CA1162927A - Heterocyclic compounds, their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

Abstrcact of the invention The 4,5,5a,6-tetrahydro-dibenz[cd,f]indoles of formula I

wherein either R1 and R2 independently are ethyl or n-propyl radicals and the R3 substituents are the same and are hydroxy or acyloxy radicals, in racemic form having the relative configuration 4R*,5aS* or in optically active isomer form having the absolute configuration 4S,5aR, are useful as central dopa-minergic stimulent agents.

Description

~ :~ 6 ~ 7 Heterocyclic compounds, their preparation and_~harma-ceutical com~ositions containing them This is a divisional of application Serial No. 380,614 filed June 25, 1981.
The present invention relates to phenanthrene derivatives, their preparation and pharmaceutical compositions containing them~
Belgian patent n 877 169 describes a class of 4,5~/5a,6-tetrahydro-dibenz[cd,f]indole derivatives havin~ stimulant activity on central dopaminergic receptors. All the compounds sp~cif:ically exemplified which have alkyl groups attached to positions 4 and 5, contain as one alkyl group a methyl group. It has been now surprisingly found that a group of (4R*r5aS*) -4,5,5a,6-etrahyd~o dibenæ[cd,f]indole derivatives having ethyl and n-propyl groups in the 4 and 5 positions, which are nowhere specifically described or suggested in this patent, possess a particularly interesting pharmacological profile, inter alia, lvng -duration of action and/or notable potency as central dopaminergic agents and good tolerability.

'~.

2 7 - 2 - 100-5~10 In accordallce with the inventioll there are provided compounds of formula I, w~erein P~l and R2 independently, are ethyl or nrpr~yl radicals, and the R3 substituents are the same and are hydroxy or acyloxy radicals, in racemic form having the relative configuration 4~*,5aS*, or in optically active isomer form having the absolute configuration 4S,5aR.
Tne acyloxy radicals are conveniently radieals of formula Ra ~ CO - (i) in which Ra is an alkyl radical, (C3 7)cycloalkyl, a ~henyl xadical or a 5- or 6-membered heterocyclic ring.
When Ra is an alkyl radi.cal,this may conveniently contain 1~17 carbon atoms, preferably 1 to 7 carbon atoms, and may be straight chain or branched chain.
,~ t ' ' ~ - ' ' ' ' - ' . . :

'.

~ lG2~7

3 --( Ra may be a substituted alkyl radical, con-taining .in -the alkyl chain conveni.ently 1-5 carbon atoms. Conveniently it is a monosubstituted alkyl radical. The substituents may be, e.g. carboxy, hydroxy, amino, (Cl 4)alkylamino, (C1 4)alko~y, di-(Cl 4)alkylamino, halogen, (Cl_4)alkylthio, phenoxy, a phenyl radical, l~pyrrolidinyl, piperidino or morpholino, and conveniently a phenyl radical Ra may also be e.g. an alkyl radical containing in the alkyl chain 1-4 carbon atoms and substituted by (C3 7)cycloalkyl.
~ en Ra is a phenyl radical or alkyl substi-tuted by a phenyl radical, the phenyl radical may be unsubstituted or contain 1, 2 or 3 identical or diffe-rent substituents, selected, for example, from halogen,trifluoromethyl, (Cl_4)alkyl, (Cl ~)alkoxy, (Cl_4)alkylthio and di-(Cl 4)alky1aminot or a methylene-dioxy group. Preferably the phen.yl ring is mono- or disubsti~u~ed.
When Ra is an alkyl substituted by a phenyl radical, Ra is preferab7y a benzyl radical. The phenyl ring may bear substituents selected, for example, from halogen~ (Cl_4)alkyl, (Cl_4)alkoxy or (Cl 4)alkyl-thio.

~1 2~

When Ra is a heterocyclic ring, this is suitably a heterocycle containing oxygen, nitrogen or sulfur as sole heteroatom, e.g. pyridine, thiophene or furan.
Preferably Ra is (cl_7)alkyl; (C3_6)cyclo alkyl; unsu~stituted phenyl; phenyl mono- or disubsti-tuted by chlorine, fluorine, trifluoromethyl, (Cl 4)alkyl or (Cl 4)alkoxy; unsubstituted benzyl;
or benzyl mono- or disubstituted by chlorine, fluorine, (Cl_4)alkyl or (Cl_4)alkoxy.
Halogen may signify chlorine, bromine or fluorine, preferably chlorine or fluorine.
In a group of compounds, Rl is n~propyl and R2 is ethyl. In another group of compounds, Rl and R2 are the same and signify ethyl or n-propyl. Preferabl~
in the compounds of formula.I the R3 substituents are hydroxy. The preferred compounds are the (4S,5aR) optical isomers.
More particularly, the invention provifles a process for the production of compounds of formula I, which comprises a) producing a compound of formula Ia ~ ~2~

HO~

wherein Rl and R2 are as defined above, by splitting the ether groups Z of a compound of formula II

~ -R2 II

wherein ~1 and R2 are defined above and Z is a splittable ether group, in racemic form having the relative configuration 4R*, 5aS*, or in optically active isomer form having the absolute configuration 4S, 5aR, or b) producing a compound of formula Ib 2 Ib .
wherein Rl and R2 are defined above and the radicals R3 are identical acyloxy radicals, by acylating a compound of formula Ia in racemic form having the relative con~iguration 4R*, ~aS* or in optically a¢tive isomer form having the absolute configuration 4S,5aR~

~!

9 ~ 7 The ether splitting process according to process a) may be effected in conventional manner for splitting ether groups. For example the reaction may be carried out by treatment of the starting materials with a strong mineral acid, e.g. hydrobromic or hydroiodic acid, at a temperature of at least 100C, preerably from 100C to the boiling point of the reaction mixture, especially at about 130C. The ether group Z is prefarably a methoxy radical.
The acylation process according to process b), may be effected in conventional manner for the selective acylation of phenolic groups in the presence of an amine function. For example there may be used, as acylating agent, a functional derivative of an acid such as acid chloride, acid bromide or the acid anhydride. Conveniently the reaction is carried out by reacting an acid chloride in the presence of tri-~luoroacetic acid at temperatures from 20C to the boiling point of the reaction mixture or in the pre-sence of pyridine at temperature from 0C to roomtemperature.
Th~ resulting compounds o~ formula I may be isolated from the reaction mixture and purified in known manner. The free base forms of compounds of formula I may be converted into acid addition salt ~`i ,I~f~ ~"

l 3, ~ Vl - 7 - ~00-5410 forms in conventional manner and vice versa. Suitable acids for salt formation are, for example, hydrochloric acid~tartaric a~id, di-0,0-p-toluoyl-D-or L-tartaric acid, and hydrobromic acid.
Racemic compounds of formula I may be obtained from racemic starting materials. Optically active isomers of formula I may be obtained from optically active precursors with the configuration (4S,5aR) or from the racemate. The 4S,5a~ enantiomer may be obtained from racemate by known methods, or example by fractional crystallization of ~iastereo-isomeric salts, e.g. their salts with (+)-di-0,0-p-toluoyl-D-tartaric acid or (-)~di-0,0-p-toluoyl-L-tartaric acid. Racemic resolution into the optically active isomers may be effected preferably at an early stage in ~he synthesis, e.g. before splitting of the ether ~roups.
The starting materials of formula II may be prepare~ by reducing compounds of formula III

Z ~ ~ III

; ~ 7 , . i, 3'~ 7 - ~ 100-5410 wherein Rl, R2 and R3 are as defined above.
The reduction may be effected convenierltly under acidic condi-tions suitable for the acidic reduction of enamines or imines, for example with zinc in an aqueous mineral acid, preferably hydrochlo-ric acid, conveniently in the presence of a mercury (II) salt, for example mercury(II) chloxide. The reaction may suitably be effected for example in ethanol, and at temperatures from 50C to the boiling point of the reaction mixture.
Starting materials of formula III may be prepared, fox example, accoxding the follo~ing reaction scheme:

A;

~ 9 ~ I00-5410 ( II I ) ~ Rl-MgBr or ter t . -butyl~1 \ R -Li lithium ~0-R ~ ~ (VI) R:2 1` ' I C2 I }~al-C0-R

_R2 ~ ~-\i butyl li thium z ~ (YIII) ~-R2 l~iborane ~U-CO-~2 (~X) ~ 1~ COOU~ ~hl ~ ~629~

( In the reaction scheme the radicals Rl, R~
and Z are as deflned above and R2 is methyl or ethyl.
The reactions may be carried out in conventional manner and the products of the above reactions may be isolated and puri~ied in known manner.
In the above intermediates the ether groups Z are conveniently methoxy.
Insofar the preparation or any particular starting material is not particularly described, this may be effected in con'ventional manner.
For example the phenanthrene derivatives which are staxting materials of formula XI, are descrihed in the Elsevier's Encyclopaedia of Organic Chemistry, vol. 13, Tricyclic compounds, Elsevier Publishing Company Inc.
New York (1946).
In the following Examples all tempera~ures are ~iven in degrees Celsius ancl are uncorrected.
EXAMPLE 1:
a) 9-(N-ethyl-N butyryl-amino)--3-bromo-3,4-dimethoxy-phenanthrene [compound of formula IVJ
A solution of 50 g 5138 mM) 9-ethylamino-8-bromo-3,4-dimethoxy-phenanthrene in 57.5 ml 5333 mM) N-ethyl-diisopropylamine and 420 ml methylene chloride is added dropwise, with stirring, under a nitrogen \, ~ ~2~7 ( atmosphere over a period of 20 minutes to a solution o~ 28.8 ml (276 m~1) butyryl chloride in 420 ml methylene chloride. During the addition the reaction mixture i5 maintai~ed at room temperature by cooling in a water bath. The resultant yellow-red solution is then worked up in known manner to afford 9-(N-ethyl-N-butyryl-amino)-8-bromo-3,4 dimethoxy-phenanthrene;
M.pt 102-104.
b) (4RS)-5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-. .

4~n-propyl-dibenz[cd,f]indole [compound of formula III]
25 g (58.14 mM) of 9-N-ethyl-N-butyryl amino)-8-bromo-3,4-dimethoxy phenanthrene are dissolved with stirring in 450 ml anhydrous tetrahydrofuran and the solution obtained is cooled to -25 with a bath of methylena chloride and dry ice. 73 ml tll6.28 mM) of a 1.7 molar solution of tert.~butyl-lithium in pentane are then added dropwise over 4 minutes. Then the temperature of the reaction mixt~re is allowed to increase to ~5 over a period of 30 minutes, the reaction mixture is poured ontG 500 ml of a mixture water and ice, extracted three times with, each time, 500 ml methylene chloride, and the organic phases are washed with water, dried and evaporated. After the product is dried in high vacuum, the~e is obtained ~,~

1 ~;2~ ~

(4RS)-5-ethyl-4,5~dihydro-4-hydroxy-9, 10-dimethoxy-4-n-propyl-dibenz[cd,f]indole in the form of a yellow green foam.
c) (~ (4R*,saS*)-5-ethyl-4,5,5a,6-tetrahydro-9,10-dimethoxy-4-n-propyl~dibenz[cd,f]indole [compound of for-mula II]
A suspension of 40.6 g (116 mM) of (4RS)-5-ethyl-4,5 dihydro-4~hydroxy-9,10-dimethoxy-4-n-propyl-dibenæ~cd,f]indole in 1060 ml ethanol is added with stirring to a suspension o 140 g of zinc dust and 31.6 g ~116 mM) of mercury tII) chloride in 1060 ml distilled water (alternatively the zinc dust/
mercury chloride may be added to the dibenz-indole).
The re~ction mixture is refluxed, 360 ml of 18~
hydrochloric acid are added dropwise over a period of 15 to 20 minutes and the mixture is refluxed overnight with stirring. The reaction mixture is cooled to room temperature, filtered and the zinc amalgam is washed with 500 ml methylene chloride. The filtrate is made alkaLine with 1 litre of concentrated NH40H
and the alkaline phase is extracted o~ce with 1 litre methylene chloride and twice with, each time, 500 ml methylene chloride. ~he combined organic phases are washed with water, dried and evaporated. The resultant oil is chromatographled on silicagel using methylene chloride with 2~ methanol as eluant to give (~)-(4R*,5aS*)-5--ethyl-4,5,5a,6-tetrahydro-9,10-dimethoxy-4-n-propyl-dibenzLcd,f]
S indole in form of an oil.
EXAMPLE 2:
The (4RS)-5-ethyl-4,5-dihydro-4-hydroxy-9, 10-dimethoxy~4-n-propyldibenz[cd,f]indole obtained in the Example lb), may also be prepared as foliows:
0 a) 9-amino-3,4-dimethoxy-phenanthrene [compound of formula X~
A mixture of 430 ml (3.08 moles) trifluoro-acetic anhydride and 430 ml (5.62 moles3 trifluoro-acetic acid is added at room temperature under a nitrogen atmosphere to 53.6 g (0.19 mole~ 3,4-dimethoxy-phenanthrene~9-car~oxylic acid and the mixture is stirred for 10 minutes. ~fter the mixture is cooled to -5, 15.2 g (0.234 mole) sodium azide are care-fully added in solid form, the mixture is stirred for 3 hours at 2, poured onto ice and the resulting suspension worked up in known manner to give 9-amino-3,4-dimethoxy-phenanthrene as a solid. The hydrochloride melts at over 215 with decomposition.
b) 9-acetylamino-3,4-dimethoxy-phenanthrene [compound of formula IX]

; `~, ~ 3.623'~7 (~
55 ml (0.319 mole) N-ethyldiisopropylamine are added to a solution of 38.2 g (0.151 mole) 9-amino-3,4-dimethoxy-phenanthrene in 200 ml methylene chloride. To the resulting mixture is added dropwise over 20 minutes a solution o~ ~0.8 ml (0.292 mole) acetyl chloride in 250 ml methylene chloride. During the addition, the temperature of the reaction mixture is maintained at 20 by cooling with an iCP bath.
The reaction mixture is stirred for 14 hours at room temperature and worked up in known manner to afford 9-acetylamino-3,4-dimethoxy-phenanthrene;
M.pt. 190-195 after recrystallisation from ethex.
c) 9-ethylamino-3,4-dimethoxy-phenanthrene [compound of formula VIII]
34 g (0.124 mole) 9-acetylamino-3,4-dimethoxy-phenanthrene in suspension in 450 ml anhydrous tetrahydrofuran are reduced with 500 ml (0.5 mole) of a molar solution of diborane in anhydrous tetrahydro~uran and worked up in known manner to give 9-ethylamino-3,4-dimethoxy-phenanthrene; M.pt. 94-95.

1 lB292 7 d) 4,5-dihydro-9, 10-dimethoxy-5-ethy_-4-oxo-dibenz-[cd,f]indole [compound of Eormula VI~
122 ml (0.2 mole) oE a 15~ solution of n-butyl-lithium in hexane are added at 0, under a nitrogen atmosphere, to a solution of 28.1 g (0.1 mole) of 9-ethylamino-3 r 4-dimethoxy-phenanthrene in 300 ml anhydrous tetrahydrofuran; the reaction mixture becomes bright red. Dxy ice is then added until the colouration disappears : the formation of a solution with yellow-green fluorescence is observed. After the temperature o~ the reaction mixture is allowed to reach room temperature, the mixture is poured onto water/ice, extracted three times with methylene chloride and the organic phase dried over sodium ~ulfate and evaporated. There is thus obtained 4,5-dihydro-9, 10-dime~hoxy-5-ethyl-4-oxo-dibenz~cd,f]-indole which melts at 125-126 (with decomposition) after crystallisation from ether/petxoleum ether.
e) ~4RS3-5-ethyl-4,5-dihydro-4-h~droxy-9, 10-dimethoxy-4-n-propyl-dibenzlcd,f3indole [compound of formula III]
2.1 ml (33mM) of a solution of _-propyl-magnesium bromide in ether are added dropwise at room temperature to a solution o 10 g (33mM~ of 4,5-dihydro-9, 10-dimethoxy-5-ethyl-4-oxo-dibenz~cd,f]indole in 300 ml anhydrous ~etrahydrofuran. After 30 minutes, .. ~
.~

23~

f a solution of ammonium chloride is added, the mixture extracted with methylene chloride and the organic phase dried and evaporated to give (4RS)-5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-n-propyl-dibenz [cd,f]indole in the form of a yellow green foam.
[IR Spectrum (CH2C12) : 3540 cm (OEI)]. The crude product is directly used ~or the next step.
EXAMPLE 3: (+)-~4R*,5aS*)-5-ethyl-4 ! 5,5a,6-tetrahydro-9,1~-dihydroxy-4-n-propyl-dibenz[cd,f]indole 20g (27.66 mM) (~)-(4R*,5aS*)-5-ethyl-4,5,5a,6-tetrahydro-9,10-dimethoxy-4-n-propyl~dibenz [cd,f]indole in 200 ml of a 47% aqueous solution of hydrobromic acid are warmed for ~ hours at reflux, at a bath temperature of 150. 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 then with ether and dried under high vacuum. There is thus obtained ~ (4R*/5aS*)-5-ethyl-4,5,5a,6-tetra-hydro-9,10-dihydroxy-4-n-propyl-dibenz[cd~f]indole hydrobromide whi~h melts at 200 with decomposition.
The following compounds may be prepared in analogous manner from the appropriate starting materials :

.~

9 ~ 7 a) (+)-(4R*,5aS*)-4,5-diethyl-4,5,5a,6-tetrahydro-9,10-dihydroxy-dibenz[cd,f]indole (hydrobromide, M.pt >175 with decompo 5 ition);
b) (+)-(4R*,5aS*)-4,5,5a,6-tetrahydro-9,10 dihydroxy-4/5-di-n-propyl-dibenz[cd~f]indole(hydrobromide~
M.pt > 190 with decomposition).
c) (+)-(4R*,5aS*)-4-ethyl-4,S,5a,6-tetrahydro-9,10-dihydroxy-5-n-propyl-dibenz[cd,f]indole.
EXAMPLE 4: (-)-(4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro-9,lO-dihydroxy-4-n-propyl-dibe-z[cd~f]indole a) (-)~(4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro-9,10-dimethoxy-4-n-propyl-dibenz[cd,f]i~dole 30 g (89 mM) of (+)-~4R*,5aS*)-5-ethyl-4,5,5a,6-tetrahydro-9,10-dimethoxy-4-n-propyl-dibenz [cd,f~indole are dissolved in 300 ml ether and a solution of 35.95 g of (-)-di-0,0-p-toluoyl-L-tartaric acid monohydrate in 300 ml ether is added with stirring. The mixture is further stirred for one hour at room temperatura, a total of l litre ether being added in portions during this period. The resultant precipitate is filtered off under suction, washed wi~h ethyl acetate until it remains light yellow, and dxied.

,1; ~
~,. ~

.

'2~

( 61.88 g of the crystals obtained from the first crystallisation are dissolved in 1 litre acetone and 300 ml methanol at reflux and the solution is filtered and concentrated until a major part of the product crystallizes out. The mixture is stirred for about 15 minutes, the product is filtered off under suction, washed with ethyl acetate until it remains colourless and dried.
The resulting product is recrystallis~d in the same manner by using 1.7 litres acetone and 35 ml methanol to give colourless crystals.
The resulting crystals are recrystallised in the same manner, by using 1~2 litres acetone and 60 ml methanol. There is thus obtained ~ t4S,5aR)-5-çthyl 4,

5,5a,6-tetrahydro-9, 10-dimethoxy-4-n-propyl-dibenz lcd,f]indole (~)-di-0,0-p-toluoyl-L-taxtrate in form of colourless crystals which melt at 178-179;
~a]D =-138 (c = 0.29 in methanol).
The following compounds may be prepared in analogous manner from the appropriate starting materials:
- (-)-(4S,5aR)-4,5-diethyl 4~5,5a,6~tetrahydro-9, 10-dimethoxy-dibenz[cd,f]indole (-)-di-0,0 p-toluoyl-L-tartrate, M.pt 187-189; [a]D =-138 ~c=0.5 in methanol); the racemic starting material ., .~

, ( is reacted first with (~)-di-0,0-p-toluoyl-D-tartaric acid instead of the L-isomer and the mother liquor obtained on crystallisation is treated with NH40H to liberate the base. The base is reacted with (-)-di-0,0-p-toluoyl-L-tartaric acid and the crystals obtained from an ether solution.

- (-)-(4S,5aR~-4,515a,6-tetrahydro-9,10-dimethoxy-4,5-di-n-propyl-dibenz[cd,f]indole (-)-di-0,0-p-toluoyl-L-tartxate, M.pt 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,]îndole Proceeding as described in Example 3, (-) (4S,5aR)-5-ethyl-4,5/5a,6-tetrahydro-9,10-dihydroxy-4-n-propyl-dibenz[cd,f]indole hydro~romide is obtained from the tartrate obtained above under a). It melts above 210; [a]20 = -64 (c = 0.245 in methanol).
The corresponding hydrochloride melts at above 185 with decomposition; [a~20 = _750 (~ = 0.28 in methanol).

The following compounds may be prepared inanalogous manner as described in Example 4b) from the appropriate starting materials:
a) (-)-(4S,5aR)-4,5-diethyl-4,5,5a,6-tetrahydro-9,10-i3 ~ 7 ( dihydroxy-dibenz[cd,f]indole hydrochloride, M.pt.200 with decornposition; [a]20 = -72 (c = 0.25 in methanol);
b) (-)-(4S,5aR)-4,5,5a,6-tetrahydro-9,10-dihydroxy-4,5~di-n-propyl-dibenz[cd,f]indole hydrochloride, M.pt > 187 with decomposition; [a]20 = -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,f3indole.
EXAMPLE 6: (+)-(4S,5aR)-5-ethyl-9,10-dibenzoyloxy-4,5,5a,6-tetrahydro-4-n-propyl-dibenz[cd,f]lndole 0.376 ml t3.23 mM) of benzoyl chloride are added dropwise with stirring, over 5 minutes and at a temperature of +5, to a solution of 600 mg (1.54 mM~ of ~ )-(4S,5aR)-5 ethyl-4,5,5a,6-tetrahydro-9, 10-dihydroxy-4-n-propyl-dibenz[cd,f~indole hydro-bxomide in 5 ml anhydrous pyridine and the reaction mixture is further stirred for 14 hours at room temperature. The mixture is then evaporated to dryness, the residue is dissolved in methylene chloride and the solution i~ washed first with a mixture of ice and a saturated solution of potassium bicarbonate, and then with water. ~rhe aqueous phases are extracted twice with methylene chloride and the combined organic .~

~ c) 2 3 2 7 ( phases are dried and evaporated. The residue is dissolved in methylene chloride and the solution evaporated under high vacuum. The procedure of dissolving the residue in methylene chloride and evaporating is repeated twice more. 550 mg of the resulting product are dissolved in acetone and this solution is added dropwise to a solution of 156 mg L(+)-tartaric acid in acetone. The resultant preci-pitate is filtered off and dr~ied to give (+)-(4S,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 crystallisa-tion in ethyl acetate/ether; [a]24 = +23.5 (c = 0.28 in methanol).
The following compoumds may ba prepared in analogous manner from the appropriate starting materials - (-)-(4S,SaR)-9,10-diacetoxy-5-ethyl-4,5,5a,6-tetrahy-dro-4-n-propyl-dibenz[cd,f]indole hydrochloride, M.pt ~188 (with decomposition); [a]20 =-99 (c = 0.28 in methanol).
- (-)-~4S,5aR)~5-ethyl-4,5,5a,6-tetrahydro-4-n-propyl-9,10-dipropionyloxy-dibenz[cd,f]indole hydro chloride, M.pt > 175 ~with decomposition) [a]D = 76 (c = 0.25 in methanol);
- (-)-(4S,5aR)~9,10-dibutyryloxy-5-ethyl-4,5,5a,6-. ' . ' ~J ~
`
'.

' .~
`.
' tetrahydro-4-n-propyl-dibenz[cd,f]indole hydrochloride, M.pt > 105 (with decomposition); [a]D = -77 (c=0.28 in methanol) - (-)-(4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro-9,10-diisobutyryloxy-4-_-propyl-dibenz[cd,f~indole hydrochloride, M.pt > 165 (with decomposition); [a]D = -96 (c=0.29 in methanol).
- t-)-(4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro 4-_-propyl--9,10-divaleryloxy-dibenz[cd,f]indole hydrochloride;
- (-)-(4S,5a~)-5-ethyl-4,5,5a,6-tetrahydro 4-n-propyl-9,10-dipivaloyloxy-dibenz[cd,f~indole hydrochloride;
- (-~-(4S,5aR)-4,5,5a,6-tetrahydro-9,10-dipropionyloxy-4,5-di-n-propyl-dibenz[cd,f]indole, M.pt. 115, [a]D = -67 (c = 0.51 in methanol).
~5 In analogous manner to Example 6, the following compounds of formula I wherein Rl and R2 are each independently ethyl or _-propyl and R3 is - acetoxy - propionyloxy ?0 ~ butyryloxy - isobutyryloxy - valeryloxy - pivaloyloxy may be prepared.

3 ~ ~

The compounds of formula I possess pharmacolo-gical activity. In particular, the compounds are indicated ~or use as central dopaminergic stimulant agents, as indicated by ~he following standard tests:
~`he dopaminergic activity of compounds of formula I was studied in the rat according the method descrihed by U. Ungerstedt in Acta Physiol. Scand., Suppl. 367, 69-93 (1971). 6-hydroxydopamine is unila-terally injected in the substantia nigra which pro-duces, after a week, unilateral degeneration of nigro-striatal pathways. Administration of from about 0.03 to a~out 1 mg/kg i.p. of the compounds of formula I to these rats leads to a notable turning behaviour of long duration contralateral to ~he lesion~
The central dopaminergic activity of compounds of formula I has been also confirmed according the following test.
Rats, 180-222 g, are placed in perspex cylinders of 30 cm diameter on a wire grid floor.
~o After 30 minutes to allow acclimatisation to the cag~, the rats are injected with the compound under invest~gation. The behaviour o~ the ra-ts is observed for 2 minutes at 30 minutes inter~Tals or 2 hours and then at 60 minutes intervals for total of up to 6 hours. The de~ree of stereotyped behaviou~ observed is ~...... S
, , - 2~ 2'.3 ~ ~ 100-5410 assessed using a scoring system based on that descri-bed by Costall, Naylor and Olley [Euro J. Pharmac.
8, 83-9~ (19721.
The scores and criteria are as follows :
1. Intermittent sniffing 2. Persistent sniffing, occasional licking 3. Licking, occasional biting 4. Intense and persistent biting.
Administered i.p. from about 0.03 to about 30 mgfkg animal body weight, the compounds of formula I induce stereotyped sniffing, licking and biting behaviour in the rat.
The compounds are therefore indicated for use as central dopaminergic stimulant agents, for example for txeating Morbus Parkinson. For this indi-cation, an indicated daily dose is from about o.l to about 20 mg, conveniently administered in divided doses 2 tc 4 times a day in unit dosage form contai-nin~ from about 0.025 to about 10 mg, or in sustained Ielease fo~m.
The compounds of the invention exhibit fur-~hermore anti-depressant activity, as indicated by the inhlbition of catalepsy induced by reserpine in mice on s.c. administration of about 0.001 mg to about 1 mgfkg of the compounds and by the inhibition of ~ !

~ 25 - 100-5410 t the catalepsy induced by tetrabenazine in rats on i.p. administration of about 0.2 to about 2 mg/kg of the compounds.
The compounds are therefore indicated for use as anti-depressant agents.
An indicated daily dosage is in the range from about 0.05 to about 2 mg, conveniently given in divided doses 2 to 4 times a day in unit dosage form containing from about o.01 mg to about 1 mg - 10 of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.
The com~ounds of forrnula I exhibit furtner-more prolactin secretion inhibition as indicated by the lowering of serum levels of prolactin of the rat after lS s.c. administration of from about 0.1 to about 1 mg/~g o~ th2 compounds, using radio-immunolo~ical techniques, e.g. described by Niswender, G.D. et al., siol. & Med.
130, 793 (196~ and Neil, J.J. et al., Endocrinology 88, 54~ (1971).
The compounds of formula I are therefore - indicated ~or use as prolactin inhi~itors,e.g. in the treatment of conditions involving hyperprolactinemia, sucn as menstrual dysfunctions, e.g. ammenorrhea and ga-lactorrhea, or hypertension of mammary carcinoma asso-ciated with elevated serum prolactin levels, or in the ~ 1 t) ~

treatment or co~ditions involving hypogonadis~, e.g.
infertility or impotence, or in the regulation of post-partem lactation.
An indicated daily dosage is in the range from about 5 to about 50 mg, conveniently given in divided doses 2 to 4 times a day in unit dosage form containing from about 1.25 mg to about 25 mg of the compounds ad~ixed with a solid or liquid pharmaceu---tical carrier or diluent.
The compounds of the invention exhibit further-more antipsychotic activity as indicate by the inhibi-tion of the locomotion in mice on s.c. administra~ion of from about 0.001 mg to about 0~1 mg/kg of the compounds and by the dopamine agonistic action on the presynaptic receptors of the rat at doses of from about 1 mg to about 10 mg/~g of ~he compounds, accordîng the ollowing test.
The dopamine agonistic action of the compounds of formula I on the presynaptic receptors was studied on the rat using the in vivo method des-cribed by J.R. Walters and coll. in Maunyn Schmiede-ber~'s Arch. Pharmacol. 296, 5-14 (1976). The dopami-nergic L~e flo~ was inhibited pharmacologically by ~-butyrolactone. The activity of the aromatic amino acid decarboxylase was inhibited by hydroxy-- ~7 - loO-5410 benzylhydrazine (I~SD 1015) and half an hour later the rats were sacrificed. The resulting accumulation of DOP~ during 30 minutes in striatal tissue was taken as a ~asure of the in vivo activity of tyrosine hydroxylase. Administration per os of the compounds reversed the effects of ~-butyrolactone in a dose dependent manner.
The compounds of formula I are therefore indicated for use as antipsychotic agents, fox example for the treatment of schizophrenia. An indicated daily dosage is in the range from a~out 0.01 to about 1 mg, conveniently given in divided dc~es 2 or 4 times a day in unit dosage form containing from about 0.0025 mg to about 0.5 mg of the compounds admixed 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-propyl-dibenz[cd,f]
indole, (~S,SaR)-4-ethyl 4,5,5a,6-tetrahydro-9,10-dihydroxy-5-n-propyl-9,10-dihydroxy-dibenz~cd,]indole, ~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-propyl-dibenz~cd,f]indole and the corresponding di-n-propionyl-and di-isobutyryl-ester-derivatives are the preferred compounds.
Tne compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. These salt forms exnibit the same order of activity as the free base forms.
The present invention also provides a pharma-c~utical composition comprising a compound of formula I, in free base form or in pharmaceutically acceptable acid addition salt ~orm~in association with a phar~aceutically acceptable diluent or carrier.
These compositi~s may be formulated in con-ventional manner so as to be, for example, a solution, 2 capsule or a tablet.

Claims (4)

Claims:

1. A process for the production of compounds of formula I

I

wherein R1 and R2 independently are ethyl or n-propyl radicals, and the R3 substituents are the same and are hydroxy or acyloxy radicals, in racemic form having the relative configuration 4R*,5aS* or in optically active isomer form having the absolute configuration 4S,5aR, which comprises a) producing a compound of formula Ia Ia in which R1 and R2 are as defined above, by splitting the ether groups Z in a compound of formula II

.29.

II

in which R1 and R2 are defined above and Z is a split-table ether group, or b) producing a compound of formula Ib Ib in which R1 and R2 are defined above and the radicals R? are identical acyloxy radicals, by acylating a compound of formula Ia, and recovering the obtained compound of formula I in free base form or an pharmaceutically acceptable acid addition salt form.

2. A compound of formula I as defined in claim 1 in free base form or in pharmaceutically acceptable acid addition salt form whenever prepared by a process as claimed in claim 1 or by an obvious chemical equivalent thereof.

. 30 .

3. The process of claim 1 wherein R1 is n-propyl, R2 is ethyl and the substituents R3 are hydroxy.

4. The compound (4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro-9,10-dihydroxy-4-n-propyl-dibenz[cd,f]indole, in free base form or a pharmaceutically acceptable acid addition salt thereof, whenever produced by the process of claims 3 or an obvious chemical equivalent thereof.

.31.