R has the meaning already indicated, which is reacted with chloroacetyl chloride, to obtain a product of formula (VIII):

 wherein R has the meaning already indicated, which is cyclized to obtain the product of formula (II) sought.  7) Medicaments, characterized in that they consist of the new morpholinylindole derivatives, as defined by the formula (I) of claim 1, as well as by their addition salts with pharmaceutically acceptable acids.  8) Medicaments, characterized in that they consist of the new morpholinylindole derivatives, as defined in one of claims 2, 3 or 4, as well as by their addition salts with pharmaceutically acceptable acids.  9) Pharmaceutical compositions, characterized in that they contain, as active ingredient, at least one of the drugs, as defined in one of claims 7 or 8.  10) As new industrial products necessary for the preparation of the derivatives corresponding to formula (I) of claim I the products of formulas (VI) and (II)

 in which R 'has the meaning already indicated.