AU593349B2

AU593349B2 - Indole derivative

Info

Publication number: AU593349B2
Application number: AU72272/87A
Authority: AU
Inventors: Henning Dr. Bottcher; Hans-Heinrich Dr. Hausberg; Klaus-Otto Dr. Minck; Christoph Dr. Seyfried
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 1986-04-30
Filing date: 1987-04-30
Publication date: 1990-02-08
Anticipated expiration: 2007-04-30
Also published as: HUT45532A; DE3614758A1; AU7227287A; ZA873138B; JPS62263181A; KR870010056A; EP0248187A3; EP0248187A2

Description

CO01MONWEALTH! OF AUSTrTALIA Form Regulation PATENTS ACT, 1952 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Short Title: Int. Cl: 5933 49 AppliCation Nuriber: Lodged: 7 2.2z7.2/-P7 -Complete Specification-Lodged, Accepted: Lapsed: Published: 'Priority: Xli/ 4 Related Art: TO BE COMPLETED BY APPEIC.ANT Nane of Applicant: MERCK PATENT GESE.LLSCHAFIT MIT BESCHRANKI!ER HAF~TUNG IAddress of Applicant: 250 Frankfurter Strasse, D-6100 Darmstadt, Germany.

Actual Inventor: Dr. Hennjing Bottcher, Dr. Hans-Heinrich Hausberg, Dr. Christoph Seyfried, Dr. Klaus-Otto Minck Address for Service:, ARTHUR S. CIAV!- CO., Patent and Trade Mark Attorneys, l1 Alfred Street, Sydney, New South Wales,, Australia, 2000.

Complete Specification for the invention entitled:

='IDR=V

The follow~ing statement is a full description cf this invention, including the best\ meth.od of performing it knoim to, me:- ASC-49 r I~ S- la- The invention relates to 3-E4-(4-phenyl-1,2,3,6- Set rhydropyridy -butyl]-5,6-methylenedioxyindole which is new, and to salts thereof.

The invention was based on the problem of finding new compounds which can be used for the preparation of medicaments.

It has been found that the substances mentioned possess valuabLe pharmacological properties and are well 10 tolerated. Thus they display, for example, an action which affects the central nervous system, preferably a calming (for example sedating, tranquilizing, neuroleptic and/or Se "anti-depressive) action. Specifically, the compounds have Sa calming action on the behaviour of mice (for method see 15 Irwin, Psychopharmacologia 13 (1968), 222-257) and inhibit in mice the climbing behaviour induced by apomorphine (for method see Costall et al, European J. Pharmacol 50 (1968), 39-50) or inhibit induced contralateral pivoting behaviour in hemi-parkinson rats (detectable by the method of 20 Ungerstedt et al. Brain Res. 24 (1970), 485-493), without 'f 'the appearance of appreciable cataleptic side-effects (for method see Dolini-Stola, Pharmakopsychiat. 6 (1973), 189- 197). The substances also inhibit the binding of tritiated dopamine agonists and antagonists to striatal recep- S- 25 tors (detectable by the method of Schwarcz et al, J.

Neuroche>iistry 34 (1980), 772-778, and Creese et al, Europearn J. Pharmacol. 46 (1977), 377-381). In addition, I the compounds inhibit the lingualmandibular reflex in narcotized rats (detectable by a method modelled on the methods of Barnett et al, European J. Pharmacol. 21 (1973), 178-182, and of Ilhan et al, European J. Pharmacol. 33 ,i i L~ si iCi L -~Y 2 (1975), 61-64). Analgesic and hypotensive effects are also found; thus the arterial blood pressure, measured directly on conscious, spontaneousLy hyptertonic rats carrying a catheter (strains SHR/NIH-MO//CHB-EMD: for method see Weeks and Jones, Proc.Soc.ExptL.BioL.Med. 104 (1960), 646-648) is Lowered after intragastric administration of the compounds.

The compound I and its physiologicaLLy acceptable acid addition salts can, therefore, be used as active compounds for medicaments and also as intermediate products for the preparation of other active compounds for medicaments.

The invention also relates to a process for the preparation of the compound and salts thereof, charac- 15 terised in that a 3-(4-X -butyl)-5,6-methylenedioxyindoLe wherein X is X or NH 2 and r X is CL, Br, I, OH or a reactive, functiont ally modified OH group is reacted with a compound of the formula III

X

2

-CH

2

CH

2

-C(C

6

H

5

)=CH-CH

2

X

3

III

2 3 i *wherein X and X can be identical or different and, if II 1 X is NH 2 are each X, or otherwise they are together NH, or a compound which otherwise corresponds to but contains one or more reducible group(s) and/or one or more 30 additional C-C- and/or C-N- bond(s) instead of one or more hydrogen atoms is treated with a reducing agent, or a compound which otherwise corresponds to but contains one or more solvolysable group(s) instead of one or more hydrogen atoms, is treated with a solvolizing agent, or a 3-[4-(3,4-di-E-4-phenylpiperidino)-butyl]-5,6methylenedioxyindole (IV) wherein r 4

P*

*4 .4

I

[t I -3 one radical E is X, CN or NH 2 the other radical E is H and X has meaning indicated is treated with an agent which eliminates HE and/or, if appropriate, the base is converted into one of its salts by treatment with an acid.

The preparation of the compound is effected, incidently, by methods known per se, such as are described in the Literature (for example in German OffenLegungsschrift 2,827,874), specifically under reaction conditions such as are known and suitable for the reactions mentioned. In this regard it is also possible to make use of variants which are known per se but are not mentioned here in detail.

The starting materials for the process claimed can, if desired, also be formed in situ, in such a way that they are not isolated from the reaction mixture, but are immediately reacted further to give the compounds of the formula I.

In the compounds of the formula II, X is preferably 20 X; accordingly, X and 3 in the compounds of the formula III preferably are tokgether NH. The radical X is preferably CL or Br; it can, however, also be I, OH or a reactive, functionally modified OH group, in particular alkylsulfonyloxy having 1-6 C atoms (for example methanesulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (for example benzenesulfonyloxy, p-toluenesulfonyloxy, 1-naphthalenesulfonyloxy or 2-naphthalenesulfonyloxy).

Accordingly, the compounds of the formula I are obtainable, in particular, by reacting 3-(4-chLorooutyl)- 30 5,6-methylenedioxyindole or 3-(4-bromobutyL)-5,6-methyLenedioxyindole with 4-phenyl-1,2,3,6-tetrahydropyridine (IIIa).

The compounds of the formulae II and III are in part known; the compounds of the formulae II and III which are not known can readily be prepared analogously to the known compounds. 3-(4-hydroxybutyl)-5,6-methyLenedioxyindoLe (IIa) is obtainabLe, for example, by reducing the corresponding carboxylic acid or its esters. The treatment with 1 a c i 12 a t t-: r a a a.a *0* a *0 a a a a #a *a r a.

4 thionyL chloride, hydrogen bromide, phosphorus tribromide or similar halogen compounds affords the corresponding halides. The corresponding sulfonyloxy compounds are obtainable from IIa by reacting it with the corresponding sulfonyl chlorides. 3-(4-iodobutyl)-5,6-methyLenedioxyindole is obtainabLe, for example, by the action of potassium iodide on the corresponding p-toluenesulfonic acid ester. 3-(4-aminobutyL)-5,6-methyLenedioxyindoLe can be prepared, for example, from the halides by means of potassium phthalimide or by reducing the corresponding nitrile The compounds of the formula III are Largely known (cf. German OffenLegungsschrift 2,060,816).

The reaction between the compounds II and III is 15 carried out by methods such as are known from the literature for the alkylation of amines. The components can be combined with one another by melting in the absence of a solvent, if appropriate in a sealed tube or in an autoclave.

It is also possible, however, to react the compounds in the 20 presence of an inert solvent. Examples of suitable solvents are hydrocarbons, such as benzene, toluene or xylene; ketones such as acetone or butanone; alcohols, such as methanol, ethanol, isopropanol or n-butanol; ethers, such as t-trahydrofuran (THF) or dioxane; amides, such as dimethylformamide (DMF) or n-methylpyrrolidone; nitriles, such as acetonitrile, and, if appropriate, also mixtures of these solvents with one another or mixtures with water.

The addition of an acid-binding agent, for example an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid and of the alkali or alkaline earth metals, preferably potassium, sodium or calcium, or the addition of an organic base, such as triethylamine, dimethylaniline, pyridine or quinoline, or an excess of the compound IIIa, can be advantageous. Depending on the conditions used, the reaction time is between a few minutes and 14 days; the reaction temperature is between about 0 and 1500, normally between 20 and 1300 I te I I

'A-

a r I r r It is also possible to obtain the compound by treating a precursor containing one or more reducible group(s) and/or one or more additional C-C- and/or C-Nbond(s) instead of hydrogen atoms, with a reducing agent, preferabLy at temperatures between -80 and +2500 and in the presence of at Least one inert solvent.

Reducible groups (groups replaceable by hydrogen) are, in particular, oxygen in a carbonyl group, hydroxyl, aryLsuLfonyLoxy (for example p-toLuenesulfonyloxy), NbenzenesuLfonyL, N-benzyl or O-benzyl.

In principle, it is possible to convert compounds containing only one of these groups or additional bonds or compounds containing, in an adjacent position, two or more of these groups or additional bonds, into by reduction.

15 It is preferable to use for this purpose nascent hydrogen or complex metal hydrides and also the Wolff-Kishner method S of reduction.

44 Preferred starting materials for the reduction correspond to the formula V Ind-L-Z (V) wherein t t Ind is the 5,6-methyLenedioxy-3-indoLyL group, L is -(CH 2 4 or a chain which corresponds to the butyl chain, but in which one or more -CH 2 group(s) have been replaced by -CO- group(s) and/or one or more hydrogen atom(s) have been *,is replaced by OH group(s), and nr tr £.-4rc-Arro-l- Pyrcn-/J. f S 30 Z is 4-phenyl-1,2,3,6-t 'p Ane and An is an anion, but wherein it is not possible at th'e same time for Z to be 4-phenyl-1,2,3,6-tetrahydropyridyl and for L to be -(CH 2 4 In the compounds of the formula V, L is preferably

-(CH

2 3

-(CH

2 2

-CO-CH

2

-CH

2

-CO-(CH

2 2

-CO-(CH

2 3

AL

0 -NT 6 -CO-(CH2)2-CO-, -(CH2)3-CHOH-, -CO-(CH2)2-CHOH-, or -CH 'OH-(CH2)2-CO Compounds of the formula V can be prepared, for example, by reacting IIea or 4-phenylpyridine with a compound of the formula VI u Ind-L-X (VI) wherein Ind, L and X have the meanings indicated above, under the conditions indicated above for the reaction between II and III.

If nascent hydrogen is used as the reducing agent, it can be produced, for example, by treating metals with weak acids or bases. Thus it is possible, for example, to Suse a mixture of zinc with an alkali metal hydroxide sol t ution or a mixture of iron with acetic acid. The use of S. sodium or another alkali metal i n an a cohol, such as ethanol, isopropanol, butanol, amylalcohol or isoamylalcohol, or phenol is also suitable. It is also possible to use an aluminium/nickel alloy in aqueous alkaline solution, if appropriate with the addition of ethanol. Sodium amalgam or aluminium amalgam in an aqueous alcoholic or aqueous e solution are also suitable for the production of the nascent hydrogen. The reaction can also be carried out in S a heterogeneous phase, in which case it is preferable to 3 use an aqueous phase and a benzene or toluene phase.

It is also particularly advantageous to employ, as e l s reducing agents, complex metal hydrides, such as LiALH4, w ater NaBH4, d iisobutyla uminium hydride S or NaAL(OCH2CH20CH3)2H2 and diborane, if desired with the addition of catalysts, such as BF3, ALC13 or LiBr. Solvents suitable for this purpose are, in particular, ethers, such as diethyl ether, di-n-butyl ether, THF, dioxane, diglyme or 1,2-dimethoxyethane, and hydrocarbons, such as benzene. Alcohols, such as methanol or ethanol, and .also water and aqueous alcohols are primarily suitable as I I -i-ii ;*:LL1- -7 solvents for a reduction with NaBH 4 Reduction by these methods is preferably carried out at temperatures between and +1500, in particular between about 0 and about 0 100° -CO- groups in acid amides,(for exampLe those of formula V wherein L is -(CH 2 3 can be reduced to give

CH

2 groups particularly advantageously by means of LiALH 4 in THF at temperatures between about 0 and 660. A reduction of the pyridinium salts of the formula V (wherein An is preferably CL or Br) can be carried out, for example, by means of NaBH 4 in water, methanol or ethanoL, if desired with the addition of a base, such as NaOH, and at temperatures between about 0 and 800.

It is also possible to reduce one or more carbonyl r.

o 15 groups to give CH 2 groups by the Wolff-Kishner method, S for example by treatment with anhydrous hydrazine in absolute ethanol under pressure at temperatures between about 150 and 2500. It is advantageous to use a sodium alcoholate as a catalyst. The reduction can also be varied in accordance with the Huang-Minlon method by carrying out the reaction with hydrazine hydrate in a high-boiling, water-miscible solvent, such as diethyLene glycol or triethylene gLycol, in the presence of an alkali, such as sodium hydroxide. As a rule, the reaction mixture is boiled for about 3-4 hours. The water is then removed by distillation and the hydrazone formed is decomposed at temperatures of up to about 2000. The Wolff-Kishner reduction can also be carried out using hydrazine at room f, temperature in dimethyl sulfoxide.

Compounds which otherwise correspond to but contain one or more solvolysable group(s) instead of one or more H atoms, can be solvolysed, in particular hydro- Lysed, to give the compound The starting materials for the solvolysis can be obtained, for exampLe, by reacting IIIa with compounds which correspond to the formula II (X but contain one or more soLvolysable group(s) instead of one or more

-II

:i? -8- H atoms. Thus, in particular, 1-acylindole derivatives (corresponding to but containing in the 1-position of the indole radical an acyl group, preferabLy an aLkanoyL, aLkyLsulfonyL or aryLsulfonyL group having in each case upto 10 C atoms, such as methanesuLfonyL, benzenesuLfonyL or p-toLuenesuLfonyL) can be hydroLysed, for example in an acid medium, or better in a neutral or alkaLine medium, at temperatures oetween 0 and 2000, to give the corresponding indoLe derivatives which are unsubstituted in the 1-position of the indoLe ring.

The basic catalysts used are preferably sodium hydroxide or carbonate, potassium hydroxide or carbonate, caLcium hydroxide or ammonia. The solvent selected is preferably water; Lower aLcohoLs, such as methanoL, or 15 ethanoL; ethers, such as THF or dioxane; sulfones, such as tetramethylene suLfone; or mixtures thereof, particularly mixtures containing water. Hydrolysis can also be carried out merely by treatment with water on its own, particuLarLy at the boil.

I 20 is aLso obtained by eLiminating HE from compounds of the formuLa IV with the formation of a doubLe bond.

Depending on the definition of E, this can be, for exampLe, an elimination of hydrogen halide, water (dehydration), a carboxyLic acid or another acid, ammonia or HCN. The starting mate.riaLs of the formula IV can be obtained, for s1 |example, by reacting II (X X) with a compound of the formula VII t 30

H

N

C

6

H

CE" VII

E

wherein E has the meaning indicated.

If one of the radicals E is Hat, this substituent can be eLiminated readily under basic reaction conditions.

The foLLowing can be used as bases: alkali metal hydroxides, -9alkali metaL carbonates, alcoholates, such as, for example, potassium tert.-butylate, or amines, such as, for example, dimethyLaniline, pyridine, coLLidine or-quinoLine; examples of solvents used are benzene, toluene, cyclohexane, THF or tert.-butanol. The amines used as bases can also be employed in an excess as the solvent. If one of the radicals E is an OH group, the dehydrating agents used are preferably acids, such as acetic acid or hydrochloric acid or mixtures of the two. It can be advantageous to add a solvent (for example water or ethanol). The elimination of acyl, alkylsulfonyl and alkoxysulfonyloxy or amino radicals can be carried out under similar conditions. An elimination of sulfonic acid radicals, for example those of mesyLates or tosylates, is effected under mild conditions by boiling 15 in DMF or dimethyl sulfoxide with alkali metal carbonates, o for example Li 2

CO

3 or with potassium acetate. Ammonia S" can be eliminated merely by heating the salts of the corresponding amino compounds (especially the 4-amino derivat, ives). HCN can be eliminated from compounds of the for- 20 mula IV (one group E is CN) in a similar manner by heating. The elimination of HE from IV is generally carried out at temperatures between 0 and about 2500, preferably between 50 and 2000 A resulting base can be converted into the appropriate acid addition salt by means of an acid. Acids suitable for this reaction are preferably those which afford physiological acceptable salts. Thus it is possible to use inorganic acids, for example sulfuric acid, hydrogen halide 5acids, such as hydrochloric acid or hydrobromic acid, phos- 33 L 30 phoric acids, such as orthophosphoric acids, nitric acid and sulfamic acid, and also organic acids, specifically aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, t; ;r' 10 2-ohenyLpropionic acid, citric acid, gLuconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesuLfonic acid or ethanesuLfonic acid, ethanedisulfonic acid, 2hydroxyethanesuLfonic acid, benzenesulfonic acid, p-toLuenesuLfonic acid, naphthaLenemonosulfonic and naphthaLenedisuLfonic acids and LauryLsuLfuric acid. Acid addition salts which are not physioLogically harmLess (for example picrates) can be suitable for isolating and purifying the base The free base can, if desired, be Liberated from its salts by treatment with strong bases, such as sodium hydroxide or carbonate or potassium hydroxide or carbonate.

The invention also relates to the use of the compound and its physioLogicaLLy acceptabLe salts for the 15 preparation of pharmaceuticaL formuLations, especiaLLy by a •non-chemicaL route. In this regard they can be brought into a suitabLe dosage form together with at Least one excipient tt t or auxiliary and, if appropriate, in combination with one or more further active compound(s).

4> t 4 20 The invention also relates to agents, especialLy pharmaceutical formulations, containing the compound I and/ or one of its physiologically acceptable salts. These S formulations can be employed as medicaments in human or veterinary medicine. Suitable excipient substances are 25 organic or inorganic substances which are suitable for enteral (for example oral) or parenteral administration or for topical application and which do not react with the new compounds, for example water, vegetable oils, benzyL alcohols, polyethylene glycols, gelatine, carbohydrates, such t 30 as Lactose or starch, magnesium stearate, talc or petroleum jelly. In particular, tablets, coated tablets, capsules, syrups, elixirs, drops or suppositories are suitable for enteral administration, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or impLants are suitable for parenteral administration, while ointments, creams or powders are suitable for topical appLication. The new compounds can also be lyophilised i .i: 1

II

F 11 and the resulting lyophilizates can be used, for example, for the preparation of injection preparations.

The formuLations indicated can be sterilised and/or contain auxiliaries, such as lubricants, preservatives, stabilisers and/or wetting agents, emulsifiers, salts for controlling the osmotic pressure, buffer substances, dyestuffs, flavourings and/or aroma substances. If desired, they can also contain one or more further active compounds, for example one or more vitamins.

The invention also relates to the use of the compound I and its physiologically acceptable salts in the therapeutic treatment of the human body or an animal body and in combating diseases, especially schizophrenia and psycho-reactive disturbances and psychopathies, depressions, 15 severe chronic pains and diseases associated with increased St blood pressure.

The compounds can also be used in the treatment of extra pyramidal disturbances.

In this regard, the substances according to the 20 invention are generally administered analogously to known preparations available commercially (thioridazine and haloperidole), preferably in dosages between about 0.2 and S' 500 mg, in particular between 0.2 and 50 mg, per dosage unit. The daily dosage is preferably between about 0.003 and 10 mg/kg of body weight.

The particular dose for each specific patient depends, however, on a very wide variety of factors, for example on the effectiveness of the particular compound ac.' employed, on age, body weight, general state of health, St 30 sex, diet, time and method of administration, rate of excretion, combination of medicaments and severity of the particular diseases to which the therapy applies. Oral administration is preferred.

In the examples below "customary working up" denotes as follows: if necessary water is added, the mixture is extracted with methylene dichloride, the phases are separated and'the organic phase is dried over sodium sulfate, 1 1 filtered and evaporated and the product is purified by chromatography over silica gel and/or by crystaLLisation.

Tempoeratures are quoted in degrees C.

Example 1 A solution of 2.52 g of 3-(4--chLorobutyL)-5,6methyLenedioxyindoLe [or 2.96 g of 3-(4-bromobutyL>--5,6methyLenedioxyindoLel and 1.6 g of 1Ila in 10 mL of acetonitriLe is stirred for 12 hours at 200 and is worked up in a Customary manner to give m.p. 108-1100, hydrach Lori de,, m. p. 26HO;fumarate m. p. 153-1551 maleate, m.p. 163-1650; malonate, m.p. 1510; succinate, m.p. 143-1440; sulfate, m.p. 233-2350.

ExampLe 2 A mixture of 4.85 g of 3-( 4 -p-toLuenesuLfonyLoxybutyL)-5,6-methyLenedioxyindoLe and 3.18 g of Iila is heated to 1300. After the exothermic reaction has sub- I sided and the mixture has cooled, it is worked up in a customary manner to give m.p. 108-1100.

ExampLe 3 20 3.43 g of 3 4 -iodobutyL)-5,6-methylenedioxyindoLe, 1.59 g of Illa and 1.5 g of anhydrous potassium carbonate in 25 ml of n-butanoL are boiled for 2 hours with stirring .94. and allowed to cool and the mixture is worked up in a customary manner to give m.p. 108-110o.

A mixture of 2.32 g of 3 4 -aminobutyl)-5,6-.methyLenedioxyindoLe (obtainable by reacting 3-(4-bromobutyL)-5,6methyLenedioxyindoLe with potassium phthaLimide and hydro- Lysing the product) and 2.15 g of 1,5-dichLoro-3-phenyL-2pentene (cf. German OffenLeguingsschrift 2,827,874) in 40 ml of acetone and 40 ml of water is boiLed for 24 hours and worked up in a customary manner. This gives M.P.

108-1,110.

13 ExampLe a) 1.62 g of N,N-carbonyLdiimidazoLe are added to a soLution of 2.47 g of 4-(5,6-methyLenedioxy-3-indoLyL)butyric acid in 10 mL of THF, the mixture is stirred for 1 hour at 200 and a solution of 1.59 g of IIIa in 50 mL of THF is then added. The mixture is stirred for 1.5 hours at 200 and worked up in a customary manner to give 3-E4oxo-4-(4-phenyL-1,2,3,6-tentr p nr I-butyL]-5,6methyLenedioxyindoLe, m.p. 161-1630 10 b) A soLution in 10 mL of THF of 3.88 g of the compound obtained in a) is added dropwise, with stirring, to a suspension of 0.38 g of LiALH 4 in 10 mL of THF. After the reaction has subsided, 5 mL of ethyL acetate are added and a n the mixture is worked up in a customary manner to give t t t C t 15 m.p. 108-1100 ExampLe 6 1 g of NaBH 4 in 20 mL of water is added, with stirring, to a solution of 4.51 g of 1-[4-(5,6-methytenedioxy-3-indoLyL)-butyLJ-4-phenyLpyridinium bromide [obtainabLe from 3-(4-bromobutyL)-5,6-methyLenedioxyindoLe and It1I4-phenyLpyridine] in 50 mL of 1N NaOH, and the mixture is then stirred for a further 3 hours at 600. Working up in .ea customary manner gives m.p. 108-1100 Example 7 1 g of 1-benzenesuLfonyL-3-C4-(4-phenyL-1,2,3,6- -A butyL-5,6-methy[Lenedioxyind oLe CobtainabLe from 1-benzenesuLfonyL-3-(4-chLorobutyL)-5,6-methyLenedioxyindoLe and IIIal is boiled for 16 hours with 0.2 g of KOH in 1.5 mL of water and 3 mL of ethanoL, and the mixture is substantiaLLy evaporated and worked up in a customary manner to give m.p. 108-1100 111:' i-:f I rc- M I 4, r r 4 *p 4 49 k 44

SF

4 t tt 14 Example 8 3.76 g of 3-[4-(4-hydroxy-4-phenyl-1-piperidyl)butyL]-5,6-methylenedioxyindoLe is heated together with mL of 1N hydrochloric acid for 2 hours at 500, and the mixture is worked up in a customary manner to give m.p. 108-110 0 The examples below relate to pharmaceutical formulations containing amines of the formula I or acid addition salts thereof: Example A: Tablets A mixture of 1 kg of hydrochLoride, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in a customary manner to give tablets, in such as way that each tablet contains 15 10 mg of active compound.

Example B: Coated tablets Tablets are compressed analogously to Example A and are then coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and dyestuff.

20 Example C: Capsules 2 kg of hydrochloride are filled into hard gelatine capsules in a customary manner, so that each capsule contains 20 mg of the active compound.

Example 0: Ampoules 25 A solution of 1 kg of hydrochloride in 60 1 of twice-distilled water is filtered under sterile conditions and filled into ampoules, which are lyophilised under sterile conditions and sealed under sterile conditions.

Each ampoule contains 10 mg of active compound.

Tablets, coated tablets, capsules and ampoules containing and/or one or more of the other physiologically acceptable acid addition salts of can be obtained analogously.

I

1 SrS 4 t t a i i; :I f: :1 i: ii ILYICi I

Claims

1. 3-[4-(4-phenyl-1,2,3,6- tetrahydro-1-pyridyl) -butyl -5,6- methylenedioxyindoLe and salts thereof.

2. Process for the preparation of the compound and salts thereof, characterised in that a 3-(4-X 1 -butyl)- ,6-methylenedioxyindoLe (II) wherein X is X or NH 2 and X is CL, Br, I, OH or a reactive, func- tionaLLy modified OH group is reacted with a compound of the formula III r 4 4 t S* t i Ill r +t C C €I rtr t. t t i t 4C 4 t 14 f X2-CH2CH2-C(C 6 H 5 )=CH-CH 2 X 3 Ctl C wherein X2 and X 3 can be identical or different and, if X is NH 2 are each X, or otherwise they are together NH, or a compound which otherwise corresponds to but contains one or more reducible group(s) and/or one or more additional C-C- and/or C-N- bond(s) instead of one or more hydrogen atoms, is treated with a reducing agent or a compound which otherwise corresponds to but contains one or more solvolysable group(s) instead of one or more hydrogen atoms, is treated with a solvolys- ing agent, or a 3 3 ,4-di-E-4-phenylpiperidino)-butyl]-5,6- methylenedioxyindole (IV) wherein one radical E is X, CN or NH 2 the other radical E is H and X has the meaning indicated, t r Ct t r C t f C I i i i 4I- -wr 1.6 00 0 00 0 00 0 0 000 9* S 0 0 0 0 00 00 0 00 0 00 0 000 *044 0 0 0 4* 0 0 4 0t 000* 4 0444 090*04 0000 0 3 0004 00 00 0 0 is treated with an agent which eliminates HE, and/or, if appropriate, the base is converted into one of its salts by treatment with an acid.

3. Process for the preparation of pharmaceutical formulations, characterised in that the compound (I) and/or one of its physiologically acceptable salts is brought into a suitable dosage form together with at least one solid, liquid or semi-liquid excipient or auxiliary and, if apppropriate, in combination with one or more active compound(s).

4. A pharmaceutical formulation characterised in that it contains the compound and/or one of its physiologically acceptable salts, together with at least one solid, liquid or semi-liquid excipient or auxiliary agent.

5. A method for the therapeutic treatment of schizophrenia, psycho-reactive disturbances, psychopathies, depressions, severe chronic pains or diseases associated with increased blood pressure, or for the treatment of extra pyramidal disturbances in a human or animal body which comprises administering to said body requiring said treatment an effective amount of the compound defined in claim 1, or its physiologically acceptable salts.

6. A compound according to claim 1, or a process according to claim 2 or 3, or a formulation according to claim 4, or a method according to claim 5 substantially as herein described with reference to any one of the foregoing examples there of. 0 1 DATED this 26th. day of October, 1989. I'll.

-7 MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER HAFTUNG By Its Patent Attorneys ARTHUR S. CAVE CO. 9* 9 9 9 4 94 44 4 449 94 9 99 99 49 4 p 4~ 4 t~ .9 tr~ I 0018Y