EP0800515A1

EP0800515A1 - DIBENZ cd,f]INDOLE DERIVATIVES

Info

Publication number: EP0800515A1
Application number: EP95943231A
Authority: EP
Inventors: Rudolf Karl Andreas Giger
Original assignee: Novartis Erfindungen Verwaltungs GmbH; Ciba Geigy AG; Novartis AG; Sandoz AG
Current assignee: Novartis Pharma GmbH; Novartis AG
Priority date: 1994-12-30
Filing date: 1995-12-29
Publication date: 1997-10-15
Also published as: CA2206519A1; AU4435896A; GB9426407D0; WO1996020927A1; ZA9511036B; JPH11504616A; IL116606A0

Abstract

1-Alkyl-9,10-dihydroxy-4,5,5a,6-tetrahydro-dibenz[cd,f]indoles of formula (I) may be used in the treatment of Morbus Parkinson, alcohol abuse and drug dependency. In said formula, R1, R2 and R3 are independently (C1-4)alkyl, in free or acid addition salt form.

Description

DIBENZrcd.flINDOLE DERIVATIVES

The present invention relates to dibenz[cd,f]indole derivatives, their preparation and pharmaceutical compositions containing them.

In accordance with the invention, there are provided l-alkyl-9,10-dihydroxy- 4,5,5a,6-tetrahydro-dibenz[cd,f]indoles and acid addition salts thereof hereinafter referred to as "the compounds of the invention".

The compounds of the invention are preferably substituted in the 4 and 5 positions of the dibenz[cd,fJindole nucleus, preferably by alkyl groups. Any alkyl group in a compound of the invention, particularly the alkyl group in position 1, is preferably (C_M)alkyl. When a compound of the invention is substituted in position 4, the configuration 4S,5aR is preferred.

More particularly the present invention provides a (4R*,5aS*) compound of formula I

wherein R,, R₂ and R₃ are independently (C_M)alkyl, in free or acid addition salt form.

The term (4R*,5aS*) according to the usual convention indicates that the compound may be in the form of the racemate or of an optically active isomer, wherein the hydrogen atoms in positions 4 and 5a of the dibenz[cd,f]indole nucleus are syn to each other. The optical isomers having the absolute configuration 4S,5aR are preferred.

Any alkyl radicals preferably are straight chain radicals. R, is preferably methyl.

R₂ is preferably methyl, ethyl or n-propyl.

R₃ has preferably 1, 2 or 3 carbon atoms, and is especially methyl, ethyl or n-propyl.

The present invention also provides a process for the production of a compound of the invention, which includes the steps of obtaining a l-alkyl-9,10-dihydroxy-4,5,5a,6- tetrahydro-dibenz[cd,f]indole or an acid addition salt thereof, by splitting the ether groups in a corresponding l-alkyl-4,5,5a,6-tetrahydro-dibenz[cd,f]indole having splittable ether groups in the 9 and 10 positions, or a precursor thereof, and recovering the desired l-alkyl-9,10-dihydroxy-4,5,5a,6-tetrahydro-dibenz[cd,f]indole as such or as an acid addition salt thereof.

More particularly, the invention provides a process for the production of a (4R*,5aS*) compound of formula I as defined above, or an acid addition salt of the compound, which comprises splitting the ether groups in a (4R*,5aS*) compound of formula II

wherein R, to R₃ are as defined above, and the Z radicals are the same or different and are splittable ether groups, or a precursor thereof, and recovering the (4R*,Sas*) compound of formula I as such or as an acid addition salt.

The ether splitting process may be effected in conventional manner for splitting ether groups.

For example the reaction may be carried out by treatment with a strong mineral acid, e.g. aqueous hydrobromic or hydroiodic acid. Suitable temperatures may be from 100 °C or higher, preferably from 100 °C to the boiling point of the reaction mixture, especially at about 130 °C.

The ether group Z is preferably (C )alkoxy, more preferably a methoxy group.

As used herein the term precursor refers to compounds which are capable of being converted into the starting materials in conventional manner, e.g. temporarily protected compounds.

The resulting compounds of the invention may be recovered from the reaction mixture and purified in known manner. The free base forms of the compounds of the invention may be converted into acid addition salt forms in conventional manner and vice versa . Suitable acids for salt formation include, for example, hydrochloric acid and methanesulfonic acid.

Racemic compounds of the invention may be obtained from racemic starting materials. Optically active isomers may be obtained from optically active precursors or from the racemate. The enantiomers may be obtained from the racemate by known methods, for example by fractional crystallization of diastereoisomeric salts, e.g. their salts with (+)-di-O,O'-p-toluoyl-D-tartaric acid or (-)-di-O.O'-p-toluoyl-L-tartaric acid. Racemic resolution into the optically active isomers may be effected before splitting of the ether groups, e.g. in a compound of formula U.

The l-alkyl-4,5,5a,6-tetrahydro-dibenzo[cd,f] indoles containing splittable ether groups in the 9 and 10 positions, may be produced by reducing an appropriate 1 -alkyl-4-hydroxy- 4,5-dihydro-dibenz[cd,f]indole having splittable ether groups in the 9 and 10 positions.

In particular the (4R*,5aS*) compounds of formula II may be prepared by reducing in conventional manner, conveniently under acidic conditions suitable for the acidic reduction of enamines or imines, a compound of formula HI

wherein Z, R„ R, and R, are as defined above.

The starting materials l-alkyl-4-hydroxy-4,5-dihydro-dibenz[cd,f]indoles having splittable ether groups in the 9 and 10 positions may be prepared according to known methods, for example as described in UK Patent 2,024,818.

For example starting materials of formula HI may be prepared according to the following reaction scheme:

DIBAH (VI)

(VII) n-Butyllithium

In the reaction scheme the radicals R„ R₂, R₃ and Z are as defined above, R₃' is hydrogen, methyl or ethyl and Hal is chlorine or bromine.

The reactions may be carried out in conventional manner and the products of the above reactions may be isolated and purified in known manner. In the above intermediates the ether groups Z are preferably methoxy.

Insofar the preparation or any particular starting material is not particularly described, this may be effected in conventional manner or in analogous manner to that described hereinafter for analogous compounds.

In the following Examples all temperatures are given in degrees Celsius and are uncorrected.

EXAMPLE 1 : (±)(4R*.5aS* -5-ethyl-4.5.5a.6-tetrahvdro-

9.10-dihvdroxv- 1 -methvl-4-n-propvl-dibenz f cd.flindole

a) 9-amino-3.4-dimethoxv-5-methvl-Dhenanthrene (compound of formula V)

A mixture of 400 ml (2.87 M) of trifluoro-acetic anhydride and 400 ml (5.22 M) of trifluoro-acetic acid is added at room temperature under a nitrogen atmosphere to 61.1 g (0.206 M) of 3,4-dimethoxy-5-methyl-phenanthrene-9-carboxylic acid and the mixture is stirred for 10 minutes. After cooling to -5°, 16.08 g (0.247 M) sodium azide are carefully added in solid form and stirred for 2 hours at 0°, then poured onto ice, extracted three times with methylene chloride and washed with a solution IN of sodium hydroxide.The aqueous phases are extracted twice with methylene chloride 2-propanol 8:2. The organic phases are combined, dried and evaporated, to give white crystals. 86 g of the resultant mixed anhydride are warmed for 2 hours under reflux in 800 ml of a solution 2N of sodium hydroxide and 800 ml ethanol and evaporated. The residue is washed with water /ice and extracted three times with methylene chloride. The organic phases are combined, dried and evaporated to give the title compound as a yellow powder. M.p. 130-133°.

b) 9-acetvlamino-3.4-dimethoxv-5-methvl-phenanthrene

(compound of formula VI)

105.7 ml (0.750 M) of N-ethyl-N,N-diisopropyl__τ_ine are added to a solution of 100.2 g (0.375 M) of 9-amino-3,4-dimethoxy-5-methyl-phenanthrene in 1000 ml methylene chloride. To the resulting mixture is added dropwise over 30 minutes a solution of 34,5 ml (0.450 M) of acetyl chloride in 250 ml methylene chloride. During the addition, the temperature of the reaction mixture is maintained at 20° by cooling with ice. The reaction mixture is stirred for 2 hours at room temperature and extracted with methylene chloride. The organic phases are washed with ice cooled 2N hydrochloric acid, water and 2N sodium bicarbonate, dried over sodium sulfate and evaporated, to give the title compound. M.p. 218-219° after crystallisation from ethanol. c) 9-ethvlamino-3.4-dimethoxv-5-methvl-phenanthrene (compound of formula VII)

1700 ml (2.05 M) of a 20% solution of diisobutylaluminium hydride in toluene are added at room temperature over a period of 45 minutes to a suspension of 105.7 g (0.342 M) of 9-acetylamino-3,4-dimethoxy-6-methyl-phenanthrene in 1500 ml anhydrous tetrahydrofuran. The mixture is then warmed with stirring under a nitrogen atmosphere for 2 hours at 80°. The reaction mixture is then cooled at 0° and under nitrogen atmosphere and a mixture of 2500 ml 2N hydrochloric acid / ice, cooled at -10°, is added by portions at such a rate that the gas evolution is maintained. The acid solution is made alkaline to pH 10 by addition at 0° of 3 litres 2N sodium hydroxide and the mixture is extracted three times with methylene chloride / 2-propanol 7:3. The organic phases are combined, washed, dried and evaporated to give the title compound as a brown oil.

d) 5-ethvl-4.5-dihvdro-9.10-dimethoxv-l-methvl-4-oxo-dibenzfcd.flindole (compound of formula DC)

661.4 ml (1.084 M) of a 15% solution of n-butyl-lithium in hexane are added at 0°, over a period of 20 minutes and under a nitrogen atmosphere, to a solution of 97 g (0.328 M) of 9-ethylamino-3,4-dimethoxy-5-methyl-phenanthrene in 1000 ml anhydrous tetrahydrofuran; the reaction mixture becomes dark red. After stirring for 30 minutes at 0°, the mixture is transferred in portions with a teflon tub with nitrogen pressure at -50° into a mixture of 500 g sodium sulfate and 500 g dry ice in 1500 ml tetrahydrofuran. After the temperature of the mixture has reached room temperature, the mixture is poured onto water / ice and extracted three times with methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated to give the title compound. M.p. 148-149° after crystallisation from ethyl acetate / hexane. e) 5-ethvl-4.5-dihvdro-4-hvdr oxv-9.10-dimethoxv-l-methvl- 4-n-propyl-dibenzrcd.flindole (compound of formula HI)

A solution of 377 ml (4.1 M) of n-propyl-bromide in 4 litres tetrahydrofuran is added over a period of 90 minutes at reflux to 99.8 g (4.1 M) of magnesium turnings and the mixture is stirred for one hour at reflux. To the resultant mixture is added dropwise over 30 minutes and under a nitrogen atmosphere a solution of 880 g (2.73 M) of 5-ethyl-4,5-dihydro-9,10-dimethoxy-l-methyl-4-oxo-dibenz[cd,f]indole in 6 litres tetrahydrofuran. The reaction mixture is warmed for 2 hours at reflux and then extracted with methylene chloride. The organic phase is washed with a saturated solution of potassium bicarbonate and with water, dried over sodium sulfate and evaporated to give the title compound in the form of a red-brown oil [IR Spectrum (CH₂C1₂): 3540 cm^'1 (OH)]. The crude product is directly used for the next step.

f) (±V(4R*.5aS*)-5-ethvl-4.5.5a.6-tetrahvdro-9.10-dimethoxv-l-methvl

-4-n-propvl-dibenzfcd.flindole (compound of formula H)

A suspension of 100 g (0.273 M) of 5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy -l-methyl-4-n-propyl-dibenz[cd,fjindole in 2000 ml ethanol is added with stirring to a suspension of 322g (4.928 M) of zinc dust and 74.3 g (0.273 M) of mercury (II) chloride in 2000 ml distilled water. The reaction mixture is refluxed, 450 ml of 18% hydrochloric acid are added dropwise over a period of 15 minutes and the mixture is refluxed overnight with stirring. The mixture is then cooled to room temperature, filtered and the zinc amalgam is washed with 500 ml methylene chloride. The filtrate is made alkaline with 1 litre of concentrated NH₄0H and extracted three times with methylene chloride (700 ml each time). The combined organic phases are washed with water, dried and evaporated. The resultant oil is chromatographed on silica gel using methylene chloride with 2% methanol to give the title compound as an oil. g) (±W4R*.5as*V5-ethyl-4.5.5a.6-tetrahvdro-9.10-dihvdroxy-l-methyl- 4-n-propvl-dibenzrcd.flindole

100 g of (±)-(4R*,5aS*)-5-ethyl-4,5,5a,6-tetrahydro-9,10-dimethoxy-l-methyl- 4-n-propyl-dibenz[cd,f]indole in 1 litre of a 47% aqueous solution of hydrobromic acid are warmed for 6 hours at reflux at a bath temperature of 150°. After evaporation of the mixture to dryness, the crystalline residue is stirred in acetone and filtered. The precipitate is washed with acetone, then with ether and dried under high vacuum, to give the hydrobromide of the title compound. M.p. of the hydrochloride: >250° with decomposition.

EXAMPLE 2: M-.4S.5aRV5-ethyl-4.5.5a.6-tetrahvdro-9.10-dihvdroxy- l-methvl-4-n-ρropvl-dibenzrcd.flindole

a) -.4S.5aR.-5-ethyl-4.5.5a.6-tetrahvdro-9.10-dimethoxy-l- nι..fryH-η-p.opyl-d.b.n ..d.flind<.l.

74.3 g (211 mM) of (±)-(4R*,5aS*)-5-ethyl-4,5,5a,6-tetrahydro-9,10-dimethoxy-l-methyl- 4-n-propyl-dibenz[cd,f]indole are dissolved in 600 ml acetone and a solution of 81.67 g (211 mM) of (-)-di-O,O'-p-toluoyl-L-tartaric acid monohydrate in 300 ml acetone is added with stirring. The mixture is further stirred for one hour at room temperature, a total of 1 litre ether being added in portions during this period. The resultant precipitate is filtered off, washed with ethyl acetate until it remains light yellow, and dried.

114.7 g of the crystals obtained from the first crystallisation are dissolved in 1 litre CH_jCl^methanol 7:3 at reflux and the solution is filtered and concentrated until a major part of the product crystallizes out. The mixture is stirred for about 15 minutes, the product is filtered off, washed with ethyl acetate until it remains colourless and dried.

48 g of the resulting product is recrystallised in the same manner by using 700 ml CH₂C1₂ / methanol 50:50 to give colourless crystals. The resulting crystals are recrystallised in the same manner by using 1.2 litres acetone and

60 ml methanol. There is thus obtained (-)-(4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro

-9, 10-dimethoxy- 1 -methyl-4-n-propyl-dibenz[cd,f]indole (-)-di-O.O'-p-toluoyl-L-tartrate in form of colourless crystals which melt at 185-198°;

[ct]_D ²⁰ = -175.4° (c = 2 in dimethylformamide). [α]_D ²⁰ of the base (oil) = -197° (c = 1,

EtOH);

b) (-W4S.5aR.-5-ethv1-4.5.5a.6-tetrahvdro-9.10-dihvdroxv- l-methvl-4-n-propvl-dibenzfcd.flindole

Proceeding as described in Example lg), (-)-(4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro -9,10-dihydroxy-l-methyl-4-n-propyl-dibenz[cd,f]indole is obtained; the methanesulfonate melts at 212-214° with decomposition ; [oc]_D ²⁰ _s -159.2° (c = 0.75 in methanol).

EXAMPLE 3:

Proceeding as described in Examples 1 and 2, the following compounds are obtained: a) (±)-(4R*,5aS*)-4,5,5a,6-tetrahydro-9,10-dimethoxy-l,5-dimethyl- 4-n-propyl-dibenz[cd,f]indole b) (±)-(4R*,5aS*)-4,5,5a,6-tetrahydro-9,10-dihydroxy-l,5-dimethyl- 4-n-propyl-dibenz[cd,f]indole. M.p. 215-217°with decomposition c) (-)-(4S,5aR)-4,5,5a,6-tetrahydro-9,l 0-dimethoxy- 1 ,5-dimethyl-4-n- propyl-dibenz[cd,f]indole. [α]_D ²⁰ of the (-)-di-O,O'-p-toluoyl-L-tartrate = -177° (c si, dimethylformamide). [α]-,²⁰ of the base = -218° (c _. 0,7, EtOH) d) (-)-(4S,5aR)-4,5,5a,6-tetrahydro-9, 10-dihydroxy- 1 ,5-dimethyl- 4-n-propyl-dibenz[cd,f]indole. The methanesulfonate melts at 201-203° with decomposition, [α]_D ²⁰ = -189° (c = 0.5, MeOH).

It is also to be appreciated that 9-amino-3,4-dimethoxy-5-methyl-phenanthrene may be converted directly into 9-emylamino-3,4-dimethyloxy-5-methyl-phenanthrene by heating with ethylamine in 2-ethoxyethanol. The l-alkyl-9,10-dihydroxy-4,5,5a,6-tetrahydro-dibenz[cd,f]indoles, in particular the compounds of formula I, and their pharmaceutically acceptable acid addition salts, hereinafter referred to as "the agents of the invention", exhibit pharmacological activity in animals and are therefore useful as pharmaceuticals.

In particular, the agents of the invention are useful as central dopaminergic stimulant agents, as indicated by standard tests, for example according to the method of U. Ungerstedt et al. [Acta Physiol. Scand. Suppl. (1971), 2g7__Suρpl. 66-93], by induction of contralateral turning of notable duration in rats (whose substantia nigra has been lesioned by a microinjection of 6-hydroxy-dopamine one week previously) after p.o. administration in an amount of about 0.03 to about 10 mg/kg animal body weight. The activity is confirmed by induction of dose dependent stereotyped sniffing, licking and biting behaviour in the rat according to the following test, after i.p. administration in an amount of about 1 to about 30 mg/kg animal body weight.

Rats, 180-222 g, are placed in perspex cylinders of 30 cm diameter on a wire grid floor. After 30 minutes to allow acclimatisation to the cage, the rats are injected with the compound under investigation. The behaviour of the rats is observed for 2 minutes at 30 minutes intervals for 2 hours and then at 60 minutes intervals for a total of up to 7 hours. The degree of stereotyped behaviour observed is assessed using a scoring system based on that described by Costall, Naylor and Olley [Europ. J. Pharmac. 1£, 83-94, (1972)].

The agents of the invention are therefore useful as central dopaminergic stimulant agents, for example for treating Mobus Parkinson.

For the above mentioned indication the appropriate dosage will, of course, vary depending upon, for example, the host, the mode of administration, and the severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained when administered at a daily dosage of from about 0.1 mg to 10 mg per kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 4 to about 30 mg, conveniently given in divided doses 2 to 4 times a day or in sustained release form. Dosage forms suitable for oral administration comprise from about 1 to about 15 mg of the agents.

The agents of the invention, in particular the compounds of formula I, are furthermore useful for preventing alcohol abuse, as indicated by the reduction of alcohol consumption in alcohol preferring rats on p.o. administration of about 0.5 to 2 mg/kg of the compounds.

Male and female rats of an alcohol preferring strain are placed in individual cages each containing an eatometer according to Fallon [Science 148. 977-8 (1965)] and two bottles fitted with double sphere valves, allowing a gravimetric determination of the quantities of food and beverage actually taken. The animals receive a vitamin rich standard chow, distilled water in one bottle and an aqueous ethanol solution (10 % per volume) in the other. Under these conditions 50 to 97 % of the absorbed liquid is taken from the bottle containing the ethanol solution, which corresponds to a daily consumption of 4 to 6 g pure ethanol by kg animal body weight, and the rats develop an ethanol addiction which appears from their increasing startle behaviour when shaking the cages during the abstinence periods.

The compounds are administered p.o. in aqueous solution and the consumption of food, water and alcohol is recorded during 12 hours and compared with the average consumption within a period of 3 days before the administration.

In this test, the alcohol consumption is significantly reduced by the administration of the agents of the invention without significant reduction of food and liquid ingestion.

The agents of the invention, in particular the compounds of formula I, are also useful for the treatment, especially the preventive treatment, of drug withdrawal symptoms in patients undergoing drug withdrawal from dependence-producing drugs, and for suppression of dependence, habituation or addiction on dependence-producing drugs.

In one test based on the method described by S.E. File in Neurosci. Meth., 1980, 2. 219-238, rats display an abstinence syndrome manifest as a reduction in social interaction, which is reversed by administration of the agents of the invention at about 0.05 to about 1 mg/kg animal body weight i.p.

In another test, rats which can self-administer themselves with cocaine over several weeks, are tested for their physical dependence liability according to the method described by N.E. Goeders et al. in Pharmacol. Biochem. Behaviour 22, 859-866 (1989). In this test, the agents of the invention cause a significant decrease in the intake of cocaine at about 0.05 to about 1 mg kg animal body weight i.p..

For the above mentioned indications the appropriate dosage will, of course, vary depending upon, for example, the host, the mode of administration, and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained when administered at a daily dosage of from about 0.1 mg to about 2 mg per kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 0.5 to about 30 mg conveniently given in divided doses 2 to 4 times a day or in sustained release form. Dosage forms suitable for oral administration comprise from about 0.1 to about 15 mg of the agents.

For all these indications the preferred compound is the compound of example 1. It has, for example, been determined that in the above mentioned Ungerstedt model, this compound induces within 7 hours 2200 contralateral turns on administration of 0.3 mg/kg p.o. or 0.1 mg/s.c, as compared to bromocriptine which induces within 7 hours 1720 contralateral turns on administration of 1 mg/kg s.c. In the above mentioned alcohol consumption model, the alcohol intake is reduced by 60 % on administration of 0.5 mg/kg p.o. of the compound of example 1, as compared to bromocriptine which reduces the intake by 70 % on administration of 4.0 mg/kg p.o.. In the above mentioned cocaine intake model, the cocaine intake is reduced by 30 % on administration of 0.1 mg/kg i.p. of the compound of example 1.

The agents of the invention in pharmaceutically acceptable acid addition salt form exhibit the same order of activity as the agents of the invention in free base form.

The agents of the invention can be administered by any conventional route, preferably orally, for example in the form of tablets or capsules, or parenterably, for example in the form of injectable solutions or suspensions.

In accordance with the foregoing, the present invention also provides an agent of the invention, for use as a pharmaceutical, in the treatment of Morbus Parkinson, in the prevention of alcohol abuse or in the treatment of drug withdrawal symptoms and suppression of dependence, habituation or addiction on dependence-producing drugs.

The present invention also provides a pharmaceutical composition comprising an agent of the invention in association with a pharmaceutical carrier or diluent. Such compositions may be manufactured in conventional manner. Unit dosage forms contain, for example, from about 0.01 mg to 15 mg of the active agent.

The present invention furthermore provides the use of the agents of the invention for the manufacture of a medicament for the treatment of Morbus Parkinson, in the prevention of alcohol abuse or in the treatment of drug withdrawal symptoms and suppression of dependence, habituation or addiction on dependence-producing drugs.

Moreover the present invention provides a method for the treatment of Morbus Parkinson, for the prevention of alcohol abuse or for the treatment of drug withdrawal symptoms and suppression of dependence, habituation or addiction on dependence-producing drugs, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of the active agent.

Claims

WHAT WE CLAIM IS:

1. A l-alkyl-9,10-dihydroxy-4,5,5a,6-tetrahydro-dibenz[cd,f]indole or an acid addition salt thereof.

2. A (4R*,5aS*) compound of claim 1 of formula I

wherein R„ R₂ and R₃ are independently (C,_,)alkyl, in free or acid addition salt form.

3. A compound of claim 1 which is (4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro- 9,10-dihydroxy-l-methyl-4-n-propyl-dibenz[cd,f]indole, in free or acid addition salt form.

4. A process for the production of a compound according to claim 1, or an acid addition salt thereof, which comprises the steps of obtaining a 1-alkyl- 9,10-dihydroxy-4,5,5a,6-tetrahydro-dibenz[cd,f]indole or an acid addition salt thereof, by splitting the ether groups in a corresponding

1 -alkyl-4,5 ,5a,6-tetrahydro

-dibenz[cd,f]indole having splittable ether groups in the 9 and 10 positions, or a precursor thereof, and recovering the desired l-alkyl-9,10-dihydroxy- 4,5,5a,6-tetrahydro-dibenz[cd,f]indole as such or as an acid addition salt thereof.

5. A process for the production of a (4R*,5aS*)compound of formula I according to claim 2, in free or acid addition salt form, which comprises splitting the ether groups in a (4R*,5aS*) compound of formula H

wherein R, to R₃ are as defined in claim 2, and the Z radicals are the same or different and are splittable ether groups, or a precursor thereof, and recovering the (4R*,5as*) compound of formula I as such or as an acid addition salt.

6. A compound of any one of claims 1 to 3 in free or pharmaceutically acceptable acid addition salt form, for use as a pharmaceutical.

7. A compound of any one of claims 1 to 3 in free or pharmaceutically acceptable acid addition salt form, for use in the treatment of Morbus Parkinson, in the prevention of alcohol abuse or in the treatment of drug withdrawal symptoms and suppression of dependence, habituation or addiction on dependence-producing drugs.

8. A pharmaceutical composition comprising a compound of any one of claims 1 to 3 in free or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.

9. The use of a compound of any one of claims 1 to 3 in free or pharmaceutically acceptable acid addition salt form, in the manufacture of a medicament for the treatment of Morbus Parkinson, in the prevention of alcohol abuse or in the treatment of drug withdrawal symptoms and suppression of dependence, habituation or addiction on dependence-producing drugs.

10. A method for the treatment of Morbus Parkinson, for the prevention of alcohol abuse or for the treatment of drug withdrawal symptoms and suppression of dependence, habituation or addiction on dependence-producing drugs, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a compound of any one of claims 1 to 3 in free or pharmaceutically acceptable acid addition salt form.