NL8103041A - HETEROCYCLIC COMPOUNDS, THEIR PREPARATIONS AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM. - Google Patents

Description

1 9- = y ~

Heterocyclic compounds, their preparation and pharmaceutical preparations containing them.

The present invention relates to phenanthrene derivatives, their preparation and pharmaceutical preparations containing them.

Belgian patent 877169 describes a class of 4.5. 5a, 6-tetrahydro-dibenz / cd, f7 indole derivatives with stimulatory effect on central dopaminergic receptors. All specially exemplified compounds having alkyl groups in positions 4 and 5 contain as one alkyl group and methyl group. It has now surprisingly been found that a group (413?, 5aS *) - 4.5, 5a, 6-tetrahydro-dibenz / cd, f7 indole derivatives with ethyl and n-propyl groups at positions 4 and 5 over which nothing is written or suggested in said patent anywhere, have a particularly interesting pharmacological profile, including long duration of action and / or remarkable potency as central dopaminergic agents and good tolerability.

The invention relates to compounds of the formula I, wherein

Rj and Rg independently represent an ethyl or 20 n-propyl radical and the substituents Rj are the same and are hydroxyl or acyloxy radicals, in racemic form with the relative configuration 4 # t, 5aSu, or in optically active isomeric form with the absolute 25 configuration 4S, 5aR.

The acyloxy radicals can be good radicals with the formula 8103041 2

Ra - CO - O - where R 1 represents an alkyl radical, (C 1 - 2 cycloalkyl, a phenyl radical or a 5- or 6-membered heterocyclic ring.

When R 1 is an alkyl radical it may well contain 1 to 17 carbon atoms, preferably 1 to 7 carbon atoms and may have a straight or branched chain.

Ra may be a substituted alkyl radical, which may well contain from 1 to 5 carbon atoms in the alkyl chain.

Conveniently, it is a mono-substituted alkyl radical. The substituents may include, for example, carboxy, hydroxy, amino, (C 1-4) alkylamino, (C 1-4) alkoxy, di- (C 1-4) alkylamino, halogen, (C 1-4) alkylthio, phenoxy, a phenyl radical, 1-pyrrolidinyl , piperidino or morpholino and well be a phenyl radical. For example, R may also be an alkyl radical having from 1 to 4 carbon atoms in the alkyl chain and substituted with (C 1 -cycloalkyl).

When R is a phenyl radical or a phenyl radical substituted alkyl, the phenyl radical may be unsubstituted or contain 1,2 or 3 identical or different substituents, for example, halogen, trifluoromethyl, (C 1-4) alkyl, C 1 -C 12 ^) alkoxy, (C 1-4) alkylthio or di- (C 1) alkylamino or a methylenedioxy group. Preferably, the phenyl ring is mono- or di-substituted.

When R 4 is a phenyl radical substituted alkyl, R is preferably a benzyl radical. The phenyl ring sl 25 may, for example, carry systituents such as halogen, (C 1-4) alkyl, (C 1-4) alkoxy or (C 1-4) alkylthio.

When R is a heterocyclic ring, it may well be a heterocycle containing oxygen, nitrogen or sulfur as the only heteroatom, for example pyridine, thiophene or furan.

Preferably, (C 1-4) alkyl, (C 1-4) cycloalkyl, unsubstituted phenyl, phenyl which is mono or disubstituted with chlorine, fluoro, trifluoromethyl, (C 1-6) alkyl or (C 1-6) alkoxy, unsubstituted benzyl, or benzyl, which is mono- or disubstituted with chlorine, fluorine, (C.,) alkyl or (C.,) alkoxy.

35 81 03 0 41 '* *

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

In a group of compounds, R 1 is n-propyl and R 2 is ethyl. In another group of compounds, Rj and the same are 5 and represent ethyl or n-propyl. Preferred are the substituents

Rg in the compounds of the formula 1 is hydroxy. The preferred compounds are the (4S, 5aR) optical isomers.

The invention also relates to a process for preparing compounds of the formula I, wherein a) a compound of the formula Ia, in which R 1 and R 1 have the above meaning, is prepared by cleavage of the ether groups Z of a compound in Formula 2, wherein R 1 and R 2 have the above meanings and Z represents a cleavable ether group. racemic form with the relative configuration 4Rx, 5aSx or in optically active isomer form with the absolute configuration 4S, 5aR, or b) preparing a compound of the formula Ib, wherein R 1 and R 2 have the above meaning and the radicals R 1 are identical acyloxy radicals, by a compound of the formula la. to acylate racemic form with the relative configuration 4Rx, 5aSx or in optically active isomeric form with the absolute configuration 4S, 5aR. The ether cleavage according to process a) can be effected in a more usual manner for cleavage of ether groups. The reaction can be carried out, for example, by treating the starting materials with a strong mineral acid at a temperature of at least 100 ° C, preferably from 100 ° C to the boiling / reaction mixture, in particular at about 130 ° C, for example hydrobromic or hydroiodic acid. The ether group Z is preferably a methoxy radical,

The acylation of process b) can be carried out in a customary manner for the selective acylation of phenolic groups in the presence of an amine function. For example, as the acylating agent, one can use a functional derivative of an acid such as an acid chloride, acid bromide or the 8103041 acid anhydride. The reaction can be carried out well with an acid chloride in the presence of trifluoroacetic acid at temperatures of 20 ° C to the boiling point of the reaction mixture or in the presence of pyridine at a temperature of 0 ° C to room temperature.

The resulting compounds of formula 1 can be removed from the reaction mixture in a known manner and purified. The free base forms of compounds of the formula 1 can be converted into acid addition salt forms in the usual manner and vice versa. Suitable acids for salt formation are, for example, hydrochloric acid, tartaric acid, di-0,0-p-toluoyl-D- or L-tartaric acid, exibromic waters, tartaric acid.

! ranemic compounds of the formula I can be obtained from starting materials: racemic. Optically active isomers of the formula 1 can be obtained from optically active precursors of the configuration (4S, 5aR) or from the racemate. The 4S, 5aRoenantiomer can be obtained from the racemate in known ways, for example by fractional crystallization of diastereoisomeric salts, for example their salts with (+) - di-0,0-p-toluoyl-D-tartaric acid 20 or (-) - di- 0.0-p-toluoyl-L-tartaric acid. Racemic cleavage in the optically active isomers is preferably performed at an earlier stage of the synthesis, for example for cleavage of the ether groups.

The starting materials of the formula II can be prepared by reduction of compounds of the formula 3, wherein R 1, R 2 and R 2 have the above meanings.

The reduction can be carried out well under acidic conditions suitable for the acid reduction of enamines or imines, for example with zinc in an aqueous inorganic acid, preferably hydrochloric acid, useful in the presence of a mercury (II) salt, for example mercury (XI) )chloride.

The reaction can be carried out well in, for example, ethanol and at temperatures from 50 ° C to the boiling point of the reaction mixture.

For example, starting materials of the formula III can be prepared according to the attached reaction scheme A.

81 03 0 4 1 'i5

In this reaction scheme, the radicals Rj, Rl and Z have the above meanings and Rl is methyl or ethyl. The reactions can be carried out in the usual manner and the products of the above reactions can be recovered and purified in known manner.

In the above intermediates, the ether groups Z may be good methoxy.

Insofar as the preparation of a particular starting material is not specifically described, it can be done in a more conventional manner. For example, phenanthrene derivatives, which are starting materials of the formula II, described in Else FourTs Encyclopaedia of Organic Chemistry, Vol. 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 I

a) 9- (N-ethyl-N-butyryl-amino) -3-bromo-3,4-dimethoxyphenanthrene / compound of the formula IV /.

A solution of 50 g or 138 {nmo * 1 ^ 9-ethylamino-8-bromo-3,4-dimethoxy-phenanthrene in 57.5 ml or SSS ^ -ethyl-diisopropylamine and 420 ml of methylene chloride is added dropwise with stirring a nitrogen atmosphere over a period of 25 minutes was added to a solution of 28.8 ml or 276 mmol of butyryl chloride in 420 ml of methylene chloride. During the addition, the reaction mixture is kept by cooling in a water bath at room temperature. The resulting yellow-red solution is then worked up in a known manner to give 9- (N-30 ethyl-N-butyrylamino) -8-br <Sn-3,4-dimethoxyphenanthrene, mp 102-104 ° C.

b) (4RS) -5-ethyl-4,5-dihydro-4-hydroxy-9,10-di-methoxy-4-n-propyl-dibenz / cd, indole / compound of the formula III /.

35 8103041 0% 6 mmol 25 g or 58.14 - .. /. 9- (N-ethyl-N-butyryl-.zf 1 amino) -8-broo-3,4-dimethoxyphenanthrene is dissolved with stirring in 450 ml anhydrous tetrahydrofuran and the resulting solution is cooled with a bath of methylene chloride and dry ice. to -25 °. Thereafter, 37 ml or mmole of 116.28 µl of a 1.7 molar solution of t-butyl lithium in pentane is added dropwise over 4 minutes. The temperature of the reaction mixture is then allowed to rise to + 5 ° over a period of 30 minutes, the reaction mixture is poured on 500 ml of a mixture of water and ice, extracted three times with 500 ml of methylene chloride each, wash the organic phases with water and dries and evaporates.

After the product is dried in high vacuum, (4 RS) -5-ethyl 1-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-n-propyl-dibenz / cd, f / indole is obtained in in the form of a yellow-green foam.

15 c) (-) - (4R * 5aS *) - 5-ethyl-4,5,5a, 6 -______ tetrahydro-9,10-dimethoxy-4-n-propyl-dibenz / cd, f / indole / compound with the formula 27 · “mmol

A suspension of 40.6 g or 116-y (4RS) -5-ethyl-4,5-dihydro-4-hydroxy-9,1O-dimethoxy-4-n-propyl-dibenz 20 / cd, findol in 1060 ml of ethanol are added with stirring to - - mmol a suspension of 140 g of zinc rod and 31.6 g of 116 ψΐ Tewik (II) chloride in 1060 ml of distilled water (optionally the zinc dust / mercury chloride can be added to the dibenzindole). The reaction mixture is heated to a reflux condenser, 360 ml of 18% hydrochloric acid is added dropwise over a period of 15-20 minutes and the mixture is heated under reflux overnight with stirring. The reaction mixture is cooled to room temperature and filtered and the zinc amalgam is washed with 500 ml of methylene chloride. The filtrate is made alkaline with 30 liters of concentrated NH 2 OH and the alkaline phase is extracted once with 1 liter of methylene chloride and twice with 500 ml of methylene chloride each time. The combined organic phases are washed with water, dried and evaporated. The resulting oil is chromatographed on silica gel using methylene chloride with 2% methanol as an eluent to give (-) - (4RX, 5aSX) -5-ethyl-4,5,5a, 6-tetrahydro- 9,10-dimethoxy-4-n-propyl-dibenz / cd, findol in the form of an oil.

Example II

The (4RS) -5-ethyl-4,5-dihydro-4-hydroxy-9,1O-dimethoxy-4-n-propyldibenz / cd, findol obtained in Example Ib) can also be prepared as follows: 9-amino-3,4-dimethoxy-phenanthrene / compound 10 of the formula 107

A mixture of 430 ml or 3.08 moles of trifluoroacetic anhydride and 430 ml or 5.62 moles of trifluoroacetic acid is added at room temperature under a nitrogen atmosphere to 53.6 g (0.19 mole) of 3,4-dimethoxyphenanthrene-9-carboxylic acid and the mixture is stirred for 10 min. After the mixture has cooled to -5 °, 15.2 g or 0.234 mole of sodium azide in solid form is carefully added and the mixture is stirred at 2 ° for three hours, poured on ice and the resulting suspension is worked up in a known manner to give 9 -amino-3,4-dimethoxyphenanthrene as a solid. The hydrochloride melts above 215 ° with decomposition.

m b) 9-Acetylamino-3,4-dimethoxyphenanthrene / compound of the formula 97.

55 ml or 0.319 mol of N-ethyl diisopropylamine is added to a solution of 38.2 g or 0.151 mol of 9-amino-3,4-dimethoxyphenanthrene in 200 ml of methylene chloride. A solution of 20.8 ml or 0.292 mol of acetyl chloride in 250 ml of methylene chloride is added dropwise over 20 minutes to the resulting mixture. During the addition, the temperature of the reaction mixture is kept at 20 ° by cooling with an ice bath. The reaction mixture is stirred at room temperature for 14 hours and worked up in a known manner to obtain 9-acetylamino-3,4-dimethoxyphenanthrene, mp 190-19 * 5 °. .. recrystallization from ether.

c) 9-Ethylamino-3,4-dimethoxyphenanthrene / compound 35 8103041

f V

8 with the formula 87.

34 g or 0.124 mol of 9-acetylamino-3,4-dimethoxyphenanthrene in suspension in 450 ml anhydrous tetrahydrofuran is reduced with 500 ml or 0.5 mol molar solution of diborane in anhydrous tetrahydrofuran and worked up in known manner to 9-ethylamino 3,4-dimethoxyphenanthrene, mp 94-95 °.

d) 4,5-dihydro-9,10-dimethoxy-5-ethyl-4-oxo-dibenz / cd, findol / compound of the formula 67.

122 ml or 0.2 mol 15% solution of 10 n-butyl lithium in hexane is added at 0 ° under a nitrogen atmosphere to a solution of 28.1 g or 0.1 mol 9-ethyl-amino-3, 4-dimethoxyphenanthrene in 300 ml anhydrous tetrahydrofuran; the reaction mixture turns bright red. Dry ice is then added until the color disappears: the formation of a solution of yellow-green fluorelenbie is observed. After the temperature of the reaction mixture is allowed to come to room temperature, the reaction mixture is poured onto water / ice, extracted three times with methylene chloride and the organic phase dried over sodium sulfate and evaporated. There is thus obtained 4,5-dihydro-20, 9,10-dimethoxy-5-ethyl-4-oxo-dibenz / cd, 7-indole, which melts at 125 DEG-126 DEG (with decomposition) after recrystallization from ether / petroleum ether.

e) (4RS) -5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-n-pronyl-dibenz / cd, findole / compound of formula 37. " ** mmol> 2.1 ml or 33% solution of n-propyl magnesium bromide in ether is added dropwise at room temperature> mmol to a solution of 10 g or 33 µl / 4,5-dihydro-9,10-dimethoxy- 5-ethyl-4-oxo-dibenz / ole, 7indole in 300 ml of anhydrous tetrahydrofuran. After 30 minutes, an ammonium chloride solution is added, the mixture extracted with methylene chloride and the organic phase dried and evaporated to yield (4RS) -5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4 -n-propy1-dibenz / cd, f7indole in the form of a yellow-green, foam.

81 03 0 4 1

V Λ V

9 / Spectrum (CE ^ Cl ^) - 3540 cm * (OH) /. The crude product is used directly for the next step.

Example III

5 (-) - (4Rx, 5aS *) - 5-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-4-n-propyl-dibenz / cd, findole.

20 g or 27.66 mm (-) - (4RX, 5aSx) -5-ethyl-4,5,5a, 6-tetrahydro-9, 10-dimethoxy-4-n-propyl-dibenz / cd, f7indole in 200 ml of 47% aqueous hydrochloric acid solution is heated at reflux temperature for 6 hours at 150 ° C. After evaporation of the reaction mixture to dryness, the crystalline residue is stirred in acetone and filtered under suction. The precipitate is washed with acetone and then with water and dried under high vacuum. There is thus obtained (-) - (4R, 5aS) -5 - * - ethyl-4,5-5a, 6-tetrahydro-9,10-dihydroxy-4-n-propyl-dibenz / cd, findol hydrobromide, which is Melts at 200 ° with decomposition.

The following compounds can be prepared analogously from the corresponding starting materials: a) (-) ~ (4RX, 5aSX) -4,5-diethy1-4,5,5a, 6-tetrahydro-9,10 dihydroxy-dibenz / cd , f7 indole (hydrobromide, mp> 175 ° with decomposition; h) (-) - (4RX, 5aSX) -4.5,5a, 6-tetrahydro-9,1O-dihydroxy-4,5-di-n-propyl-dibenz / cd, f / indole (hydrobromide, 2 ^ mp> 190 ° with decomposition c) (-) - 4RX, 5aS *) 4-ethyl-4,5,5a, 6-tetra-hydro-9,10-dihydroxy- 5-n-propyl-dibenz / cd, f7indole.

Example IV: (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10 -____ a) (-) - (4S, 5aR) -5-ethyl-1-4, 5,5a, 6-tetrahydro-9,10-dimethoxy-4-n-propyl-dibenz / cd.f7indole.

mmol 35 30 g or 89: / ^ (-) - (4RX, 5aSX) -5-ethyl-4,5,5a, 6-8103041 ψ 10 tetrahydro-9,10-dimethoxy-4-n-propyl-dibenz / cd, f7-indole is dissolved in 300 ml of ether and a solution of 35.95 g of (-) - di-0.0, p-toluyol-L-tartaric acid monohydrate in 300 ml of ether is added with stirring. The mixture is stirred for an additional hour at room temperature, during which time a total of 1 liter of ether is added. The resulting precipitate is filtered off under suction, washed with ethyl acetate until light yellow and dried.

61.88 g of crystals obtained from the first crystallization are dissolved in 1 liter of acetone and 300 ml of methanol under reflux, and the solution is filtered and concentrated until most of the product crystallizes out. The mixture is stirred for about 5 minutes and the product is filtered off under suction, washed with ethyl acetate until it remains colorless and dried.

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

The resulting crystals are recrystallized in the same manner "using 1.2 liters of acetone and 60 ml of methanol. This gives (-) - (4S, 5aR) -5-ethyl-4,5-5a, 6-tetrahydro- 9.10-dimethoxy-4-n-propyl-dibenz / cd, f7indole (-) - di-0,0-p-toluoyl-L-tartrate in the form of colorless crystals, melting at 178-179 °, / α / =138 ° C (0.29 in methanol).

The following compounds can be prepared analogously from the corresponding starting materials: - (-) - (4S, 5aR) -4,5-diethy1-4,5,5a, 6-tetrahydro-9,10-dimethoxy -dibenz / cd, f7indole (-) - di-0,0-p-toluoyl-L-30 tartrate, mp 187-189 ° / a7 = -138 ° (c = 0.5 in methanol); The basic starting material is reacted with (+) - di-0,0-p-toluoyl-D-tartaric acid instead of the L-isomer and the mother liquor obtained by crystallization is treated with NH 2 OH to liberate the base. The base is reacted with (-) - di-0,0-p-toluoyl-L-35 tartaric acid and the crystals obtained from an ether solution.

81 03 0 41 4 ί% π - (-) - (4S, 5aR) -4,5,5a, 6-tetrahydro-9,1O-dimethoxy-4,5-di-n-propyl-dibenz / cd, f / indole (-) -di-0,0-p-ΛΛ toluoyl-L-tartrate, mp 165-166 ° / a? D = -123 ° (c = 0.27 in methanol).

B) (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-4-n-propyl-dibenz / cd, findole.

Acting as described in example III, (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-4-n-propy1-dibenz / cd, f7indole is obtained hydrobromide from the tartrate obtained from top a). It melts above 210 ° C / pp 7 = 64 ° (c * 0.245 in methanol).

The corresponding hydrochloride melts above 185 ° with decomposition, α7p * 75 ° (c = 0.28 in methanol).

15

Example V

The following compounds can be prepared analogously as described in Example Vb) from the corresponding starting materials: • ^ a) (-) - (4S, 5aR) -4,5-diethyl-4,5,5a, 6-tetrahydro- 9,10-dihydroxy-dibenz / cd, f7indole hydrochloride, ΛΛ mp 200 ° with decomposition / 77ρ = -72 (c * 0.25 in methanol), b) (-) - (4S, 5aR) -4.5 .5a, 6-tetrahydro-9, 10-dihydroxy-4,5-di-n-propyl-dibenz / cd, f7 indole hydrochloride, mp> 187 ° decomposition / ^7 ^ e -58.5 ° (c = 0.35 in methanol).

c) (-) - (4S, 5aR) -4-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-5-n-propyl-dibenz / cd, f7indole. Hydrochloride mp 198- 200 ° C with decomposition / 27.66 ° C (c = 0.5 in methanol).

Example VI: (+) - (4S, 5aR) -5-ethyl-9,10-dibenzoyloxy 4,5,5a, 6-30-tetrahydro-4-n-propyl-dibenz / cd, f / indole.

mmol.

0.376 ml or 3.23 '' benzoyl chloride is added dropwise with stirring over 5 minutes and at a temperature of + 5 ° to a solution of 600 mg or mmol 1.54 / - (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-35-4-n-propyl-dibenz / cd, f / indole hydrobromide in 5 ml anhydrous 8103041> 12 pyridine and the reaction mixture is stirred for an additional 14 hours at room temperature The mixture is then evaporated to dryness, the residue is dissolved in methylene chloride and the solution is first washed with a mixture of ice and a saturated potassium bicarbonate solution and then with water The aqueous phase is extracted twice with methylene chloride and the combined organic phase are dried and evaporated. The residue is dissolved in methylene chloride and the solution is evaporated under high vacuum. The procedure of dissolving the residue in methylene chloride and evaporation is repeated two more times. 550 mg of the resulting product is dissolved in acetone and the This solution is added dropwise to 156 mg of L (+) tartaric acid in acetone. The resulting precipitate is filtered and dried to (+) - (4S, 5aR) -5-ethyl-9,10-dibenzoyloxy-4,5,5a, 6-15 tetrahydro-4-n-propyl-dibenz / cd, f7 indole L (+) tartrate, it melts at 161-162 ° after recrystallization from ethyl acetate / ether, / q / = + 23.5 ° (c = 0.28 in methanol).

The following compounds can be prepared analogously from the corresponding starting materials: 20 - (-) - (4S, 5aR) -9, J0-diacetoxy-5-ethyl-4,5,5a, 6-tetrahydro-4-n-propy1-dibenz / cd, f7indole hydrochloride, mp> 188 ° decomposition; / a7 ^ ~ ”99 ° (c = 0.28 in methanol), - (-) - (4S, 5aR) -5-ethyl-4,5,5a, tetra-hydro-4-n-propyl-9, 10-dipropionyloxy-dibenz / cd, f7indole hydrochloride, mp> 175 ° under decomposition, / a7 ^ = ~ 76 ° (c> 0.25 in methanol) - (-) - (4S, 5aR) -9, 10-dibutyryloxy-5-ethyl-4,5,5a, 6-tetrahydro-4-n-propyl-dibenz / cd, f7 indole hydrochloride, mp> 105 ° decomposition / "/ ^" "- 77 ° (c- 0.28 in methanol 30 - (-) - (4S, 5aR) -5-ethyl-1, 4,5,5a, 6-tetrahydro-9,10-diisobutyryloxy-4-n-propyl-dibenz / cd, 7indole hydrochloride, mp> 165 ° with decomposition / α / = = -96 ° (c = 0.29 in methanol).

8103041 13 - (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-4-n-propyl-9,1O-divaleryloxy-dibenz / cd, f7 indole hydrochloride; - (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6, tetrahydro-4-n-propyl-9,10-dipivaloyoxy-dibenz / cd, phenol hydrochloride; - (-) - (4S, 5aE) -4,5,5a, 6-tetr ^ 4r ^ lOT.de 9,10-dipropionyloxy-4,5-di-n-propyl-dihenz / cd, f7indole / mp 115 / / Α7] ^ -67 ° (c = 0.51 L in methanol).

10 In an analogous manner with example VI

the following compounds can be prepared of the formula 1, wherein R 1 and R 2 are each independently ethyl or n-propyl and are: - acetoxy 15 “propionyloxy - butyryloxy - isobutyryloxy - valeryloxy - pivaloyloxy 20

The compounds of the formula I have pharmacological action. In particular, the compounds are indicated for use as a central dopaminergic stimulant, as evidenced by the following state tests: The dopaminergic activity of compounds of formula 1 was tested on the rat using the method described by U. Ungerstedt in Acta Physiol . Scand., Suppl. 367, 69-93 (1971)). 6-Hydroxydopamine is injected unilaterally into the substantia, generating unilatral degeneration of nigrostriatal pathways after one week. Administration from about 0.03 to about 1 mg / kg i.p. of the compounds of the formula I in these rats leads to a remarkably long-term spinning drag counter-lateral to the injury.

The central dopaminergic effect of compound 81 03 0 4 1

V

14 things with formula 1 have also been confirmed with the following test:

Rats weighing 180-222 g are placed in 30 cm centerline press pex cylinders on a wire mesh bottom. After the rats are allowed to acclimatize in the cage for 30 minutes, they are injected with the compound to be tested.

The behavior of the rats is observed for 2 minutes at 30 minute intervals for 2 hours and then at 60 minute intervals to 6 hours total. The degree of observed stereotype behavior is determined using a rating system based on that described by Costall, Naylor and Olley / Euro J. Pharmac. 18, 83-94 (1972 ?.

The ratings and criteria are as follows: 15 1 »Interrupted sniffing 2. Continuous sniffing,

Licking from time to time.

3. Licking, biting from time to time.

4. Intensive and persistent biting.

20 Administered i.p. from about 0.03 to about 30 mg / kg body weight, the compounds of formula 1 elicit stereotypical sniffing, licking and biting behavior in the rat.

The compounds are therefore indicated for use as a central dopaminergic stimulant, for example, for the treatment of Morbus Parkinson. For this indication, an indicated daily dose is about 0.1 to about 20 mg, which may well be administered 2 to 4 times daily in divided doses in dosages containing from about 0.025 to about 10 mg or in a sustained release form.

The compounds of the invention additionally exhibit an antidepressant activity, as evidenced by the inhibition of reserpine-induced catalepsy in the subcutaneous administration of from about 0.001 mg to about 1 mg / kg of the compounds and by the inhibition of the tetrabenazine. 81 030 41 15 induced catalepsy in rats upon intraperitoneal administration of about 0.2 to about 2 mg / kg of the compounds.

The compounds are therefore indicated for use as an antidepressant.

An indicated daily dose is in the range of about 0.05 to about 2 mg, which may well be administered 2 to 4 times daily in divided doses in a dosage unit containing about 0.01 mg to about 1 mg of the compounds, mixed with a solid or liquid pharmaceutical carrier or diluent.

The compounds of formula 1 additionally exhibit prolactin secretion inhibition, as evidenced by the decrease in serum levels of prolactin in the rat after subcutaneous administration from about 0.1 to about 1 mg / kg of the compounds using radioimmunologic methods, described, for example, by Niswender, GD et al.,

Biol. & Med. 130 793 (1969) and Neil, J.J. et al., Endocrinology 88, 548 (1971).

The compounds of formula 1 are therefore indicated for use as prolactin inhibitors, for example in the treatment of conditions in which hyperprolactinemia occurs, for example menstrual dysfunction, eg ammerrhoea and galactorrhoea, or hypertension of breast carcinoma, accompanied by elevated serum prolactin levels, or The treatment of conditions involving hypogonadism, for example, infertility or impotence, or in the regulation of postpartem lactation.

An indicated daily dose is in the range of about 5 to 50 mg, which may well be administered in divided doses 2 to 4 times 30 daily in dosage units containing about 1.25 mg to about 25 mg of the compounds mixed with a solid or liquid pharmaceutical carrier or diluent.

The compounds of the invention further exhibit antipsychotic activity as evidenced by the inhibition of mouse locomotion when administered sucutaneously from about 0.001 mg to about 0.1 mg / kg of the compounds and by the dopamine agonistic action on the presynaptic receptors. In the rat: at doses from about 1 mg to about 10 mg / kg of the compounds of the following experiment.

The dopamine agonistic activity of the compounds of formula 1 on the presynaptic receptors was examined in the rat using the in vivo-10 method described by J.R. Walters and coll. in Naunyn Schmiede Mountain's Arch. Pharmacol. 296, 5-14 (1976). The dopaminergic impulse current was pharmacologically inhibited with γ-butyrolactone. The activity of the aromatic amino acid decarboxylase was inhibited by hydroxybenzylhydrazine (NSD 1015) and the rats were sacrificed half an hour and a half later # The resulting 30 min accumulation of D0PA in striatal tissue was taken as a measure of the in vivo activity of tyrosine hydroxylase . Oral administration of the compounds reverted the effects of γ-butyrolactone in a dose-dependent manner.

The compounds of the formula I are therefore indicated for use as antipsychotic agents, for example for the treatment of schizophrenia. * An indicated daily dose is in the range of about 0.01 to about 1 mg, which is taken well 2 to 4 times a day. the dosage dose may be administered in dosage units containing from about 0.0025 mg to about 0.5 mg of the compounds mixed with a solid or liquid pharmaceutical carrier or diluent.

The preferred indication is the anti-parkinson indication.

The compounds (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-4-n-propy1-dibenz / cd, f / indole, (4S, 5aR) - 4 -ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-5-n-propyl-9,10-dihydroxy-dibenz / cd, f7indole, (4S, 5aR) -4,5-diethy 1-4,5,5a, 6-tetrahydro-9,10-dihydroxy-dibenz / cd, f7indole and (4S, 5aR) -4,5,5a, 6-tetrahydro-9,10-dihydroxy-4, 5-di-n-propyl-dibenz / cd, f7indole and the corresponding 8103041 * J.

Preferred di-n-propionyl and di-isobutyryl ester derivatives are the preferred compounds.

The compounds of formula 1 can be administered in the form of a pharmaceutically acceptable acid addition salt. These salt forms exhibit the same order of action as the free base forms.

The invention also relates to a pharmaceutical composition containing a compound of the formula 1 in free base form or in pharmaceutically acceptable acid addition salt form, optionally in combination with a pharmaceutically acceptable diluent or carrier.

These preparations can be prepared in the usual way, for example as a solution, capsule or tablet.

15 8103041

Claims (19)

1. A method of preparing a compound of formula 1, wherein Rj and R2 independently represent an ethyl or n-propyl radical and the substituents Rj are the same and represent hydroxy or acyloxy radicals, in racemic form with the relative configuration 4R, 5aS, or in optically active isomer form, the absolute configuration 4S, 5aR, characterized by the fact that 10 a) a compound of the formula la, in which R1 and R2 have the above meaning, is prepared by cleavage of the ether groups Z of a compound of formula 2, wherein R 1 and R 2 have the above meanings and Z represents a cleavable ether group, in racemic form with the relative configuration 4RX, 5aSx, or in optically active isomer form with the absolute configuration 4S , 5aR, or b) prepare a compound of the formula Ib, wherein R 1 and R 2 have the above meaning and the radicals R 1 are identical aceloxy radicals, by acylation of a compound with the formula 1a in: racemic form with the relative configuration 4R, 5aS or in optically active isomeric form with the absolute configuration 4S, 5aR. 2. A method of preparing a compound of the formula 1, defined as in claim 1, substantially as described above in connection with one of examples III-VI. 3, A compound of the formula 1 obtained according to the method of claim 1. 810303041 4. A compound of the formula 1 as defined in claim 1. Compound according to claim 5 4, characterized in that each R 1 represents hydroxyl. Compound according to claim 4, characterized in that each represents acyloxy. A compound according to claim 6, characterized in that each acyloxy radical has the formula R - CO - O - a, in which R 1 is an alkyl radical, (C 1 -y) cycloalkyl, a phenyl radical or a 5- or 6-membered heterocyclic ring. 15 A compound according to claim 7, characterized in that R_C00 represents propionyloxy. "1 1" * 3. 9. A compound according to claim 7, characterized in that R @ represents C00-isobutyryloxy. Compound according to any one of claims 4 to 9, characterized in that R 1 and R 1 are each ethyl. Compound according to any one of claims 4 to 9, characterized in that R 1 and R 2 are each n-propyl. Compound according to any one of claims 4 to 9, characterized in that R 1 is ethyl and R 1 is propyl. 30 Compound according to any one of claims 4 to 9, characterized in that R 1 is n-propyl and R 2 is ethyl. Compound according to any one of claims 81 03 0 41 4 to 13, characterized in that it is in racemic form X X with the relative configuration 4R, 5aS. Compound according to any one of claims 5 to 13, characterized in that it is in optically active isomer form with the absolute configuration 4S, 5aR. 16. (i) - (4RX, 5aSx) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-4-n-propyl-dibenz / cd, f / indole. 17. (-) - (4RX, 5aSx) -4,5-diethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-dibenz / cd, findol. 18. (-) - (4RX, 5aSx) -4,5,5a, 6-tetrahydro-9,10-dihydroxy-4,5-di-n-propyl-dibenzZcd, 7indole. 19. (-) - (4RX, 5aSx) -4-ethyl-4,5,5a, 6-tetrahydro-9,1Q-dihydroxy-5-n-propyl-dibenz / cd, findole. 20. (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10, dihydroxy-4-n-propyl-dibenz / cd, findol. 21. (4S, 5aR) -4-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-5-n-propyl-dibenz / cd, findol. 22. (4S, 5aR) -4,5-diethyl-4,5-5a, 6-tetrahydro-9,1O-dihydroxy-dibenz / cd, findol. 23. (4S, 5aR) -4,5,5a, 6 'tetrahydro-9,10-30 dihydroxy-4,5-di-n-propy1-dibenz / cd, findol. 24. (4S, 5aR) -5-ethyl-9,10-dibenzoyloxy-4,5,5a, 6-tetrahydro-4-n-propyl-dibenz / cd, findol. 35 81 03 0 4 1 * 9 25. (4S, 5aR) -9,10-diacetoxy-5-ethyl-4,5,5a, 6-tetrahydro-4- * n-propyl-dibenz / cd, f / indole. 26. (4S, 5aR) -5-ethyl, 4,5,5a, 6, tetra-hydro-4-n-propyl-9,1O-dipropionyloxy-dibenz / cd, findol. 27. (4S, 5aR) -9,10-dibutyryloxy-5-ethyl-4,5,5a, 6-tetrahydro-4-n-propyl-dibenz / cd, findol. 28. (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-diisobutylryloxy-4-n-propyl-dibenz / cd, findole. 29. (4S, 5aR) -4,5,5a, 6-tetrahydro-9,10-dipropionylaxy-4,5-di-n-propyl-dibenz / cd / indole. 15 A compound according to any one of claims 4 to 29, characterized in that it is in free base form. 31. A compound according to any one of the preceding claims 4 to 29, characterized in that it is in the form of an acid addition salt. 32. Pharmaceutical formulation; characterized in that it contains a compound according to any one of claims 25 to 29 in free base form or in the form of a pharmaceutically acceptable acid addition salt, optionally combined with a pharmaceutical carrier or diluent. 8103041 R »^ί ^ Ύ oh Λ VSrrr“ fVrY '-N — R * -N-R *. 1 la R * Y ^ r'τΎ '*' zY; i ^ / ^ rVR '-N — R, -N — R £ 1b 2 -N - Rj. 3 i i SflHDOZ AG, in Basel Switzerland 81 0 3 0 4 1 -m fc. .OH TYTYri 3 / yRi “Mg Br or \ Rt-Ü 2 \ z ϊΠ z'y ^^ r ^ ° 6 ICjL ^ l Βι- ^ WJ ^ J —- n-r2 Ri fcot Hal-CO-Rj 'zyVi Br ^ ÓCl Li 7 ^^^ 'nH-r4 *. Ί1-1- '- t Ri In-butyl lithium «juOuu 8 y NH-R» [Diborane Z g NH-CO-R, 1 Ri-CO-Hal Z. 1 f) NaN,, f jf ^) ^ ILj - * "iY] ^ ® COOH 11 81 03 0 41 SANDOZ 'AG. In Basel, Switzerland