DE3124086A1 - HETEROCYCLIC COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THESE COMPOUNDS - Google Patents

Description

Case 100-5410

Heterocyclic compounds, processes for their preparation and pharmaceutical compositions containing these compounds

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

Belgian patent no. 877 169 describes a class of 4,5,5a, 6-tetrahydro-dibenz [cd, f] indole derivatives, which have a stimulating effect on the central dopaminergic receptors. All specifically listed compounds which have alkyl groups in the 4 and 5 positions contain one as an alkyl group Methyl group. It has now been found, surprisingly, that a group of (4R *, 5aS *) - 4,5,5a, 6-tetrahydro-dibenz [cd, f] indole derivatives, which ethyl and n-propyl groups have in positions 4 and and which are not detailed in this patent specification are described or listed, a particularly interesting pharmacological Spectrum have, among other things, a long-lasting effect and / or a remarkable effectiveness as a central dopaminergic marriage Agents, as well as good tolerance.

_m ι » _M

100-5410

The invention relates to compounds of the formula I.

-R.

(D

R and R, independently of one another, represent an ethyl or n-propyl group and
ι both
mean oxy groups,

the two R "substituents are identical and are hydroxy or acyl

- 6 - 100-5410

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 conveniently groups of the formula

R-CO-O-

wherein R is an alkyl group, a cycloalkyl group of 3-7 carbons

atoms, a phenyl group or a 5-6 membered heterocyclic Ring means.

If R denotes an alkyl group, this suitably has usually 1-17 carbon atoms, preferably 1-7 carbon atoms, and can be straight-chain or branched.

R can be a substituted alkyl group, those in the alkyl chain a

suitably contains 1-5 carbon atoms. Appropriately it is 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 amino, halogen, alkylthio with 1-4 carbon atoms, phenoxy, a phenyl group, 1-pyrrolidinyl, piperidino or morpholino, and conveniently a phenyl group. R can also be, for example, an alkyl group having 1-4 carbon atoms in the alkyl chain and is substituted by a cycloalkyl group having 3-7 carbon atoms.

If R is a phenyl radical or an alkyl group which is substituted by a phenyl radical, the phenyl ring can be unsubstituted or be substituted by 1, 2 or 3 identical or different substituents selected from halogen, trifluoromethyl, Alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, alkylthio with 1-4 carbon atoms and di- (C.) Al-

1-4

-Y- "" '100-5410

kylamino or selected from a methylenedioxy group. The phenyl ring is preferably mono- or disubstituted.

If R is an alkyl group substituted by a phenyl radical

R is preferably a benzyl radical. The phenyl ring can carry substituents which, for example, consist of halogen, Alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, and alkylthio of 1-4 carbon atoms can.

If R stands for a heterocyclic ring »it is conveniently a heterocyclic ring containing oxygen, Has nitrogen or sulfur as the only heteroatom, for example around the pyridine, thiophene or furan radical.

Preferably R is an alkyl group with 1-7 carbon

el

atoms, a cycloalkyl group with 3-6 carbon atoms, an unsubstituted one Phenyl or a phenyl which is mono- or disubstituted by chlorine, fluorine, trifluoromethyl, alkyl having 1-4 carbon atoms or alkoxy of 1-4 carbon atoms, an unsubstituted one Benzyl or a benzyl which is mono- or disubstituted by chlorine, fluorine, an alkyl group with 1-4 carbon atoms or a Alkoxy group with 1-4 carbon atoms.

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

In a group of compounds, R 1 denotes an n-propyl group and R is an ethyl group, in another group of compounds R and R are identical and represent an ethyl or n-propyl group. In the compounds of the formula I, the R substituents mean preferably a hydroxy group. The preferred compounds are the (4S, 5aR) optical isomers.

100-5410

The invention also relates to a process for the preparation of compounds of the formula I, which is characterized in that one either

a) to compounds of the formula Ia

OH

(Ia)

in which R ₁ and R "have the above meaning, obtained by removing the ether groups Z of compounds of the formula II

! I I

(II)

wherein R ₁ and R "have the above meaning, and Z represents a splittable group, in racemic form with the relative configuration 4R *, 5aS * or in the form of an optically active isomer with the absolute configuration 4S, 5aR, splits, or b) to Compounds of the formula Ib

^R * (Ib)

-R-

where R and R have the above meaning, and the radicals R 'iden-

JL ju * 3

Table mean acyloxy groups, obtained by adding compounds of the formula Ia, in racemic form with the relative configuration 4R *, 5aS * or in the form of an optically active isomer 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

-9- ' "■ ΪΟΟ-5410

Mineral acid, for example an acid or hydrobromic iodine water material, at temperatures of at least 100 ⁰ C, preferably from 100 ⁰ C to the boiling point of the reaction mixture, especially at about 130 ⁰ C. The ether group Z is preferably a methoxy group.

The acylation described in process b) can be carried out in a manner known per se using the processes known for the selective acylation of phenol groups in the presence of amino groups. For example, as the acylating agent is a functional derivative of an acid, for example an acid chloride, acid bromide or _s, may be used an acid anhydride. 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 the formula I obtained can in a known manner isolated from the reaction mixture and purified, the Free bases of the compounds of the formula I can be converted into acid addition salts and vice versa in a known manner Acids suitable for salt formation are, for example, hydrochloric acid, tartaric acid, di-O, O-p-toluoyl-D- or L-tartaric acid and hydrobromic acid.

The racemates of the formula I can be prepared from racemic starting compounds can be obtained. The optically active isomers of the formula I can be obtained from the corresponding optically active starting compounds with the configuration (4S, 5aR) or from the racemates. The 4S, 5aR enantiomer can be obtained in a known manner from the racemate can be obtained, for example by fractional crystallization of the diastereoisomeric salts, for example

- 10 - 100-5410

their salts with (+) - di-0,0-p-toluoyl-D-tartaric acid or (-) - di-0,0-p-toluoyl-L-iic acid. The separation of the racemates into the optically active isomers is preferably carried out earlier Stage of the synthesis, for example before the splitting of the ether groups.

The starting compounds of the formula II can be prepared by adding compounds of the formula III

• 'II I n «

(III)

in which R, R "and Z have the above meanings, reduced.

The reduction is conveniently carried out under acidic, for the _; Reduction of enamines or Iiainen suitable. Conditions, for example with the aid of zinc in aqueous mineral acid, preferably hydrochloric acid, conveniently in the presence of a mercury (II) salt, for example mercury (II) chloride. The reduction is conveniently carried out, for example, in ethanol and at temperatures from 50 ⁰ C to the boiling point of the reaction mixture.

The starting compounds of the formula III can, for example, according to following reaction scheme:

100-5410

tert -butyl ^ lithium /

(III)

R.-MgBr or R ₁ -Li

N-CO-R,

0 (VI)

HaI-CO-R.

(V)

NaN ₃

(XI)

COOH co.

(VII)

I η-butyllithium

(VIII)

(IX)

(X)

- 12 - 100-5410

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

In the above intermediate products, the ether groups are preferably Z Methoxy groups.

If the preparation of individual starting compounds is not described, these can be prepared in the usual way. For example, the phenanthrene derivatives - the starting compounds of the formula XI - are described in Elsevier ¹ s Encyclopaedia of Organic Chemistry, Volume 13, Tricyclic compounds, Elsevier Publishing Company Inc., New York (1946).

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

EXAMPLE 1

a) 9- (N-

(Compound of formula IV)

A solution of 50 g (138 mM) 9-ethylamino-8-bromo-3,4-dimetoxyphenanthrene in 57.5 ml (333 mM) N-ethyl-diisopropylamine and 420 ml of methylene chloride is added dropwise while stirring in nitrogen atmosphere and within 20 minutes, to a solution of 28.8 ml (276 mM) butyryl chloride in 420 ml of methylene chloride. During the encore the reaction mixture is cooled by cooling in a water bath kept at room temperature. The yellow-red solution obtained in this way is then worked up in a known manner, with the 9- (N-ethyl-N-butyryl-amino) -8-bromo-3,4-di-ethoxy-phenanthrene is obtained. M.p. 102-104 °.

b) i ^ R ^ -S-A ^ th ^ l- ^ S-dihjrdro ^ -hydroxy ^, 10-dime thoxy-4-n ^ grogyl-

(Compound of formula III)

- 13 - 100-5410

25 g (58.14 mM) 9- (N-ethyl-N-butyrylamino) -8-broin-3,4-dimethoxyphenanthrene are dissolved in 450 ml of anhydrous tetrahydrofuran with stirring and the resulting solution is heated to -25 ° 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 over a period of 4 minutes. The temperature of the reaction mixture is then allowed to rise to + 5 ° within 30 minutes, the reaction mixture is poured into 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 evaporated she an. After drying the product in a high vacuum, the (4RS) -5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy * 4 ~ £ '~ propyl-dibenz [cd _s flindole is obtained in the form of a yellow-green foam.

c) i'll ^ RiiSaS ^ -S ^ Aethy ^ l - ^^ Sa ^ ö ^

i (compound of formula II)

A suspension of 40.6 g (116 mM) (4RS) -5-ethyl-4,5-dihydro-4-hydroxy-9.10 ^< dLmethoxy-4-iv-propyl-dibenz [cd, f] indole in 1060 ml of ethanol is added with stirring to a suspension of 140 g of zinc powder and 31.6 g (116 mM) of mercury (II) chloride in 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 18% hydrochloric acid are added dropwise over a period of 15 to 20 minutes and the mixture is refluxed 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 methylene chloride and twice, each time with 500 ml of methylene chloride The combined organic phases are washed with water, dried and evaporated

- 14 - 100-5410

chromatographed on a silica gel column using methylene chloride with 2% methanol as the eluent. This gives (±) - (4R *, 5aS *) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxy-4-ii-propyl-dibenz [cd, f] indole in Form of an oil. EXAMPLE 2

The (4RS) -5-ethyl-4,5-dihydro-A-hydroxy- ^ 10-dimethoxy- ^ - propyl-dibenzCcdifjindole obtained in Example Ib) can also be prepared as follows:
a) 2z ^^ B2z2A £ läiSßtho ^^ 2.henanthren_ (compound of formula X) A mixture of 430 ml (3.08 M) trifluoroacetic anhydride and 430 ml (5.62 M) trifluoroacetic acid is 53, 6 g (0.19 M) 3,4-dimethoxy-. phenanthrene-9-carboxylic acid is added and the mixture is stirred for 10 minutes. After the mixture has cooled to -5 °, 15.2 g (0.234 M) sodium azide in solid form are carefully added, the mixture is stirred for 3 hours at 2 °, poured onto ice and the suspension obtained is worked up in the usual way, the 9-amino-3,4-dimethox) phenanthrene is obtained in solid form. The hydrochloride melts from 215 ° with decomposition.

k) 2l ^ £ S £ Ziä5iS2l2i £ lii2 £ iilS. ^: iZ; Ei} £ S.äS £]} I £ S (compound of formula IX)

55 ml (0.319 M) N-ethyldiisopropylamine are added to a solution of 38.2 g (0.151 M) 9-amino-3,4-dimethox3rphenanthrene in 200 ml of methylene chloride. A solution of 20.8 ml (0.292 M) acetyl chloride in 250 ml methylene chloride is added dropwise to the resulting mixture over a period of 20 minutes. During the addition, the temperature of the reaction mixture is kept at 20 ° by cooling with ice. The reaction mixture is during 14

Stirred for hours at room temperature and worked up in a known manner, 9-acetylamino-3,4-dimetoxyphenanthrene is obtained (melting point 190-195 ° after recrystallization from ether).

^c) -Z ^^^ Zi ^ i ^ i ^^ iBSZ ^ ^^^ yioiSZEiiSS ^{211 11 (Vert>} indung of formula VIII)

34 g (0.124 M) 9-acetylamino-3 _> 4-dimethaxy ~ 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 the usual way. 9-Ethylainino-3,4-dimethoxyphenanthrene is obtained in this way; M.p.

94-95 °.

d) ^ S-Dihjrdr o-9ilO ^ itjjS.thcHCZ-'S-aeth ^ l-4-oxo-dibenz [^ c ^ fHndol (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) g-ethylamino-S ^ -dimethoxy- phenanthrene added to 300 ml of anhydrous tetrahydrofuran; the reaction mixture turns light red. Then dry ice is 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, f3indole _s which melts at 125-126 ° (with decomposition), after recrystallization from ether / petroleum ether.

(Compound of formula III)

2.1 ml (33 mM) of a solution of n-propylmagnesium 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-oxo ~ dibenz [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-AeAyI ^ ₉ 5-dihydro-4-hydroxy-9, 10-dimethoxy-4-n-propyl-dibenz [cd, f] indole is thus obtained in the form of a yellow-green foam. [IR spectrum (CH Cl): 3540 cm (OH)],

.- 31240SG

-iSO-5410

The raw product is used directly for the next stage. EXAMPLE 3

grogyl-dibenz [cd, fj indole

20 g (27.66 eM) (i) - (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, at a Bath temperature of 150 °, heated to reflux for 6 hours. After the reaction mixture has evaporated to dryness, will the crystalline residue is stirred in acetone and filtered off. The deposited precipitate is washed with acetone, then with Ether and dried in a high vacuum. This gives the (-) - (4R *, 5aS *) - 5-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-'4-nj-propyl-dibenz [cd, f] indole hydrobromide, which 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-dihydroxydibenz [cdjf] indole (Hydrobromide, m.p.> 175 ° with decomposition);

b) (-) - (4R *, 5aS *) - 4,5,5a, 6-tetrahydro-9,10-dihydroxy-4,5-di-n-propyldibenz [cd, fJindole (Hydrobromide melting point> 190 ° with decomposition) j

c) (-) - (4R *, 5aS *) - 4-Ethy1-4,5,5a, 6-tetrahydro-9, 10-dihydroxy-5-n-propyl-dibenz [cd, f] indole.

EXAMPLE 4

p_y_l-dibenz [cd _z f] indole

a) (-) - (4S, 5aR) ~ 5-ethyl-4,5.5a, 6-tetrahydro-9.10-dimethoxy-4-ngro ££ l-dibenz [cd _A f] indole

30 g (89 ml ·!) (-) - (4R *, 5aS *) - 5-ethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxy-4-n-propyl-dibenz [cd, f] indole are dissolved in 300 ml of ether and a solution of 35.95 g of (-) - di-

Ο, Ο-p-toluoyl-L-tartaric acid monohydrate in 300 ml of ether 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 that has precipitated out is drained off? triert, washed with ethyl acetate until it is light yellow and dried.

61.88 g of the 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 15 minutes, the product is filtered off washed with Essigester _s until it is colorless and dried.

The product obtained is recrystallized in the same manner using 1.7 liters of acetone and 35 ml Methanol, whereby colorless crystals are obtained.

The obtained 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 _s 6-tetrahydro-9,1O-dimethoxy-4-n-propyl-dibenz [cd, f] indole (-) -di-0,0-p-toluoyl-L-tartrate in the form of colorless crystals at 178-179 °

20th
melt; [α] = -138 ° (c = 0.29 from methanol).

Using suitable starting materials, the following compounds can be produced in a similar way:
- (~) - (4S, 5aR) -4,5-diaethyl-4,5,5a, 6-tetrahydro-9,1O-dimethoxydibenz [cd, f] indole (-) - di-0,0-p- toluoyl-L-tartrate, m.p. "187-189 ° 5

20th
[α] = -138 ° (c = 0.5 from methanol); the racemic starting

- product is first reacted with (+) - di-0,0-p-toluoyl-D-tartaric acid instead of the L-isomer, and the mother liquor obtained during crystallization is treated with NH OH to liberate the base. The base is reacted with di-0 _s 0-p-toluoyl-L-iieinsMure and the crystals are obtained from an ether solution (-) -.

- 18 - 100-5410

- (-) - (4S, 5aR) -4,5,5a _s 6-tetrahydro-9,10-dimethoxy-4,5-di-n-propyldibenz [cd, f] indole (-) - di-0, 0-p -toluoyl-L-tartrate, m.p. 165-166 °;

20th
[aJ _D - -123 ° (c * 0.27 from methanol).

The procedure described in Example 3 is followed and, starting from the tartrate obtained under a), (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-4 is obtained -n-propyl-dibenz [cd, f]

on

indole hydrobromide. It melts from 210 °; [a] JJ = -64 ° (c = 0.245 from methanol).

The corresponding hydrochloride melts below 185 °

20th
Decomposition; [α] »-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-Diaethy1-4,5,5a, 6-tetrahydro-9,10-dihydroxydibenz [cd, f] indole hydrochloride, mp * 200 ° with decomposition;

20th
M ₀ = -72 ° (c = 0.25 from methanol);

b) (-) - (4S, 5aR) -4,5,5a, 6-tetrahydro-9,10-dihydroxy-4,5-di-n-propyldibenz [cd, f] indole hydrochloride, m.p. y 187 ° below Decomposition;

20th
[α] * = -58.5 ° (c = 0.35 from methanol);

c) (-) - (4S, 5aR) -4-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-5-npropyl-dibenzicdjfjindolb / hydrochloride, mp 198-2OO ° (decomp.) ; [a] _D = -66 ^c EXAMPLE 6 / (c-0.5 from HbOH).

(^ ■) - (4S, 5aR) -5-ethyl-9,10-dibenzoyloxy-4 ₎ 5,5a _> 6-tetrahydro-4-n-propyl-dibenz tcd, fJindole

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-dihydroxy-4-n-propyl-dibenz [cd, f] indole hydrobromide in 5 ml of anhydrous pyridine is 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

- 19 - "" "100-5410

first with a mixture of ice and a saturated potassium bicarbonate solution, and then washed with water. The aqueous phases are extracted twice with methylene 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 solution of the residue in methylene chloride and the evaporation are repeated twice. 550 mg of the product thus obtained are dissolved in acetone and this solution is added dropwise to a solution of 156 mg of L (+) - tartaric acid in acetone. The deposited precipitate is filtered off and dried. This gives (+) - (4S _s 5aR) -5-ethyl-9, 10-dibenzoyloxy-4,5,5a, 6-tetrahydro-4-n_-propyl-dibenz [cd, f] indole-L ( +) - tartrate; it melts at 161-162 ° after recrystallization from a mixture of ethyl acetate and ether; [α] ^ = + 23.5 ° (c = 0.28 from methanol).

Using suitable starting materials you can the following connections can be established in an analogous manner:

- (-) - (4S, 5aR) -9, 10-diacetoxy-5-ethy1-4,5,5a, 6-tetrahydro-4-n-

propyl-dibenz [cd, f] indole hydrochloride, m.p.> 188 ° (with decomposition

20th
settlement); [aL * = -99 ° (c = 0.28 from methanol);

- (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-4-n-propyl-9,10-di-

propionyloxy-dibenz [cd, f] indole hydrochloride, m.p.> 175 ° (below

20th
Decomposition); [or] _ = -76 ° (c = 0.25 from methanol);

- (-) - (4S, 5aR) -9,10-dibutyryloxy-5-ethyl-4,5,5a, 6-tetrahydro-4-iv-propyl-dibenz [cd, f] indole hydrochloride, m.p.> 105 ° (with decomposition); [er] ^ ⁰ = -77 ° (c = 0.28 from methanol);

- (- 3- (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-diisobutyryloxy-4-n-propyl-dibenz [cd, f] indole hydrochloride, m.p. ⁰ (under decomposition

20th
settlement); [α] = -96 ° (c = 0.29 from methanol); - (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-4-n_-propyl-9,10-divaleryloxydibenz [cd, f] indole hydrochloride;

- (-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-4-E-propyl-9 _s 10-dipivaloyloxydibenz [cd, f] indole hydrochloride;

- 20 - 100-5410

- (-) - (4S, 5aR) -4,5,5a, 6-tetrahydro-9,10-dipropionyloxy-4,5-di-n-

propyl-dibenz [cd, f] indole hydrochloride, mp, 115 °; [a] = -67 ° (c = 0.51 from methanol).

In a manner analogous to that described in Example 6, the following compounds of the formula I, wherein R and R ", independently from each other, an ethyl or n-propyl group and R "

- acetoxy

- propionyloxy

- butyryloxy

- isobutyryloxy

- valeryloxy

- pivaloyloxy

mean to be produced.

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

The dopaminergic effect of the compounds of the formula I was studied on the rat, according to that of U. Ungerstedt in Acta Physiol. Scand. Suppl. 367 , 69-93 (1971). The unilateral injection of 6-hydroxydopamine into the substantia nigra causes a unilateral degeneration of the nigrostriatal pathways after one week. 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 was expressed in the fact that the rats rotated in the direction of the non-denervated side.

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

Rats weighing between 180 and 222 g were used in Perspex cylinders with a diameter of 30 cm on one

- 21 - 100-5410.

Latticed floor laid »After the rats had been given 30 minutes to settle in. the cage to get used to them was _s the injected compound to be tested "The behavior of the rats was observed for 2 minutes ,, and at intervals of 30 minutes ₉ iiährend 2 hours then at intervals of 60 minutes, a total of up to 6 hours" The degree of the observed stereotypical behavior was assessed using the rating system described by Costall, Naylor and Olley [Euro "J" Pharmaco ^ S ₃ 83-94 (1972) 3 "
The following rating criteria were applied:

1) Intermittent sniffing

2) Constant sniffing, occasional licking

3) licking, occasional biting

4) Intense and prolonged biting.

Awake peritoneal administration in doses between about 0.03 and about 30 mg / kg body weight ;, the compounds dissolved the Formally I in the rats a stereotypical sniffing;, licking and Bite out »

The compounds of formula I can therefore be of Parkinson's disease "are used to stimulate the central dopaminergisehen receptors _a example zut treatment for this indication is based on the suitable daily dose of between about O ₅ I and about 20 mg and is suitably 2 to 4 aal daily in the form of Single doses, which _{contain between about O 9} 025 and about 10 mg, or also administered in sustained-release form »

The compounds of the formula I also have antidepressant properties, as can be seen in the inhibition of catalepsy caused by reserpine in the mouse, after subcutaneous administration of about 0.001 mg to about 1 mg / kg of the compounds of the formula I and in the inhibition in the rat catalepsy caused by tetrabenazine after intraperitoneal administration of about O ₈ 2 to about 2 mg / kg of the compounds of the formula I.

- 22 - 100-5410

The compounds of the formula I can therefore be used as antidepressants.

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

The compounds of formula I also cause a

Inhibition of prolactin secretion, which results from the lowering of the prolactin

spiegeis in the serum of the rat, after subcutaneous administration of about 0.1 to about 1 mg / kg of the compounds of the formula I, using radioimmunological techniques, for example as described by GD Niswender and others in Biol. & Med. 130 , 793 ( 1969) and JJ Neil and others in Endocrinology j88 ^ 548 (1971).

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

The suitable daily dose is between about 5 and about 50 mg and is expediently taken 2 to 4 times a day in the form administered by single doses, which are about 1.25 mg to about 25 mg of the compounds of the formula I in addition to solid or liquid Contain carrier substances or diluents.

The compounds of formula I also have antipsychotic properties, which result from the inhibition of locomotion the mouse, after subcutaneous administration of about 0.001 to about 0.1 mg / kg of the compounds of the formula I, and from the dopamine agonist Effect on the presynaptic receptors of the

- 23 - 100-5410

Rat with doses between about 1 mg and about 10 mg / kg of the compounds the formula Ij emerges from the following experiment ·.

The dopamine agonistic effect of the compounds of the formula I on the presynaptic receptors x ^ urde in the rat according to that of JR Walters and coworkers in Naunyn Schmiedeberg's Arch. Pharmacol. 296, 5-14 (1976) described in vivo method investigated. The dopaminergic impulse flow was pharmacologically inhibited by means of if-butyrolactone. The action of the aromatic amino acid decarboxylase was inhibited Pleaseis hydroxybenzyl hydrazine (NSD 1015) and half an hour later the rats were sacrificed. The resulting DOPA accumulation during 30 minutes in the striatal tissue was taken as a hatred for the in vivo effect of tyrosine hydroxylase.

The compounds of the formula I can therefore be used as antipsychotics, for example for the treatment of schizophrenia. The appropriate Tagesdosi is administered 2 to 4 times daily zxdLschen about 0 "and 01 mg etxra 1 and is zxv'eckmässigerweise in the form of single doses comprising about ;, O _s OO25 mg to about 0 ₀ 5 mg of the compounds of formula I contain in addition to solid or liquid carriers or diluents =

The preferred indication is the anti-Parkinson's indication »

The compounds (4S _S) 5aR) -S-ethyl-4 _! , 5 ₂ 5a _a 6-tetrahydro-9 _s 10-dihydroxy-4-n-propyl-dibenz [cd, f [indole (4S ₅ 5aR) -4-ethyl-4,5 ₁₎ 5a ₅ 6-tetrahydro-9 _i , 10-dihydroxy-5-n _j -propyl-9 _s 10-dihydro: iy-difoenz [cd _s f3 indole _s (4S _f 5aR) -4 "S-diaethyl-4 _g 5 _s 5a ₅ 6-tetrahydro- 9 "10-dihydroxy-dibenztcds.flindole and (4S ₅ 5aR) -4 _s 5p5a ₅ 6-tetrahydro-9 _s 10'-dihydroxy-4 _a 5-di-n-propyl-dibenz [cd:, f] indole and the corresponding di-n-propionyl and di-isobutyl ester derivatives are the preferred compounds.

- 24 - 100-5410

The compounds of the 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 medicaments, the compounds of the formula I, in the form of the free bases or in Form their acid addition salts contain, in addition to carrier substances or diluents.

These remedies, for example a solution, a capsule or a tablet, can be prepared by conventional methods will.

37OO / GR / RA

Claims (8)

SANDOZ-PATENT-GtIBH 7850 Lörrach Case 100-5410 patent claims 1. Compounds of formula I (D wherein R and R, independently of one another, are an ethyl or n-propyl group and the two R substituents are identical and are hydroxy or acyloxy 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, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy-4-i3- propyl-dibenz [cd, £] indole. 3. The (4S, 5aR) -4-ethyl-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. 124086 5. The (4S, 5aR) -4,5,5a, 6-tetrahydro-9,10-dihydroxy-4,5-di-n-propyl-dibenz [cdjf] 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 Form of pharmaceutically acceptable acid addition salts with pharmaceutical carriers or diluents. 8. Process for the preparation of compounds of the formula I according to Claim 1, characterized in that either a) to compounds of the formula Ia • HO • (Ia) arrives, wherein R and R are defined in claim 1, by in the compounds of formula II (II) wherein R and R are as defined in claim 1, and Z is a splittable Represents ether group that splits ether groups Z, or
b) to compounds of the formula Ib 1ΌΟ-541Ο (Ib) arrives, wherein R. e R are as defined in claim 1, and the radicals R 'are identical and each mean acyloxy groups by acylating compounds of the formula Ia.