WO1982000143A1

WO1982000143A1 - Heterocyclic compounds,method for preparing such compounds and pharmaceutical compositions containing them

Info

Publication number: WO1982000143A1
Application number: PCT/CH1981/000069
Authority: WO
Inventors: Ag Sandoz; R Giger
Original assignee: Ag Sandoz
Priority date: 1980-06-27
Filing date: 1981-06-24
Publication date: 1982-01-21
Also published as: GB8325760D0; CY1399A; FI75153B; ES515568A0; ES8300701A1; GB2136418B; YU159481A; NZ197529A; ES8400088A1; CA1155447A; SE449222B; ES8400089A1; FR2485530A1; IE811421L; KE3749A; IE51341B1; AU7202881A; FI75153C; AT380875B; ES515567A0

Abstract

Compounds of 4, 5, 5a, 6-tetrahydro-dibenz(cd,f) indole having the formula I (FORMULA) wherein R1 and R2, independently from each other, represent an ethyl or n-propyl group, and wherein the substituents R3 are the same and represent hydroxy- or acyloxy- groups, these compounds, either in their racemic form of relative configuration 4R*, 5aS*, or in their optically active isomeric form of absolute configuration 4S, 5aR, are particularly efficient for the stimulation of dopaminergical central receptors.

Description

Heterocyclic compounds, process for their. Production and pharmaceutical compositions containing these compounds

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The invention relates to heterocyclic compounds, processes for their preparation and pharmaceutical compositions containing these compounds.

Belgian Patent No. 877169 describes a class of 4,5,5a, 6-tetrahydro-dibenz [cd, f] indole derivatives which have a stimulating effect on the central dopaninergic receptors. All specifically listed compounds which have alkyl groups in positions 4 and 5 contain a methyl group as an alkyl group. It has now surprisingly been found that a group of (4R *, 5aS *) - 4,5,5a, 6-tetrahydro-dibenz [cd, f] indole derivatives which contain ethyl and n-propyl groups in positions 4 and 5 and which are not described or listed in detail in this patent, have a particularly interesting pharmacological spectrum, including a long-lasting effect and / or a remarkable effectiveness as central anti-inflammatory agents, and good tolerance. The invention relates to compounds of the formula I.

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R ₁ and R ₂ , independently of one another, are an ethyl or n-propyl group and the two R ₃ substituents are identical and denote hydroxyl or acyloxy groups,

in racemic form with the relative configuration 4R *, 5aS * or in the form of an optically active isomer with the absolute configuration 4S, 5aR.

The acyloxy groups are expediently groups of the formula R _a - CO - O - in which R _{a is} an alkyl group, a cycloalkyl group with 3-7 carbon atoms, a phenyl group or a 5-6 membered heterocyclic ring.

If R _{a is} an alkyl group, this conveniently has 1-17 carbon atoms, preferably 1-7 carbon atoms, and can be straight-chain or branched.

R _a can be a substituted alkyl group which suitably contains 1-5 carbon atoms in the alkyl chain. It is expediently a monosubstituted alkyl group. Examples of the corresponding substituents are carboxy, hydroxy, amino, alkylamino with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, di- (C alkylamino, halogen, alkylthio with 1-4 carbon atoms, phenoxy, a phenyl group, 1-pyrrolidinyl, piperidino or morpholino, and expediently a phenyl group R _a can also be, for example, an alkyl group which contains 1-4 carbon atoms in the alkyl chain and is substituted by a cycloalkyl group having 3-7 carbon atoms.

If R _{a is} a phenyl radical or an alkyl group which is represented by a

Phenyl radical is substituted, means that the phenyl ring can be unsubstituted or substituted by 1, 2 or 3 identical or different substituents which consist of halogen, trifluoromethyl, alkyl having 1-4 carbon atoms, alkoxy mi 1-4 carbon atoms, alkylthio with 1-4 carbon atoms and di- (C _{1 -4} ) al kylamino or selected from a Kethylenendioxygruppe. The phenyl ring is preferably mono- or disubstituted.

If R _{a is} an alkyl group substituted by a phenyl radical, R _{a is} preferably a benzyl radical. The phenyl ring can carry substituents which can be selected, for example, from halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms and alkylthio with 1-4 carbon atoms.

If R _{a stands} for a heterocyclic ring, it is expediently a heterocyclic ring which contains oxygen,

Has nitrogen or sulfur as the only heteroate, for example around the pyridine, thiophene or furan residue.

R _a preferably represents an alkyl group having 1-7 carbon atoms, a cycloalkyl group having 3-6 carbon atoms, an unsubstituted phenyl or a phenyl which is mono- or disubstituted by chlorine, fluorine, trifluoromethyl, alkyl having 1-4 carbon atoms or alkoxy 1-4 carbon atoms, an unsubstituted benzyl or a benzyl which is non- or disubstituted by chlorine, fluorine, an alkyl group with 1-4 carbon atoms or an alkoxy group with 1-4 carbon atoms.

Halogen can be chlorine, bromine or fluorine, preferably chlorine or fluorine.

In a group of compounds, R _{1 represents} an n-propyl group and R _{2 represents} an ethyl group. In another group of compounds, R ₁ and R _{2 are} identical and represent an ethyl or n-propyl group. In the compounds of formula I, the R ₃ substituents are preferably a hydroxyl group. The preferred compounds are the optical (4S, 5aR) isomers. The invention also relates to a process for the preparation of compounds of the formula I, which is characterized in that either a) to compounds of the formula Ia

wherein R ₁ and R _{2 have the} above meaning, is obtained by the ether groups Z of compounds of formula II

wherein R ₁ and R _{2 have the} above meaning, and Z represents a cleavable group, cleaved in facemic form with the relative configuration 4R *, 5aS * or in the form of an optically active isomer with the absolute configuration 4S, 5aR, or b) Compounds of formula Ib

in which R ₁ and R _{2 have the} above meaning, and the radicals R ' ₃ denote identical acyloxy groups, by using compounds of Forrel Ia, in. racemic form with the relative configuration 4R *, 5aS * or in the form of an optically active Isomers with the absolute configuration 4S, 5aR, acylated.

The ether cleavage described in process a) can be carried out in a manner known per se. For example, the reaction can be carried out by treating the starting material with a strong Mineral acid, for example a hydrochloric acid or hydroiodic acid, at temperatures of at least 100 ° C., preferably from 100 ° C. to the boiling point of the reaction mixture, in particular at about 130 ° C. The ether group Z is preferably a methoxy group.

The acylation described in process b) can be based on. known manner using the methods known for the selective acylation of phenol groups in the presence of amino groups. For example, a functional derivative of an acid, for example an acid chloride, can be used as the acylating agent.

Acid bromide or an acid anhydride can be used. The reaction is expediently carried out with the aid of acid chlorides in the presence of trifluoroacetic acid at temperatures from 20 ° C. to the boiling point of the reaction mixture or in the presence of pyridine at temperatures from 0 ° C. to room temperature.

The compounds of formula I obtained can be isolated and purified in a known manner from the reaction mixture. The free bases of the compounds of formula I can be converted in a known manner into acid addition salts and vice versa. Acids suitable for salt formation are, for example, hydrochloric acid, tartaric acid, di-0.0-p-toluoyl-D- or L-wainic acid and hydrobromic acid.

The racemates of the formula I can be obtained from racemic starting compounds. The optically active isomers of the formula I can be obtained from the corresponding optically active starting compounds having the configuration (4S, 5aR) or from the racemates. The 4S, 5aR enantiomer can be obtained from the racemate in a known manner, for example by fractional crystallization of the ciastereoisomeric salts, for example of their salts with (+) - di-0,0-p-toluoyl-D-tartaric acid or (-) - di-0,0-p-toluoyl-L-tartaric acid. The racemates are preferably separated into the optically active isomers in an earlier stage of the synthesis, for example before the ether groups are split up.

The starting compounds of formula II can be prepared by using compounds of formula III

where R ₁ , R ₂ and Z have the above meaning, reduced.

The reduction is conveniently carried out under acid. conditions suitable for the reduction of enamines or inines, for example with the aid of zinc in aqueous mineral acid, preferably hydrochloric acid, advantageously in the presence of a mercury (II) salt, for example mercury (II) chloride. The reduction is conveniently carried out e.g. in Aethsnol and at temperatures from 50 ° C to the boiling point of the reaction mixture.

The starting compounds of the formula III are known, for example, according to the following implementation scheme:

In the reaction scheme, R ₁ , R ₂ and Z have the above meaning and R ' ₂ represents a methyl or ethyl group. The reactions can be carried out in a conventional manner, and the products obtained can be isolated and purified in a known manner.

In the above intermediates, the ether groups Z are preferably methoxy groups.

If the production of individual output connections is not described, these can be produced in the usual way. For example, the phenanthrene derivatives - the starting compounds of formula XI - are described in Elsevier's Encyclopaedia of Organic Chemistry, Volume 13, Tricyclic Compounds, Elsevier Publishing Company Inc., New York (1946).

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

EXAMPLE 1 a) 9- (N-ethyl-N-butyrylamino) -3-bromo-3,4-dimethosyphenanthrene (compound of the formula IV)

A solution of 50 g (138 mM) of 9-ethylamino-S-bromo-3,4-dimetoxy-phenanthrene in 57.5 ml (333 mM) of N-ethyl-diisopropylamine and 420 ml of ethylene chloride is added dropwise, with stirring in a nitrogen atmosphere and added within 20 minutes to a solution of 28.8 ml (276 mM) butyryl chloride in 420 ml methylene chloride. During the addition, the reaction mixture is kept at room temperature by cooling in a water bath. The yellow-red reading thus obtained is then worked up in a known manner, the 9- (N-ethyl-N-butyrylamino) -8-bromo-3,4-dimethoxy-phenanthrene being obtained. M.p. 102-104 °.

dibenz [cd, f] indole (compound of the formula III) 25 g (58.14 mM) 9- (N-ethyl-N-butyrylamino) -8-bromo-3,4-dimethoxy-phenanthrene are dissolved in 450 ml of anhydrous tetrahydrofuran with stirring and the solution obtained is brought to -25 ° with Cooled using a bath of methylene chloride and dry ice. 73 ml (116.28 mM) of a 1.7 molar solution of tert. Butyllithium in pentane are then added dropwise within 4 minutes. Then the temperature of the reaction mixture is allowed to rise to + 5 ° within 30 minutes, the reaction mixture is poured onto 500 ml of a mixture of water and ice, extracted three times, each time with 500 ml of methylene chloride, and the organic phases are washed with water, dried and she evaporates. After drying the product under high vacuum, the (4RS) -5-ethyl-4, 5-dihydro-4-hydroxy-9,10-dimethoxy-4-nrpropyl-dibenz [cd, f] -indole is obtained in the form of a yellow-green foam. c) (±) - (4R *, 5as *) - 5-ethyl-4, -5,5a, 6-tetrahydro-9,10-dimethoxy-4-n propyl-dibenz [cd, f] indole (compound of Formula II)

A suspension of 40.6 g (116 mM) (4RS) -5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-n-ρropyl-dibenz [cd, f] indole in 1060 ml of ethanol is stirred with a suspension of 140 g of zinc powder and 31.6 g (116 mM) of mercury (II) chloride in

Added 1060 ml of distilled water (the zinc powder-mercury chloride mixture can also be added to the dibenzindole). The reaction mixture is heated to reflux, 360 ml of 182. Hydrochloric acid are added dropwise within 15 to 20 minutes and the mixture is heated to reflux with stirring overnight. The reaction mixture is 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 ammonium hydroxide and the alkaline phase is extracted, once with 1 liter of ethylene chloride and twice, each time with 500 ml of methylene chloride. The combined organic phases are washed with water, dried and evaporated. The oil obtained is Chromatographed on a silica gel column using methylene chloride with 2% methanol as the fluid. This gives the (±) - (4R *, 5aS *) - 5-ethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxy-4-n-propyl-dibenz [cd, f] indole in Shape of an oil. EXAMPLE 2

The (4RS) -5-ethyl-4,5-di-hydro-4-hydroxy-9,10-dimethoxy-4-n-propy1-dibenz [cd, f] indole obtained in Example 1b) can also be prepared as follows are: a) 9-amino-3,4-dimethoxy-phenanthrene (compound of the formula X) A mixture of 430 ml (3.08 M) trifluoroacetic anhydride and 430 ml (5.62 M) trifluoroacetic acid is added at room temperature under a nitrogen atmosphere 53.6 g (0.19 M) of 3,4-dimethoxyphenanthrene-9-carboxylic acid were added and the mixture was stirred for 10 minutes. After the mixture has been cooled to -5 °, 15.2 g (0.234 M) of sodium azide in solid form are carefully added, the mixture is stirred at 2 ° for 3 hours, poured onto ice and the suspension obtained is worked up in a conventional manner, whereby the 9-amino-3,4-dimethoxy-phenanthrene is obtained in solid form. The hydrochloride melts from 215 ° with decomposition. b) 9-acetylamino-3,4-dimethoxyphenanthrene (compound of the formula IX)

55 ml (0.319 M) of N-ethyldiisopropylamine are added to a solution of 38.2 g (0.151 M) of 9-amino-3,4-dimethoxyphenanthrene in 200 ml of methylene chloride. A solution of 20.8 ml (0.292 M) of acetyl chloride in 250 ml of methylene chloride is added dropwise to the resulting mixture within 20 minutes. During the addition the temperature of the reaction mixture is maintained by means of Kihlung ^¬ with ice at 20 °. The reaction mixture is stirred for 14 hours at room temperature and worked up in a known manner, the 9-acetylamino-3,4-dimetoxy-phenenthrene being obtained (mp. 190-195 ° after recrystallization from ether). c) 9-acetylamino-3,4-dimethoxyphenanthrene (compound of the formula VIII) 34 g (0.124 M) of 9-acetylamino-3,4-dimethoxy-phenanthrene suspended in 450 ml of anhydrous tetrahydrofuran are reduced with 500 ml (0.5 M) of a molar solution of diborane in anhydrous tetrahydrofuran and worked up in a conventional manner. This gives 9-acetylamino-3,4-dimethoxyphenanthrene; Mp 94-95 °. d) 4,5-dihydro-9,10-dimethoxy-5-ethyl-4-oxodibenz [cd, f] indole

(Compound of formula VI)

122 ml (0.2 M) of a 15% solution of n-butyllithium in hexane, at 0 ° and under a nitrogen atmosphere, to a solution of 28.1 g (0.1 M) of 9-ethylamino-3,4-dimethoxy -phenanthrene in 300 ml of anhydrous tetrahydrofuran; the reaction mixture turns bright red. Dry ice is then added until the discoloration disappears; the formation of a solution with yellow-green fluorescence can be observed. After the temperature of the reaction mixture has reached room temperature, the mixture is poured onto a mixture of water and ice, extracted three times with methylene chloride and the organic phase is dried over sodium sulfate and evaporated. This gives 4,5-dihydro-9,10-dimethoxy-5-ethyl-4-oxodibenz [cd, f3 indole, which melts at 125-126 ° (with decomposition) after recrystallization from ether / petroleum ether. e) i4RS) -5-ethyl-4,5-dihydro-4-hydroxy-9, 10-dimethoxy-4-n-propyl-dibenz [cd, f3 indole (compound of the formula III) 2.1 ml (33 mM ) a solution of n-propyl magnesium bromide in ether are added dropwise at room temperature to a solution of 10 g (33 mM) of 4,5-dihydro-9,10-dimethoxy-5-ethyl-4-oxodibenz [cd, f] indole in 300 ml of anhydrous tetrahydrofuran. After 30 minutes, an ammonium chloride solution is added, the mixture is extracted with methylene chloride and the organic phase is dried and evaporated. The (4RS) -5-ethyl-4,5-di hydro-4-hydroxy-9, 10-dimethoxy-4-n-propyl-dibenz [cd, f] indo is thus obtained in the form of a yellow-green foam. [IR spectrum (CH ₂ Cl): 3540 The raw product is used directly for the next stage. EXAMPLE 3 (±) - (4R *, 5aS *) -5 ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-4-n propyl-dibenz [cd, f] indole 20 g (27, 66 mM) (±) - (4R *, 5aS *) - 5-ethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxy-4 - n-propyl-dibenz [cd, f] indole in 200 ml of a 47% aqueous solution of hydrobromic acid are heated at a bath temperature of 150 ° for 6 hours at reflux. After the reaction mixture has been evaporated to dryness, the crystalline residue is stirred in acetone and filtered off. The precipitate is washed with acetone, then with

Ether and dried in a high vacuum. This gives (±) - (4R *, 5aS *) 5-ethyl-4,5,5a, 6-tetrahydro-9, 10-dihydroxy-4-n-propyl-dibenz [cd, f] indole hydrobromide that melts at 200 ° with decomposition.

Using the appropriate starting materials, the following compounds can be prepared in a similar way: a) (±) - (4R *, 5aS *) -4, 5-diaethyl-4, 5.5a, 6-tetrahydro-9, 10-dihydroxy- dibenz [cd, f] indole (hydrobromide, mp> 175 ° with decomposition); b) (±) - (4R *, 5aS *) - 4,5,5a, 6-tetrahydro-9,10-dihydroxy-4,5-di-n-propyl-dibenz [cd, f] indole (hydrobromide mp .> 190 ° with decomposition); c) (±) - (4R *, 5aS *) - 4-ethyl-4, 5.5a, 6-tetrahycro-9,10-dihydroxy-5-n-propyl-dibenz [cd, f] indole. EXAMPLE 4

(-) - (4S, 5aR) -5-ethyl-pyl-dibenz] cd, f] indole a) (-) - (4S,) -5-ethyl-4,5,5a, 6-tetrahydro-9, 10-dimethoxy-4-n-propyl-dibenz [cd, f] indole

30 g (89 mM) (±) - (4R *, 5aS *) - 5-ethyl-4,5,5a, 6-tetra-hydro-9,10-dimethoxy-4-n-propyl-dibenz [cd, f] indole are dissolved in 300 ml of ether and a solution of 35.95 g (-) - di- 0.0-p-toluoyl-L-tartaric acid monohydrate in 300 ml of ether was added. The mixture is stirred for a further hour at room temperature, during which time a total of 1 liter of ether is added in portions. The precipitate is filtered off, washed with ethyl acetate until it is light yellow and dried.

61.88 g of the crystals obtained from the first crystallization are refluxed in 1 liter of acetone and 300 ml of methanol, and the solution is filtered and concentrated until most of the product crystallizes out. The mixture is stirred for about 15 minutes, the product is filtered off, washed with ethyl acetate until it is colorless and dried,

The product obtained is recrystallized in the same manner using 1.7 liters of acetone and 35 ml of methanol to obtain colorless crystals.

The crystals obtained are recrystallized in the same manner using 1.2 liters of acetone and 60 ml of methanol. The (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetra-hydro-9,10-dioethoxy-4-n-propyl-dibenz [cd, f] indole ( -) - di-0,0-p-toluoyl-L-tartrate in the form of colorless crystals which melt at 178-179 °; [α] _D ²⁰ = -138 ° (c = 0.29 from methanol).

The following compounds can be prepared in a similar manner using suitable starting materials: - (-) - (4S, 5aR) -4,5-diaethyl-4,5,5a, 6-tetrahydro-9,10-disethoxy-dibenz [cd, f3indole (-) - di-0,0-p-toluoyl-L-tartrate, Scp. 187-189 °; [α] _D ²⁰ = -138 ° (c = 0.5 from methanol); the racemic starting material is first reacted with (+) - di-0,0-p-toluoyl-D-tartaric acid instead of the L-isomer, and the mother liquor obtained in the crystallization is treated with NH 0H to liberate the base. The base is reacted with (-) - di-0,0-p-toluoyl-L-tartaric acid and the crystals are obtained from an ether solution. _ (-) - (4S, 5aR) -4,5,5a, 6-tetrahydro-9,10-dimethoxy-4,5-di-n-propy1- dibenz [cd, f] indole (-) - di- 0.0-p-toluoyl-L-tartrate, mp 165-166 °; [α] _D ²⁰ = -123 ° (c - 0.27 from methanol). b) (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydro-4-n-propyl-dibenz [cd, f] indole

The procedure is as described in Example 3 and, starting from the tartrate obtained under a), the (-) - (4S, 5aR) -5-

Ethyl 4,5,5a, 6-tetrahydro-9,10-dihydroxy-4-n-ρropyl-dibenz [cd, f] indole hydrobromide. It melts from 210 °; [α] _D ²⁰ = -64 ° (c = 0.245 from methanol).

The corresponding hydrochloride melts below 185 °

Decomposition; [α] _D ²⁰ = -75 ° (c = 0.28 from methanol).

EXAMPLE 5

Using the appropriate starting materials, the following compounds can be prepared as described in Example 4b): a) (-) - (4S, 5aR) -4,5-diaethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy - dibenz [cd, f] indole hydrochloride, mp. 200 ° with decomposition; [α] _D ²⁰ = -72 ° (c = 0.25 from methanol); b) (-) - (4S, 5aR) -4,5,5a, 6-tetrahydro-9,10-dihydroxy-4,5-di-n-propyl-dibenz [cd, f] indole hydrochloride, mp y 187 ° with decomposition; [α] _D ²⁰ --58.5 ° (c = 0.35 from methanol); c) (-) - (4S, 5aR) -4-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-5-n-propyl-dibenz [cd, f] indole. EXAMPLE 6

(+) - (4S, 5aR) -5-ethyl 1-9, 10-dibenzoyloxy-4,5,5a, 6-tetrahydro-A-n-propyl-dibenz [cd, f] indole

0.376 ml (3.23 mM) benzoyl chloride are added dropwise with stirring within 5 minutes and at + 5 ° to a solution of 600 mg (1.54 mM) (-) - (4S, 5aR) -5-ethyl-4,5, 5a, 6-tetrahydro-9,10-dihydrosy-4-n-propyl-dibenz [cd, f] indole hydrobromide in 5 ml of anhydrous pyridine are added and the reaction mixture is stirred for a further 14 hours at room temperature. The mixture is then evaporated to dryness, the residue is dissolved in methylene chloride and the solution first with a mixture of ice and a saturated potassium bicarbonate solution, and then washed with water. The aqueous phases are extracted twice with ethylene chloride and the combined organic phases are dried and evaporated. The residue is dissolved in methylene chloride and the solution is evaporated in a high vacuum. The reading of the residue in methylene chloride and evaporation are repeated two more times. 550 mg of the product thus obtained are dissolved in acetone and this solution is added dropwise to a solution of 156 mg L (+) tartaric acid in acetone. The precipitate is filtered off and dried. This gives the (+) - (4S, 5aR) -5-ethyl-9,10-dibenzoyloxy-4,5,5a, 6-tetrahydro-4-n-propyl-di-benz [cd, f] indole- L (+) - tartrate; it melts at 161-162 ° after recrystallization from a mixture of ethyl acetate and ether; [α] _D ²⁰ - + 23.5 ° (c = 0.28 from methanol).

The following compounds can be prepared in an analogous manner using suitable starting products:

- (-) - (4S, 5aR) -9, 10-diacetoxy-5-ethyl-4, 5, 5a, 6-tetrahydro-4-n-propyl-dibenz [cd, f] indole hydrochloride, mp> 188 ° (with decomposition); [α] _D ²⁰ = -99 ° (c = 0.28 from methanol);

- (-) - (4S, 5aR) -5-ethyl-4, 5, 5a, 6-tetrahydro-4-n-propyl-9, 10-di-propionyloxy-dibenz [cd, f3 indole hydrochloride, mp.> 175 ° (with decomposition); [α] _D ²⁰ = -76 ° (c = 0.25 from methanol);

- (-) - (4S, 5aR) -9,10-dibutyryloxy-5-ethyl-4,5,5a, 6-tetrahydro-4-n-propyl-dibenz [cd, f] indole hydrochloride, mp> 105 ° (with decomposition); [α] _D ²⁰ = -77 ° (c = 0.28 from methanol); - (-) - (4S, 5aR) -5-ethyl 1-4, 5.5a, 6-tetrahydro-9, 10-diisobutyryloxy-

4-n-propyl-dibenz [cd, f] indole hydrochloride, mp. > 165 ° (with decomposition); [α] _D ²⁰ = -96 ° (c = 0.29 from methanol); - (-) - (4S, 5aR) -5-ethyl 1-4, 5, 5a, 6-tetrahydro-4-n-propy 1-9, 10-divaleryloxy-dibenz [cd, f] indole hydrochloride;

- (-) - (4S, 5aR) -5-ethyl 1-4, 5.5a, 6-tetrahydro-4-n-propyl-9,10-dipivaloyloxy-dibenz [cd, f] indole hydrochloride; - (-) - (4S, 5aR) -4,5, 5a, 6-tetrahydro-9, 10-diρropionyloxy-4,5-di - n-propyl-dibenz [cd, f] indole, mp. 115 ° ; [α] _D ²⁰ = -67 ° (c = 0.51 from

Methanol).

In an analogous manner to that described in Example 6, the following compounds of the formula I, in which R ₁ and R ₂ , independently of one another, can be an ethyl or n-propyl group and R ₃

- acetoxy

- propionyloxy

- butyryloxy - isobutyryloxy

- valeryloxy

- pivaloyloxy mean, are produced.

The compounds of formula I have pharmacological properties. In particular, they exert a stimulating effect on the central dopaminergic receptors, as can be seen from the following standard experiments.

The dopaminergic effect of the compounds of the formal I was studied in the rat, according to that of U. Ungerstedt in Acta Physiol. Scand. Suppl. 367, 69-93 (1971). After one week, the unilateral injection of 6-hydroxydopεmin into the substantia nigra causes unilateral degeneration of the nigrostriatal pathways. After intraperitoneal administration of a dose between about 0.03 and about 1 mg / kg of the compounds of the formula I, a long-lasting activation was found in the rats, which manifested itself in the fact that the rats rotated in the direction of the undenervated side.

The stimulating effect of the compounds of the formula I on the central dopaminergic receptors was confirmed on the basis of the following experiment.

Rats weighing between 180 and 222 g were placed in Perspex cylinders with a diameter of 30 cm on one latticed floor laid. After allowing the rats 30 minutes to get used to the cage, the compound to be tested was injected. The behavior of the rats was observed for 2 minutes, at intervals of 30 minutes, for 2 hours and then at intervals of 60 minutes for a total of up to 6 hours. The degree of stereotypical behavior observed was determined from that of Costall, Kaylor and Olley [Euro. J. Pharmac. 18, 83-94 (1972) 3 described evaluation system. The following evaluation criteria were applied:

1) Intermittent sniffing

2) Continuous sniffing, occasional licking

3) Licking, occasional biting

4) Intense and persistent biting. Kach peritoneal administration in doses between about

0.03 and about 30 mg / kg body weight, the compounds of the formula I triggered a stereotypical sniffing, elicking and biting in the rats.

The compounds of the formula I are therefore known to be used to stimulate the central dopaminergic receptors, for example for the treatment of Parkinson's disease. For this indication, the suitable daily dose is between about 0.1 and about 20 mg and is expediently administered 2 to 4 times a day in the form of single doses which contain between about 0.025 and about 10 mg, or also in pvetard form.

The compounds of the formula I also have antidepressant properties, such as the inhibition of catalepsy caused by reserpine in the mouse, after subcutaneous administration of from about 0.001 mg to about 1 mg / kg of the compounds of the formula I and the inhibition of those in the rat catalepsy caused by tetrabenazine after intraperiteneal administration of about 0.2 to about 2 mg / kg of the compounds of formula I. The compounds of formula I can therefore be used as anti depressants.

The suitable daily dose is between about 0.05 and 2 mg and is expediently administered 2 to 4 times a day in the form of single doses which contain about 0.01 mg to about 1 mg of the compounds of the formula I in addition to solid or liquid carriers or

Contain diluents administered.

The compounds of formula I also cause

Inhibition of prolactin secretion resulting from lowering the level of prolactin in the serum of the rat after subcutaneous administration of about 0.1 to about 1 mg / kg of the compounds of formula I using radio-immunological techniques, for example as described by GD.Niswender and others in Biol. & Med. 130, 793 (1969) and JJ Keil and others described in Endocrinology 88, 548 (1971).

The compounds of formula I can therefore be used as prolactin inhibitors, for example for the treatment of conditions which include hyperprolactinemia, such as menstrual disorders, for example amenorrhea and galactorrhea, or hypertension, breast cancer in connection with an increased level of prolactin in the serum, or for treatment hypogcnadism, for example sterility or impotence, or to regulate postnatal lactation.

The suitable daily dose is between about 5 and about 50 mg and is expediently administered 2 to 4 times a day in the form of single doses which contain about 1.25 mg to about 25 mg of the compounds of the formula I in addition to solid or liquid

Carrier substances or diluents included.

The compounds of formula I also have antipsychotic properties, which results from the inhibition of locomotion in the mouse, after subcutaneous administration of about 0.001 to about 0.1 mg / kg of the compounds of formula I, and from the do-paminagonistic effect on the presynaptic Receptors of Rat at doses between about 1 mg and about 10 mg / kg of the compounds of formula I, according to the following experiment;

The dopamine agonistic effect of the compounds of the formula I on the presynaptic receptors was determined in the rat according to the method described by J.R. Walters and co-workers in Naunyn Schmiede.erg's Arch. Pharmacol. 296, 5-14 (1976) described in vivo method. The dopaminergic impulse flow was inhibited pharmacologically by means of α-butyrolactone. The action of the aromatic amino acid decarboxylase was inhibited by means of hydroxybenzylhydrazine (NSD 1015) and the rats were sacrificed half an hour later. The resulting DOPA accumulation in striatal tissue over 30 minutes was taken as a measure of the in vivo action of tyrosine hydroxylase. After oral administration of the compounds of the formula I, a reversal of the effects of the α-butyrolactone was found in a dose-dependent manner.

The compounds of the formula I can therefore be used as antipsychotics, for example for the treatment of schizophrenia. The suitable daily dose is between about 0.01 and about 1 mg and is expediently administered 2 to 4 times a day in the form of single doses which contain about 0.0025 mg to about 0.5 mg of the compounds of the formula I in addition to solid or liquid carriers or diluents.

The preferred indication is anti-parkin diction.

The compounds (4S, 5aR) -5-ethyl 1-4, 5, 5a, 6-tetrahydro-9, 10-dihydroxy-4-n-propyl-dibenz [cd, f [indole, (4S, 5aR) -4 -Aethyl-4, 5, 5a, 6-tetrahydro-9, 10-dihydroxy-5-n-propyl-9, 10-dihydroxy-di-benz [cd, f] indole, (4S, 5aR) -4, 5-diaethyl-4, 5, 5a, 6-tetrahydro-9, 10-dihydroxy-dibenz [cd, f] indole and (4S, 5aR) -4,5, 5a, 6-tetrahydro-9, 10-dihydroxy- 4,5-di-n-propyl-dibenz [cd, f] indole and the corresponding di-n-propionyl and di-isobutyl ester derivatives are the preferred compounds, The compounds of formula I can be administered in the form of their pharmacologically acceptable acid addition salts. These salts have the same effect as the free bases. The present invention also relates to medicinal products which contain compounds of the formula I, in the form of the free bases or in the form of their acid addition salts, in addition to carrier substances or diluents.

These remedies, for example a solution, a capsule or a tablet, can be produced by customary methods.

Claims

1. Compounds of formula I.

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R ₁ and R ₂ , independently of one another, are an ethyl or n-propyl group and the two R ₃ substituents are identical and hydroxyl or acyl oxy groups. mean in racemic form with the relative configuration 4R *, 5aS * or in the form of an optically active isomer with the absolute configuration 4S, 5aR.

2. The (4S, 5 aR) -5-ethyl-4, 5,5a, 6th tr ahydro-9, IC-dihydroxy-4-n-propyl-dibenz [cd, f] indole.

3. The (4S, 5aR) -4-ethyl 1-4, 5, 5a, 6-tetrahydro-9, 10-dihydroxy-5-n-propyl-dibenz [cd, f] indole.

4. The (4S, 5aR) -4, 5-diaethyl-4, 5, 5a, 6-tetrahydro-9, 10-dihydroxy-dibenz [cd, f] indole.

5. The (4S, 5aR) -4,5,5a, 6-tetrahydro-9,10-dihydroxy-4,5-di-n-propyl-dibenz [cd, f] indole.

6. A compound according to claims 1 to 5, in the form of free bases or in the form of acid addition salts.

7. A pharmaceutical composition containing compounds according to claims 1 to 5 in the form of the free bases or in the form of pharmaceutically acceptable acid addition salts together with pharmaceutical carriers or diluents.

8. A process for the preparation of compounds of formula I according to claim 1, characterized in that either a) to compounds of formula Ia

arrives, wherein R ₁ and R ₂ are defined in claim 1 by in the compounds of formula II

wherein R ₁ and R _{2 are} as defined in claim 1, and Z represents a cleavable ether group which cleaves ether groups Z, or b) to give compounds of the formula Ib

arrives, wherein R ₁ e R _{2 are} as defined in claim 1, and the radicals R ' _{3 are} identical and each represent acyloxy groups by acylating compounds of the formula Ia.