JPH11504616A - Dibenz [cd, f] indole derivative - Google Patents

Abstract

  (57) [Summary] 1-alkyl-9,10-dihydroxy-4,5.5,5a, 6-tetrahydro-dibenz [cd, f] indole may be used for the treatment of Parkinson's disease, alcohol dependence and drug dependence.

Description

The present invention relates to dibenz [cd, f] indole derivatives, their production and pharmaceutical compositions containing them. The present invention provides 1-alkyl-9,10-dihydroxy-4,5.5,5a, 6-tetrahydro-dibenz [cd, f] indole and its acid addition salt (hereinafter referred to as "the compound of the present invention"). You. The compounds of the invention are preferably substituted at the 4- and 5-positions of the dibenz [cd, f] indole nucleus, preferably by an alkyl group. The alkyl group, especially the alkyl group at the 1-position, in the compound of the present invention is preferably (C _1-4 ) alkyl. When the 4-position of the compound of the present invention is substituted, the configuration 4S, 5aR is preferred. More specifically, the invention relates to compounds of formula I in free or acid addition salt form. [Wherein R ₁ , R ₂ and R ₃ are independently (C _1-4 ) alkyl] provided is a (4R *, 5aS *) compound represented by the formula: The term (4R *, 5aS *) according to normal practice is the racemic or optically active isomer in which the hydrogen atom compounds at the 4- and 5a-positions of the dibenz [cd, f] indole nucleus are synth with each other. Indicates what is possible. Optical isomers having the complete configuration 4S, 5aR are preferred. The alkyl groups are preferably straight-chain groups. R ₁ is preferably methyl. R ₂ is preferably methyl, ethyl or n- propyl. R ₃ preferably has 1, 2 or 3 carbon atoms, especially methyl, ethyl or n-propyl. The present invention also provides for the separation of the ether group of the corresponding 1-alkyl-4,5,5a, 6-tetrahydro-dibenz [cd, f] indole or its precursor having a separable ether group at the 9- or 10-position. And recovering the desired 1-alkyl-9,10-dihydroxy-4,5,5a, 6-tetrahydro-dibenz [cd, f] indole itself or an acid addition salt thereof. The present invention provides a method for producing a compound of the present invention, which comprises the step of obtaining dihydroxy-4,5.5,5a, 6-tetrahydro-dibenz [cd, f] indole or an acid addition salt thereof. More specifically, the present invention provides compounds of formula II Wherein R ₁ to R ₃ have the same meanings as defined above and Z is the same or different and are separable ether groups, and the ether group in the (4R *, 5aS *) compound or a precursor thereof is separated. (4R *, 5aS *) compound of formula I or an acid of the compound as described above, including recovering the (4R *, Sas *) compound of formula I itself or an acid addition salt thereof. A method for producing an addition salt is provided. The ether separation process can be carried out in a conventional manner for separating ether groups. For example, the reaction may be performed by treatment with a strong inorganic acid, such as aqueous hydrobromic or hydroiodic acid. Suitable temperatures can be from 100 ° C. or higher, preferably from 100 ° C. to the boiling point of the reaction mixture, especially about 130 ° C. Each of the ether groups Z is preferably (C _1-4 ) alkoxy, more preferably a methoxy group. As used herein, the term precursor refers to a compound that can be converted to a starting material in a known manner, for example, a temporary protected compound. The resulting compounds of the present invention can be recovered and purified from the reaction mixture by known methods. The free base forms of the compounds of the invention may be converted into acid addition salts in a conventional manner, and vice versa. Suitable acids for salt formation include, for example, hydrochloric acid and methanesulfonic acid. The racemates of the present invention can be obtained from racemic starting materials. Optically active isomers can be obtained from optically active precursors or racemates. Enantiomers may be prepared by known methods, for example, diastereoisomeric salts such as (+)-di-O, O'-p-toluoyl-D-tartaric acid or (-)-di-O, O'- It can be obtained by fractional recrystallization of a salt with p-toluoyl-D-tartaric acid. Racemic decomposition into optically active isomers can be performed, for example, before separation of the ether group in the compound of formula II. 1-Alkyl-4,5,5a, 6-tetrahydro-dibenzo [cd, f] indoles containing a separable ether group at the 9- and 10-positions are suitable 1-alkyl groups having a separable ether group at the 9- and 10-positions. -Alkyl-4-hydroxy-4,5-dihydro-dibenz [cd, f] indole. In particular, the (4R *, 5aS *) compounds of formula II can be prepared in a known manner, conveniently under acidic conditions suitable for the acidic reduction of enamine or imine. [Wherein, Z, R ₁ , R ₂ and R ₃ have the same meanings as described above]. The starting materials 1-alkyl-4-hydroxy-4,5-dihydro-dibenz [cd, f] indoles having a suitable separable ether group at the 9-position and the 10-position are prepared by known methods, for example, in GB 2 No. 024,818. For example, a starting material of formula III can be prepared by the following reaction scheme: In the reaction scheme, the groups R ₁ , R ₂ , R ₃ and Z have the meanings as defined above, R ₃ ′ is hydrogen, methyl or ethyl and Hal is chlorine or bromine. The reaction can be performed in a known manner, and the products of the reaction can be isolated and purified in a known manner. In the above intermediate, the ether group Z is preferably methoxy. Unless a preparation method or a specific starting material is specified, this can be performed by a known method or a method similar to that described below for an analogous compound. In the following examples, all temperatures are Celsius and uncorrected. Example 1: ( ±) (4R *, 5aS *)-5-ethyl-4,5,5a, 6-tetrahydro- 9,10-dihydroxy-1-methyl-4-n-propyl-dibenz [cd, f ] i Ndoru a) 9-amino-3,4-dimethoxy-5-methyl - phenanthrene (compound of formula V) trifluoroacetic anhydride 400ml (2.87M) and trifluoroacetic acid 400m l (5.22M) Is added to 61.1 g (0.206 M) of 3,4-dimethoxy-5-methyl-phenanthrene-9-carboxylic acid at room temperature under a nitrogen atmosphere and the mixture is stirred for 10 minutes. After cooling to −5 ° C., 16.08 g (0.247 M) of sodium azide were carefully added in solid form, stirred for 2 hours at 0 ° C., poured on ice, extracted three times with methylene chloride and extracted with 1N sodium hydroxide. Wash with solution. The aqueous phase is extracted twice with methylene chloride 2-propanol 8: 2. The organic phases are combined and evaporated to dryness to give white crystals. 86 g of the mixed anhydride obtained are heated under reflux with 800 ml of 2N sodium hydroxide solution and 800 ml of ethanol for 2 hours and evaporated. The residue is washed with water / ice and extracted three times with methylene chloride. Combine the organic phases and evaporate to dryness to give the title compound as a yellow powder. Mp. 130-133 [deg.]. b) 9-Acetylamino-3,4-dimethoxy-5-methyl-phenanthrene (compound of formula VI) 105.7 ml (0.750 M) of N-ethyl-N, N-diisopropylamine in 1000 ml of methylene chloride To a solution of 100.2 g (0.375 M) of 9-amino-3,4-dimethoxy-5-methyl-phenanthrene. To the resulting mixture, a solution of 34.5 ml (0.450 M) of acetyl chloride in 250 ml of methylene chloride is added dropwise over 30 minutes. During the addition, the reaction temperature is maintained at 20 ° by cooling with ice. The reaction mixture is stirred at room temperature for 2 hours and extracted with methylene chloride. Wash the organic phase with ice-cold 2N hydrochloric acid, water and 2N sodium bicarbonate, dry over sodium sulfate and evaporate to give the title compound. After crystallization from ethanol, Mp. c) 9-Ethylamino-3,4-dimethoxy-5-methyl-phenanthrene (compound of formula VII) 1700 ml (2.05 M) of a 20% solution of diisobutylammonium hydride in toluene are added to 9 ml of anhydrous tetrahydrofuran in 1500 ml. To a suspension of 105.7 g (0.342 M) of -acetylamino-3,4-dimethoxy-6-methyl-phenanthrene is added at room temperature over 45 minutes. The mixture is then warmed to 80 ° for 2 hours with stirring under a nitrogen atmosphere. The reaction mixture is then cooled to 0 ° under a nitrogen atmosphere and 2500 ml of a -10 ° cooled 2N HCl / ice mixture are added in small portions at a rate such that gas evolution is sustained. The acid solution is made alkaline to pH 10 by adding 3 liters of 2N sodium hydroxide at 0 ° C. 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-ethyl-4,5-dihydro-9,10-dimethoxy-1-methyl-4-o Kiso - dibenz [cd, f] indole (compound of formula IX) n-butyl in hexane - Lithium Of a 9% ethyl-9,3-dimethoxy-5-methyl-phenanthrene in 100 ml of anhydrous tetrahydrofuran at 0 ° for 20 minutes under nitrogen atmosphere at 0 °. .328M); the reaction mixture becomes dark red. After stirring for 30 minutes at 0 °, the mixture is transferred in small portions at −50 ° under nitrogen pressure via a Teflon tube to a mixture of 500 g of sodium sulfate and 500 g of dry ice in 1500 ml of 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. Dry the combined organic phases over sodium sulfate and evaporate to give the title compound. After crystallization with ethyl acetate / hexane, Mp. 148-49 [deg.]. e) 5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-1 -methyl-4-n-propyl-dibenz [cd, f] indole (compound III) n- in 4 l of tetrahydrofuran A solution of 377 ml (4.1 M) of propyl-bromide is added at reflux over 90 minutes to 99.8 g (4.1 M) of magnesium turnings and the mixture is stirred at reflux for 1 hour. The resulting mixture was added to a mixture of 5-ethyl-4,5-dihydro-9,10-dimethoxy-1-methyl-4-oxo-dibenz [cd, f] indole in 6 liters of tetrahydrofuran under a nitrogen atmosphere for 30 minutes. 880 g (2.73 M) of the solution are added dropwise. The reaction mixture is warmed at reflux for 2 hours and then extracted with methylene chloride. The organic phase is washed with a saturated solution of potassium hydrogen carbonate and water, dried over sodium sulfate and evaporated to give the title compound in the form of a red-brown oil [IR spectrum (CH ₂ Cl ₂ ): 3540 cm ⁻¹ ( OH)]. The crude product is used directly in the next step. f) ( ±)-(4R *, 5aS *)-5-ethyl-4,5,5a, 6-tetrahydro-9,10- dimethoxy-1-methyl-4-n-propyl-dibenz [cd, f] India Lumpur (compound of formula II) ethanol 2000ml of 5-ethyl-4,5-dihydro-4-hydroxy - 9,10-dimethoxy-1-methyl -4-n-propyl - dibenz [cd, f A suspension of 100 g (0.273 M) of indole is stirred with a suspension of 322 g (4.928 M) of zinc powder and 74.3 g (0.273 M) of mercury (II) chloride in 2000 ml of distilled water. Added. The reaction mixture is refluxed, 450 ml of 18% hydrochloric acid are added dropwise over 15 minutes and the mixture is refluxed with stirring overnight. The mixture is then cooled to room temperature, filtered and the zinc amalgam is washed with 500 ml of methylene chloride. The filtrate is made alkaline with 1 liter of concentrated NH ₄ OH and extracted three times with methylene chloride (700 ml each). The combined organic phases are washed with water and evaporated to dryness. The resulting oil is chromatographed on silica gel using methylene chloride with 2% methanol to give the title compound as an oil. g) ( ±)-(4R *, 5aS *)-5-ethyl-4,5,5a, 6-tetrahydro-9,10- dihydroxy-1-methyl-4-n-propyl-dibenz [cd, f] in Doll 47% aqueous solution of one liter of hydrobromic acid (±) - (4R *, 5aS *) - 5- ethyl -4,5,5a, 6- tetrahydro-9,10-dimethoxy-1-methyl -4- 100 g of n-propyl-dibenz [cd, f] indole are warmed at reflux at a bath temperature of 150 ° for 6 hours. After evaporating 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 bromate of the title compound. Mp of hydrochloride: decomposed,> 250 °. Example 2: ( -) (4R, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10- dihydroxy-1-methyl-4-n-propyl-dibenz [cd, f] in A ) ( -) (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10 -dimethoxy-1-methyl-4-n-propyl-dibenz [cd, f] indole ( ±)-(4R *, 5aS *)-5-ethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxy-1-methyl-4-n-propyl-dibenz [cd, f] indole 74 0.3 g (211 mM) was dissolved in 600 ml of acetone, and a solution of 81.67 g (211 mM) of (-)-di-O, O'-p-toluoyl-L-tartaric acid hydrate in 300 ml of acetone was stirred. Added. The mixture is further stirred at room temperature for 1 hour, during which a total of 1 liter of ether is added in portions. The precipitate obtained is filtered off, washed with ethyl acetate until pale yellow and dried. 114.7 g of the crystals obtained in the first crystallization are dissolved in 1 liter of 7: 3 CH ₂ Cl ₂ / methanol at reflux, the solution is filtered and concentrated until most of the product crystallizes out. The mixture is refluxed for about 15 minutes, the product is filtered off, washed with ethyl acetate until colorless and dried. 48 g of the product obtained are recrystallized with 700 ml of 50:50 CH ₂ Cl ₂ / methanol using the same method to give colorless crystals. The crystals obtained are recrystallized using 1.2 g of acetone and 60 ml of methanol using the same method. Therefore, (-)-(4S, 5aR) -5-ethyl-4,5.5,5a, 6-tetrahydro-9,10-dimethoxy-1-methyl-4-n-propyl-dibenz [cd] in the form of colorless crystals [, f] indole (-)-di-O, O'-p-toluoyl-L-tartaric acid is obtained and melts at 185-198 °; [α] _D ²⁰ = -175.4 ° (c in dimethylformamide = 2). [Α] _D ²⁰ = -197 ° of base (oil) (c = 1 in EtOH). b) ( -)-(4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10- dihydroxy-1-methyl-4-n-propyl-dibenz [cd, f] india in the method described in Lumpur example 1g), (-) - ( 4S, 5aR) -5- ethyl -4,5,5 a, 6- tetrahydro-9,10-dihydroxy-1-methyl -4-n To give -propyl-dibenz [cd, f] indole; the methanesulfonate decomposes and melts at 212-214 °; [α] _D ²⁰ = −159.2 ° (c = 0.75 in methanol). Example 3 In the manner described in Examples 1 and 2, the following compounds are obtained: a) (±)-(4R *, 5aS *)-4,5,5a, 6-tetrahydro-9,10-dimethoxy -1,5-dimethyl-4-n-propyl-dibenz [cd, f] indole b) (±)-(4R *, 5aS *)-4,5,5a, 6-tetrahydro-9,10-dihydroxy- 4,5-Dimethyl-4-n-propyl-dibenz [cd, f] indole. Mp. c) (-)-(4S, 5aR) -4,5,5a, 6-tetrahydro-9,10-dimethoxy-1,5-dimethyl-4-n-propyl-dibenz [cd, f] indole. [Α] _D ²⁰ = -177 ° (c = 1, dimethylformamide) for (−)-di-O, O′-p-toluoyl-L-tartaric acid. [Α] _D ²⁰ = −218 ° (c = 0.7, EtOH) of the base d) (−)-(4S, 5aR) -4,5,5a, 6-tetrahydro-9,10-dihydroxy-1, 5-Dimethyl-4-n-propyl-dibenz [cd, f] indole. Methanesulfonate decomposes and melts at 201-203 °, [α] _D ²⁰ = -189 ° (c = 0.5, MeOH). 9-amino-3,4-dimethoxy-5-methyl-phenanthrene can also be converted directly to 9-ethylamino-3,4-dimethyloxy-5-methyl-phenanthrene by heating with ethylamine in 2-ethoxyethanol. It is obvious. 1-Alkyl-9,10-dihydroxy-4,5.5,5a, 6-tetrahydro-dibenz [cd, f] indole, especially the compound of formula I and its pharmaceutically acceptable acid addition salts (hereinafter referred to as " The "drugs of the present invention") have pharmacological activity in animals and are therefore useful as medicaments. In particular, the agents of the invention may be used in standard tests, e.g. Ungerstedt et al. [Acta Physiol. Scand. Suppl. (1971), 387. Suppl. 66-93], after administration of po in an amount of about 0.03 to about 10 mg / kg of animal body weight, the rats (the substantia nigra were exposed to 6-hydroxy- It is a central dopaminergic stimulant, as shown by the apparently sustained contralateral rotation in (disease by microinjection of dopamine). This activity is confirmed in rats following the administration of ip in an amount of about 1 to about 30 mg / kg of animal body weight, by the induction of odor-licking, chewing and chewing behaviors in a dose-dependent manner. A 180-222 g rat is placed on a wire grid in a 30 cm diameter organic glass cylinder. After 30 minutes to acclimate to the cage environment, rats were injected with compound under investigation. The behavior of the rats is observed for 2 minutes at 30 minute intervals for up to 2 hours and then at 60 minute intervals for a total of 7 hours. The rates of typological behavior were determined by Costall, Naylor and Olley [Europ. J. Pharmac. 18, 83-94, (1972)]. The agents of the present invention are therefore useful as dopaminergic stimulants, for example, in the treatment of Parkinson's disease. For the above-mentioned indications, the appropriate dosage will of course vary depending, for example, on the host, the route of administration and the severity of the condition to be treated. However, it is generally indicated that satisfactory results are obtained in animals when a daily dose of about 0.1 to 10 mg / kg of animal body weight is administered. For large mammals, e.g., humans, the indicated daily doses range from about 4 to about 30 mg, conveniently administered in divided doses two to four times daily or in sustained release form. Dosage units suitable for oral administration contain from about 1 to about 15 mg of the drug. The agents of the present invention, in particular the compounds of formula I, may also be administered to alcohol-loving rats at a dose of about 0.5 to 2 mg / kg of the compound, as indicated by reduced alcohol consumption, as indicated by reduced alcohol consumption. It is also useful for prevention. Eatometer according to Fallon [Science 148, 977-8 (1965)], respectively, which allows gravimetric quantification of food and beverages actually consumed by male and female rats of alcohol-loving species And into individual cages with two bottles with a two-sphere valve. Animals receive a vitamin-enriched standard diet, distilled water in one bottle and aqueous ethanol solution (10% / volume) in the other. Under these conditions, 50 to 97% of the preferred water was taken from the bottle containing the ethanol solution, which corresponds to a daily consumption of 4 to 6 g of pure ethanol per kg of animal body weight, and the rats had an alcohol dependent The disease developed, which is evident from the surprising increase in behavior when shaking the cage during the abstinence period. Compounds are administered po in aqueous solution and food, water and alcohol consumption is recorded for 12 hours and compared to the average consumption for 3 days prior to dosing. In this test, administration of the agents of the present invention significantly reduces alcohol consumption without a significant decrease in food and liquid intake. The agents of the present invention, in particular the compounds of formula I, are useful for the treatment of drug withdrawal symptoms in patients who are withdrawing the drug for an addictive drug, in particular prophylactic treatment and addiction, addiction or It is also useful for routine control. SE File, Neurosci. In a test based on the method described in Meth, 1980, 2, 219-238, rats were reversible after administration of about 0.05 to about 1 mg / kg of animal body weight ip ip of a drug of the invention, showing a social interaction. Shows abstinence syndrome, evidenced as a decrease. In other studies, a tendency for physical dependence was demonstrated in rats capable of self-administration of cocaine over several weeks by NE. Goeders et al., Pharmacol. Biochem. Behavior was tested according to the method described in Behavior 33, 859-866 (1989). In this test, the agents of the invention result in a significant reduction in cocaine intake at about 0.05 to about 1 mg / kg body weight of animal ip. For the above-mentioned indications, the appropriate dosage will of course vary depending, for example, on the host, the route of administration and the severity of the condition to be treated. However, it is generally indicated that satisfactory results are obtained in animals when a daily dose of about 0.1 to 2 mg / kg of animal body weight is administered. For large mammals, e.g., humans, the indicated daily doses range from about 0.5 to about 30 mg, conveniently administered in divided doses two to four times daily or in sustained release form. Dosage units suitable for oral administration contain from about 0.1 to about 15 mg of the drug. For all these indications, the preferred compounds are those of Example 1. For example, in the Ungerstedt model described above, this compound is 0.3 mg / kg p.o. or 0.1 mg / sc compared to bromocriptine, which induces 1720 contralateral rotation within 7 hours at 1 mg / kg sc. Trigger 2200 contralateral rotation within 7 hours. In the above alcohol consumption model, the administration of 0.5 mg / kg po of the compound of Example 1 suppresses the intake by 60% as compared with bromocriptine which suppresses the alcohol intake by 70% at the administration of 4.0 mg / kg po. . In the above cocaine intake model, administration of 0.1 mg / kg ip of the compound of Example 1 suppresses cocaine intake by 30%. Pharmaceutically acceptable salt forms of the agents of the present invention exhibit similar activity as free base forms of the agents of the present invention. The agents of the present invention can be administered by conventional routes, preferably orally, eg, in the form of tablets or capsules, or parenterally, eg, in the form of injectable solutions or suspensions. In accordance with the foregoing, the invention also relates to the use of a medicament for the treatment of Parkinson's disease, for the prevention of alcohol dependence or for the treatment of drug withdrawal symptoms and for the control of the dependence, addictive or addictive nature of addictive drugs. An agent of the invention is provided. The invention also provides a pharmaceutical composition comprising an agent of the invention together 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 active agent. The present invention further relates to a drug of the present invention in the manufacture of a medicament for treating Parkinson's disease, preventing alcohol dependence or treating drug withdrawal symptoms, and inhibiting the dependence, addiction or addiction of a drug produced by dependence. Provides use of. Still further, the invention includes administering a therapeutically effective amount of a drug to a patient, treating Parkinson's disease, preventing alcohol dependence or treating drug withdrawal symptoms in a patient in need thereof, and an addictive drug. Of addiction, addiction or addiction.

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, M C, NL, PT, SE), OA (BF, BJ, CF, CG , CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, LS, MW, SD, SZ, U G), AM, AT, AU, BB, BG, BR, BY, C A, CH, CN, CZ, DE, DK, EE, ES, FI , GB, GE, HU, IS, JP, KE, KG, KP, KR, KZ, LK, LR, LT, LU, LV, MD, M G, MN, MW, MX, NO, NZ, PL, PT, RO , RU, SD, SE, SG, SI, SK, TJ, TM, TT, UA, UG, US, UZ, VN

Claims (1)

Claims: 1.1-Alkyl-9,10-dihydroxy-4,5,5a, 6-tetrahydro-dibenz [cd, f] indole or an acid addition salt thereof. 2. Formula I in free or acid addition salt form (4R *, 5aS *) compound according to claim 1, wherein R ₁ , R ₂ and R ₃ are independently (C _1-4 ) alkyl. 3. (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-1-methyl-4-n-propyl-dibenz [cd, f] indole in free or acid addition salt form The compound according to claim 1, which is 4. Separating the ether group of 1-alkyl-4,5,5a, 6-tetrahydro-dibenz [cd, f] indole or a precursor thereof having a separable ether group at the ninth or tenth position, 1-alkyl-9,10-dihydroxy-4,5 by recovering the alkyl-9,10-dihydroxy-4,5,5a, 6-tetrahydrodibenz [cd, f] indole itself or its acid addition salt. A process for producing a compound according to claim 1, which comprises the step of obtaining 5,5,6, -tetrahydro-dibenz [cd, f] indole or an acid addition salt thereof. 5. Formula II Wherein R ₁ to R ₃ are the same as defined in claim 2 and Z is the same or different and are separable ether groups. An ether group in the (4R *, 5aS *) compound or a precursor thereof 3. A free or acid addition salt form of formula (4R *) according to claim 2, which comprises separating and recovering the (4R *, Sas *) compound of formula I itself or an acid addition salt thereof. , 5aS *) Method for producing compounds. 6. 4. A compound according to any one of claims 1 to 3 in free or acid addition salt form for use as a medicament. 7. Free or pharmaceutically acceptable for the treatment of Parkinson's disease, for the prevention of alcohol dependence or for the treatment of drug withdrawal symptoms and for the use as a medicament for the control of dependence, addictive or addictive dependence of the drug produced 4. A compound according to claim 1 in a possible acid addition salt form. 8. A pharmaceutical composition comprising a compound according to any of claims 1 to 3 in free or pharmaceutically acceptable acid addition salt form together with a pharmaceutical carrier or diluent. 9. Free or pharmaceutically acceptable acid addition in the manufacture of a medicament for the treatment of Parkinson's disease, for the prevention of alcohol dependence or for the treatment of drug withdrawal symptoms and for the control of the dependence, addiction or addiction of the drug produced. Use of a compound according to any of claims 1 to 3 in salt form. 10. A method for treating Parkinson's disease in a patient in need of treatment comprising administering to the patient a therapeutically effective amount of a compound according to any of claims 1 to 3 in free or pharmaceutically acceptable acid addition salt form. Methods of treatment, prevention of alcohol dependence or treatment of drug withdrawal symptoms and suppression of dependence-producing drug dependence, addiction or addiction.