NZ204616A - 4,5-dialkyl-9,10-dialkoxy-4,5,5a,6-tetrahydrodibenz(cd,f)indoles - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £04616 Under provbions cf Regu-t iation 23 (j) £'^e "■ Specification has been ante-da*ed| 2046.16 jCtffeC$) Xirh rp.,**;']:??.

Coirmicte Specification Filed: ^ Class: Pub^nation Date: .. If ?. PO .fcwrrral, No: J 2 VJ. l- 8 Initials PA^~ OfBCg 17 JAN 1985 HS SSiCTSS Divided from No. 197529 No.: Date: NEW ZEALAND PATENTS ACT , 1953 COMPLETE SPECIFICATION HETEROCYCLIC COMPOUNDS, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM XP^ We, SANDOZ LTD., 35 Lichtstrasse, CH-4002 Basle, Switzerland, a Swiss Body Corporate, hereby declare the invention for which K/ we pray that a patent may be granted to5Kt#/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - (followed by la) .4.616; The present invention relates to phenanthrene derivatives, their preparation and pharmaceutical compositions containing them.

This application is divided out of Specification No. 197529, which is the parent application of this divisional application.

New Zealand Patent Specification Noi 190786 describes a class of 4,5,5a,6-tetrahydro-dibenz(cd,flindole derivatives having stimulant activity or. 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 (4RT,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 tolerabilitv. -la- I7JANS98S 2.046.1:6 In accordance with Specification No. 197529 there are provided compounds; of formula I, wnerexn R^ and R2 independently, are ethyl or nrprccyl radicals, and the substituents are the same and are hydroxy or acyloxy radicals, in raceraic form having the relative configuration 4R*,5aS*, or in optically active isomer fcrra having the absolute configuration 4S,5aR.

The acyloxy radicals are conveniently radicals of formula R - CO - O -a in which R is an alkyl radical, (C.. -J cycloalkvl, a j— I a phenyl radical or a 5- or 6-membered heterocyclic ring.

When R is an alkvl radical, this rnav a - - conveniently contain 1-17 carbon atoms, preferably 1 to 7 carbon atoms, and may be straight chain or branched chain. ... .. 3 204616 Ra may be a substituted alkyl radical, containing in the alkyl chain conveniently 1-5 carbon atoms. Conveniently it is a monosubstituted alkyl radical. The substituents may be, e.g., carboxy, hydroxy, amino, (_4)a IkyI amino, (Cj_4)alkoxy, d I — (C-j _4)a I ky I ami no, halogen, (Ci_4)alkylthio, phenoxy, a phenyl radical, 1-pyrrolidInyI, plperidino 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)cyclo-alkyI .

When Ra 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 different substituents, selected, for example, from halogen, tr i f I uoromethy I, (C-j —4) a I ky I, (C^_4)alkoxy, (Ci_4)alkylthio and di-(Ci_4)alkyI ami no, or a methyIenedioxy group. Preferably the phenyl ring Is mono- or disubstituted.

When Ra is an alkyl substituted by a phenyl radical, Ra is preferably a benzyl radical. The phenyl ring may bear substituents selected, for example, from halogen, (C]_4>a|ky|, (Cj_4)alkoxy or (C-|_4)al ky I th io.

When Ra is a heterocyclic ring, this is suitably a heterocycle containing oxygen, nitrogen or sulfur as sole heteroatom, e.g. pyridine, thlophene or furan.

Preferably Ra is (C^_7)alky|; (C3_g)cycloalkyI ; unsubstituted phenyl; phenyl mono- or dIsubstituted by chlorine, fluorine, tr i f I uoromethy I, (C-| —4) a I ky I or (C^ .4 )al koxy; unsubstituted benzyl; or benzyl mono- or disubstituted by chlorine, fluorine, (Ci_4)a IkyI or (C-| _4) a I koxy. 17 JAN 1S85 4 2-0461 6 Halogen may signify chlorine, bromine or fluorine, preferably chlorine or fluorine.

In a group of compounds, Is n-propyl and R2 Is ethyl. In another group of compounds, R^ and R2 are the same and signify ethyl orn-propyl. Preferably In the compounds of formula I the R3 substituents are hydroxy. The preferred compounds are the (4S,5aR) optical Isomers.

More particularly, Specification No. 197,529 provides a process for the production of compounds of formula I, which comprises a) producing a compound of formula la la wherein R^ and R2 are as defined above, by splitting the ether groups Z of a compound of formula II wherein R^ and R2 are defined above and Z Is a spllttable ether group, In racemic form having the relative configuration 4R*,5aS*, or In-optical ly active isomer form having the absolute - •'\l .-1- VA'j »« ■' 17 JAN 1535 204616 configuration 4S,5aR, or b) producing a compound of formula lb lb wherein R-j and R2 are defined above and the radicals R3'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.

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. hydrobromlc or hydroiodlc acid, at a temperature of at least 100°C, preferably from 100°C to the boiling point of the reaction mixture, especially at about 130°C. The ether group Z is preferably 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 an acid chloride, acid bromide or the acid anhydride.

- .. A.. 17 JAN 1985 6 204616 Conveniently the reaction is carried out by reacting an acid chl.oride in the presence of trifIuoroacetic 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. reaction mixture and purified in known manner. The free base forms of compounds of formula I may be converted Into acid addition salt forms In conventional manner and vice versa. Suitable acids for salt formation are, for example, hydrochloric acid, tartaric acid, di-0,0-p-toluoyl-D- or L-tartaric acid, and hydrobromic acid. 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 diastereoisomeric salts, e.g. their salts with (+)-di-0,0-p-toluoyI-D-tartaric acid or (-)-di-0,0-p-toluoyI-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 The resulting compounds of formula I may be Isolated from the Racemic compounds of formula I may be obtained from racemic 7 204616 wherein R^, R2 and Z are as defined above.

The reduction may be effected conveniently under acidic, conditions suitable for the acidic reduction of enamlnes and [mines, 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.

Accordingly, the present Invention provides a process for the production of a compound of formula II 1 I wherein Z Is a splittable ether group and R^ and R2 Independently are ethyl and n-propyl radicals, In racemic form having the relative configuration 4aR*, 5aS*, or an optically active form having the absolute configuration 4S, 5aR, which comprises reducing a compound of formuai III to CO o f; ti . o (I wsv: ;i I I I wherein R^, R2 and Z are as defined above.

The Invention also provides the compounds of formula II. Starting materials of formula III may be prepared, for example, according to the following reaction scheme: .46.16 (in) tcrt .-buLyl <1 lithium / A llal-CO-R.

(V) Nil-R, (VI) .Li (VII) ' J n-buCylli llitniua Nll-R, (VIII) Diborane (IX) 204616 9 In the reaction scheme the radicals Ri, R2 and Z are as defined 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 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 El sevler's Encyclopaedia of Organic Chemistry, Vol. 13, Tricyclic compounds, Elsevier Publishing Company Inc., New York (1946).

In the following Examples all temperatures are given In degrees Celsius and are uncorrected. The same examples are used for both the parent and the divisional specifications. 204616 F XAMPI F 1 : a) 9-(N-ethy I -N-butyrvI-am i no)-3-bromo-3.4-dimethoxv-ohenanthrene (compound of formula IV) A solution of 50 g (138 mM) 9-ethyI amino-8-bromo-3,4-dimethoxy-phenanthrene in 57.5 ml (333 mM) N-ethyI-diisopropyI ami ne and 420 ml methylene chloride is added dropwise, with stirring, under a nitrogen atmosphere over a period of 20 minutes to a solution of 28.8 ml (276 mM) 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 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 portionwise to the stirred mixture and the precipitate Is filtered off under suction, washed with petroleum ether and dried, to afford 9-(N-ethyI-N-butyryI-ami no)-8-bromo-3,4-d imethoxy-phenanthrene; M.pt. 102-104°. b) (4RS)-5-ethvI-4 r 5-d i hy dro-4-hydroxv-9.10-d imethoxv-4-n-propyI -dibenzfcd.f1indole Ccompound of formual II G g (58.14 mM) of 9-(N-ethyI-N-butyryI-amino)-8-bromo-3,4-dimethoxy phenanthrene are dissolved with stirring in 450 ml anhydrous tetrahydrofuran and the solution obtained is cooled to -25° ith a bath of methylene chloride and dry ice. 73ml (116.28 11 204616 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 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 fn high vacuum, there Is obtained (4RS)-5-ethyI-4,5-dihydro-4-hydroxy-9,10-dImethoxy-4-fl-propyI-dibenzCcd,fUIndole in the form of a yellow green foam. c) (±)-(4R*.5aS*)-5-ethyI-4.5.5a.6-tetrahydro-9.10-dfmethoxy-4-n-propyI-dibenzfcd.f1indole Ccompound of formula I 13 A suspension of 40.6 g (116 mM) of (4RS)-5-ethy1-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-n-propyI-dibenzCcd,fjindole in 1060 ml ethanol Is added with stirring to a suspension of 140 g of zinc dust and 31.6 g (116 mM) of mercury (II) chloride in 1060 ml distilled water (alternatively the zinc dust/mercury chloride may be added to the d i benz-1 ndol e). The reaction mixture is refluxed, 360 ml of 18j£ 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 NH4OH and the alkaline phase is extracted once with 1 I itre methylene chloride and twice with, each time, 500 ml methylene chloride. The combined organic phases are washed with water, dried and evaporated. The resultant oil is chromatographed on silicagel using methylene chloride with 2% 12 4616 methanol as eluant to give (±)-(4R*,5aS*)-5-ethy1-4,5,5a,6-tetra-hydro-9,10-d1methoxy-4-n-propyl-dlbenz[Icd,fIIlndole In form of an oil EXAMPLE 2: The (4RS)-5-ethyI-4,5-d 1 hydro-4-hydroxy-9,10-dImethoxy-4-n-propyIdIbenzCcd,f]tndole obtained In the Example lb), may also be prepared as follows: a) 9-amIno-3.4-dImethoxy-phenanthrene [compound of formula X] A mixture of 430 ml (3.08 moles) tr If IuoroacetIc anhydride and 430 ml (5.62 moles) trlfIuoroacetIc acid Is added at room temperature under a nitrogen atmopshere to 53.6 g (0.19 mole), 3,4-dImethoxy-phenanthrene-9-carboxy I Ic acid and the mixture Is stirred for 10 minutes. After the mixture Is cooled to -5°, 15.2 g (0.234 mole) sodium azIde are carefully 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-acetyI amIno-3.4-d1methoxv-phenanthrene Ccompound of formula IX] 55 ml (0.319 mM) N-ethyIdIisopropyI amine are added to a solution of 38.2 g (0.151 mM) 9-am!no-3,4-dimethoxy-phenanthrene 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 /<$?/ ^ 13 204616 chloride In 250 ml methylene chloride. During the addition, the temperature of the reaction mixture Is maintained at 20° by cooling with an Ice bath. temperature, then poured onto 2N hydrochloric acid and extracted with methylene chloride. The organic phase Is washed with a 2N sodium hydroxide solution and with water, dried and evaporated, to afford 9-acetyI amino-3,4-dImethyoxy-phenanthrene; c) 9-ethyI amino-3.4-dImethoxy-phenanthrene Ccompound of formula suspension In 450 ml anhydrous tetrahydrofuran are reduced with 500 ml (0.5 mM) of a molar solution of diborane In anhydrous tetrahydrofuran and worked up In known manner to give 9-ethyI amino-3,4-dfmethoxy-phenanthrene; M.pt. 94-95°. d) 4.5-dIhvdro-9.10-d!methoxy-5-ethyl-4-oxo-dibenzl~cd. fllndole Ccompound of formula VG 122 ml (0.2 mo Ie) of a 15$ solutIon of n-butyI-I IthIum In hexane are added at 0°, under a nitrogen atmosphere, to a solution of 28.1 g (0.1 mole) of 9-ethyI am Ino-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 with yellow-green fluorescence Is observed.

The reaction mixture Is stirred for 14 hours at room M.pt. 190-195° after recrystalIIsatIon from ether.

VI I I] 34 g (0.124 mM) 9-acetyI am Ino-3,4-dImethoxy-phenanthrene In 204616 14 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 sulfate and evaporated. There Is thus obtained 4,5-dfhydro-9,10-dimethoxy-5-ethyl-4-oxo-dibenz[cd,f]indoie which melts at 125-126° (with decomposition) after crystallisation from ether/petroleum ether. e) (4RS)-5-ethy I -4.5-d I hy dro-4-hy droxy-9.10-d Imethoxy-4-n-propy I -dibenz fed. f~l i ndol e [compound of formula III] 2.1 ml (33 mM) of a solution of n-propyI-magnesIum bromide In ether are added dropwise at room temperature to a solution of 10 g (33 mM) of 4,5-d I hydro-9,10-d imethoxy-5-ethy I -4-oxo-dibenz[cd,f]-Indole In 300 ml anhydrous tetrahydrofuran. After 30 minutes, a solution of ammonium chloride Is added, the mixture extracted with methylene chloride and the organic phase dried and evaporated to give (4RS )-5-ethy I -4,5-d i hydro-4-hy droxy-9,10-d I methoxy-4-ji-propy I -d f benz-[cd,f]Indole in the form of a yellow green foam. [IR Spectrum (CH2CI2): 3540 cm~^ (OH)]. The crude product is directly used for the next step.

EXAMPLE 3: ( ±)-(4R*.5aS*)-5-ethyl-4.5.5a.6-tetrahydro-9P10-dIhvdroxy-4-n-propyI-dlbenzfcd.flindole g (27.66 mM) (±)-(4R*,5aS*)-5-ethyI-4,5,5a,6-tetrahydro- 2046.1 aqueous solution of hydrobromic acid are warmed for 6 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-ethyI-4,5,5a,6-tetrahydro-9,10-dIhydroxy-4-n-propyI-dIbenzCcd,fHIndole hydrobromlde which melts at 200° with decomposition.

The following compounds may be prepared In analogous manner from the appropriate starting materials: a) (±)-(4R*,5aS*)-4,5-d Iethy I -4,5,5a, 6-tetrahy dro-9,10-d I hydroxy-dIbenz[cd,f]lndole(hydrobromlde, M.pt > 175° with decomposition); b) (±)-(4R*,5aS*)-4,5,5a,6-tetrahydro-9,10-dlhydroxy-4,5-dl-n-propy I-dIbenzCcd,fHIndole(hydrobrom!de, M.pt > 190° with decomposIt Ion). c) (±) - (4R*, 5aS* )-4-ethy I -4,5, 5a, 6-tetrahy dro-9,10-d i hydroxy-5-H-propyI-dIbenzCcd,fDIndole.

EXAMPLE 4: (-)-(4S. 5aR)-5-ethv I -4.5.5 a. 6-tetrahydro-9.10-d I hydroxy-4-n-proDy 1 -d1benzfcd.fit ndole A 16 204616 a) (-)-(4S.5aR)-5-ethy I-4.5.5a.6-tetrahydro-9. lO-drmethoxyM-n-propv I-d 1 benzfcd. f ~1 f ndol e g (89 mM) of (±)-(4R*,5aS*)-5-ethy1-4,5,5a,6-tetrahydro-9,10-dImethoxy-4-n-propyI-dIbenzQcd,fUlndole are dissolved In 300 ml ether and a solution of 35.95 g of (-)-d1-0,0-p-toluoyl-L-tartarlc acid monohydrate In 300 ml ether Is added with stirring. The mixture Is further stirred for 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.

Ilsatlon 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 crystal IIzes 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 recrystalIIsed In the same manner by using 1.7 I Itres 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 (-)-(4S,5aR)-5-ethyI-4,5,5a,6-tetrahydro-9,10-dimethoxy-4-H-propy I-d ibenzCcd, fH I ndol e (-)-dI-0,0-p-toluoyl-L-tartrate In form In methanol).

The following compounds may be prepared In analogous manner from the appropriate starting materials: 61.88 g of the crystals obtained from the first crystal- ?0 of colourless crystals which melt at 178-179°; Ca3 q =-138° (c= 0.29 17 2046 i 6 (-)-(4S,5aR)-4,5-d I e+hyI-4,5,5a,6-tetrahydro-9,10-d Imethoxy-dibenzCcd,fUIndole (-)-dI-O,O-p-toluoyI-L-tartrate, M.pt on 187-189°; C°G g = -138° (c=0.5 In methanol); the racemic starting material Is reacted first with C+)-d1-0,0-p-toluoyI-D-tartarlc acid Instead of the L-Isomer and the mother liquor obtained on crystallisation is treated with NH4OH to I I berate the base. The base Is reacted with (-)-d1-0,0-p-toluoyI-L-tartarlc acid and the crystals obtained from an ether solution. (-)-(4S,5aR)-4,5,5a,6-tetrahydro-9,10-dtmethoxy-4,5-dI-ji-propy I-dIbenzCcd,fHIndole (-)-dl-O,0-p-toluoyl-L-tartrate, M.pt on 165-166°; CaUd = -123° (c = 0.27 in methanol). b) (-)-(4S.5aR)-5-ethyI-4.5.5a.6-tetrahydro-9.10-dIhydroxy-4-n-propyI-dibenzfcd.flIndole Procedlng as described In Example 3, (-)-(4S,5aR)-5-ethyI- 4,5,5a,6-tetrahydro-9,10-d i hydroxy-4-ji-propyI-dIbenzCcd, f31ndol e hydrobromide Is obtained from the tartrate obtained above under a). on It melts above 210°; CaHq = -64° (c = 0.245 In methanol).

The corresponding hydrochI or Ide melts at above 185° with ; • 20 decomposition; CaHq = "75° (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-dIethyI-4,5,5 a,6-tetrahydro-9,10-d i hydroxy-dIbenzCcd,f]Indole hydrochloride, M.pt. 200° with 'J;t7 janvks 18 204616 decomposition; CcGq = -72° (c = 0.25 In methanol); b) (- )-(4S,5aR)-4,5,5a, 6-tetrahy dro-9,10-d I hydroxy-4,5-d I-n-propy I - dIbenzCcd,f3lndole hydrochI orIde, M.pt > 187° with decomposition; CoGq = -58.5° (c = 0.35 in methanol). c) (-)-(4S,5aR)-4-ethy I -4,5,5 a, 6-tetrahy dro-9, IO-dIhydroxy-5-n- propyI-dIbenzCcd,f]indole hydrochI oride, M.pt 198-200°C with 20 decomposItIon,CcG q = -66° (c = 0.5 in methanol).

FXAMPI F 6: (+)-(4S.5aR)-5-ethv1-9.10-dIbenzov I oxy-4.5.5a.6-tetrahydro-4-n-propy I -d i benzfcd.fli ndole 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-ethyI-4,5,5a,6-tetrahydro-9,10-dIhydroxy-4-fl-propyI-dIbenzCcd,f31ndole 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 combined organic 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 17 JANivSS - jBli l' If T I I l E2G0VED 19 204616 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-ethyI-9,10-d i benzoyIoxy-4,5,5a,6-tetrahydro-4-fl-propy I -dIbenzCcd, fU-Indole L(+)tartrate; it melts at 161-162° after crystallisation in ry A ethyl acetate/ether; C<*II q = +23.5° (c = 0.28 in methanol).

The following compounds may be prepared in analogous manner from the appropriate starting materials (-)-(4S,5aR)-9,10-diacetoxy-5-ethyl-4,5,5a,6-tetrahydro-4-n- propyl-dibenzCcd,fHindole hydrochloride, M.pt > 188° (with decomposition); C°G p= -99° (c = 0.28 In methanol); (-)-(4S,5aR)-5-ethyI-4,5,5a,6-tetrahydro-4-n-propyI-9,10- dipropionyIoxy-dibenzCcd,f^indole hydrochloride, M.pt > 175° (with decomposition); C°G g = -76° (c = 0,25 In methanol); (-)-(4S,5aR)-9,10-di butyryIoxy-5-ethyl-4,5,5a,6-tetrahydro-4-n- propyI-dibenzCcd,fHindole hydrochloride, M.pt > 105° (with decomposition); CaH q = -77° (c = 0.28 in methanol) (-)-(4S,5aR)-5-ethyI-4,5,5 a,6-tetrahydro-9,10-dIi sobutyryIoxy-4- H-propyI-dibenzCcd,f3indole hydrochloride, M.pt > 165° (with decomposition); CaD ^ = -96° (c = 0.29 in methanol). (-)-(4S,5aR)-5-ethyI-4,5,5a,6-tetrahydro-4-n-propyI-9,10- dIvaieryIoxy-dibenzCcd,fHindole hydrochloride; (-)-(4S,5aR)-5-ethyI-4,5,5a,6-tetrahydro-4-n-propyI-9,10- di p ival oy I oxy-d i benzCcd, f Hi ndol e hydrochloride; (-)-(4S,5aR)-4,5,5a, 6-tetrahy dro-9,10-d I prop iony I oxy-4,5-d i -jq- propyl-dibenzCcd,f3indole, hydrochloride M.pt. 115°; CaH q = -67° (c = 0.51 in methanol).

In analogous manner to Example 6, the following compounds of formula I wherein R] and R2 are each independently ethyl or ( 17 JAN< 204616 H-propyl and R3 is acetoxy propionyloxy bu+yryloxy isobutyryloxy valeryloxy pivaloyloxy may be prepared.

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. Ungers+edt 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 nigrostrIatal pathways.

Administration of from about 0.03 to about 1mg/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 XX 1 21 204616 behaviour observed Is assessed using a scoring system based on that described by Costal I, Naylor and 01 ley [Euro J. Pharmac. 18P 83-94 (1972)].

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 mg/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 example for treating Morbus Parkinson. For this Indication, an Indicated dally dose is from about 0.1 to about 20 mg, conveniently administered In divided doses 2 to 4 times a day In unit dosage form containing from about 0.025 to about 10 mg, or in sustained release form.

The compounds of the Invention exhibit furthermore antidepressant activity, as Indicated by the Inhibition of catalepsy Induced by reserplne In mice on s.c. administration of about 0.001 mg to about 1 mg/kg of the compounds and by the Inhibition of 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 0.01 mg to about 1 mg of the 22 204 616 compounds admixed with a solid or liquid pharmaceutical carrier or dlIuent.

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 mg/kg of the compounds, using radio-Immunological techniques, e.g. described by NIswender, G.D., et al., Proc. Soc. Exp. Biol. & Med. 150P 793 (1969) and Nell, J.J., et al., Endocrinology 88P 548 (1971).

The compounds of formula I are therefore Indicated for use as prolactin Inhibitors, e.g. In the treatment of conditions Involving hyperprolactInemla, such as menstrual dysfunctions, e.g. ammenorrhea and galactorrhea, or hypertension of mammary carcinoma associated with elevated serum prolactin levels, or In the treatment of conditions involving hypogonadism, e.g. infertility or Impotence, or In the regulation of post-partem lactation.

An Indicated dally 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 d11uent.

The compounds of the Invention exhibit furthermore antipsychotic activity as Indicated 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 t mg to about 10 mg/kg of the compounds, according the following test. 11 23 204616 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 Schmiedeberg's Arch. Pharmacol. 296. 5-14 (1976). The dopaminergic impulse flow was inhibited pharmacologically by y-butyrolactone. The activity of the aromatic amino acid decarboxylase was inhibited by hydroxybenzyI -hydrazine (NSD 1015) and half an hour later the rats were 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 y-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 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 d iIuent.

The preferred indication Is the anti-parkinson indication.

The compounds (4S,5aR)-5-ethyI-4,5,5a,6-tetrahydro-9,10-d ihydroxy-4-n-propy I-di benzCcd,fJi ndole, (4S,5aR)-4-ethyI-4,5,5a,6-tetrahydro-9,10-d I hy droxy-5-n-propy I -9,10-d i hydroxy-d I benzCcd, f H-indole, (4S,5aR)-4,5-diethyI-4,5,5a,6-tetrahydro-9,10-dihydroxy-dibenzCcd,fH i ndole and (4S,5aR)-4,5,5a,6-tetrahydro-9,10-dihydroxy-4,5-dI-fl-propyI-dIbenzCcd,f]indole and the corresponding di-n-propionyI - and di-isobutyryI-ester-derivatives are the preferred 24 204616 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.

Patent Specification No. 197529 also provides a pharmaceutical composition comprising a compound of formula I, In free base form or In pharmaceutical Iy acceptable acid addition salt form, In association with a pharmaceutical Iy 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. 17 JANEC5 204616

Claims (12)

WHAT WE CLAIM IS:

1. A process for the production of a compound of formula II wherein Z Is a spllttable ether group and Rl and R2 Independently are ethyl and n-propyl radicals. In racemic form having the relative configuration 4aR*, 5aS* or an optically active form having the absolute configuration 4S, 5aR, which comprises reducing a compound of formula III I I I •26 204616 wherein R^, R2 and Z are as defined above.

2. A compound of formula II whenever produced by a process of claim 1.

3. A compound of formula II as defined In claim 1.

4. A compound of claim 2 or 3 wherein Z Is me+hoxy.

5. A compound of claim 2, 3 or 4 In optically active form having the absolute configuration 4S, 5aR.

6. A compound of claim 2, 3, 4 or 5 wherein R^ is n-propyl and R2 Is ethyI .

7. A compound of claim 3 which Is (-)(4S,5aR)-5-ethyI-4,5,5a,6-tetrahydro-9,10-dImethoxy-4-n-propy i-dIbenzCcd, fH i ndole.

8. A compound of claim 5 in the form of the (-)-d1-0,0-p-toluoyI -L-tartrate acid addition salt.

9. A compound of claim 2, 3, 4 or 5 wherein R^ and R2 are each n-propyl or each ethyl.

10. A compound of claim 9 which Is (-) (4S,5aR)-4,'5,5a,6-tetrahydro- 9,1 0-dImethoxy-4,5-di-n-propyI-dIbenzCcd,f]Indole in the form of the (-) dl-0,0-p- toluoyI-L-tartrate acid addition salt. >•' J" 27 204616

11. A compound of claim 9 which is (-) (4S,5aR)-4,5-dIethy1-4,5,5a,6- tetrahydro-9,10-dImethoxy-dIbenzCcd,fHindole in the form of the (-) d[-0,0-p-toluoyI-L-tartrate acid addition salt.

12. A process for the production of a compound of formula II as defined In Claim 1 substantially as hereinbefore described with reference to example 1. Tgsnts Af?UCANTI