FR2492824A2 - 4-Piperidinyl indole derivs. - with dopaminergic activity e.g. for treating Parkinsons disease and excessive prolactin secretion - Google Patents

Abstract

Indole derivs. of formula (I), within the general scope of the parent patent, and their acid addn. salts are new. (X is methyl and Y is 3-piperidinyl (cpd. Ia) or 1-propyl-3-piperidinyl (Ib); or X is H and Y is 1-ethyl-3-piperidinyl (Ic) or 1-ethyl-1,2,5,6-tetrahydro-3-pyridinyl (Id)). Specificed salts are the hydrochloride of (Ia); the oxalate of (Ib); the neutral fumarate of (Ic) and the phosphate of (Id). (I) are useful as dopaminergic stimulants; some also have adrenergic and serotoninergic activities. They are useful for treating extrapyramidal neurological disorders (e.g. Parkinson's disease); excessive secretion of prolactin (e.g. hypogonadism); cerebral senescence; vertebrobasal insufficiency; arterial hypertension; peripheral circulator disorders; and arteriopathy of the legs. All cpds. were tolerated at doses of 60 mg or more per kg, intraperitoneally in mice, without any deaths.

Description

In its French patent application filed on June 12, 1979 under number 79 - 14,976 the applicant described and claimed new indole derivatives and their salts, their preparation process and their application as medicaments.

dans laquelle
- R représente un atome d'hydrogène, un radical alkyle renfermant de 1 à 8 atomes de carbone, ou un radical aralkyle renfermant de 7 à 12 atomes de carbone,
- X représente un atome d'hydrogène ou un radical alkyle renfermant de 1 à 8 atomes de carbone,
- Y représente un atome dshydrogène ou un atome d'halogène,
- Z représente un atome d'hydrogène, un radical alkyle ou hydroxyalkyle renfermant de 1 à 8 atomes de carbone, un radical aryloxyalkyle renfermant de 7 à 12 atomes de carbone, un radical aralkyle renfermant de 7 à 12 atomes de carbone éventuellement substitué par un ou plusieurs atomes d'halogène, par un ou plusieurs radicaux alcoxy renfermant de 1 à 4 atomes de carbone, par un ou plusieurs radical alkyle renfermant de 1 à 4 atomes de carbone, ou par un ou plusieurs radicaux OH, CF3, OCF31NO2 ou NH2, ou Z représente un radical cycloalkylalkyle renfermant de 4 à 12 atomes de carbone, un radical alkenyle renfermant de 3 à 8 atomes de carbone ou un radical.alkynyle renfermant de 3 à 8 atomes de carbone et,
- ou bien a et b représentent chacun un atome d'hydrogène, - ou bien a représente un atome d'hydrogène et b représente un radical hydroxyle ou un radical alcoxy renfermant de 1 à 8 atomes de carbone,
- au bien a et b forment ensemble une double liaison carbone-carbone, ainsi que leurs sels d'addition avec les acides des composés de formule (I)
Le brevet principal a revendiqué également un procédé de préparation des dérivés de l'indole répondant à la formule (I) ci-dessus, ainsi que de leurs sels.The main patent has more particularly described new indole 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 8 carbon atoms, or an aralkyl radical containing from 7 to 12 carbon atoms,
- X represents a hydrogen atom or an alkyl radical containing from 1 to 8 carbon atoms,
- Y represents a hydrogen atom or a halogen atom,
- Z represents a hydrogen atom, an alkyl or hydroxyalkyl radical containing from 1 to 8 carbon atoms, an aryloxyalkyl radical containing from 7 to 12 carbon atoms, an aralkyl radical containing from 7 to 12 carbon atoms optionally substituted by a or more halogen atoms, by one or more alkoxy radicals containing from 1 to 4 carbon atoms, by one or more alkyl radicals containing from 1 to 4 carbon atoms, or by one or more OH, CF3, OCF31NO2 or NH2 radicals , or Z represents a cycloalkylalkyl radical containing from 4 to 12 carbon atoms, an alkenyl radical containing from 3 to 8 carbon atoms or an alkynyl radical containing from 3 to 8 carbon atoms and,
- either a and b each represent a hydrogen atom, - or else a represents a hydrogen atom and b represents a hydroxyl radical or an alkoxy radical containing from 1 to 8 carbon atoms,
- to good a and b together form a carbon-carbon double bond, as well as their addition salts with the acids of the compounds of formula (I)
The main patent also claimed a process for the preparation of the indole derivatives corresponding to formula (I) above, as well as their salts.

 The main patent also claimed the application as medicaments of the derivatives corresponding to the general formula (I) above, and their pharmaceutically acceptable salts, as well as the pharmaceutical compositions containing, as active principle, one or more of the derivatives of general formula (I) and / or their pharmaceutically acceptable salts.

 The purpose of this application for a certificate of addition is to illustrate the invention described in the main patent with new examples.

 It relates more particularly to the indole derivatives corresponding to formula (I) of the main patent, the names of which follow - 1-methyl 4- (3-piperidinyl) 1indole, - 1-methyl 4- (1-propyl 3 -piperidinyl) 1indole, - 4- (1-ethyl 3-piperidinyl) 1H-indole, - 4- (1-ethyl 1,2,5,6-tetrahydro 3-pyridinyl) 1H-indole and their salts addition with mineral or organic acids.

 These derivatives can be prepared by the process described in the main patent application.

 Examples of such a preparation are given below in the experimental part.

 The addition salts with mineral or organic acids can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, formic, propionic, benzolic, maleic, fumaric, succinic, tartaric acids. , citric, oxalic, glyoxylic, aspartic, alkanesulfonic, such as methane or ethanesulfonic, arylsulfonic, such as benzene or paratoluene sulfonic and arylcarboxylic acids.

Among the preferred derivatives of the invention, there are more particularly - 1-methyl 4- (3-piperidinyl) 1H-indole hydrochloride, - 1-methyl 4- (1-propyl 3-piperidinyl) 1H oxalate -indole, - neutral fumarate of 4- (1-ethyl 3-piperidinyl) 1H-indole, - phosphate of 4- (ethyl 1,2,5,6-tetrahydro 5-piperidinyl)
1H-indole.

à l'action d'un agent de méthylation ou de benzylation pour obtenir un composé de formule (III) :

dans laquelle ' représente un radical méthyl ou benzyl, que l'on transforme en dérivé organomagnésien pour obtenir un composé de formule (fiv) ::

que l'on condense avec la N-benzyl 3-pipéridone pour obtenir un composé de formule

puis,
- ou bien dans le cas où Ri représente un radical méthyl soumet le composé de formule (IA) à l'action d'un agent de clivage du groupement benzyle porté par l'azote du groupe ment pipéridinyle pour obtenir le composé de formule (IB) ::

que l'on soumet à l'action d'un agent de clivage du groupement hydroxyle pour obtenir le composé de formule (I) correspondant, puis si désiré, soumet ce dernier à l'action d'un agent capable d'introduire un radical propyl, pour obtenir le composé de formule (IC)

The present application for an addition certificate also relates to a process for the preparation of the derivatives corresponding to formula (I) of the main patent defined above as well as their salts, characterized in that 1 1on submits a compound of formula ( II)

to the action of a methylating or benzylating agent to obtain a compound of formula (III):

in which 'represents a methyl or benzyl radical, which is transformed into an organomagnesium derivative to obtain a compound of formula (fiv):

which is condensed with N-benzyl 3-piperidone to obtain a compound of formula

then,
- Or in the case where Ri represents a methyl radical subjects the compound of formula (IA) to the action of a cleavage agent of the benzyl group carried by the nitrogen of the piperidinyl group to obtain the compound of formula (IB ) ::

which is subjected to the action of an agent for cleavage of the hydroxyl group in order to obtain the corresponding compound of formula (I), then if desired, submits the latter to the action of an agent capable of introducing a radical propyl, to obtain the compound of formula (IC)

que lton soumet, à l'action d'un agent de clivage du groupement benzyle porté par le noyau pipéridinyle, pour obtenir le composé de formule (IE)

puis soit soumet ledit composé de formule (IE) à l'action d'un agent de clivage du groupement hydroxyle pour obtenir le composé de formule (I) correspondant que l'on soumet à l'action d'un agent capable d'introduire un radical éthyl, pour obtenir le composé de formule (IF)

soit soumet ledit composé de formule (IE) à l'action d'un agent capable d'introduire un radical éthyl puis soumet le composé obtenu à l'action d'un agent de deshydratation pour obtenir le composé de formule (I) correspondant comportant en 3,4 une double liaison carbone-carbone, et si désiré, soumet chacun des composés de formule (I) obtenus précédemment à l'action d'un acide pour en former le sel.- Or in the case where R 'represents a benzyl group, subjects the compound of formula (IA) to the action of a selective cleavage agent of the benzyl group carried by the nucleus of the indole to obtain the compound of formula (ID)

which is subjected to the action of a cleavage agent of the benzyl group carried by the piperidinyl ring, in order to obtain the compound of formula (IE)

then either subject said compound of formula (IE) to the action of an agent for cleavage of the hydroxyl group in order to obtain the corresponding compound of formula (I) which is subjected to the action of an agent capable of introducing an ethyl radical, to obtain the compound of formula (IF)

either subject said compound of formula (IE) to the action of an agent capable of introducing an ethyl radical then subject the compound obtained to the action of a dehydrating agent to obtain the corresponding compound of formula (I) comprising in 3,4 a carbon-carbon double bond, and if desired, subjects each of the compounds of formula (I) obtained above to the action of an acid to form its salt.

 In a proffered embodiment of the process of the invention, the methylating or benzylating agent is preferably a methyl or benzyl halide, for example, a chloride, a bromide or a methyl iodide OR of benzyl.

 the formation of magnesium of formula (IV) is carried out by reacting the magnesium on the compound of formula (iii) in an appropriate solvent, preferably in tetrahydrofuran in the presence of a small amount of dibromoethane.

 the cleavage agent of the benzyl group carried by the piperidinyl ring is hydrogen in the presence of a catalyst, for example, hydrogen in the presence of palladium.

- To perform the cleavage of the hydroxyl group, lithium is used in liquid ammonia at a temperature below -40 C, by example - 60 C.

- The introduction of the ethyl or propyl radical is carried out by means of a halide, such as a chloride, a bromide, an ethyl or propyl iodide, - the cleavage agent of the benzyl group carried by the nucleus of indole is sodium in liquid ammonia at low temperature, - the dehydrating agent is preferably a strong acid such as hydrochloric acid or oxalic acid or even phosphoric anhydride.

 As indicated in the main application, the addition salts of the abovementioned derivatives can be prepared according to conventional methods, for example, by reacting, in substantially stoichiometric proportions, a mineral or organic acid with said derivatives.

 The product of formula (II) and the N-benzyl 3-piperidone used as starting materials are known products.

 The derivatives which are the subject of the present application have very interesting pharmacological properties; they are endowed, in particular, with certain dopaminergic stimulating properties whether or not accompanied by activities at the adrenergic and serotonergic level.

 These properties are illustrated later in the experimental part.

 These properties justify the use of the new indole derivatives and their salts as medicaments.

The present application thus also relates to the application, as medicaments, of the new indole derivatives defined above, as well as their addition salts with pharmaceutically acceptable acids.

Among the medicaments of the invention, there are chosen, very particularly - 1-methyl 4- (3-piperidinyl) H-indole hydrochloride, - 1-methyl 4- (1-propyl 3-piperidinyl) 1 indole oxalate , - the neutral fumarate of 4- (1-ethyl 3-piperidinyl) 1H-indole, - the phosphate of 4- (1-ethyl 1,2,5,6-tetrahydro 3-piperidinyl)
1H-indole.

 The medicaments which are the subject of the present invention find, for example, their use in the treatment of neurological syndromes of extrapyramidal origin, for example, in the treatment of Parkinson's disease and in the treatment of post-encephalitic parkisonian syndromes, they may also be used in the treatment of hypersecretion of prolactin by the anterior pituitary gland, for example, in the treatment of hypogonadism in women and men.

They can also be used in the treatment of cerebral senescence, vertebrobasilar insufficiency, high blood pressure, peripheral circulatory disorders and in the treatment of arteriopathies of the lower limbs and their tropical complications.

 The usual variable dose depending on the derivative used, the subject treated and the condition in question, can be, for example, from 5 mg to 100 mg per day of the derivative of Example 1 orally in humans, for the treatment of Parkinson's disease, or for the treatment of cerebral senescence.

 A subject of the invention is finally pharmaceutical compositions which contain at least one aforementioned derivative or one of its addition salts with pharmaceutically acceptable acids, as active principle.

As medicaments, the derivatives which are the subject of the present application and their addition salts with pharmaceutically acceptable acids can be incorporated into pharmaceutical cosoosions intended for the digestive or penal route.
These pharmaceutical compositions can be, for example, solid or liquid and be present in the pharmaceutical forms commonly used in human medicine, such as, for example, tablets, simple or coated, capsules, capsules, granules, suppositories, preparations injectables; they are prepared according to the usual methods. The active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, butter cocoa, aqueous vehicles or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

 there will now be given, without implied limitation, examples of implementation of the invention.

Example 1: 1-Methyl 4- (3-iéridinyl) 1H-indole hydrochloride.

Stage A: formation of the magnesian.

 12 g of magnesium are introduced into 155 cm3 of hydrofuran tetra, brought to reflux, a solution of 38 g of 1-methyl 4-shloro 1H-indole and 4.5 cm3 of 1,2-dibromoethane in 115 cm3 of is slowly introduced tetrahydrofuran, after priming using a few drops of methyl iodide, maintains reflux for 6 hours, then cools to 450C and obtains a solution which is used as it is below.

Stabe B: 3/1-methyl 1H-indole-4-yl / 1- hydrochloride (phenyl methyl) 3-piperidinol.

 A solution of N-benzyl 3-piperidone prepared from 50 g of K-benzyl 3-piperidone hydrochloride, in 115 cm3 of tetrahydrofuran, is introduced dropwise into the solution obtained in stage A, solution for 2 hours, refluxing cool, stir for 16 hours, cool in an ice bath, add dropwise 200 cm3 of ammonium chloride in saturated solution, filter, rinse with water and ethyl acetate, decant, extract again ethyl acetate, washed with an aqueous solution; sodium orure and distills dry under reduced pressure. The residue is taken up in ether, extracted with N hydrochloric acid, basified, reextracted with ethyl acetate and distilled to dryness under reduced pressure. 73.4 g of crude product are obtained, which is purified by chromatography on silica column (eluent: cyclohexanetriethylamine 9-1). The product is taken up in methylene chloride, filtered, distilled to dryness under reduced pressure and 60.5 g of the base of the expected product are obtained.

 Precaration of the hydrochloride.

 The product obtained above is dissolved in 300 cm3 of ethyl acetate, a solution of hydrochloric acid in ethyl acetate is added dropwise to pH = 4, ice-cream 16 hours, drained, washed with water ethyl acetate, dried at 500 ° C. under vacuum and obtained 59.6 g of expected product F = 2500 ° C.

Stage C: 3- (1-methyl 1H-indole-4-yl) 3-piperidinol hydrochloride.

 Hydrogenated at 40 ° C. 50 g of hydrochloride of 3- / 1methyl 1H-indole-4-yl / 1 - tphenyl methyl) 3-piperidinol in 1.5 liters of methanol in the presence of 15 g of palladium on activated carbon. Then allowed to cool, filter the catalyst and dry distilled in vacuo. 37 g of the expected product are obtained. Rf = 0.3, Support: silica - Eluent: chloroform methanol-triethylamine (6-3-1).

Stage D: 1-methyl 4- (3-piperidinyl) 1H hydrochloride indole.

 a) formation of the base.

 5.14 g of 3- (1-methyl-1H-indol-4-yl) 3-piperidinol hydrochloride, 80 cm3 of tetrahydrofuran and 40 cm3 of anhydrous ethanol are introduced at -40 ° C. into 400 cm3 of ammonia. . 2.8 g of lithium are then introduced in one hour and thirty minutes in small portions. The ammonia is allowed to evaporate at ambient temperature, then the residue is taken up in 400 cm3 of water. Extracted with chloroform at 10% methanol, washed with water and dried. The solvents are filtered and removed. A product is obtained which is used as is in the following step.

 b) formation of the hydrochloride.

 The above product is dissolved in ethanol, then a saturated solution of hydrochloric acid in methanol is added to pH = 4. Filtered, washed with ethanol, dried, recrystallized the product obtained from ethanol, and thus obtained 3.0 g of the desired product, F w 270 C.

Analysis: C14 H19 Cl N2 = 250.775
Calculated: C% 67.05 H% 7.64 Cl% 14.14 N% 11.17
Found: 67.2 7.6 14.1 11.1
The starting 4-chloro 1-methyl 1H-indole can be prepared as follows
Heated to 40 C, with stirring for 4 hours, 60 g of 4-chloro 1 indole with 400 cm of benzene, 200 cm3 of a 50% sodium hydroxide solution. 68 g of n-tetrabutylammonium hydrogen sulphate and 68 cm of methyl iodide, cooled, decanted, reentered the aqueous phase with ethyl acetate, washed the combined organic phases with a saturated aqueous solution of sodium chloride , dry, dry distilled under reduced pressure; purifies by chromatography on silica (eluent: cyclohexane-benzene 8-2) and obtains 63.85 g of the expected product.

Example 2: 1-methyl 4- (1-propyl 3-piperidinyl) oxalate I Findole.

 5 g of the product of Example 1 in 50 cm3 of dimethylformamide are stirred under an inert atmosphere, 6.3 g of sodium carbonate, 2.05 cm3 of propyl iochre are added, the mixture is stirred for 16 hours, poured into 250 cm3 d water, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride, dried, distilled to dryness under reduced pressure, purified by chromatography on silica (eluent: cyclohexane-chloroform-triethylamine (6-3- 1). And thus isolates 4.9 g of the base of the expected product.

 Oxalate formation.

 Hot dissolved in 15 cm3 of ethanol, 4.8 g of the above product, added a solution of 2.36 g of oxalic acid in 10 cm3 of ethanol, allowed to cool, initiates crystallization, ice for 16 hours, drain, wash with ethanol, dry at 500C under reduced pressure, recrystallize from methanol and obtain 5.68 g of the expected product PFO -1670C.

Analysis: C19 H26 N2 04 = 346.427
Calculated: 0% 65.87 H% 7.57 N% 8.09
Found: 66.2 7.6 8.1
Example 3: Neutral fumarate of 4-2-ethyl 3-piperidin (1) Hindole.

Stage A: 4-chloro 1- (phenyl methyl) 1H-indole.

 The mixture is heated to 600C with vigorous stirring, for 4 hours, a mixture containing 16.9 g of 4-chloro 1H-indole.

170 cm3 of banzene, 85 cm3 of a 50% sodium hydroxide solution, 1.89 g of n-tetrabutylammonium hydrogen sulphate and 16.6 cm3 of benzyl chloride.

Cool to room temperature, decant, wash the organic phase with water, dry and remove the solvents. 30.2 g of a product are obtained which is chromatographed on silica eluting with cyclohexane. Is thus isolated 22.8 g of desired product melting at 58 - 609C
Stage B: 1- (phenyl methyl) 3- / 1- (phenyl methyl) 1H-indole-4yl / 3-piperidinol (and hydrochloride)
a) formation of magnesium
113 g of magnesium are introduced into 200 cm3 of tetrahydrofuran. The mixture is heated to reflux, then a solution of 184 g of 4-chloro 1- (phenyl methyl) 1H-indole and of 20 cm3 of 1,2-dibromoethane in 300 cm3 of tetrahydrofuran is slowly introduced. The reaction mixture is maintained at reflux. for 3 hours and cools it to 300 C. A solution is obtained which is used as it is below.

b) 1- (nhenYl methyl) 3- / l- (Dhenyl methyl) 1H-indol 4-yl / 3- piperidinol (hydrochloride)
A solution of 128 g of N-benzyl 3-piperidone in 250 cm3 of tetrahydrofuran is introduced into the solution obtained in paragraph a) without exceeding 350C. The mixture is heated at reflux for 2 hours, cooled to 2O0C and slowly introduced 1 liter of ammonium chloride in saturated aqueous solution.

The reaction mixture is taken up in 2 liters of ethyl acetate and filtered. Decanting is carried out, extraction with ethyl acetate is continued, washing with water, drying and removing the solvents. 330 g of a product are obtained which is chromatographed on silica (eluent: cyclohexane, triethylamine 9-1).

 218.4 g of a product are thus obtained which is dissolved in ethyl acetate. Extraction is carried out with 1N hydrochloric acid. The acidic aqueous phase is made alkaline with ammonia, and extracted with ethyl acetate.

 The organic phase is dried and 100 cm 3 of a saturated solution of hydrochloric acid in ethyl acetate are added. The hydrochloride is filtered, washed with ethyl acetate and with ether and dried.

 194 g of the desired product are obtained, melting at 1850C.

By recrystallization from ethyl acetate at 10% methanol, the pure product melting at 1900C is obtained.

 c) release of the base.

 The corresponding base is freed by treatment with sodium hydroxide and the desired product is obtained by extraction with ethyl acetate and evaporation of the solvent.

Stage C: 3- (1H-inodl -4-yl) 1-phenyl methyl 3-piperidinol hydrochloride.

 a) formation of the base.

 A solution containing 14.8 g of 1- (phenyl methyl) 3 / 1- (phenyl methyl) 1H-indol-4-yl / 3-piperinol in 250 cm3 of tetrahydrofuran is introduced into -40 ° C. - ammonia. 1.5 g of sodium are gradually added while maintaining the temperature at -40 C. At the end of the reaction, ammonium chloride is added until the blue color obtained previously becomes discolored. The residue is taken up in water, decanted and extracted with ethyl acetate. Wash with dry water and remove the solvents. 12 g of a product are obtained, which product is used as it is in the following stage.

 b) formation of the hydrochloride.

 The product obtained in Stage A is dissolved in ethyl acetate and a saturated solution of hydrochloric acid in ethyl acetate is added. Filtered, washed with ethyl acetate and dried. 12.7 g of sought product is obtained, melting at 228-230 C.

Stage D: 3- (1H-indol-4-yl) 3-piperidinol hydrochloride.

 Hydrogenated at 60 ° C., 12.7 g of 3- (1Hindol-4-yl) 1- phenyl methyl 3-piperidinol hydrochloride in 500 cm3 of methanol; in the presence of 3.6 g of palladium activated carbon. Filtered, concentrated to dryness and 9 g of the desired product are obtained, which product is used as it is for the next stage.

Stage E: 4- (3-Piperidinyl) 1H-indole hydrochloride.

 a) formation of the base.

 Is introduced at -40 C in 100 cm of ammonia, 1.2 g of 3- (1H-indol-4-yl) 3-piperidinol hydrochloride, 20 om3 of tetrahydrofuran and 10 cm3 of anhydrous ethanol. 700 mg of lithium are then introduced in one hour in small portions.

The ammonia is allowed to evaporate at room temperature, then the residue is taken up in 100 cm3 of water. Extracted with chloroform at 10% methanol, washed with water and dried. The solvents are filtered and removed. 950 mg of a product are obtained which is chromatographed on silica (eluent: chloroform, methanol, triethylamine 7-2-1). 665 mg of the desired product are isolated.

 b) formation of the hydrochloride.

 2.3 g of 4- (3-piperidinyl) 1H-indole, prepared as indicated in Stage A, are dissolved in 50 cm 3 of ethyl acetate, then a saturated solution of hydrochloric acid in acetate is added. 'ethyl. Filtered, washed with ethyl acetate, dried and recrystallized the product obtained in acetonitrile to 20% methanol. Cn thus obtains 2.2 g of the desired product.

Stage F: Neutral fumarate of 4- (1-ethyl 3-piperidinyl) 1H- indole.

 a) base.

The mixture is stirred for 5 hours under an inert atmosphere 4.4 g of 4- (3-piperidinyl) 1H-indole hydrochloride in 90 cm3 of dimethylformamide with 5.9 g of sodium carbonate and 1.7 cm3 of ethyl bromide, taken up in water, extracted with ethyl acetate, washed with water, dried, filtered, evaporated to dryness under reduced pressure, at 500 ° C., and purified by chromatography on silica (eluent: cyclohexane-chloroform-triethylamine 6- 3-1)
4.3 g of the expected product are obtained.

 b) neutral fumarate.

 The above product is dissolved in 200 cm3 of isopropanol, 2.3 g of fumaric acid are added, the mixture is heated under reflux for 15 minutes, ice, filter, dried under reduced pressure, crystallized from methanol and 4.3 is obtained. g of the expected product PF # 265 C.

Analyst: C17 H22 N202 = 286.377
Calculated: 0% 71.30 H% 7.74 N% 9.78
Found: 71.5 7.8 9.7
Example 4: 4- (1-Ethyl 1,2,5,6-tetrahydro 3pyridinyl) 1H-indole phosphate.

Stage A: 1-ethyl 3- (1H-indol-4-yl) 3-piperidinol.

 Agitation is carried out for 4 hours under an inert atmosphere 10 g of 3- (1 H -indol-4-yl) 3-pteridinol hydrochloride (obtained in stage D of Example 3) in 200 cm 3 of dimethylformamide, with 13.44 g of sodium carbonate and 4.2 cm3 of ethyl bromide It is taken up in water, extracted with ethyl acetate, washed with water, dried, filtered, brought to dryness under reduced pressure at 50 ° C., purified by militia chromatography (eluent cyclohexane-chloroform-triethylamine 6-3-1) and obtains 6.6 g of a product used as it is for the following stage.

stage B: Dinyl phosphate) 1H-indole.

 a) base.

Is heated to reflux for 4 hours, with stirring and inert atmosphere 6.6 g of the above product in 300 cm3 of an aqueous solution of hydrochloric acid N, cooled, alkalized to pH - 10 using detergent. soda, extract with ethyl acetate, wash with saturated aqueous sodium chloride solution, dry, filter, bring to dryness at 500C under reduced pressure, purify by chromatography on silica (eluent: chloroform-methanol 9-1) , recrystallizes from isopropyl ether and obtains in 2 jets 3.95 g of base PF # 1240C
b) phosphate.

 2.95 g of base is dissolved above in 300 cm3 of isopropanol, a solution of 10% phosphoric acid in isopropanol is added until pH = 4, the mixture is heated at reflux for 15 minutes, ice, filter, dry under reduced pressure, recrystallize from an ethanol-methanol mixture 50-50 and obtain 3.1 g of the expected product PFO = 2120C.

Analysis: C15 H21 N2 04 P = 324.317
Calculated: 0% 55.55 Bh 6.53 N% 8.64 P% 9.55
Found: 55.4 6.5 8.6 9.3
Example 5
Tablets have been prepared with the formula - 1-methyl 4- (3-piperidinyl) hydrochloride
1H-indole .................................... 10 mg - Excipient qs for one tablet finished at. .. 100 mg
(Details of excipient: lactose, starch, talc,
magnesium stearate).

Example 6
Tablets have been prepared having the formula - 1-methyl 4- (1-propyl 3-piperidinyl) oxalate
1H-indole ....................................... 20 mg - Excipient qs for one tablet finished at ......... 100 mg
(Details of excipient: lactose, starch, talc,
magnesium stearate).

Example 7
Tablets with the formula - 4- (1-ethyl 1,2,5,6-tetrahydro 3-pyri phosphate) have been prepared
dinyl) 1H-indole ................................. 20 mg - Excipient qs for a tablet finished at 100 mg
(Details of excipient: lactose, starch, talc,
magnesium stearate).

Pharmacological study:
1) Stereotypical behavior in rats.

 Doparminergic agonists, such as apormorphine, administered generally lead to stereotypical behavior in rats.

 Techn ~ gue: The compound studied is injected IP into batches of 5 rats weighing 160 + 15 g.

 The animals are placed immediately after injection in Plexiglas boxes (20 X 27 X 17 cm) containing wood chips and observed every thirty minutes for three hours. Intensity. stereotyped movements is numbered from O to 6 according to the following assessment criteria: the animal is asleep (O), awake but immobile (1) turns in the box (2), sniffs (3), licks (4), touches the shavings with the teeth or chews (5), bites the shavings or has an intense knock (6) (Psychopharmacology 68, 15-23 (1980).

 The product of example n01 exhibited stereotypical behavior at the dose of 50 mg / kg.

 2) Rotational behavior after unilateral lesion of the nigrostriatal bundle by 6-hydroxydopamine.

Technical:
The lesion is carried out in male rats of approximately 220 g by unilateral injection into the nigrostriated dopaminergic bundle, of 8 g of 6-hydroXydopamine in solution at 2 g / l (U. Ungerstedt, Acta Physiol. Scand. 1971, 82, suppl 367, 69-93).

 In such animals, dopaminergic agonists such as apomorphine, administered generally, form a rotational behavior in the contralateral direction to the injured side.

 The test compound is administered at least 5 weeks after the injury. The animals are placed in an automated rotometer which makes it possible to count the number of rotations carried out by each animal in both directions.

Under the conditions of the experiment, the following results were obtained - the product of Example 2 causes counter rotations
lateral from the dose of 2 mg / Kg.

 3) Potentiation of stereotypies caused by dexamphetamine.

 The tests are carried out on batches of 5 male rats weighing 150 to 180 g. Each animal is placed individually in a wire cage (29 X 25 X 17 cm) containing a few pieces of broken wood.

 A dose of 3 mg / kg of dexamphetamine sulfate is injected intraperitoneally half an hour after the intraperitoneal administration of the product studied. The behavior of the animals is noted from half an hour to half an hour for 5 hours with the rating recommended by HALLItZELL et al.

(Brit. J. Pharmacol. 1964, j2, 330-350).

 The animal is asleep (O), it is awake, but immobile (1), it turns in the cage (2), it sniffs the key cover (3), it licks the walls (4), it touches the shavings or bars of the cage with the teeth (5), it bites the shavings or bars of the cage (6).

 The products of Examples 1, 3 and 4 potentiate stereotypies at the dose of 3 mg / kg, and the product of Example 2 at the dose of 0.6 mg / kg.

 4) - Study of acute toxicity.

 The lethal DLo doses of various compounds have been evaluated after intraperitoneal administration in mice.

 The maximum dose that causes no mortality is called DL0.

 The results obtained are as follows DLo - product of Example 1 - 80 mg / kg - product of Example 2 = 60 mg / kg - product of Example 3: 60 mg / kg - product of Example 4 "60 mg / kg

Claims (7)

CLAIMS 1) - The derivatives corresponding to formula (I) of the main patent whose names follow - 1-methyl 4- (3-piperidinyl) 1H-indole, - 1-methyl 4- (1-propyl 3-piperidinyl ) 1H-indole, - 4- (1-ethyl 3-piperidinyl) 1H-indole, - 4- (1-ethyl 1,2,5,6-tetrahydro-3-pyridinyl) 1H-indole, as well as their addition salts with mineral and organic acids. 2) - 1-methyl 4- (3-piperidinyl) indole hydrochloride 3) - 1-methyl 4- (1-propyl 3-piperidinyl) 1Ho indole oxalate. 4) - Neutral fumarate of 4- (1-ethyl 3-piperidinyl) 1Hindole. 5) - 4- (1-Ethyl 1,2,5,6-tetrahydro 3-pyridinyl) ÎH-indole phosphate. 6) - Process for preparing the compounds of formula (I) as defined in any one of claims 1 to 5, characterized in that a compound of formula (II) is subjected

 to the action of a methylating or benzylating agent to obtain a compound of formula (III)

 in which R 'represents a methyl or benzyl radical, which is transformed into an organomagnesium derivative to obtain a compound of formula (IV),

 which is condensed with N-benzyl 3-piperidone to obtain a compound of formula (IA)

 then,  - Or in the case where R 'represents a methyl radical subjects the compound of formula (IA) to the action of a cleavage agent of the benzyl group carried by the nitrogen of the piperidinyl group to obtain the compound of formula (IB )

  which is subjected to the action of a cleavage agent of the hydroxyl group in order to obtain the corresponding compound of formula (I), then if desired, submits the latter to the action of an agent capable of introducing a radical propyl, to obtain the compound of formula

 - Or in the case where R 'represents a benzyl group, subjects the compound of formula (TA) to the action of a selective cleavage agent of the benzyl group carried by the nucleus of the indole to obtain the compound of formula (ID)

 which is subjected to the action of a cleavage agent of the benzyl group carried by the piperidinyl ring, to obtain the compound of formula (IE)

 then either subject said compound of formula (IE) to the action of a hydroxyl group cleavage agent to obtain the corresponding compound of formula (I) which is subjected to the action of an agent capable of introducing an ethyl radical, to obtain the compound of formula Ir

 either subject said compound of formula (IE) to the action of an agent capable of introducing an ethyl radical then subject the compound obtained to the action of a dehydrating agent to obtain the corresponding compound of formula (I) comprising at 3 , 4 a carbon-carbon double bond, and if desired, subjects each of the compounds of formula (I) obtained above to the action of an acid to form its salt. 7) - Medicines, characterized in that they consist of new derivatives as defined by claim 1, as well as their addition salts with pharmaceutically acceptable acids. 8) - Medicines, characterized in that they consist of new derivatives as defined in one of claims 2,3,4 or 5. 9) - Pharmaceutical compositions, characterized in that they contain, as active principle, at least one of the medicaments as defined in one of claims 7 or 8.