NZ197529A

NZ197529A - 4,5-dialkyl-9,10-di(hydroxy or acyloxy)-4,5,5a,6-tetrahydrodibenz(cd,f)indoles

Info

Publication number: NZ197529A
Application number: NZ197529A
Authority: NZ
Inventors: R K A Giger
Original assignee: Sandoz Ltd
Priority date: 1980-06-27
Filing date: 1981-06-25
Publication date: 1984-07-06
Also published as: ES515568A0; SE8103983L; PT73258B; GB2136418B; FI811922L; KE3749A; GB8325760D0; ES8300701A1; PH22773A; FI75153B; AT380875B; NL8103041A; SG62087G; IE51341B1; GB2136418A; SE449222B; CY1399A; ES515567A0; IT8148776A0; ES8400088A1

Description

New Zealand Paient Spedficaiion for Paient Number 1 97529 197529 I Priority1 Dats{s); 7-71 .'£.9} I CompSsta Specification Filed: . b.' „a.l Clc53s: .WR KO.Vx hb I Pubticafion Data: ...... r.

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' V,. ;* 2 5 JUW1981 NEW ZEALAND i&ECBVED PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION HETEROCYCLIC CCMPOINDS, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM X/We, SANDOZ LTD., 35 Lichtstrasse, CH-4002 Basle, Switzerland, a Swiss Body Corporate, hereby declare the invention for which 3lX/ we pray that a patent may be granted to aooe/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - (followed by la) IS7529 - la - Heterocyclic compounds, their preparation and pharmaceutical compositions containing them The present invention relates to phenanthrene derivatives, their preparation and pharmaceutical compositions containing them.

New Zealand Patent Specification No. 190786 describes a class of 4,5,5a,6-tetrahydro-dibenz[cd,f]indole derivatives having stimulant activity on central dopaminergic receptors. All the compounds specifically 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*,5aS*)-4,5,5a,6-tetrahydro-dibenz[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 specification, possess a particularly interesting pharmacological profile, inter alia, long duration: of action and/or notable potency as central dopaminergic agents and good tolerability. t 975 - 2 - £00-5 410 In accordance with the invention there are provided compounds of formula I, wherein R1 and R2 independently, are ethyl or nrprcpyl radicals, and the R^ 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.

The acyloxy radicals are conveniently radicals of formula R - CO - O - cl in which R is an alkyl radical, (C_ n)cycloalkyl, cl / a phenyl radical or a 5- or 6-membered heterocyclic ring.

When R is an alkyl radical,this may cl conveniently contain 1-17 carbon atoms, preferably 1 to 7 carbon atoms, and may be straight chain or branched chain. 1 97 5 2 9 R may be a substituted alkyl radical, con- d taining in the alkyl chain conveniently 1-5 carbon atoms. Conveniently it is a monosubstituted alkyl radical. The substituents may be, e.g., carboxy, 5 hydroxy, amino, (C^^)alkylamino, (C^4)alkoxyf di-(C^_4)alkylamino, halogen, (C1-4)alkylthio, phenoxy, a phenyl radical, 1-pyrrolidiny1, piperidino or morpholino, and conveniently a phenyl radical, may also be e.g. an alkyl radical containing in the 10 alkyl chain 1-4 carbon atoms and substituted by (C3_?)cycloalkyl.

When Rfl is a phenyl radical or alkyl substituted by a phenyl radical, the phenyl radical may be unsubstituted or contain 1, 2 or 3 identical or diffe-15 rent substituents, selected,for example,from halogen, trif luoromethy 1, (C^_^)alkyl, (C^^) alkoxy, (C1_4)alkylthio and di-(C;1_4") alky lamino, or a methylene-dioxy group. Preferably the phenyl ring is mono- or disubstituted.

When R is an alkyl substituted by a phenyl a radical, R is preferably a benzyl radical. The ct phenyl ring may bear substituents selected, for example, from halogen, (C1_4> alkyl, (C1_4) alkoxy or (C^Jalkyl-thio. 1 975 - 4 - 100 5119- When R& is a heterocyclic ring, this is suitably a heterocycle containing oxygen, nitrogen or sulfur as sole heteroatorn, e.g. pyridine, thiophene or furan.

Preferably R& is (C^^) alkyl; (C3_g)cyclo-alkyl; unsubstituted phenyl; phenyl mono- or disubsti-tuted by chlorine, fluorine, trifluoromethy1, (C^_^)alkyl or (C^_4)alkoxy; unsubstituted benzyl; or benzyl mono- or disubstituted by chlorine, fluorine, (Cj_4)alkyl or (c1-4)alkoxy.

Halogen may signify chlorine, bromine or fluorine, preferably chlorine or fluorine.

In a group of compounds, R^ is n-propyl and R2 is ethyl. In another group of compounds, R^ and R2 are the same and signify ethyl or n-propyl. Preferably in the compounds of formula I the R^ substituents are hydroxy. The preferred compounds are the (4S,5aR) optical isomers.

More particularly the invention provides a process for the production of compounds of formula I, which comprises a) producing a compound of formula la 1 97 5 2 -100 5410 la wherein . R^ and R^ are as defined above, by splitting the ether groups Z of a compound of formula II II wherein R^ and R^ 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 lb lb wherein and R2 are defined above and the radicals R^ are identical acyloxy radicals/by acylating a compound of formula la in racemic form having the relative configuration 4R*,5aS* or in optically active isomer form having the absolute configuration 4S,5aR. - 6 1 975° 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 mate-5 rials with a strong mineral acid,e.g. hydrobromic or hydroiodic acid, at a temperature of at least 100°C, preferably from lOO°C to the boiling point of the reaction mixture, especially at about 130°C.The ether group" Z is preferably a methoxy radical. 10 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 15 acid such an acid chloride, acid bromide or the acid anhydride. Conveniently the reaction is carried out by reacting an acid chloride in the presence of tri-fluoroacetic acid at temperatures from 20°C to the boiling point of the reaction mixture or in the presence of pyridine at temperature from 0°C to room temperature.

The resulting compounds of 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 1 97 5 2 j.00 5410 forms in conventional manner and vice versa. Suitable acids for salt formation are, for example, hydrochloric acid,tartaric acid, di-0,O-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,5aR enantiomer may be obtained from racemate by known methods, for example by fractional crystallization of diastereo-isomeric salts, e.g. their salts with (+)-di-0,O-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 the synthesis, e.g. before splitting of the ether groups.

The starting materials of formula II may be prepared by reducing compounds of formula III 1S7529 wherein R^, and Z are as defined above.

The reduction may be effected conveniently under acidic conditions suitable for the acidic reduction of enamines or imines, for example with zinc in an aqueous mineral acid, preferably hydrochloric acid, conveniently in the presence of a mercury (II) salt, for example mercury(II) chloride. The reaction may suitably be effected for example in ethanol, and at temperatures from 50°C to the boiling point of the reaction mixture.

Starting materials of formula III may be prepared, for example, according to the following reaction scheme: 1975 2 9 •100 5410 (III) tert.-butyl A lithium ' t Hal-CO-R, (XI) (V) R -MgBr or R^-Li NaN3 COOH 0 (VI) t CO, R- (VII) t n-butyllithi thium (VIII) NH-R, Diborane (IX) NH-CO-R^ R^-CO-Hal (X) In the reaction scheme the radicals R^, R^ and Z are as defined above and R^ is methyl or ethyl. The reactions may be carried out in conventional manner and the products of the above reactions may be isolated and purified in known manner.

In the above intermediates the ether groups Z are conveniently methoxy.

Insofar as the preparation of any particular starting material is not particularly described, this may be effected in conventional manner.

For example the phenanthrene derivatives which are starting materials of formula XI, are described in the Elsevier's Encyclopaedia of Organic Chemistry, vol. 13, Tricyclic compounds, Elsevier Publishing Company Inc. New York (19 46).

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

EXAMPLE 1 : a) 9-JN-ethvl-N-butvryl-a^ino)_~3-^£0^0-3^4-0100 thoxv-_ [compound of formula IV] A solution of 50 g (133 mM) 9-ethylamino-3-bromo-3,4-dimethoxy-phenanthrene in 57.5 ml (333 nM) N-ethy1-aiisopropylamine and 420 ml methylene chloride is added dropwise, with stirring, under a nitrogen 197520 atmosphere over a period of 20 minutes to a solution of 28.8 ml ( 276 roM) butyryl chloride 'in'420 ml methylene chloride. During the addition the reaction mixture is maintained at room temperature by cooling in a water bath.

The resultant yellow-red solution is then .stirred for 4 hours at room temperature and the reaction mixture is partitioned between methylene chloride and 2N sulphuric acid. The aqueous phase is extracted twice, each time with 300 ml methylene chloride, and then the. organic phases 10 are dried and evaporated. The residue is dissolved at 40° in 200 ml ether and the product is allowed to crystallize out. 200 ml petroleum ether are added prtionwise to the stirred mixture and the precipitate is filtered off under suction, washed with petroleum ether and dried, to 15 afford 9 -(N-ethy 1 - N-butyryl-amir.o)-8-5romo-3,4-dimethoxy-phenanthrene; M.pt, 102-104°. b) i111 > § :dihydro^4;h^droxy- 9^ 1 0- dimethoxy^ ^iQiQEOG^lldi^enz[cd^fDindole [compound of formula III] g (58.14 roM) of 9-(N-ethyl-N-butyryl-ami no)-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 methylene chloride and dry ice. 73 ml (116.28 mM) of a 1.7 molar solution of tert. butyl-1ithium in pentane are then added dropwise over 4 25 minutes. Then the temperature of the reaction mixture is allowed to increase to +5° over a period of 30 minutes, the reaction mixture is poured onto 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, there is obtained 1 97 5 2 - 12 - IQQ-E^ie— (4RS)-5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-n-propy1-dibenz [cd, f ] indole in the form of a yellow green foam. c) J*) -_(4R*i5aS*2-5-ethy 1-4^5 , Sa^G-tetrahydro-O , 10- [expound °f for mula II] A suspension of 40.6 g (116 mM) of (4RS)-5-ethy1-4 , 5-dihydro-4-'nydroxy-9 , lO-dimethoxy-4-n-propy 1-dibenz[cd,f]indole in 1060 ml ethanol is added with stirring to a suspension of 140 g of zinc dust 10 and 31.6 g (116 mM) of mercury (IIT chloride in 1060 ml distilled water ( alternatively the zinc dust/mercury chloride may be added to the dibenz-indole).The reaction mixture is refluxed, 360 ml of 18% hydrochloric acid are added dropwir.e over a 15 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 20 concentrated NH40H and the alkaline phase is extracted once with 1 litre methylene chloride and twice with, each time, 500 ml methylene chloride. The combined organic phases are washed with water, dried and 1975 29 100-5 410 evaporated. The resultant oil is chromatographicd on silicagel using methylene chloride with 2% methanol as eluant.to give (-)-(4R*,5aS*)-5-ethy1-4,5,5a,6- tetrahydro-9,10-dimethoxy-4-n-propy1-dibenz[cd,f ] 5 indole in form of an oil.

EXAMPLE 2: The (4RS)-5-ethy1-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-n-propyldibenz[cd,f]indole obtained in the Example lb), may also be prepared as follows : 10 a) 9-amino-3^4-dimethoxY-ghenanthrene [compound of formula X) A mixture of 4 30 ml (3.OS moles) trifluoro-acetic anhydride and 4 30 ml (5.62 moles) trifluoro-acetic acid is added at room temperature under a 15 nitrogen atmosphere to 53.6 g (0.19 mole) 3,4- dimethoxy-phenanthrene-9-carboxylie acid and the mixture is stirred for 10 nvLnutes.After the mixture is ccoled to -5°, 15.2 g (0.234 mole) sodium azide are carefully added in solid form, the mixture is stirred for 20 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-acet^lamino-3 , 4-dimethoxy-ghenanthrene [compound 25 of formula IX] -1 4- 197529 5 ml (0.319 mM) N-ethy 1 dii so propyl amine are added to a solution of 38.2 g (0.151 mM) 9-amino-3,4-dimeth.oxy--phenanth.rene in 200 ml methylene chloride. To.the resulting mixture is added dropwise over 20 minutes a solution of 20.8 ml (0.292 mM) acetyl chloride in 250 ml methylene chloride. During the addition, the temperature of the reaction mixture is maintained at 20° by cooling with a ice bath.

The reaction mixture is stirred for 14 hours at 10 room temperature, then poured onto 2N hydrochloric acid and extracted with methylene chloride. The organic phase is washed with a 2N sodium hydroxide solution and with water, dried and eveporated, to afford 9-acetyl amino-3,4-dime thexy-phenanthrene; W.pt. 190-1 95° after re crystal 1 is at ion from ether. c) ^r^t-^l^lD^I^iil^lIPi^hoxy-pFienanthrene [compound of formula VITT] 34 g (0.124 mM) 9-acety1 am ino-3 ,4-dimethoxy-phenanthrene in suspension in 450 ml anhydrous tetrahydrofuran are reduced with 500 ml (0.5 mM) of a molar solution of diborane in anhydrous tetrahydrofuran and worked up in known manner to give 9-ethylamino-3,4-dimethoxy-phenanthrene; M.p t. 94-95' • O 1 975 2 9 - 15 - -100 5410 d) 4i5-dihY<3ro-9 ^lO-dime thoxy-5-e thy 1-4-oxo-dibenz - [cd^f]indole [compound of formula VII 122 ml (0.2 mole) of a 15% solution of _ xv-butyl-lithium in hexane are added at 0°, under a 5 nitrogen atmosphere , to a solution of 28.1 g (O.1 mole) of 9-ethylamino-3,4-dimethoxy-phenanthrene in 300 ml anhydrous tetrahydrofuran; the reaction mixture becomes bright red.Dry ice is then added until the colouration disappears : the formation of a solution 10 with yellow-green fluorescence is observed. After the temperature of 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 15 sulfate and evaporated. There is thus obtained 4,5-dihydro-9,lO-dimethoxy-5-ethy1-4-oxo-dibenz[cd,f]— indole which melts at 125-126° (with decomposition) after crystallisation from ether/petroleum ether. e) J4RS)-5-ethy1-4^5-din^dro-4-hydroxy-9^10-dimethoxy-20 4-n-jorojny l-dibenz_[cdLf ] indole_ [compound of formula III] 2.1 ml (33 mM) of a solution of n-propyl-magnesium bromide in ether are added dropwise at room temperature to a solution of 10 g (33 mM) of 4,5-dihydro-9,10-dimethoxy-5-ethy1-4-oxo-dibenz[cd,f]indole in 25 300 ml anhydrous tetrahydrofuran. After 30 minutes, 1975 -3:00 5 41-e- a solution of ammonium chloride is added, the mixture extracted with methylene chloride and the organic phase dried and evaporated to give (4RS)-5-ethy1-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-n-propy1-dibenz 5 [cd,f]indole in the form of a yellow green foam.

[IR Spectrum (CH^Cl^) : 3540 cm ^ (Oil)]. The crude product is directly used for the next step.

EXAMPLE 3 ; ( —R* , 5aS*)_-5-ethy 1-4 , tc trahYdro- 20 g (27.66 nuM) {-) - ( 4R* , 5aS*)-5-e thy 1- 4,5,5a,6-tetrahydro-9,lO-dime thoxy-4-n-propy1-dibenz [cd,f]indole in 200 ml of a 47% aqueous solution of hydrobromic acid are v/armed for 6 hours at reflux, at a bath temperature of 150°. After evaporation 15 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-ethy1-4,5,5a,6-tetra-20 hydro-9,10-dihydroxy-4-n-propy1-dibenz[cd,f]indole hydrobromide which melts at 200° with decomposition.

The following compounds may be prepared in analogous manner from the appropriate starting materials : 1 9/5 2 - 17 - ao0-5-4ie- a) (-)-(4R*,5aS*)-4,5-die thy1-4,5,5a,6-tetrahydro-9,lO-dihydroxy-dibenz[cd,f]indole(hydrobromide, M.pt >175° with decomposition); + b) (-)-(4R*,5aS*)-4,5,5a,6-tetrahydro-9,lO-dihydroxy-5 4,5-di-n-propyl-dibenz[cd,f]indole(hydrobromide, M.pt ^>190° v/ith decomposition). c) (-)-(4R*,5aS *)-4-ethy1-4,5, 5a,6-tetrahydro-9,10-dihydroxy-5-n-propy1-dibenz[cd,f]indole.

EXAMPLE 4 : (-)-(4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro-10 9,10-dihydroxy-4-n-propy1-d ibenz[ cd,f] indole a) J-).~ dimethoxy-4-n-propy1-dibenz[cd^f|indole g (89 mM) of (-)-(4r*,5aS*)-5-ethy1-15 4,5,5a,6-tetrahydro-9,10-dimethoxy-4-n-propy1-dibenz lcd,f]indole are dissolved in 300 ml ether and a solution of 35.95 g of (-)-di-O,0-p-toluoy1-L-tartaric acid monohydrate in 300 ml etlier is added with stirring. The mixture is further stirred for 20 one hour at room temperature, a total of 1 litre ether being added in portions during this period. The resultant precipitate is filtered off under suction, washed with ethyl acetate until it remains light yellow, and dried. 1 975 2 iee-5^ie- 61.88 g of the crystals obtained from tiie first crystallisation are dissolved in 1 litre acetcne and 3CO 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 recrystallised in the Scime manner by using 1.7 litres acetone 10 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 (-)-(4S,5aR)-5-ethy1-4,5,5a,6-tetrahydro-9,10-dimethoxy-15 4-n-propy1-dibenz[cd,f]indole (-)-di-0,0-p-toluoyl-L-tartrate in form of colourless crystals which melt at 178-179°; [a)^° =-138° (c= 0.29 in methanol).

The following compounds may be prepared in analogous manner from the appropriate starting 20 materials: - {-)-(4S,5aR)-4,5-diethyl-4(5,5a,6-tetrahydro- 9, lO-diine thoxy-dibenz [cd, f ] indole ( - ) - di-0,0-p- 2 0 q toluoyl-L-tartrate, M.pt 187-189°; ta3D = -138 (c=0.5 in methanol); the racemic starting material 1 97 5 2 - 19 - -100 5410 is reacted first with (+)-di-O,O-p-toluoyl-D- tartaric acid instead of the L-isomer and the mother liquor obtained on crystallisation is treated with NH,OH to liberate the base. The base is reacted 4 with (-)-di-0,O-p-toluoyl-L-tartaric acid and the crystals obtained from an ether solution. - (-)-(4S,5aR)-4,5,5a,6-tetrahydro-9,10-dimethoxy-4,5-di-n-propy1-dibenz[cd,f]indole (-)-di-O,0-p-toluoyl-L-tartrate, M.pt 165-166°; [a]^° = -123° (c = 0.27 in methanol), b) MS,5aR)-5-eth^l-4L5i5ai6-tetrahYdrO39i10- dih^d roxy-4 - n-gr opy 1-dibenz^cd^ f]_ indole Proceding as described in Example 3, (-)-(4S,5aR)-5-ethy1-4,5,5a,6-tetrahydro-9,10-dihydroxy-4-n-propy1-dibenz[cd/f]indole hydrobromide is obtained from the tartrate obtained above under a). It melts above 210°; [a]^^ = -64° (c = 0.245 in methanol).

The corresponding hydrochloride melts at above 185° with decomposition; [a]20 = -750 LJ ' " — (c.= 0.28 in methanol). ' EXAMPLE 5:' .

The following compounds may be prepared in analogous manner as described in Example 4b) from the appropriate starting materials: a) (-)-(4S, 5aR)-4,5-diethy 1-4,5,5a,6-tetrahydro-9,10- 1 97 5 dihydroxy-'-dibenz [cd,f] indole hydrochloride, M.pt. 200° with decomposition; [a]p0 = -72° (c = 0.25 in methanol); k) (-) - (4S , 5aR) - 4 , 5 , 5a, 6-tetrahydro-9 , lO-dihydroxy-4,5-di-n-propy1-dibenz [cd, f] indole hydrochloride, M. pt 187° with decomposition; [c0^° = -58.5° (c = 0.35 in methanol), c)(-)-(4S,5aR)-4-ethy1-4,5,5a,6-tetrahydro-9,10-dihydroxy 5-n-propy1-dibenz[cd,f]indole .

EXAMPLE 6 : (+)- (4S, 5aR)-5-ethy 1-9 , lO-dibenzoyloxy- 4,5,5a,6-tetrahydro-4-n-propy1-dibenz[cd,f] indole 0.376 ml (3.23 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-ethy1-4,5,5a,6-tetrahydro-9 ,10-dihydroxy-4-iv-propy 1-dibenz [cd, f ] indole hydrobromide 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 is washed first with a mixture of ice and a saturated solution of potassium bicarbonate, and then with water. The aqueous phases are extracted twice with methylene chloride and .the ccmbined orcjanic 1 97 5 29 _ 21 - jbOO-541-Q- 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 precipitate is filtered off and dried -to give (+}-(4s/5aR)-5-ethy1-9,10-dibenzoyloxy- 4,5,5a, 6-tetrahydro-4-jn_-propy 1-dibenz [ cd, f ] indole M + ) tartrate; it melts at 161-162° after crystallisa- 24 tion in ethyl acetate/ether; = +23.5° (c - 0.28 in methanol)* The following compounds may be prepared in analogous manner from the appropriate starting materials - . (r)-(4S,5aR)-9,10-diacetoxy-5-ethy1-4,5,5a,6-tetrahy- dro-4-n-propy1-dibenz[cd,f]indole hydrochloride, M.pt ">188° (with decomposition); [a]-99° (c = 0.28 in methanol); - (-)- (4S,5aR)-5-ethy1-4,5,5a,6-tetrahydro-4-n-propy 1-9 ,lO-dipropionyloxy-dibenz[cd,f]indole hydrochloride, M.pt >175° (with decomposition); [a]^°= -76° (c = 0.25 in methanol); - (-)-(4S,5aR)-9,10-dibutyryloxy-5-ethy1-4,5,5a,6- 1 97 5 2 - 22 - -^OO 5110 • tetrahydro-4-n-propy 1-d.ibenz [cd, f ] indole hydrochloride,. M.pt >105° (with deccrnpceition); "77° (c^O.28 in methanol) - ( -) - (4S , 5aR)-5-ethy1-4,5,5a,6-tetrahydro-9,10- x d i isobu tyry loxy - 4-ri-propy l-dibenz[od,f] indole hydrochloride, M.pt >165^ (with decomposition); Mp =—96° (c=0,29 in methanol). - (-)-(4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro-4-n-propy 1-9 ,lO-divaleryloxy-dibenz[cd,f]indole hydrochloride; - (-)-(4S,5aR)-5-ethy1-4,5,5a,6-tetrahydro-4-n-propy 1-9,10-dipivaloyloxy-dibenz[cd,f]indole hydrochloride; - (-)- (4S,5aR)-4,5,5a,6 - tetrahydro-9 ,10-dipropionyloxy- 4,5-di-n-propy1-dibenz[cd,f]indole, M.pt. 115°; [al20 =- 67° (c = 0.51 in methanol).

L j D In analogous manner to Example 6, the following compounds of formula I wherein R^ and R^ are each independently ethyl or n-propyl and R^ is - acetoxy - propionyloxy - butyryloxy - isobutyryloxy - valeryloxy - pivaloyloxy may be prepared . *97 5 29 - 23 - -190-5110 The compounds of formula I possess pharmacological activity- In particular, the compounds are indicated for use as central dopaminergic stimulant agents, as indicated by the following standard tests: The dopaminergic activity of compounds of formula I was studied in the rat according the method described by U. Ungerstedt in Acta Physiol. Scand., Suppl. 367, 69-93 (1971). 6-hydroxydopamine is unilaterally injected in the substantia nigra which produces, after a week, unilateral degeneration of nigro-striatal pathways- Administration of from about 0.03 to about 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 the 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.

After 30 minutes to allow acclimatisation to the cage, the rats are injected with the compound under investigation. The behaviour of the rats is observed for 2 minutes at 30 minutes intervals for 2 hours and then at 60 minutes intervals for total of up to 6 hours. The degree of stereotyped behaviour observed is 1 9 / 5 - 24 - 100"5 410- assessed using a scoring system based on that described by Costall, Naylor and Olley [Euro J. Pharmac. 18, 83-94 (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 10 30 nig/kg 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 15 example for treating Morbus Parkinson. For this indication, an indicated daily dose is from about O.l to about 20 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.02 5 to about 10 mg, or in sustained 20 release form.

The compounds of the invention exhibit furthermore anti-depressant activity, as indicated by the inhibition of catalepsy induced by reserpine in mice on s.c. administration of about 0.001 mg to about 25 1 mg/kg of the compounds and by the inhibition of - 197529 the catalepsy induced by tetrabenazine in rats on i.p. administration of about 0.2 to about 2 rag/kg of the coro.pounas.

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 rr.g, conveniently given in divided doses 2 to 4 times a day in unit dosage form containing from about 0.01 rag to about 1 mg of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.

The compounds of formula I exhibit furthermore prolactin secretion inhibition as indicated by the lowering of serum levels of prolactin of the rat after s.c. administration of from about 0.1 to about 1 rcg/kg of the compounds, using radio-immunological techniques, e.g. described by r7i swendcr, G.D., et al., Proc. Soc. Exp Biol. & Med. 130, 793 (1969) and Neil, J.J.,et al., Endocrinology Q8_, 548 (1971) .

The compounds of formula I are therefore indicated for use as prolactin inhibitors,e.g. in the treatment of conditions involving hyperprolactinemia, such as menstrual dysfunctions, e.g. ammcr.orrhea and ga lactorrhca, or hypertension of mammary carcinoma associated with elevated serum prolactin levels, or in the 1 975 29 treatment of conditions involving hypogonadism, 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 admixed with a solid or liquid pharmaceutical carrier or diluent.

The compounds of the invention exhibit furthermore antipsychotic activity as indicate by the inhibition of the locomotion in mice on s.c. administration 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/kg of the compounds, according the following 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 described by J.R, Walters and coll. in Naunyn Schmiede-berg's Arch. Pharmacol. 29 6, 5-14 (1976). The dopaminergic impulse flow was inhibited pharmacologically by ^-butyrolactone. The activity of the aromatic amino acid decarboxylase was inhibited by hydroxy- 1 975 _ 27 - 100—5410 benzylhydrazine (NSD 1015) and half an hour later the rats ware sacrificed. The resulting accumulation of DOPA during 30 minutes in striatal tissue was taken as a measure 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, for example for the treatment of schizophrenia. An indicated daily dosage is in the range from about 0.01 to about 1 mg, conveniently given in divided doses 2 or 4 tines 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-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,f]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-propy1-dibenz[cd,f]indole

Claims

1 975 2 9 - 28 - -100- 5410 and the corresponding di-n-propiony1-and di-isobutyryl-ester-derivatives are the preferred compounds. The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. These salt forms exhibit the same order of activity as the free base forms. The present invention also provides a pharmaceutical composition comprising a compound of formula I, in free base form or in pharmaceutically acceptable acid addition salt form,in association with a pharmaceutically acceptable diluent or carrier. These compositions may be formulated in conventional manner so as to be, for example, a solution, a capsule or a tablet. I 975 29 - 29 - 1.00 5 410 WHAT fWli CLMM

1. A process for the production of a compound of formula I wherein and R£ independently are ethyl or n-propyl radicals, 5 and the R^ 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 10 the absolute configuration 4S,5aR, which comprises a) producing a compound of formula la HO- la wherein and are as defined above, by splitting the ether groups Z of a compound of formula II - 30 - 1 975 29 JUDO 5 410- wherein R^ and R^ are defined above and Z is a splittable ether group, in racemic form having the relative configuration 4R*,5aS*,or in TOtically active isaner form having the absolute configuration 4S, 5aR, or b) producing a compound of formula lb wherein R^ and R£ are defined above and the radicals R^ are identical acyloxy radicals,by acylating a compound of formula la in racemic form having the relative configuration 4R*,5aS* or in optically active isomer form having the absolute configuration 4S,5aR.

2. A process for the production of a compound of formula I defined in Claim 1 substantially as hereinbefore described with reference to any one of the examples 3 to 6.

3. A compound of formula I whenever produced by a process as claimed in Claim 1. - 31 - 187529

4. A compound of formula I as defined in Claim 1.

5. A compound of Claim 4 wherein each R^ is hydroxy. 5

6. A compound of Claim 4 wherein each is acyloxy.

7. A compound of claim 6 wherein each acyloxy radical is of formula R - CO - O-a 10 wherein R is (C-.J cycloalkyl, or a 5- or 6-membered ci / heterocyclic ring.

8. A compound of Claim 6 wherein R^ is propionyloxy. 15

9. A compound of Claim Q wherein R^ is isobutyryloxy.

10. A compound of any one of Claims 4 to 9 wherein R-^ and are each ethyl.

11. A compound of any one of Claims 4 to 9 wherein R^ and R^ are each n-propyl.

12. A compound of any one of Claims 4 to 9 wherein R-^ is ethyl and R2 is n-propyl.

13. A compound of any one of Claims 4 to 9 wherein R^ is n-propyl and R^ is ethyl. 25

14. A compound of any one of Claims 4 to 13 20 1 975 29 - 32 - 000-5-4^©- in racemic form having the relative configuration 4R*,5aS *.

15. A compound of any one of Claims 4 to 13 in optically active isomer form having the absolute configuration 4S,5aR.

16. (-)-(4R*,5aS*)-5-ethyl-4,5,5a,6-tetra-hydro-9,10-dihydroxy-4-n-propy1-dibenz[cd,f]indole.

17. (i)-(4R*,5aS*)-4,5-diethyl-4,5,5a,6-tetrahydro-9,10-dihydroxy-dibenz[cd,f]indole,

. . 18. (-) - (4R*, 5aS*), 5 , 5a, 6-tetrahydro-9 ,10- aihydroxy-4,5-di-n-propy1-dibenz[cd,f]indole,

19. (-)-(4R*,5aS *)-4-ethyl-4,5,5a,6-tetrahydro-9 ,10-dihydroxy-5-n-propy1-dibenz[cd,f]indole.

20. (4S,5aR)-5-ethy1-4,5,5a,6-tetrahydro-9,10-dihydroxy-4-n-propy1-dibenz[cd,f]indole.

21. (4S,5aR)-4-ethy1-4,5,5a,6-tetrahydro-9,10-dihydroxy-5-n-propy1-dibenz[cd,f]indole.

22. (4S,5aR)-4,5-diethyl-4,5,5a,6-tetra-hydro-9,10-dihydroxy-dibenz[cd,f]indole.

23. (4S,5aR)-4,5,5a,6-tetrahydro-9,10-dihydroxy- 4, 5-di-n-propy1-dibenz[cd,f]indole.

24. (4S,5aR)-5-ethy1-9,10-dibenzoyloxy-4,5,5a,6-tetrahydro-4-n-propy1-dibenz[cd,f]indole. 197520 33 5 10

25 . (4S, 5aR) -9, lO-diacetoxy- 5-ethy 1-4, 5, 5a, 6-tetrahydro-4-n-propy1-dibenz[cd,f]indole.

26. (4S, 5aR)-5-ethy1-4,5,5a,6-tetrahydro-4-n-propyl-9,10-dipropionyloxy-dibenz[cd,f] indole.

27. (4S, 5aR)-9,10-dibutyryloxy-5-ethyl-4,5, 5a,6-tetrahydro-4-n-propy1-dibenz[cd,f]indole.

28. (4S,5aR)-5-ethy1-4,5,5a,6-tetrahydro-9,10-diisobutyryloxy-4-n-propy1-dibenz[cd,f]indole.

29. (4S,5aR)-4,5,5a,6-tetrahydro-9,10-dipropiony loxy- 4 , 5-di-n-propy1-dibenz[cd,f]indole.

30. A compound of any one of Claims 4 to 29 in acid addition salt form.

31. A pharmaceutical composition which comprises a compound of any one of Claims 4 to 29, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. DATEC " \ ,gg^ /' / / J / /