FI75153C - PHARMACOLOGICAL ACTIVITIES FOR FARMING AGAINST PHARMACOLOGICAL ACTIVITIES (4R *, 5AS *) - 4,5,5A, 6-TETRAHYDRO-DIBENS / CD, F / INDOLDERIVAT. - Google Patents

Description

! 75153

The present invention relates to a process for the preparation of new pharmacologically active (4R *, 5as *) - 4,5,5a, 6-tetrahydro-dibenz [cd, f] -indole derivatives. 5,5a, 6-Tetrahydro-dibenz [cd, f] -indole for the preparation of derivatives of formula 10 wherein R 1 is -N-R 2 wherein and R 2 are ethyl or n-propyl, and the R 1 substituent -t are the same groups, either hydroxy groups or acyloxy groups of the formula R-O-O-, in which R is phenyl or alkyl having 1 to 4 carbon atoms, which compounds are in racemic form, the relative configuration being 4R *, 5aS *, or in the form of an optically active isomer having an absolute configuration of 4S, 5aR, and for the preparation of salts of these compounds.

BE Patent No. 877,169 discloses 4,5,5α, 6-tetrahydrodibenz, cd, f / indole derivatives which have a stimulating effect on central nervous system dopaminergic receptors. All the separately mentioned compounds having alkyl groups in the 4- and 5-positions contain a methyl group as one alkyl group.

It has now surprisingly been found that (4R *, 5aS *) - 4,5,5a, 6-tetrahydrodibenz [cd, f) indole derivatives having ethyl and / or n-propyl groups in the 4- and 5-positions are pharmacologically very interesting e.g. due to its long duration of action and / or significant efficacy as central nervous system dopaminergic agents and good tolerability.

2 75153

The process according to the invention for the preparation of the compounds of the formula I is characterized in that a) a compound of the formula 5 is prepared

0H

h °

ίο | I I

-n-r2 wherein and R2 are as defined above, by cleavage of the ether groups Z from a compound of formula “v JL .XjL.

YVVv -n-r2 wherein R1 and R2 are as defined above, and Z is a cleavable ether group, and each compound is in racemic form with a relative configuration of 4R *, 5aS *, or is in the form of an optically active isomer, wherein absolute the configuration is 4S, 5aR, or b) preparing a compound of formula

r, 3 | ^ N

35 R '-N'R2

II

3,75153 wherein and have the same meaning as above, and the groups R 'are the same acyloxy groups of the above formula R -C 0-O- by acylation of a compound of formula Ia in racemic form with a relative configuration of 4R * , 5aS *, or is in the form of an optically active isomer, the absolute configuration being 4S, 5aR, and, if necessary, isolating the compound of formula I in the form of the free base or salt.

The cleavage of the ether according to a) can be carried out in the usual manner. The reaction can be carried out, for example, by treating the starting material with a strong acid, such as hydrobromic acid or hydroiodic acid, at a temperature of at least 100 ° C, preferably 100 ° C, and especially at about 130 ° C. The ether group Z is preferably methoxy.

The acylation according to b) can be carried out in the usual manner, in which case, for example, acid chloride, acid bromide or acid anhydride can be used as the acylating agent. The reaction is preferably carried out by reacting the acid chloride 20 in the presence of trifluoroacetic acid at 20 ° C to the boiling point of the reaction mixture, or in the presence of pyridine at 0 ° C to room temperature.

The compounds of formula I formed can be isolated from the reaction mixture and purified in a known manner.

The free base forms of the compounds of formula I may be converted into an acid addition salt in the usual manner and vice versa. Suitable salt-forming acids are, for example, hydrochloric acid, tartaric acid, di-O-O-p-toluoyl-D- or L-tartaric acid and hydrobromic acid.

Racemic compounds of formula I may be obtained from racemic starting materials. The optically active isomers of formula I can be obtained from optically active precursors having a configuration of 4S, 5aR, or a racemate. The 4S, 5aR enantiomer can be obtained from the racemate by known methods, e.g. by fractional crystallization of diastereoisomeric salts, e.g. salts of (+) - di-O-O-p-toluoyl-D-tartaric acid or (-) - di-OOp -toluoyl-L-tartaric acid 4 75153. The racemic separation into optically active isomers is preferably carried out at an early stage of the synthesis, e.g. before cleavage of the ether groups.

The starting materials of formula I can be prepared by reduction of compounds of formula z

Z I i OH

10 \ _R III

—N-r2 where and R2 have the same meaning as above.

The reduction is preferably carried out under acidic conditions suitable for the reduction of enamine and imines, in an acidic medium, e.g. zinc, in an aqueous solution of a mineral acid, preferably hydrochloric acid, preferably in the presence of a salt of mercury (II) such as mercury (II) chloride. The reaction is carried out, for example, in ethanol and at a temperature of 50 ° C - the boiling point of the reaction mixture.

The starting materials of formula III can be prepared e.g. according to the following reaction scheme.

Il 5 75153 z 1 ί 1 / oh (iii> I XR1 X ^ / 'X.jX N R2 f ^^^ R ^ MgBr tai -Li 4 Z ^ tert.-butyl- [II _ o / z. / K / k ^ A / u lithium / | (I [I (VI) —n'R2

Z ^ 1 //. “A

^ X ^ XjX ^ <IV) c ° 2

1 of XX

yV1 / ". I / (VII) f XXXXXj-Li

Hal-CO-R1 | R2

A

z / n-butyllithium

z Br Z

XXI 1VI Z ^ rX ^ M

I (VIII) NH-R2 ΐ I diborane

Z XX

^ XM

NH-CO-R 2

A

R1 2 ~ CO-Hal 2 XX) I li J 2 χχ

NaN3 z i I

ΐ T - * \ / XxXXX <x> xXXxx ΐ C00H k \ / 1

X ^ XX ^ NH

(xi) 6 75153

In the reaction scheme, R 1 and Z have the same meaning as above, and R 1 is methyl or ethyl. The reactions can be carried out in the usual manner, and the products obtained from the reactions can be isolated and purified in a conventional manner.

In the above intermediates, the ether group Z is preferably methoxy.

If the preparation of a particular starting material is not specifically described, it can be prepared in the usual manner. For example, phenanthrene derivatives of formula IX are described in Elsevier's Encyclopaedia of Organic Chemistry, Vol. 13, Tricyclic compounds, Elsevier Publishing Company Inc.,

New York (1946).

The compounds of formula I are pharmacologically effective. The compounds are particularly intended for use as dopaminergic stimulants of the central nervous system, as shown in the following standard experiments.

The dopaminergic activity of the compounds of formula I was studied in rats by the method described in U. Ungerstedt, Acta Physiol. Scand. Suppl. 367 (1971), ss.

20 69-93. Unilateral injection of 6-hydroxydopamine

Substatia to the nigra caused unilateral degeneration of the nigrostrial conduction pathways after a week. When these rats were administered about 0.03 to about 1 mg / kg of the compounds of formula I intraperitoneally, a clear and prolonged turning behavior was observed which was opposite to injury.

The following table shows the compound of Example 4b, (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-4-n-propyldibenz / cd, f7indole (Compound A), as well as with the compound of Example 14 of FI Application No. 30 79 1912, (-) - (4S, 5aR) -5-ethyl-4,5,5a-tetrahydro-9,1O-dihydroxy Results obtained with -4-methyldibenz-f-indole (Compound B).

7 75153

Dopaminergic activity of compound A according to the invention and known compound B:

Dose (mg / kg) Total number of rounds 5 ~

Compound A 0.3 2,434 ± 213

Compound B 1 683 1 345 10 These results show that the compound prepared according to the invention is about 10 times more active than the compound according to FI application No. 79 1912. In addition, the duration of action of the known compound is only 4 hours, while the duration of action of the new compound is more than 7 hours.

The dopaminergic activity of the compounds of formula I against the central nervous system was also confirmed by the following experiment.

Rats, weighing 180-220 g, were placed in Perspex cylinders with a diameter of 30 cm and a metal wire-20 mesh as a base. After acclimatization to the cage for 30 minutes, the rats were injected with the test compound. The behavior of the rats was monitored every 2 minutes for 30 minutes for 2 hours and then every 60 minutes for a total of 6 hours. The degree of coercive behavior observed was assessed using a scoring system 25 based on the method described by Costall, Naylor, and Olley (Euro J. Pharmac. 18 (1972), pp. 83-94).

The scoring and criteria were as follows: 1) Intermittent sniffing 2) Continuous sniffing, random licking 3) Licking, occasional biting 4) Intense and continuous biting

Upon intraperitoneal administration of about 0.03 to about 30 mg / kg body weight of the compounds of formula I, rats exhibited 35 forced sniffing, licking and chewing behaviors.

β 75153 Thus, the compounds are useful as central nervous system dopaminergic stimulants, e.g. in the treatment of Parkinson's disease. The daily dose indicated for this indication is about 0.1 to about 20 mg, suitably administered in divided doses of 5 to 4 times a day in a unit dose of about 0.025 to about 10 mg or in sustained release form.

In addition, the compounds of the invention are antidepressantly effective in inhibiting reserpine-induced catalepsy in mice by subcutaneous injection of about 0.001 to about 1 mg / kg of compounds, and in rats by intraperitoneal injection of tetrabenazine-induced catalepsy. 0.2 to about 2 mg / kg of compound.

Thus, the compounds are also useful as antidepressants. In this case, a suitable daily dose is about 0.05 to about 15 mg given in divided doses 2 to 4 times a day in a unit dose of about 0.01 to about 1 mg of the compounds in admixture with a solid or liquid pharmaceutical carrier or diluent.

In addition, the compounds of formula I have an inhibitory effect on prolactin secretion, which can be demonstrated by their ability to reduce the serum prolactin level in rats after subcutaneous injection of about 0.1 to about 1 mg / kg of the compound. The assay uses radioimmunoassay methods described by e.g. G. D. Niswender et al., Biol. & Med. 130 25 (1969), p. 793 and J. J. Neil et al., Endocrinology 88 (1971), p. 548.

Thus, the compounds of formula I are also suitable for use as prolactin inhibitors, e.g. in the treatment of conditions associated with proliferation of prolactin in the blood, such as menstrual disorders, e.g. involving underdeveloped gonads, e.g., infertility or impotence, 35 or in regulating postpartum milk secretion.

9 75153

A suitable daily dose is about 5 to about 50 mg administered in divided doses 2 to 4 times a day in a unit dose of about 1.25 to about 25 mg of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent.

In addition, the compounds of the invention are of antipsychotic value, as evidenced by their ability to inhibit motility in mice when injected subcutaneously from about 0.001 to about 0.1 mg / kg of compounds.

They also have agonistic dopamine activity at the presynaptic receptors of ro-10 tan at a dose of about 1 to about 10 mg / kg of compound according to the following experiment.

The agonistic effect of the compounds of formula I on dopamine receptors at presynaptic receptors was studied in rats by the in vivo method described by J. R. Walters 15 et al., Naunyn Schmiedeberg's Arch. Pharmacol. 296 (1976), ss. 5 - 14. Dopaminergic impulse current was pharmacologically inhibited by ‘Y’ -butyrolactone. Aromatic amino acid decarboxylase activity was inhibited by hydroxybenzylhydrazine (NSD 1015) and 1/2 hour later the rats were sacrificed. The resulting accumulation of dopam over 30 minutes in banded tissue was considered a measure of tyrosine hydroxylase activity in vivo. Oral administration of the compounds reversed the effects of Y'-butyrolactone in a dose-dependent manner.

The compounds of formula I are useful as antipsychotic agents, e.g. in the treatment of schizophrenia. A suitable daily dose is about 0.01 to about 1 mg given in divided doses 2-4 times a day in a unit dose of about 0.0025. 0.5 mg of the compounds in admixture with a solid or liquid pharmaceutical carrier or diluent.

The recommended indication is the antiparkinsonian indication.

Particularly preferred compounds are: (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-4-n-propylbenzene [cd, f] indole, 35 ( 4S, 5aR) -4-ethyl-4,5,5a, 6-tetrahydro-9,1O-dihydroxy-5-n-propyl-9,10-dihydroxydibenz [cd, f] indole, 10,751,5 3 (4S, 5aR) -4,5-Diethyl-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-prop-yldibenz [cd, f] indole, 5 and their corresponding di-n-propionyl and diisobutyryl ester derivatives.

The compounds of formula I may be administered in the form of a pharmaceutically acceptable acid addition salt. These salt forms are as effective as the free base forms.

The present invention also provides a pharmaceutical composition comprising a compound of formula I in the form of a free base or a pharmaceutically acceptable acid addition salt, and a pharmaceutically acceptable carrier or diluent.

These compositions may be formulated in a conventional manner, for example, into solutions, capsules or tablets.

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

Example 1 a) 9- (N-ethyl-N-butyrylamino) -3-bromo-3,4-dimethoxyphenanthrene (compound of formula IV)

A solution of 50 g (138 mmol) of 9-ethylamino-8-bromo-3,4-dimethoxyphenanthrene in 57.5 ml (333 mmol) of N-ethyldiisopropylamine and 420 ml of methylene chloride was added dropwise with stirring. under nitrogen for 20 minutes to a solution of 28.8 mL (276 mmol) of butyryl chloride in 420 mL of methylene chloride. During the addition, the reaction mixture was kept at room temperature by cooling in a water bath. The resulting yellow-reddish solution 30 was further treated in a known manner to give 9- (N-ethyl-N-butyrylamino) -8-bromo-3,4-dimethoxyphenanthrene, m.p. 102-104 ° C.

II 11 75153 b) (4RS) -5-Ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-n-propyldibenz / cd, N-indole (compound of formula III)

25 g (58.14 mmol) of 9- (N-ethyl-5'-N-butyrylamino) -8-bromo-3,4-dimethoxyphenanthrene were dissolved in 450 ml of anhydrous tetrahydrofuran with stirring, and the resulting solution was cooled to -25 ° C. in a bath containing methylene chloride and carbon ice. 73 ml (116.28 mmol) of a 1.7-m-pentane solution of tert-butyllithium were then added dropwise over 4 minutes. The temperature of the reaction mixture was then allowed to rise to + 5 ° C over 30 minutes, the reaction mixture was poured into 500 ml of a mixture of water and ice and extracted with 3 x 500 ml of methylene chloride. The organic phases were washed with water, dried and evaporated. After drying the product, (4RS) -5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-n-propyldibenz <{cd, f, 7indole was obtained as a yellow-green foam.

c) (1) - (4R *, 5aS *) - 5-ethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxy-4-n-propyldibenz / cd, f7indole 20 (compound of formula II)

Suspension of 40.6 g (116 mmol) of (4RS) -5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-n-propyl-dibenz [cd, f] indole 1060 in ethanol, was added with stirring to a suspension of 140 g of zinc dust and 31.6 g (116 mmol) of mercuric chloride in 1060 ml of distilled water (alternatively zinc dust / mercuric chloride can be added to dibenzindole). The reaction mixture was heated under reflux, 36 ml of 18% hydrochloric acid was added dropwise over 15 to 20 minutes, and the mixture was heated under reflux and stirred overnight. The reaction mixture was cooled to room temperature, filtered and the zinc amalgam was washed with 500 ml of methylene chloride. The filtrate was basified with 1 liter of concentrated ammonium hydroxide solution and the base phase was extracted with 1 x 1 liter of methylene chloride and 2 x 500 ml of methylene chloride. The combined organic phases were washed with water, dried and evaporated. The resulting oil was chromatographed on silica gel eluting with methylene chloride containing 2% methanol to give (i) - (4R *, 5aS *) - 5-ethyl-4,5,5a, 6-tetrahydro-9,10 -dimethoxy-4-n-propyldibenz [cd, f7-indole as an oil.

5 Example 2

The (4RS) -5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-n-propyldibenz [cd, E] indole obtained in Example 1 b) can also be prepared as follows: a) 9-amino- 3,4-dimethoxyphenanthrene (compound of formula X)

A mixture of 430 ml (3.08 mol) of trifluoroacetic anhydride and 430 ml (5.62 mol) of trifluoroacetic acid was added to 53.6 g (0.19 mol) of 3,4-dimethoxyphenanthrene-9 at room temperature and under a nitrogen blanket. carboxylic acid and the mixture were stirred for 10 minutes. After cooling to -5 ° C, 15.2 g (0.234 mol) of solid sodium azide was carefully added and stirred for 3 hours at 2 ° C, poured onto ice and the resulting suspension was filtered in the usual manner to give 9-amino-3.4 -dimethoxyphenanthrene as solid. The melting point of the hydrochloride was above 215 ° C, with decomposition.

b) 9-Acetylamino-3,4-dimethoxyphenanthrene (compound of formula IX)

55 ml (0.319 mol) of N-ethyldiisopropylamine were added to a solution of 38.2 g (0.151 mol) of 9-amino-3,4-25-dimethoxyphenanthrene in 200 ml of methylene chloride. To the resulting mixture was added dropwise over 20 minutes a solution of 20.8 ml (0.292 mol) of acetyl chloride in 250 ml of methylene chloride. During the addition, the temperature of the reaction mixture was maintained at 20 ° C by cooling in an ice bath. The reaction mixture was stirred for 14 hours at room temperature, and worked up in the usual manner to give 9-acetylamino-3,4-dimethoxyphenanthrene, m.p. 190-195 ° C after recrystallization from ether.

II

13 751 53 c) 9-Ethylamino-3/4-dimethoxyphenanthrene (compound of formula VIII) 34 g (0.124 mol) of 9-acetylamino-3,4-dimethoxyphenanthrene as a suspension in 450 ml of anhydrous tetrahydro-5-furan were reduced to 500 ml. : 11a (0.5 mol) of a 1-M anhydrous tetrahydrofuran solution of diborane, and was worked up in the usual manner to give 9-ethylamino-3,4-dimethoxyphenanthrene, m.p. 94-95 ° C.

d) 4,5-Dihydro-9,10-dimethoxy-5-ethyl-4-oxo-dibenz [cd, 7indole (compound of formula VI) 122 ml (0.2 mol) of 15% hexane in n-butyllithium solution was added at 0 ° C under nitrogen to a solution of 28.1 g (0.1 mol) of 9-ethylamino-3,4-dimethoxyphenanthrene in 300 ml of anhydrous tetrahydrofuran. Reaction mixture 15 turned bright red. So much carbon dioxide ice was added that the color disappeared and a solution formed which fluoresced yellow-green. The reaction mixture was allowed to warm to room temperature, the mixture was poured into a mixture of water and ice, extracted 3x with methylene chloride and the organic phase was dried over sodium sulfate and evaporated. There was thus obtained 4,5-dihydro-9,10-dimethoxy-5-ethyl-4-oxodibenz [cd, f] indole, m.p. 125-126 ° C (decomposes) after crystallization from ether-petroleum ether.

e) (4RS) -5-Ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-n-propyldibenzZcd, E7indole (Compound of Formula III III)

At room temperature, 2.1 ml (33 mol) of an ethereal solution of n-propylmagnesium bromide were added dropwise to a solution of 10 g (33 mol) of 4,5-dihydro-9,10-dimethoxy-5-ethyl-4-oxodibenzene, indole in 300 ml of anhydrous tetrahydro-30 furan. After 30 minutes, ammonium chloride solution was added, the mixture was extracted with methylene chloride, the organic phase was dried and evaporated to give (4RS) -5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-n-propyl- dibents ^ cd, f / indole as a yellow-green foam. IR spectrum δ 35 (Ct ^ Cl 2: 3540 cm (OH) ^ 7. The crude product was used directly in the next step.

14 75153

Example 3 (±) - (4R *, 5aS *) - 5-ethyl-4 / 5.5a / 6-tetrahydro-9,10-dihydroxy-4-n-propyldibenz / cd, f-indole 20 g (27, 66 mmol) (±) - (4R *, 5aS *) - 5-ethyl-5 4,5,5a, 6-tetrahydro-9,10-dimethoxy-4-propyldibenz [cd, t] indole in 200 ml 47% the aqueous hydrobromic acid solution was heated under reflux for 6 hours at an incubation temperature of + 150 ° C. The reaction mixture was evaporated to dryness, the crystalline residue was stirred in acetone and filtered off with suction. The precipitate was washed with acetone and then ether and dried under high vacuum. There was thus obtained (ί) - (4R *, 5aS *) - 5-ethyl-4,5,5a, 6-tetrahydro-9,1O-dihydroxy-4-n-propyldibenz [cd, findole hydrobromide, m.p. 200 ° C, dec.

The following compounds can be prepared analogously from the appropriate starting materials: (±) - (4R *, 5aS *) - 4,5-diethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxydibenz / cd, f / indole (hydrobromide, m.p. above 175 ° C, dec.), (±) - (4R *, 5aS *) - 4,5,5a, 6-tetrahydro-9,10-dihydroxy-4,5-di-20 n-propyldibenz [cd, f] indole (hydrobromide, m.p. above 190 ° C, dec.) and (-) - (4R *, 5aS *) - 4-ethyl-4,5,5a, 6-tetrahydro-9, 10-dihydroxy-5-n-propyldibenz [cd, f] indole.

Example 4 (-) - (4S, aR) -5-Ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-4-n-propyldibenzo [f] indole a) (-) - ( 4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxy-4-n-propyldibenz [trans] indole 30 g (89 mmol) of (1) - (4R *) were dissolved. , 5aS *) - 5-ethyl-30'-4,5,5a, 6-tetrahydro-9,10-dimethoxy-4-n-propyldibenz-cd, f-indole in 300 ml of ether and a stirred solution of 35.95 g of (-) - di-O-O-p-tololyl-L-tartaric acid monohydrate in 300 ml of ether. Stirring was continued for one hour at room temperature, during which time a total of 1 liter of ether was added portionwise. The precipitate formed was filtered off with suction and washed with ethyl acetate until the color remained pale yellow, and dried.

tl is 75153

61.88 g of crystals from the first crystallization were dissolved in 1 liter of acetone and 300 ml of methanol at reflux temperature, and the solution was filtered and concentrated until the product was largely crystallized.

The mixture was stirred for about 15 minutes, the product was isolated by suction filtration and washed with ethyl acetate until colorless, and dried.

The resulting product was recrystallized in the same manner using 1.7 liters of acetone and 35 ml of methanol to give colorless crystals.

The obtained crystals were recrystallized in the same manner using 1.2 liters of acetone and 60 ml of methanol to give (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxy-4 -n-propyldibenz [cd, f] indole - (-) - di-O-O-tolu-15-yl L-tartrate as colorless crystals, m.p. 178-179 ° C, = -138 ° (c = 0.29 in methanol).

The following compounds can be prepared analogously from the appropriate starting materials: (-) - (4S, 5aR) -4,5-diethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxy-20-dibenz [cd, f] indole- ( -) - di-O-O-p-toluoyl L-tartrate, m.p. 187-189 ° C, = “138 ° (c = 0.5 in methanol). The racemic starting material was first reacted with (+) - di-O-O-p-toluoyl-D-tartaric acid instead of the L-isomer, and the mother liquor obtained in crystallization was treated with ammonium hydroxide-25a to liberate the base. The base was reacted with (-) - di-O-O-p-toluoyl-L-tartaric acid and crystallized from ether.

(-) - (4S, 5aR) -4,5,5a, 6-Tetrahydro-9,10-dimethoxy-4,5-di-n-propyldibenz [cd, f, 7indole- (-) - di-O- O-p-toluoyl L-tartrate 30, m.p. 165-166 ° C, = -123 ° C (c = 0.27 in methanol).

, 6,751,5 b) (-) - (4S / 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-4-n-propyldibenz / cd, f-indole Continuing as described in Example 3, (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-5 4-n-propyldibenz [cd, f] indole hydrobromide was obtained as described above. a) the tartrate obtained, m.p. above 210 ° C, = “64 ° (c = 0.245 in methanol).

The corresponding hydrochloride m.p. is above 185 ° C, dec., = -75 ° (c = 0.28 in methanol).

10 Example 5

The following compounds can be prepared as described in Example 4 b) from the appropriate starting materials: (-) - (4S, 5aR) -4,5-diethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxydibenz / cd, f-indole hydrochloride , sp. 200 ° C, decomp., Δ = -72 ° (c = 0.25 in methanol), (-) - (4S, 5aR) -4,5,5a, 6-tetrahydro-9,10-dihydroxy-4,5- di-n-propyl dibenz / cd, f-indole hydrochloride, m.p. above 187 ° C, ha-v 20 o so, [JXJD = -58.5 (c = 0.35 in methanol), and (-) - (4S, 5aR) -4-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-20 5-n-propyldibenz [cd, f] indole hydrochloride, m.p. 198-200 ° C, dec., -66 ° (c = 0.5 in methanol).

Example 6 (+) - (4S, 5aR) -5-Ethyl-9,10-dibenzoyloxy-4,5,5a, 6-tetrahydro-4-n-propyldibenz [cd, f] indole 25 was added dropwise with stirring over 5 minutes. At + 5 ° C 0.376 ml (3.23 mmol) of benzoyl chloride in a solution of 600 mg (1.54 mmol) of (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro -9,10-dihydroxy-4-n-propyldibenz / cd, β-indole hydrobromide in 5 ml of anhydrous pyridine and stirring of the reaction mixture was continued for 14 hours at room temperature. The mixture was evaporated to dryness, the residue was dissolved in methylene chloride and the solution was washed first with a mixture of ice and saturated potassium carbonate solution and then with water. The aqueous phases were extracted twice with methylene chloride and the combined organic phases were dried and evaporated. The residue was dissolved in methylene chloride and evaporated under high vacuum.

17 7 51 5 3

Dissolution in methylene chloride and evaporation were repeated twice more. 550 mg of the product formed was dissolved in acetone, and this solution was added dropwise to a solution of 156 mg of L (+) - tartaric acid in acetone. The formed precipitate 5 was isolated by filtration to give (+) - (4S, 5aR) -5-ethyl-9,10-dibenzoyloxy-4,5,5a, 6-tetrahydro-4-n-propyldibenz [cd, f] indole L (+) - tartrate, m.p. 161-162 ° C after crystallization from ethyl acetate-ether, -23.5 ° (c = 0.28 in methanol).

The following compounds can be prepared analogously from the appropriate starting materials: (-) - (4S, 5aR) -9,10-diacetoxy-5-ethyl-4,5,5a, 6-tetrahydro-4-n-propyldibenz [cd, f] indole hydrochloride, m.p. above 188 ° C, dec., = -99 ° (c = 0.28 in methanol), 15 (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-4-n- propyl 9,10-dipropionyloxydibenz / cd, f7indole hydrochloride, m.p. above 175 ° C, dec., = -76 ° (c = 0.25 in methanol), (-) - (4S, 5aR) -9,10-dibutyryloxy-5-ethyl-4,5,5a, 6-tetra- hydro-4-n-propyldibenz / cd, f-indole hydrochloride, m.p. above 20 105 ° C, with decomposition, - ~ 77 ° (c = 0.28 in methanol), (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,1O-di -isobutyryloxy-4-n-propyldibenz / cd, indole hydrochloride, m.p. above 165 ° C, with decomposition, (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-4 -n-propyl-25,1,1-divaleryloxidebenz [cd, f] indole hydrochloride, (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-4-n-propyl-9, 10-dipivaloyloxydibenz / cd, f, indole hydrochloride, and (-) - (4S, 5aR) -4,5,5a, 6-tetrahydro-9,10-dipropionyloxy-4,5-di-n-propyldibenz / cd, f ^ indole hydrochloride, m.p. 115 ° C, 30 = "67 ° (c = 0.51 in methanol),

In a manner similar to Example 6, compounds of formula I wherein R 1 and R 2 are ethyl or n-propyl and R 1 is acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy or pivaloyloxy can be prepared.

Claims (4)

A process for the preparation of new pharmacologically active (4R *, 5aS *) - 4,5,5a, 6-tetrahydro-dibenz [cd, f] -indole derivative-5 women of the formula r3 R1 j | TT 1 is -N-R 2 wherein and R 2 are ethyl or n-propyl, and the R 1 substituents are the same groups, either hydroxy groups or acyloxy groups of formula R -CO-O-, wherein R is C 1-6 phenyl or 1 - alkyl having 4 carbon atoms, in racemic form with a relative configuration of 4R *, 5aS *, or in the form of an optically active isomer with an absolute configuration of 4S, 5aR, and for the preparation of salts of these compounds, characterized in that a ) to prepare a compound of formula 25H HO JL R1 n [I Ia 30. N-R2 wherein R1 and R2 are as defined above, by cleaving the ether groups Z from a compound of formula 35 II 19 751 53 ZII - n-r2 wherein R1 and R2 are as defined above and Z is a cleavable ether group, and which compound is in racemic form, wherein the relative configuration is 4R *, 5aS *, or is in the form of an optically active isomer, wherein the absolute configuration is 4S, 5aR, or b) a compound of formula r, 3 AA 2 ° I is prepared I 1 -n-r 2 wherein R 1 and R 2 are as defined above and the groups R '2 are the same acyloxy groups of the above formula R 1 -CO-O- by acylation of a compound of formula Ia in racemic form with a relative the configuration is 4R *, 5aS *, or is in the form of an optically active isomer, the absolute configuration being 4S, 5aR, and, if necessary, isolating the compound of formula I in the form of the free base or salt. 35 20 7 5 1 5 3 For the preparation of pharmacologically active substances (4R *, 5aS *) - 4,5,5a, 6-tetrahydro-dibenz [cd, f] indole-5 derivatives with formula 10 -N-R2 is R1 and R2 is ethyl- or n-propyl, and the substituent R1 is a diseased group, the moiety is a hydroxyl group or an acyloxy group with the formula R - CO - 0 is R1 is phenyl or 15 is alkyl 1-4 cholatomers, in the form of a racemic form, colors in relative configurations of 4R *, 5aS *, or in the form of optically active isomers, colors in a non-cellular configuration of 4S, 5aR, as well as in terms of optical formations därav, fig 20 a) en förening med formelnel 0H / U- JL. r 1 Ia - N-R2 of R1 and R2 of the group consisting of three, the genome of which represents a further group of compounds Z and one of the forms of formula 30 2 35 -n-r2 of R1 and R2 of the group of the group