GB2024818A - Phenanthrene derivatives, their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

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

SPECIFICATION Phenanthrene derivatives, their preparation and pharmaceutical compositions containing them The present invention relates to phenanthrene derivatives, their preparation and pharmaceutical compositions containing them.

In accordance with the invention there are provided phenanthrene derivatives, i.e. 4, 5, 5a, 6 tetrahydrodibenz [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 hydrolysable under physiological 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 9 and/or 10 positions.

More preferably, the invention provides compounds of formula I,

wherein R, is hydrogen, (C,~,0) alkyl, (C3-7) cycloalkyl or (C,,) cycloalkyl - (C1 < ) alkyl, R2 is (C,,) alkyl, and the R3 substituents are the same and are hydroxy or acyloxy radicals.

R, is preferably an alkyl radical. When R, 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 radicals. These may be radicals of formula R,-CO-O- in which Ra is unsubstituted or substituted alkyl; (C,,) cycloalkyl; a phenyl radical, or a 5 - or 6 membered heterocyclic ring.

When Ra is an alkyl radical, this may conveniently 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, containing in the alkyl chain conveniently 1-5 carbon atoms. Conveniently it is a monosubstituted alkyl radical.

Examples of substituents are carboxy, hydroxy, amino, (C1-4) alkylamino, (C, 4) alkoxy, di - (C,) alkylamino, halogen, (C1-4) alkylthio, phenoxy, a phenyl radical, 1 - 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 (C3-7) cycloalkyl.

When Ra is a phenyl radical or alkyl substituted by a phenyl radical, the phenyl radical may be unsubstituted or contain 1,2 or3 identical or different substituents, selected for example from halogen, trifluoromethyl, (C,,) alkyl, (C1--4) alkoxy, (C, < ) alkylthio and di - (C1-4) 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 halogen, (C1-4) alkyl, (C1-4) alkoxy or (C,,) alkylthio.

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

Preferably Ra is (C,,) alkyl; (C3-6) cycloalkyl; unsubstituted phenyl; phenyl mono- or disubstituted by chlorine, fluorine, trifluoromethyl, (C1~4) alkyl or (C,,) alkoxy; unsubstituted benzyl; or benzyl mono- or disubstituted by chlorine, fluorine, (C1--4) alkyl or (C1--4) alkoxy.

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

Representative groups of compounds are those of formula I'

in which R2 is as defined above, and of formula I"

in which R2 is as defined above and the Rta substituents are identical and are unsubstituted or substituted (C,,,) alkyl; (C3-7) cycloalkyl; a phenyl radical; or a 5- or 6-membered heterocyclic ring.

R2 is conveniently (C1-4) alkyl. Rta is conveniently (c,,) alkyl, (C3-7) cycloalkyl, (C37) cycloalkyl - (C,,) 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, f] indole containing at least one hydroxy or acyloxy substituent in one or both of the fused benzene rings, 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 corresponding compound containing at least one splittable 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 at least one hydroxy sub stituent in one or both of the fused benzene rings.

More particularly, the invention provides a process for the production of compounds of formula I, which comprises a) producing a compound of formula la

in which Ri and R2 are as defined above, by splitting the ether groups Z of a compound of for mula 11

in which R1 and R2 are defined above and Z is a splittable ether group, or b) producing a compound of formula Ib

in which R1 and R2 are defined above and the radicals R'3 are identical acyloxy radicals, by acylating a compound of formula la.

The ether splitting process of the invention, in particular process a), may be effected in conventional manner for splitting ether groups. For example the reaction may be carried out by treatment of the starting materials with a strong mineral acid, e.g. hydrobromic or hydroiodic acid, at a temperature of at least 100"C, preferably from 1000C to the boiling point of the reaction mixture, especially at 1300C. The ether group(s), in particular the groups Z, is/are preferably arylalkoxy or alkoxy containing up to 10 carbon atoms, especially a benzyloxy, ethoxy or methoxy radical, more preferably a methoxy radical.

The acylation process of the invention, in particular process b), may be effected in conventional mannerforthe selective acylation of phenolic groups in the presence of an amine function. For example there may be used, as acylating agent, a functional derivative of an acid such as acid chloride, acid bromide or the acid anhydride. Conveniently the reaction is carried out by reacting an acid chloride in the presence of trifluoroacetic acid at temperatures from 20"C to the boiling point of the reaction mixture or in the presence of pyridine at temperatures from 0 C to room temperature.

The 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 corresponding 4,5 - dihydro - dibenz[cd, f] indole which is correspondingly substituted, or oxo substituted at the 4 - position when a compound unsubstituted atthe4- position is desired.

Particularly, the compounds of formula Il may be produced by reducing the 5a, 6- double bond, and where present, the 4 - oxo - group, in a compound of formula Ill,

in which R2 and the radicals Z are as defined above, and either X is hydrogen and Y is the same as R1, or X and Ytogether are oxa.

The reduction may be effected conveniently by methods conventionally used forthe reduction of enamines 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) chloride The reaction may suitably be effected in an organic solvent, for example a lower alkanol, e.g. ethanol, and at temperatures from 50"C to the boiling point of the reaction mixture. Underthese conditions, any 4 - oxo group present is simultaneously reduced.

The resulting compounds of the invention may be isolated from the reaction mixture and purified in known manner. The free base forms may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids for saltformation are hydrochloric acid, hydrobromic acid and methanesulphonic acid.

The compounds of the invention possess an asymetric carbon atom in the 5a position and can be obtained as a racemate or as one of the optically active forms, i.e. as an individual enantiomer. When the nucleus is substituted in the 4 - position, in particularwhen R, 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 crystallization of diastereoisomeric salts, e.g. their salts with (+) or (-) tartaric or di - p - toluoyl - I - 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) monosubstituted 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 Illa

in which R2 and the radicals Z are as defined above, may be prepared for example according the following reaction scheme:

In the reaction scheme the radicals Z and R2 are as defined above, R'2 is hydrogen or (C1) alkyl, Hal is iodine, bromine or chlorine and Alk is lower alkyl.

The reactions may be carried out in conventional 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 IV with sodium azide in presence of trifluoroacetic acid and trifluoroacetic anhydride followed by hydrolysis with base. The acylation of compounds of formula V may for example be carried out with a compound of formula R"2 - CO - Hal in which Hal is as defined above and R"2 is (C1 < ) alkyl, in the presence of an acid acceptor, e.g. N- ethyldiisopropylamine. When R'2 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 diborane.The preparation of compounds of formula VIII may suitably be effected by reacting the compound of formula VII with a chloroformate in an organic solvent and in the presence of an acid acceptor, e.g. N - ethyldiisopropylamine. Treatment of compounds of formula VIII with for example an alkyl- or acryl - lithium compound, preferablyn - butyllithium or tert. - butyllithium in tetrahyd rofuranihexane at temperatures ranging from -11 0 C to OOC affords the compounds of formula Illa.

The remaining 4- oxo - substituted starting materials in process c) may be produced in analogous manner.

Compounds of formula Illb

in which the radicals Z and R1 and R3 are as defined above, may be prepared for example according the following reaction scheme wherein the radicals Z, R1, R2 and Hal are as defined above and ArPis an anion:

The reactions 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 - CO - R'1 in which R'1 is the same as R1 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 R1 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 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 tetrahydrofuran/hexane at temperatures ranging from -11 0 C to 0 C affords the compounds of formula Xl. The dehydration of compounds of formula Xl may for example be carried out with a mineral acid, for example hydrochloric acid in ethereal solution. The salts of formula XII may be reduced to Illb with sodium borohydride in tetrahydrofuran.

The starting materials of formula X may also be prepared by conventional manner from the compounds of formula VII by acylation with compounds of formula R1- CO - Hal as described above.

The compounds of formula Xl in which R, is R'1 as defined above may also be prepared in conventional manner from compounds of formula Illa by reaction with compounds of formula R'1 - Li in which R'1 is as defined above. The compounds of formula Xl in which R1 is hydrogen may also be prepared in conventional manner from compounds of formula Illa by reduction with LiAIH4.

The compounds of formula Illb in which R1 is methyl, may also be prepared according the follow ing reaction scheme wherein the radicals Z and R2 are as defined above, HaP-is chloride, bromide or iodide, ArP is chloride, bromide, iodide, CH3 - SO or C2H5SOpand either Rx is hydrogen and Ry is bromomethyl or Rx and Ry together are =CH3:-

The alkylation of compounds of formula XIII may be effected for example by reaction with compounds offormulaAn-R2 in which R2 is as defined above and 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, dioxane or tetrahydrofuran, at temperatures from 0 C to 50"C, 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 temperatures from 0 C to 50"C, preferably at room temperature, conveniently in an inert organic solvent, for example an halogenated hydrocarbon, e.g. methylene chloride, chloroform ortetrachlorocarbon, preferably chloroform. The reaction with N - bromosuccinimide may be carried out conveniently at temperatures from 0 C to 50"C, preferably at room temperature in the presence of water and optionally an organic solvent, e.g. dioxane, tetrahydrofuran, 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 800, preferably between 80"C and 110"C, particularly at 100"C, 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 R1 substituent other than hydrogen may be produced in manner analogous to that described above for compounds Illb.

The products of the above reactions may be iso lated and purified in known manner.

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-tetrahydro - dibenz[cd, f] indoles hav ing 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 ben zene ring, b) 4,5 - dihydro - dibenz[cd, fj. indoles bearing at least one hydrogen attached to the carbon atom at position 4 and having at least one splittable ether group on any of positions 1 to 3 and 7 to IC, c) 4,5 - dihydro - 4 - oxo - dibenz[cd, f] indoles having only one or two splittable ether groups in any of positions 7 to 10, and having no further oxy substituents in the nucleus.

Particularly compounds of formula Ill'a,

wherein R2 is as defined above, the ring B having only one or two splittable ether groups and no further oxy substituent being present in the nucleus, compounds of formula Ill'b

wherein R, 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'

wherein R1, R3 and Hal are as defined above, and the ring A and/or B contains at least one splittable ether group (of which compounds --------- Illa, Illb and V are examples), are by virtue 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 to 10 positions. Conveniently the eher group or groups are (C, < ) 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 R, 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.

Example (SaRS) - 4, 5, Sa, 6 - tetrahydro - 9, 10 dimethoxy -5 - methyl - dibenz[cd, f] indole (compound of formula II) 544 ml (0.06M) of a 3 h aqueous solution of mercuric chloride are added under nitrogen atmosphere and stirring to 272 g (41.7M) of zinc dust and the mixture is stirred for 5 minutes at room temperature.

A suspension of 40 g (0.316M) of 4,5 - dihydro - 9, 10 -dimethoxy-5-methyl- 1 fez -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 off is washed with 1600 ml of a 1:1 mixture of methylene chloride and ethanol. The filtrate is cooled with a ice bath, made alkaline with 4 litres of concentrated NH40H and extracted three times with methylene chloride (2000 ml each time).

The combined organic phases are dried, filtered and evaporated to give the (SaRS) - 4, 5, 5a, 6 - tetrahydro -9, 9,10- dimethoxy- 5- methyl - dibenz[cd, f] indole (M.pt. 126-128" with decomposition aftercrystallization from ether). NMR 100 Mz (CDCl3): 8 2.66 ppm (3H,s,N - CH3), 4.25 (1 H,d,1 1Hz, C - 4aH).

The starting material may be prepared as follows: a) A mixture of 860 ml (6.16M) trifluoroacetic anhydride and 860 ml (11.24 M) trifluoroacetic acid is added at room temperature under a nit rogen 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 care fully 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 suspended in 2.5 1 ethanol and the reaction mix ture is refluxed. After addition of 1680 ml 2N sodium hydroxide, the resulting yellow clear sol ution is refluxed for 45 minutes. The solution is cooled at room temperature, extracted with methylene chloride and the organic phase dried and evaporated. The resulting 9 - amino - 8 bromo - 3,4 - dimethoxy - phenanthrene melts at 107-108".

b) 19,4 ml (0.346 M) formic acid are added drop wise over 5 minutes to a suspension of 64.5 g (0.397 M) N, N - carbonyl - diimidazole in 387 ml absolute tetrahydrofuran, and stirred for 30 minutes at room temperature. This solution is added dropwise, over 5 minutes at 0-3 , to a sol ution of 100 g (0.301 M) amino - 8- bromo - 3, 4- dimethoxy- phenanthrene in 1600 ml tet rahydrofuran and the reaction mixture is stirred for 16 hours. After cooling at1 00 the mixture is filtered and the crystals are washed with ether and dried in a vacuum. The resulting 8 - bromo 9 - formylamino - 3,4 - dimethoxyphenanthrene melts at 191 - 1930.

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 anhydr ous 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 tetrahyd rofuran evaporated off at normal pressure. 900 ml ethanol are added to the hot aqueous solu tion and the ethanol evaporated off at normal pressure. 900 ml ethanol is added and evapo rated off in a rotary evaporator. The addition of 900 ml ethanol and evaporation 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. 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 about 500 ml hot methanol and methylene chloride is added to form a solu tion of about 1 litre. The methylene chloride is removed by heating in a rotatory evaporator mak ing 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- dimethoxy- phenanthrene are dissolved under a nitrogen atmosphere in 700 ml anhydr ous 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 tempera ture and extracted with 500 ml 2N hydrochloric 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 - phenant hrene. (M.pt. 100-110").

e) 101.8 ml (0.167 M) of a 1,64 molar solution ofn 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- phenanthrene in 1890 ml of tetrahydrofuran and 630 mln - hexane stirred at -1 OS0 under a nitrogen atmosphere.

The reaction mixture is stirred at the same temperature for 25 minutes and subsequently allowed to warm upto +100. After careful addi tion of 200 ml water, the reaction mixture is further diluted with 1500 ml water and extracted three times with methylene chloride (1500 ml each time). The combined organic phases are dried, filtered and evaporated, to give 4, 5 dihydro - 9, - dimethoxy- 5 - methyl - 4 - oxo dibenz [cd, f] indole (M.pt. 151-152 after crystal lization from ether/petroleum ether).

Example 2 From the appropriate compounds of formula Illa, the following compounds of formula II may be obtained in analogous manner to Example 1: (SaRS) -5 - ethyl - 5, 5a, 6 - tetrahydro 9, 10 dimethoxy- dibenz[cd, f] indole (oil) NMR 60 (CDCl3): a 4.40 ppm (1H, dd, 10Hz and homo allylic coupling of 1Hz, C - 4aH), 1.3 (3H, t, 7Hz, NCH2CH3) (SaRS) - 5, 5a, 6 - tetrahydro -9,10 - dimethoxy 5 n-propyl-dibenz[cd,f] indole (oil) NMR 60 MHz (CDC13):: 8 4.40 ppm (1H, dd, 10Hz and homo - allylic coupling of 1Hz, C - 4aH) 1.00 (3H, t, 7HZ, NCH2CH2CH3).

The starting materials may be obtained as follows: a) 110 ml (0.638 M) N - ethyldiisopropylamine are added to a solution of 100 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 M) 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 cool ing 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 - dimethoxy -9 - propionylamino - phenanthrene (M.pt. 192-193 ).

b) In analogous manner to Examples 1 c) to 1 e), 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).

Example3 5- ethyl-4, 5, Sa, 6- tetrahydro - 9, 10 dimethoxy -4 - methyl - dibenz [cd, f] indole (compound of formula II) a) 8- bromo - 9 - ethylamino - 3,4 - dimethoxy - phenanthrene 9 - acetylamino - 8 - bromo - 3,4 - dimethoxy phenanthrene is reduced by using diborane in analogous manner to Example 1c) to produce 8 - bromo - 9 - ethylamino - 3,4 - dimethoxy phénanthrene. (M.pt. 103-105 after crystalliza tion from ether).

b) 9- (N- acetyl 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) 14RSJ-5-ethyl-4,5- drydro-4-hydroxy-9, 10 - dimethoxy - 4 - methyl dibenz [cd, f] indole i) 10 ml (20 mM) of a 2 molar solution of tert. butyl - lithium in pentaneare added at-150 to a solution of 4.04g (10 mM)9-(N-acetyl-N- ethyl) amino - 8 - bromo - 3,4- dimethoxy phenanthrene in 130 ml anhydrous tetrahyd rofuran and 50 ml n - hexane. The temperature of the reaction mixture is allowed 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, 10-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 600 to a solution of 1 g (3.3 mM) 4,5 - dihydro - 9, 10 - dimethoxy 5 - ethyl - 4 - oxo - dibenz [cd, f] indole [prepared in Example 2b)j in 30 ml anhydrous tetrahyd rofuran. 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 - dihydro -4- hydroxy-9, 9,10 - dimethoxy-4- methyl - dibenz [cd, f] indole as a dark green oil [IR Spectrum (CH2CI2): 3550 cm-1 (OH)]. The crude product is worked up further directly.

d) 5- ethyl-9, 10 - dimethoxy - 4 - methyl - dibenz [cd,f] indolínium chloride 2 ml (10.5 mM) of a saturated ethereal hyd rochloric 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, where upon 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] indolinium chloride which is used immediately for the next reaction.

e) (4RS)-5-ethyl-4,5-dihydro-9, 10 - dimethoxy -4-methyl- dibenz[cd, f] indole 100mg(0.33mM)of5-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 tet rahydrofuran 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 dimethoxy - 4 - methyl - dibenz [cd, f] indole as a green oil.

NMR 60 MHz (CDCl3): 8 1.2 ppm (3H,t,7Hz, NCH2CH3), 1.49 (3H, d, 7Hz, C 4 - CH3), 3.5 (2H, q, 7Hz, NCH2CH3), 4.88 (1 H, q, 7Hz, C 4-H),6.2(1H,s,C-6-H),8.98 (1H,d,18Hz,C-1 -H).

IR (CH2CI2): 1635 cm-' ( > C=C-N) f) 5-ethyl-4,5,5a,6-tetrabydro-9, 10 dimethoxy - 4 - methyl- dibenz [cd, f] indole By reducing the (4RS) - 5 - ethyl - 4, 5 - dihydro - 9, 10 - dimethoxy- methyl dibenz[cd, f] indole in analogous manner to Example 1, there is obtained the title compound as a mixture of the two racemates (oil). The individual racemates may be separated by chromatography on silica gel.

i) (+) - (4RP, 5aSP): NMR 100 MHz (CDCl3): @ 1.42 (3H, d, 6Hz, C 4a-CH3), ii) (+) - (4RP, 5aRP): NMR 100MHz(CDCl3):@1.18(3H,d,7Hz,C- 4P-CH3).

Example 4 The following (4RS) - 4, 5 - dihydro -9,10 dimethoxy - dibenz [cd, f] indoles of formula Illb wherein R1 and R2 are as shown in the Table, are produced in analogous mannerto Examples3a) -3e) from the appropriate starting materials (the free bases of formula Illb are obtained as an oil having similar characterization NMR data as described in Example 3e).

R1 R2 x,ai R1 = i CE' CH3 ii CH3 "-C3H7 CH3 CH3 isbCjH7 iv CN3 "C4Hs V C H CE' 25 3 vi n-C3H7 CN3 vii iso-C3H, CE'3 viii n-C4H9 CN3 ix Sec.-C489 013 x tert.-cqag (313 xi D 5 11 CN3 xii -CH2-013-CH3-013 013 3 - ICN3 xiii -CH2-C-CH3 013 013 xiv CN-CH2CN3 CN3 C2H5 xv -n-C6H13 013 / CN2 xvi C\I! 013 CHI The compounds of formula Illb 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, Sa, 6 - tetrahydro - 9, 10 - dimethoxy - 4, 5 - dimethyl - dibenz [cd, 23 indoles [compound of formula 11] a) (-I-(6aR-5,6,6a,7- tetrahydro- 70, 11 dimethoxy - 6, 6 - dimethyl - 4H - dibenzo [de, g] 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 tetrahydro - 10, 11 - dimethoxy - 6 - methyl - 4H dibenzo[de, g] quinoline in 100 ml methylene chloride and the mixture is refluxed for 30 minutes.After cooling, ether is added to the rea ction 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) (9RS) -9,10 - dihydro - 3,4 - dimethoxy -9 dimethylamino -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, 6a, - tetrahydro - 10,11 - dimethoxy- 6,6 dimethyl - 4H - dibenzo [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 phase is neutralised with sodium bicarbonate, made alkaline at pH 9 with 50 ml of a 20% sodium hydroxide solution and extracted three times with methylene 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: 1090).

c) (4RS) - 4,5 - dihydro -9,10 - dimethoxy - 4,5 - dimethyl - dibenz kd, f] indole 17.5 g (57 mM) of(9RS) - 9,10- dihydro - 3,4- dimethoxy - 9 - dimethyl amino - 8 - vinyl phenanthrene are added to a stirred suspension of 10.2g(57mM)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 (SaRS) - 4, 5, 5a, 6 tetrahydro - 10 - dimethoxy -5,5 - dimethyl - 4 - methylene - dibenz [cd, f] indolinium bromide (sintering at 1350 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 yield (4RS) - 4, 5 - dihydro - 9, 10 - dimethoxy - 4,5 - dimethyl - dibenz [cd, f] indole as an oil.

The (4RS) - 4, 5- dihydro - 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 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 -9,10 - 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 - dihydro - 9, 10 - dimethoxy - 4,5 - dimethyl - dibenz [cd, f] indole by heating in ethanolamine as described above.

d) 4, 5, 5a, 6- tetrahydro - 9, 10- dimethoxy- 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 is 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 - dimethoxy - 4, 5 - dimethyl - dibenz [cd, f] indole in 400 ml ethanol are added and the mix ture is warmed to 50-60 for one hour. After addi tion 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 Na2SO4 and evaporated to give the 4, 5, 5a, 6 - tetrahydro - 9, 10 - dimethoxy - 4,5 - dimethyl - dibenz [cd, f] indole as mixture of two race mates in form of the free base. The mixture of the two racemates is chromatographed 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 (i) - (4R*, 5aS*) -4,5, 5a, - tetrahydro - 9,10- dimethoxy - 4,5 - dimethyl - dibenz [cd, f] indole.

NMR spectrum of the base (CDCI3 90MHz): 8 1.44 ppm (3H, d, 6Hz, C - 4a - CH3) M.pt of the corresponding hydrochloride: up 185 (with decomposition).

The fractions 250-330 contain the (t) - (4R, 5aR*)- 4,5,5a,6 - tetrahydro - 9, 10 - dimethoxy - 4,5 - dimethyl - dibenz[cd, f indole. NMR spec trum of the base (CDCl3, MHz): ô 1.24 ppm (3H, d, 7Hz, C - 4ss - CH3) M.pt of the correspond ing hydrochloride : from 200 (with decomposi tion).

Example 6 In analogous manner to Example 5, the following compounds of formu la II may be produced from the appropriate starting materials (the free bases of the compounds of formula II are obtained as an oil).

( (+!-(4R,SaS)-and (+)-(4R,5aF)-5- ethyl - 4,5, 5a, 6 - tetrahydro - 4 - methyl - 9, 10- dimethoxy- dibenz[cd, f] indole; (ii) ()-(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-S - isopropyl - 9, 10 - dimethoxy - dibenz [cd, f] indole; (iv) ()-(4Rr,SaS)-and ()-(4R1,5aRr)-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 mM) (i) - (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 (-) - ta rtrate of the (-) - (4S, 5aR) - 4,5, 5a, 6 - tetrahydro - 9, 10 dimethoxy- 4,5 - dimethyl - dibenz[cd, f indole crystallized. Decomposition: 183 -190 ; [&alpha;]20D = -120.6 (H2O, c = 0,5).The corresponding hydroch loride obtained in known manner decomposed at 210-255 ; [a] 20D = -140' (H2O, c = 0,5).

The mother liquors remaining from the crystallization 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 (11 ml) (+) tartaric acid in 11 ml ethanol/ethyl acetate (1:1). After stirring for one hour at room temperature, the (+) - tartrate of the (+) - (4R, 5aS) - 4, 5, 5a, 6 - tetrahydro - 9, 10 - dimethoxy - 4,5 - dimethyl dibenz cd, indolecrystallized. Decomposition: 185 - 190 ; a] 20D = + 116 (H2O, c = 0.5).The hydrochloride obtained in known manner decomposed at 215-230 ; [a] 20D = + 140 (H2O, c = 0.5).

The following compounds may be obtained in analogous manner from the (i) - (4R*, Saff) 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, 59S)- 4, 5, 5a, 6 - tetrahydro - 9, 10 - dimethoxy - 4,5 - dimethyl dibenz [cd, f] indole.Decomposition: 177-180 ; [&alpha;] 20D = + 116 (H2O, c = 0.5) Decomposition of the corresponding hydrochloride: 160-164 ; [a] 20D= + 160 (H2O,c=0.5) - the (+) - tartrate of (-) - (4R, SaR)-4,5, 5a, 6 tetrahydro -9, 10 - dimethoxy - 4,5 - dimethyl dibenz[cd,f] indole. Decomposition: 178-182 ; [a] 20D = =-114 (H3O, c = 0.5). Decomposition of the corresponding hydrochloride: 158-162 ; [a] 20D = -156' (H2O, c = 0.5).

The following compounds may also be obtained in analogous manner from the (i) - (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; [&alpha;]20D = +96 (HȎ, c = 0.5).

The corresponding hydrochloride obtained in known manner decomposed at 185-188 ; [&alpha;] 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] 20D = -102.4 (H2O, c = 0.5). The corresponding hydrochloride obtained in known manner decomposed at 189-190 ; [a] 20D = -122'(H2O, c = 0.5).

Example 8 ()-(4R*,5aS*) -4,5, Sa, 6 - tetrahydro - 9, 10- dihydroxy-4, 5- dimethyl dibenz [cd, f]indole (compound of for mula I) 16.8g (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 for3 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 (DMSO): 8 1.81 (3H, d, 5Hz,C-4a-CH3) Examples 9-39 In manner analogous to Example 8 and using corresponding starting materials, compounds of formula la may be obtained, in which R1 and R3 are as shown in the following Table.

Ex. R1 R2 Configuration Decomposition 20 3 (H20, ===== ====== 9 CH3 CH3 ()-(4R*,SaR*) 185 l) 10 CH3 CH3 (-)-(4S.5aS) 185 1) [&alpha;]D20 = -97 11 CH3 CH3 (+)-(4R,5aS) 185 1) [[&alpha;;]D20 = +96 12 CH3 CH3 (+)-(4S,5a5) 215 1) [&alpha;] D20 = +136 13 CH3 CH3 (-)-(4R,5aR) 205 1) [&alpha;;]D 20= -135 14 CH3 C2H5 (-)-(4S,5aR) > 280 2) [a] 20 -65,7 15 CH3 C2H5 ()-(4R*,SaR*) 195 1) 16 CH3 C2H5 ()-(4R*,5aS*) 190 1) 17 CH3 n-C3H7 ()-(4R*,5aR*) 160'1) 16 CH3 n-C3H7 ()-(4R*,5aS*) ' 1601) 19 CH3 iso-C3H7 ()-(4R*,5aR*) 205 1) 20 CH3 iso-C3H7 ()-(4R*,Sa8*) 220 1) 21 CH3 n-C4Hg ()-(4R*,5aR*) 160 1) 22 CH3 n-C4H5 ()-(4R*,5aS*) 210 1) 23 H CH3 ()-(5aRS) 270-275 2)

necoaposition Ex R1 R2 Configuration 20 =o (H20, O ======== = ======== =============== ===============~0.5) 24 H C2H5 (±)-(5aHE) 224002) 25 H E 3 7 (-) - (SaRS) 258-2601) 26 C2H5 CH3 (~)~ (4R*,SaR*) > 175 2) 27 C2H5 CH3 (+)-(4R*,5aS+) )19502) 28 iso-C3H CH3 (+)-(4R*,5aR*) > 225 2) 29 iso-C3H CH3 (+)-(4R*,5aS*) > 200 30 n-C3H7 CH3 (!)-(4R*SaR*) > 215 2) 31 q-C3H7 CH3 (+)()Ha,5,g) > 185 2) 32 tert=C4H9 CH3 (f-(4R*,5aR*) 284-285 - + 2702722) 33 tsrtoC4Hg CH3 (-)-(4R*,SaS*) 34 sec.-C4N CH3 ()(4Ha,5,R*) 263-26502) 35 =c,C4H9 CH3 (-)-(4H',5a5') 285-286 2) 36 n-C4Hg CH3 (+)-(4R*.5aR*) 27202) 37 n-CqHg CH3 (!)(4R*,SaS*) 269-27102) 38 -CH4H2 CH3 (+)-(4R*,saR") 170 2) CH2 CH2 + ' 39 01;;tH2 CH3 (-+)-(4H*,5as*) 258-261a2) 1 1) Hydrochloride 2) Hydrobromide Example 40 ()-(4R*, 5aS*)-9, 10 - dibenzoyloxy - 4,4, 5a, 6- tetrahydro - 4,5- dimethyl -dibenz[cd, F[indole[compound of formula 4.7 ml (40.6 mM) of benzoyl chloride are added to a solution of 1.3 9 (4.31 mM)of()-(4R,5aS*)-4,5, 5a,6 - tetrahydro - 9, 10 - dihydroxy- 4,5 - dimethyl dibenz[cd,f] indole hydrochloride in 12 mltrif- luoroacetic 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 evaporated. The residue is purified by chromatographythrough a column of 165 g silica gel using methylene chloride/methanol (97:3) as eluant to give pure ()-(4R*, 5aS*)-9,10-dibenzoyloxy- 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 100 MHz (DMSO): ô 1.39 ppm (3H, d, 6Hz, C 4&alpha;-CH3).

Examples 41- 105 In manner analogous to Example 40 and using corresponding starting materials, compounds of formula

may be obtained, in which R1, R2 and R"3 are as shown in the following Table.

TABLE II

lx. 11 Rz I R3 (o130 ~ t.

41 II 013 C1 18919101)7) 42 H -C2H5 012 1850 1) 7) 43 H -n-C3H7 -CHZ 210-2130 1) 7) 44 H -fl-C3H7 -C2g5 210-21391)7) 45 -C13 -C2H5 tCF3 214219 2) 7) 46 013 -C2H5 210-21302)7) 47 013 -C2H5 eBr 232-23902)7) 48 H3 C2Hb Cu2 19820o02)7) 49 013 -C2Hg tC1 235238 (00)2fl(O8)32.80 9 so 013 -c2ii5 oC1 12In22305) 7) 20 I(MeH)+28.40 51 013 -n-C3H7 CH 158-16993)7) 52 7) 52 013 -fl-C3H7 CE'NC1K

8oooooOOiti= lx. 1L 12 13 talD (c-O.S) 53 013 -fl-C3H7 (CH2) 3~CH3 155-181- 7) 54 013 -n-C3H7 -C2H5 205~207O 317 ) 55 CH3 -C2H5 < SOCH3 170-17502)7) '3CH3 56 -C9 -C2Hg 4+0CH3 - 161-16P5)7) ACH3 1a1D (HCO9)+18.f .

57 -13 2H5 C1 17902)7) 58 013 -C2H5 CY 188~19002) 7) > 18f6)7) .

59 013 -C2H5 60 -C83 -C2H5 OOCH3 169-17302)7) or 81 013 -C2H5 w OCH3 1 a1 D OleOR) 126

lx. R1 R2 R3 Doocoooaiti0' Ea)20 =so~ s w ~ase~~~ssseesx s (c-o.5) 82 CH3 -C2H5 epoch 19820002) 7) - 001 63 013 -C2H5 C 3 20320502)7) 013 64 -CH3 -CH3 -CE2 218-22302)7) 65 -CH3 -Cu3 22102)7) 66 -CH2 -CE3 -EH(I 21302)7) 013 67 CE'3 -CH3 -C82) 2-CH3 19j19902)7) 68 CE'3 CE'3 013 204"2)7) 69 CE'3 -1-C87 -iso-C3H7 21003)7) 70 -CE3 n-C3H7 201-20702)7) 71 013 -u-C3 -tert. -C H 71 -CH3 -n-C3H7 tert. -C4Ng 19319702)7) 72 -CE13 -n-C3H7 -iso-C3H7 20802)7) 72 -CE3 -C2H5 CE3 ; 205-20702)7) 74 -CE1 -C2H5 CE33 21005)7) \=I [o]$QIeOH)+15.4

Ex. R1 R2 B2 R3 90000000itioo 3 to120 w~~ss s 75 013 -C2H5 < 206-20s"2)1) . CH3 76 CH3 -C2H5 H3C 194-19602)7) H3C 77 013 CH3 15 & 740 3)1) 78 013 -CE3 -tert.-C4Hg 20602)7) 79 i 013 CH3 -iso-C3H7 194-20202)7) 80 ; CH3 013 < 215-23506)7) 1a1D (H20)~56 0 2 81 013 -CE3 -isC3H7 215-22506) 7) :12o (H20) 1880 82 CH3 -C2Hg 165-18002) 7) 83 013 -C2H5 < 180-19503)7) 84 3 C2ES 214-22105)7) . [ 3 D (MeO8) 112

80C',p Ex. Rl R2 R3 Deco position ~ ts 85 -CH3 -c H -tert.-C4Hg 170-18502)7) 86 -CE3 2 S -C2H5 -tert. -C4H9 18or6)7) 20 [a]$(NeOli)-111S 87 -CE3 -C2H5 -tert.-C4Hg 225~23So3)7) 88 -CE3 2 -iso-C3H7 Ijg~ 15002)7) 89 -CE3 -C2Hg -iso-C3H7 220~230o 3) 7) 90 -CE3 -C2E5 -CH2-DCHJ 136-142 )7) CH30CE'3 -CH7)' 91 -CE3 -C2H8 CH2 < 0CH3 (a) DO(MeO6) -65 .1 136ia2)7) 92 013 C2H5 CE2cu CH3 93 013 -C3H5 133-14002)7) CH3O 94 -CH3 C2HS -CH 4C1 200-212 95 -CE3 -C2Hg 01razzCl 123-1330)7) X C [a]D tMeO11)-66,2 lx. R1 12 R3 Decepositi (oi2O ssssseso= 96 -CE3 -C2H5 0121 198-203 7) 97 013 -C2H5 CH2Cp 154-16102)7) 98 -CH -C285 -CE2 136-142o6)7) [rr](HeOli)-76.T 91 99 013 C2HS -C2E5 239-244"2)8) 100 -CE3 -C2Hg -CH29C1 1871glo2)b) .1 101 -CE3 -C2H5 CH31 210-21202)8) 102 CE'3 -C2Hg 9::1 199-214

lx. Ii R2 3 Decoapositioa ~ ~~I~~~~ (,-o.5) 103 CE'3 -C2H5 9 184-18902)7) 104 -CE3 -C2H5 F 184-l9o'2)7) F 105 013 -CE3 -01 (ai2o(KeoE)727O 1) (+) (5aRS) 2) (+) (4RP, 5aS) 3) (+) - (4RB, 5aRI*) 4) (-) (4R,5aS) 5) (+) (4S,5aR) 6) (-)(4S,5aR) 7) Hydrochloride 8) Methanesulphonate The end products of the invention, in particular the compounds of formula I, possess pharmacological activity. In particular, the compounds are indicated for use are as central dopaminergic stimulant agents, as indicated by standard tests, for example according to the principles 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 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 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 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 2. Persistent sniffing, occasional licking 3. Licking, occasional biting 4. Intense and persistent biting.

In these tests the compounds are administered 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. Forthis indication, an indicated daily dose is from about 0.5 to about 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, 74,81,82,84,85,86,90,91,9495,97,98and 105 are particularly interesting, in particular compounds of Examples 50, 57 and 64.

The compounds 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 an end product of the invention, in particular 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 tablet

Claims (122)

CLAIMS:

1. A4, 5, 5a, 6-tetrahydro- dibenz[cd, f] indole having at least one oxy substituent in one or both of the fused benzene rings, at least one said oxy substituent being hydroxy or acyloxy when the nucleus is unsubstituted in the 4 position.

2. A compound of claim 1, wherein there are only two said oxy groups present.

3. A compound of claim 2, wherein the oxy groups are present in the 9 and 10 positions.

4. A compound of any one of claims 1 to 3 wherein the oxy group or groups are selected from hydroxy and acyloxy groups.

5. A compound of formula I

wherein R1 is hydrogen or (C1,,) alkyl, (C3-7) cycloalkyl, or (C3-7)cycloalkyl - (C1-4) alkyl, R2 is (C15) alkyl, and the R3 substituents are the same and are hydroxy or acyloxy radicals.

6. A compound of claim 5 wherein each R3 is hydroxy.

7. A compound of claim 6 wherein R, is methyl.

8. A compound of claim 5 wherein each R3 is an acyloxy radical.

9. A compound of claim 5 or 8 wherein each acyloxy radical is of formula R,- CO-O- wherein Ra is an unsubstituted or substituted alkyl radical, (C27) cycloalkyl, a phenyl radical, or a 5 - or 6 - membered heterocyclic ring.

10. Acompound of claim 9 wherein ( i) the alkyl radical is unsubstituted alkyl of 1 to 17 carbon atoms, an alkyl radical of 1 to 4 carbon atoms monosubstituted by (C37) cyc loalkyl or an alkyl radical of 1 to 5 carbon atoms monosubstituted by halogen, hyd roxy, (C1-4) alkoxy, amino, (C1 < ) alkylamino, di - (C, < ) alkylamino, carboxy, (C,,) alkyl thio, phenoxy, 1 - pyrrolidinyl, piperidino, morpholino, by phenyl unsubstituted or bea ring 1,2 or 3 identical or different sub stituents chosen from halogen, trif luoromethyl, (C1--4) alkyl, (C,,) alkoxy, (C1-4) alkylthio, di - (C1) alkylamino, or by phenyl substituted by methylenedioxy, ( ii) the phenyl radical is a phenyl unsubstituted or bearing 1,2 or 3 identical or different sub stituents chosen from halogen, trif luoromethyl, (C,,) alkyl, (C1-4) alkoxy, (C1-4) alkylthio, and di - (C1-4) alkylamino, or is methylenedioxyphenyl, and (iii) the 5 or 6 membered heterocyclic ring has oxygen, nitrogen or sutphur as the sole heteroatom.

11. A compound of claim 10 wherein the monosubstituted alkyl radical is substituted by di - (C, < ) alkylamino, halogen, (C1-4) alkoxy (C1-4) alkylthio, phenoxy, (C,) cycloalkyl, or phenyl bearing up to 3 substituents independently chosen from halogen, alkyl (C1-4)r alkoxy (C, < ) or alkylthio (C-4).

12. A compound of claim 8 wherein R1 is methyl and R3 is acyloxy of formula Rta - CO - 0 - in which R', is unsubstituted alkyl of 1 to 17 carbon atoms; an alkyl radical of 1 to 4 carbon atoms monosubstituted by (C3-7) cycloalkyl; an alkyl radical of 1 to 5 carbon atoms monosubstituted by halogen, hydroxy, (C1-4) alkoxy, amino, (C,) alkylamino, di - (C,) alkylamino, carboxy, (C1-4) alkylthio, phenyl, phenoxy 1 - pyrrolidinyl, piperidino, or morpholino; (C3-7) cycloalkyl; a phenyl unsubstituted or bearing 1,2 or 3 identical or different substituents chosen from halogen, (C1-4) alkyl, (C1-4) alkoxy, (C1-4) alkylthio, and di (C1,) alkylamino; a methylenedioxyphenyl or a 5 or 6 - membered heterocyclic ring.

13. A compound of claim 6 which is 4,5, 5a, 6 tetrahydro - 9, 10 - dihydroxy - 4,5 - dimethyl - dibenz [cd, f] indole.

14. A compound of claim 6 wherein R, and R3 are respectively methyl and ethyl.

15. A compound of claim 6 wherein R, and R2 are respectively methyl and n - propyl.

16. A compound of claim 6 wherein R, and R2 are respectively methyl and isopropyl.

17. A compound of claim 6 wherein R, and R2 are respectively methyl and n - butyl.

18. A compound of claim 6 wherein R, and R2 are respectively ethyl and methyl.

19. A compound of claim 6 wherein R, and R2 are respectivelyisopropyl and methyl.

20. A compound of claim 6 wherein R, and R2 are respectivelyn - propyl and methyl.

21. A compound of claim 6 wherein R, and R2 are respectivelytert. - butyl and methyl.

22. A compound of claim 6 wherein R, and R2 are respectively sec. - butyl and methyl.

23. A compound of claim 6 wherein R1 and R2 are respectivelyn - butyl and methyl.

24. Acompound of claim 6 wherein R, and R2 are respectively cyclopropyl and methyl.

25. A compound of claim 6 wherein R, and R2 are respectively hydrogen and methyl.

26. A compound of claim 6 wherein R, and R3 are respectively hydrogen and ethyl.

27. A compound of claim 6 wherein R1 and R2 are respectively hydrogen andn - propyl.

28. A compound of any one of claims 13 to 27 in racemic form.

29. A compound of any one of claims 13 to 27 in optically active form.

30. A compound of any one of claims 13 to 24 in optically active form which has the configuration 4S, SaR or4R, 5aR.

31. ( +) - (4R,5aS) - 4, Sa, - tetrahydro - 9,10 - dihydroxy - 4, 5 - dimethyl - dibenz [cd, f] indole.

32. (-) - (4S, 5aR) - 4,5, spa, - tetrahydro - 9, 10 - dihydroxy - 4, 5 - dimethyl - dibenz [cd, f] indole.

33. (+)-(4S, 5aS)-4, 5, 5a, 6-tetrahydro- 9, 10dihydroxy - 4, 5 - dimethyl - dibenz [cd, f] indole.

34. (-) - (4R, 5aR) - 4,5,5a,6 - tetrahydro - 9, 10 - dihydroxy - 4, 5 - dimethyl - dibenz [cd, f] indole.

35. (-) - (4S,5aR) - 5 - ethyl - 4, 5, Sa, 6 - tet- rahydro -9, 10 - dihydroxy - 4 - methyl - dibenz [cd, f] indole.

36. A compound of claim 8 which is 9, 10 - dibenzoyloxy - 4, 5,5a,6 - tetrahydro - 4, 5 - dimethyl - dibenz [cd, f] indole.

37. A compound of claim 8 wherein R1, R2 and R3 are respectively H, methyl and p - chlorobenzoyloxy.

38. A compound of claim 8 wherein R1, R2 and R3 are respectively H, ethyl and phenylacetyloxy.

39. A compound of claim 8 wherein R1, R2 and R3 are respectively H,n - propyl and phenylacetyloxy.

40. A compound of claim 8 wherein R1, R3 and R3 are respectively H, n - propyl and propionyloxy.

41. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl andp -trifluorobenzoyloxy.

42. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl andp - fluorobenzoyloxy.

43. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl andp - bromobenzoyloxy.

44. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl and phenylacetyloxy.

45. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl,n - propyl and cyclohexylcarbonyloxy.

46. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, n - propyl and cyclopropyl ca rbonyloxy.

47. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl,n - propyl and pen ta noyloxy.

48. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, n - propyl and propionyloxy.

49. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl and 3,4 - dimethoxy benzoyloxy.

50. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl andp - chlorobenzoyloxy.

51. A compound of claim 8 wherein R, R2 and R3 are respectively methyl, ethyl and o - chlorobenzoyloxy.

52. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl andp - methoxybenzoyloxy.

53. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl and m - methoxybenzoyloxy.

54. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl and o - methoxyben zoyloxy.

55. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, methyl and phenylacetyloxy.

56. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, methyl and cyclohexyl carbonyloxy.

57. A compound of claim 8 wherein Rt, R3 and R3 are respectively methyl, methyl and cyclopropylcarbonyloxy.

58. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, methyl and butyryloxy.

59. A compound of claim 8 wherein R1, R3 and R3 are respectively methyl, methyl and acetyloxy.

60. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, n - propyl and iso butyryloxy.

61. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, n - propyl and benzoyloxy.

62. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, n - propyl and pivaloyloxy.

63. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl andp - methylbenzoyloxy.

64. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl and m - methyl benzoyloxy.

65. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl and o - methyl ben zoyl oxy.

66. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, methyl and pivaloyloxy.

67. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, methyl and isobutyryloxy.

isobutyryloxy.

68. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl and benzoyloxy.

69. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl and pivaloyloxy.

70. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl and isobutyryloxy.

71. A compound of claim 8 wherein R1, Rp and R3 are respectively methyl, ethyl andp - methoxyphenylacetyloxy.

72. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl and m - methoxyphenylacetyloxy.

73. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl and o - methoxyphenylacetyloxy.

74. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl andp chlorophenylacetyloxy.

75. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl and m ch lorophenylacetyloxy.

76. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl and o chlorophenylacetyloxy.

77. A compound of claim 8 wherein Rj, R2 and R3 are respectively methyl, ethyl and 2,6- dichlorophenylacetyloxy.

78. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl and 2,4 - dichlorophenylacetyloxy.

79. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl and 3,4 - dich lorophenylacetyloxy.

80. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl and m - chloroben zoyloxy.

81. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl andm - fluoroben zoyloxy.

82. A compound of claim 8 wherein R1, R2 and R3 are respectively methyl, ethyl and o - fluorobenzoyloxy.

83. A compound of any one of claims 36 to 82 in racemic form.

84. A compound of any one of claims 36 to 82 in optically active form.

85. A compound of any one of claims 36 and 41 to 82 in optically active form and which has the configuration 4S, 5aR or 5aR.

86. (-) - (4R, 5aS) - 9,10 - di (p - chloroben- zoyloxy) -5 - ethyl - 4, 5, Sa, 6 - tetrahydro - 4 - methyl - dibenz [cd, f] indole.

87. (+) - (4S,5aR) - 9,10 - di (p - chloroben- zoyloxy) -5 - ethyl - 4,5, Sa, 6 - tetrahydro - 4 - methyl - dibenz[cd, f] indole.

88. (+) - (45, 5aR) - 9,10- di- (3,4- dimethox- ybenzoyloxy) - 5 - ethyl - 4,5, Sa, 6 - tetrahydro - 4 - methyl - dibenz [cd, f] indole.

89. (-) - (4S,5aR) - 9,10 - di (o - chloroben- zoyloxy) -5 - ethyl - 4,5, Sa, 6 - tetrahydro - 4 - methyl - dibenz[cd, f] indole.

90. (+) - (4S,5aR) - 9,10 - di (p - methoxyben- zoyloxy) -5 - ethyl - 4,5, Sa, 6 - tetrahydro - 4 - methyl - dibenz [cd, f] indole.

91. (+) - (45, SaR) - 9, 10 - di (p - methoxyben- zoyloxy) - 5 - ethyl - 4,5, Sa, 6 - tetrahydro - 4 - methyl - dibenz [cd, f] indole.

92. (-)-(4S, 5aR)- 9, 10 - dibenzoyloxy - 4,5, 5a, 6 - tetrahydro - 4,5 - dimethyl - dibenz [cd, f] indole.

93. (-)-(4S,5aR)- 9, 10 - diisobutyryloxy - 4,5, Sa, 6 - tetrahydro - 4,5 - dimethyl - dibenz [cd, f] indole.

94. (+) - (4S,5aR) - 9,10 - dibenzoyloxy- 5 - ethyl - 4,5, Sa, 6 - tetrahydro - 4 - methyl - dibenz [cd, f] indole.

95. (-) - (4S,5aR) - 5 - ethyl - 4, 5,5a,6 - tet- rahydro - 4 - methyl - 9, 10 - dipivaloyloxy - dibenz [cd, f] indole.

96. (-)-(4S,5aR)-9, 10-di (p- methox yphenylacetyloxy) -5 - ethyl - 4,5,5a,6 6- tetrahydro - 4-methyl-dibenz[cd,f] indole.

97. () - (4S,5aR) - 9,10 - di (p - chlorophenylac tyloxy) - 5 - ethyl -4,5, spa, 6 - tetrahydro - 4 - methyl -dibenz[cd,f] indole.

98. (-) (4S,5aR) - 9,10 - di (o - chlorophenylacetyloxy) -5 - ethyl - 4,5, 5a, 6 - tetrahydro - 4 - methyl - dibenz [cd, f] indole.

99. (-) - (4S,5aR) - 4, 5, Sa, 6 - tetrahydro - 4, 5 - dimethyl 9, 10 - di (phenylacetyloxy) dibenz[cd, ss indole.

100. A compound of any one of claims 1 to 99 in free base form.

101. A compound of any one of claims 1 to 99 in acid addition salt form.

102. A process for the production of a 4,5,5a,6 tetrahydro - dibenz [cd, f] indole having at least one oxysubstituentin one or both of the fused benzene rings, at least one such oxy substituent being hyd roxy or acyloxy when the nucleus is unsubstituted in the 4-position, which comprises i) obtaining a compound containing at least one ether group in one or both of the fused ben zene rings by reducing the 5a, 6 - double bond of a corresponding 4,5- dihydro - dibenz rcd, f] indole which is correspondingly substituted, or oxo - substituted at the 4 - position when a compound unsubstituted at the 4 - position is desired, or ii) 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 corresponding compound con taining at least one splittable ether group in one or both of the fused benzene rings, or iii) obtaining a compound containing at least one acyloxy substituent in one or both of the fused benzene rings by acylating a correspo nding compound containing at least one hyd roxy substituent in one or both of the fused benzene rings.

103. A process for the production of compounds of formula I as defined in claim 5 which comprises a) producing a compound of formula la

in which R1 and R2 are as defined in claim 5, by splitting the ether groups Z in a compound of formula II

in which R1 and R2 are defined in claim 5, and Z is a splittable ether group, or b) producing a compound of formula Ib

in which R1 and R2 are defined in claim 5 and the radicals R'3 are identical acyloxy radicals, by acylating a compound of formula la.

104. A process for the production of a compound of formula I as defined in claim 103 substantially as hereinbefore described with reference to any one of Examples8to 105.

105. A compound whenever produced bythe process of claim 102 or 103.

106. A 4,5, 5a, 6 - tetrahydro - dibenz [cd, f] indole having at least one ether group in one or both of the fused benzene rings and being substituted in the 4-position of the nucleus.

107. A pharmaceutical composition which comprises a compound of any one of claims 1 to 99 and 105 and 106, in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.

108. A4, 5, Sa, 6 - tetrahydro - dibenz [cd, f] indole having at least one ether group on any of the fused benzene rings, with the proviso that when more than one ether group is present they are attached to the same fused benzene ring.

109. A compound of claim 108whereinthereare two ether groups present an they are in the 9 and 10 positions.

110. A compound of formula Il

wherein Z is a splittable ether group and R1 and R3 are as defined in claim 5.

111. A compound of claim 110 wherein the splittable ether group Z is (C1q) alkoxy and R1 is methyl.

112. A4, 5 - dihydro - dibenzCcd, f] indole bearing at least one hydrogen attached to the carbon atom at position 4 and having at least one splittable ether group on any of positions 1 to 3 and 7 to 10.

113. A compound of formula IlI'b

wherein R1 and R2 are as defined in claim 5, and the ring A and/or B contains at least one splittable ether group.

114. A compound of claim 113whereinthe9and 10 positions are substituted by the ether groups.

115. A compound of claim 114 wherein the ether groups are (C1) alkoxy and R1 is methyl.

116. A4, 5-dihydro-4- oxo- dibenz[cd, indole having only one ortwo splittable ether groups in any of positions 7 to 10, and having no further oxy substituent in the nucleus.

117. Acompound of formula Ill'a

wherein R2 is as defined in claim 5, the ring B having only one or two splittable ether groups and no further oxy substituent being present in the nucleus.

118. A compound of claim 117 wherein there are two ether groups present and these are in the 9 and 10 positions.

119. A compound of claim 118 wherein the ether groups are (C1q) alkoxy.

120. Acompound of formula V'

wherein Hal is bromine, chlorine or iodine and the rings A and/or B contain at least one splittable ether group.

121. Acompoundofclaim 120 wherein there are two ether groups present and they are in positions 9 and 10.

122. A compound of claim 121 wherein the ether groups are (C1q) alkoxy.