IE52591B1 - New indole derivatives,process for preparing them,and pharmaceutical compositions containing them - 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

The present invention relates to new indole derivatives and their salts, processes for preparing them and pharmaoeuti cal compositions containing them.

In our Patent Specification. No. 49906 (1207/80) we have described and claimed new indole derivatives which are compounds of the general formula: (I) in which - E 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, - Ϊ represents a hydrogen atom or a halogen atom, - Z represents a hydrogen atom, an alkyl or hydroxy15 alkyl radical containing from 1 to 8 carbon atoms, an aryloxyalkyl radical containing from 7 to 1? carbon etoms, an aralkyl radical containing from 7 bo 12 carbon atoms, impossibly substituted by one or more halogen atoms, by one J - 2 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,CPj, OCF^t N02 or NHg, or Z represents a cycloalkylalkyl radical containing from 4 to 12 carbon atoms, an alkenyl raclidal 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 ja represents a hydrogen atom and b represents 10 a hydroxyl radical or an alkoxy radical containing from 1 to 8 carbon atoms, - or a and b together form a carbon-carbon double bond, as well as their pharmaceutically acceptable acid addition salts.

The above-mentioned Patent Specification also claims a process for preparing the indole derivatives corresponding to the formula (I) above, as well as their salts.

Furthermore, our Patent Specification claims the use as medicaments of the derivatives corresponding to the general formula (I) above and of their pharmaceuticallyacceptable salts, as well as the pharmaceutical compositions containing, as active principle, one or more of the derivatives of general formula (I) and/or their pharmaceuti25 cally-acceptable salts.

We have now found that certain other derivatives falling within general formula (I) of the main invention are new and useful medicaments and the present Application is one for a Patent of Addition to the Patent granted - 3 for the main invention. Xn-particular, the present invention is directed to indole derivatives corresponding to the formula (I) whose names are as follows: - l-methyl-4-(3-piperidyl)-lH-indole, - l-methyl-4-(l-propyl-’3-piperidyl)-lH-indole, - 4-(l-ethyl-3-piperidyl)-lH-indole, and - 4-{l-ethyl-l,2,5,6-tetrahydro-3-pyridyl)-lH-indole and their addition salts with mineral or organic acids.

These derivatives can be prepared by the process described in the main Patent Specification.

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

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

Among the preferred derivatives of the invention there are considered, more particularly; - the hydrochloride of l-methyl-4-(3-piperidyl)-lH-indole, - the oxalate of l-methyl-4-(l-propyl-3-piperidyl)-lH-indole, - the neutral fumarate of 4-(l-ethyl-3-piperidyl)-lH-indole and - the phosphate of 4-ft-ethyl-l,2,5,6-tetrahydro-3- pyridyl)lH-indole.

The subject of the present Application for a Patent - 4 of Addition is also a process for preparing these new derivatives defined above, as well as their salts, characterised in that a compound of formula (II): (II) t; is subjected to the action of a methylation or benzylation agent to obtain a compound of formula (III): (III) K' in which R' represents a methyl or benzyl radical, which is converted into an organorangnesium derivative to obtain a compound of formula (IV): (IV) - 5 which is condensed with N-benzyl 3-piperidone to obtain a compound of formula (1^); - either, in the cane in which R' represents a 5 methyl radical, the compound of formula (1^) is subjected to the action of an agent for cleaving the benzyl group borne by the nitrogen of the piperidyl group to obtain the compound of formula (lg): Cu which is subjected to the action the hydroxyl group to obtain the piperidine compound and then, if subjected to the of an agent for cleaving corresponding 3-(4-indolyl) desired, the latter is 52591 t action of an agent capable of introducing a propyl radical, to obtain the compound of formula (Ιθ): (Ic) - or, in the case in which R' represents a benzyl group, the compound of formula (1^) is subjected to the action of an agent for selectively cleaving the benzyl group borne by the nucleus of the indole to obtain the compound of (In) which is subjected to the action of an agent for cleaving the benzyl group borne by the piperidyl nucleus·, to obtain the compound of formula (IE): (I,) then either the said compound of formula (lg) is subjected to the action of an agent for cleaving the hydroxyl group to obtain 3-(H-indolyl)piperidine which is subjected to the action of an agent capable of introducing an ethyl radical, to obtain the compound of formula (I.,.): n-c2h5 (Ip) or the said compound of formula (lg) is subjected to the action of an agent capable of introducing an ethyl radical then the compound obtained is subjected to the action of a dehydrating agent to obtain the corresponding compound containing at 5,4- a carbon-carbon double bond and, if desired, each of the ^wo compounds obtained above is subjected to the action of an acid to form the salt thereof· In a preferred method of carrying out the process of the invention, - the methylation or bqnzylation agent is preferably a methyl or benzyl halide, for example a methyl or benzyl chloride, bromide or iodide, - the formation of the magnesium derivative of formula (IV) is effected by reacting magnesium with the compound of formula (III) in an appropriate solvent, preferably in tetrahydrofuran in the presence of a small amount of dibromoethane, - the agent for cleaving the benzyl group borne by the piperidyl nucleus is hydrogen in the presence of a catalyst, for example hydrogen in the presence of palladium, - in order to carry out the cleaving of the hydroxyl group lithium in liquid ammonia is used at a temperature below -40°C, for example -60°C, - the introduction of the ethyl or propyl radical is carried out by means of a halide, such as an ethyl or propyl chloride, bromide or iodide, - the agent for cleaving the benzyl group borne by the nucleus of the indole is sodium in liquid ammonia at low temperature, and - the dehydrating agent is preferably a strong acid such as hydrochloric acid or oxalic acid or else phosphoric anhydride.

As indicated in the main Specification, the addition salts of the aforementioned derivatives can be prepared - 9 according to standard methods, for example, by reacting, in substantially stoichiometric proportions, a mineral or organic acid with the said derivatives.

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

The derivatives, which form the subject of the present Application, possess very interesting pharmacological properties: they are endowed, in particular, with certain dopaminergic stimulating properties accompanied or unaccompanied by activity at the adrenergic and serotinergic level.

These properties are illustrated further on in the experimental portion.

These properties justify the use of the new indole derivatives and of their salts as medicaments. The subject of the present Application is, therefore, also the use, as medicaments, of the new indole derivatives defined above, as well as of their addition salts with pharmaceutically-acceptable acids.

Among the medicaments of the invention there are considered, in particular: - the hydrochloride of l-methyl-4-(3-piperidyl)-lH-indole, - the oxalate of l-methyl-4-(l-propyl-3-piperidyl)-lH-indole, - the neutral fumarate of 4-(l-ethyl-3-piperidyl)-lH-indole and - the phosphate of 4-(l-ethyl-l,2,5,6-tetrahydro-3pyridyl)-lH-indole.

The medicaments, which also form the subject of the present 53591 - 10 invention, are used, for example, in the treatment of neurological syndromes of extrapyramidal origin, for example in the treatment of Parkinsons disease and in the treatment of post-encephalitic parkinsonian syndromes, and they can also be used in the treatment of hypersecretion of prolactin by the antehypophysis, for example in the treatment of hypogonadism in woman and in man. They can also be used in the treatment of cerebral senescence, vertebrobasilary insufficiency, arterial hypertension and peripheral circulatory disorders and in the treatment of arteriopathy of the lower limbs and of theirtrophtc complications.

• The usual dose, which can be varied according to the derivative used, the subject treated and the complaint concerned, can be, for example, from 5 to 100 mg per day of the derivative of Example 1 by oral route in man for the treatment of Parkinsons disease or for the treatment of cerebral senescence.

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

As medicaments, the derivatives, which form the subject of the present Application, and their addition salts with pharmaceutically-acceptable acids can be mixed with pharmaceutical compositions intended for the digestive or parenteral route.

These pharmaceutical compositions can be, for example, - 11 solid or liquid and can be presented in the pharmaceutical forms currently used in human medicine such as, for example, plain or sugar-coated compressed tablets, gelatin capsules, capsules, granules, suppositories and injectable preparations: they are prepared according to the usual methods. The active principle or principles can he mixed with excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives There will now be given examples of carrying out the invention. 52581 Example 1; Hydrochloride of l-methyl-4-(3-piperidyl) -lH-indole.

Stage A: Formation of the magnesium derivative g of magnesium are introduced into 155 cm of tetrahydrofuran, the whole is taken to reflux, a solution 3 of 38 g of l-methyl-4-chloro-lH-indole and 4.5 cm of 3 1,2-dibromoethane in 115 cm of tetrahydrofuran is introduced slowly, after initiating using a few drops of methyl iodide, the refluxing is maintained for 6 hours, the whole is then cooled to 45°C and a solution is obtained which is used as it is hereinafter.

Stage B: Hydrochloride o_f_ (phenylmethylj A solution of N-benzyl-3-piperidone, prepared from 3 g of N-benzyl-3-piperidone hydrochloride, m 115 cm of tetrahydrofuran is introduced, drop by drop, into the solution obtained in Stage A, the whole is heated for 2 hours at reflux, allowed to cool, agitated for 16 hours 3 and cooled in an ice bath, 200 cm of ammonium chloride in saturated solution are added, drop by drop, the whole is filtered, rinsed with water and with ethyl acetate, decanted, extracted again with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and distilled to dryness under reduced pressure. The residue is taken up with ether, extracted with N hydrochloric acid, rendered alkaline, re-extracted with ethyl acetate and distilled to dryness under reduced pressure. 73.4 g of crude product are obtained which is purified by chromatography on a column of silica (eluant: cyclohexane/triethylamine 9:1). The product is - I? taken up with methylene chloride, filtered and distilled to dryness under reduced pressure and 60.5 6 of tue base of the expected product are obtained, is Preparation of the hydrochloride.

The product obtained above is dissolved in 300 cmof ethyl acetate, a solution of hydrochloric acid in ethyl acetate is added, drop by drop,until pH = 4, the whole is chilled for 16 hours, separated, washed with ethyl acetate and dried at 50°C under vacuum and 59-6 S of expected product are obtained, M.Pt. a 25O°C.

G: Hydrochloride. of_3^(l-meW^;l-lH-indpl-_4-2O-J2.ΡΪΡ®.Γΐ^ΐηΏ.^ g of hydrochloride of'3-tl-methyl-lH-indol —4-ylJ l-(phenyl methyl)-3-piperidinol in 1.5 litres of methanol are hydrogenolysed at 40°C in the presence of 15 g of palladised active charcoal. The whole is then left to cool, the catalyst is filtered off and the remainder is distilled to dryness under vacuum. 37 g of the expected product are obtained, ftf = 0.3, Support : silica - Eluant: chloroform / methanol / triethylamine (6:3:1)· Stage D: Hydrochloride. £f—lzinetl^l,-4yX32pjj)£rid2l2.--lH-ind£le. a) formation of the base. -14 g of hydrochloride of 3-(l-methyl-lH-indol-4-yl)3-piperidinol, 80 cra^ of tetrahydrofuran and 40 cm^ of anhydrous ethanol are introduced at -40°C into 400 cm^ of ammonia. 2.8 g of lithium are then introduced, over one hour thirty minutes, in small portions. The ammonia is allowed to evaporate at ambient temperature, then the residue - 14 3 is taken up with 400 cm of water. It is extracted with chloroform containing 10% of methanol, washed with water and dried. It is filtered and the solvents are driven off. A product is obtained which is used as it is in the following stage. b) formation of the hydrochloride The above product is dissolved in ethanol, then a saturated solution of hydrochloric acid in ethanol is added until pH = 4. The whole is filtered, washed with ethanol and dried, the product obtained is recrystallised In,ill uUmimI -III'I 3.0 ) Of 3ul|f,ht jlPu I l)Ui. obtained, M.Pt. = 270° C.

Analysis : C^H^gCl Ng = 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-l-methyl-lH-indole can be prepared as follows: g of 4-chloro-lH-indole with 400 cm^ of benzene, 200 cm3 of a 50% solution of sodium hydroxide, 68 g of 3 n-tetrabutylantmonium hydrogensulphate and 68 cm of methyl iodide are heated to 40°C, under agitation for 4 hours, cooled and decanted, the aqueous phase is re-extracted with ethyl acetate, the combined organic phases are washed with a saturated aqueous solution of sodium chloride, dried, distilled to dryness under reduced pressure and purified by chromatography on silica (eluant: cyclohexane/benzene, 8:2) ji-I ('· i. »6 ,j of ...--0.,-101) prnduji are obtained. - 15 Example 2 : Oxalate of l-methyl-4-(1-propyl—3-piperidyl) -lH-indole g of the product of Example 1 in 50 cm of dimethyl-formamide are agitated under inert atmosphere 6.3 g of sodium carbonate and 2v05 cm3 of propyl iodide are added, the whole is agitated for 16 hours, poured into 250 cn? of water, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride, dried, distilled to dryness under reduced pressure and purified by IQ chromatography on silica (eluant: cyclohexane/chloroform /triethylamine, 6:3:1), and 4.9 g of the base of the expected product are thus isolated.

Formation of the oxalate 4.8 g .of the product above are dissolved, with 3 heating, in 15 cm of ethanol, a solution of 2.36 g of 3 oxalic acid in 10 cm of ethanol is added, the whole is left to cool, crystallisation is initiated, the whole is chilled for 16 hours, separated, washed with ethanol, dried at 50°C under reduced pressure and recrystallised from ethanol and 5.68 g of the expected product are obtained, M.Pt. —167*C.

Analysis : C-jgHggNj 0^ = 346.427 Calculated: C% 65.87 H% 7.57 H% 8.09 Found: 66.2 7.6 8.1 Example 3 : Neutral fumarate of 4-(l-ethyl-3-piperidyl) -1H-indole.

Stag_e_A: 4-chloro-l-(phenyl methyJJ-lH-indole.

A mixture containing 16.9 g of 4-chloro-lH-indole, - 16 3 3 170 cm of benzene, 85 cm of a 50% solution of sodium hydroxide, 1.89 g of n-tetrabutylammonium hydrogensulphate and 16.6 cm3 of benzyl chloride are heated to 60°C under strong agitation for 4 hours.

It is cooled to ambient temperature and decanted, the organic phase is washed with water and dried and the solvents are driven off. 30.2 g of a product are obtained which is chromatographed on silica eluting with β cyclohexane. 22.8 g of product sought, melting at 58-60 C, are thus isolated.

Stage B : l-(phenyl methyl)-3jJl-(phenyl methyl)-lH-indol -4-yl]-3-piperidinol (and hydrochloride). a) Formation of the magnesium derivative. 113 g of magnesium are introduced into 200 cm3 of tetrahydrofuran. The whole is heated to reflux then a solution of 184 g of 4-chloro-l-(phenyl methyl)-lH-indole and 20 cm3 of 1,2-dibromoethane in 300 cm3 of tetrahydrofuran is introduced slowly. The reaction mixture is maintained at reflux for 3 hours and it is cooled to 30°C. A solution is obtained which is used as it is hereinafter. b) l-(phenyl methyl)-3-[l-(phenylmethyl)-lH-indol-4-yl]-3-piperidinol (hydrochloride).

A solution of 128 g of N-benzyl-3-piperxdone in 250 cm3 of tetrahydrofuran is introduced into the solution obtained in paragraph a) without exceeding 35°c. The whole is heated to reflux for 2 hours and cooled to 20°C and 1 litre of ammonium chloride in saturated aqueous solution is introduced slowly. The reaction mixture is taken up with 2 litres of -17-. ethyl acetate and. filtered. One decants, the extraction with ethyl acetate is continued, the extract is washed with water and dried and the solvents are driven off. 530 g of a product are obtained which is chromatographed on silica (eluant: cyclohexane / triethylamine, 9sl). 218.4 g of a product are thus obtained which is dissolved in ethyl acetate. The solution is extracted with IN hydrochloric acid. The aqueous acidic phase is rendered alkaline with ammonia and extracted with ethyl acetate. x The organic phase is dried and 100 cur 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 product sought, melting at 185°C are obtained. By recrystallisation from ethyl acetate containing 10% of methanol, the pure product, melting at 190°C, is obtained. c) release of the base.

The corresponding base is released by treating with sodium hydroxide and the product sought is obtained by extracting with ethyl acetate and evaporating the solvent. Stag£ C: f^drochloride of_3£lH~indo d. ino 1. a) formation of the base.

A solution containing 14.8 g of l-(phenyl methyl)- 3~Cl-(phenyl methyl)-lH-indol-4-yl]-3-piperidinol in 250 cm^ of tetrahydrofuran is introduced, at -40°C into 500 cm^ of - 18 ammonia. Gradually 1.5 g of sodium are added, the temperature being maintained at -40°C. At the end of the reaction ammonium chloride is added until discolouration of the blue tint obtained above, The residue is taken up wib(i water, decanted and extracted with ethyl acetate. It is washed with water and dried and the solvents are driven off. 12 g of a product are obtained which 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. The whole is filtered, washed with ethyl acetate and dried. 12.7 g of product sought, melting at 228-230°C, are obtained.

Stage_D_j_ Hydrochloride. of_ 3-J lHjindol-4-ylJ-3_ -piperidino 1^ 12.7 g of hydrochloride of 3-(lH-indol-4-yl)-l -phenyl methyl-3-piperidinol in 500 cm3 of methanol are hydrogenated at 60°C in the presence of 3.6 g of palladised active charcoal. The whole is filtered and concentrated to dryness and 9 g of the product sought are obtained which is used as it is for the following stage.

Stage E : Hydrochloride_of_42(^ggigerid^lJ^lH^indole a) formation of the base 1.2 g of hydrochloride of 3-(lH-indol-4-yl)-3 -piperidinol hydrochloride, 20 cn? of tetrahydrofuran and 10 cn3of anhydrous ethanol are introduced, at -40°C, into 100^cm of ammonia. Then over one hour in small portions, 700 mg of lithium are - 19 introduced. The ammonia is allowed to evaporate at ambient temperature, then the residue is taken up with 100 cm3 of water. This is extracted with chloroform containing 10% of methanol, washed with water and dried.

It is filtered and the^solvents are driven off. 950 mg of a product are obtained which is chromatographed on silica (eluant: chloroform/methanol/triethylamine, 7:2:1). 665 mg of the product sought are isolated. b) formation of the hydrochloride 2.3 g of 4-(3-piperidyl)-lH-indole, prepared as is indicated in Stage A, are dissolved in 50 cm3 of ethyl acetate and a saturated solution of hydrochloric acid in ethyl acetate is then added. The whole is filtered, washed with ethyl acetate and dried and the 15 product obtained is recrystallised from acetonitrile CL'iil sluing 20* of methanol. 2.2 g of the product nought are thus obtained.

Stage F : Neutral fumarate_of-^(.l-ethyl^^EiEeridyl^lH -indole. a) base 4.4 g of hydrochloride of 4-(3-piperidyl)-lH -indole hydrochloride in 90 cn? of dimethylformamide are agitated, for 5 hours under inert atmosphere, with 5.9 g of sodium carbonate and 1.7 cm? of ethyl bromide, the whole is taken up with water, extracted with ethyl acetate, washed with water, dried, filtered, evaporated to dryness under reduced pressure at 50°C and purified by chromatography on silica (eluant: cyclohexane/ chloroform/triethylamine, 6:3:1), 4,3 g of the expected 3θ product are obtained. 53581 - 20 b) neutral fumarate.

The product above is dissolved in 200 cm^ of isopropanol, 2.5 g of funaric acid are added, the whole is heated to JA reflux for 15 minutes, chilled, filtered, dried under reduced pressure and crystallised from methanol and 4.3 g of the expected product are obtained, M.Pt. — 265°0.

Analysis : 0^ ’ 286.577 Calculated: (¾ 71.30 M 7.74 Ww 9.78 Found 71.5 7-8 9.7 Example 4: Phosphate of 4-(l-ethy[- 1 ,?,f's6-tetmhydro-3-pyridyl)-lH-indole. jltage. Δ·' i-^hF'^Jri.lH-indol.-A-vl^-T.-ni^er^idinol.. lOg of hydrochloride of 5-(lH-indol-4-yl)-5~piperidinol (obtained in Stage D of Example 5) in 200 cm^ of dimethylformamide are agitated for 4 hours, under inert atmosphere, with 15.44 g of sodium carbonate and 4.2 cm^ of ethyl bromide. The whole is taken up with water, extracted with ethyl acetate, washed with water, dried, filtered, brought to dryness under reduced pressure at 5θ°0 snd purified by chromatography on silica (eluant: cyclohexane / chloroform / triethylamine, 6:5^1) and 6.6 g of a product, used as it is for the following stage, are obtained.

Stage B: Rrasjohate £fthyl-^)2, _5,6-£et^rah2dr o^_ 3ZP£rid£l_)_-lH-indo_l£._ a) base. 7, 6.6 g of the product above in 500 cm' of an N aqueous solution of hydrochloric acid are heated to reflux for 4 hours under agitation and inert atmosphere, cooled, rendered alkaline to pH = 10 using sodium hydroxide solution, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride, dried, filtered, brought to dryness at 5kP°C under reduced pressure, purified by chromatography on silica (eluant: chloroform/methanol, 9:1) and recrystallised from isopropyl ether and 3.95 g of base are obtained in two yields, M.Pt—124 C. b, phosphate 2.95 g of base above are dissolved in 300 cm^ of isopropanol, a 10% solution of phosphoric acid in isopropanol is added until pH = 4, the whole is heated to reflux for 15 minutes, chilled, filtered, dried under reduced pressure and recrystallised from an ethanol/ methanol mixture 50:50, and 3.1 g of the expected product are obtained, Analysis : C1c Η51 Calculated: C% 55.55 M.Pt. = 212 C. Ojj P = 324.317 P% 9.55 H% 6.53 N% 8.64 20 Found: 55.4 6,5 8.6 9.3 Example 5: Compressed tablets were prepared, corresponding to the formula: - hydrochloride of 1-methyl-4-(3-piperidyl)25 lH-indole........................................ 10 mg »» - Excipient q.s. for one compressed tablet up to .. 100 mg * * ’ * ' V.» ··.*.*' (Detail of the excipient: lactose, starch, talc, magnesium stearate.) - 22 Example 6: Compressed tablets were prepared, corresponding to the formula: Λ - oxalate of 1-methyl 4-(l-propyl5 3-piperidyl)-lH-indole ........................... 20 mg - Excipient q.s. for one compressed tablet up to ..................................... 100 mg (Detail of the excipient: lactose, starch, talc, magnesium stearate).

Example 7: Compressed tablets were prepared, corresponding to the formula: - phosphate of 4-(l-ethyl-1,2,5,6-tetrahydro -3-pyridyl)-lH-indole ............................. 20 mg - Excipient q.s. for one compressed tablet up to .................................... ICO mg (Detail of the excipient: lactose, starch, talc, magnesium stearate).

Pharmacological study. 1) Stereotyped behaviour in the rat.

Dopaminergic agonists, such as apomorphine, administered by general route, cause in rats stereotyped behaviour. Technioue: The compound studied is injected by intraperitoneal route into hatches of 5 rats weighing 160 i 15 g.

The animals are placed immediately after the injection in boxes made of Plexiglas (20 x 27 x 17 cm) containing wood shavings and are observed every thirty minutes for three 2591 - 23 hours. The intensity of the stereotyped movements is numbered from 0 to 6 according to the following evaluation criteria: the animal is asleep (0), awake but motionless (1), turns round in the box (2), sniffs (3), licks (4), touches the shavings wi,th its teeth or gnaws (5), bites the shavings or displays intense gnawing (6) (Psychopharmacology 68, 15-23 (1980)).

The product of Example I caused stereotyped behaviour at the dose of 50 mg/kg. 2) Rotation behaviour after unilateral lesion of the niqrostriatal bundle with 6-hydroxydopamine.

Technique: The lesion is effected in male rats of about 220 g by unilateral injection into the dopaminergic nigrostriated bundle of 8 jjg of 6-hydroxydopamine in 2 jig/jJl solution (U. Ungerstedt, Acta Physiol. Scand. 1971, 82, suppl. 367, 69-93).

In such animals the dopaminergic agonists such as apomorphine, administered by general route, cause 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 automated rotometer which enables the number of rotations made by each animal in both senses to be counted.

Under the conditions of the experiment, the following results were obtained: - 24 52581 t - the product of Example 2 causes contra-lateral rotations from the dose of 2 mgAg. 3) Potentiation of the stereotypy caused, by dexamphet amine.

The tests are carried out on hatches of 5 male rats of 150-180 g. Each animal is placed individually in a latticed cage (29 x 25 x 17 cm) containing a few fragments of wood shavings.

A dose of 3 mg/kg of dexamphetamine sulphate is injected by intraperitoneal route half an hour after the intraperitoneal administration of the product studied. The behaviour of the animals is noted from half-hour to half-hour for 5 hours with the marking recommended by HALLIWELL and Colleagues (Brit. J. Pharmacol. 1964·, 23, 35Ο~35θ)· The animal is asleep (0), it is awake but motionless (1), it turns round in the cage (2), it sniffs the cover thereof (3), it licks the walls thereof (4), it touches the shavings or the bars of the cage with its teeth (5), it bites the shavings or the bars of the cage (6).

The products of Examples 1, 3 and 4 potentiate stereotypy at the dose of 3 mg/kg, and the product of Example 2 at the dose of 0.6 mg/kg. 4) Study of the acute toxicity.

The lethal doses LDq of different compounds were evaluated after administration by intraperitoneal route in the mouse.

LDq is the maximum dose not causing any mortality. - 25 The - product - product - product - product results obtained are of Example 1 of Example 2 of Example 3 of Example 4 as follows: LD0 — 80 mg/kg d 60 mg/kg i; 60 mgAg CY 60 mgAg5

Claims (10)

1. A compound selected from: l-methyl-4-(3-piperidyl)-lH-indole, l-methyl-4-(l-propyl-3-piperxdyl)-lH-xndole, 4-(l-ethyl-3-pxperxdyl)-lH-indole, and 5 4-(1-ethyl-1,2,5,6-tetrahydro-3-pyridyl)-ΙΗ-indole.

2. A compound according to Claim 1 in the form of a pharmaceutically acceptable acid addition salt with a mineral or an organic acid.

3. l-methyl-

4. -(3-piperxdyl)-lH-indole hydrochloride. TO 4. l-methyl-4-(l-propyl-3-piperidyl)-lH-indole oxalate.

5. A neutral fumarate of 4-(l-ethyl-3-piperidyl) -lH-indole.

6. 4-(1-ethyl-l,2,5,6-tetrahydro-3-pyridyl)15 ΙΗ-indole phosphate.

7. A process for the preparation of a compound claimed in any one of the preceding claims, which process comprises reacting a compound of the (II) with a methylation or benzylation agent to obtain a compound of the formula: (III) in which H' represents a methyl or benzyl group, which is 5 converted into an organomagnesium derivative of the formula: (IV) which in turn is condensed with N-benzyl-5-pipe,ridone to obtain a compound of the formula: - 28 HO then - either, in the case in which S' represents a methyl group, the compound of formula (I A ) is subjected to the action of an agent for cleaving the benzyl group carried by 5 the nitrogen of the piperidyl ring to obtain the compound of the formula: HI CH. which is subjected to the action of an agent for cleaving the hydroxyl group to obtain the corresponding 3-piperidyl compound then, if desired, the latter is subjected to the action of an a^ent capable of introducing a propyl group, to obtain the compound of the formula: - or, in the case in which fi 1 represents a benzyl -roup, the compound of formula (1^) is subjected to the action of an agent for selectively cleaving the benzyl group carried by the indole nucleus to obtain the compound of the formula: H which is subjected to the action of an agent for cleaving the benzyl group carried by the piperidyl ring, to obtain the compound of the formula: HO (i E ) - 30 then, either the said compound of formula (I £ ) is subjected to the action of an agent for cleaving the hydroxyl group to obtain the corresponding 3-piperidyl compound which 5 is subjected to the action of an agent capable of introducing an ethyl group, to obtain the compound of formula: - or the said compound of formula (1^,) is subjected to the action of an agent capable of introducing an ethyl group and the compound so obtained is subjected to the action of a 10 dehydrating agent to obtain the corresponding compound containing a carbon-carbon double bond at the 3,4 position, each of the compounds obtained as above being subjected, if desired, to the action of an acid to form the corresponding salt thereof. 15

8. A process according to claim 7 substantially as hereinbefore described with reference to any one of the specific Examples.

9. A compound according to any one of Claims 1 to 6 when prepared by a process according to Claim 7 or Claim 8. 52581 - 31

10. A pharmaceutical composition, which composition comprises, as active ingredient, a compound according to any one of Claims 1 to 6 or 9, together with a pharmaceutically acceptable excipient or carrier. Dated this· nth day of December 1980.