CA1108156A - Phenanthrene derivatives, their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

Case 100-5040 Abstract of the invention The 4,5,5a,6-tetrahydro-dibenz[cd,f]indoles having at least one oxy substituent in one or both of the fused benzene rings, at least one such oxy substituent being hydroxy or acyloxy when the nucleus is unsubstituted in the 4-position, are useful as central dopaminergic stimulant agents.

Description

1~81~6 Phenanthrene derivatives, their preparation and pharma-ceutical compositions containing them The present invention relates to phenanthrene derivatives, their preparation and pharmaceutical compo-sitions containing them, In accordance with the invention there are pro-vided phenanthrene derivatives, i.e. ~,5,5a,6-tetrahydro-dibenz[cd,f]indoles having at least one oxy substituent in one or both of the fused benzene rings, at least one such oxy substituent being hydroxy or acyloxy when the nucleus is unsubstituted in the 4-position.
The oxy substituent(s) may be for example hydroxy or a group which is hydrolysabIe under physiolo-gical conditions to a hydroxy group, e.g. an acyloxy group. Alternatively it may be an ether group.Conveniently the 4 position is substituted, e.g. by a cycloalkyl or alkyl radical.

. .
Conveniently the compounds of the invention contain up to 4, preferably 2 oxy substituents.
Conveniently the oxy substituents are in the "
.

: ~

- 2 - 100-5040 . ~ .
` 9 and/or 10 positions.
More preferably,the invention provides compounds of formula I, wherein ;~ 5 Rl is hydrogen , (Cl_10)alkyl, (C3_7)cycloalkyl or (C3_7)~Ycloalkyl-(cl 4)alkyl, ~: R2 is (Cl_5)alkyl~ and the R3 substituents are the same and are hydroxy or .
carboxylic acyloxy radicals.
Rl is preferably an alkyl radical. When Rl is an alkyl radical, this contains conveniently 1 to 6 carbon - atoms and may for example signify methyl.
Conveniently,R2 is an alkyl radical containing 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms.
The R3 substituents are preferably acyloxy radi-cals. These may be ~adicals of formula a in which R is unsubstituted or substituted alkyl;
(C3 7)cycloalkyl; a phenyl radical, or a 5- or 6-membered ~ .;

, ,, B~i

- 3 - 100-5040 heterocyclic ring.
When R is an alkyl radical, this may convenier~tly contain 1-17 carbon atoms, preferably 1 to 7 carbon atoms,and may be straight chain or branched chain.
Ra may be a substituted alkyl radical, con-taining in the alkyl chain conveniently 1-5 carbon atoms. Conveniently it is a monosubstituted alkyl radical.
Examples of substituents are carboxy,~ydroxy, amino, (Cl_4) alkylamino, (Cl 4)alkoxy,di-(C1 4)alkylamino, halogen, (Cl 4)alkylthio, phenoxy, a phenyl radical, l-pyrrolidinyl, piperidino or morpholino, conveniently however a phenyl radical. Ra may also be e.g. an alkyl radical containing in the alkyl chain 1-4 carbon atoms and substituted by (C~ 7)cycloalkyl.
When R 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_4)alkoxy, ~Cl_4~alkyl-thio and di-(Cl 4)alkylamino, or a methylenedioxy group.
Preferably the phenyl 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

- 4 - 100-5040 halogen, (Cl_4)alkyl, (Cl_4)alkoxy or (Cl 4)alkylthio.
When R 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)cy y unsubstituted phenyl; phenyl mono- or disubstituted by chlorine, fluorine, trifluoromethyl, (C1 4)alkyl or (Cl 4)alkoxy; unsubstituted benzyl; or benzyl mono- or disubstituted by chlorine, fluorine, (Cl 4)alkyl or .~10 (C1 4)alkoxy ; Halogen may signify chlorine, bromine or fluorine, preferably chlorine or fluorine.
Representative groups of cor~ound~ are those of formula I' H0 ~ ~RC2~3 I' in which R2 is as defined above, and of formula I"
,,~ .
R'-C00 ~
:~ R -C00 _ ~ CR23 I"

. ' I ~ .

- 5 - 100-5040 in which R2 is as defined above and the R' substituents are identical and are unsubstituted or substituted (Cl 17)alkyl; (C3 7)cycloalkyl; a phenyl radical;
- 5 or a 5- or 6-membered heterocyclic ring.
R2 is conveniently (Cl 4)alkyl. Ra is conve-niently (C1 4)alkyl, (C3 7)cycloalkyl, (C3 7)cycloalkyl-(Cl 2)alkyl, phenyl, phenyl monosubstituted by chlorine or methoxy, or benzyl.
The compounds of the invention may be prepared in manner known per se.
: For example a 4,5,5a,6-tetrahydro-dibenz~cd,]
indole containing at least one hydroxy or acyloxy substituent in one or both of the fused benzene rings, ~:~ 15 may be produced by a process which comprises ; a) obtaining a compound containing at least one hydroxy substituent in one or both of the fused benzene : . rings by splitting the ether group~s) in a correspon-ding compound containing at least one splittable ~ 20 ether group in one or both of the fused benzene : . rings, or b) obtaining a compound containing at least one acyloxy substituent in one or both of the fused benzene rings , by acylating a corresponding compound containing -, 3'`~

- 6 - 100-5040 at least one hydroxy substituent in one or both ~- of the fused benzene rings.
More particularly, the invention provides a process for the prGduction of compounds of formula I, which comprises a~ producing a compound of formula Ia ~N-R2 in which Rl and R2 are as defined above, by splitting the ether groups Z of a compound of formula II

~' .
in which Rl and R2 are defined above and Z is a split-table ether group, or b) producing a compound of formula Ib .

,

- 7 - 100-5040 Rj ~

Ib ~
in which Rl and R~ are defined above and the radi-cals R3 are identical acyloxy radicals, by acylating a compound of formula Ia.
The ether splitting process of the invention, in particular process a), may be effected in conven-tional 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, preferably from 100C to the boiling point of the reaction mixture, especially at 130C.
The ether group(s), in particular the groups Z, is/are preferably arylalkoxy or alkoxy containing up to lO carbon atoms, especially a benzyloxy, ethoxy or methoxy radical, more preferably a methoxy radical.
The acylation process of the invention,in parti-cular 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 ~ 20 used, as acylating agent, a functiona] derivative of an :'''' ' ' . . , ' ~ ' .

.' ' :,. : ~

- 8 - 100-5040 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 20C to the boiling point of the reaction mixture or in the presence of pyridine at temperatures from 0C to room tempera-ture.
The 4,5,5a,6-tetrahydro-dibenz[cd,f]indoles containing at least one ether group in one or both . .
of the fused benzene rings, which are starting materials in process a~and some of which are also end products of the invention , may be produced by process c) which comprises reducing the 5a,6- double bond of a corres-ponding 4,5-dihydro-dibenz[cd,f]indole which is corres-lS pondingly substituted, or oxo-substituted at the 4-posi-tion when a compound unsubstituted at the 4-position is desired.
Particularly, the compounds of formula II may ; ~e produced by reducing the 5a,6- double bond, and, where present, the 4-oxo-group, in a compound of formula III, ~ ~ ~ R2 III

, . . .

:
' : ' -: - - . ~

- 9 - 100-5040 in which R2 and the radicals Z are as defined aboye, and either X is hydrogen and Y is the same as Rl, or X
and Y together are oxo.
The reduction may be effected conveniently by methods conventionally used for the reduction of ena-mines or imines, for example with zinc in an aqueous mineral acid, preferably hydrochloric acid, optionally in presence of a mercury (II) salt, for example mercury (II)ehloride. The reaetion may suitably be effeeted in an organie solvent, for example a lower alkanol, e.g.ethanol, and at temperatures from 50C to the boiling point of the reaetion mixture. ~nder these eonditions, any 4-oxo group present is simultaneously redueed.
The resulting eompounds of the invention may be isolated from the reaetion mixture and purified in known manner. The free base forms may be eonverted into aeid addition salt forms in eonventional manner and viee versa. Suitable acids for sa]t formation are hydrochlorie aeid, hydrobromie aeid and methane-sulphonie acid.
The compounds of the invention possess an asymetric carbon atom in the 5a position and can be obtained as a raeemate or as one of the optically aetive forms, i.e. as an individual enantiomer.

' ' $~

- 10 - 100-5040 When the nucleus is substituted in the 4-position, in particular when Rl in formula I is other than hydrogen, the compounds of the invention possess two asymetric carbon atoms in the 4 and 5a positions and therefore two racemates may exist. Starting from optically active starting materials, there may be obtained optically active end products. From racemic starting materials, there are obtained racemic end products. The individual racemates may be separated into the enantiomers by known methods, for example by fractional crystalliza-, tion of diastereoisomeric salts, e.g. their salts with (+) or (-)tartaric or di-p-toluoyl-Q- or d-tartaric acid. The resolution of the racemates may be effected after the final step of the synthesis or optionally in an earlier step. Preferably the isomer separation is effected before splitting of the ether groups.
The starting materials in process c) mono-substituted at the 4-position, in particular compounds of formula III in which X is hydrogen and Y is other than hydrogen, possess an asymetric carbon atom in position 4. On reducing these compounds, a second asymetric carbon atom is formed in the position 5a.
Compounds of formula IIIa .:

~ ~-R IIIa in which R2 and the radicals Z are as defined above, may be prepared for example according ~he f~llowing reaction scheme :-:

:
. ' - ' . ' - ~

COOH ~H\2 IV ~

~11 R2 ~NH-CO-R2 VII
VI

~\~a l --,~ I I I a VIII

In the reaction scheme the radicals Z and R2 are as defined above, R2 is hydrogen or (Cl 4~alkyl, Hal is iodine, bromine or chlorine and Alk is lower alkyl.
; The reactions may be carried out in conventional ~ 5 manner.

.

"

The compounds of formula V may be prepared according to a modification of the Curtius reaction, for example by reacting the acid of formula I~ with sodium azide in presence of trifluoroacetic acid and trifluoroacetic anhydride followed by hydrolysis with base. The acyla-tion of compounds of formula V may for example be carried out with a compound of formula R2'-C0-Hal in which Hal is as defined above and R'2 is (Cl 4)alkyl, in the presence of an acid acceptor, e.g. N-ethyldiisopropylamine. When R2 is hydrogen, the reaction may be carried out by reacting the compound of formula V with formic acid in the presence of N,N-carbonyldiimidazole. The compounds of formula VI may for example be reduced with dib~rane.The prepara-; tion of ccmpounds of formula VIII ma~ suitabl~ be effected by reacting the compound of formula VII with a chloroformatein an organic solvent and in the presence of an acid accep-tor, e.g. N-ethyldiisopropylamine. Treatment of compounds of formula VIII with for example an alkyl- or aryl-lithium compound, preferably n-butyllithium or tert,-butylli-thium in tetrahydrofuran/hexane at temperatures rangingfrom -11~C to 0C affords the compounds of formula IIIa.
The remaining 4-oxo-substituted starting mate-rials in process c) mav be ~roduced in analogous manner.
Compounds of formula IIIb . ~

, , ~ . .. .

; .

- ~ -, " . . . - , .

~I R~ IIIb in which the radicals Z and Rl and R2 are as defined above, may be prepared for example according the following reaction scheme wherein the radicals Z, Rl, R2 and Hal are as defined above and An~ is an anion:-~H 2 ~I n - c o- R l . , .

Z~ Z--~R-COlRl ' . ~ ' .

An~
XII
'~ . ' ,, .

, ' - ' .

~. ~ , - ' ' The reastions may be carried out according to known methods.
The acylation of compounds of formula V may be effected for example by reacting a compound of formula Hal-C0-Rl in which Ri is the same as Rl except that it may not signify hydrogen and Hal is as defined above, in the presence of an acid acceptor, e.g. N-ethyldiisopropylamine. When Rl is hydrogen, the reaction may be carried out by reacting the compound of formula V
with formic acid in the presence of N,N-carbonyldiimi-dazole. The compounds of formula IX may suitably be alkylated with an alkyl iodide under the conditions of a phase transfer catalysis reaction, for example in presence of tetrabutylammonium hydrogen sulphate.
Treatment of compounds of formula X with for example n-butyllithium or tert.-butyllithium in tetrahydro-furan/hexane at temperatures ranging from -110C to 0C affords the compounds of formula XI. The dehydra-tation of compounds of formula XI may for example be carried out with a mineral acid, for example hydro-chloric acid in ethereal solution. The salts of formula XII may be reduced to IIIb with sodium borohydride in tetrahydrofuran.
; The starting materials of formula X may also ... . .

.' ' , .
~ - ' ' 8~

- 16 ~ 100-5040 be prepared by conventional manner from the compounds of formula VII by acylation with compounds of formula Rl-C0-Ha1 as described above.
The compounds of formula XI in which Rl is Ri as defined above may also be prepared in conventional manner from compounds of formula IIIa by reaction with compounds of formula Ri-Li in which Ri is as defined above.The compounds of formula XI in which P~l is hydrogen may also be prepared in conventional manner from compounds of formula IIIa by reduction with LiAlH4.
The compounds of formula IIIb in which Rl is - methyl, may also be prepared according the following reaction scheme wherein the radicals Z and R2 are as defined above, Hal is chloride,bromide or iodide, ; 15 An~ is chloride, bromide, iodide, CH3-S04~ or C2H5S04~ and either Rx is hydrogen and Ry is bromo-methyl or Rx and Ry together are =CH2 :-; " . ' :

:

~H)3 1~ ~h3 XI I I XIV

\ /

~1~3 ~ ~ CH;
. XVI ' R2 :' XV
~ /
IIIb (wherein Rl is CH3) The alkylation of compounds of formula XIII may be effected for example by reaction with compounds of : formula An-R2 in which R2 i9 as defined above and . 5 An is chlorine, bromine or iodine, or when R2 is methyl or ethyl, with dimethyl- or diethylsulphate. The ring ., opening of compounds of formula XIV may be carried out conveniently with an alkaline metal alcoholate, preferably potassium tert.-butylate in dimethoxyethane, ~' 10 dioxane or tetrahydrofuran, at temperatures from oC

.... .. . . . . . . . .
,~ : - : :

- ~ :
.. . - . . . .
.
' , ' - ' :, , to 50C,preferably at room temperature.
The preparation of compounds of formula XVI
from compounds of formula XV may be carried out under oxidative conditions for example with bromine or a halogen liberating compounds, e.g. N-bromosuccinimide.
The regioselective cyclofunctionalisation of XV to XVI with bromine may be effected at te~xratures from 0C
to 50C, preferably at room temperature, conveniently in an inert organic solvent, for example an halogenated ; 10 hydrocarbon, e.g. methylene chloride, chloroform or tetrachlorocarbon, preferably chloroform. The reaction with N-bromosuccinimide may be carried out conveniently at temperatures from 0C to 50C, preferably at room temperature in the presence of water and optionally an organic solvent, e.g. dioxane, tetra-hydrofuran, methylene chloride and chloroform. The demethylation of the obtained quaternary compounds of formula XVI followed by rearrangement is conveniently carried out at temperatures higher than 80, preferably between 80C and 110C, particlllarly at 100C, in an organic solvent, e.g. benzene, dimethylformamide or ethanolamine, preferably ethanolamine.
The remaining starting materials of process c) in which the 4-position is unsubstituted or substituted by an ~1 substitutent other than hydrogen may be produced in manner ` . ~

- :. , .:

.' .

, - 19 - ~ 100-5040 analogous to that described above for compounds IIIb.
The products of the above reactions may be isolated and purified in known mannex.
Insofar the preparation of any particular starting material is not particularly described, this may be effected in conventional or analogous manner.
It is to be appreciated that certain of the above compounds may exist in optically active forms.
Certain of the starting materials are new and are particularly useful intermediates for the preparation of pharmacologically active compounds, and form part of the invention.
Thus the following compounds by virtue of the functional groups present, e.g. ether groups, ketone groups, double bonds in the 5a-6 positions,are valuable intermediates:-a) 4,5,5a,6~tetrah~dro -dibenz[cd,f]indoles having at least one splittable ether group in one or both of the fused benzene rings, with the proviso that when more than one ether group is present the groups are attached to the same fused benzene ring, b) 4,5-dihydro-dibenz[cd,f]indoles bearing at least one hydrogen attached to the carbon atom at position 4 and having at least one splittable ether group on ~-~ 25 any of positions 1 to 3 and 7 to 10, ., ~ .

.... - , :
' ~
- - ~ ' - ' . ' ' ' -, . :

, r3Çi c) 4,5-dihydro 4-oxo-dibenz[cd,f]indoles having only one or two splittable e-ther groups in any of positions 7 to 10, and having no further oxy substituents in the nucleus.
Particularly compounds of formula III'a, 1~
~ ~2 III'a wherein R2 is as defined above, the ring B having only one or two splittable ether groups and no further oxy substituent . 10 being present in the nucleus, compounds of formula III'b ~1 ~ Rl III'b wherein ~II-R2 Rl and R2 are as defined above and the ring A and/or B
contains at least one splittable ether group, and compounds of formula V' .
. ~

~ 2 V

~ Rlv~;

wherein Rl, R2 and ~al are as defined above, and the ring A and/or s contains at least one splittable ether group (of which compounds --------------------------~~~~~~~~
IIIa, IIIb and V are examples),are by ~irtue of the functional groups present, in particular the ether and amino groups and the halogen atom,valuable intermediates for the preparation of a wide variety of compounds.
In the above intermediates conveniently there are two ether groups present, e.g. in the 9 and 10 positions.
Conveniently the ether group or groups are (Cl 4)alkoxy.
In the following Examples all temperatures - are given in degrees Celsius and are uncorrected.
The absolute configurations of the optically active compounds of formula II corresponding to Example 7 and in which Z is methoxy and Rl and R2 are methyl, were determined by X-ray analysis. The absolute configuration of the other optically active compounds of formula II were established by analogy on the basis of their optical rotation. It is assumed that the compounds of formula I prepared from the corresponding compounds of formula II have the same absolute configuration.

- 22 ~ 10C-5040 Example 1 (5aRS)-4L5,5a,6-tetrah~dro-9,10-dimethoxy-5-methyl-dibenz~cd,flindole (compound of formula II) 544 ml (0.06M) of a 3% aqueous solution of mercuric chloride are added under nitrogen atmosphere and stirring to 272 g (41.7M) of zinc dust and the mix-ture is stirred for 5 minutes at room temperature. A
suspension of 40 g (0.316M) of 4,5-dihydro-9,10-dime-thoxy-5-methyl-4-oxo-dibenz[cd,f]indole in 544 ml ethanol is added as well as 3400 ml 2N hydrochloric acid.
The reaction mixture is warmed to 65 and maintained - for 30 minutes at this temperature. After addition of 272 ml 37~ hydrochloric acid, the reaction mixture is stired at 65 for 16 hours. After cooling to 10, the suspension is filtered. The zinc dust filtered ofl is washed with 1600 ml of a 1:1 mixture of methylene chlo-ride and ethanol. The filtrate is cooled with a ice bath, made alkaline with 4 litres of boncentrated NH40H
and extracted three times with methylene chloride (2000 ml each time). The combined organic phases are dried, filtered and evaporated to give the (5aRS)-4,5, 5a,6-tetrahydro-9,10-dimethoxy-5-methyl-dibenz[cd,f]
indole (M.pt. 126-128 with decomposition after crystal-- lization from ether). NMR 100 Mz (CDC13): S2.66 ppm (3H,s,N-CH3), 4.25 (lH,d,llHz, C-4aH).

, The starting material may be prepared as follows:
a) A mixture of 860 ml (6.16M) trifluoroacetic anhydride and 860 ml tll.24 M) trifluoroacetic acid is added at room temperature under a nitrogen atmosphere to 140.0 g (0.380 M) 8-bromo-3,4-dimethoxy-phenanthrene-9-carboxylic acid and the mixture is stirred for 10 minutes. The resulting brown limpid mixture is cooled to -5 and 30.4 g (0.468 M) sodium azide are carefully added in solid form. After 3 hours stirring at 2, the reaction mixture is poured onto ice, and ; the resulting suspension filtered and washed with 1.4 litres water. The white crude product is suspen-ded in 2.5 1 ethanol and the reaction mixture is re-fluxed. After addition of 1680 ml 2N so~iu~ hydroxide, the resulting yellow clear solution is refluxed for 45 minutes. The solution is cooled at room tem-perature, extracted with methylene chloride and the organic phase dried and evaporated. The resulting 9-amino-8-bromo-3,4-dimethoxy-phenanthrene melts at :
`` 20 107-108.
; b) 19,4 ml (0.346 M)formic acid are added dropwise over 5 minutes to a suspension of 64.5 g (0.397 M) N,N-- carbonyl-diimidazole in 387 ml absolute tetrahydro-furan, and stirred for 30 minutes at room temperature.
This solution is added dropwise, over 5 minutes at o ~ .
~.

:........... . .
, .~ .

, 0-3,to a solution of lC0 g (0.301 M) 9-amlno-8-brom~
3,4-dimethoxy-phenanthrene in 1600 ml tetrahydro-furan and the reaction mixture is stirred for 16 hours. After cooling at -10 the mixture is filte-red and the crystals are washed with ether and dried in a vacuum. The resulting 8-bromo-9-formylamino-3,4-dimethoxyphenanthrene melts at 191-193.
c) 1000 ml (1.0 M) of a molar solution of diborane in anhydrous tetrahydrofuran are quickly added under a nitrogen atmosphere to a suspension of 90 g (0.249 M) of 8-bromo-9-formylamino-3,4-dimethoxy-phenanthrene in 900 ml anhydrous tetrahydrofuran.
The resultant solution is refluxed for 4 1/2 hours and then stirred at room temperature for 16 hours. After the mixture is cooled to -5, 1800 ml of 2N sodium hydroxide are added dropwise over 5 minutes. The reaction mixture is heated to reflux and the tetra-hydrofuran evaporated off at normal pressure. 900 ml ethanol are added to the hot aqueous solution and the ethanol evaporated off at normal pressure. 900 ml ethanol is added and evaporated off in a rotary evaporator. The addition of 900 ml ethanol and eva-poration off is repeated twice more. The solid yellow coloured residue is added to 900 ml methylene chloride and 900 ml water and shaken with 900 ml ice.

,. ~
.

.

~ 3 ~
-The organic phase is separated and the aqueous phase extracted three times with methylene chloride (900 ml each time). The combined organic phases are dried and evaporated. The resulting oil is emulsified in S about 500 ml hot methanol and methylene chloride is added to form a solution of about ] litre. The methy-lene chloride is removed by heating in a rotator~ eva-porator making certain however that no formation of two phases occurs. The solution is cooled to -10 to give the 8-bromo-9-methyl-amino-3,4-dimethoxy- ~-~
phenanthrene; it melts to 75-77.
d) 70 g (0.202 M) of 8-bromo-9-methylamino-3,4-dimetho-xy-phenanthrene are dissolved under a nitrogen atmos-phere in 700 ml anhydrous methylene chloride and 139 ml (0.808 M) of N-ethyldiisopropylamine and 38 ml (0.404 M) of ethyl chloroformate are added.
The reaction mixture is stirred for 16 hours at room temperature and extracted with 500 ml 2N hydro-chloric acid. The organic phase is separated and shaken with 500 ml of a saturated potassium bicarbo-nate solution. The aqueous phase is extracted three times with methylene chloride (250 ml each time).
The combined organic phases are dried, evaporated and the residual ethyl chloroformate is eliminated by heating at 70 in a vacuum. Crystallization from ~ ~ .

~- ' , . .
:.., ether/petroleum ether afford 8-bromo-9-(N-ethoxy-carbonyl-N-methyl)amino-3,4-dimethoxy-phenanthrene.
(M.pt. iOO-110).
e) 101.8 ml (0.167 M) of a 1,64 molar solution of n-butyllithium in hexane are added over 10 minutes, to a solution of 70 g (0.167 M) of 8-bromo-9-(N-ethoxycarbonyl-N-methyl)amino-3,4-dimethoxy-phenan-threne in 1890 ml of tetrahydrofuran and 630 ml n-hexane stirred at -105 under a nitrogen atmosphere.
The reaction mixture is stirred at the same tempera-ture for 25 minutes and subsequently allowed to warm up to +10. After careful addition of 200 ml water, the reaction mixture is further diluted with 1500 ml water and extracted three times with methy-lene chloride (1500 ml each time). Ilhe col.~ined orga-nic phases are dried, filtered and evaporated, to give 4,5-dihydro-9,10-dimethoxy-5-methyl-4-oxo-dibenz[cd,f]indole (M.pt. 151-152 after crystalli-zation from ether/petroleum ether).
Example 2 ; From the appropriate compounds of formula IIIa, the following compounds of formula II may be obtained in analogous manner to Example 1:
(5aRS)-5-ethyl-4,5,5a,6-tetrahydro-9,10-dimethoxy-dibenz[cd,f]indole (oil) ,~

~'~

- ~

NMR 60 MHz (CDCl3): ~4.40 ppm (lH, dd, lOHz and homo allylic coupling of lHz , C-~aH), 1.3 (3H,t,7Hz,NCH2CH3) (5aRS)-4,5,5a,6-tetrahydro-9,10-dimethoxy-5-n-propyl-dibenz[cd,f]indole (oil) NMR 60 MHz tCDC13):~ 4.40 ppm (lH,dd,lOHæ and homo-allylic coupling of lHz, C-4aH) 1.00(3H,t,7Hz,NCH CH CH ) The starting materials may be obtained as follows:
a) llO ml (0.638 M) N-ethyldiisopropylamine are added to a solution of lOO g (0.302 M) 9-amino-8-bromo-3,4-dimethoxy-phenanthrene in 500 ml methylene chloride. A solution of 41.6 ml (0.585 ~) acetyl chloride in 500 ml methylene chloride is added dropwise in 20 minutes to this mixture. During the addition, the temperature of the reaction mixture is maintained at 20 by cooling with a ice bath. After stirring for 16 hours at room temperature, the mixture is 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 yield the 9-acetyl-amino-8-bromo-3,4-dimethoxy-phenanthrene (M.pt. 200-202 after crystallization from ether).
In analogous manner there is obtained 8-bromo-3,4-dime-~: i ~.

.
:

.

thoxy-9-propionylamino-phenanthrene (M.pt. 192-193).
b) In analogous manner to Examples lc) to le), the following compounds may be obtained:
5-ethyl-4,5-dihydro-9,10-dimethoxy-4-oxo-dibenz [cd,f]indole ~M.pt. 125-126 with decomposition), 4,5-dihydro-9,10-dimethoxy-4-oxo-5-n-propyl-dibenz [cd,f]indole (M.pt. 103-105 with decomposition).
Example 3 5-ethyl-4,5,5a,6-tetrahydro-9,10-dimethoxy-4-methyl-dibenz[cd,f~indole ______ ____________________ (compound of formula II) a) 8-bromo-9-ethylamino-3,4-dimethoxv-phenanthrene 9-acetylamino-8-bromo-3,4-dimethoxy-phenanthrene is reduced by using diborane in analogous manner to Example lc) to produce 8-bromo-9-ethylamino-3,4-dimethoxy-phenanthrene. (M.pt. 103-105 after crys-; tallization from ether).
b) 9-(N-acetyl-N-ethyl)amino-8-bromo-3,4-dimethoxy-phenanthrene - 8-bromo-9-ethylamino-3,4-dimethoxy-phenanthrene is reacted with acetyl chloride in analogous manner to Example 2a) to produce 9-(N-acetyl-N-ethyl)-amino-8-bromo-3,4-dimethoxy-phenanthrene. (M.pt. 189 after crystallization from ethyl acetate).
c) (4RS)-5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-methyl-dibenz[cd,f~indole .

.
: . .

' ' ' ' ' . ~

.~ 6 i) 10 ml (20 mM) of a 2 molar solution of tert.-butyl-lithium in pentane are added at -105 to a solution of 4.04 g (10 mM) 9~(N-acetyl-N-ethyl) amino-8-bromo-3,4-dimethoxy-phenanthrene in 130 ml anhydrous tetrahydrofuran and 50 ml n-hexane.
The temperature of the reaction mixture is allo-wed to reach room temperature and the mixture is poured onto ice. After extraction with methylene chloride, the organic phase is washed with water, dried and evaporated. The resulting crude (4RS)-5~ethyl-4,5-dihydro-4-hydroxy-9,lo-dimethoxy-4-methyl-dibenz[cd,f]indole in form of a yellow-brown foam is reacted further directly.
` ii) 2,1 ml (3.3 mM) of a 5% ethereal methyllithium .~
solution are added dropwise at -60 to a solu-tion of 1 g (3.3 mM) 4,5-dihydro-9,10-dimethoxy-~ . . .
5-ethyl-4-oxo-dibenz[cd,flindole ~prepared in , . .
Example 2b)] in 30 ml anhydrous tetrahydrofuran.
The reaction mixture is allowed to reach room temperature and kept at this temperature for 30 ; minutes. The mixture is made alkaline with a 2N
sodium hydroxide solution and extracted with methylene chloride. The organic phase is dried , ,, , and evaporated to give the (4RS)-5-ethyl-4,5-i, dihydro-4-hydroxy-9,10-dimethoxy-4-methyl-dibenz . .

,, ,~.
. . . .

' .
' ' . ' ! ' , ' , ~ ''' ' , ' ' , ' [cd,f]indole as a dark green oil [IR Spectrum (CH2C12~: 3550 cm (OH)]. The crude product is worked up further directly.
d) chlorlde - 2 ml (10.5 mM) of a saturated ethereal hydro-chloric acid solution are added to 3.2 g (10 mM) crude (4RS)-5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-methyl-dibenz[cd,f]indole dissolved in 30 ml ether, whereupon a red product precipitates. After stirring for 30 minutes, the product is filtered to give - 5-ethyl-9,10-dimethoxy-4-methyl-dibenz[cd,f]indoli-nium chloride which is used immediately for the next reaction.
e) (4RS)-5-ethyl-4,~dihydro-9,10-dimetnox~-4-methyl-dibenz [cd,~]indole ;~ 100 mg (0.33 mM) of 5-ethyl-9,10~dimethoxy-4-methyl-dibenz[cd,f]indolinium chloride are added to a solution of 12.5 mg (0.33 mM) sodium borohydride in 3 ml anhydrous tetrahydrofuran and 3 ml ethanol.
After a vigorous reaction, the mixture is stirred for 15 minutes. 3 ml water are added and the mixture is extracted with methylene chloride. The organic phase is washed with water, dried and evaporated to give the (4RS)-5-ethyl-4,5-dihydro-9,10-~ . ~
:~ .

;6 - 3~- - 100-5040 dimethoxy-4-methyl-dibenz[cd,f]indole as a green oil.
NMR 60 MHz (CDC13): ~1.2 ppm (3H,t,7Hz,NCH2CH3), 1.49 (3H,d,7Hz, C-4-CH3), 3-5 (2H~q~7Hz~ NcH2~H3), 4.88 (lH,q,7Hz, C-4-H), 6.2 (lH,s, C-6-H), 8.98 (lH,d,8Hz,C-l-H).
IR (CH2C12) : 1635 cm 1 (,C=C-N) f) 5-ethyl-4,5,5a,6-tetrahydro-9,10-dimethoxy-4-methyl-dibenz[cd,f]indole By reducing the (4RS)-5-ethyl-4,5-dihydro-9,10-dime-thoxy-4-methyl-dibenz[cd,f]indole in analogous . .
; manner to Example 1, there is obtained the title ~- compound as a mixture of the two racemates (oi-l).
The individual racemates may be separated by chroma-~; tography on silica gel.
: ~ .
; i) (-)-(4R*,5aS*):
NMR 100 ~z (CDC13): ~1.42(3H,d,6Hz, C-4a-CH3), ii) (-)-(4R*,5aR*):
NMR 100 ~z (CDC13): ~1.18(3H,d,7Hz, C-4~-CH3).
Example 4 The following (4RS)-4,5-dihydro-9,10-dimethoxy-dibenz[cd,f]indoles of formula IIIb wherein Rl and R2 .,.
~- are as ~hown in the Table, are produced in analogous manner to Examples 3a)-3e) from the appropriate star-~'' ' , ~ ~
.;, ~ , , .
, ................................................ .

1~8i.~6 -32 - lO0-5040 ting materials (the free bases of formula IIIb are ob-tained as an oil having similar characterization NMR
data as described in Example 3e).
. . _. . . _______ . .
Example Rl R2 ============ ====================: =================
i CH3 CH3 ii CH3 n-C3H7 : iii CH3 iso-C3H7 iv CH3 n-C4Hg v C2H5 CH3 vi n~C3H7 CH3 vii iso-c H CH3 viii n-C4Hg CH3 . ix sec.-C4Hg CH3 ;: x tert.-C4H9 CH3 xi - 5 ll CH3 xii CH3 CH3 1~3 .
xiii 2 .1 3 CH3 20 xiv -CH-CH2-CH3 CH3 xv -n-C6Hl3 CH3 . , ~ CH2 xvi ¦ -CH ¦ ¦ CH3 _ _ _ _ .

- : ~

The compounds of formula IIIb may be directly transformed in the corresponding 9,10-dimethoxy compounds of formula II in manner analogous to that of the Example 3b).
Example 5 4,5,5a,6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenz[cd,flindoles [compound of formula II¦
a) (-)-(6aR)-5,6,6a,7-tetrahydro-10, ~ 0,~
dimethyl-4~l-dibenzo[de~]quinolinium iodide 100 ml (1.6 M) methyl iodide are added to a solution of 100 g (0.34 M) (-)-(6aR)-5,6,6a,7-tetra-hydro-10,11-dimethoxy-6-methyl-4H-dibenzo[de,g]quino-line in 100 ml methylene chloride and the mixture is refluxed for 30 minutes. After cooling, ether is added to the reaction mixture and the precipitate is filtered and dried to give (-)-(6aR)-5,6,6a,7-tetrahydro-10,11-dimethoxy-6,6-dimethyl-4H-dibenzo [de,g]quinolinium iodide (decomposition at 173-176).
b) 8_vinyl-phenanthrene 13.9 g (124 mM) potassium tert.-butylate are dissolved under a nitrogen atmosphere in 560 ml tetrahydrofuran and 47 g (112 mM) (-)-(6aR)-5,6,6a,7-tetrahydro-10,11-dimethoxy-6,6-dimethyl-4H-dibenzo . .

- -34 - 1~0-5040 [de,g]quinolinium iodide are added. The mixture is stirred at room temperature for one hour, poured onto ice and 560 ml of 10% hydrochloric acid are added. The mixture is washed with ether. The aqueous f 5 phase is neutralised with sodium bicarbonate, made ~; alkaline at pH 9 with 50 ml of a 20~ sodium hydro-xide solution and extracted three times with methy-lene chloride (500 ml each time). The combined methylene chloride extracts are dried and evaporated.
The residue is purified by chromatography on 1 kg of silica gel using ether as eluant, to give (9RS)-9,10-dihydro-3,4-dimethoxy-9-dimethylamino-8-vinyl-phenanthrene (M.pt : 109).
,~ c) ~ :~ro-9,l~ ~L~-b~-4,5-dimeth ~ dibenz i 15 [cd,f]indole 17.5 g (57 mM) of (9RS)-9,10-dihydro-3,4-dime-thoxy-9-dimethylamino-8-vinyl-phenanthrene are added to a stirred suspension of 10.2 g ($7 mM) N-bromo-; succinimide in 55 ml water. The reaction mixture , ::
becomes warm and after some minutes the product precipitates. After about one hour the mixture is cooled with a ice bath and the precipitate is , . ; .
, filtered to give (5aRS)-4,5,5a,6-tetrahydro-9,10-dimethoxy-5,5-dimethyl-4-methylene-dibenz[cd,f]indo-linium bromide (sintering at 135 and melting at ' ' .
!

. .

165). The crude product is worked up further directly.
19.7 g (50.7 mM) of the resultant indolinium bromide in 100 ml ethanolamine are stirred at 100 for one hour. The reaction mixture is poured onto ice/water and extracted three times with methylene chloride (300 ml each time). The combined methylene chloride extracts are dried and evaporated to yie~ (4RS)-4,5-dihydro-9,10-dimethoxy-4,5-dimethyl-dibenz[cd,f]indole as an oil.
The (4RS)-4,5-dihydro-9,10-dimethoxy-4,5-- dimethyl-dibenz[cd,f]indole may also be prepared ' as follows :
A solution of 2.7 g (0,86 ml; 17 mM) bromine in 15 ml chloroform is added dropwise at room temperature to a solution of 4.8 g (15.5 mM) . . .
~ (9RS)-9,10-dihydro-3,4-dimethoxy-9-dimethyl-amino-; 8-vinyl-phenanthrene in 45 ml chloroform. After the reaction, the mixture is cooled with an ice bath.
The resultant precipitate is filtered and washed with 10 ml chloroform and 100 ml ether to give ., ~
4-bromomethyl-4,5,5a,6-tetrahydro-9,lo-dimethoxy-5,5-dimethyl-dibenz[cd,f]indolinium bromide (sintering at 132 and melting at 154-158). The product is transformed directly in (4RS)-4,5-' .

- 36 - 10~5040 dihydro 9,10-dimethoxy-4,5-dimethyl-dibenz[cd,f]
indole by heating in ethanolamine as described above.
d~ 4,5,5a,6-tetrahvdro-9,10-dimethox -4,5-dimethyl-dibenz!,cd,f ? indole 400 ml (44.2 mM) of a 3~ aqueous solution of mercuric chloride are added to 200 g (330 mM) of zinc dust. The mixture ~s stirred for 5 minutes and -2500 ml 2N hydrochloric acid are added. A solution of 15.7 g (50 mM) (4RS)-4,5-dihydro-9,10-dumethoxy-4,5-dimethyl-dibenz[cd,f]indole in 400 ml ethanol are added and the mixture is warmed to 50-60 for one hour. After addition of 200 ml 37~ hydrochloric acid , the mixture is stirred at 90 for 14 hours.
The mixture is cooled, the zinc dust filtered and the filtrate made alkaline at pH 10 with an ammonia , .
solution. The mixture is extracted three times with methylene chloride (1000 ml each time) and the combined methylene chloride extracts are dried over Na2S04 and evaporated to give the 4,5,5a,6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenz[cd,f]
indole as mixture of two racemates in form of the ; free base. The mixture of the two racemates is chro-matographied over 1.8 kg of silica gel using fractions of 50 ml of methylene chloride/methanol (98.5 : 1.5) as eluant.

' The fractions 125-240 contain the (-)-(4R,*5~*~
4,5,5a,6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenz[cd,f]indole. NMR spectrum of the base (CDC13 90 MHz) :51.44 ppm (3H,d,6Hz, c-4a-CH3~
M.pt of the corresponding hydrochloride : up 185 (with decomposition).
The fractions 250-330 contain the (-)-(4R*,5aR~)-4,5,5a,6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenz [cd,f]indole. NMR spectrum of the base (CDC13,90 MHz):
~1.24 ppm (3H,d,7Hz,C-4~-CH3) -M.pt of the correspon-ding hydrochloride : from 200 (with decomposition).
Example 6 In analogous manner to Example 5, the following compounds of formula II may be produced from the ~-~ 15 appropriate starting materials (the free bases of the compounds of formula II are obtained as an oil).
;~ (i) (-)-(4R*,5aS*)-and (-)-(4R*,5aR*)-S-ethyl-4,5,5a,6-, tetrahydro-4-methyl-9,10-dimethoXy-dibenz[cd,f]
indole;
tii) ~-)-(4R*,5as*)- and (-)-(4R*,5aR*)-4,5,5a,6-tetrahydro-4-methyl-5-n-propyl-9,10-dimethoxy-dibenz[cd,f]indole;
(iii) (-)-(4R*,5aS*)-and (-)-(4R*,5aR*)-4,5,5a,6-tetrahydro-4-methyl-5-isopropyl-9,lo-dimethoxy-dibenz[cd,f]indole;
:

'' ~ - :' :

(iv) (-)-(4R*,5aS*)- and (-)-(4R*,5aR*)-5-n-butyl-4,5,5a,6-tetrahydro-4-methyl-9,10-dimethoxy-dibenz [cd,f]indole.
Example 7 A solution of 5 g (18 m~) (-)-(4R*,5aS*)-4,5,5a,6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenz[cd,f]
indole in form of the base in 10 ml ethyl acetate and 0.5 ml methanol is added to a solution of 3.3 g (22 mM) (-)-tartaric acid in 22 ml ethanol/ethyl acetate (1:1) and the mixture is stirred for one hour at room temperature, whereupon the (-)-tartrate of the (-)-(4S,5aR)-4,5,5a,6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenz[cd,f]indole crystallized. Decomposition :
183-190; [a]D = -120.6 (~2~ c = 0,5).The corresponding hydrochloride obtained in kncwn manner deco~posed at 210-255;
[]D = -140 (H20, c = 0,5).
The mother liquors remaining from the crystalli-zation of the tartrate are made alkaline with potassium carbonate and the mixture is extracted with methylene chloride. The combined organic extracts are washed neutral, dried and evaporated. The residue (about 2.5 g;
9 mM) is mixed with 1.65 g (llml) (+)tartaric acid in

11 ml ethanol/ethyl acetate (1:1). After stirring for one hour at room temperature, the (+)-tartrate of the .

~, ' : :

~.

1;?~6 (+)-(4R,5aS)-4,5,5a,6~etrahydro-9,10-dimethoxy-4,5-dimethyl-dibenz[cd,f]indole crystallized. Decomposi-tion : 185-190; [a]D = ~ 116 (H20, c = 0,5). The hydrochloride obtained in known manner decomposed at 215-230; [a]D = + 140 (H20, c = 0.5).
The following compounds may be obtained in analogous manner from the (-)-(4R*5aR~-4,5,5a,6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenz[cd,f]
indole (in the form of the free base) :
- the (-)-tartrate of (+)-(4S,5aS)-4,5,5a,6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenz[cd,f]indole.
Decomposition : 177-180 ; [a]D = +116(H20,c = 0.5) Decomposition of the corresponding hydrochloride :
- 160-164; [a]D = -~ 160 (H20, c = 0 5j - 15 - the (+)-tartrate of (-)-(4R,5aR)-4,5,5a,6-tetra-hydro-9,10-dimethoxy-4,5-dimethyl-dibenz[cd,f]indole.
! Decomposition : 178-182; [a]D = -114 (H20, c=0.5).
Decomposition of the corresponding hydrochloride :
15~-162; [a]D = -156 (H20, c = 0.5).
The following compounds may also be obtained in analogous manner from the (-)-(4R*,5aS*~5-ethyl-4,5,5a,6-tetrahydro-9,10-dimethoxy-4-methyl-dibenz [cd,f]indole (in the form of the free base):
- the (-)-tartrate of (+)-(4R,5aS)-5-ethyl-4,5,5a,6-~: "

tetrahydro-9,10-dimethoxy-4-methyl-dibenz[cd,f]indole;
[~]D = +96 (H20, c = 0.5). The corresponding hydrochloride obtained in known manner decomposed at 185-188~; [a]D = +121 (H20, c = 0.5~.
- the (~)-tartrate of (-)-(4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro-9,10-dimethoxy-4-methyl-dibenz[cd,f]indole;
[a]D = -102.4 (H20, c = 0.5). The corresponding hydrochloride obtained in known manner decomposed at 189-190; [~]D = -122 (H20, c = 0.5).
Example 8 (-)-(4R*,5aS*)-4,5,5a,6-tetrahydro-9,10-di-hydroxy-4,5-dimethyl-dibenz[cd,f]indole (compound of formula I) ; 16.8 g (53.8 mM) (-)-(4R*,5aS*)-4,5,5a,6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenz[cd,f]indole are dissolved in 400 ml of a 47% aqueous solution of hydrobromic acid and the solution is warmed for 3 hours at 130. After evaporation of the mixture the residue is dissolved in ethanol and the solvent is evaporated.
Crystallization of the residue from methanol/ether affords the hydrobromide of the title compound. The corresponding hydrochloride obtained in known manner decomposed at 185; NMR 100 MHz (DMS0) : ~ 1.81 (3H,d, 5Hz, C-4~-CH3) .~ ' `, .
: ~ .

~lQ~
- ~1 100-5040 Exam~les 9 -39 .
In manner analogous to Example 8 and using corresponding starting materials, compounds of formula Ia may be obtained, in which Rl and R2 are as shown in the following Table.

'~ ' .

- 42 ~ 100-5040 === =T~ r~

9 CH3 CH3 (-)-(4R*,5aR*) 18sol) 10 CH3 CH3 (-)-(4S,5aR) [ ]D

11 CH3 CH3 (+)-(4R,5aS) [ ]D

12 CH3 CH3 (~)-(4S,5aS) 2l50l)

13 CH3 CH3 (-)-(4R,5aR) [ ]20_ 135

14 CH3 C2H5 (~)~(4S,5aR) ~280 ) CH3 C2H5 (-)-(4R*,5aR*) 195l) 16 CH3 C2H5 (-)-(4R*,5aS.*) lgoOl) 17 CH3 n~C3H7 (-)-(4R*,5aR*) 1801) 18 CH3 n~C3H7 (-)-(4R*~5aS*) 18ool) 19 CH3iso_C3H7 (-)-(4R*,5aR*) 205 ) CH3 ~-C3H7 (_)_(4R*,5aS*) 2201) 21 CH3 n-C H (-)-(4R*,5aR*) 16ool) i. 22 CH3 n-C4Hg (-)-(4R*,5aS*) 210ol) 23 H CH3 (-)-(5aRS) 270-275 ) . ~ , .
.

_ .
~Ex. ~ R1 ~ 2 ~ C~ figur~tion ¦ Dec npos tion 24 HC2H5 (-3-(5aRS) ~240 . 25 H n~C3H7 (-)-(5aRS) 258-260 ) .. 26 C2H5 CH3 (-)-(4R*,5aR*) ~175 ) 27 C2H5 CH3 (_)~(4R*,5aS*) >195 ) 28 1so_C3H/ CH3 (-)-(4R*,5aR*) >225 ) 29 1so-C3M7 CH3 (-)-(4R*,5aS*) ~200 ) n~C3H7 CH3 (-)-(4R*,5aR*) ~215o2) 31 n~C3H7 CH3 (-)-(4R*,SaS*) ~1852) 32 tert.~4Hg CH3 (-)-(4R*,5aR*) 284-285 33 ~ CH3 (-)-(4P~*~SaS*) 270-272 ) 34 sec.C4Hg CH3 (-)-(4R*,5aR*) 263-265 ) 35 secrc4H9 CH3 (-)-(4R*,5aS*) 285-2862) 36 n-C4HgCH3 (-)-(4R*,5aR*) 27202) 37 n-C4HgCH3 (-)-(4R*,5aS*) 269-2712) :: CH
38 -CH /1 2 CH3 (-+)-(4R*,5aR*) 1702) . 2 .
., ' CH2 +
39 -CH <¦ CH3 (-)-(4R*,5aS*) 258-261 ) _ CH2 _ ~

1) Hydrochloride 2) Hydrobromide ., .
, Examp]e 40 (~ 4R*,5aS*)-9,10-dibenzoyloxv-4,4,5a, G-tetrah~,,dro-4,5-dimethyl-dibenz[cd,f]
indole [compound of formula I]
4.7 ml (40.6 mM) of benzoyl chloride are added to a solution of 1.3 g (4.31 mM) of (-)-14R*,SaS*)-4,5,5a,6-tetrahydro-9,10-dihydroxy-4,5-dimethyl-dibenz [cd,f]indole hydrochloride in 12 ml trifluoroacetic acid and the mixture is refluxed for one hour. After evaporation of the reaction mixture, the residue is extracted three times with methylene chloride (100 ml each time) and the combined organic extracts are dried over sodium sulphate and e~-aporated. The residue is purified by chromatography through a column of 165 g silica gel using methylene chloride/methanol (97:3) as eluant to give pure (-)-(4R*,5aS*)-9,10-di-benzoyloxy-4,5,5a,6-tetrahydro-4,5-dimethyl-dibenz [cd,f]indole. The hydrochloride melts at 215-225 (with decomposition) after crystallization from ether/acetone; NMR lO0 MHz (DMS0) : ~1.39 ppm (3H,d,6Hz, C-4a-CH3).
Examples 41-105 In manner analogous to Example 40 and using corresponding starting materials, compounds of formula . . .

,.
"

.
.
: - - . - :

l~Q8~

R3-C01~2 may be obtalned, in which Rl, R2 and R3 are as shown ln U-e following Table.

.

':~
~ ' .
~ .
.:. .

. ~ .

~ . .
,' .
.
~; ' .

.
-.

.

TABLE II
, _ . .. _ . _ Ex. Rl R2 R3 Decomposition =~~3= ==~=8=--= =8=r=~==== =======~============ __================
41 H -CH3 ~ Cl 189~191ol)7) 42 H --C2H5 -CH2 ~ 185 1)7) 43 H -n-C3H7-CH2 ~ 210-213 ) ) 44 H -n-C H -C2H5 210-2l3ol)7) -CH3 -C2H5- ~ CF3 214-2l902)7) 46 -CH3 -C2H5 ~ 210-213 ) ) 47 -CH3 -C2H5 ~ Br 232_23902)7) 48 -CH3 -C2H5 ,2 ~ 196-200o )7) 49 -CH3 -C2H5 ~ Cl 235_238o4)7) . [~]D0~MeOH)-32,8 .

-CH3 -C2H5 ~ Cl 221_22305)7) [Q] D (MeO~) +28.4 2 -CH3 -n-c3H7 -CH /¦ 205-212 ) ) .
.~ .

--. ~ . .
- - , --' . ; ~ ' ' ~, .

- '.

_ . . ~ . .
Ex. R R R~ Decomposition , 1 2 3 [~]DO (c=0.5) ~ == D= ==lD=~_3 ====Y=~=-== ===========~======== __================

53 -CH3 -n-C H -(CH2)3-CH3 155-161o3)7) 54 -CH3. -n-C 3H7 -CzH5 205-2070 )7) -Cl13 -C2H5 ~ OCH3 170-175 ) ) 56 -CH3 -C2H5 ~ -OCH3 161-163 ) ) ~ OCH3 [ a] D (MeOH)+18.8 57 -CH3 -C2H5 ~ Cl l7902)7) 58 -CH3 -C2H5 C ~ 188-190o2)7) 59 -CH3 -C2~15 C ~ . [ a] 20(MeOH)-21 2 :' . 60 -CH3 -C2H5 ~ OCH3 169-l7302)7) .' ¦ 61 ¦ -CH3 ~ ~ ¦.14-2455)7)~

.

A Ex. Rl -- 2 3 Decomposition l ~a]D (c=0.5) ===_= ==n~=~__= ~===_GG===== =~n===========_=_=== ~n===============:
62 -CH3 ~C2H5 ~ OCH3 198-2ooo2)7) 63 -CH3 -C2H5 ~ 203-2050 )7) . CH30 64 -CH3 -CE~3 -CH2 ~ 218-22302)7) : 65 -CH3 -CH3 CH 2212)7) .; 66 -CH3 -CH3 -CH/ ¦ 213~)7) 67 -CH3 -CH3 -CH2)2-CH3 193-l9902)7) 68 -CH3 -CH3 -CH3 204o2)7) 69 -CH3 -n-C3H7 -iso-C3~7 2103)7) 70 -CH3 -n-C3H7 ~ . 201-207 ) ) 71 -CH3 -n-C3H7 ~ ter t . -C 4Hg 193_l9702)7) . 72 -CH3 -n-C3H7 -i~o-C H 20802)7) 73 -CM3 ~C2H5 ~ CE13 205-207 ) ) 74 -CH -C H ~ 2105)7) 3 2 5 _ ~C~
: ~ 3 [~]20(MeOH)+15.4 ',"
. ., - : : .
:~ :

- 49 - 100 50~0 Al Ex. Rl R2 Rll Decomposition ===S: ====~==~= =~=~S0~=~=S ==~========G=-====== _========-=======
75 -CH3 -C2H5 ~ 206-208o2)7) . . CH3 76 -CH3 -C2H5 H3C 194-196o2)7) 77 -CH3 -CH3 ~ 158-174 ) ) 78 -CH3 -CH3 -tert.-C4Hg 2o602)7) 79 -CH3 -CH3 -iso-C H 194-2o2o2)7) 80 ¦ -CH3 ¦-CH3 l _ ~) ¦ . IS-235 81 --CH3 -CH3 -iso-C H 215-22506)7) . [a]DO(H20)-166 82 -CH3 -C2H5 ~ 165-180 )7) 83 ¦ -CH3 ¦ 2 ¦ (~ ¦ 80-l9S )7) ¦

84 -CH3 -C2H5 _~ 214-221 ) ) [ ~D (MeOH)~120 .

'' :
' ~

. - 50 - lOC-5040 _ . .
Ex. 1 R2 _ Decomposition . -5=~= =~ S=~= =3========== =_= =====~==~====== __~=============== ., 85 -CH3 2 5 -tert.-C4Hg 170-l85o2)7) 86 -CH3 2 5 -tert.-C4Hg 1806)7) . - [~]D (MeoH)~ 2o 87 -CH3 2 5 -tert.-C4Hg 225_23503)7) 88 -CH3 2 5 -iso-C H 135 - l5002)7) 89 -CH~ 2 5 -iso-C H 220-23oo )7) 90 -CH3-C2H5 -CH2 ~ OCH3 136-142o )7) 91 -CH32 5 -CH2 ~ OCH3 [a]DO(MeOH)-65.1 92 ¦ -CH3 ¦ -C2HS ¦ 2 ~ ¦ 1 6-1422)7~ ¦

93 -CH3 -C2H5 -CH2 ~ 133-l40o2)7) 94 -CH3 -C2H5 -CH2 ~ Cl 200-212 ) ) 9-5 -CH3 2 5 -CH ~ Cl L23-133 ) ~
[~]D (MeOH)-66,2 .
~,:, , .
., ~.
.

'' ' ~ ~ ' ' '. .' '' :

:
~ -~ . . .

- 51 - 10~ 5040 i Ex . Rl R2 - - A Decompos i tion [~,,] 20 (c=O. 5) ===-~ ==~C=-~= -S~D~S~=~ J=~-===3==_=S======= __================
96-CH3 -C2H5-CH2~ 19 9-2030 2 ) 7 ) . 1 ~ 97-CH3 -C2H5-CH2~ . 154-l6lo2) 7) '. ' C

98-CH3 -C2H5-CH2~ 136-142 )7) Cl [~]D (MeOH)-76.3 . C
99-CH3 -C2H5-CH2-~ 239_24402) 8) .~ Cl 100-CH3 -C2H5-CH2~Cl 187-191 ) ) . Cl ' ~` . 101-CH3 -C2H5-CH2~Cl 210-2l2o 2 ) 8 ) 102-CH3 -C2H5 4~ 199-2l40 2 ~ 7) . -~Cl 81;:~

Ex. Rl R2 ~ [~]20 (c=0.5) ===: =V~==3== ~ ===== =====~=====-========= =C================

103 -CH3 -C2H5 ~ . 184-189 ) ) 104 -CK3 ~ 2 ~ 84-1902)7) 105 -CH3 -CH3 -CH2 ~ 208-210 ) ) . ~ L ~
' ' .

1) (-) (5aRS) ..2) (-) (4R*,5aS*) 3) (-) (4R*,5aR*) 4) (-) (4R,5aS) 5) (+) (4S,5aR) 6) (-) (4S,5aR) 7) Hydrochloride . 8) Methanesulphonate .:
, , , : .

l~Q~

The end products of the invention,in particular the compounds of formula I, possess pharmacological activity. In particular, the co~rg?ounds are indicated for use are as central dopaminergic stimulant agents, as indicated 5 by standard tests, for example according to the prin-ciples of U. Ungerstedt Acta Physiol.Scand.Suppl. (1971) 367, 69-93, by induction of contralateral turning in rats whose substantia nigra has been lesioned by a microinjection of 6-hydroxydopamine and by induction 10 of dose dependent stereotyped sniffing, licking and biting behaviour in the rat according to the following test:
Rats, 180-222 g, are placed in perspex cylinders of 30 cm diameter on a wire grid floor. After 30 minutes 1~ 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 7 hours. The degree of 20 stereotyped behaviour observed is assessed using a scoring system based on that described by Costall, Naylor and Olley [Euro J. Pharmac. 18, 83-94 (1972)].
The scores and criteria are as follows:
1. Intermittent sniffing ~ -, :, ' 3~

2. Persistent sniffiny, occasional licking 3. Licking, occasional biting 4. Intense and persistent biting.
In these tests the compounds are administered 5 i.p. from 0.03 to 30 mg/kg animal body weight.
The compounds are therefore indicated for use as central dopaminergic stimulant agents, for example for treating Morbus Parkinson. For this indication, an indicated daily dose is from about 0.5 to about 10 100 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.1 to about 50 mg, or in sustained release form.
The compounds of Examples 50, 54 to 61, 64, 73, 74, 81, 82,84, 85, 86~90J 91, 94 95, 97, 98 and 105 are

15 particularly interesting, in particular compounds of Examples 50, 57 and 64.
The compounds may be administered in pharma-ceutically acceptable acid addition salt form. These salt forms exhibit the same order of activity as the 20 free base forms.
The present invention also provides a pharmaceu-tical composition comprising an end product of the invention, in particular a compound of forlrula I, in free base form or in pharmaceutically acceptable 25 acid addition salt form in association with a pharma-~;

:
, '. , .~ ceutically acceptable diluent or carrier.
These compositions may be formulated in con-ventional manner so as to be for example a solution, - a capsule or tablet.
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Claims (4)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

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

I

and pharmaceutically acceptable acid addition salts thereof, wherein R1 is hydrogen, (C1-10)alkyl, (C3-7) cycloalkyl, or (C3-7)cycloalkyl-(C1-4)alkyl, R2 is (C1-5)alkyl, and the R3 substituents are the same and are hydroxy or carboxylic acyloxy radicals, 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

II

in which R1 and R2 are defined above and Z is a splittable ether group, and b) when a compound is required of formula Ib Ib in which R1 and R2 are defined above and the radicals R? are identical carboxylic acyloxy radicals, acylating a compound of formula Ia, and when a pharmaceutically acceptable salt is required, reacting the product obtained with a corresponding acid.

2. A compound of formula I

(I) wherein R1 is hydrogen, (C1-10)alkyl, (C3-7) cycloalkyl, or (C3-7)cycloalkyl-(C1-4)alkyl, R2 is (C1-5)alkyl, and the R3 substituents are the same and are hydroxy or carboxylic acyloxy radials, or a pharmaceutically acceptable acid addition salt thereof, whenever produced by the process of claim 1 or an obvious chemical equivalent thereof.

3. The process of claim 1 wherein R1 is methyl, R2 is ethyl, R3 is p-chloro-benzoyloxy and having the (+) (4S,5aR) configuration.

4. The compound (+)-(4S,5aR)-5-ethyl-9,10-di-)p-chloro-benzoyloxy)-4,5,5a,6-tetrahydro-4-methyl-dibenz [cd,f]indole, or a pharmaceutically acceptable acid addition salt thereof, whenever produced by the process of claim 3 or an obvious chemical equivalent thereof.