IE49906B1 - New indole derivatives,process for preparing them,and pharmaceutical compositions containing them - Google Patents

Abstract

For the Contracting States : BE, CH, LI, DE, FR, GB, IT, LU, NL, SE 1. Compounds with the formula (I) : see diagramm : EP0021924,P23,F1 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 hydroalkyl 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 possibly substituted by one 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 radicals OH, CF3 , OCF3 , NO2 or NH2 or Z represents a cycloalkyl-alkyl 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 a represents a hydrogen atom and b represents a hydroxyl radical or an alkoxy radical containing from 1 to 8 carbon atoms, - or a and b together form a double carbon-carbon bond as well as the salts of addition with acids of the compounds with the formula (I). For the Contracting State : AT 1. Process for the preparation of compounds with the formula (I) : see diagramm : EP0021924,P25,F1 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 hydroalkyl 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 possibly substituted by one 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 radicals OH, CF3 , OCF3 , NO2 or NH2 or Z represents a cycloalkyl-alkyl 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 a represents a hydrogen atom and b represents a hydroxyl radical or an alkoxy radical containing from 1 to 8 carbon atoms, - or a and b together form a double carbon-carbon bond as well as the salts of addition with acids characterized in that a compound with the formula (I). see diagramm : EP0021924,P25,F2 in which X represents a hydrogen atom or an alkyl radical containing from 1 to 8 carbon atoms and Hal represents a halogen atom is submitted to the action of an alkylation or aralkylation agent, so as to obtain a compound with the formula (III) : see diagramm : EP0021924,P25,F3 in which R' represents an alkyl radical containing from 1 to 8 carbon atoms or an aralkyl radical containing from 7 to 12 carbon atoms, which is converted into an organo-magnesium derivative, so as to obtain a compound with the formula (IV) : see diagramm : EP0021924,P25,F4 which is condensed with N-benzyl 3-piperidone, so as to obtain a compound with the formula (IA ) : see diagramm : EP0021924,P26,F5 then, if desired - either the compound with the formula (IA ) is submitted to the action of a dehydratation agent, so as to obtain a compound with the formula (IB ) : see diagramm : EP0021924,P26,F6 which if desired, in the case where R' represents a benzyl radical is submitted to the action of a selective cleavage agent for the benzyl group carried by the nucleus of the indole, so as to obtain a compound with formula (IC ) : see diagramm : EP0021924,P26,F7 which, if desired, is submitted to the action of a cleavage agent for the benzyl group carried by the tetrahydropyridinyl nucleus, so as to obtain the compound of the formula (ID ) : see diagramm : EP0021924,P26,F8 - or the compound with the formula (IA ) is submitted to the action of a cleavage agent for the benzyl group carried by the nitrogen of the piperidinyl group, so as to obtain a compound with the formula (IE ) : see diagramm : EP0021924,P26,F9 which if desired is submitted to the action of a dehydratation agent, so as to obtain a compound with the formula (IF ) : see diagramm : EP0021924,P26,F10 - or, in the case where R' represents a benzyl group the compound with the formula (IA ) is submitted to the action of a selective cleavage agent for the benzyl group carried by the indole nucleus, so as to obtain a compound with the formula (IG ) : see diagramm : EP0021924,P26,F11 which, if desired, is submitted to the action of a cleavage agent for the benzyl group carried by the piperidinyl nucleus so as to obtain a compound with the formula (IH ) : see diagramm : EP0021924,P26,F12 then, if desired, each of the compounds obtained which respond to the formula (I) in which Z represents a hydrogen atom is submitted to the action of an agent able to introduce a radical Z', Z' having the same significante as Z, set out in claim 1, with the exception of hydrogen, so as to obtain the corresponding compounds with the formula (I) in which the nitrogen atom of the piperidinyl nucleus carries a radical Z' and, if desired, - either each of the compounds obtained responding to the formula (I) in which b represents a hydroxyl radical is submitted to the action of an etherification agent, so as to obtain the corresponding compounds with the formula (I) in which b represents an alkoxy radical containing from 1 to 8 carbon atoms, - or each of the compounds obtained responding to the formula (I) in which b represents a hydroxyl radical is submitted to the action of a dehydratation agent, so as to obtain the corresponding compounds with the formula (I) in which a and b together form a double carbon-carbon bond, - or each of the compounds obtained responding to the formula (I) in which b represents a hydroxyl radical, is submitted to the action of a cleavage agent for the hydroxyl group, so as to obtain the corresponding compounds with the formula (I) in which a and b each represent a hydrogen atom and, if desired each of the compounds with the formula (I) so obtained is submitted to the action of a halogenation agent able to introduce a halogen atom Hal in position 3 of the indole, so as to obtain the corresponding compound with the formula (I) in which Y represents a halogen atom, and if desired, each of the compounds with the formula (I) previously obtained is submitted to the action of an acid so as to form its salt.

Description

The subject of the present invention is new derivatives of indole, their preparation process, their application as medicaments and the pharmaceutical compositions containing them.

The subject of the invention is compounds with the 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 to 8 carbon atoms.

- Y represents a hydrogen atom or a halogen atom.

- I 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, possibly substituted by one or several halogen atoms, by one or several alkoxy radicals containing from 1 to 4 carbon atoms, by one or several alkyl radicals containing from 1 to 4 carbon atoms, or by one or several OH, CFg, OCFg, NOg or NHg radicals, or Z represents a cycloalkylalkyl radical containing 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 a represents a hydrogen atom and b represents a hydroxyl radical or an alkoxy radical containing from 1 to 8 carbon atoms, -or a and Jb together form a carbon-carbon double bond, as well as the salts of addition with acids of the compounds with formula (I).

The salts of addition with mineral or organic acids can, for example, be the salts formed with the following acids: hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, propionic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonic such as methane sulphonic, and aryl sulphonic such as benzene sulphonic.

When R represents an alkyl radical, it would preferably be a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or n-pentyl radical.

When R represents an aralkyl radical, it would preferably be a benzyl radical.

When X represents an alkyl radical, it would preferably be an alkyl radical containing from 1 to 4 carbon atoms and in particular a methyl, an ethyl, an n-propyl or an n-butyl radical.

When Y represents a halogen atom, it would preferably be a chlorine or a bromine atom.

When Z represents an alkyl or a hydroxyalkyl radical, alkyl preferably represents a methyl, an ethyl, an n-propyl or isopropyl, an n-butyl or isobutyl, an n-pentyl or an n-hexyl radical.

When Z represents an aryloxyalkyl radical, it would preferably be a phenyloxyethyl or a phenyloxypropyl radical.

When I represents an aralkyl radical, aralkyl is preferably understood to be a benzyl, phenethyl or phenylpropyl radical.

When Z represents an aralkyl radical substituted by one or several halogen atoms, by halogen is preferably understood a chlorine or a bromine atom.

When Z represents an aralkyl radical substituted by one or several alkyl radical, by alkyl is preferably understood a methyl or an ethyl radical.

When Z represents an aralkyl radical substituted by one or several alkoxy radicals, alkoxy is preferably understood to be a methoxy or ethoxy radical.

When Z represents a cycloalkylalkyl radical, it is preferably a cyclopropyl alkyl radical, for example, a cyclopropylmethyl, a cyclopropylethyl or a cyclopropyl n-propyl radical.

When Z represents an alkenyl radical, it is preferably an allyl radical.

When Z represents an alkynyl radical, it is preferably a propargyl radical.

When b^ represents an alkoxy radical, it is preferably a methoxy or an ethoxy radical.

Among the compounds of the invention, there can be cited in particular the compounds with the formula (I) for which Y represents a hydrogen atom, as well as their salts of addition with acids, those for which X represents a hydrogen atom as well as their salts of addition with acids, those for which Z represents a hydrogen atom as well as their salts of addition with acids, those for which Z represents an alkyl radical containing from 1 to 4 carbon atoms or an aralkyl radical containing from 7 to 12 carbon atoms as well as their salts of addition with acids. Further there can be cited the compounds with the formula (I) for which a and ]> together form a carbon-carbon double bond as well as their salts of addition with acids, those for which a and b each represent a hydrogen atom as well as their salts of addition with acids, as well as those for which a represents a hydrogen atom and b a hydroxy radical or a methoxy radical as well as their salts of addition with acids.

Among the compounds of the invention, there cap be cited quite specially: -4-(l-propyl 1,2,5,6-tetrahydropyrid-3-yl) IH-indole, -4-(l-methyl piperid-3-yl} IH-indole, -4-((1-methyl l,2,5,6-tetrahydropyrid-3-yl) IH-indole, -4-(piperid-3-yl) IH-indole, -4-(l,2,5,6-tetrahydropyrid-3-yl) IH-indole and -4-(l-propyl piperid-3-yl) IH- indole, as well as their salts of addition with acids.

The compounds of formula (I) and their salts present very useful pharmacological properties: in particular they exhibit dopaminergical stimulating properties, accompanied or not by activities at the adrenergical and serotoninergical level.

These properties allow the compounds of the invention to be used in the treatment of very numerous and varied pathological diseases or disorders; they can, for example, be used in the treatment of neurological syndromes of extra-pyramidal origin, for example, in the treatment of Parkinson's disease and in the treatment of postencephalitic Parkinsonian syndromes; they can equally be used in the treatment of hypersecretion of prolactin by the anterior hypophysis, for example, in the treatment of female or male hypogonadism.

The compounds of the invention can also be used in the treatment of cerebral senescence, of vertebrobasilary insufficiency, of arterial hypertension, of peripheral circulatory troubles and in the treatment cf arteriopathies of the lower members and of their trophic complications.

The subject of the invention is therefore as medicaments, the compounds of the formula (I) as well as their salts of addition with therapeutically acceptable acids.

The subject of the invention especially is, by way of 15 medicaments, the previously named compounds, as well as their salts of addition with therapeutically acceptable acids.

The usual dose, variable according to the product used, the subject treated and the disease concerned, can, for example, be from 5 to 100 mg per day by oral route for man for the treatment of Parkinson's disease or for treatment of cerebral senescence.

The subject of the invention is also the pharmaceutical compositions which contain at least one aforementioned derivative or one of its salts of addition with pharmaceutically acceptable acids by way of active principle.

As medicaments, the derivatives responding to formula (I) and their salts of addition with pharmaceutically acceptable acids can be incorporated in pharmaceutical compositions intended for the digestive or the parenteral route. Λ9906 These pharmaceutical compositions can, for example, be solid or liquid and can be presented in the pharmaceutical forms currently used in human medicine, such, for example, as plain or sugar-coated compressed tablets, gelules, capsules, granules, suppositories and injectable preparations; they are prepared according to the usual methods. The active principle or principles can be incorporated with the excipients usually employed in pharmaceutical compositions, such as talc, gum arabie, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and preservatives.

The subject of the invention is equally a process for the preparation of compounds with the formula (I) as previously defined, characterised in that a compound with the formula (II): in which X represents a hydrogen atom or an alkyl radical containing from 1 to 8 carbon atoms and Hal represents a halogen atom, is submitted to the action of an alkylation or aralkylation agent, in order to obtain a compound with the formula (III): (III) in which R' represents an alkyl radical containing from 1 to 8 carbon atoms or an aralkyl radical containing from 7 to 12 carbon atoms, which is transformed into an organo-magnesium derivative, in order to obtain a compound with the formula (IV): which is condensed with N-benzyl 3-piperidone, in order to obtain a compound with the formula (IA) 49806 which if desired, - either the compound with the formula (1^) is submitted to the action of a dehydration agent in order to obtain a compound with the formula (Ιβ): R' which, if desired, in the case where R' represents a benzyl radical, is submitted to the action of a selective cleavage agent of the benzyl group carried by the indole nucleus in order to obtain a compound with the formula (Iq): which, if desired, is submitted to the action of a cleavage agent of the benzyl group carried by the tetrahydropyridinile nucleus in order to obtain a compound with the formula (Ιθ): I H - or the compound with the formula (1^) is submitted to the action of a cleavage agent of the benzyl group carried by the nitrogen of the piperidyl group in order to obtain a compound with the formula (IE): R' (IE> 48906 which, if desired, is submitted to the action of a dehydration agent in order to obtain a compound with the formula (Ip): R* oi, in the case where R1 represents a benzyl group, the compound 5 with the formula (1^) is submitted to the action of a selective cleavage agent of the benzyl group carried by the indole nucleus in order to obtain a compound with the formula (Ιθ): H 49806 which, if desired, is submitted to the action of a cleavage agent of the benzyl group carried by the piperidyl nucleus, in order to obtain a compound with the formula (1^): then, if desired, each of the compounds obtained responding to the formula (I) in which Z represents a hydrogen atom, is submitted to the action of an agent able to introduce a radical 1' , Z' having the same significance as Z with the exception of hydrogen, in order to obtain corresponding compounds with the formula (I) in which the nitrogen atom of the piperidyl nucleus carries a radical Z*, and, if desired, - either each of the compounds obtained responding to formula (I) in which b represents a hydroxyl radical is submitted to the action of an etherification agent in order to obtain the corresponding compounds of formula (I) in which b represents an alkoxy radical containing from 1 to 8 carbon atoms, - or each of the compounds obtained responding to formula (I) in which b represents a hydroxyl radical is submitted to the action of a dehydration agent in order to obtain the corresponding compounds with the formula (I) in which a and b together form a carbon-carbon double bond - or each of the compounds obtained responding to formula (I) in which b represents a hydroxyl radical is submitted to the action of a cleavage agent for the hydroxyl group in order to obtain corresponding compounds with the formula (I) in which a and b each represent a hydrogen atom, and, if desired, each of the compounds with formula (I) so obtained is submitted to the action of a halogenation agent able to introduce a halogen atom Hal in position 3 of the indole, in order to obtain the corresponding compound with the formula (I) in which Y represents a halogen atom, and, if desired, each of the compounds with the formula (I) previously obtained is submitted to the action of an acid so as to form the salt.

It will appear clearly to an expert that the process of the invention comprises a certain number of optional stages which can be carried out in different orders.

The invention is naturally not limited either to a number of these stages, or to a fixed order for these stages. The invention is thus extended to processes including any number of the optional stages indicated, in whatever order these stages are carried out.

In a preferred method of carrying out the process of the invention: - as starting product with the formula (II) a product is used in which Hal represents a chlorine or a bromine atom: - the alkylation or aralkylation agent is an alkyl or aralkyl halide, for example, an alkyl or aralkyl chloride, bromine or iodide. Λ99Ο6 - the magnesium derivative formation of formula (IV) is carried out, either by making the magnesium react on the compound with the formula (III) in an appropriate solvent, preferably in tetrahydrofuran, in the presence of a small quantity of di bromoethane, or by an exchange reaction with an organo-metallic derivative such for example as butyl lithium. - the dehydration agent is a strong acid such as hydrochloric acid or oxalic acid or even phosphoric anhydride; - the cleavage agent of the benzyl group carried by the indole nucleus is sodium in ammonia at a low temperature; - if a^ and b do not together represent a double bond, the cleavage agent for the benzyl group carried by the piperidyl nucleus is hydrogen in the presence of a catalyst, for example, hydrogen in the presence of palladium; - in order to cleave the benzyl group in the compound with the formula (1^), it is preferably made to react with ethyl chloroformate in order to form the corresponding ethyl carbamate which is hydrolyzed, preferably in an alkaline medium in order to obtain the compound with the formua (Ip). - the introduction of the radical Z' is carried out by means of a Z'-Hal halide in which Hal represents a chlorine, bromine or iodine atom; - the etherification agent of the OH group is an alcohol in anhydrous acid medium; - in order to effect the cleavage of the OH group, lithium is used in liquid ammonia at a low temperature, for example at -35 to -60°C. - the halogenation agent able to introduce a halogen atom in position 3 of the indole, is an N-halosuccinimide, for example the N-chloro or the N-bromo succinimide, in an appropriate solvent, for example, dioxan: - the formation of the salts is effectuated according to classical methods.

Compound»with the formula in which: - A represents a halogen atom Hal, or a radical MgHal in which Hal represents a halogen atom, - X represents a hydrogen atom or an alkyl radical containing from 1 to 8 carbon atoms, - R1 represents an alkyl radical containing from 1 to 8 carbon atoms, or an aralkyl radical containing from 7 to 12 carbon atoms, obtained during the putting in operation of the process of the invention are new products.

The products with the formula (II) used as starting products are products known in a general manner, they can be prepared, for example, according to the process described in Gazz· Chim. Ital. 88, 1147, (1958).

The N-benzyl 3-piperidone, also used as a starting product is a known product, commercially sold.

The following examples illustrate the invention without at the same time limiting it.

EXAMPLE 1 l-(phenyl methyl) 3-0-(phenyl methyl) IH-indol-4-ylJ 3-piperidinol (hydrochloride). _§£53§.A:___4;chlgro_l;(phenyl_methyll_lH;indgle A mixture containing 16.9 g of 4-chloro IH-indole, 170 cm of benzene, 85 cm of a 50% solution of sodium hydroxide, 1.89g of hydrogeno-sulphate of n-tetrabutylammonium and 16.6 cm of benzyl chloride is heated at 60°C for 4 hours under strong agitation. It is then cooled to ambient temperature, decanted, the organic phase is washed with water, dried and the solvents expelled. 30.2 g of a product is obtained which is chromatographed on silica by elution with cyclohexane. In this way 22.8 g of the product sought is isolated, melting at 58-60°C Stage B: l-(pheny1 methyl) 3-{j-(phenyl methyl) lH-indol-4-ylJ 3B2B§riiiinol__£and_hYdrochloridei.. a) formation of the magnesium derivative. 113 g of magnesium is introduced into 200 cm of tetrahydrofuran. This is heated to reflux, then a solution of 184 g of 4-chloro l-(phenyl methyl) IH-indole and 20 cm of 1,2-dibromoethane in 300 cm of tetrahydrofuran is introduced slowly. The reactional mixture is kept at reflux for 3 hours and then cooled to 30°C. A solution is obtained which is used just as it is hereafter. b) 1-(phenyl methyl) 3-[l-(phenyl methyl) IH-indol-4-yl] 3-piperidinol (hydrochloride).

Into the solution obtained at paragraph a) a solution of 128 g of q N-benzyl 3-piperi done in 250 cm of tetrahydrofuran is introduced without the temperature exceeding 35°C. This is heated to reflux for 2 hours, cooled to 20°C, and 1 litre of ammonium chloride in saturated aqueous solution is introduced slowly. The reactional mixture is taken up by 2 litres of ethyl acetate and filtered. It is decanted, and the extraction with ethyl acetate continued, then washed with water, dried and the solvents expelled. 330 g of a product is obtained which is chromatographed on silica (eluant: cyclohexane - triethylamine 9-1).

In this way 218.4 g of a product is obtained which is then dissolved in ethyl acetate. It is extracted with IN hydrochloric acid. The aqueous acid phase is alkalized with ammonia and extracted with ethyl acetate. q The organic phase is dried and to it is added 100 cm of a saturated solution of hydrochloric acid in ethyl acetate. The hydrochloride is filtered, washed with ethyl acetate and with ether and dried. 194 g of the product sought is obtained, which melts at 185°C. By recrystallization in ethyl acetate with 10% of methanol, the pure product, melting at 190°C is obtained. c) Liberation of the base.

The corresponding base is liberated by treating with sodium hydroxide, and by extraction with ethyl acetate and evaporation of the solvent, the product sought is obtained.

EXAMPLE 2: 3-(lH-indol-4-yl) 1-phenyl methyl 3-piperidinol hydrochloride §tage_A:__formation_gf_the_base.

At -40°C a solution containing 14.8 g of l-(phenyl methyl) 3-{T-(phenyl methyl) IH-indol-4-yf] 3-piperidinol in 250 cm3 of tetrahydrofuran is introduced into 500 cm of ammonia. 1.5 g of sodium is added progressively while maintaining the temperature at -40°C.

At the end of the reaction, ammonium chloride is added until the blue tint previously obtained disappears. The residue is taken up with water, decanted and extracted with ethyl acetate, then washed with water, dried, and the solvents expelled. 12 g of a product is obtained which is used just as it is in the following stage.

Stage_B: fonnation_of_the_hydrochloride.

The product obtained at Stage A is dissolved in ethyl acetate, and a saturated solution of hydrochloric acid in ethyl acetate is added to it. This is filtered, [the residue] is washed with ethyl acetate and dried. 12.7 g of the product sought is obtained, which melts at 228-230°C.

EXAMPLE 3: 4-[j-(phenyl methyl) 1,2,5,6 tetrahydropyrid-3-yl] IH-indole oxalate.

Stage_Ai__formation_of_the_base.

A mixture of 8 g of 3(1H-indol-4-yl) l-(phenyl methyl) 3-piperidinol hydrochloride in 200 cm of IN hydrochloric acid is heated to reflux. The solution so obtained is cooled to 20-25°C, then the reactional mixture is poured into a mixture of ice and water. Concentrated ammonia is added, [the organic phase] is extracted with ethyl acetate, dried, the solvent is evaporated and 6.35 g of a product is obtained which is chromatographed on silica by elution with a mixture of cyclohexane-triethylamine (9-1). g of the Droduct sought is isolated.

A8806 Stage_B · f2 CDS ϊ 122 _2f - ίίΐθ_ 2* 3ΐ3ί§Λ 3.6 g of the product prepared at Stage A is dissolved in 200 cm of isopropanol and 1.5 g of dihydrated oxalic acid is added. This is taken to reflux with addition of methanol. The methanol is expelled under reduced pressure, and a precipitate is obtained. This is cooled to 0°C, the solid matter is separated and dried. 4.2 g of the desired product, melting at 202°C, is obtained.

EXAMPLE 4: 3-(lH-indol-4-y1) 3-piperidinol and hydrochloride.

Stage_A: Hydrochloride. 12.7 g of 3-(1H-indol-4-yl) 1-(phenyl methyl) 3-piperidinol hydrochloride is hydrogenated at 60°C in 500 cm3 of methanol in the presence of 3.6 g of palladized carbon. After filtration and concentration to dryness, g of the product sought is obtained which is used just as it is for the following stage.

Stage_B: Base.

The corresponding base is liberated by treating the product obtained at Stage A with sodium hydroxide in aqueous solution, and the product sought is obtained by extraction with ethyl acetate.

EXAMPLE 5: Neutral oxalate of 3-(lH-indol-4-yl)-1-methyl-3-piperidinol. 3tage_A: §z£iyzlQ8ol-4-^fli3l-meth^l-32B2Berid1 nol. 13.3 g of 3-(1H-indol-4-yl) 3-piperidinol is introduced into 120 cm3 of methanol, then at 0 to 5°C, 5.8 g of a 40% solution of formol in water Jjs added]. This is agitated for 15 minutes, and then 4.9 g of 95% sodium borohydride is added. Water is added, and [the organic phase? is extracted by a solution of chloroform with 20% of methanol, washed with water, dried on magnesium sulphate, filtered, and the solvents are expelled. 11.8 g of the desired crude product is obtained which is purified by recrystallization in benzene. In this way 9 g of pure product melting at 145°C is obtained.

Stage_B: Formation_of_the_oxalate. 4.5 g of the product prepared at Stage A is dissolved in 500 cm of hot isopropanol, then 1.2 g of dihydrated oxalic acid is introduced into the solution so obtained. 200 cm of methanol is added and (the mixture] is taken to reflux. The methanol is evaporated. The mixture is iced, the liquid and solid phases are separated and the crystals obtained are dried. In this way 4.95 g of the product sought, melting at 250°C, is obtained.

EXAMPLE 6: Neutral oxalate of 4-(l-methy1 1,2,5,6 tetrahydropyrid-3-yl) IH-indole.

Stage_A; f9ES2ii9D-9f_ih®.^se.

A solution containing 4.8 g of 1-methyl 3-(lH-indol-4-yl) 3piperidinol in 150 cm of IN hydrochloric acid is heated to reflux for 5 hours. It is then cooled, diluted with water, concentrated ammonia is added, and it is extracted with chloroform with 10% of methanol.

In this way 4.4 g of a product is obtained which is chromatographed on silica by elution with a cyclohexane, chloroform and triethylamine mixture (6-3-1). 2.8 g of the product sought, melting at 175°C, is isolated in this way.

Stage_B: formation_of_the_oxalate. 2.4 g of the product prepared at Stage A is dissolved in 200 cm of isopropanol at reflux. Then 630 mg of dihydrated oxalic acid is introduced. The precipitate obtained is dissolved by addition of methanol. The mixture is concentrated to about 100 cm , then iced and filtered, and in this way 2.6 g of the desired product, melting at 232°C is obtained.

EXAMPLE 7: 4-(l-propyl 1,2,5,6 tetrahydropyrid-3-yl) IH-indole, acid fumarate.

Stage_A: 3-(lH-indo1-4-yl) 1-propyl 3-piperidinol.

A suspension containing 6 g of 3(lH-indol-4-yl) 3-piperidinol hydrochloride, 120 cm of dimethyl formamide, 7.5 g of sodium carbonate and 2.8 cm of propyl iodide is maintained under agitation at ambient temperature for 4 hours. It is taken up with water and extracted with ethyl acetate. In this way, after elimination of the solvent, 5.5 g of a product is obtained which is purified by chromatography on silica by elution with a cyclohexane, chloroform and triethylamine mixture (6-3-1). 4.85 g of the desired product is isolated which is used just as it is in the following stage.

Stage_8: Acid_fumatate_of_4-(l-progyl_l1225i6_tetrahydropyrid;3;yl)_lH;indole a) formation of the base. 4.8 g of 3-(lH-indol-4-yl) 1-propyl 3-piperidinol is introduced into 150 cnF of IN hydrochloric acid. The mixture obtained is taken to reflux for 2 hours. It is then cooled to ambient temperature, alkalized and extracted with ethyl acetate. After drying on magnesium sulphate, filtering and eliminating the solvent, 4.3 g of the product sought is obtained, which is purified by chromatography on silica by elution with a cyclohexane, chloroform and triethylamine mixture (6-3-1). 2.9 g of the desired product is obtained. b) formation of the acid fumarate. o 2.7 g of the base prepared at Stage A is dissolved in 200 cm of ethanol and 1.3 g of fumaric acid is introduced. The acid is seen to dissolve and then the fumarate crystallizes. The solid and liquid phases are separated and the product obtained is recrystallized in ethanol, and 2.8 g of product melting at 168°C is obtained.

EXAMPLE 8; 3-(lH-indo1-4-yl) l-(2-phenyl ethyl) 3-piperidinol.

A suspension containing 6 g of 3-(lH-indol-4-yl) 3-piperidinol 3 hydrochloride, 120 cm of dimethylformamide, 7.5 g of sodium carbonate and 3.9 cm^ of $-phenyl ethyl bromide is heated to 50°C for 3 hours.

The reactional mixture is poured into water and extracted with ethyl acetate. After drying on magnesium sulphate, filtering and expelling the solvent, 8.9 g of a product is obtained which is purified by chromatography on silica by elution with a cyclohexane, chloroform and triethylamine mixture (6-3-1). In this way 6.9 g of the desired product is isolated which is utilized just as it is in the following example.

EXAMPLE 9: Acid fumarate of 4-{j-(2-phenyl ethyl) 1,2,5,6-tetrahydropyrid-3-yl]lH-indoIe.

Stage_A: formation_of_the_base. 6.3 g of 3-(lH-indol-4-yl) l-(2-phenyl ethyl) 3-piperidinol is q introduced into 150 cm of IN hydrochloric acid. The solution so obtained is heated for 2 hours 30 minutes. It is then cooled to 20-25°C, diluted with water, alkalized by addition of sodium hydroxide solution and extracted with ethyl acetate. 6.2 g of a product is obtained which is chromatographed on silica by elution with a cyclohexane, chloroform and 48906 triethylamine mixture (6-3-1). In this way 4.7 g of the product sought is isolated.

Stage_B: Acid_fumarate_of_the_product_grepared_at_Stage_A. 4.7 g of the product prepared at Stage A is dissolved in 100 cm of hot isopropanol and 1.8 g of fumaric acid is added. The product crystallizes, and it is redissolved at reflux by adding 200 cm of isopropanol [The solution] is then concentrated to 200 cm3, iced, solid and liquid phases are separated and 5.4 g of a product is obtained which is recrystallized in ethyl acetate with 60% of methanol. 3.9 g of the required product melting at 205°C is obtained in this way.

EXAMPLE 10: Neutral fumarate of 4-(1-methyl piperid-3-yl) IH-indole.

Stage_A: formation_of_the_base. 3 cm of tetrahydrofuran, 20 cm of anhydrous ethanol and g of 3-(lH-indol-4-yl)-l-methyl-3-piperidinol are introduced under agitation at -40°C into 200 cm3 of ammonia. Then there is introduced progressively in small fractions and always at -40°C, 2.6 g of lithium.

This is still kept under agitation at -40°C for half an hour and the reactional mixture obtained is treated with an addition of ammonium chloride.

The ammonia is allowed to evaporate to ambient temperature, and after taking up with water and extracting with ethyl acetate, 4.65 g of a product is obtained which is chromatographed on silica by elution with a chloroformmethanol (95-5) mixture. In this way 3 g of the desired product melting at 151°C is obtained.

Stage B: formation of the neutral fumarate. 2.7 g of the product prepared at Stage A is dissolved in 100 cm of isopropanol and 800 mg of fumaric acid is added. This is heated to reflux and made to dissolve by addition of methanol. The solution is filtered hot, and methanol is expelled under vacuum at 40°C, [the remainder] is iced, and filtered, washing with isopropanol and drying.

In this way 3 g of the desired product melting at 260°C is obtained.

EXAMPLE 11: 4-(piperid-3-yl) IH-indol hydrochloride.

StageA: format:on_of_the_base. 1.2 g of 3-(1H-indol-4-yl)-3-piperidinol hydrochloride, 20 cm of tetrahydrofuran and 10 cm3 of anhydrous ethanol are introduced at -40°C ο into 100 cm of ammonia. Then over one hour 700 mg of lithium is introduced in small fractions. The ammonia is allowed to evaporate at ambient temperature, then the residue is taken up by 100 cm of water.

This is extracted with chloroform with 10% of methanol, washed with water and dried. After filtering and expelling the solvents, 950 mg of a product is obtained which is chromatographed on silica (eluant: chloroform, methanol, triethylamine 7-2-1). 665 mg of the desired product is isolated.

Stage_B: fonjation_of_the_hydrochloride. 2.3 g of 4-(piperid-3-yl)-H-indole prepared as indicated at Stage A 3 is dissolved in 50 cm of ethyl acetate, then a saturated solution of hydrochloric acid in ethyl acetate is added. After filtering, washing with ethyl acetate, drying and recrystailizng the product obtained in acetonitrile with 20% of methanol, 2.2 g of the product sought is thus obtained.

EXAMPLE 12: Neutral oxalate of 4-(1,2,5,6-tetrahydropyrid-3-yl)- IH-indole. stage_A: fo™ation_of_the_basei 7.6 g of 3-(lH-indol-4-yl) 3-piperidinol is heated to reflux for one hour in 300 cm^ of IN hydrochloric acid. It is then cooled to 2O~25°C, ammonia is added, it is extracted with chloroform with 20% of methanol, and 7 g of a product is obtained which is chromatographed on silica (eluant: chloroform, acetone, triethylamine 6-3-1). 3.4 g of a product is obtained which is triturated with acetone and with ether, washed with ether and dried. 3 g of the product sought is obtained, which melts at 156°C.

Stage_B: formation_of_the_neutral_oxalate. g of 4-(l,2,5,6-tetrahydropyrid-3-yl) IH-indole prepared as ο indicated in Stage A is dissolved in 30 cm of isopropanol and 1.9 g of dihydrated oxalic acid is added. 3.8 g of the expected product is isolated, which is reerystallized in methanol. In this way, 3.3 g of pure product melting at 230°C is obtained.

EXAMPLE 13: 4-(3-methoxy piperid-3-yl) IH indole oxalate. 5ii33inethoxy_piperid;3;yl)_lH;indole. 1.5 g of 3(IH-indol-4-yl)3-piperidinol hydrochloride is dissolved in 3 3 a solution containing 20 cm of methanol and 10 cm of a saturated solution of hydrochloric acid in methanol. The solution obtained is maintained at 20~25°c for 7 hours. The reactional mixture is then poured into water and alkalized by addition of sodium hydroxide. 48906 The precipitate obtained is filtered, washed with water and dried.

In this way 900 mg of the desired product is obtained, which is purified by recrystallization in ethyl acetate. In this way the desired product melting at 212°C is obtained. §tage_B: formation_of_the_oxa1ate. 2.55 g of the product obtained at Stage A is dissolved in 200 cnF of isopropanol at 40-^50°C, then 1.4 g of dihydrated oxalic acid is added.

The product is redissolved by addition of methanol. [The solution] is concentrated to 100 cm and iced, and after filtering and drying 2.7 g 10 of the desired product melting at 218°C is obtained.

EXAMPLE 14: Hydrochloride of l-(phenyl methyl) 4-(1,2,5,6 tetrahydropyrid-3-yl) IH-indole.

Stage_A: Hydrochloride of 30-phenyl methyl) lH-indole-4-yfJ 3-piperidinol. 14.4 g of hydrochloride of l-(phenyl methyl) 3- [l-(phenyl methyl) "I 1H-indol-4-yl; 3-piperidinol (obtained at Example 1) is hydrogenated in 600 cm of methanol in the presence of 4.3 g of 10% palladium black. After allowing to return to ambient temperature, filtering out the catalyst, washing with methanol and expelling the solvents under reduced pressure at 40°C, 10.65 g of the expected product is obtained. Rf: 0.35 (silica 20 chloroform - methanol - triethylamine 7-2-1).

Stage_B: l;iBhenyl_niethyl)_4;(li2,516;tetrahydropyrid23;yl)_lH3indole.

A solution of 10.4g of hydrochloride of 3-[l-(phenyl methyl) lH-indol4-yl; 3-piperidinol in 500 cm^ of N hydrochloric acid is heated to reflux for 2 hours. After cooling, diluting with water, adding sodium hydroxide solution, extracting with ethyl acetate, and evaporating, 7 g of a residue is obtained which is chromatographed on silica by elution with a mixture of cyclohexane, chloroform and triethylamine (6-3-1). In this way 4.7 g of the product sought is ohtained in the form of a brown oil.

Stage_C: fonnati on_of_the_hydrochl ori de.

The 4.7 g of the product prepared at Stage B is dissolved in •3 200 cm of ethyl acetate, then a saturated solution of hydrochloric acid in ethyl acetate is introduced at 0°C-5°C. After filtering, washing with ethyl acetate, and drying under vacuum at 40°C, 4.7 g of the product sought melting at 168°C is obtained after re-crystallization in isopropanol.

EXAMPLE 15: Acid oxalate of l-(phenyl methyl) 4-|j-(phenyl methyl) 1,2,5,6tetrahydropyri d-3-yfj 1H-i ndole.

Stage_A: l-(phenyl methyl) 4-[_l-phenyl methyl) 1,2,5,6-tetrahydropyrid-3-yT] lH;indole. g of l-phenyl methyl 3-[l-(phenyl methyl) lH-indol-4-yl] 3-piperidinol (obtained at Example 1) is introduced into 2000 cm3 of N hydrochloric acid, [the mixture is] heated to reflux for 7 hours, left one night at ambient temperature, diluted with water, alkalized with sodium hydroxide solution, and extracted with ethyl acetate, after salting out with potassium carbonate. Jhe product! is washed with water, dried on magnesium sulphate, filtered, and the solvents are expelled. 55 g of the desired crude product is obtained, which is purified by chromatography on silica (eluant: chloroform-acetone 9-1). In this way 31 g of purified product in the form of a brown oil is obtained. 5tage_B: ί2Π52ίΪ2ΰ-2ί.ί!ΐ2_2£Ϊ^-2ϊ2ΐϊί§· Ο 3.6 g of the product prepared at Stage A is dissolved in 200 cm of ethanol at 40°C, then into the solution so obtained, 1.2 g of dihydrated . 49906 oxalic acid is introduced. [The mixture] is filtered hot, concentrated 3 to about 100 cm , iced, filtered and the crystals obtained are washed and dried. In this way 3.8 g of the product sought, melting at 154°C, is obtained.

EXAMPLE 16: Neutral succinate of 4- [l-(phenyl methyl) piperid-3-yT] lH-indole. Stage_A: 4-0-(phenyl methyl) piperid-3-yl] IH-indole.

A solution containing 33.5 g of 1-phenyl methyl 4-[l-(phenyl methyl) 1,2,5,6-tetrahydropyrid-3-ylj ΙΗ-indole (obtained at Example 15) in 300 cm2 of tetrahydrofuran and 500 cm3 of ammonia is agitated at -50°C for 2 hours. Then, at -40°C, 8.5 g of sodium is introduced, ammonium chloride is added, the ammonia is allowed to evaporate, the residue is taken up with water and extracted with ethyl acetate. In this way, 26.80 g of a product is obtained which is chromatographed on silica by elution with a mixture of cyclohexane-chloroform-triethylamine (6-3-1). 22.3 g of the product sought is thus isolated in the form of an oil.

Stage_B: formation of the neutral succinate. g of the product prepared at Stage A is dissolved in 300 cm of isopropanol at reflux. Then 1.6 g of succinic acid is introduced, the q precipitate formed is redissolved by adding 200 cm of isopropanol and 200 cm3 of methanol, [the mixture] is filtered hot, and concentrated to about 200 cm . After icing, filtering, washing and drying under vacuum 4 g of the product sought, melting at 210°C, is obtained.

EXAMPLE 17: Neutral fumarate of 4-(1-propyl-pi perid-3-yl) IH-indole. stage_A: 1;{1;ΒΕ2ΒΥΐ:ΒίΒ2ί1^:3:Υΐ 1_1!3;ίΒ22ΐ2· Into 70 cm of dimethylformamide, 3.5 g of 4-(piperid-3-yl) 1Hindole (prepared at Example 11), then 3.8 g of sodium carbonate and 2.2 cm* 3 of propyl iodide are introduced. After agitating for 5 hours, precipitating with water and extracting with ethyl acetate, the organic phase is washed with water, dried on magnesium sulphate, filtered and the solvent expelled. 4.1 g of the crude desired product is obtainted which is purified by chromatography on silica (eluant: cyclohexanechloroform-triethylamine 6-3-1). In this way 3.9 g of the expected product is obtained.

Stage_B: foraation_of_the_neutral_fumarate.

The 3.9 g of the product prepared at Stage A is dissolved in 200 cm3 of isopropanol, then into the solution so obtained 1 g of fumaric acid is introduced; after heating to reflux for 10 minutes, and concentrating to about 100 cm , crystallization is initiated. The liquid is separated off and the crystals obtained are washed and dried. 3.5 g of the desired product, melting at 185°C, is thus obtained.

EXAMPLE 18: 3-< 1-methyl lH-indol-4-yl] l-(phenyl methyl) 3-piperidinol hydrochloride.

Stage_A:. £2ΰϋ2ϊί2Β_2ί-5!32-ΠΙ29Β22Ϊ25!-^2ΕίΥ2ίίΥ2· g of magnesium is introduced into 155 cm of tetrahydrofuran and taken to reflux, then a solution of 38 g of 1-methyl 4-chloro 1H-indole and 4.5 cm3 of 1,2-dibromoethane in 115 cm3 of tetrahydrofuran is introduced slowly, after priming with a few drops of methyl iodide. The reflux is maintained for 6 hours, then after cooling to 45°C a solution is obtained which is used just as it is in the following. 499 06 Stage_B; 3p-methyl 1 H-indol-4-yl] l-(phenyl methyl)3-piperidinol hydrochloride.

Into the solution obtained at Stage A, a solution of 1-benzyl 3piperidone (prepared from 50 g of 1-benzyl 3-piperidone hydrochloride) in q 115 cm of tetrahydrofuran is introduced drop by drop and heated for b 2 hours at reflux; [the solution] is then allowed to cool, agitated for hours, cooled on an ice bath, 200 cm of a saturated solution of ammonium chloride is added drop by drop, and after filtering, rinsing with water and with ethyl acetate, decanting, extracting again with ethyl acetate and washing with salt ivater, it is distilled to dryness under reduced pressure.

The residue is taken up with ether, extracted with N hydrochloric acid, alkalized, re-extracted with ethyl acetate and distilled to dryness under reduced pressure. 73,4 g of crude product is obtained which is purified by chromatography on a silica column (eluant: cyclohexane-triethylamine 9-1).

The product is taken up with methylene chloride, filtered, distilled to dryness under reduced pressure and 60.5 g of the base of the expected product is obtained.

Preparation of the hydrochloride.

The product obtained above is dissolved in 300 cm of ethyl acetate, drop by drop of a solution of hydrochloric acid in ethyl acetate is added to pH=4, [the mixture] is iced for 16 hours, the liquid is separated off, [the residue] is washed with ethyl acetate, dried at 50°C under vacuum and 59.6 g of the expected product, melting point 250°C, is obtained.

Analysis: C-21 H25 Cl N,0 = 356.90 Calculated: C% 70.67 H% 7.06 N2 7.85 CU 9.93 Found: 70.4 6.9 7.9 10.1 The 4-chloro 1-methyl IH-indole for starting can be prepared as follows: 48906 g of 4-chloro IH-indole with 400 cm3 of benzene, 200 cm3 of a 50% solution of sodium hydroxide, 68 g of n-tetrabutylammonium Hydrogen sulphate and 68 cm3 of methyl iodide are heated to 40°C under agitation for 4 hours; jthe mixture] is then cooled and decanted, the aqueous phase is re-extracted with ethyl acetate, the reunited organic phases are washed with salt water, dried on magnesium sulphate, distilled to dryness under reduced pressure, purified by chromatography on silica (eluant: cyclohexane-benzene 8-2), and 63.85 g of the expected product is obtained.

EXAMPLE 19: 3-(l-methyl 1H-indol-4-yl) 3-piperidinol. g of 3-[j-methyl lH-indol-4-yf] l-(pheny1 methyl) 3-piperidinol hydrochloride is hydrogenated in 1.5 litres of methanol in the presence of 15 g of palladium black. After allowing to cool, filtering out the catalyst and distilling to dryness under vacuum, 37 g of the expected product is obtained. Rf = 0.3, support: silica - eluant : chloroformmethanol -tri ethyl amine (6-3-1).

EXAMPLE 20: Neutral oxalade of 1-methyl 4-(l,2,5,6-tetrahydropyrid-3-yl) IH-indole.

Stage_A: l;Sethyl_4;(l i^i^iNtetrahydroByri d:3^yl)_lH^indole.

A solution containing 12 g of 3-(1-methyl IH-indol-4-yl) 3-piperidinol hydrochloride in 360 cm3 of N hydrochloric acid is heated to reflux for 4 hours. It is then cooled in an ice bath, sodium hydroxide solution is added until the pH is alkaline, and after extraction with methylene chloride, washing with salt water, drying on magnesium sulphate and distilling to dryness under reduced pressure, a crtide product is obtained ,- 4-99 06 which is chromatographed on silica with an eluant of a chloroformacetone-triethyl amine (6-3-1) mixture. In this way 6 g of the product sought is isolated.

Stage_B: formation_of_the_neutral_oxalate.

The 6 g of the product prepared at Stage A is dissolved in 3 cm of isopropanol, then 1.75 g of oxalic acid in solution in 35 cm of isopropanol is introduced; after icing, separating the solid and liquid phases, washing with isopropanol, drying at 50°C under vacuum and re-crystallization in methanol, 5.4 g of the product sought, melting at 230°C, is obtained.

EXAMPLE 21: 3-(l-methyl lH-indol-4-yl) 1-propyl 3-piperidinol. g of 3-(l-methyl IH-indol-4-yl) hydrochloride is introduced into 240 cm3 of dimethylformamide, 14.5 g of sodium carbonate and 6 cm3 of propyl iodide are added; [the mixture] is agitated for 20 hours, then after dilution with water, extraction with ethyl acetate, washing with salt water, drying and distillation to dryness under reduced pressure, g of crude product is obtained which is purified by chromatography on silica (eluant: cyclohexane-triethyl amine 9-1). 8.2 g are thus obtained of the purified product, with Rf = 0.2.

EXAMPLE 22: Acid oxalate of 1-methyl 4-(l-propyl 1,2,5,6-tetrahydropyrid-3-yl) IH-indole. 3tage_A: l3mgthyl_42£l2BE2Eyl_l’?i546;tetrahydrogyrid;3;yl)_lH;indole.

A solution containing 8.2 g of 3-(l-methyl IH-indolr4-yl) 1-propyl o 3-piperidinol in 250 cm of N hydrochloric acid is heated to reflux for 48906 hours. After cooling on an ice-bath, adding sodium hydroxide solution to an alkaline pH, extraction with methylene chloride, washing with salt water, drying and distilling to dryness under reduced pressure, a crude product is obtained which is chromatographed on silica by elution with a cyclohexane-triethylamine mixture (9-1). 6,2 g of the product sought, with Rf = 0.2 is thus isolated.

Stage_B: formation.of_the_acid_oxalate.

The 6.2 g of the product prepared at Stage A is dissolved in 62 cm of isopropanol, then 3 g of oxalic acid in solution in 30 cm of isopropanol is introduced; the precipitate obtained is re-dissolved hot, crystallization is initiated, then after icing for 16 hours, separating off the liquid phase, washing with isopropanol, drying under vacuum and recrystallization in ethanol, 7.5 g of the product sought melting at 163°C is obtained.

EXAMPLE 23: l-methyl 3-(l-methyl lH-indol-4-yl)3-piperidinol. 16,5 g of 3-(l-methyl 1H-indol-4-yl) 3-piperidinol hydrochloride is dissolved in 20 volumes of water, iced and alkalized by sodium hydroxide.

By extraction with ethyl acetate, washing with water, drying on magnesium sulphate and distilling to dryness under reduced pressure, a residue is obtained which is dissolved in 150 cm3 of methanol; Lthis solution] is cooled to 10°C, 7 cm3 of a 40% formaldehyde solution is added, then after 15 minutes it is cooled to +5°C and little by little 5 g of sodium hydroboride is added. After agitating for one hour, diluting with water, extracting with methylene chloride, washing with water, drying and distilling to dryness under reduced pressure, 15 g of crude product sought, melting at 80°C is obtained, 4-3906 which after purification by chromatography on silica (eluant cyclohexanetriethyl amine 9-1) melts at 90°C.

EXAMPLE 24: Acid oxalate of 1-methyl 4-(l-methy1 l,2,5,6-tetrahydropyrid-3-yl) IH indole.

Stage_A: ^methyl J-flgmethyl^l^^e-tetrahydrogyrid^vl^H^indole.

A solution containing 15 g of 1-methyl 3-(l-methyl Ifl-indol-4-yl) 3-piperidinol in 500 cm3 of N hydrochloric acid is heated to reflux for 3 hours, cooled to ambient temperature, agitated for 16 hours, cooled on an ice bath and alkalized by addition of sodium hydroxide solution. After extraction with ethyl acetate, washing with salt water, drying on magnesium sulphate and distilling to dryness under reduced pressure, 13 g of a product is obtained which is chromatographed on silica by elution with a cyclohexane-chloroform-triethylamine mixture (6-3-1). 8.7 g of the product sought is thus isolated. §tage_B: formation_of_the_acid oxalate.

The 8.7 g of the produce prepared at Stage A is dissolved in 87 cm3 of isopropanol, a solution of 2.4 g of oxalic acid in 48 cm of isopropanol is added, then, after initiating crystallization, icing for 16 hours, separating off the liquid phase, washing with isopropanol, and drying at 50°C under vacuum, 4.3 g of the product sought, melting at 173°C, is obtained.

EXAMPLE 25: 1-(cyclopropyl methyl) 3-(1H-indol-4-yl) 3-piperidinol. g of 3-(1H-indol-4-yl) 3-piperidinol (hydrochloride) is introduced q into 250 cm of dimethylformamide, 17.8 g of sodium carbonate and 6.4 g of chloromethylcyclopropane are added; [the mixture] is agitated under inert atmosphere at 70°C for 8 hours, then for 15 hours at ambient temperature, 4-9906 it is taken up with water, extracted with ethyl acetate, washed with water, dried on magnesium sulpate, filtered, and the solvent expelled at 50°C under reduced pressure. 13.6 g of the crude product sought is obtained, which is purified by chromatography on silica (eluant: cyclohexane5 chloroform-triethylamine 6-3-1). 10 g of the expected product is thus obtained, (Rf = 0.15).

EXAMPLE 26: 4-0-( cycl opropyl methyl) l,2,5,6-tetrahydropyrid-3-yl_ IH-indole phosphate.

Stage A: 4-(1-(cyclopropyl methyl) l,2,5,6-tetrahydropyrid-3-yl| IH-indole.

A solution containing 10 g of l-(cyclopropyl methyl) 3-(lH-indoleο 4-yl) 3-piperidinol in 300 cm of IN hydrochloric acid is heated to reflux for 6 hours. After cooling to ambient temperature, adding 300 cm^ of water, extracting with ethyl acetate, washing with salt water, drying and expelling the solvent under reduced pressure, 9.1 g of a product is obtained which is chromatographed on silica by elution with a chloroform-methanol mixture (95-5). 5.4 g of the product sought (Rf = 0.10) is thus isolated.

Stage_B: formation_of_the_ghosghate. 4.9 g of the product prepared at Stage A is dissolved in 300 cm of isopropanol. Then a solution of phosphoric acid with 10% of isopropanol is introduced until the pH is acid. After filtering, washing with isopropanol, drying under vacuum at 50°C, and re-crystallizing j[first in a mixture of ethanol and methanol, then in water, 4.5 g of the product sought, melting at 230°C is obtained, 4-99 06 EXAMPLE 27: l-(2-propenyl) 3-(1H-indol-4-yl) 3-piperidinol. g of 3-(lH-indol-4-yl) 3-piperidinol (hydrochloride) is introduced 1 into 350 cm of dimethylformamide, 22.9 g of sodium carbonate and 7.6 cnr of allyl bromide are added, then [the mixture] is agitated at ambient temperature under inert atmosphere for 2 hours. The mixture is taken up again by 1 litre of v/ater and 500 cm of ethyl acetate, decanted, the organic phase is washed with water, dried and the solvents are expelled under reduced pressure. 17 g of the crude desired product is obtained, which is purified by chromatography on silica (eluant : cyclohexane-chloroformtriethyl amine 6-3-1). 14 g of the purified product (Rf = 0.15) is thus obtained.

EXAMPLE 28: Neutral oxalate of 4-[l-(2-propenyl) 1,2,5,6-tetrahydropyrid-3-ylj IH-indole. Stage_A£ 4-[j-(2-propenyl) 1,2,5,6-tetrahydropydrid-3-yl] IH-indole.

A solution containing 14 g of l-(2-propenyl) 3-{IH-indol-4-yl) 3-piperidinol in 400 cm3 of IN hydrochloric acid is heated to reflux for 4 hours. [lhe mixture] is cooled, alkalized with sodium hydroxide solution, and potassium carbonate is added, then, after extraction with ethyl acetate, drying and expelling the solvent under reduced pressure, 12.7 g of a product is obtained which is chromatographed on silica by elution with a mixture of chloroform-acetone (9-1). 6.85 g of the product sought (Rf = 0.15) is thus isolated.

Stage_B: f°G5ati2Q_°f_ihe_rieutral_oxalate. 6.8 g of the product prepared at Stage A is dissolved in 400 cm of isopropanol at reflux. Then 3.6 g of dihydrated oxalic acid is introduced, 499 0 6 and reflux is maintained for about 15 minutes. After icing, filtering and drying, 6.4 g of the product sought, melting at 225°C, is obtained.

Example of pharmaceutical compositions. 1) Compressed tablets responding to the following formula have been made up: - neutral fumarate of 4-(1-methyl piperidin-3-yl) lH-indole.........10 mg. - excipient (talc, starch, magnesium stearate) q.s. for a tablet finished at....................................150 mg. 2) Compressed tablets have been prepared responding to the formula: - neutral succinate of 4-[l-(phenyl methyl) 1,2,5,6-tetrahydro3-pyridyf] IH-indole............................................. 5 mg. excipient q.s. for a tablet finished at......................... 100 mg. (detail of excipient : lactose, starch, talc, magnesium stearate). 3) Compressed tablets have been prepared responding to the formula: - neutral fumarate of 4-(l-propyl 3-piperidyl) lH-indole ............ 2 mg excipient q.s. for a tablet finished at ........................... 100 mg.

(Detail of excipient: lactose, starch, talc, magnesium stearate). 4) Compressed tablets have been prepared responding to the formula: neutral oxalate of 4-Q-(2-propeny1) 1,2,5,6-tetrahydropyrid20 3-yl] IH-indole ................................................... 5 mg excipient q.s. for a tablet finished at ......................... 100 mg.

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

Pharmacological study. 1) Rotation behaviour after unilateral injury of the nigrostriatal 25 bundle by 6-hydroxydopamine.

Technique The lesion is effected in male rats of about 220 g by unilateral injection in the dopaminergic nigrostriated bundle of 8 pg of 6-hydroxydopamine in solution at 2 pg/pl. (U. Ungerstedt, Acta Physiol. Scand. 1971, 82, suppl. 367, 69-93). 4-9906 In such animals, the direct dopaminergic contestants such as apomorphine, administered by general route cause a rotation behaviour in the direction contra-lateral to the injured side.

The compound studied is administered at least 5 weeks after the lesion. The animals are placed in an automatized rotameter which enables the number of rotations made by each animal in the two directions to be counted.

In the conditions of the test, the following results have been obtained: the products of examples 7 and 10 caused contra-lateral rotations with a dose of upwards of 2 mg/kg; the products of examples 6 and 12 caused contra-lateral rotations with a dose of upwards of 5 mg/kg; the product of example 11 caused contra-lateral rotations with a dose of upwards of 10 mg/kg; the products of examples 17 and 28 caused contra-lateral rotations upwards of doses of 4 and 5 mg/kg respectively.

The results obtained show that the products possess useful dopaminergic stimulating properties. 2) Determination of the hypotensive activity of the products of examples and 10.

The hypotensive activity was studied on male rats of Strague Dawley 3.P.F. strain, weighing about 300 g and anaesthetized with nembutal (50 mg/kg by intravenous route).

The product tested is administered by intravenous route in the jugular vein. 40906 The carotid arterial pressure is measured before and after administration of the product tested.

It has been determined that the products of examples 6 and 10, at a dose of 1 mg/kg, presented a clear hypotensive activity. 3) Study of hypobaric anoxia in mice.

Male mice of a weight of 20 to 22 g are used, unfed for 5 hours, divided into groups of 10 animals. The survival time is determined of mice placed in a sealed enclosure in which the pressure is reduced to 90 mm of mercury by means of a pump. The products studied are administered by oral route thirty minutes before the test. The controls do not receive any product.

The following results correspond to the increase in survival time referred to the 50 mg/kg 106% 10 mg/kg 67% 2 mg/kg 30% 25 mg/kg 108% 5 mg/kg 26% 25 mg/kg 44% ( ( Product of example 7 25 m9/k9 ( Product of example 12 4) Platelet anti-aggregating effect.

The study of platelet aggregation is carried out according to the method of Born (J. Physiol. 1963, 168 , 178) with the aid of Mustard's aggregometer.

Male New Zealand rabbits are used. Blood is extracted by cardiac puncture. After slow centrifuging of the blood collected, a plasma is obtained rich in platelets which is adjusted to the numerical concentration of 300,000 platelets/mm3. As aggregating agent collagen at 40 mcg/ml incubated for 5 minutes at 33° is used. yi The products under study are introduced in variable concentrations in the plasma rich in platelets.

The variation in the transmission of a beam of light through a tube containing the plasma rich in platelets is measured. When aggregations form the quantity of light transmitted is greater and the optical density diminishes.

The inhibition of aggregation induced by the collagen for each product at different doses is determined.

The following are the results obtained: Product Final molar concentration % diminution of aggregation Product of 1X10-3 100% example 13 1X10-4 42% 1X105 22% Product of 1X1o'3 100% example 10 1X10-4 76% 1X1 o'5 11% Product of 1X10"3 100% example 11 1X10*4 100% 1X1 o’5 24% 489 0 6 ) Study of acute toxicity.

The lethal doses LDQ are evaluated of different compounds after administration by intra-peritoneal route in mice.

The maximum dose not causing any mortality is called LDQ.

The following are the results obtained: LDo - product of example 6 - 60 mg/kg - product of example 7 Z. 80 - - product of example 10 a; 80 - - product of example 11 az 60 - - product of example 12 si 80 - - product of example 13 60 - - product of example 17 ad 40 - - product of example 28 —200 -

Claims (18)

1. Compounds v/ith the formula (I) R in which: 5 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, 10 L represents a hydrogen atom, an alkyl or a 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, possibly substituted by one or more halogen atoms, by one or more alkoxy radicals containing from 1 to 4 carbon atoms, by one or more alkyl 15 radicals containing from 1 to 4 carbon atoms or by one or more OH, CFg, OCFg, N0 2 or NH 2 radicals, or Z represents a cycloalkyl-alkyl radical containing from 4 to 12 carbon atoms, an alkenyl radical 4-89 0 6 containing from 3 to 8 carbon atoms, or an alkynyl radical containing from 3 to 8 carbon atoms, and either a and each represent a hydrogen atom, or a represents a hydrogen atom and ji represents a hydroxyl radical or an alkoxy radical containing from 1 to 8 carbon atoms, or a and b together form a double carbon-carbon bond, as well as the salts of addition with acids of the compounds with the formula (I).

2. Compounds with the formula (I) as defined in claim 1, for which Y represents a hydrogen atom, as well as their salts of addition with acids.

3. Compounds with the formula (I) as defined in claim 1 or 2, for which X represents a hydrogen atom, as well as their salts of addition with acids.

4. Compounds with the formula (I) as defined in claim 1, 2 or 3, for which Z represents a hydrogen atom, as well as their salts of addition with acids.

5. Compounds with the formula (I) as defined in any one of the claims 1, 2 or 3, for which Z represents an alkyl radical containing from 1 to 4 carbon atoms or an aralkyl containing from 7 to 12 carbon atoms, as well as their salts of addition with acids.

6. Compounds with the formula (I) as defined in any one of claims 1 to 5, for which a and b together form a double carbon-carbon bond, as well as their salts of addition with acids.

7. Compounds with the formula (I) as defined in any one of claims ! to 5 for which a and b each represents a hydrogen atom, as well as their salts of addition with acids. 4 9 9 0 6

8. Compounds with the formula (I) as defined in any one of claims 1 to 5 for which a represents a hydrogen atom and b represents a hydroxyl radical or a methoxy radical as well as their salts of addition with acids. 5

9. The 4-(piperidin-3-yl) IH-indole as well as its salts of addition with acids.

10. The 4-(l,2,5,6-tetrahydropyridin-3-y1) IH-indole as well as its salts of addition with acids.

11. Preparation process for the compounds with the formula (I) 10 as defined in any one of the claims 1 to 10 wherein a compound with the formula (II) in which X represents a hydrogen atom or an alkyl radical containing from 1 to 8 carbon atoms and Hal represents a halogen atom is 15 submitted to the action of an alkylation or aralkylation agent, so as to obtain a compound with the formula (III): (ΠΙ) in which R' represents an alkyl radical containing from 1 to 8 carbon atoms or an aralkyl radical containing from 7 to 12 carbon atoms, which is converted into an organo-magnesium derivative so as to obtain a compound of the general formula (IV): which is condensed with N-benzyl 3-piperidone so as to obtain a compound, with the formula (1^): - 499 06 then, if desired, and in any order either the compound with the formula (1^) is submitted a dehydration agent, so as to obtain a compound v/ith the to the action of formula (Ι β ): (Ir benzyl radical, for the 5 which, if desired, in the case where R‘ represents a is submitted to the action of a selective cleavage agent benzyl group carried by the nucleus of the indole, so as to obtain a compound with formula (I c ): H which, if desired, is submitted to the action of a cleavage agent for the benzyl group carried by the tetrahydropyridyl nucleus so as to obtain the compound of the formula (Ιθ): 5 or the compound with the formula (1^) is submitted to the action of a cleavage agent for the benzyl group carried by the nitrogen of the piperidinyl group, so as to obtain a compound with the formula (Ip): which, if desired, is submitted to the action of a dehydration agent 10 so as to obtain a compound with the formula (Ip): . 49906 or, in the case where R' represents a benzyl group, the compound with the formula (1^) is submitted to the action of a selective cleavage agent for the benzyl group carried by the indole nucleus in order to 5 obtain a compound of the general formula (1^): which, if desired, is submitted to the action of a cleavage agent for the benzyl group carried by the pi peridinyl nucleus, in order to obtain a compound of the general formula (1^): HO 499 0 6 V\,/S I then, if desired, each of the compounds obtained corresponding to the formula (I) in which Z represents a hydrogen atom is submitted to the action of an agent able to introduce a radical 1' , 1' having the same significance as Z, as defined in claim 1, with the exception of hydrogen, so as to obtain the corresponding compounds with the formula (I) in which the nitrogen atom of the piperidinyl nucleus carries a radical Z’, and, if desired, either each of the compounds obtained corresponding to the 10 formula (I) in which b represents a hydroxyl radical is submitted to the action of an etherification agent, so as to obtain the corresponding compound of the formula (I) in which represents an alkoxy radical containing from 1 to 8 carbon atoms, or each of the compounds obtained corresponding to formula (I) in 15 which b represents a hydroxyl radical is submitted to the action of a dehydration agent, so as to obtain the corresponding compound of the formula (I) in which a and b together form a carbon-carbon double bond, or each of the compounds obtained corresponding to the formula (I) in which J) represents a hydroxyl radical is submitted to the action of a cleavage agent for the hydroxyl group, so as to obtain the corresponding compounds with the formula (I) in which a and b each represent a hydrogen atom, and, if desired, each of the compounds of the formula (I) so obtained is submitted to the action of a halogenation agent able to introduce a halogen atom Hal in position 3 of the indole, so as to obtain the corresponding compound with formula (I) in which Y represents a halogen atom, and, if desired, each of the compounds of the formula (I) previously obtained is submitted to the action of an acid so as to form its salt.

12. Process according to claim 11, wherein the different optional stages are carried out in any order whatsoever.

13. As medicaments, the compounds with the formula (I), as defined in any one of the claims 1 to 8 as well as their salts of addition with pharmaceutically acceptable acids.

14. As medicaments, the pharmaceutically acceptable compounds with the formula (I), as defined in any one of the claims 9 or 10.

15. As medicament: -4-(piperidin-3-yl) IH-indole hydrochloride.

16. The pharmaceutical compositions containing as active principle at least one of the medicaments as defined in claims 13, 14 or 15.

17. A process for the preparation of compounds of claim 1 substantially as described herein with reference to the Examples.

18. The compounds of claim 1 whenever prepared by a process as claimed in any of claims 11, 12 or 17.